J. Org. Chem. 2023, 88, 4504-4518

pubs.acs.
org/joc Article
Ring-Opening Cyclization (ROC) of Aziridines with Propargyl

Alcohols: Synthesis of 3,4-Dihydro‑2H‑1,4-oxazines
Bharat Singh, Manish Kumar, Gaurav Goswami, Indresh Verma, and Manas K. Ghorai*
Cite This: J. Org. Chem. 2023, 88, 4504−4518 Read Online
ACCESS Metrics & More Article Recommendations *

sı Supporting Information
See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.
ABSTRACT: Activated aziridines react with propargyl alcohols in the presence of

Zn(OTf)2 as the Lewis acid catalyst following an SN2-type ring-opening mechanism
Downloaded via INDIAN INST OF TECH KANPUR on March 30, 2024 at 06:23:36 (UTC).
to furnish the corresponding amino ether derivatives. Those amino ethers further
undergo intramolecular hydroamination via 6-exo-dig cyclization in the presence of
Zn(OTf)2 as the catalyst and tetrabutylammonium triflate salt as an additive under
one-pot two-step reaction conditions. However, for nonracemic examples, ring-
opening and cyclization steps were conducted under two-pot conditions. The
reaction works well without any additional solvents. The final 3,4-dihydro-2H-1,4-
oxazine products were obtained with 13 to 84% yield and 78 to 98% enantiomeric
excess (for nonracemic examples).
■ INTRODUCTION
There are numerous reports on N,O-heterocycles, especially
oxacycles.6 There are a number of reports for the synthesis
of 3,4-dihydro-2H-1,4-oxazine derivatives via Lewis acid/base-
aromatic ring-fused heterocycles, for their syntheses and promoted regioselective 6-exo-dig cyclization of amino
biological activities.1,2 Interestingly, among N,O-heterocycles, propargyl ethers,7 N-protected alkynyl amino alcohols,8 N-
1,4-oxazine frameworks were found in several natural products, protected alkynals/alkynones,9 epoxy-ynamides,10 etc. Other
which display important bioactivities.3 Oxazines are the approaches for the synthesis of oxazines include the Pd(II)-
precursors to substituted morpholines, which are of great catalyzed aerobic oxidative cyclization of 3-aza-5-alkenols,11
significance in medicinal chemistry and chemical biology. 2,5- Rh(II)-catalyzed reaction between 1-tosyl-1,2,3-triazoles and
and 2,6-Disubstituted morpholines are of pharmacological and epoxides/glycidols/halohydrins,12 Lewis-acid-mediated gemi-
biological importance, as shown in Figure 1.4,5 Moreover, nal acylation of 2-methoxyoxazolidines with five- or six-
morpholine derivatives are used as chiral auxiliaries/templates membered acyloins followed by heterocyclization,13 and Ir(I)-
for the synthesis of α-hydroxy acids/carboxamide and catalyzed intramolecular asymmetric allylic substitution re-
action.14
Nucleophilic ring-opening followed by cyclization from
aziridines provides excellent routes to high-value N-hetero-
cyclic synthetic targets.15−20 There are some interesting reports
for the synthesis of 1,4-oxazines from aziridines via ring-
opening cyclization with α-diazocarbonyl compounds and
propargyl alcohols as well.21 However, most of them have
synthetic limitations, such as the following: strategy cannot
provide enantioenriched products (Scheme 1c),21b studies
were directed toward only alkyl aziridines and aryl propargyl
alcohols (Scheme 1a),21c or the cyclization step was shown to
be endo-selective providing the seven-membered rings
(Scheme 1b).21d
Received: December 29, 2022

Published: March 27, 2023
Figure 1. Bioactive compounds containing substituted morpholine.
© 2023 American Chemical Society https://doi.org/10.1021/acs.joc.2c03093

4504 J. Org. Chem. 2023, 88, 4504−4518
The Journal of Organic Chemistry pubs.acs.org/joc Article
Scheme 1. Reaction of N-Activated Aziridines with Propargyl Alcohols
Scheme 2. Ring-Opening of (±)-2-Phenyl-N-tosylaziridine (1a) with Propargyl Alcohol (2a) Followed by Zn(OTf)2-Assisted
6-exo-dig Cyclization of 3aa
For almost two decades, our group has been extensively that the enantioenriched 3,4-dihydro-2H-1,4-oxazines can
involved in the synthesis of a wide array of N-heterocycles of easily be accessed via ROC/DROC of enantiopure aziridines
contemporary biological and pharmacological interest via SN2- with propargyl alcohols in the presence of Zn(OTf)2. In
type nucleophilic ring-opening of activated aziridines/azeti- continuation of our research activities in this area, we have
dines followed by cyclization following either ROC or domino successfully developed a highly regioselective synthetic route to
ring-opening cyclization (DROC) strategies.22 Recently, we 3,4-dihydro-2H-1,4-oxazines via Lewis-acid catalyzed SN2-type
have reported Zn(OTf)2-catalyzed stereoselective synthesis of ring-opening of activated aziridines with propargyl alcohols,
hexahydroimidazo[1,2-a]quinolones via SN2-type ring-opening followed by intramolecular hydroamination (6-exo-dig cycliza-
hydroarylation−hydroamination cascade cyclization of acti- tion) under solvent-free conditions (Scheme 1d); herein, we
vated aziridines with N-propargylanilines.22a We anticipated report our preliminary results as a full paper.
4505 https://doi.org/10.1021/acs.joc.2c03093
J. Org. Chem. 2023, 88, 4504−4518
■ RESULTS AND DISCUSSION

Our study commenced with the reaction of (±)-2-phenyl-N-
Table 2. Optimization Studied for the Synthesis of (±)-5-
Methyl-2-phenyl-4-tosyl-3,4-dihydro-2H-1,4-oxazine 4aaa
tosylaziridine (1a) with propargyl alcohol (2a) in the presence
of 10 mol % of Zn(OTf)2 as Lewis acid at room temperature to
furnish the corresponding ring-opening product 3aa as a single
regioisomer in 82% yield (Scheme 2). Next, 3aa was subjected
to 10 mol % of Zn(OTf)2 in dichloroethane (0.5 mL) solvent
at room temperature and no product was observed. The
reaction was studied by increasing the temperature up to 50 °C yield
and then up to 85 °C, and no product was formed in both entry reaction condition (%)b
cases. To our delight, with the addition of 1.0 equiv 1c Zn(OTf)2 (0.1), Bu4N+OTf− (1.0), DCM (1.0 mL), 85 61
Bu4N+OTf− as an additive at 85 °C, product (±)-4aa was °C, Ar, 40 h
obtained in 60% yield as a single regioisomer in 72 h (Scheme 2 Zn(OTf)2 (0.1), Bu4N+OTf− (1.0), CH3CN (1.0 mL), 85 70
2). Product 4aa was characterized by spectroscopic data, and °C, Ar, 10 h
the structure was confirmed by X-ray crystallographic analysis 3 Zn(OTf)2 (0.1), Bu4N+OTf− (1.0), toluene (1.0 mL), 85 34
°C, Ar, 60 h
(see the SI). 4 Zn(OTf)2 (0.1), Bu4N+OTf− (1.0), CCl4 (1.0 mL), 85 °C, 47
To optimize the reaction conditions in terms of better yields, Ar, 6 h
shorter reaction time, and selectivity, a number of Lewis acids, 5 Zn(OTf)2 (0.1), Bu4N+OTf− (1.0), dioxane (1.0 mL), 85 -
solvents, additives, and temperatures were screened. First, °C, Ar, 72 h
different Lewis acid catalysts were studied for the nucleophilic 6 Zn(OTf)2 (0.1), Bu4N+OTf− (1.0), DMSO (1.0 mL), 85 -
°C, Ar, 72 h
ring-opening of (±)-2-phenyl-N-tosylaziridine with propargyl
7 Zn(OTf)2 (0.1), Bu4N+OTf− (1.0), DMF (1.0 mL), 85 -
alcohol (Table 1, entries 1−6). Although similar yields were °C, Ar, 72 h
8 Zn(OTf)2 (0.1), Bu4N+OTf− (1.0), 85 °C, Ar, 4h 80
Table 1. Screening of Lewis Acids for the Nucleophilic 9 Zn(OTf)2 (1.0), Bu4N+OTf− (1.0), 85 °C, Ar, 1 h 76
Ring-Opening of Racemic (±)-2-Phenyl-N-tosylaziridine 10 Zn(OTf)2 (0.1), 85 °C, Ar, 84 h 50
(1a) with Propargyl Alcohol (2a)a 11 Bu4N+OTf− (1.0), 85 °C, Ar, 72 h -
12 Zn(OTf)2 (0.1), Bu4N+OTf− (0.1), 85 °C, Ar, 8 h 63
13 Zn(OTf)2 (1.0), Bu4N+OTf− (0.1), 85 °C, Ar, 7 h 53
14 Zn(OTf)2 (0.1), [tBu3PH]+BF4− (1.0), 85 °C, Ar, 42 h -
15 Zn(OTf)2 (0.1), Bu4N+PF6− (1.0), 85 °C, Ar, 42 h -
16 Zn(OTf)2 (0.1), Bu4N+HSO4− (1.0), 85 °C, Ar, 42 h -
17 Zn(OTf)2 (0.1), Bu4N+NO3− (1.0), 85 °C, Ar, 42 h -
s. no. Lewis acid time % yield 18 Zn(OTf)2 (0.1), Et4N+(CH3C6H4SO3)−(1.0), 85 °C, Ar, 33
42 h
1. BF3•OEt2 5 min 78
19 Zn(OTf)2 (0.1), Bu4N+(BF4)− (1.0), 85 °C, Ar, 42 h 55
2. Cu(OTf)2 15 min 73 d
20 Zn(OTf)2 (0.1), Bu4N+OTf− (1.0), 85 °C, 42 h 50
3. Zn(OTf)2 20 min 84
21 Zn(OAc)2 (0.1), Bu4N+OTf− (1.0), 85 °C, Ar, 24 h -
4. LiClO4 12 h NR a
5. Yb(OTf)3 10 min 80
Unless otherwise stated, all the reactions were carried out with 0.182
mmol (60 mg, 182 M) of 3a. bYield of the isolated product. cReaction
6. Sc(OTf)3 10 min 80
a
was performed in a sealed tube. dReaction was carried out in the open
Unless otherwise stated, all the ring-opening reactions were carried air.
out with 1.0 equiv (0.183 mmol, 3.66 M) of 1a, 2.0 equiv (0.366
mmol) of 2a, and 10 mol % (0.018 mmol) of Lewis acid in
dichloromethane (50 μL) as the solvent at room temperature.
the best condition in hand, we screened the amount of Zn-salt
and additives (entries 9−13). Generation of 4aa with 50%
yield in the absence of additive in 84 h (entry 10) and no
obtained in all the cases (except LiClO4), because of easy reaction in the absence of Zn-salt (entry 11) indicates that Zn
handling, functional group tolerance, low cost, stability, salt is necessary for the reaction.
nontoxicity,23 and its further use in the cyclization step, We also checked the viability of various ammonium and
Zn(OTf)2 was chosen as the best Lewis acid catalyst (entry 3). phosphonium salts as the additives on our reaction protocol,
We screened different solvents, Zn catalysts, and additives product 4aa was obtained with 33 to 55% yields, in the case of
(Table 2). On changing the solvent from 1,2-dichloroethane to ammonium salts having better-leaving counter anions (entries
dichloromethane, the reaction was completed in 40 h to 18−19), and no reaction was observed in the case of
furnish product 4aa in 61% yield (entry 1). In the case of ammonium salts with poor leaving counter anions (entries
acetonitrile, toluene, and carbon tetrachloride as the solvents, 14−17). Finally, we concluded that Bu4N+OTf− is the best
4aa was obtained in 70, 34, and 47% yields, respectively additive for cyclization. 50% yield of 4aa in the open air (entry
(entries 2−4). However, no product was formed when 1,4- 20) shows that the reaction is not so sensitive to air and
dioxane, dimethyl sulfoxide, and N,N-dimethylformamide were moisture and no reaction was observed in the case of weak
employed as the solvents (entries 5−7). Interestingly, on Lewis acids like Zn(OAc)2 (entry 21). From the above
increasing the concentration of the reaction mixture, a decrease screening, we found that 10 mol % of Zn(OTf)2 and 1.0 equiv
in reaction time and an increase in yield of product 4aa were of Bu4N+OTf− are the best conditions for the intramolecular
observed. This result inspired us to perform the reaction in a hydroamination step (entry 8).
solvent-free condition, and to our delight, 4aa was obtained in The strategy was made more practical as a general
80% yield in 4 h (entry 8). The solvent-free condition being methodology by performing the reaction under one-pot
J. Org. Chem. 2023, 88, 4504−4518
conditions. (±)-2-Phenyl-N-tosylaziridine was treated with 2.0 opening of alkyl aziridines (1t,u) at 50 °C, followed by
equiv propargyl alcohol (2a) in DCM solvent, and after cyclization, led to the formation of the corresponding products
removal of solvent, the crude was subjected to cyclization 4ta and 4ua in 50 and 38% yields, respectively. The reaction of
conditions to give product 4aa in 78% overall yield (Scheme bulky substituted (±)-2-(naphthalene-2-yl)-1-tosylaziridine
3). (1v) took place at 50 °C, and after the cyclization, the final
product 4va was obtained only at 40% yield. In the case of
Scheme 3. One-Pot Synthesis of (±)-5-Methyl-2-phenyl-4- cyclic aziridine 1w, only a trace amount of the product was
tosyl-3,4-dihydro-2H-1,4-oxazine (4aa) obtained (Scheme 5).
In the case of the reaction of (±)-2-phenyl-N-tosyl aziridines
with (±)-but-3-yn-2-ol (2b) and (±)-1-phenylprop-2-yn-1-ol
(2c), the corresponding products 4ab and 4ac were obtained
in 46 and 13% yields, respectively (Scheme 6). In contrast, no
cyclized product was obtained in the case of 2-methyl-but-3-
yn-2-ol as a nucleophile.
The synthetic significance of our methodology was further
To investigate the electronic effect of the N-sulfonyl group, a demonstrated by the synthesis of nonracemic dihydro-2H-1,4-
wide range of racemic (±)-2-phenyl-1-(aryl/alkylsulfonyl)- oxazines (Scheme 7) by employing enantiopure aziridine as
aziridines (1b−g) were studied with 2a and the corresponding the starting substrate. We assumed that there would be no
2H-1,4-oxazine derivatives 4ba−ga were obtained in moderate change in enantiomeric excess in the cyclization step because
to good yields (Scheme 4). There is not much difference in the no chiral center is involved during the cyclization, so we
optimized our protocol in the nucleophilic ring-opening of the
Scheme 4. Substrate Scope for Aziridines Having Various N- enantiopure aziridine step, as shown in Table 3. From various
Sulfonyl-Protecting Groups (±)-1b−1g with 2aa screenings (entries 1−23, Table 3), we found that dropwise
addition of a solution of (R)-1a (in DCM) in 5 mol % of
Zn(OTf)2, 1.0 equiv of Bu4N+HSO4− (TBAHS) in DCM
solvent at 0 °C provides ring-opening product (S)-3aa, in 80%
yield with 84% ee, best-optimized condition (entry 5).
The enantiopure (R)-2-phenyl-N-tosylaziridine, (R)-1a
(>99% ee), was reacted with 2a under optimized reaction
conditions (method B), leading to the formation of non-
racemic 3,4-dihydro-2H-1,4-oxazine (S)-4aa in 65% yield and
a
Unless otherwise stated, all of the ring-opening steps were carried 84% enantiomeric excess. The strategy was generalized with
out in 1.0 equiv of aziridine 1b−g, 2.0 equiv of propargyl alcohol other aziridines (S)-1m, (S)-1t, and (S)-1u and 2a, and the
(2a), and 10 mol % of Zn(OTf)2 in dichloromethane (50 μL). corresponding nonracemic 3,4-dihydro-2H-1,4-oxazine deriva-
tives (S)-4ma, (S)-4ta, and (S)-4ua were obtained in 35−80%
ring-opening time whether EDG or EWG is present in the N- yields with 78−98% enantiomeric excess (Scheme 7). A
protecting group, but a significant effect on the reaction time decrease in enantiomeric excess of the product is probably due
and yield was observed in the hydroamination step. In the case to partial racemization of the starting material in the presence
of 4ca, time and yield are 4 h and 68%, respectively, while for of Lewis acid during the reaction. On increasing the scale of
the 4fa-containing NO2 group, reaction time increases to 48 h the reaction of 1a (2.0 g, 7.317 mmol, 1.0 equiv) with 2a (844
and yield decreases to 37%. Probably EWG decreases the μL, 14.633 mmol, 2.0 equiv) in DCM (500 μL) followed by
nucleophilicity of N, and the hydroamination step becomes cyclization under a one-pot optimized protocol, the final
slow. product 4aa was obtained in 52% (1.253 g, 3.805 mmol) yield.
The methodology was further generalized with a variety of The plausible mechanistic pathway is shown in Scheme 8.
(±)-2-aryl-N-tosylaziridines (1h−u) with 2a (Scheme 5). 2- Based on our experimental observations, we believe that the
Aryl-N-tosylaziridines with electron-donating 4-Me and 4-t-Bu ring-opening of N-activated aziridine 1 with propargyl alcohol
substituents 1h,i were subjected to ring-opening/cyclization (2a) follows the SN2-type pathway established by our group
protocol giving 4ha and 4ia in 51 and 54% yields, respectively. earlier.4a The Lewis acid Zn(OTf)2 activates aziridine 1 to
However, in the case of halo substituents (1j−o), the generate the adduct 1a′. It undergoes SN2-type nucleophilic
corresponding products 4ja−oa were obtained in moderate attack with propargyl alcohol (2a) to generate intermediate
to good yields. In the case of o-, m-, and p-Br-substituted 3a′, which, after deprotonation, is transformed into the ring-
aziridines (1j,k), the corresponding products 4ja, 4ka, and 4la opening product 3a. We believe that the zinc-coordinated
were obtained in 65, 60, and 75% yields, respectively. On alkyne species gets further activated in the presence of dipolar
increasing the electronegativity, o-, p-Cl, and p-F (1m−o), the quaternary ammonium salt. The activation of the alkyne π-
corresponding products 4ma, 4na, and 4oa were obtained in system leads to the generation of the intermediate 3b′, which
84, 72, and 69% yields, respectively. On further increase in the undergoes intramolecular hydroamination via 6-exo-dig cycliza-
electronegativity as in p-CF3 (1p), the corresponding product, tion to generate intermediate 4a′, which on deprotonation-
4pa, was isolated in only 57% yield. In the case of a protonation followed by exo-endo conversion afforded product
diastereomeric mixture of 2-methyl-3-phenyl-1-tosylaziridine 4, and the catalyst is regenerated. Moreover, tetrabutylammo-
(1q), the corresponding products nium trifluoromethanesulfonate salts might also participate in
4qa and 4q′a (cis and trans confirmed by X-ray crystallo- the regeneration of the catalyst system.
graphic analysis; see the SI) was obtained in 61% overall yield Pd-C-catalyzed reduction of (S)-4aa (84% ee) produced the
with a 2.5:1 diastereomeric ratio. The nucleophilic ring- corresponding morpholine derivative 5a as an inseparable
J. Org. Chem. 2023, 88, 4504−4518
Scheme 5. Substrate Scope with Respect to Racemic (±)-2-Aryl-N-tosyl-aziridines with 2aa
a
Unless otherwise stated, the ring-opening step was carried out in 1.0 equiv of 1h−v, 2.0 equiv of 2a, and 10 mol % of Zn(OTf)2 in
dichloromethane (50 μL) solvent at room temperature. Cyclization steps were carried out with 1.0 equiv of Bu4N+OTf−, Ar environment at 85 °C.
b
Isolated yield of the product. cThe regioisomeric ratio was calculated from crude NMR. dRing-opening reaction was carried out at 50 °C in
tetrahydrofuran (50 μL) solvent.
Scheme 6. Substrate Scope with Respect to Propargyl Scheme 7. Synthesis of Enantioenriched Oxazines via ROC
Alcohols with Racemic (±)-2-Phenyl-N-tosyl Aziridines of Enantiopure Aziridines 1 with 2aa
a
Unless otherwise stated, the ring-opening step was carried out in 1.0
equiv of 1a, 2.0 equiv of 2b−d, and 10 mol % of Zn(OTf)2 in
dichloromethane (50 μL) solvent at room temperature. The
cyclization step was carried out with 1.0 equiv of Bu4N+OTf−, Ar
environment at 85 °C.
a
Unless otherwise stated, reactions were carried out with 1.0 equiv of
(1), 0.1 mL of (2a), 5 mol % Zn(OTf)2, and 1.0 equiv of TBAHS in
dry dichloromethane (0.5 mL) at 0 °C. Cyclization steps were carried
mixture of diastereomers (dr 20:1). When 5a was subjected to out with 10 mol % Zn(OTf)2 and 1.0 equiv of Bu4N+OTf− under an
Ar environment. bRing-opening reactions were carried out at 50 °C
Na/C10H8-mediated desulfonylation conditions, the com- temperature in tetrahydrofuran solvent.
pound 5b with free N-H can be isolated in 80% overall yield
as a single diastereomer (Scheme 9).
■ CONCLUSIONS
In conclusion, we have successfully developed an efficient and
■ GENERAL INFORMATION
Compounds were purified by flash column chromatography on
200−400 mesh silica gel using a combination of ethyl acetate
simple strategy for the synthesis of 3,4-dihydro-2H-1,4-
and petroleum ether as the eluent. Analytical thin-layer
oxazines in 13 to 84% yields and excellent enantioselectivity chromatography (TLC) was carried out using silica gel 60
(ee up to 98%) via Zn(OTf)2-catalyzed ROC of activated F254 pre-coated plates, UV light, and an iodine chamber to
aziridines with propargyl alcohols. We believe that this mild visualize the course of the reactions. Unless noted, all reactions
protocol will be helpful for organic chemists to synthesize were carried out in oven-dried glassware under an atmosphere
substituted oxazines and morpholines. Further work is in of argon using anhydrous solvents. All reagents were purified
progress. before use following the Perrin and Armerego24 and Vogel
J. Org. Chem. 2023, 88, 4504−4518
Table 3. Optimization Studied for the Nucleophilic Ring- Scheme 8. A Plausible Mechanism for the Synthesis of 3,4-
Opening Enantiopure (R)-1-Phenyl-N-tosylaziridine (1a) Dihydro-2H-1,4-oxazine Derivatives
with Propargyl Alcohol 2aa
entry reaction condition % yield ee %

