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Synthesis, evaluation and application of novel bifunctional N,N-di-

isopropylbenzylamineboronic acid catalysts for direct amide formation
between carboxylic acids and amines{{
Kenny Arnold,a Andrei S. Batsanov,a Bryan Daviesb and Andrew Whiting*a
Received 6th August 2007, Accepted 13th November 2007
First published as an Advance Article on the web 22nd November 2007
DOI: 10.1039/b712008g

Three new derivatives of N,N-di-isopropylbenzylamine-2-boronic acid have been prepared by

directed metallation-borylation methods, to derive the 3-fluoro, 3-methoxy and 5-trifluoromethyl
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systems. The addition of an electron withdrawing group does increase the reactivity of such
systems to act as improved direct amide formation catalysts under the most ambient conditions
employed to date. In contrast, an electron donating group does result in considerable lowering of
catalyst reactivity. DoE studies have been used to identify the ideal reaction conditions under
which these types of catalysts should be used, typified by the parent system N,N-di-
isopropylbenzylamine-2-boronic acid. This shows best performance at a 5 mol% loading and
under higher dilution conditions, which most likely reflect the drying capacity of the solvent.

Introduction refluxing toluene where possible, and certainly below refluxing

xylene or mesitylene for example; and (3) zero propensity to
A generally applicable, efficient direct amide formation from proto-deboronation, and hence acting a source of boric acid.
amines and carboxylic acids, via the corresponding ammonium This resulted in the demonstration that ortho-N,N-di-isopro-
salt, that proceeds under relatively ambient conditions remains pylbenzylaminoboronic acid system 1 has a bifunctional
elusive. Since the first report of ammonium carboxylate catalytic effect for direct amide formation reactions involving
pyrolyses,1 there have been various developments in the benzoic acid, and it could be used using refluxing fluoroben-
intervening years, including relatively small reductions in zene temperatures.10 Under these conditions, proto-deborona-
temperature,2 the use of various acid catalysts3 and microwave tion does not compete and a comparison of the rates of amide
assistance.4 However, none of these approaches have provided formation between various boron-based catalysts under two
a solution to facile direct amide formation, and the more usual different sets of reaction conditions clearly showed the
stoichiometric activation methods remain by far the most enhanced activity of catalyst 1 for the more difficult substrates
utilised approach.5 Initial reports of the application of organo- under the milder set of reaction conditions. In this paper, we
boron compounds to assist amide formation,6 has resulted in report our further studies aimed at better understanding the
the development of several useful boronic acid catalysts,7 factors that control catalyst activity, including the synthesis
however, the report that boric acid alone is an efficient catalyst of further examples of these bifunctional aminoarylboronic
under azeotropic conditions8 shows the need to be wary about acids and an examination of their comparative reactivity in
the mode of action of electron deficient arylboronic acids and the direct amide condensation versus existing systems. We also
there is still a need to develop systems with higher reactivity, report associated optimisation of reaction conditions for
and at lower temperatures. To this end, we demonstrated the different substrate combinations using statistical design of
use of bifunctional amino-boronic acid derivatives9 for direct experiments (DoE) methods to gain a further insight into the
amide formation, and examined the previously essentially key reaction parameters that affect reactivity.
unaddressed issue of the competing degree of direct thermal
amide formation. Our major aim was to develop catalytic
systems which exhibit: (1) general reactivity for all types of
amine and carboxylic acid substrates; (2) lower reaction
temperatures to relatively ambient conditions, i.e. lower than

a
Department of Chemistry, Durham University, South Road, Durham, Results and discussion
UK, DH1 3LE E-mail: andy.whiting@durham.ac.uk
b
GlaxoSmithKline Research & Development Ltd., Gunnels Wood Road, We decided to access novel derivatives of system 1, i.e. systems
Stevenage, Hertfordshire, UK, SG1 2NY
{ Electronic supplementary information (ESI) available: General of type 2, in which the hindered N,N-di-isopropylaminobenzyl
experimental methods, X-ray crystallographic data for compounds function was retained, since in previous work, clear benefit
6a and 10, and 1H, 13C, 11B and 19F NMR spectra (as appropriate) for over the less hindered N,N-dimethyl system was demon-
compounds 4a, 5a, 6a, 4b, 5b, 6b, 4c, 8, 9, 10 and 1-morpholin-4-yl-4- strated.10 In addition, the new systems 2 were chosen with
phenylbutan-1-one. See DOI: 10.1039/b712008g
{ CCDC reference numbers 632237 and 632238. For crystallographic the specific aim of testing the effect of changing the Lewis
data in CIF or other electronic format see DOI: 10.1039/b712008g acidity of the boronic acid function by suitable choice of the

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functional group X, i.e. comparing electron withdrawing and react with the borate electrophiles (ca. 12 h), resulting in the
electron donating substituents. isolation of pinacol ester 5b in good yield. It is worth noting
that metallation-borylation of amide 4b fails to proceed at all
Catalyst synthesis with n-butyllithium, whereas the alkyllithium source has no
significant effect upon the metallation of 4a. In addition,
The synthesis of new catalysts based on system 2, started
attempted metallation of methoxy-substituted system 4b with
with the fluoro- and methoxybenzylboronic acid, 6a and b,
respectively (Scheme 1). Hence, N,N-di-isopropyl-3-fluoro- lithium di-isopropylamide, followed by triisopropyl borate
benzylamine-2-boronic acid 6a was prepared starting with resulted in the formation of ester 5b, but in only 11 % yield.
3-fluorobenzoyl chloride 3a, resulting in the formation of Having obtained boronate ester 5b, reduction was attempted
amide 4a, upon reaction with di-isopropylamine, which was as for 5a, resulting in only low yields amino-boronic acid 6b
then subjected to directed metallation. Following several (10 %). It appears that the methoxy system 6b has increased
attempts to achieve directed ortho-metallation of 4a, attempts water solubility compared to 6a, and therefore, suitable
to directly isolate the corresponding boronic acid proved changes to the work up procedure (THF evaporation and
unsuccessful, and it was decided to access the pinacol ester 5a minimisation of aqueous solution and solvent volumes)
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in order to simplify isolation and purification. Hence, reaction resulted in a reasonably efficient isolation of 6b, which after
of amide 4a with sec-butyllithium followed by trimethylborate, subsequent recrystallisation gave a 50 % yield (Scheme 1).
followed by hydrolysis and esterification with pinacol derived In order to compare catalysts of type 2, systems with
the boronate ester 5a (Scheme 1). different electronic properties were required. Several attempts
The reduction method chosen to convert the pinacol ester 5a were made to access the system 6c, via formation of the
was selected in order to achieve both amide reduction and corresponding amide 4c (Scheme 1). However, all attempts to
deprotection of the boronate ester in one step.9b Although the achieve deprotonation of 4c to access boronate 5c led to the
reduction proceeded well using sodium borohydride-trimethyl- formation of intractable complex products, which is not in
silyl chloride, isolation of the amino-boronic acid 6a proved contradiction with other unsuccessful attempts to achieve
troublesome, due to its high water solubility. However, use of lithiation of nitroaryl systems.11 As an alternative to the nitro-
an acidification-neutralisation sequence during the work up substituted system, the final catalyst prepared was the
allowed direct extraction of the amino-boronic acid 6a, which trifluoromethyl-substituted system, i.e. 10, which proved
could then be efficiently precipitated to give pure product in reasonably straightforward to access, as outlined in Scheme 2.
72 % yield. Thus, amidation of acid chloride 7 provided amide 8 in 98 %
The same strategy was employed in order to synthesise yield. Directed ortho-metallation under the same conditions as
N,N-di-isopropyl-3-methoxybenzylamine-2-boronic acid 6b. used for systems 5 (n- or s-BuLi-TMEDA) led to a mixture of
As before, the amidation of acid chloride 3b was facile, effici- ortho- and para-CF3 boronates, with low total conversion (ca.
ently providing di-isopropylamide 4b (Scheme 1). However, 10 %). A number of attempts at improvement (increasing
the directed metallation of 4b proved problematic at first, and reaction temperature, metallation time, etc.) failed to improve
resulted in low conversion to the pinacol ester 5b, i.e. sec- matters and alternative metallating agents were examined. A
butyllithium-TMEDA, 278 uC. This was solved by allowing mixture of potassium tert-butoxide and BuLi12 gave no
much longer reaction times for the intermediate aryllithium to reaction, however, use of lithium di-isopropylamide afforded
the para-CF3-substituted boronate 9 selectively and in high