1 Zn(OTf)2 (5.0 mol %), Bu4N+OTf− (2.0 equiv), 0 86 68
°C, 2 min
2 Zn(OTf)2 (5.0 mol %), Bu4N+OTf− (2.0 equiv), 0 86 67
°C, 5 min
3 Zn(OTf)2 (5.0 mole%), TBAHS (2.0 equiv), 0 °C, 80 79
2 min
4 Zn(OTf)2 (5.0 mole%), TBAHS (2.0 equiv), 80 77
DCM (0.5 mL), 0 °C, 5 min
5b Zn(OTf)2 (5.0 mol %), TBAHS (1.0 equiv), 80 84
DCM (0.5 mL), 0 °C, 20 min
6b Zn(OTf)2 (5.0 mol %), TBAHS (1.0 equiv), 60 84
toluene (0.5 mL), 0 °C, 15 min
7 Zn(OTf)2 (5.0 mol %), Bu4N+OTf− (1.0 equiv), 88 69
DCM (0.5 mL), −10 °C, 8 min guidelines.25 The monosubstituted N-Ts aziridines (1) were
8 Zn(OTf)2 (5.0 mol %), Bu4N+OTf− (2.0 equiv), 90 68 prepared from different styrene derivatives following a reported
DCM (0.5 mL), −10 °C, 6 min procedure.26 Chiral mono-substituted N-Ts aziridines were
9b Zn(OTf)2 (5.0 mol %), TBAHS (1.0 equiv), DCM 91 82 prepared from the corresponding amino alcohol following a
(0.5 mL), −10 °C, 24 min
b reported procedure,27 and propargyl alcohols (2) were
10 Zn(OTf)2 (5.0 mol %), TBAHS (0.5 equiv), 78 65
Bu4NOTf (0.5 equiv), DCM (0.5 mL), 0 °C, 27 commercially received from TCI Chemicals. All commercial
min reagents were used as received. The 1H NMR (400 and 500
11 (NH4)2S2O8 (1.0 equiv), DCM (0.5 mL), 0 °C, 5 98 69 MHz) and 13C NMR (100 and 125 MHz) data were recorded
min with CDCl3 as solvent at room temperature unless specified
12b Zn(OTf)2 (5.0 mol %), TBAHS (1.0 equiv), 93 80 otherwise. The chemical shifts (δ) are reported in ppm and
CH3CN (0.5 mL), −10 °C, 10 min
13b,c Zn(OTf)2 (5.0 mol %), TBAHS (1.0 equiv), DCM 91 81 coupling constants (J) in Hz. 1H NMR spectra were recorded
(0.5 mL), −10 °C, 50 min with tetramethylsilane (δ = 0.00 ppm) as an internal reference.
13
14 b ,c
Zn(OTf)2 (5.0 mol %), TBAHS (1.0 equiv), DCM 89 80 C NMR spectra were recorded with CDCl3 (δ = 77.0 ppm)
(0.5 mL), −20 °C, 72 min as an internal reference. 1H NMR splitting patterns are
15b,c Zn(OTf)2 (5.0 mol %), TBAHS (1.0 equiv), DCM 86 83 designated as singlet (s), doublet (d), triplet (t), quartet (q),
(0.5 mL), −30 °C, 2 h
16d Zn(OTf)2 (5.0 mol %), TBAHS (1.0 equiv), DCM 65 79
doublet of doublet (dd), multiplet (m), etc. HRMS data were
(0.5 mL), −40 °C, 4.5 h recorded using an ESI mass spectrometer (TOF). IR spectra
17b Zn(OTf)2 (5.0 mol %), TBAHS (1.0 equiv), DCM 80 87 were logged in the KBr pallet. Enantiomeric excesses (% ee)
(0.5 mL), −30 °C, 22 min were determined by HPLC using AS-H analytical columns
b
18 Zn(OTf)2 (5.0 mol %), TBAHS (1.0 equiv), DCM 70 90 (detection at 254 nm). Melting points were determined using a
(0.5 mL), −40 °C, 35 min
hot-stage apparatus and are uncorrected. Optical rotations
19 LiClO4 (10.0 mol %), TBAHS (1.0 equiv), 88 63
CH3CN (0.5 mL), 85 °C, 30 min were measured using a 6 mL cell with a 50 mm path length and
20b BF3.OEt2 (10 mol %), TBAHS (1.0 equiv), DCM 80 83 are reported as [α]25D (c in gm per 100 mL solvent) at 25 °C.
21e
(0.5 mL), −40 °C, 12 min
BF3.OEt2 (10 mol %), TBAHS (2.0 equiv), DCM
(0.5 mL), −40 °C, 10 min
78 76 ■ EXPERIMENTAL SECTION
General Procedure for the Synthesis of 5-Methyl-2-phenyl-
22b Zn(OTf)2 (5.0 mol %), TBAHS (2.0 equiv), THF 76 78 4-tosyl-3,4-dihydro-2H-1,4-oxazine Derivatives. Method A. In a
(0.5 mL), −40 °C, 1.5 h single-neck RB flask, aziridine 1 (1.0 equiv), propargyl alcohol 2 (2.0
23b,e Zn(OTf)2 (5.0 mol %), TBAHS (1.0 equiv), 53 90 equiv), Lewis acid (10 mol %), and DCM (2.0 times of propargyl
toluene (0.5 mL), −40 °C, 60 min alcohol in μL) were taken, and the reaction mixture was stirred for an
appropriate time at an appropriate temperature in an Ar atmosphere.
a
Unless noted otherwise, reactions were carried out by taking (R)-1a The progress of the reaction was monitored by TLC using 20% ethyl
(0.183 mmol, 1.0 equiv, 366 M, >99% ee), Lewis acid, ammonium acetate in petroleum ether. After completion of the reaction, the
salt, and 0.1 mL of propargyl alcohol 2a in a single-neck RB and left solvent was removed under reduced pressure. After the addition of
for stirring at a given temperature. bSolution of chiral 1a (in 0.5 mL tetrabutylammonium triflate in the same pot under an Ar atmosphere,
DCM) was added dropwise in a stirred solution of Zn(OTf)2, the reaction mixture was kept for stirring at 85 °C on an oil bath for
R4N+X−,, and propargyl alcohol. cDuring addition, the solution of an appropriate time. The reaction was monitored by TLC. After
(R)-1a was kept at the reaction mixture temperature. dReaction was completion, the reaction was quenched with aq. ammonium chloride
not completed in a given time, and the starting aziridine was and the mixture was extracted with ethyl acetate. The combined
recovered. eLewis acid was added dropwise in a stirred solution of 1a, organic layer was dried over anhydrous Na2SO4, and the solvent was
R4N+X−, and propargyl alcohol 2 in DCM (0.1 mL). The evaporated under reduced pressure. The crude concentrate was
enantiomeric excess of 3aa was determined by HPLC (AD-H, purified by flash column chromatography on a silica gel using 5%
isopropanol/n-hexane = 10/90, 1.0 mL min−1, 720 psi), tR = 19 min, ethyl acetate in petroleum ether as the eluent to afford the pure
22 min. product 4.
J. Org. Chem. 2023, 88, 4504−4518
Scheme 9. Reduction Followed by Desulfonylation of 5-Methyl-2-phenyl-4-tosyl-3,4-dihydro-2H-1,4-oxazine (4aa)
Method B. In a single-neck RB flask, propargyl alcohol 2 (0.1 mL), crystalline solid, mp 51−53 °C in 84% (51 mg, 0.154 mmol)
Lewis acid (5 mol %), and tetrabutylammonium hydrogensulfate (1.0 yield; Rf 0.33 in 20% ethyl acetate in petroleum ether; IR υmax
equiv) in anhydrous solvent (0.1−0.3 mL) were taken, and the (KBr, cm−1) 3280, 2923, 2853, 2120, 1597, 1493, 1452, 1326,
reaction mixture was stirred at an appropriate temperature for an
1158, 1072, 814; 1H NMR (500 MHz, CDCl3) δ 7.72 (d, 2H, J
appropriate time. Nonracemic aziridine 1 (1.0 equiv) solution in an
appropriate solvent (0.5 mL) was added dropwise within a particular = 8.0 Hz), 7.33−7.31 (m, 3H), 7.29 (d, 2H, J = 8.0 Hz), 7.22−
duration of time (5−20 min). The progress of the reaction was 7.20 (m, 2H), 4.97 (d, 1H, J = 8.6 Hz), 4.55 (dd, 1H, J = 9.7,
monitored by TLC using 20% ethyl acetate in petroleum ether. After 4.0 Hz), 4.06 (dd, 1H, J = 16.0, 2.9 Hz), 3.81 (dd, 1H, J =
completion, the reaction was quenched with aq. ammonium chloride 15.5, 2.3 Hz), 3.25−3.20 (m, 1H), 3.06−3.01 (m, 1H), 2.42−
and the mixture was extracted with ethyl acetate. The combined 2.41 (m, 4H); 13C{1H} NMR (125 MHz, CDCl3) δ 143.4,
organic layer was dried over anhydrous Na2SO4, and the solvent was 137.3, 136.9, 129.7, 128.8, 128.75, 127.1, 126.8, 79.3, 79.0,
evaporated under reduced pressure. The crude concentrate was 74.9, 55.9, 49.0, 21.5; HRMS (ESI-TOF) m/z: [M + Na]+
purified by flash column chromatography on a silica gel using 8% calcd for C18H19NO3SNa 352.0978; found 352.0978.
ethyl acetate in petroleum ether as the eluent to obtain the pure
product 3. Next, product 3 was treated with Zn(OTf)2 (10 mol %)
(±)-5-Methyl-2-phenyl-4-tosyl-3,4-dihydro-2H-1,4-
and Bu4N+OTf− (1.0 equiv) in an Ar medium at 85 °C on an oil bath oxazine (4aa). The general method A described above was
for an appropriate time. The progress of the reaction was monitored followed when racemic (±)-2-phenyl-N-tosyl aziridine 1a (52
by TLC using 10% ethyl acetate in petroleum ether. After completion mg, 0.190 mmol, 1.0 equiv) was treated with propargyl alcohol
of the reaction and usual workup as mentioned above, the crude 2a (22 μL, 0.380 mmol, 2.0 equiv) in the presence of
concentrate was purified by flash column chromatography on a silica Zn(OTf)2 (7 mg, 0.019 mmol, 10 mol %) in DCM (44 μL) at
gel using 5% ethyl acetate in petroleum ether as the eluent to furnish RT for 20 min. After completion, the crude was treated with
the pure product 4. Bu4N+OTf− (68 mg, 1.0 equiv) as an additive, in an Ar
environment at 85 °C on an oil bath for 6 h to obtain (±)-4aa
■ SELECTED SPECTRAL DATA
General Procedure for the Synthesis of (±)-2-Phenyl-
as a white solid: mp 116−118 °C in 78% (47 mg, 0.149 mmol)
yield; Rf 0.60 (in 20% ethyl acetate in petroleum ether); IR
N-tosyl Aziridine (1a). In a double-neck RB flask, anhydrous υmax (KBr, cm−1) 3065, 2965, 2927, 1660, 1596, 1495, 1453,
chloramine-T (2.762 g, 9.601 mmol, 1.1 equiv) and PTAB 1261, 1209, 1167, 1088, 814; 1H NMR (500 MHz, CDCl3) δ
(328 mg, 0.873 mmol, 0.1 equiv) were taken in an Ar 7.72 (d, 2H, J = 8.0 Hz), 7.40 (d, 2H, J = 8.0 Hz), 7.35−7.29
environment, and after the addition of CH3CN (15 mL), the (m, 3H), 7.09−7.06 (m, 2H), 6.17 (s, 1H), 4.11 (dd, 1H, J =
reaction mixture was stirred for 30 min at room temperature. 14.3, 2.3 Hz), 3.77 (dd, 1H, J = 10.3, 2.29 Hz), 2.98 (dd, 1H, J
Next, styrene (1.0 mL, 8.728 mmol, 1.0 equiv) was added in a = 14.3, 9.7 Hz), 2.46 (s, 3H), 2.10 (d, 3H, J = 0.8 Hz);
13
dropwise manner and stirring was continued at the same C{1H} NMR (125 MHz, CDCl3) δ 144.2, 137.1, 134.8,
temperature for 5 h. After completion, the reaction was 132.7, 130.0, 128.6, 128.5, 127.5, 125.8, 111.9, 72.7, 50.7, 21.6,
quenched with water and the mixture was extracted with ethyl 18.2; HRMS (ESI-TOF) m/z: [M + H] + calcd for
acetate. The combined organic layer was dried over anhydrous C18H20NO3S 330.1159; found 330.1167.
Na2SO4, and the solvent was evaporated under reduced (±)-4-((4-(tert-Butyl)phenyl)sulfonyl)-5-methyl-2-
pressure. The crude concentrate was purified by flash column phenyl-3,4-dihydro-2H-1,4-oxazine (4ba). The general
chromatography on a silica gel using 5% ethyl acetate in method A described above was followed when (±)-1-((4-
petroleum ether as the eluent to afford the pure product (±)-2- (tert-butyl)phenyl)sulfonyl)-2-phenylaziridine 1b (100 mg,
phenyl-N-tosyl aziridine (1a) as a white crystalline solid (mp 0.317 mmol, 1.0 equiv) was treated with propargyl alcohol
88−89 °C) in 58% (1383 mg, 5.062 mmol) yield. Rf = 0.43 in 2a (38 μL, 0.634 mmol, 2.0 equiv) in the presence of
20% ethyl acetate in petroleum ether; IR υmax (KBr, cm−1) Zn(OTf)2 (12 mg, 0.032 mmol, 10 mol %) in DCM (50 μL)
3036, 2958, 1667, 1594, 1494, 1458, 1379, 1156; 1H NMR at RT for 23 min. After completion, the crude was treated with
(500 MHz, CDCl3) δ 7.87 (d, 2H, J = 8.6 Hz), 7.33 (d, 2H, J = Bu4N+OTf− (124 mg, 0.317 mmol, 1.0 equiv) as an additive, in
8.0 Hz), 7.29−7.26 (m, 3H), 7.22−7.20 (m, 2H), 3.77 (dd, an Ar environment at 85 °C on an oil bath for 6 h to obtain
1H, J = 7.4, 4.0 Hz), 2.98 (d, 1H, J = 7.4 Hz), 2.43 (s, 3H), (±)-4ba as a gummy liquid in 66% (78 mg, 0.209 mmol) yield;
2.38 (d, 1H, J = 4.6 Hz); 13C{1H} NMR (125 MHz, CDCl3) δ Rf 0.52 (in 10% ethyl acetate in petroleum ether); IR υmax
144.7, 135.2, 135.1, 129.8, 128.6, 128.4, 128.0, 126.6, 41.1, (KBr, cm−1) 3065, 2962, 2924, 2852, 1661, 1594, 1495, 1355,
36.0, 21.7; HRMS (ESI-TOF) m/z: [M + H]+ calcd for 1265, 1209, 1197, 1170, 1085, 838; 1H NMR (400 MHz,
C15H16NO2S 274.0897; found 274.0896. CDCl3) δ 7.76 (d, 2H, J = 8.5 Hz), 7.60 (d, 2H, J = 8.5 Hz),
(±)-4-Methyl-N-(2-phenyl-2-(prop-2-yn-1-yloxy)- 7.32−7.28 (m, 2H), 7.07−7.04 (m, 2H), 6.17 (s, 1H), 4.09
ethyl)benzenesulfonamide (3aa). The general method A (dd, 1H, J = 14.6, 2.4 Hz), 3.77 (dd, 1H, J = 9.8, 2.4 Hz), 2.98
described above was followed when racemic (±)-2-phenyl-N- (dd, 1H, J = 14.6, 9.8 Hz), 2.10 (d, 3H, J = 1.2 Hz), 1.35 (s,
tosyl aziridine 1a (50 mg, 0.183 mmol, 1.0 equiv) was treated 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 157.3, 137.2, 135.0,
with propargyl alcohol 2a (21 μL, 0.366 mmol, 2.0 equiv) in 132.6, 128.7, 128.6, 127.6, 126.4, 125.9, 112.2, 73.1, 50.8, 35.4,
the presence of Zn(OTf)2 (7 mg, 0.018 mmol, 10 mol %) in 31.2, 18.2; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
DCM (44 μL) at RT for 20 min to get 3aa as a white C21H26NO3S 372.1628; found 372.1642.
J. Org. Chem. 2023, 88, 4504−4518
(±)-4-((4-Methoxyphenyl)sulfonyl)-5-methyl-2-phe- m/z: [M + H]+ calcd for C17H17FNO3S 334.0908; found

nyl-3,4-dihydro-2H-1,4-oxazine (4ca). The general method 334.0910.
A described above was followed when (±)-1-((4- (±)-5-Methyl-4-((4-nitrophenyl)sulfonyl)-2-phenyl-
methoxyphenyl)sulfonyl)-2-phenylaziridine 1c (100 mg, 3,4-dihydro-2H-1,4-oxazine (4fa). The general method A
0.346 mmol, 1.0 equiv) was treated with propargyl alcohol described above was followed when (±)-1-((4-nitrophenyl)-
2a (42 μL, 0.692 mmol, 2.0 equiv) in the presence of sulfonyl)-2-phenylaziridine 1f (100 mg, 0.329 mmol, 1.0
Zn(OTf)2 (13 mg, 0.035 mmol, 10 mol %) in DCM (50 μL) equiv) was treated with propargyl alcohol 2a (40 μL, 0.658
at RT for 25 min. After completion, the crude was treated with mmol, 2.0 equiv) in the presence of Zn(OTf)2 (12 mg, 0.033
Bu4N+OTf− (135 mg, 0.346 mmol, 1.0 equiv) as an additive, in mmol, 10 mol %) in DCM (50 μL) at RT for 18 min. After
an Ar environment at 85 °C on an oil bath for 4 h to obtain completion, the crude was treated with Bu4N+OTf− (129 mg,
(±)-4ca as a white solid: mp 78−80 °C in 68% (81 mg, 0.235 0.329 mmol, 1.0 equiv) as an additive, in an Ar environment at
mmol) yield; Rf 0.50 (in 10% ethyl acetate in petroleum 85 °C on an oil bath for 48 h to obtain (±)-4fa as a yellow
ether); IR υmax (KBr, cm−1) 3067, 2928, 2849, 1660, 1595, semi solid in 37% (44 mg, 0.122 mmol) yield; Rf 0.32 (in 10%
1577, 1497, 1352, 1309, 1262, 1208, 1163, 1090, 834; 1H ethyl acetate in petroleum ether); IR υmax (KBr, cm−1) 3071,
NMR (400 MHz, CDCl3) δ 7.76 (d, 2H, J = 8.5 Hz), 7.35− 3032, 2925, 2851, 1661, 1494, 1454, 1404, 1358, 1209, 1170,
7.29 (m, 3H), 7.10−7.04 (m, 4H), 6.17 (d, 1H, J = 1.2 Hz), 1087, 837; 1H NMR (400 MHz, CDCl3) δ 8.44−8.41 (m,
4.09 (dd, 1H, J = 14.6, 2.4 Hz), 3.88 (s, 3H), 3.81 (dd, 1H, J = 2H), 7.98−8.01 (m, 2H), 7.37−7.31 (m, 3H), 7.10−7.08 (m,
9.8, 2.4 Hz), 2.96 (dd, 1H, J = 14.6, 9.8 Hz), 2.09 (d, 3H, J = 2H), 6.20 (d, 1H, J = 1.2 Hz), 4.17 (dd, 1H, J = 14.5, 2.4 Hz),
1.2 Hz); 13C{1H} NMR (100 MHz, CDCl3) δ 163.4, 137.2, 3.97 (dd, 1H, J = 9.8, 2.4 Hz), 3.10 (dd, 1H, J = 14.5, 9.8 Hz),
132.8, 129.7, 129.6, 128.7, 128.6, 125.9, 114.6, 112.1, 72.9, 2.08 (d, 3H, J = 1.2 Hz); 13C{1H} NMR (100 MHz, CDCl3) δ
55.8, 50.8, 18.3; HRMS (ESI-TOF) m/z: [M + H]+ calcd for 150.3, 144.1, 136.5, 133.4, 128.9, 128.8, 128.7, 125.8, 124.7,
C18H20NO4S 346.1108; found 346.1114. 111.3, 73.7, 50.7, 18.0; HRMS (ESI-TOF) m/z: [M + H]+
(±)-5-Methyl-2-phenyl-4-(phenylsulfonyl)-3,4-dihy- calcd for C17H17N2O5S 361.0853; found 361.0852.
dro-2H-1,4-oxazine (4da). The general method A described (±)-5-Methyl-4-(methylsulfonyl)-2-phenyl-3,4-dihy-
above was followed when (±)-2-phenyl-1-(phenylsulfonyl)- dro-2H-1,4-oxazine (4ga). The general method A described
aziridine 1d (100 mg, 0.387 mmol, 1.0 equiv) was treated with above was followed when (±)-1-(methylsulfonyl)-2-phenyl-
propargyl alcohol 2a (47 μL, 0.774 mmol, 2.0 equiv) in DCM aziridine 1g (100 mg, 0.506 mmol, 1.0 equiv) was treated with
(50 μL) solvent in the presence of Zn(OTf)2 (14 mg, 0.039 propargyl alcohol 2a (61 μL, 1.012 mmol, 2.0 equiv) in the
mmol, 10 mol %) at RT for 20 min. After completion, the presence of Zn(OTf)2 (18 mg, 0.051 mmol, 10 mol %) in
crude was treated with Bu4N+OTf− (151 mg, 0.387 mmol, 1.0 DCM (50 μL) at RT for 12 h. After completion, the crude was
equiv) as an additive, in an Ar environment at 85 °C on an oil treated with Bu4N+OTf− (198 mg, 0.506 mmol, 1.0 equiv) as
bath for 6 h to obtain (±)-4da as a white solid: mp 63−65 °C
an additive, in an Ar environment at 85 °C on an oil bath for
in 60% (73 mg, 0.232 mmol) yield; Rf 0.31 (in 10% ethyl
3.5 h to obtain (±)-4ga as a gummy liquid in 60% (76 mg,
acetate in petroleum ether); IR υmax (KBr, cm−1) 2923, 2853,
0.304 mmol) yield; Rf 0.39 (in 20% ethyl acetate in petroleum
1660, 1447, 1352, 1168, 1088, 802; 1H NMR (400 MHz,
ether); IR υmax (KBr, cm−1) 3312, 3064, 3030, 2956, 2926,
CDCl3) δ 7.85−7.82 (m, 2H), 7.65−7.58 (m, 3H), 7.34−7.28
2854, 1667, 1497, 1454, 1343, 1158, 1087, 832; 1H NMR (400
(m, 3H), 7.07−7.05 (m, 2H), 6.17 (d, 1H, J = 1.2 Hz), 4.11
MHz, CDCl3) δ 7.40−7.31 (m, 5H), 6.22 (s, 1H), 4.84 (dd,
(dd, 1H, J = 14.6, 2.4 Hz), 3.75 (dd, 1H, J = 9.8, 2.4 Hz), 2.99
(dd, 1H, J = 14.6, 9.8 Hz), 2.10 (d, 3H, J = 1.2 Hz); 13C{1H} 1H, J = 9.2, 2.4 Hz), 4.16 (dd, 1H, J = 14.0, 2.4 Hz), 3.18 (dd,
NMR (100 MHz, CDCl3) δ 137.9, 137.1, 133.4, 132.9, 129.5, 1H, J = 14.6, 9.2 Hz), 2.89 (s, 3H), 1.99 (d, 3H, J = 1.2 Hz);
13
128.7, 128.6, 127.6, 126.0, 112.0, 73.0, 50.8, 18.2; HRMS (ESI- C{1H} NMR (100 MHz, CDCl3) δ 137.2, 131.6, 128.8,
TOF) m/z: [M + H]+ calcd for C17H18NO3S 316.1002; found 128.7, 126.1, 112.0, 75.0, 50.3, 40.4, 17.4; HRMS (ESI-TOF)
316.1003. m/z: [M + H]+ calcd for C12H16NO3S 254.0846; found
(±)-4-((4-Fluorophenyl)sulfonyl)-5-methyl-2-phenyl- 254.0844.
3,4-dihydro-2H-1,4-oxazine (4ea). The general method A (±)-5-Methyl-2-(p-tolyl)-4-tosyl-3,4-dihydro-2H-1,4-
described above was followed when (±)-1-((4-fluorophenyl)- oxazine (4ha). The general method A described above was
sulfonyl)-2-phenylaziridine 1e (109 mg, 0.393 mmol, 1.0 followed when (±)-2-(p-tolyl)-1-tosylaziridine 1h (100 mg,
equiv) was treated with propargyl alcohol 2a (47 μL, 0.786 0.348 mmol, 1.0 equiv) was treated with propargyl alcohol 2a
mmol, 2.0 equiv) in the presence of Zn(OTf)2 (14 mg, 0.039 (42 μL, 0.696 mmol, 2.0 equiv) in the presence of Zn(OTf)2
mmol, 10 mol %) in DCM (50 μL) at RT for 20 min. After (13 mg, 0.035 mmol, 10 mol %) in DCM (50 μL) at RT for 15
completion, the crude was treated with Bu4N+OTf− (154 mg, min. After completion, the crude was treated with Bu4N+OTf−
0.393 mmol, 1.0 equiv) as an additive, in an Ar environment at (136 mg, 0.348 mmol, 1.0 equiv) as an additive, in an Ar
85 °C on an oil bath for 6 h to obtain (±)-4ea as a gummy environment at 85 °C on an oil bath for 3 h to obtain (±)-4ha
liquid in 52% (68 mg, 0.204 mmol) yield; Rf 0.86 (in 20% as a gummy liquid in 52% (62 mg, 0.181 mmol) yield; Rf 0.43
ethyl acetate in petroleum ether); IR υmax (KBr, cm−1) 2922, (in 10% ethyl acetate in petroleum ether); IR υmax (KBr, cm−1)
2851, 1732, 1659, 1590, 1493, 1453, 1356, 1292, 1208, 1168, 2923, 2852, 1659, 1597, 1516, 1494, 1355, 1305, 1206, 1168,
1086, 836; 1H NMR (400 MHz, CDCl3) δ 7.86−7.83 (m, 1088, 813; 1H NMR (400 MHz, CDCl3) δ 7.70 (d, 2H, J = 7.9
2H), 7.34−7.25 (m, 5H), 7.09−7.07 (m, 2H), 6.19 (s, 1H), Hz), 7.38 (d, 2H, J = 8.5 Hz), 7.12 (d, 2H, J = 7.9 Hz), 6.95
4.10 (dd, 1H, J = 14.6, 2.4 Hz), 3.85 (dd, 1H, J = 10.4, 2.4 (d, 2H, J = 7.9 Hz), 6.15 (s, 1H), 4.08 (dd, 1H, J = 14.6, 2.4
Hz), 3.01(dd, 1H, J = 14.6, 10.4 Hz), 2.08 (s, 3H); 13C{1H} Hz), 3.73 (d, 1H, J = 9.7 Hz), 2.96 (dd, 1H, J = 14.6, 9.8 Hz),
NMR (100 MHz, CDCl3) δ 165.4 (d, J = 255.9 Hz), 136.9, 2.45 (s, 3H), 2.32 (s, 3H), 2.09 (s, 3H); 13C{1H} NMR (100
134.3 (d, J = 2.9 Hz), 133.1, 130.3 (d, J = 8.6 Hz), 128.8, MHz, CDCl3) δ 144.2, 138.5, 135.0, 134.2, 132.8, 130.1, 129.4,
125.9, 116.9, 116.7, 111.8, 73.2, 50.7, 18.2; HRMS (ESI-TOF) 127.6, 125.8, 112.0, 72.8, 50.8, 21.7, 21.2, 18.3; HRMS (ESI-
J. Org. Chem. 2023, 88, 4504−4518
TOF) m/z: [M + Na]+ calcd for C19H21NNaO3S 366.1135; 132.4, 131.7, 130.3, 130.1, 129.0, 127.6, 124.5, 122.9, 112.4,
found 366.1140. 72.2, 50.7, 21.7, 18.2; HRMS (ESI-TOF) m/z: [M + H]+ calcd
(±)-2-(4-(tert-Butyl)phenyl)-5-methyl-4-tosyl-3,4-di- for C18H19BrNO3S 408.0264; found 408.0267.
hydro-2H-1,4-oxazine (4ia). The general method A (±)-2-(4-Bromophenyl)-5-methyl-4-tosyl-3,4-dihy-
described above was followed when (±)-2-(p-tolyl)-1- dro-2H-1,4-oxazine (4la). The general method A described
tosylaziridine 1i (100 mg, 0.303 mmol, 1.0 equiv) was treated above was followed when (±)-2-(4-bromophenyl)-1-tosylazir-
with propargyl alcohol 2a (37 μL, 0.607 mmol, 2.0 equiv) in idine 1l (100 mg, 0.285 mmol, 1.0 equiv) was treated with
the presence of Zn(OTf)2 (11 mg, 0.030 mmol, 10 mol %) in propargyl alcohol 2a (34 μL, 0.570 mmol, 2.0 equiv) in the
DCM (50 μL) at RT for 20 min. After completion, the crude presence of Zn(OTf)2 (10 mg, 0.028 mmol, 10 mol %) in
was treated with Bu4N+OTf− (119 mg, 0.303 mmol, 1.0 equiv) DCM (50 μL) at RT for 25 min. After completion, the crude
as an additive, in an Ar environment at 85 °C on an oil bath for was treated with Bu4N+OTf− (56 mg, 0.285 mmol, 1.0 equiv)
5.5 h to obtain (±)-4ia as a gummy liquid in 54% (63 mg, as an additive in an Ar environment at 85 °C on an oil bath for
0.164 mmol) yield; Rf 0.36 (in 10% ethyl acetate in petroleum 5 h to obtain (±)-4la as a white solid: mp 58−60 °C in 75%
ether); IR υmax (KBr, cm−1) 2962, 2927, 2868, 1659, 1597, (86 mg, 0.212 mmol) yield; Rf 0.24 (in 10% ethyl acetate in
1515, 1493, 1461, 1355, 1214, 1167, 1088, 814; 1H NMR (400 petroleum ether); IR υmax (KBr, cm−1) 2965, 2926, 2852,
MHz, CDCl3) δ 7.70 (d, 2H, J = 7.9 Hz), 7.36 (dd, 4H, J = 1660, 1596, 1490, 1443, 1354, 1208, 1167, 1089, 815, 687; 1H
15.3, 7.9 Hz), 7.00 (d, 2H, J = 7.9 Hz), 6.15 (s, 1H), 4.10 (dd, NMR (400 MHz, CDCl3) δ 7.69 (d, 2H, J = 7.9 Hz), 7.45 (d,
1H, J = 14.6, 1.8 Hz), 3.72 (d, 1H, J = 8.5 Hz), 2.98 (dd, 1H, J 2H, J = 7.9 Hz), 7.38 (d, 2H, J = 7.3 Hz), 6.96 (d, 2H, J = 7.9
= 14.6, 9.8 Hz), 2.45 (s, 3H), 2.09 (s, 3H), 1.28 (s, 9H); Hz), 6.14 (s, 1H), 4.07 (d, 1H, J = 14.6 Hz), 3.77 (d, 1H, J =
13
C{1H} NMR (100 MHz, CDCl3) δ 151.7, 144.2, 135.0, 9.8 Hz), 2.92 (dd, 1H, J = 14.6, 9.8 Hz), 2.45 (s, 3H), 2.08 (s,
134.2, 132.9, 130.0, 127.7, 125.6, 112.0, 72.7, 50.7, 34.7, 31.3, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 144.4, 136.3, 135.1,
21.7, 18.3; HRMS (ESI-TOF) m/z: [M + H]+ calcd for 132.4, 131.9, 130.1, 127.6, 127.5, 122.6, 112.4, 72.4, 50.6, 21.7,
C22H28NO3S 386.1785; found 386.1793. 18.2; HRMS (ESI-TOF) m/z: [M + H] + calcd for
(±)-2-(2-Bromophenyl)-5-methyl-4-tosyl-3,4-dihy- C18H19BrNO3S 408.0264; found 408.0268.
dro-2H-1,4-oxazine (4ja). The general method A described (±)-2-(2-Chlorophenyl)-5-methyl-4-tosyl-3,4-dihy-
above was followed when (±)-2-(2-bromophenyl)-1-tosylazir- dro-2H-1,4-oxazine (4ma). The general method A described
idine 1j (100 mg, 0.285 mmol, 1.0 equiv) was treated with above was followed when (±)-2-(2-chlorophenyl)-1-tosylazir-
propargyl alcohol 2a (34 μL, 0.570 mmol, 2.0 equiv) in the idine 1m (100 mg, 0.326 mmol, 1.0 equiv) was treated with
presence of Zn(OTf)2 (10 mg, 0.028 mmol, 10 mol %) in propargyl alcohol 2a (39 μL, 0.651 mmol, 2.0 equiv) in the
DCM (50 μL) at RT for 1 h. After completion, the crude was presence of Zn(OTf)2 (12 mg, 0.033 mmol, 10 mol %) in
treated with Bu4N+OTf− (112 mg, 0.285 mmol, 1.0 equiv) as DCM (50 μL) at RT for 50 min. After completion, the crude
an additive in an Ar environment at 85 °C on an oil bath for 8 was treated with Bu4N+OTf− (128 mg, 0.326 mmol, 1.0 equiv)
h to obtain (±)-4ja as a solid: mp 94−96 °C in 65% (76 mg, as an additive in an Ar environment at 85 °C on an oil bath for
0.184 mmol) yield; Rf 0.27 (in 10% ethyl acetate in petroleum 6.5 h to obtain (±)-4ma as a solid: mp 100−102 °C in 84%
ether); IR υmax (KBr, cm−1) 3061, 2921, 2850, 1666, 1597, (99 mg, 0.274 mmol) yield; Rf 0.38 (in 10% ethyl acetate in
1568, 1494, 1437, 1350, 1265, 1162, 1091, 814, 690; 1H NMR petroleum ether); IR υmax (KBr, cm−1) 2924, 2853, 1732,
(400 MHz, CDCl3) δ 7.78 (d, 2H, J = 8.5 Hz), 7.49 (d, 1H, J = 1665, 1597, 1494, 1443, 1352, 1166, 1089, 812, 579; 1H NMR
7.9 Hz), 7.33−7.27 (m, 4H), 7.17−7.13 (m, 1H), 6.18 (d, 1H, (400 MHz, CDCl3) δ 7.75 (d, 2H, J = 8.5 Hz), 7.33 (d, 2H, J =
J = 1.2 Hz), 4.53 (dd, 1H, J = 9.8, 2.4 Hz), 4.38 (dd, 1H, J = 8.5 Hz), 7.30−7.20 (m, 4H), 6.18 (s, 1H), 4.46 (dd, 1H, J =
14.6, 2.4 Hz), 2.86 (dd, 1H, J = 14.0, 9.8 Hz), 2.42 (s, 3H), 9.8, 2.4 Hz), 4.36 (dd, 1H, J = 14.6, 2.4 Hz), 2.86 (dd, 1H, J =
2.10 (d, 3H, J = 1.2 Hz); 13C{1H} NMR (100 MHz, CDCl3) δ 14.0, 9.8 Hz), 2.42 (s, 1H), 2.11 (d, 1H, J = 1.2 Hz); 13C{1H}
144.0, 136.6, 135.8, 132.9, 132.2, 130.0, 129.0, 128.0, 127.9, NMR (100 MHz, CDCl3) δ 144.0, 135.5, 135.0, 132.3, 131.8,
127.8, 121.6, 112.2, 72.6, 48.9, 21.7, 18.2; HRMS (ESI-TOF) 129.9, 129.6, 127.8, 127.7, 127.4, 112.2, 70.2, 48.9, 21.7, 18.3;