Scheme 1 Synthesis of fluoro- and methoxy-substituted amino- Scheme 2 Synthesis of trifluoromethyl-substituted amine-boronic
boronic acids 6. acid.

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yield (95 %). Subsequent initial attempts at reduction of the Table 1 Selected bond distances (Å)
amide 9 using borane-dimethyl sulfide in THF at reflux failed
1 6a 10
to give an observable reaction, however, using the TMSCl-
borohydride conditions resulted in formation of boronic acid C(2)–B 1.588(2) 1.5965(14) 1.5876(17)
10 after work up, albeit via a slow reaction, which resulted in B–O(1) 1.356(2) 1.3547(13) 1.3575(15)
B(1)–O(2) 1.366(2) 1.3581(13) 1.3609(16)
only 40 % conversion in 40 h. The solution to this problem was O(1)…N 2.637(1) 2.607(1) 2.623(1)
to simply decrease the reaction concentration used for the C(1)–C(2) 1.412(2) 1.4204(12) 1.4169(16)
reduction conditions, which resulted in complete conversion C(1)–C(7) 1.522(2) 1.5171(13) 1.5187(16)
C(7)–N 1.480(1) 1.4837(12) 1.4795(15)
in 24 h (Scheme 2), and after modification of the work up
conditions used for amino-boronic acids 6, the trifluoro-
methyl-boronic acid 10 was obtained in 60 % yield after dimers by pairs of hydrogen bonds O(2)–H…O(1)[1–x, 1–y,
recrystallisation. 1–z]. There are only marginal differences in bond distances
between 1, 6a and 10 (Table 1). It is interesting to note that the
Comparison of crystal structures trifluoromethyl system 10 exhibits a shorter C–B bond length
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compared with the fluoro system 6a, however, it is little

Crystals of both 6a and 10, which were suitable for single
different to the non-substituted system 1 (see Table 1). This
crystal X-ray analysis, were readily prepared, however, the
probably suggests that there is not a major difference in Lewis
methoxy derivative 6b evaded attempts to derive good quality
acidity between systems 1 and 10, though 6a might be slightly
crystals. However, fluoro and trifluoro derivatives 6a and 10,
less Lewis acidic. Unfortunately, we cannot compare these
respectively, are essentially isostructural with one another and
solid state structures with the methoxy derivative 6b, and 11B
also with the analogue 1.9b Molecular conformations are also
NMR also does not seem to suggest significant differences
similar (Fig. 1). The C(1)BO(1)O(2) moiety is planar and
in the properties of the boronic acid function, which show
inclined to the benzene ring plane by 25.8u (6a) or 21.8u (10).
resonances at d 28.8,9b 28.4, 29.3 and 28.5 for 1, 6a, 6b and 10,
The larger twist in 6a obviously is caused by steric repulsion
respectively.
between the F and O(2) atoms. One hydroxyl group, O(1)H,
forms an intramolecular hydrogen bond with the amino N
Catalyst optimisation using design of experiments (DoE)
atom, which is slightly pyramidalised, with the mean C–N–C
angle of 113u. Molecules are linked into centrosymmetric To gain an insight into the key reaction parameters that
influence the direct amide condensation, a DoE study was
carried out on the formation of amide 13 catalysed by 1
(eqn (1)).13 Four factors were examined (Table 2) and to
simplify subsequent analysis of the results, separate designs
were carried out for fluorobenzene and toluene. Temperature
could not be included as a factor in these individual studies, as
it has been shown previously that azeotropic reflux is desired
to enable the reaction to proceed. A 2-level fractional factorial
design of 8 experiments was selected14 and 4 centre points
were included to provide a measure of variation and indicate
curvature.

ð1Þ
The results of the study of the reaction in fluorobenzene
are summarised in Fig. 2 in the form of a half-normal
probability plot in which the factors having the greatest
influence appear towards the right-hand side of the graph. It
can be seen that catalyst loading, time, and the two-factor
interaction of catalyst loading and time are the most important
factors, whilst acid stoichiometry and concentration have

Table 2 Factors and ranges chosen for the factorial design

Factor Low Centre High

1 (mol%) 1 5.5 10
Acid (equiv) 0.8 1.1 1.4
Conc/M 0.1 0.3 0.5
Fig. 1 X-ray molecular structures of 6a (top) and 10. Thermal
Time/h 4 12 20
ellipsoids are drawn at 50 % probability level.

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Fig. 2 Half normal plot visualizing the most important factors determining yield in the direct amide condensation in fluorobenzene.

no significant effect.15 The centre points in the interaction stoichiometry still has no significant effect (Fig. 4).15 However,
graph (Fig. 3) show no significant deviation from the linear concentration and catalyst loading are now involved in an
relationship plotted, i.e. there is no significant curvature, and interaction, with the model suggesting that in order to increase
the linear relationship plotted is a good representative model. yields of amide 13, both low concentration and higher catalyst
Thus, the DoE suggests, in order to increase yield of amide 13, loading are required (Fig. 5). The interaction graph shows
catalyst loading and time should be increased. Although significant curvature indicating that the design space is over an
increasing reaction time is a possibility, increasing the loading optimum. Since catalyst loading is the most important effect,
of 1 beyond 10 mol% would be undesirable. this appears to indicate that similar yields of amide 13 could be
The same design run in toluene shows catalyst loading is obtained if the loading of 1 is decreased below 10 mol%.
again the most important effect, followed by time, and acid In fact, the centre points indicate that a catalyst loading of

Fig. 3 Interaction graph for the direct amide condensation in fluorobenzene.