m/z: [M + H]+ calcd for C18H19BrNO3S 408.0264; found HRMS (ESI-TOF) m/z: [M + H]+ calcd for C18H19ClNO3S
408.0274. 364.0769; found 364.0785.
(±)-2-(3-Bromophenyl)-5-methyl-4-tosyl-3,4-dihy- (±)-2-(4-Chlorophenyl)-5-methyl-4-tosyl-3,4-dihy-
dro-2H-1,4-oxazine (4ka). The general method A described dro-2H-1,4-oxazine (4na). The general method A described
above was followed when (±)-2-(3-bromophenyl)-1-tosylazir- above was followed when (±)-2-(4-chlorophenyl)-1-tosylazir-
idine 1k (100 mg, 0.285 mmol, 1.0 equiv) was treated with idine 1n (100 mg, 0.326 mmol, 1.0 equiv) was treated with
propargyl alcohol 2a (34 μL ml, 0.570 mmol, 2.0 equiv) in the propargyl alcohol 2a (39 μL, 0.651 mmol, 2.0 equiv) in the
presence of Zn(OTf)2 (10 mg, 0.028 mmol, 10 mol %) in presence of Zn(OTf)2 (12 mg, 0.033 mmol, 10 mol %) in
DCM (50 μL) at RT for 35 min. After completion, the crude DCM (48 μL) at RT for 20 min. After completion, the crude
was treated with Bu4N+OTf− (112 mg, 0.285 mmol, 1.0 equiv) was treated with Bu4N+OTf− (76 mg, 0.326 mmol, 1.0 equiv)
as an additive in an Ar environment at 85 °C on an oil bath for as an additive in an Ar environment at 85 °C on an oil bath for
5 h to obtain (±)-4ka as a semi-solid 60% (70 mg, 0.170 5 h to obtain (±)-4na as a solid: mp 98−100 °C in 72% (85
mmol) yield; Rf 0.25 (in 10% ethyl acetate in petroleum mg, 0.234 mmol) yield; Rf 0.52 (in 10% ethyl acetate in
ether); IR υmax (KBr, cm−1) 2923, 2853, 1732, 1660, 1596, petroleum ether); IR υmax (KBr, cm−1) 2923, 2852, 1657,
1569, 1493, 1461, 1354, 1167, 1088, 813, 696; 1H NMR (400 1597, 1492, 1456, 1353, 1260, 1166, 1087, 813, 578; 1H NMR
MHz, CDCl3) δ 7.70 (d, 2H), 7.43−7.38 (m, 3H), 7.19 (t, 1H, (400 MHz, CDCl3) δ 7.70 (d, 2H, J = 7.9 Hz), 7.38 (d, 2H, J =
J = 7.8 Hz), 7.00 (d, 1H, J = 7.8 Hz), 6.15 (s, 1H), 4.09 (dd, 7.9 Hz), 7.30−7.28 (m, 2H), 7.01 (d, 2H, J = 8.5 Hz), 6.14 (s,
1H, J = 14.2, 2.3 Hz), 3.77 (dd, 1H, J = 10.0, 2.3 Hz), 2.93 1H), 4.07 (dd, 1H, J = 14.0, 1.8 Hz), 3.78 (dd, 1H, J = 9.8, 2.4
(dd, 1H, J = 14.6, 10.1 Hz), 2.45 (s, 3H), 2.08 (s, 3H); Hz), 2.93 (dd, 1H, J = 14.0, 9.8 Hz), 2.45 (s, 3H), 2.08 (d, 3H,
13
C{1H} NMR (100 MHz, CDCl3) δ 144.4, 139.5, 135.0, J = 1.2 Hz); 13C{1H} NMR (100 MHz, CDCl3) δ 144.4, 135.7,
J. Org. Chem. 2023, 88, 4504−4518
135.0, 134.4, 132.5, 130.1, 128.9, 127.6, 127.2, 112.3, 72.3, cm−1) 3064, 3030, 2983, 2930, 1736, 1661, 1597, 1495, 1451,
50.7, 21.7, 18.2; HRMS (ESI-TOF) m/z: [M + H]+ calcd for 1352, 1240, 1169, 1087, 814; 1H NMR (500 MHz, CDCl3) δ
C18H19ClNO3S 364.0769; found 364.0759. 7.74 (d, 2H, J = 8.0 Hz), 7.38 (d, 2H, J = 8.0 Hz), 7.32−7.29
(±)-2-(4-Fluorophenyl)-5-methyl-4-tosyl-3,4-dihydro- (m, 2H), 7.25−7.23 (m, 1H), 7.08 (d, 2H, J = 7.4 Hz), 6.12
2H-1,4-oxazine (4oa). The general method A described (d, 1H, J = 1.2 Hz), 4.24−4.19 (m, 1H), 3.81 (d, 1H, J = 2.3
above was followed when (±)-2-(4-fluorophenyl)-1-tosylazir- Hz), 2.41 (s, 3H), 2.11 (d, 3H, J = 1.2 Hz), 0.84 (d, 3H, J =
idine 1o (100 mg, 0.343 mmol, 1.0 equiv) was treated with 6.9 Hz); 13C{1H} NMR (125 MHz, CDCl3) δ 144.0, 137.3,
propargyl alcohol 2a (42 μL, 686 mmol, 2.0 equiv) in the 134.8, 131.3, 129.9, 128.3, 127.7, 127.4, 125.3, 109.8, 74.6,
presence of Zn(OTf)2 (12 mg, 0.034 mmol, 10 mol %) in 53.3, 21.5, 18.6, 10.8; HRMS (ESI-TOF) m/z: [M + H]+ calcd
DCM (50 μL) at RT for 18 min. After completion, the crude for C19H22NO3S 344.1315; found 344.1316.
was treated with Bu4N+OTf− (134 mg, 0.343 mmol, 1.0 equiv) (4q′a, trans) IR υmax (KBr, cm−1) 2955, 2926, 2869, 1671,
as an additive in an Ar environment at 85 °C on an oil bath for 1494, 1458, 1346, 1209, 1166, 1086, 813; 1H NMR (500
4 h to obtain (±)-4oa as a white fine crystalline solid: mp MHz, CDCl3) δ 7.19−7.18 (m, 3H), 7.15−7.13 (m, 2H), 7.06
130−132 °C in 69% (82 mg, 0.237 mmol) yield; Rf 0.37 (in (d, 2H, J = 8.6 Hz), 6.92 (d, 2H, J = 8.0 Hz), 5.91 (d, 1H, J =
10% ethyl acetate in petroleum ether); IR υmax (KBr, cm−1) 1.1 Hz), 5.01 (d, 1H, J = 1.7 Hz), 4.74−4.70 (m,1H), 2.26 (s,
2927, 2852, 1660, 1512, 1494, 1414, 1354, 1284, 1224, 1169, 3H), 1.73 (d, 3H, J = 1.1 Hz), 1.40 (d, 3H, J = 6.9 Hz);
814; 1H NMR (400 MHz, CDCl3) δ 7.70 (d, 2H, J = 7.9 Hz), 13
C{1H} NMR (125 MHz, CDCl3) δ 142.7, 139.1, 138.6,
7.38 (d, 2H, J = 7.9 Hz), 7.06−6.98 (m, 4H), 6.14 (d, 1H, J = 129.4, 128.4, 127.4, 126.8, 126.6, 125.3, 111.6, 79.2, 53.6, 21.4,
1.2 Hz), 4.07 (dd, 1H, J = 14.6, 2.4 Hz), 3.78 (dd, 1H, J = 9.8, 18.3, 17.1; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
2.4 Hz), 2.94 (dd, 1H, J = 14.6, 9.8 Hz), 2.45 (s, 3H), 2.08 (d, C19H21NO3SNa 366.1135; found 366.1134.
3H, J = 1.2 Hz); 13C{1H} NMR (100 MHz, CDCl3) δ 162.8 3-Ethyl-5-methyl-2-phenyl-4-tosyl-3,4-dihydro-2H-
(d, J = 247.2 Hz), 144.3, 135.0, 133.0 (d, J = 3.8 Hz), 132.6, 1,4-oxazine (4ra) and 2-Ethyl-5-methyl-3-phenyl-4-
130.1, 127.6 (d, J = 11.5 Hz), 115.8, 115.6, 112.2, 72.4, 50.8, tosyl-3,4-dihydro-2H-1,4-oxazine (4r′a). The general
21.7, 18.2; HRMS (ESI-TOF) m/z: [M + H]+ calcd for method A described above was followed when 2-ethyl-3-
C18H19FNO3S 348.1064; found 348.1056. phenyl-1-tosylaziridine 1r (100 mg, 0.332 mmol, 1.0 equiv)
(±)-5-Methyl-4-tosyl-2-(4-(trifluoromethyl)phenyl)- was treated with propargyl alcohol 2a (40 μL, 0.664 mmol, 2.0
3,4-dihydro-2H-1,4-oxazine (4pa). The general method A equiv) in the presence of Zn(OTf)2 (12 mg, 0.033 mmol, 10
described above was followed when (±)-1-tosyl-2-(4- mol %) in DCM (50 μL) at RT for 6 h. After completion, the
(trifluoromethyl)phenyl)aziridine 1p (100 mg, 0.293 mmol, crude was treated with Bu4N+OTf− (130 mg, 0.332 mmol, 1.0
1.0 equiv) was treated with propargyl alcohol 2a (35 μL, 0.586 equiv) as an additive in an Ar environment at 85 °C on an oil
mmol, 2.0 equiv) in the presence of Zn(OTf)2 (11 mg, 0.029 bath for 16 h to obtain (±)-4ra as gummy liquid and (±)-4r′a
mmol, 10 mol %) in DCM (50 μL) at RT for 10 h. After
as white crystalline solid: (mp 65−67 °C of 4r′a) in 58%
completion, the crude was treated with Bu4N+OTf− (115 mg,
overall yield (69 mg, 0.192 mmol, 2:1 in diastereomeric ratio);
0.293 mmol, 1.0 equiv) as an additive in an Ar environment at
Rf 0.26 and 0.09, respectively, (in 10% diethyl ether in
85 °C on an oil bath for 3 h to obtain (±)-4pa as a white solid:
petroleum ether); (4ra, cis) IR υmax (KBr, cm−1) 3065, 3030,
mp 120−122 °C in 57% (66 mg, 0.167 mmol) yield; Rf 0.46
2969, 2931, 2876, 1661, 1597, 1496, 1452, 1352, 1261, 1208,
(in 10% ethyl acetate in petroleum ether); IR υmax (KBr, cm−1)
1089, 814; 1H NMR (500 MHz, CDCl3) δ 7.75 (d, 2H, J = 8.0
2930, 1661, 1598, 1420, 1355, 1325, 1167, 1089, 814; 1H
Hz), 7.38 (d, 2H, J = 8.0 Hz), 7.31 (t, 2H, J = 7.4 Hz), 7.26−
NMR (400 MHz, CDCl3) δ 7.71 (d, 2H, J = 7.9 Hz), 7.59 (d,
2H, J = 7.9 Hz), 7.39 (d, 2H, J = 7.9 Hz), 7.22 (d, 2H, J = 7.9 7.23 (m, 1H), 7.09 (d, 2H, J = 7.4 Hz), 6.12 (s, 1H), 3.99−
Hz), 6.17 (d, 1H, J = 1.2 Hz), 4.11 (dd, 1H, J = 14.6, 2.4 Hz), 3.96 (m, 1H), 3.85 (d, 1H, J = 2.3 Hz), 2.42 (s, 3H), 2.13 (d,
3.87 (dd, 1H, J = 10.4, 1.8 Hz), 2.94 (dd, 1H, J = 14.6, 10.3 3H, J = 1.5 Hz), 1.30−1.22 (m, 1H), 1.02−0.97 (m, 1H), 0.86
Hz), 2.45 (s, 3H), 2.10 (d, 3H, J = 1.2 Hz); 13C{1H} NMR (t, 3H, J = 6.9 Hz); 13C{1H} NMR (125 MHz, CDCl3) δ
(100 MHz, CDCl3) δ 144.5, 141.5, 141.1, 135.0, 132.3, 130.8 144.0, 137.3, 134.8, 131.9, 129.9, 128.3, 127.6, 127.5, 125.3,
(d, J = 32.6 Hz), 127.6, 130.2, 125.7 (d, J = 3.8 Hz), 124.0 (d, J 109.6, 74.7, 59.2, 21.6, 18.6, 16.4, 10.6; HRMS (ESI-TOF) m/
= 272 Hz), 112.5, 72.4, 50.6, 21.7, 18.2; HRMS (ESI-TOF) z: [M + Na]+ calcd for C20H23NO3SNa 380.1291; found
m/z: [M + H]+ calcd for C19H19F3NO3S 398.1033; found 380.1289.
398.1016. (4r′a, trans) IR υmax (KBr, cm−1) 3064, 3030, 2968, 2931,
3,5-Dimethyl-2-phenyl-4-tosyl-3,4-dihydro-2H-1,4- 2877, 1672, 1598, 1495, 1450, 1347, 1206, 1166, 1090, 814;
1
oxazine (4qa) and 2,5-Dimethyl-3-phenyl-4-tosyl-3,4- H NMR (500 MHz, CDCl3) δ 7.25−7.20 (m, 3H), 7.18−7.17
dihydro-2H-1,4-oxazine (4q′a). The general method A (m, 2H), 6.99 (d, 2H, J = 8.6 Hz), 6.93 (d, 2H, J = 8.6 Hz),
described above was followed when 2-methyl-3-phenyl-1- 5.97 (d, 1H, J = 1.2 Hz), 5.23 (s, 1H), 4.61−4.58 (m, 1H),
tosylaziridine 1q (100 mg, 0.348 mmol, 1.0 equiv) was treated 2.31 (s, 3H), 1.87−1.74 (m, 6H), 1.13 (t, 3H, J = 8.3 Hz);
13
with propargyl alcohol 2a (42 μL, 0.697 mmol, 2.0 equiv) in C{1H} NMR (125 MHz, CDCl3) δ 142.5, 139.3, 138.3,
the presence of Zn(OTf)2 (13 mg, 0.035 mmol, 10 mol %) in 129.3, 128.4, 127.3, 127.0, 126.9, 125.2, 111.3, 77.2, 59.6, 24.8,
DCM (50 μL) at RT for 2 h. After completion, the crude was 21.4, 17.4, 11.1; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
treated with Bu4N+OTf− (136 mg, 0.348 mmol, 1.0 equiv) as C20H24NO3S 358.1472, found 358.1480.
an additive in an Ar environment at 85 °C on an oil bath for 16 5-Methyl-2-phenyl-3-propyl-4-tosyl-3,4-dihydro-2H-
h to obtain 4qa (white crystalline solid) and 4q′a (white 1,4-oxazine (4sa) and 5-Methyl-3-phenyl-2-propyl-4-
crystalline solid) as pure solid compounds: mp 68−70 °C and tosyl-3,4-dihydro-2H-1,4-oxazine (4s′a). The general
95−97 °C in 61% overall yield (73 mg, 0.212 mmol, 5:2 in method A described above was followed when 2-phenyl-3-
diastereomeric ratio) yield; Rf 0.29 and 0.17, respectively (in propyl-1-tosylaziridine 1s (100 mg, 0.317 mmol, 1.0 equiv)
10% diethyl ether in petroleum ether); (4qa, cis) IR υmax (KBr, was treated with propargyl alcohol 2a (38 μL, 0.635 mmol, 2.0
J. Org. Chem. 2023, 88, 4504−4518
equiv) in the presence of Zn(OTf)2 (12 mg, 0.032 mmol, 10 815; 1H NMR (500 MHz, CDCl3) δ 7.55 (d, 2H, J = 8.6 Hz),
mol %) in DCM (50 μL) at RT for 8 h. After completion, the 7.25 (d, 2H, J = 8.0 Hz), 5.89 (d, 1H, J = 1.2 Hz), 3.96 (dd,
crude was treated with Bu4N+OTf− (124 mg, 0.317 mmol, 1.0 1H, J = 14.3, 2.3 Hz), 2.78 (dd, 1H, J = 14.3, 9.7 Hz), 2.49−
equiv) as an additive in an Ar environment at 85 °C on an oil 2.46 (m, 1H), 2.7 (s, 3H), 1.95 (d, 3H, J = 1.2 Hz), 1.52−1.59
bath for 42 h to obtain (±)-4sa as semi-solid and (±)-4s′a as (m, 1H), 0.74 (dd, 6H, J = 6.9, 2.3 Hz); 13C{1H} NMR (125
white solid: (mp 94−96 °C of 4s′a) in 48% overall yield (56 MHz, CDCl3) δ 143.8, 135.1, 132.3, 129.8, 127.4, 111.5, 75.6,
mg, 0.152 mmol, 16:9 in diastereomeric ratio); Rf 0.27 and 46.7, 30.1, 21.5, 18.1, 17.80, 17.77; HRMS (ESI-TOF) m/z:
0.10, respectively (in 10% diethyl ether in petroleum ether); [M − H]+ calcd for C15H20NO3S 294.1159; found 294.1160.
(4sa, cis) IR υmax (KBr, cm−1) 3064, 3029, 2960, 2930, 2872, (±)-5-Methyl-2-(naphthalen-2-yl)-4-tosyl-3,4-dihy-
1660, 1597, 1495, 1451, 1353, 1204, 1168, 1089, 814; 1H dro-2H-1,4-oxazine (4va). The general method A described
NMR (400 MHz, CDCl3) δ 7.74 (d, 2H, J = 8.5 Hz), 7.37 (d, above was followed when (±)-2-(naphthalen-2-yl)-1-tosylazir-
2H, J = 7.9 Hz), 7.33−7.29 (m, 2H), 7.26−7.22 (m, 1H), 7.08 idine 1v (100 mg, 0.305 mmol, 1.0 equiv) was treated with
(d, 2H, J = 7.3 Hz), 6.13 (d, 1H, J = 1.2 Hz), 4.08−4.04 (m, propargyl alcohol 2a (37 μL, 0.610 mmol, 2.0 equiv) in the
1H), 3.82 (d, 1H, J = 2.4 Hz), 2.41 (s, 3H), 2.12 (d, 3H, J = presence of Zn(OTf)2 (11 mg, 0.030 mmol, 10 mol %) in THF
1.2 Hz), 1.47−1.40 (m, 1H), 1.30−1.20 (m, 2H), 0.89−0.82 (50 μL) at 50 °C on an oil bath for 5 h. After completion, the
(m, 1H), 0.78 (t, 3H, J = 7.3 Hz); 13C{1H} NMR (125 MHz, crude was treated with Bu4N+OTf− (119 mg, 0.305 mmol, 1.0
CDCl3) δ 144.0, 137.3, 134.8, 132.0, 129.9, 128.3, 127.6, equiv) as an additive in an Ar environment at 85 °C on an oil
127.5, 125.2, 109.6, 74.6, 57.6, 25.4, 21.6, 19.1, 18.6, 13.7; bath for 6 h to obtain (±)-4va as a solid: mp 112−114 °C in
HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C21H25NO3SNa 40% (46 mg, 0.122 mmol) yield; Rf 0.40 (in 10% ethyl acetate
394.1448; found 394.1446. in petroleum ether); IR υmax (KBr, cm−1) 2924, 2852, 1659,
(4s′a, trans) IR υmax (KBr, cm−1) 2958, 2928, 2872, 1672, 1597, 1493, 1443, 1352, 1262, 1166, 1088, 815; 1H NMR (400
1598, 1495, 1450, 1378, 1203, 1165, 813; 1H NMR (500 MHz, CDCl3) δ 7.82−7.80 (m, 3H), 7.75 (d, 2H, J = 7.9 Hz),
MHz, CDCl3) δ 7.25−7.20 (m, 3H), 7.18−7.17 (m, 2H), 6.99 7.57 (s, 1H), 7.49−7.47 (m, 2H), 7.41 (d, 2H, J = 7.9 Hz),
(d, 2H, J = 8.0 Hz), 6.93 (d, 2H, J = 8.6 Hz), 5.97 (s, 1H), 7.17 (d, 1H, J = 7.9 Hz), 6.22 (s, 1H), 4.2 (dd, 1H, J = 14.6,
5.21 (s, 1H), 4.69−4.66 (m, 1H), 2.32 (s, 3H), 1.83 (s, 3H), 2.4 Hz), 3.99 (d, 1H, J = 9.7 Hz), 3.06 (dd, 1H, J = 14.0, 9.8
1.80−1.76 (m, 1H), 1.73−1.68 (m, 1H), 1.61−1.56 (m, 2H), Hz), 2.46 (s, 3H), 2.12 (s, 3H); 13C{1H} NMR (125 MHz,
1.04 (t, 3H, J = 7.4 Hz); 13C{1H} NMR (125 MHz, CDCl3) δ CDCl3) δ 144.3, 135.1, 134.6, 133.3, 133.2, 132.8, 130.1,
142.5, 139.3, 138.3, 129.3, 128.4, 127.3, 127.0, 126.9, 125.2, 128.6, 128.1, 127.8, 127.6, 126.6, 126.5, 125.1, 123.4, 112.2,
111.3, 77.4, 58.0, 34.0, 21.4, 19.8, 17.4, 14.0; HRMS (ESI- 73.0, 50.8, 21.8, 18.3; HRMS (ESI-TOF) m/z: [M + H]+ calcd
TOF) m/z: [M + H]+ calcd for C21H26NO3S 372.1628; found for C22H22NO3S 380.1315; found 380.1329.
372.1635. (±)-5,6-Dimethyl-2-phenyl-4-tosyl-3,4-dihydro-2H-
(±)-3,5-Dimethyl-4-tosyl-3,4-dihydro-2H-1,4-oxazine 1,4-oxazine (4ab). The general method A described above
(4ta). The general method A described above was followed was followed when (±)-2-phenyl-1-tosylaziridine 1a (100 mg,
when (±)-2-methyl-1-tosylaziridine 1t (100 mg, 0.473 mmol, 0.366 mmol, 1.0 equiv) was treated with propargyl alcohol
1.0 equiv) was treated with propargyl alcohol 2a (57 μL, 0.947 (±)-2b (58 μL, 0.732 mmol, 2.0 equiv) in the presence of
mmol, 2.0 equiv) in the presence of Zn(OTf)2 (17 mg, 0.047 Zn(OTf)2 (13 mg, 10 mol %) in DCM (50 μL) at RT for 30
mmol, 10 mol %) in THF (50 μL) at 50 °C for 12 h. After min. After completion, the crude was treated with Bu4N+OTf−
completion, the crude was treated with Bu4N+OTf− (185 mg, (143 mg, 0.366 mmol, 1.0 equiv) as an additive in an Ar
0.473 mmol, 1.0 equiv) as an additive in an Ar environment at environment at 85 °C on an oil bath for 8 h to obtain (±)-4ab
85 °C on an oil bath for 5 h to obtain (±)-4ta as a sticky liquid as a gummy liquid in 46% (58 mg, 0.168 mmol) yield; Rf 0.40
in 50% (63 mg, 0.236 mmol) yield; Rf 0.76 (in 10% ethyl (in 10% ethyl acetate in petroleum ether); IR υmax (KBr, cm−1)
acetate in petroleum ether). IR υmax (KBr, cm−1) 2964, 2926, 2926, 2856, 1664, 1596, 1493, 1454, 1351, 1209, 1166, 1088,
2853, 1659, 1598, 1494, 1449, 1350, 1211, 1167, 1088, 813; 814; 1H NMR (400 MHz, CDCl3) δ 7.71 (d, 2H), 7.36 (d,
1
H NMR (400 MHz, CDCl3) δ 7.61 (d, 2H, J = 8.5 Hz), 7.30 2H, J = 7.9 Hz), 3.34−7.27 (m, 3H), 7.10−7.08 (m, 2H), 4.06
(d, 2H, J = 8.5 Hz), 5.92 (s, 1H), 3.96 (dd, 1H, J = 14.0, 2.4 (dd, 1H, J = 14.0, 3.0 Hz), 3.95 (dd, 1H, J = 10.3, 3.0 Hz),
Hz), 3.03−3.11 (m, 1H), 2.81 (dd, 1H, J = 14.0, 9.8 Hz), 2.42 2.88 (dd, 1H, J = 14.6, 10.3 Hz), 2.44 (s, 3H), 2.14 (s, 3H),
(s, 3H), 1.99 (d, 3H, J = 1.2 Hz), 1.06 (d, 3H, J = 6.7 Hz); 1.90 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 144.0,
13
C{1H} NMR (125 MHz, CDCl3) δ 143, 135.5, 132.0, 129.8, 140.4, 137.6, 135.5, 129.9, 128.6, 128.4, 127.6, 125.7, 105.8,
127.2, 111.4, 67.6, 50.1, 21.6, 17.9, 17.8; HRMS (ESI-TOF) 73.2, 50.6, 21.6, 17.7, 17.1; HRMS (ESI-TOF) m/z: [M +
m/z: [M + H]+ calcd for C13H18NO3S 268.1002; found H]+calcd for C19H22NO3S 344.1315; found 344.1317.
268.1007. (±)-5-Methyl-2,6-diphenyl-4-tosyl-3,4-dihydro-2H-
(±)-3-Isopropyl-5-methyl-4-tosyl-3,4-dihydro-2H-1,4- 1,4-oxazine (4ac). The general method A described above
oxazine (4ua). The general method A described above was was followed when (±)-2-phenyl-1-tosylaziridine 1a (100 mg,
followed when (±)-2-isopropyl-1-tosylaziridine 1u (100 mg, 0.366 mmol, 1.0 equiv) was treated with propargyl alcohol
0.418 mmol, 1.0 equiv) was treated with propargyl alcohol 2a (±)-2c (89 μL, 0.732 mmol, 2.0 equiv) in the presence of
(51 μL, 0.836 mmol, 2.0 equiv) in the presence of Zn(OTf)2 Zn(OTf)2 (13 mg, 0.037 mmol, 10 mol %) in DCM (50 μL)
(15 mg, 0.042 mmol, 10 mol %) in THF (50 μL) at 50 °C for at RT for 45 min. After completion, the crude was treated with
2 h. After completion, the crude was treated with Bu4N+OTf− Bu4N+OTf− (143 mg, 0.366 mmol, 1.0 equiv) as an additive in
(164 mg, 0.418 mmol, 1.0 equiv) as an additive in an Ar an Ar environment at 85 °C on an oil bath for 10 h to (±)-4ac
environment at 85 °C on an oil bath for 4 h to obtain (±)-4ua as a white solid: mp 152−156 °C in 13% (19 mg, 0.048 mmol)
as a sticky liquid in 38% (47 mg, 0.159 mmol) yield; Rf 0.76 yield; Rf 0.40 (in 10% ethyl acetate in petroleum ether); IR
(in 10% ethyl acetate in petroleum ether). IR υmax (KBr, cm−1) υmax (KBr, cm−1) 2923, 2853, 1640, 1597, 1493, 1455, 1358,
2961, 2925, 1658, 1599, 1495, 1463, 1328, 1235, 1160, 1093, 1227, 1165, 1088, 801; 1H NMR (500 MHz, CDCl3) δ 7.55
J. Org. Chem. 2023, 88, 4504−4518
(d, 2H, J = 8.0 Hz), 7.39−7.21 (m, 12H), 4.37−4.31 (m, 2H), 1H, J = 1.2 Hz); 13C{1H} NMR (100 MHz, CDCl3) δ 144.0,
3.07 (dd, 1H, J = 14.3, 10.3 Hz), 2.42 (s, 3H), 1.91 (s, 3H); 135.5, 135.0, 132.3, 131.8, 129.9, 129.6, 127.8, 127.7, 127.4,
13
C{1H} NMR (125 MHz, CDCl3) δ 143.9, 143.2, 137.5, 112.2, 70.2, 48.9, 21.7, 18.3; HRMS (ESI-TOF) m/z: [M +
137.0, 135.7, 130.0, 129.7, 128.8, 128.6, 127.9, 127.7, 127.0, H]+ calcd for C18H19ClNO3S 364.0769; found 364.0785.
126.0, 112.3, 74.8, 50.7, 21.7, 18.0; HRMS (ESI-TOF) m/z: (S)-3,5-Dimethyl-4-tosyl-3,4-dihydro-2H-1,4-oxazine
[M + H]+ calcd for C24H24NO3S 406.1472; found 406.1468. ((S)-4ta). The general method B described above was followed
(S)-5-Methyl-2-phenyl-4-tosyl-3,4-dihydro-2H-1,4-ox- when (S)-2-methyl-1-tosylaziridine 1t (50 mg, 0.237 mmol, 1.0
azine ((S)-4aa). The general method B described above was equiv, >99% ee) was treated with propargyl alcohol 2a (0.1
followed when dry DCM (0.5 mL) solution of (R)-2-phenyl- mL), Zn(OTf)2 (4 mg, 0.012 mmol, 5 mol %), and
N-tosyl aziridine 1a (50 mg, 0.183 mmol, 1.0 equiv, >99% ee) Bu4N+HSO4− (80 mg, 0.237 mmol, 1.0 equiv) in dry THF
was treated with a reaction mixture of propargyl alcohol 2a (0.5 mL) at 50 °C for 2 h. After completion, the reaction was
(0.1 mL), Zn(OTf)2 (3 mg, 0.009 mmol, 5 mol %), and quenched with NH4+Cl−, and after the workup, the crude was
Bu4N+HSO4− (62 mg, 0.183 mmol, 1.0 equiv) at 0 °C for 20 purified by flash column chromatography to obtain (S)-3ta in
min in a dropwise manner. After completion, the reaction was 48% yield (30 mg, 0.112 mmol). Next, (S)-3ta (30 mg, 0.112
quenched with NH4+Cl−, and after the workup, the crude was mmol, 1.0 equiv) was treated with Zn(OTf)2 (4 mg, 0.012
purified by flash column chromatography to obtain (S)-3aa in mmol, 10 mol %) as the catalyst and Bu4N+OTf− (44 mg,
80% yield (48 mg, 0.146 mmol). Next, (S)-3aa (48 mg, 0.146 0.112 mmol, 1.0 equiv) as an additive in an Ar environment at
mmol, 1.0 equiv) was treated with Zn(OTf)2 (5 mg, 0.015 85 °C on an oil bath for 5 h to obtain (S)-4ta as a gummy
mmol, 10 mol %) as the catalyst and Bu4N+OTf− (57 mg, liquid in 74% (22 mg, 0.083 mmol) yield (35% overall yield).
0.146 mmol, 1.0 equiv) as an additive in an Ar environment at [α]25D +150.0 (c 0.140 in C2H4Cl2) for a >98% ee sample. The
85 °C on an oil bath for 4 h to obtain (S)-4aa as a white solid: optical purity was determined by chiral HPLC (AS-H,
mp 116−118 °C in 81% (39 mg, 0.118 mmol) yield (65% isopropanol/n-hexane = 1/99, flow rate = 1.0 mL/min, l =
overall yield). [α]25D −242.96 (c 0.150 in C2H4Cl2) for a > 254 nm) tR = 15.41 min (minor), 18.62 min (major); Rf 0.76
84% ee sample. Optical purity was determined by chiral HPLC (in 10% ethyl acetate in petroleum ether). IR υmax (KBr, cm−1)
(AS-H, isopropanol/n-hexane = 1/99, flow rate = 1.0 mL/ 2964, 2926, 2853, 1659, 1598, 1494, 1449, 1350, 1211, 1167,
min) tR = 28.88 min (major), 65.88 min (minor), Rf 0.60 (in 1088, 813; 1H NMR (400 MHz, CDCl3) δ 7.61 (d, 2H, J = 8.5
20% ethyl acetate in petroleum ether); IR υmax (KBr, cm−1) Hz), 7.30 (d, 2H, J = 8.5 Hz), 5.92 (s, 1H), 3.96 (dd, 1H, J =
3280, 2923, 2853, 2120, 1597, 1493, 1452, 1326, 1158, 1088, 14.0, 2.4 Hz), 3.11−3.03 (m, 1H), 2.81 (dd, 1H, J = 14.0, 9.8
814; 1H NMR (500 MHz, CDCl3) δ 7.72 (d, 2H, J = 8.0 Hz), Hz), 2.42 (s, 3H), 1.99 (d, 3H, J = 1.2 Hz), 1.06 (d, 3H, J =
7.40 (d, 2H, J = 8.0 Hz), 7.35−7.29 (m, 3H), 7.09−7.06 (m, 6.7 Hz); 13C{1H} NMR (125 MHz, CDCl3) δ 143, 135.5,
2H), 6.17 (s, 1H), 4.11 (dd, 1H, J = 14.3 Hz, 2.29 Hz), 3.77 132.0, 129.8, 127.2, 111.4, 67.6, 50.1, 21.6, 17.9, 17.8; HRMS
(dd, 1H, J = 10.3, 2.29 Hz), 2.98 (dd, 1H, J = 14.3, 9.7 Hz),
(ESI-TOF) m/z: [M + H]+ calcd for C13H18NO3S 268.1002;
2.46 (s, 3H), 2.10 (d, 3H, J = 0.8 Hz); 13C{1H} NMR (125
found 268.1007.
MHz, CDCl3) δ 144.2, 137.1, 134.8, 132.7, 130.0, 128.6, 128.5,
(S)-3-Isopropyl-5-methyl-4-tosyl-3,4-dihydro-2H-1,4-
127.5, 125.8, 111.9, 72.7, 50.7, 21.6, 18.2; HRMS (ESI-TOF)
oxazine ((S)-4ua). The general method B described above
m/z: [M + H]+ calcd for C18H20NO3S 330.1159; found
was followed when (S)-2-isopropyl-1-tosylaziridine 1u (50 mg,
330.1167.
(R)-2-(2-Chlorophenyl)-5-methyl-4-tosyl-3,4-dihydro- 0.209 mmol, 1.0 equiv, >94% ee) was treated with propargyl
2H-1,4-oxazine ((R)-4ma). The general method B described alcohol 2a (0.1 mL), Zn(OTf)2 (4 mg, 0.010 mmol, 5 mol %),
above was followed when dry DCM (0.5 mL) solution of (S)- and Bu4N+HSO4− (71 mg, 0.209 mmol, 1.0 equiv) in dry THF
2-(2-chlorophenyl)-1-tosylaziridine 1m (50 mg, 0.162 mmol, (0.5 mL) at 50 °C on an oil bath for 2 h. After completion, the
1.0 equiv, >82% ee) was treated with a reaction mixture of reaction was quenched with NH4+Cl− and purified by flash
propargyl alcohol 2a (0.1 mL), Zn(OTf)2 (3 mg, 0.008 mmol, column chromatography to obtain (S)-3ua in 51% yield (31
5 mol %) and Bu4N+HSO4− (55 mg, 0.162 mmol, 1.0 equiv) at mg, 0.106 mmol). Next, (S)-3ua (31 mg, 0.106 mmol, 1.0
0 °C for 60 min in a dropwise manner. After completion, the equiv) was treated with Zn(OTf)2 (4.0 mg, 0.011 mmol, 10
reaction was quenched with NH4+Cl−, and after the workup, mol %) as the catalyst and Bu4N+OTf− (42 mg, 0.106 mmol,
the crude was purified by flash column chromatography to 1.0 equiv) as an additive in an Ar environment at 85 °C on an
furnish (R)-3ma in 97% yield (57 mg, 0.157 mmol). Next, oil bath for 4 h to obtain 4ua as a gummy liquid in 70% (22
(R)-3ma (57 mg, 0.157 mmol, 1.0 equiv) was treated with mg, 0.074 mmol) yield (36% overall yield). [α]25D +61.429 (c
Zn(OTf)2 (6 mg, 0.016 mmol, 10 mol %) as the catalyst and 0.140 in C2H4Cl2) for a >92% ee sample. Optical purity was
Bu4N+OTf− (61 mg, 0.157 mmol, 1.0 equiv) as an additive in determined by chiral HPLC analysis (AS-H, isopropanol/n-
an Ar environment at 85 °C on an oil bath for 5 h to obtain hexane = 1/99, flow rate = 1.0 mL/min, l = 254 nm) tR = 09.91
(R)-4ma as a white solid (mp 100−102 °C) in 80% yield (47 min (major), 15.14 min (minor); Rf 0.76 (in 10% ethyl acetate
mg, 0.129 mmol). [α]25D −202.78 (c 0.360 in C2H4Cl2) for a > in petroleum ether). IR υmax (KBr, cm−1) 2961, 2925, 1658,
77% ee sample. Optical purity was determined by chiral HPLC 1599, 1495, 1463, 1328, 1235, 1160, 1093, 815; 1H NMR (500
(AS-H, isopropanol/n-hexane = 1/99, flow rate = 1.0 mL/min, MHz, CDCl3) δ 7.55 (d, 2H, J = 8.6 Hz), 7.25 (d, 2H, J = 8.0
l = 254 nm) tR = 29.51 min (major), 65.94 min (minor), Rf Hz), 5.89 (d, 1H, J = 1.2 Hz), 3.96 (dd, 1H, J = 14.3, 2.3 Hz),
0.38 (in 10% ethyl acetate in petroleum ether); IR υmax (KBr, 2.78 (dd, 1H, J = 14.3, 9.7 Hz), 2.49−2.46 (m, 1H), 2.7 (s,
cm−1) 2924, 2853, 1665, 1597, 1494, 1476, 1443, 1352, 1205, 3H), 1.95 (d, 3H, J = 1.2 Hz), 1.59−1.52 (m, 1H), 0.74 (dd,
1166, 1089, 812; 1H NMR (400 MHz, CDCl3) δ 7.75 (d, 2H, J 6H, J = 6.9, 2.3 Hz); 13C{1H} NMR (125 MHz, CDCl3) δ
= 8.5 Hz), 7.33 (d, 2H, J = 8.5 Hz), 7.30−7.20 (m, 4H), 6.18 143.8, 135.1, 132.3, 129.8, 127.4, 111.5, 75.6, 46.7, 30.1, 21.5,
(s, 1H), 4.46 (dd, 1H, J = 9.8, 2.4 Hz), 4.36 (dd, 1H, J = 14.6, 18.1, 17.80, 17.77; HRMS (ESI-TOF) m/z: [M − H]+ calcd
2.4 Hz), 2.86 (dd, 1H, J = 14.0, 9.8 Hz), 2.42 (s, 1H), 2.11 (d, for C15H20NO3S 294.1159; found 294.1160.
J. Org. Chem. 2023, 88, 4504−4518
5-Methyl-2-phenylmorpholine (5b). (1) In a double-