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Fig. 4 Most important factors determining yield in the direct amide condensation in toluene.

5.5 mol% gives a similar effect, whilst the concentration effect Catalyst evaluation
suggests that reaction rate is limited by azeotropic removal
of water, and therefore, low concentration is beneficial We have previously shown10 that the boronic acid 1, and
(vide infra). In order to model the curvature, a central related systems, promote amidation reactions, which are
composite design (CCD) could be employed to augment the highly substrate dependent and that the use of more difficult
existing design. Although the DoE study was carried out on substrates under lower temperature conditions (refluxing
the formation of amide 13, the information obtained can fluorobenzene) exposes differences in catalyst activity. With
clearly be used as a basis to start to improve the isolated yields this in mind, the new catalysts were evaluated and compared
of more problematic substrates (vide infra) and hence, these using the reaction between benzoic acid and benzylamine
results have been taken into account in the catalyst evaluation. (eqn (1)), and it had already been shown that the direct

Fig. 5 Interaction graph for the direct amide condensation in toluene.

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Table 3 Isolated yields for the direct amide condensation catalysed

by 1
Yield
Entry Solvent 1 (mol %) Time/h Product (%)

1 PhF 0 24 16
10 68

2 PhF 0 24 2
10 70

3 Toluene 0 22 0a
1 46a

4 PhF 0 24 4
10 67
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5 PhF 0 22 10b
10 53
Fig. 6 Yield verus time data for catalysed and thermal direct amide
condensation between benzoic acid and benzylamine in refluxing
fluorobenzene. 6 PhF 0 24 1
10 50

(uncatalysed) thermal formation of amide 13 under these

conditions is non-existent.10 The results of this comparison are 7 PhF 0 48 0
10 55b
shown in Fig. 6.
The addition of a para-trifluoromethyl group (catalyst 10)
Toluene 5 24 71
is beneficial to rate of formation of N-benzylbenzamide 13, 10 75
compared to the unsubstituted system 1, whereas the addition
of the ortho-fluorine function, i.e. catalyst 6a, decreases
8 PhF 0 24 0
reaction rate to a small extent (Fig. 6). While the differences 10 11
between catalysts 1, 6a and 10 are not substantial, increasing
the electron density of the phenyl ring by incorporating a
methoxy group, i.e. catalyst 6b, leads to a significant decrease Toluene 0 24 0
5 24 16
in reaction rate. This results in only 28 % conversion to amide 10 30 21
11 in 28 h using 6b compared to ca. 63 % conversion for
catalysts 1, 10 and 6a, which have all reached their equilibrium 9 PhF 0 48 0b
conversions at around this time period. The efficiency of water 10 52b
removal determines the equilibrium position, therefore affect-
ing both final conversion and reaction rate, as demonstrated Toluene 0 24 0
by the reaction catalysed by 1 without dehydration, along with 5 49
the results obtained from the DoE study (vide supra). 10 71

10 PhF 0 24 0
Application of catalyst 1 for direct amide formation 10 15

Although the trifluoromethylbenzylboronic acid 10 is the

superior catalyst according (vide supra), the difference between Toluene 0 30 7
5 42
1 and 10 is not substantial (see Fig. 6). Hence, coupled with the 10 59
commercial availability of catalyst 1 and the results of the DoE
a b
optimised reaction conditions in hand (vide supra), we needed Under argon. Determined by HPLC.
to evaluate the scope and limitations of the direct amide
condensation catalysed by 1. A variety of carboxylic acids and
amines were examined refluxing fluorobenzene where possible, The results shown in Table 3 show that the majority of
or if necessary in toluene if conversion to amide was slow, and reactions did not proceed to 100 % completion after 48 h,
over reaction times of up to 48 h. The results of the reactions though good to high isolated yields could be achieved in most
generalised by eqn (2), are shown in Table 3. cases. Fluorobenzene is certainly a suitable and practical
azeotropic solvent for many of the more reactive amide
formation reactions, i.e. entries 1, 2, 4, 5, 6, 7 and 9 (Table 3)
using 10 mol% of catalyst 1. Importantly, at this temperature
ð2Þ
(85 uC) there is a clear advantage to using the catalyst
compared to the corresponding thermal conditions. For less