neck RB, 4aa (100 mg, 0.304 mmol, 1.0 equiv) and Pd-C (10%
■ AUTHOR INFORMATION
Corresponding Author
Pd) (32 mg, 0.030 mmol, 10 mol %) were introduced in an Manas K. Ghorai − Department of Chemistry, Indian Institute
inert environment and 5.0 mL of dry ethanol was added to it, of Technology, Kanpur 208016, India; orcid.org/0000-
and the reaction mixture was stirred at RT. After 5 min, H2-gas 0002-0472-4757; Phone: (+91)-512-2597518;
was purged with the help of a balloon and stirring was Email: mkghorai@iitk.ac.in; Fax: (+91)-512-2596806
continued at RT for 36 h. The reaction was monitored by
TLC. After completion, the reaction mixture product was Authors
filtered out with the help of a celite pad. After the usual Bharat Singh − Department of Chemistry, Indian Institute of
workup, the crude concentrate was used for the next step. The Technology, Kanpur 208016, India
1 Manish Kumar − Department of Chemistry, Indian Institute of
H NMR of the crude reaction mixture indicated that the
product (Rf 0.33 in 5% ethyl acetate in petroleum ether) was a Technology, Kanpur 208016, India
mixture of diastereomers (dr 20:1). Gaurav Goswami − Department of Chemistry, Indian Institute
(2) In a double-neck RB, Na (3.04 mmol, 10 equiv) was of Technology, Kanpur 208016, India
taken in Ar environment and a solution of naphthalene (3.04 Indresh Verma − Department of Chemistry, Indian Institute of
mmol, 10 equiv in 5 mL of THF) was added to it. The reaction Technology, Kanpur 208016, India
mixture was kept for stirring at room temperature. After 5 min, Complete contact information is available at:
the color of the reaction mixture started to change from https://pubs.acs.org/10.1021/acs.joc.2c03093
colorless to green color, indicating the beginning of the
generation of naphthyl radicals. After 1 h, the solution became Notes
dark green and then the reaction mixture was transferred to The authors declare no competing financial interest.
−78 °C; after 10 min a solution of the crude product
(obtained from the first step) in THF (5 mL) was added
dropwise and the reaction was monitored by TLC. The
■ ACKNOWLEDGMENTS
M.K.G. is grateful to IIT Kanpur and SERB (DST/
reaction was completed in 1 h, quenched by a saturated CHM2019478), India, for the financial support. B.S. thanks
solution of NH4Cl, and left for stirring for 10 min at the same CSIR, and M.K., G.G., and I.V. thank IIT Kanpur, India, for
temperature. After ethyl acetate and water workup, the the research fellowships.
combined organic layer was washed with 50% NaOH solution
(10 mL) three times. The crude product was purified on
neutral alumina using 25% ethyl acetate in petroleum ether to
afford pure 5b as a single diastereomer as a light-yellow liquid
■ REFERENCES
(1) (a) Witt, J. O.; McCollum, A. L.; Hurtado, M. A.; Huseman, E.
D.; Jeffries, D. E.; Temple, K. J.; Plumley, H. C.; Blobaum, A. L.;
in 80% yield (43 mg, 0.243 mmol). IR υmax (KBr, cm−1) 3305, Lindsley, C. W.; Hopkins, C. R. Synthesis and characterization of a
2924, 2854, 1645, 1495, 1452, 1381, 1262, 1102; 1H NMR series of chiral alkoxymethyl morpholine analogs as dopamine
(500 MHz, CDCl3) δ 7.40−7.34 (m, 4H), 7.30−7.27 (m, 1H), receptor 4 (D4R) antagonists. Bioorg. Med. Chem. Lett. 2016, 26,
4.51 (dd, 1H, J = 8.6, 2.9 Hz), 3.84 (dd, 1H, J = 10.9, 2.9 Hz), 2481−2488. (b) Roughley, S. D.; Jordan, A. M. The Medicinal
3.70 (dd, 1H, J = 11.5, 2.9 Hz), 3.18 (dd, 1H, J = 12.6, 8.6 Chemist’s Toolbox: An Analysis of Reactions Used in the Pursuit of
Hz), 3.08−3.04 (m, 1H), 2.93 (dd, 1H, J = 12.6, 2.9 Hz), 2.00 Drug Candidates. J. Med. Chem. 2011, 54, 3451−3479. (c) Wijtmans,
(bs, 1H), 1.30 (d, 3H, J = 6.9 Hz); 13C{1H} NMR (125 MHz, R.; Vink, M. K. S.; Schoemaker, H. E.; Van Delft, F. L.; Blaauw, R. H.;
Rutjes, F. P. J. T. Biological relevance, and synthesis of C-substituted
CDCl3) δ 140.5, 128.5, 127.6, 126.3, 78.2, 71.4, 47.4, 46.9,
morpholine derivatives. Synthesis 2004, 5, 641−662.
16.9; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C11H16NO (2) (a) Fang, Y.; Zhang, S.; Li, M.; Xiong, L.; Tu, L.; Xie, S.; Jin, Y.;
178.1227; found 178.1236. Liu, Y.; Yang, Z.; Liu, R. Optimisation of novel 4, 8-disubstituted
dihydropyrimido[5,4-b][1,4]oxazine derivatives as potent GPR 119
■ ASSOCIATED CONTENT
Data Availability Statement
agonists. J. Enzyme Inhib. Med. Chem. 2020, 35, 50−58. (b) Shao, X.;
Pak, S.; Velagapudi, U. K.; Gobbooru, S.; Kommaraju, S. S.; Low, W.-
K.; Subramaniam, G.; Pathak, S. K.; Talele, T. T. Synthesis of 2,3-
The data underlying this study are available in the published dihydrobenzo[b][1,4]dioxine-5-carboxamide and 3-oxo-3,4-
article and its Supporting Information. dihydrobenzo[b][1,4]oxazine-8-carboxamide derivatives as PARP1
inhibitors. Bioorg. Chem. 2020, 102, 104075−107589. (c) Mal, A.;
*
sı Supporting Information
Wani, I. A.; Goswami, G.; Ghorai, M. K. Synthesis of Nonracemic 1,4-
The Supporting Information is available free of charge at Benzoxazines via Ring-Opening/Cyclization of Activated Aziridines
https://pubs.acs.org/doi/10.1021/acs.joc.2c03093. with 2-Halophenols: Formal Synthesis of Levofloxacin. J. Org. Chem.
2018, 83, 7907−7918.
Copies of 1H and 13C{1H} NMR spectra of the (3) (a) Ko, Y. O.; Jeon, H. J.; Jung, D. J.; Kim, U. B.; Lee, S.-G.
compounds, HPLC chromatograms for the enantiomeric Rh(II)/Mg(OtBu)2-Catalyzed Tandem One-Pot Synthesis of 1,4-
excess determination, and details of single-crystal X-ray Oxazepines and 1,4-Oxazines from N-Sulfonyl-1,2,3-triazoles and
analysis of the compounds (PDF) Glycidols. Org. Lett. 2016, 18, 6432−6435. (b) Asahina, Y.; Takei, M.;
Kimura, T.; Fukuda, Y. Synthesis and Antibacterial Activity of Novel
Accession Codes Pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic Acid Derivatives Car-
rying the 3-Cyclopropylaminomethyl-4-substituted-1-pyrrolidinyl
CCDC 2113282 and 2202229−2202231 contain the supple-
Group as a C-10 Substituent. J. Med. Chem. 2008, 51, 3238−3249.
mentary crystallographic data for this paper. These data can be (c) Croom, K. F.; Goa, K. L. Levofloxacin. Drugs 2003, 63, 2769−
obtained free of charge via www.ccdc.cam.ac.uk/data_request/ 2802.
cif, or by emailing data_request@ccdc.cam.ac.uk, or by (4) (a) Ghorai, M. K.; Shukla, D.; Bhattacharyya, A. Syntheses of
contacting The Cambridge Crystallographic Data Centre, 12 Chiral β- and γ-Amino Ethers, Morpholines, and Their Homologues
Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033. via Nucleophilic Ring-Opening of Chiral Activated Aziridines and
J. Org. Chem. 2023, 88, 4504−4518
Azetidines. J. Org. Chem. 2012, 77, 3740−3753. (b) Gharpure, S. J.; (14) Wang, Y.; Zhang, W.-Y.; You, S.-L. Ketones and Aldehydes as
Prasad, J. V. K. Stereoselective Synthesis of C-Substituted Morpholine O-Nucleophiles in Iridium-Catalyzed Intramolecular Asymmetric
Derivatives using Reductive Etherification Reaction: Total Synthesis Allylic Substitution Reaction. J. Am. Chem. Soc. 2019, 141, 2228−
of Chelonin C. J. Org. Chem. 2011, 76, 10325−10331. (c) Ghorai, M. 2232.
K.; Shukla, D.; Das, K. Enantioselective Syntheses of Morpholines and (15) (a) Takeda, Y.; Sameera, W. M. C.; Minakata, S. Palladium-
Their Homologues via SN2-Type Ring Opening of Aziridines and Catalyzed Regioselective and Stereospecific Ring-Opening Cross-
Azetidines with Haloalcohols J. Org. Chem. 2009, 74, 7013−7022. Coupling of Aziridines: Experimental and Computational Studies. Acc.
(5) (a) Hajós, M.; Fleishaker, J. C.; Filipiak-Reisner, J. K.; Brown, M. Chem. Res. 2020, 53, 1686−1702. (b) Li, D.; Wang, L.; Zhu, H.; Bai,
T.; Wong, E. H. F. The Selective Norepinephrine Reuptake Inhibitor L.; Yang, Y.; Zhang, M.; Yang, D.; Wang, R. Catalytic Asymmetric
Antidepressant Reboxetine: Pharmacological and Clinical Profile. Reactions of α-Isocyanoacetates and meso-Aziridines Mediated by an
CNS Drug Rev. 2004, 10, 23−44. (b) Georgopapadakou, N. H.; in-Situ-Generated Magnesium Catalytic Method. Org. Lett. 2019, 21,
Walsh, T. J. Antifungal Agents: Chemotherapeutic Targets and 4717−4720. (c) Suzuki, S.; Asako, T.; Itami, K.; Yamaguchi, J.
Immunologic Strategies. Antimicrob. Agents Chemother. 1996, 40, Modular synthesis of heptaarylindole. Org. Biomol. Chem. 2018, 16,
279−291. (c) Baloch, R. I.; Mercer, E. I. Inhibition of sterol Δ8 → Δ7- 3771−3776. (d) Lin, T. Y.; Wu, H.-H.; Feng, J.-J.; Zhang, J. Transfer
isomerase and Δ14-reductase by fenpropimorph tridemorph and of Chirality in the Rhodium-Catalyzed Chemoselective and
fenpropidin in cell-free enzyme systems from Saccharomyces cerevisiae. Regioselective Allylic Alkylation of Hydroxyarenes with Vinyl
Phytochemistry 1987, 26, 663−668. Aziridines. Org. Lett. 2017, 19, 2897−2900.
(6) (a) Pansare, S. V.; Adsool, V. A. A Concise, Enantioselective (16) (a) Xing, S.; Wang, C.; Gao, T.; Wang, Y.; Wang, H.; Wang, H.;
Approach to (−)-Quinic Acid. Org. Lett. 2006, 8, 2035−2037. Wang, K.; Zhu, B. Construction of 4-spiroannulated tetrahydroiso-
(b) Pansare, S. V.; Adsool, V. A. Enantioselective Synthesis of quinoline skeletons via a sequential ring opening of aziridines and
Functionalized Medium-Sized Oxacycles. Org. Lett. 2006, 8, 5897− Pictet−Spengler reaction. New J. Chem. 2022, 46, 2553−2558.
5899. (c) Pansare, S. V.; Jain, R. P. Enantioselective Synthesis of (S)- (b) Wani, I. A.; Goswami, G.; SK, S.; Mal, A.; Sayyad, M.; Ghorai,
(+)-Pantolactone. Org. Lett. 2000, 2, 175−177. M. K. A synthetic route to 1,4-disubstituted tetrahydro-β-carbolines
(7) Zulys, A.; Dochnahl, M.; Hollmann, D.; Lohnwitz, K.; and tetrahydropyranoindoles via ring-opening/Pictet-Spengler reac-
Herrmann, J.-S.; Roesky, P. W.; Blechert, S. Intramolecular Hydro- tion of aziridines and epoxides with indoles/aldehydes. Org. Biomol.
amination of Functionalized Alkenes and Alkynes with a Homoge- Chem. 2020, 18, 272−287. (c) Das, B. K.; Pradhan, S.;
nous Zinc Catalyst. Angew. Chem., Int. Ed. 2005, 44, 7794−7798. Punniyamurthy, T. Stereospecific Ring-Opening and Cycloisomeriza-
(8) (a) Yao, L.-F.; Wang, Y.; Huang, K.-W. Synthesis of morpholine tion of Aziridines with Propargylamines: Synthesis of Functionalized
or piperazine derivatives through gold-catalyzed cyclization reactions Piperazines and Tetrahydropyrazines. Org. Lett. 2018, 20, 4444−
of alkynylamines or alkynylalcohols. Org. Chem. Front. 2015, 2, 721− 4448. (d) Liao, Y.; Zhou, B.; Xia, Y.; Liu, X.; Lin, L.; Feng, X.
725. (b) Vandavasi, J. K.; Hu, W.-P.; Chen, H.-Y.; Senadi, G. C.; Asymmetric [3 + 2] Cycloaddition of 2,2′-Diester Aziridines to
Chen, C.-Y.; Wang, J.-J. A New Approach to 1,4-Oxazines and 1,4- Synthesize Pyrrolidine Derivatives. ACS Catal. 2017, 7, 3934−3939.
Oxazepines via Base-Promoted Exo Mode Cyclization of Alkynyl (e) Sayyad, M.; Mal, A.; Wani, I. A.; Ghorai, M. K. A Synthetic Route
Alcohols: Mechanism and DFT Studies. Org. Lett. 2012, 14, 3134− to Chiral Tetrahydropyrroloindoles via Ring-Opening of Activated
3137. Aziridines with 2-Bromoindoles Followed by Copper-Catalyzed C-N
(9) Cambeiro, F.; López, S.; Varela, J. A.; Saá, C. Vinyl Cyclization. J. Org. Chem. 2016, 81, 6424−6432. (f) Xing, S.; Ren, J.;
Dihydropyrans and Dihydrooxazines: Cyclizations of Catalytic Wang, K.; Cui, H.; Li, W.; Yan, H. Lewis acid promoted three-
Ruthenium Carbenes Derived from Alkynals and Alkynones. Angew. component reactions of aziridines, arenes and aldehydes: an efficient
Chem., Int. Ed. 2014, 53, 5959−5963. and diastereoselective synthesis of cis-1,4-disubstituted tetrahydroiso-
(10) (a) Anitha, M.; Shankar, M.; Kumara Swamy, K. C. Reactivity quinolines. Tetrahedron 2015, 71, 6290−6299. (g) Yang, D.; Wang,
of epoxy-ynamides with metal halides: nucleophile (Br/Cl/OH)- L.; Han, F.; Li, D.; Zhao, D.; Cao, Y.; Ma, Y.; Kong, W.; Sun, Q.;
assisted tandem intramolecular 5-exo-dig or 6-endo-dig cyclisation and Wang, R. Highly Enantioselective Ring-Opening Reactions of
AgF2-promoted oxidation. Org. Chem. Front. 2019, 6, 1133−1139. Aziridines with Indole and Its Application in the Building of C3-
(b) Kumari, A. L. S.; Reddy, A. S.; Kumara Swamy, K. C. Transition Halogenated Pyrroloindolines. Chem. − Eur. J. 2014, 20, 16478−
Metal-Free Cascade Cyclization of Epoxy-Ynamides: To Go for 1,3- 16483.
Oxazines or 1,4-Oxazines? Org. Lett. 2016, 18, 5752−5755. (17) (a) Nicastri, K. A.; Zappia, S. A.; Pratt, J. C.; Duncan, J. M.;
(c) Maheswara, M.; Lee, Y. Y.; Kang, E. J. AgOTf-Catalyzed Guzei, I. A.; Fernández, I.; Schomaker, J. M. Tunable Aziridinium
Cycloisomerization of Alkynyl Oxiranes for Dihydro-1,4-oxazine Ylide Reactivity: Noncovalent Interactions Enable Divergent Product
Synthesis. Synlett 2012, 23, 2481−2484. Outcomes. ACS Catal. 2022, 12, 1572−1580. (b) Coin, G.; Montal,
(11) Broggini, G.; Beccalli, E. M.; Borsini, E.; Fasana, A.; Zecchi, G. O. D. F. D.; Dubourdeaux, P.; Latour, J.-M. Expedient Synthesis of 2-
Intramolecular Oxidative Pd (II)-Catalyzed Alkoxylation of 3-Aza-5- Iminothiazolidines via Telescoping Reactions Including Iron-Cata-
alkenols with O2 as Sole Oxidant: Mild Conditions for the Synthesis lyzed Nitrene Transfer and Domino Ring-Opening Cyclization
of 1,4-Oxazine Derivatives. Synlett 2011, 2, 227−230. (DROC). Eur. J. Org. Chem. 2021, 443−448. (c) Zuo, Q.; Shi, Z.;
(12) (a) Jones, K. D.; Nutt, M. J.; Comninos, E.; Sobolev, A. N.; Zhan, F.; Wang, Z.; Lin, J.-S.; Jiang, Y. TfOH-catalyzed formal [3+2]
Moggach, S. A.; Miura, T.; Murakami, M.; Stewart, S. G. A One-Pot cycloaddition of N-tosylaziridine dicarboxylates and nitriles: Synthesis
Reaction of α-Imino Rhodium Carbenoids and Halohydrins: Access of tetrafunctionalized 2-imidazolines. Tetrahedron Lett. 2020, 61,
to 2,6-Substituted Dihydro-2H-1,4-oxazines. Org. Lett. 2020, 22, 151576−151580. (d) Hajra, S.; Bhosale, S. S.; Hazra, A.; Kanaujia, N.
3490−3494. (b) Ko, Y. O.; Jeon, H. J.; Jung, D. J.; Kim, U. B.; Lee, S.- The one pot asymmetric synthesis of 3,3′-pyrrolidonyl spiroxindoles
G. Rh(II)/Mg(OtBu)2-Catalyzed Tandem One-Pot Synthesis of 1,4- via a regio- and stereoselective domino reaction. Org. Biomol. Chem.
Oxazepines and 1,4-Oxazines from N-Sulfonyl-1,2,3-triazoles and 2019, 17, 8140−8148. (e) Tu, L.; Li, Z.; Feng, T.; Yu, S.; Huang, R.;
Glycidols. Org. Lett. 2016, 18, 6432−6435. (c) Ma, X.; Pan, S.; Wang, Li, J.; Wang, W.; Zheng, Y.; Liu, J. Access to Imidazolidines via 1,3-
H.; Chen, W. Rhodium-Catalyzed Transannulation of N-Sulfonyl- Dipolar Cycloadditions of 1,3,5-Triazinanes with Aziridines. J. Org.
1,2,3-triazoles and Epoxides: Regioselective Synthesis of Substituted Chem. 2019, 84, 11161−11169. (f) Hajra, S.; Saleh, S. K. A.; Hazra,
3,4-Dihydro-2H-1,4-oxazines. Org. Lett. 2014, 16, 4554−4557. A.; Singh, M. S. Organocatalytic Domino Reaction of Spiroaziridine
(13) Moulins, J. R.; Hughes, J. A.; Doyle, L. E.; Cameron, T. S.; Oxindoles and Malononitrile for the Enantiopure Synthesis of
Burnell, D. J. Two Rearrangement Pathways in the Geminal Acylation Spiro[dihydropyrrole-3,3′-oxindoles]. J. Org. Chem. 2019, 84,
of 2-Methoxyoxazolidines Leading to Substituted 1,4-Oxazines. Eur. J. 8194−8201. (g) Bhattacharyya, A.; Shahi, C. K.; Pradhan, S.;
Org. Chem. 2015, 1325−1332. Ghorai, M. K. Stereospecific Synthesis of 1,4,5,6-Tetrahydropyrimi-
J. Org. Chem. 2023, 88, 4504−4518
dines via Domino Ring-Opening Cyclization of Activated Aziridines J.; Tung, C.-H.; Xing, L.-B.; Xu, Z. Breaking aziridines to construct
with α-Acidic Isocyanides. Org. Lett. 2018, 20, 2925−2928. morpholines with a gold (I)-catalyzed tandem ring-opening and
(18) (a) Lee, S. G.; Kim, S.-G. Electrochemical Oxidation with cycloisomerization reaction. Org. Biomol. Chem. 2016, 14, 10973−
Lewis-Acid Catalysis Leads to Trifluoromethylative Difunctionaliza- 10980. (c) Wang, L.; Liu, Q.-B.; Wang, D.-S.; Li, X.; Han, X.-W.;
tion of Alkenes Using CF3SO2Na. Tetrahedron Lett. 2018, 74, 3671− Xiao, W.-J.; Zhou, Y.-G. Tandem Ring-Opening/Closing Reactions of
3678. (i) Mal, A.; Sayyad, M.; Wani, I. A.; Ghorai, M. K. Domino N-Ts Aziridines and Aryl Propargyl Alcohols Promoted by t-BuOK.
Ring-Opening Cyclization of Activated Aziridines with Indoles: Org. Lett. 2009, 11, 1119−1122. (d) Bera, M.; Roy, S. Silver(I)-
Synthesis of Chiral Hexahydropyrroloindoles. J. Org. Chem. 2017, Catalyzed Dual Activation of Propargylic Alcohol and Aziridine/
82, 4−11. (b) Wang, B.; Liang, M.; Tang, J.; Deng, Y.; Zhao, J.; Sun, Azetidine: Triggering Ring-Opening and Endo-Selective Ring-Closing
H.; Tung, C. H.; Jia, J.; Xu, Z. Gold/Lewis Acid Catalyzed in a Cascade. J. Org. Chem. 2009, 74, 8814−8817.
Cycloisomerization/Diastereoselective [3+2] Cycloaddition Cascade: (22) (a) Pradhan, S.; Chauhan, N.; Shahi, C. K.; Bhattacharyya, A.;
Synthesis of Diverse Nitrogen-Containing Spiro Heterocycles. Org. Ghorai, M. K. Stereoselective Synthesis of Hexahydroimidazo[1,2-
Lett. 2016, 18, 4614−4617. (c) Kaicharla, T.; Jacob, A.; Gonnade, R. a]quinolines via SN2-Type Ring-Opening Hydroarylation-Hydro-
G.; Biju, A. T. AgOTf-catalyzed dehydrative [3+2] annulation of amination Cascade Cyclization of Activated Aziridines with N-
aziridines with 2-naphthols. Chem. Commun. 2017, 53, 8219−8222. Propargylanilines. Org. Lett. 2020, 22, 7903−7908. (b) Tarannum, S.;
(d) Xing, S.; Ren, J.; Wang, K.; Cui, H.; Xia, T.; Zhang, M.; Wang, D. Sk, S.; Das, S.; Wani, I. A.; Ghorai, M. K. Stereoselective Syntheses of
Facile, Efficient and Diastereoselective Construction of Indane-Fused Highly Functionalized Imidazolidines and Oxazolidines via Ring-
Pyrrolidin-2-ones via a Potassium Hydroxide-Catalyzed Domino Opening Cyclization of Activated Aziridines and Epoxides with
Reaction. Adv. Synth. Catal. 2016, 358, 3093−3099. Amines and Aldehydes. J. Org. Chem. 2020, 85, 367−379.
(19) (a) Xing, S.; Wang, Y.; Jin, C.; Shi, S.; Zhang, Y.; Liao, Z.; (23) (a) Lühl, A.; Nayek, H. P.; Blechert, S.; Roesky, P. W. Zinc−
Wang, K.; Zhu, B. Construction of Bridged Aza- and Oxa-[n.2.1] zinc bonded decamethyldizincocene Zn2(η5-C5Me5)2 as catalyst for
Skeletons via an Intramolecular Formal [3+2] Cycloaddition of the inter- and intramolecular hydroamination reaction. Chem.
Aziridines and Epoxides with Electron-Deficient Alkenes. J. Org. Commun. 2011, 47, 8280−8282. (b) Mukherjee, A.; Sen, T. K.;
Chem. 2022, 87, 6426−6431. (b) Eshon, J.; Nicastri, K. A.; Schmid, S. Ghorai, P. K.; Samuel, P. P.; Schulzke, C.; Mandal, S. K. Phenalenyl-
C.; Raskopt, W. T.; Guzei, I. A.; Fernández, I.; Schomaker, J. M. Based Organozinc Catalysts for Intramolecular Hydroamination
Intermolecular [3+3] ring expansion of aziridines to dehydropiperi- Reactions: A Combined Catalytic, Kinetic, and Mechanistic
dines through the intermediacy of aziridinium ylides Nat. Commun. Investigation of the Catalytic Cycle. Chem. − Eur. J. 2012, 18,
2020, 11, 1273−1280. (c) Elwrfalli, F.; Esvan, Y. J.; Robertson, C. M.; 10530−10545. (c) Nisa, R. U.; Ayub, K. Mechanism of Zn(OTf)2
Aïssa, C. Regioselective cycloaddition of potassium alkynyltrifluor- catalyzed hydroamination-hydrogenation of alkynes with amines:
oborates with 3-azetidinones and 3-oxetanone by nickel-catalysed C-C insight from theory. New J. Chem. 2017, 41, 5082−5090.
bond activation. Chem. Commun. 2019, 55, 497−500. (d) Lin, T.-Y.; (24) Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory
Wu, H.-H.; Feng, J. J.; Zhang, J. Chirality Transfer in Rhodium(I)- Chemicals, 3rd ed.; Pergamon Press: Oxford, 1988.
Catalyzed [3 + 2]-Cycloaddition of Vinyl Aziridines and Oxime (25) Furniss, B. S.; Hannaford, A. J.; Smith, P. W. G.; Tatchell, A. R.
Ethers: Atom-Economical Synthesis of Chiral Imidazolidines. Org. Vogel’s Textbook of Practical Organic Chemistry, 5th ed.; Longman
Lett. 2018, 20, 3587−3590. (e) Xing, S.; Gu, N.; Wang, X.; Liu, J.; Group, U.K. Ltd., 1989.
Xing, C.; Wang, K.; Zhu, B. Substitution-Controlled Selective (26) Jeong, J. U.; Tao, B.; Sagasser, I.; Henniges, H.; Sharpless, K. B.
Formation of Hexahydrobenz[e]isoindoles and 3-Benzazepines via Bromine-Catalyzed Aziridination of Olefins. A Rare Example of
In(OTf)3-Catalyzed Tandem Annulations. Org. Lett. 2018, 20, 5680− Atom-Transfer Redox Catalysis by a Main Group Element. J. Am.
5683. (f) Pazos, M.; González, B.; Suescun, L.; Seoane, G.; Carrera, I. Chem. Soc. 1998, 120, 6844−6845.
Production of enantiopure β-amino-γ-hydroxyesters from benzoic (27) Groeper, J. A.; Eagles, J. B.; Hitchcock, S. R. A facile, one-pot
acid by a selective formal aminohydroxylation. Tetrahedron Lett. 2017, synthesis of Ephedra-based aziridines. Tetrahedron: Asymmetry 2009,
58, 2182−2185. (g) Xing, S.; Cui, H.; Gu, N.; Li, Y.; Wang, K.; Tian, 20, 1969−1974.
D.; Qin, J.; Liu, Q. AgOTf-catalyzed sequential synthesis of 4-
isoquinolones via oxidative ring opening of aziridines and aza-Michael
addition. Org. Biomol. Chem. 2017, 15, 8308−8312.
(20) (a) Dolfen, J.; Vervisch, K.; Kimpe, N. D.; D’hooghe, M.
LiAlH4-Induced Selective Ring Rearrangement of 2-(2-Cyanoethyl)-
aziridines toward 2-(Aminomethyl)pyrrolidines and 3-Aminopiper-
idines as Eligible Heterocyclic Building Blocks. Chem. − Eur. J. 2016,
22, 4945−4951. (b) Xing, S.; Ren, J.; Wang, K.; Cui, H.; Yan, H.; Li,
W. Diastereoselective Synthesis of Substituted Tetrahydroisoquino-
lines and Isoindolines via a Silver(I) Triflate-Promoted Tandem
Reaction. Adv. Synth. Catal. 2016, 358, 532−538. (c) Ji, M.-K.;
Hertsen, D.; Yoon, D.-H.; Eum, H.; Goossens, H.; Waroquier, M.;
Speybroeck, V. V.; D’Hooghe, M.; Kimpe, N. D.; Ha, H.-J.
Nucleophile-Dependent Regio- and Stereoselective Ring Opening of
1-Azoniabicyclo[3.1.0]hexane Tosylate. Chem. − Asian J. 2014, 9,
1060−1067. (d) Dolfen, J.; Kenis, S.; Hecke, K. V.; Kimpe, N. D.;
D’hooghe, M. Selective Synthesis of Functionalized Trifluoromethy-
lated Pyrrolidines, Piperidines, and Azepanes Starting from 1-Tosyl-2-
(trifluoromethyl)aziridine. Chem. − Eur. J. 2014, 20, 10650−10653.
(e) Sun, H.; Huang, B.; Lin, R.; Yang, C.; Xia, W. Metal-free one-pot
synthesis of 2-substituted and 2,3-disubstituted morpholines from
aziridines. Beilstein J. Org. Chem. 2015, 11, 524−529.
(21) (a) Fang, S.; Zhao, Y.; Li, H.; Zheng, Y.; Lian, P.; Wan, X.
[3+3]-Cycloaddition of α-Diazocarbonyl Compounds and N-
Tosylaziridines: Synthesis of Polysubstituted 2H-1,4-Oxazines
through Synergetic Catalysis of AgOTf/Cu(OAc)2. Org. Lett. 2019,
21, 2356−2359. (b) Zhang, S.; Shan, C.; Zhang, S.; Yuan, L.; Wang,
J. Org. Chem. 2023, 88, 4504−4518