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reactive substrates, however, for example entries 8 and 10, the analysis provides a graphic example of the potential of
use of toluene and 5 or 10 mol% catalyst loading was necessary such direct amide formation processes over conventional
in order to provide an improvement in the isolated yields of acylation methods.
each of the amides (see Table 3). Although increasing the The synthesis of novel substituted analogues of the
reaction temperature (i.e. refluxing toluene) increases reaction bifunctional catalyst 1 has allowed us to begin to further
rates, the associated thermal reactions also become more probe the subtleties of the direct amide formation involving
significant in certain cases, making it harder to fully evaluate arylboronic acid-mediated catalysis. The addition of electron
catalyst-derived performance alone. For example, reaction of withdrawing functions to the aryl ring of 1, for example
4-phenylbutyric acid and benzylamine (entry 1, Table 3) shows trifluoromethyl derivative 10, certainly results in increased
a significant thermal contribution, as previously reported.10 catalytic activity for amide formation, which reinforces the
Interestingly, aniline reacts relatively well in toluene in the view that such catalysts act by forming mixed anhydride-type
presence of only 1 mol% of catalyst 1, however, the reaction analogues,10 and the electron withdrawing group increases
must be carried out under an inert atmosphere to prevent the leaving group ability during the amide formation step.
amine oxidation (entry 3, Table 3). The case of benzoic acid In terms of practical applications, either catalyst 1 or 10 is
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and 4-phenylbutylamine (entry 7, Table 3) demonstrates the suitable for direct amide formation under the most ambient
non-linear relationship between catalyst loading and yield, as conditions employed to date, though commercial availability
observed in the DoE, with no significant difference between a 5 makes the use of 1 more attractive currently. Less hindered
and 10 mol% loading of catalyst 1. Only in the case of amine systems10 or more electron rich aryl systems, such as 6b,
morpholine benzoylamide (entry 8, Table 3), could the isolated are considerably less efficient. DoE studies on the use of
yield not be increased to a reasonable level by changing either catalyst 1 show that catalyst loadings above 5 mol% are not
catalyst loading or solvent boiling point. This highlights the required, and most interestingly, that the water-removing
need for further improvements in these types of direct amide capacity of the solvent is an important aspect to consider
formation reactions in the future, however, the majority of during routine use of these types of catalysts. In order to
carboxylic acid–amine combinations are readily susceptible to optimise reactions in the most time efficient manner, higher
this type of straightforward, clean amide formation. dilutions are preferred. Clearly, alternative drying agents,
perhaps employed in situ, could have a major impact upon
Summary and conclusions both the rate, and hence the general applicability of these
processes. Further studies along these and related directions
The direct reaction of amine with carboxylic acid remains the
are underway and will be reported in due course.
most attractive approach to preparing amide bonds in terms of
avoiding reactive and toxic activated carboxylic acid deriva-
tives, or use of in situ activating agents.5 These types of Experimental
reactions are arguably best carried out without catalysis where N,N-Di-isopropyl-3-fluorobenzamide 4a
possible, however, reaction conditions remain harsh in order
to accomplish these types of direct thermal amide formation.1,2 To a stirred solution of 3-fluorobenzoyl chloride (2.68 g,
The next most green alternative is arylboronic or boric acid 16.9 mmol) in dry Et2O (40 mL) under Ar at 0 uC, was
catalysed direct amide formation, which offers generally more added dry di-isopropylamine (6.0 mL, 42 mmol) dropwise. The
attractive reaction conditions of lower temperature reactions reaction was allowed to warm to rt, stirred for 18 h and then
(refluxing fluorobenzene, toluene or xylene) and low catalyst quenched with 5% (w/v) HCl (25 mL). The organic layer was
loadings (1–10 mol%). In terms of green chemistry, the ability separated and washed again with 5 % (w/v) HCl (2 6 25 mL),
to recover and re-use the azeotropic solvents employed is then brine (25 mL), 5 % (w/v) NaOH (2 6 25 mL), brine
important, and hence, the only by-product for this direct (25 mL), dried over MgSO4, and concentrated under vacuum
amide formation is water. Carboxylic acids and amines can be to afford amide 4a as a white solid; yield: 3.40 g (90%); mp 74–
combined in a 1 : 1 stoichiometry, and with suitable reaction 76 uC; 1H NMR (500 MHz, CDCl3): d = 1.17 (br s, 6H,
engineering, yields can be high, though dependent upon (CH3)2CH), 1.54 (br s, 6H, (CH3)2CH), 3.55 (br s, 1H,
solvent boiling point, substrate combination and efficiency of (CH3)2CH), 3.81 (br s, 1H, (CH3)2CH), 7.01–7.11 (m, 3H,
the water removal (vide supra). Compared with, for example, ArH), 7.37 (td, JHH = 8.0 Hz and JFH = 5.5 Hz, 1H, ArH); 13C
an acid chloride-mediated reaction, this type of catalysed NMR (100.6 MHz, CDCl3): d = 20.9 (br s, (CH3)2CH), 46.2
direct amide formation reaction is much more atom efficient. (br s, (CH3)2CH), 51.1 (br s, (CH3)2CH), 113.2 (d, 2JFC =
For example, for the reaction shown in entry 7, Table 3 in 22 Hz, ArC), 115.9 (d, 2JFC = 21 Hz, ArC), 121.5 (d, 4JFC =
toluene, the effective mass yield (EMY)16 is 1525%, assuming 3 Hz, ArC), 130.5 (d, 3JFC = 8 Hz, ArC), 141.1 (d, 3JFC = 7 Hz,
that both solvent and molecular sieves are recovered and ArC–CONiPr2), 162.9 (d, 1JFC = 247 Hz, ArC-F), 169.7 (d,
4
re-used efficiently, and a 5 mol% catalyst loading. This JFC = 2 Hz, CONiPr2); 19F NMR (376.3 MHz; CDCl3): d =
compares with preparing the same amide using, for example, 5a-112.5 (m); IR (film): nmax (inter alia) = 3072, 2971, 1629 (s),
thionyl chloride to prepare the acid chloride, followed by 1583, 1437, 1344 (s), 1140 cm21; lmax(MeCN)/nm 200 (e/dm3
direct reaction with the amine stoichiometrically and using no mol21 cm21 12400), 267 (1400); MS (ES): m/z (%) = 246.1260
additional base, giving an EMY of 87%. Clearly, the use of (100) [M + Na]+. [C19H13NOFNa]+ requires 246.1265;
acylation transfer agents and bases will significantly reduce the elemental analysis (%): calcd. for C13H18NOF: C 69.93, H
EMY for the acid chloride-based route, hence overall, this 8.13, N 6.27; found: C 69.73, H 8.07, N 6.10.