J. Org. Chem. 2023, 88, 4504-4518

Uploaded by

Document Informationclick to expand document information

Copyright:

Available Formats

J. Org. Chem. 2023, 88, 4504-4518

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

J. Org. Chem. 2023, 88, 4504-4518

Uploaded by

Copyright:

Available Formats

pubs.acs.

Ring-Opening Cyclization (ROC) of Aziridines with Propargyl

ACCESS Metrics & More Article Recommendations *

ABSTRACT: Activated aziridines react with propargyl alcohols in the presence of

Received: December 29, 2022

Figure 1. Bioactive compounds containing substituted morpholine.

© 2023 American Chemical Society https://doi.org/10.1021/acs.joc.2c03093

Scheme 1. Reaction of N-Activated Aziridines with Propargyl Alcohols

■ RESULTS AND DISCUSSION

Scheme 5. Substrate Scope with Respect to Racemic (±)-2-Aryl-N-tosyl-aziridines with 2aa

entry reaction condition % yield ee %

Scheme 9. Reduction Followed by Desulfonylation of 5-Methyl-2-phenyl-4-tosyl-3,4-dihydro-2H-1,4-oxazine (4aa)

(±)-4-((4-Methoxyphenyl)sulfonyl)-5-methyl-2-phe- m/z: [M + H]+ calcd for C17H17FNO3S 334.0908; found

5-Methyl-2-phenylmorpholine (5b). (1) In a double-

You might also like