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19
N,N-Di-isopropyl-3-fluoro-2-(4,4,5,5-tetramethyl- F NMR (376.3 MHz, CDCl3): d = 2104.5 (m); IR (film):
[1,3,2]dioxaborolan-2-yl)-benzamide 5a nmax (inter alia) = 3307, 2971, 2539, 1604, 1565, 1450 (s), 1385
(vs), 1144 (s) cm21; lmax(MeCN)/nm 194 (e/dm3 mol21 cm21
To a stirred solution of 4a (5.0 g, 22.4 mmol) and TMEDA
10000), 216 (6970), 272 (1280); MS (ES): m/z (%) = 254.1722
(4.0 mL, 26.9 mmol) in dry THF (50 mL) under Ar at 278 uC,
(100, [M + H]+. [C13H22BFNO2]+ requires 246.1265); ele-
was added n-BuLi (16.8 mL, 1.6 M, 26.9 mmol) dropwise over
mental analysis (%): calcd. for C13H29BFNO2: C 61.69, H 8.36,
10 min. Mixture left to stir for 1 h and then trimethyl borate
N 5.53; found: C 61.53, H 8.41, N 5.30.
(3.0 mL, 26.9 mmol) was added rapidly. Mixture allowed to
reach rt (2 h) and then quenched with 20% (w/v) HCl (10 mL),
N,N-Di-isopropyl-3-methoxybenzamide 4b
followed by addition of pinacol (3.2 g, 26.9 mmol). Mixture
extracted into ether (3 6 20 mL) and the organic extracts To a stirred solution of m-anisoyl chloride (0.82 mL, 6 mmol)
washed with sat. aq. NaHCO3 (3 6 20 mL) and brine (2 6 in dry Et2O (25 mL) under Ar at 0 uC, was added dry di-
20 mL). Extracts were dried over MgSO4 and concentrated isopropylamine (2.1 mL, 15 mmol) dropwise. The reaction was
under vacuum. Column chromatography on silica gel (hexane : allowed to warm to rt, stirred for 3 h and then quenched with
EtOAc, 2 : 1) afforded pinacol boronate 5a as a white 5% (w/v) HCl (25 mL). The organic layer was separated and
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crystalline solid; yield: 5.16 g (66%); mp 104–106 uC; 1H NMR washed again with 5% (w/v) HCl (2 6 25 mL), brine (25 mL),
(500 MHz, CDCl3): d = 1.19 (br s, 6H, (CH3)2CH), 1.33 (s, 5% (w/v) NaOH (2 6 25 mL), brine (25 mL), dried over
12H, 4 6 Me), 1.54 (br s, 6H, (CH3)2CH), 3.54 (br s, 1 H, MgSO4, and concentrated under vacuum to afford amide 4b as
(CH3)2CH), 3.98 (br s, 1H, (CH3)2CH), 6.98–7.04 (m, 2H, a white solid; yield: 1.38 g (98%); mp 92–93 uC; 1H NMR
ArH), 7.32 (td, JHH = 8.0 Hz and JFH = 5.5 Hz, 1H, ArH); 13C (500 MHz, CDCl3): d = 1.16 (br s, 6H (CH3)2CH), 1.54 (br s,
NMR (125.7 MHz, CDCl3): d = 20.6 (br s, (CH3)2CH), 25.0 6H, (CH3)2CH), 3.53 (br s, 1H, (CH3)2CH), 3.83 (s, 3H,
(pinacol CH3), 46.6 (br s, (CH3)2CH), 51.2 (br s, (CH3)2CH), OCH3), 3.86 (br s, 1H, (CH3)2CH), 6.86 (s, 1H, ArH), 6.89 (d,
83.6 (pinacol C–O), 116.0 (d, 2JFC = 25 Hz, ArC), 120.8 (d, J = 8.0 Hz, 1H, ArH), 6.91 (d, J = 8.0 Hz, 1H, ArH), 7.61 (t,
4
JFC = 4 Hz, ArC), 131.5 (d, 3JFC = 9 Hz, ArC), 144.9 (d, J = 8.0 Hz, 1H, ArH); 13C NMR (125.7 MHz, CDCl3): d =
3
JFC = 9 Hz, ArC–CONiPr2), 166.3 (d, 1JFC = 249 Hz, ArC-F), 20.8 ((CH3)2CH), 46.0 (br s (CH3)2CH), 51.0 (br s, (CH3)2CH),
170.3 (d, 4JFC = 3 Hz, CONiPr2); 11B NMR (128.4 MHz, 55.4 (OCH3), 111.1 (ArC), 114.7 (ArC), 117.8 (ArC), 129.7
CDCl3): d = 26.9; 19F NMR (376.3 MHz, CDCl3): d = (ArC), 140.3 (ArC-OMe), 159.7 (ArC-CONiPr2)), 170.9
2103.2 (s); IR (film): nmax (inter alia)=2973, 2930, 2361, 1617 (CONiPr2); IR (film): nmax (inter alia) = 3090, 2974, 1621
(s), 1439, 1335 (vs), 1144 (s) cm21; lmax(MeCN)/nm 197 (vs), 1578, 1340 (vs), 1293, 1032 cm21; lmax(MeCN)/nm 200
(e/dm3 mol21 cm21 28100), 242 (3320), 271 (1220); MS (ES): (e/dm3 mol21 cm21 21300) and 280 (2290); MS (ES): m/z (%) =
m/z (%) = 721.4 (60), 699.5 (25), 372.2 (100, [M + Na]+), 236.1646 (100, [M + H]+. [C14H22NO2]+ requires 236.1645);
350.2295 (48, [M+H]+. [C19H30BFNO3]+ requires 350.2297); elemental analysis (%): calcd. for C14H21NO2: C 71.46, H 8.99,
elemental analysis (%): calcd. for C19H29BFNO3: C 65.34, H N 5.95; found: C 71.45, H 9.07, N 5.81.
8.37, N 4.01; found: C 65.41, H 8.46, N 3.99.
N,N-Di-isopropyl-3-methoxy-2-(4,4,5,5-tetramethyl-
N,N-Di-isopropyl-3-fluorobenzylamine-2-boronic acid 6a [1,3,2]dioxaborolan-2-yl)-benzamide 5b
To a stirred solution of 5a (5.16 g, 14.8 mmol) and NaBH4 To a stirred solution of 4b (1.75 g, 7.44 mmol) and TMEDA
(5.6 g, 148 mmol) in dry THF (70 mL) under Ar was added (1.56 mL, 10.4 mmol) in dry THF (25 mL) under Ar at 278 uC,
TMSCl (37.6 mL, 296 mmol) and the mixture stirred at reflux was added s-BuLi (7.44 mL, 1.4 M, 10.4 mmol) dropwise over
for 20 h. Reaction quenched by slow addition of 5% (w/v) HCl 10 min. Mixture left to stir for 90 min and then triisopropyl
then 20% (w/v) HCl taking the aqueous layer to pH 1, and borate (1.89 mL, 8.18 mmol) was added rapidly. Mixture
extracted into Et2O (1 6 50 mL, 3 6 100 mL). Sat. aq. allowed to reach rt overnight (19 h) and then quenched with
NaHCO3 was added taking the aqueous layer to pH 7 and the 20% (w/v) HCl (6 mL), followed by addition of pinacol (0.97 g,
mixture was extracted into Et2O (3 6 100 mL). Organic 8.18 mmol). Mixture allowed to stir for 10 min before being
extracts were combined and washed with brine (2 6 100 mL), extracted into ether (3 6 20 mL) and the organic extracts
dried over MgSO4 and concentrated under vacuum. Slow washed with sat. aq. NaHCO3 (3 6 10 mL), and brine
crystallisation from MeCN provided crystals suitable for single (20 mL). Extracts were dried over MgSO4 and concentrated
crystal X-ray analysis.{ Recrystallisation from DCM-hexane under vacuum. Column chromatography on silica gel (hexane :
afforded boronic acid 6a as a white solid; yield: 2.71 g (72%); EtOAc, 1 : 1) afforded pinacol boronate 5b as a white solid;
mp 110–111 uC; 1H NMR (500 MHz, CDCl3): d = 1.10 (d, J = yield: 2.05 g (76%); mp 90–91 uC; 1H NMR (500 MHz,
7.0 Hz, 12H, (CH3)2CH), 3.08 (septet, J = 7.0 Hz, 2H, CDCl3): d = 1.19 (br s, 6H, (CH3)2CH), 1.35 (s, 12H, 4 6 Me),
(CH3)2CH), 3.82 (s, 2H, ArCH2), 6.97–7.03 (m, 1H ArH), 1.54 (br s, 6H, (CH3)2CH), 3.50 (br s, 1H, (CH3)2CH), 3.81 (s,
7.07 (d, J= 7.5 Hz, 1H, ArH), 7.30 (td, JHH = 7.5 Hz and 3H, OMe), 4.00 (br s, 1H, (CH3)2CH), 6.82 (d, J = 8.0 Hz, 2H,
JFH = 6.5 Hz, 1H, ArH), 9.27 (br s, 2H, B(OH)2); 13C NMR ArH), 7.28 (1H, t, J = 8.0 Hz, ArH); 13C NMR (125.7 MHz,
(125.7 MHz, CDCl3): d = 19.9 ((CH3)2CH), 47.7 ((CH3)2CH), CDCl3): d = 20.7 (br s, (CH3)2CH), 25.0 (pinacol CH3), 46.3
52.0 (d, 4JFC = 2 Hz, ArCH2), 115.4 (d, 2JFC = 28 Hz, ArC), (br s, (CH3)2CH), 51.0 (br s, (CH3)2CH), 55.8 (OMe), 83.5
127.7 (d, 4JFC = 2 Hz, ArC), 131.7 (d, 3JFC = 11 Hz, ArC), (pinacol C–O), 110.7 (ArC), 117.3 (ArC), 130.3 (ArC), 144.0
144.7 (d, 3JFC = 8 Hz, ArCCH2NiPr2), 168.0 (d, 3JFC = 244 Hz, (ArC-CONiPr2), 163.4 (ArC-OMe), 171.4 (CONiPr2); 11B
ArC-F); 11B NMR (128.4 MHz, CDCl3): d = 28.4; NMR (128.4 MHz, CDCl3): d = 29.0; IR (film): nmax (inter

This journal is ß The Royal Society of Chemistry 2008 Green Chem., 2008, 10, 124–134 | 131
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alia) = 2973, 1615 (s), 1431, 1335 (vs), 1146 cm21; MS (ES): calcd. for C13H18N2O3: C 62.38, H 7.25, N 11.19; found: C
m/z (%) = 362.2497 (100, [M + H]+. [C20H33BNO4]+ requires 62.34, H 7.27, N 11.18.
362.2497); elemental analysis (%): calcd. for C20H32BNO4: C
66.49, H 8.93, N 3.88; found: C 66.22, H 8.98, N 3.82. N,N-Di-isopropyl-3-trifluoromethylbenzamide 8
To a stirred solution of 3-(trifluoromethyl)benzoyl chloride
N,N-Di-isopropyl-3-methoxybenzylamine-2-boronic acid 6b
(1.78 mL, 12 mmol) in dry Et2O (30 mL) under Ar at 0 uC, was
To a stirred solution of 5b (0.99 g, 2.74 mmol) and NaBH4 added dry di-isopropylamine (4.24 mL, 30 mmol) dropwise.
(1.04 g, 27.4 mmol) in dry THF (50 mL) under Ar was added The reaction was allowed to warm to rt, stirred for 2 h and
TMSCl (6.95 mL, 54.8 mmol) and the mixture stirred at reflux then quenched with 5% (w/v) HCl (25 mL). The organic layer
for 21 h. Reaction quenched by slow addition of 5% (w/v) HCl was separated and washed again with 5% (w/v) HCl (25 mL),
(7 mL) and THF removed in vacuo. A further portion of 5% then brine (25 mL), 5% (w/v) NaOH (2 x 25 mL), brine
(w/v) HCl (15 mL) was added (aqueous layer to pH 1) and (25 mL), dried over MgSO4, and concentrated under vacuum
extracted into Et2O (1 6 25 mL, 2 6 15 mL). Et2O extracts to afford amide 8 as a white solid; yield: 3.23 g (98%); mp 58–
washed with 5% (w/v) HCl (5 mL) and combined aqueous 59 uC; 1H NMR (500 MHz, CDCl3): d = 1.17 (br s, 6H,
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phase washed with Et2O (2 6 10 mL). Aqueous neutralised (CH3)2CH), 1.53 (br s, 6H, (CH3)2CH), 3.57 (br s, 1H,
with NaOH (s) then 20% (w/v) NaOH until no further (CH3)2CH), 3.72 (br s, 1H, (CH3)2CH), 7.47–7.54 (m, 2H,
precipitation of white solid was observed (pH 9). The mixture ArH), 7.57 (s, 1H, ArH), 7.63 (d, J = 8.5 Hz, 1H, ArH); 13C
was extracted into DCM (3 6 15 mL), organic extracts were NMR (100.6 MHz, CDCl3): d = 20.8 ((CH3)2CH), 46.3 (br s,
combined, washed with brine (15 mL), dried over MgSO4 and (CH3)2CH), 51.3 (br s, (CH3)2CH), 122.8 (q, 3JFC = 4 Hz,
concentrated under vacuum. Recrystallisation from hexane ArC), 123.9 (q, 1JFC = 273 Hz, CF3), 125.6 (q, 3JFC = 4 Hz,
afforded boronic acid 6b as a white solid; yield: 0.36 g (50%); ArC), 129.1 (ArC), 129.2 (ArC), 131.1 (q, 2JFC = 33 Hz,
mp 164–165 uC; 1H NMR (400 MHz, CDCl3): d = 1.11 (d, J = ArC-CF3), 139.6 (ArC-CONiPr2), 169.5 (CONiPr2); 19F NMR
6.8 Hz, 12H, (CH3)2CH), 3.10 (septet, J = 6.8 Hz, 2H, (376.3 MHz, CDCl3): d = 263.2 (s); IR (film): nmax = 2970,
(CH3)2CH), 3.80 (s, 2H, ArCH2), 3.89 (s, 3H, OMe), 6.90 (d, 1621 (s), 1373, 1311 (s), 1162, 1123 cm21; lmax(MeCN)/nm 200
J = 8.0 Hz, 1H, ArH), 6.93 (d, J = 7.6 Hz, 1H, ArH), 7.31 (dd, (e/dm3 mol21 cm21 22300), 252 (7150); MS (ES): m/z (%) =
JHH = 8.4 Hz and JFH = 7.6 Hz, 1H, ArH), 9.75 (br s, 274.1413 (100, [M + H]+. [C14H19F3NO]+ requires 274.1413);
2H, B(OH)2); 13C NMR (100.6 MHz, CDCl3): d = 19.9 elemental analysis (%): calcd. for C14H18F3NO: C 61.53, H
((CH3)2CH), 47.5 ((CH3)2CH), 52.4 (ArCH2), 56.0 (OMe), 6.64, N 5.13; found: C 61.24, H 6.59, N 4.96.
110.5 (ArC), 125.6 (ArC), 131.2 (ArC), 144.8 (ArC), 164.8
(ArC-OMe); 11B NMR (128.4 MHz, CDCl3): d = 29.3; IR N,N-Di-isopropyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-
(KBr): nmax (inter alia) = 3414, 2965, 1597 (s), 1466 (s), 1249 yl)-5-trifluoromethyl-benzamide 9
(s), 1084 cm21; MS (ES): m/z (%) = 266.1923 (100, [M + H]+.
To a stirred solution of 6 (1.01 g, 3.70 mmol) in dry THF
[C14H25BNO3]+ requires 266.1922); elemental analysis (%):
(20 mL) under Ar at 278 uC, was added LDA (2.47 mL, 1.8 M,
calcd. for C14H24BNO3: C 63.42, H 9.12, N 5.28; found: C
4.44 mmol) dropwise over 15 min. Mixture left to stir for
63.82, H 9.04, N 5.16.
70 min and then triisopropyl borate (0.94 mL, 4.07 mmol) was
added rapidly. Mixture allowed to reach rt overnight (17 h)
N,N-Di-isopropyl-3-nitrobenzamide 4c
and then quenched with 20% (w/v) HCl (6 mL), followed by
To a stirred solution of 3-nitrobenzoyl chloride (1.41 g, addition of pinacol (0.48 g, 4.07 mmol). Mixture allowed to
6.71 mmol) in dry Et2O (25 mL) under Ar at 0 uC, was added stir for 15 min before being extracted into ether (2 6 20 mL,
dry di-isopropylamine (2.7 mL, 19 mmol). The reaction was 1 6 10 mL) and the organic extracts washed with sat. aq.
allowed to warm to rt, stirred for 18 h and then quenched with NaHCO3 (3 6 10 mL), and brine (20 mL). Extracts were
5% (w/v) HCl (25 mL). The organic layer was separated and dried over MgSO4 and concentrated under vacuum. Column
washed again with 5% (w/v) HCl (2 6 25 mL), then brine chromatography on silica gel (hexane : EtOAc, 4 : 1) afforded
(25 mL), 5% (w/v) NaOH (2 6 25 mL), brine (25 mL), dried pinacol boronate 9 as a white solid; yield 1.40 g (95%); mp
over MgSO4, and concentrated under vacuum to afford amide 130–131 uC; 1H NMR (500 MHz, CDCl3): d = 1.13 (d, J =
4c (1.66 g, 87%) as a white solid; yield: 1.66 g (87%); mp 78– 6.5 Hz, 6H, (CH3)2CH), 1.32 (s, 12H, 4 x Me), 1.58 (d, J =
79 uC; 1H NMR (500 MHz, CDCl3): d = 1.21 (br s, 6H, 6.5 Hz, 6H, (CH3)2CH), 3.53 (m, 1H, (CH3)2CH), 3.63 (m, 1H,
(CH3)2CH), 1.56 (br s, 6H, (CH3)2CH), 3.52 (br s, 1H, (CH3)2CH), 7.39 (s, 1H, ArH), 7.56 (d, J = 8.5 Hz, 1H, ArH),
(CH3)2CH), 3.55 (br s, 1H, (CH3)2CH), 7.60 (t, J= 8.1 Hz, 1H, 7.91 (d, J = 7.5 Hz, 1H, ArH); 13C NMR (125.7 MHz; CDCl3):
ArH), 7.67 (d, J = 8.1 Hz, 1H, ArH), 8.20 (s, 1H, ArH), 8.25 d = 20.3 ((CH3)2CH), 20.5 ((CH3)2CH), 25.0 (pinacol CH3),
(d, J = 8.1 Hz, 1H, ArH); 13C NMR (125.7 MHz, CDCl3): 46.1 ((CH3)2CH), 51.2 ((CH3)2CH), 84.4 (pinacol C-O), 121.4
d = 20.9 (br s, (CH3)2CH), 46.5 (br s, (CH3)2CH), 51.5 (q, 3JFC = 4 Hz, ArC), 123.9 (q, 1JFC = 273 Hz, CF3), 124.1 (q,
3
(br s, (CH3)2CH), 121.2 ArC), 123.8 (ArC), 130.0 (ArC), JFC = 4 Hz, ArC), 132.5 (q, 2JFC = 33 Hz, ArC-CF3), 136.2
132.0 (ArC), 140.5 (ArC-CONiPr2), 148.3 (ArC-NO2), 168.4 (ArC), 145.6 (ArC-CONiPr2), 169.9 (CONiPr2); 11B NMR
(CONiPr2); IR (film): nmax = 2930, 1625 (s), 1527, 1438, 1334, (160.3 MHz, CDCl3): d = 29.8; 19F NMR (470.3 MHz; CDCl3)
1153; lmax(MeCN)/nm 194 (e/dm3 mol21 cm21 24000), 252 d = 263.5 (s); IR (film): nmax = 2978, 1627 (s), 1312 (vs),
(6960); MS (ES): m/z (%) = 273.1203 (100, [M+Na]+. 1132 (vs) cm21; MS (ES): m/z (%) = 400.2265 (100, [M + H]+.
[C13H18N2O3Na]+ requires 273.1210); elemental analysis (%): [C20H30BF3NO3]+ requires 400.2265); elemental analysis (%):

132 | Green Chem., 2008, 10, 124–134 This journal is ß The Royal Society of Chemistry 2008
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calcd. for C20H29BF3NO3: C 60.17, H 7.32, N 3.51; found: C micro-Soxhlet apparatus loaded with activated 3Å molecular
60.37, H 7.34, N 3.38. sieves under argon. Solid reagents were added using the
ReactArray as standard solutions (0.5 M in fluorobenzene).
N,N-Di-isopropyl-5-trifluoromethylbenzylamine-2-boronic acid Naphthalene (0.35 mmol, 15 mol%) and amine (2.33 mmol)
10 were added to the reaction vessels at ambient temperature. The
appropriate amount of fluorobenzene was then added to each
To a stirred solution of 7 (1.00 g, 2.50 mmol) and NaBH4
reaction vessel in order to give a final reaction volume of
(0.95 g, 25.0 mmol) in dry THF (50 mL) under Ar was added
10 mL. After heating to reflux, carboxylic acid (2.33 mmol)
TMSCl (6.35 mL, 50.0 mmol) and the mixture stirred at reflux
was added to the stirred solution. Reactions were sampled
for 21 h. Reaction quenched by slow addition of 5% (w/v) HCl
(50 mL) at 2 or 4 h intervals (24 or 48 h reaction time,
(7 mL) and THF removed in vacuo. A further portion of 5%
respectively). Samples were quenched with MeCN (950 mL),
(w/v) HCl (5 mL) was added (aqueous layer to pH 1) and
diluted once (50 mL in 950 mL MeCN) mixed and analysed by
extracted into Et2O (3 6 15 mL). Et2O extracts washed with
HPLC (gradient MeCN (0.05% TFA) : water (0.05% TFA)
5% (w/v) HCl (5 mL) and combined aqueous phase washed
0 : 100 to 100 : 0 over 15; 1 mL min21; tr = 9.12 min).
with Et2O (2 6 10 mL). Aqueous neutralised to pH 7 with
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Naphthalene was used as an internal standard, with response

NaOH (s) then 20% (w/v) NaOH and extracted into DCM
factors calculated automatically by ReactArray DataManager.
(3 6 15 mL). Combined organic extracts were washed with
brine (15 mL), dried over MgSO4 and concentrated under
General procedure for isolation of amides (fluorobenzene)
vacuum. Recrystallisation from MeCN-H2O afforded boronic
acid 10 as a white crystalline solid (crystals suitable for single A round-bottomed flask was equipped with stirrer bar,
crystal X-ray analysis{); yield: 0.45 g (60%); mp 115–116 uC; pressure equalising dropping funnel (in vertical neck) with a
1 soxhlet thimble containing CaH2 (y1 g), followed by a
H NMR (400 MHz, CDCl3): d = 1.14 (d, J = 6.8 Hz, 12H,
(CH3)2CH), 3.13 (septet, J = 6.8 Hz, 2H, (CH3)2CH), 3.90 (s, condenser. The appropriate carboxylic acid (5 mmol), followed
2H, ArCH2), 7.47 (s, 1H, ArH), 7.55 (d, J = 7.6 Hz, 1H, ArH), by fluorobenzene (50 mL), and amine (5 mmol) were added,
8.10 (d, J = 8.0 Hz, 1H, ArH), 10.28 (br s, 2H, B(OH)2); 13C followed by 1 (117.6 mg, 0.5 mmol). The mixture was allowed
NMR (100.6 MHz, CDCl3): d = 19.8 ((CH3)2CH), 47.9 to stir at reflux for 22, 24 or 48 h, before being concentrated
((CH3)2CH), 51.9 (ArCH2), 123.8 (q, 3JFC = 4 Hz, ArC), 124.2 under vacuum. The residue was then redissolved in DCM
(q, 1JFC = 272 Hz, CF3), 127.0 (q, 3JFC = 4 Hz, ArC), 132.0 (q, (25 mL), washed with brine (25 mL), 5% (w/v) HCl (25 mL),
2
JFC = 32 Hz, ArC-CF3), 137.3 (ArC), 143.2 (ArC); 11B NMR brine (25 mL), 5% (w/v) NaOH (25 mL), brine (25 mL), dried
(128.4 MHz, CDCl3): d = 28.5; 19F NMR (376.3 MHz, over MgSO4, and the solvent evaporated under vacuum.
CDCl3): d = 263.3 (s); IR (film): nmax = 3324, 2978, 1328 (s),
1166 (s), 1112 (vs) cm21; MS (ES): m/z (%) = 304.2 (100, [M + N-Benzyl-4-phenylbutyramide:17 yield: 0.86 g (68%)
H]+); elemental analysis (%): calcd. for C14H21BF3NO2: C
55.47, H 6.98, N 4.62; found: C 55.22, H 6.85, N 4.46. N-4-Phenylbutyl-4-phenylbutyramide:10 yield: 1.03 g (70%)

1-Morpholin-4-yl-4-phenylbutan-1-one: yield: 0.78 g (67%)

General procedure for DoE on formation of N-benzylbenzamide
1
H NMR (400 MHz, CDCl3): d = 1.98 (quintet, J = 7.6 Hz,
Benzoic acid (1, 3 or 5 mmol) was weighed into ReactArray
2H, CH2), 2.31 (t, J = 7.6 Hz, 2H, CH2), 2.68 (t, J = 7.6 Hz,
tubes to give appropriate reaction concentration (0.1, 0.3 or
2H, CH2), 3.35–3.39 (m, 2H, morphlino), 3.58–3.68 (m, 4H,
0.5 M) followed by catalyst 1 (1, 5.5 or 10 mol%). ReactArray
morpholino), 7.16–7.22 (m, 3H, ArH), 7.25–7.31 (m, 2H,
azeotroping condenser set assembled, naphthalene (25 mol%)
ArH); 13C NMR (100.6 MHz, CDCl3): d = 26.7 (CH2), 32.2
as a 0.5 M standard solution, and fluorobenzene or toluene
(CH2), 35.4 (CH2), 42.0 (CH2N), 46.1 (CH2N), 66.8 (CH2O),
were added to give a final reaction volume of 10.6 mL. Mixture
67.1 (CH2O), 126.1 (ArC), 128.5 (ArC), 128.6 (ArC), 141.7
heated to reflux under nitrogen and benzylamine (1, 3 or
(ArC), 171.6 (CON); IR (film): nmax (inter alia) = 2856, 1647
5 mmol) was added. Reaction stirred at reflux with sampling at
(vs), 1433 (s), 1116 (s) cm21; MS (ES): m/z (%) = 234.2 (100)
4 h intervals. Samples were subjected to the following quench/
[M + H]+; elemental analysis (%): calcd. for C14H19NO2: C
dilution protocols:
72.07, H 8.21, N 6.00; found: C 71.91, H 8.24, N 6.12.
N 0.1 M: 90 mL into 910 mL MeCN
N 0.3 M: 50 mL into 1650 mL MeCN
N-(1-Phenylethyl)-4-phenylbutyramide:7f yield: 0.71 g (53%)
N 0.5 M: 100 mL into 900 mL MeCN, 176 mL into 824 mL MeCN
Samples were mixed and analysed by HPLC (MeCN (0.05% N-Benzylbenzamide:18 yield: 0.53 g (50%)
TFA) : water (0.05% TFA) 0 : 100 to 100 : 0 over 15 min;
1 mL min21; tr = 9.12 min). Naphthalene was used as an N-Phenyl-4-phenylbutyramide7a
internal standard.
To a stirred solution of 4-phenylbutyric acid (0.821 g, 5 mmol)
in toluene (50 mL), was added aniline (0.46 mL, 5 mmol)
General procedure for catalyst screen on N-benzylbenzamide
followed by catalyst 4c (11.8 mg, 0.05 mmol). The mixture was
formation
allowed to stir at reflux for 22 h, before being concentrated
The appropriate catalyst (0.233 mmol, 10 mol%) was manually under vacuum. The residue was then redissolved in Et2O (25 mL),
weighed into each reaction vessel, followed by assembly of a washed with brine (25 mL), 5% (w/v) HCl (25 mL), brine (25 mL),

This journal is ß The Royal Society of Chemistry 2008 Green Chem., 2008, 10, 124–134 | 133
 View Article Online

5% (w/v) NaOH (25 mL), brine (25 mL), dried over MgSO4, References
and the solvent evaporated under vacuum; yield: 0.60 g (50%).
1 A. W. Hofmann, Chem. Ber., 1882, 15, 977–978.
2 (a) J. A. Mitchell and E. E. Reid, J. Am. Chem. Soc., 1931, 53,
N-(1-Phenyl)ethylbenzamide19 1879–1883; (b) D. Davidson and P. Newman, J. Am. Chem. Soc.,
1952, 74, 1515–1516; (c) B. S. Jursic and Z. Zdravkovski, Synth.
Catalyst 1 (54.8 mg, 0.233 mmol) was weighed into a Commun., 1993, 23, 2761–2770.
ReactArray tube, followed by assembly of a micro-Soxhlet 3 (a) Y. I. Leitman and M. S. Pevzner, Zh. Prikl. Khim., 1963, 36,
632–639; (b) W. Walter, H. Besendorf and O. Schnider, Helv.
apparatus loaded with activated 3Å molecular sieves under
Chim. Acta, 1961, 44, 1546–1554.
argon. Solid reagents were added using the ReactArray as 4 (a) M. P. Vazquez-Tato, Synlett, 1993, 506–506; (b) L. Perreux,
standard solutions (0.5 M in fluorobenzene). Naphthalene A. Loupy and F. Volatron, Tetrahedron, 2002, 58, 2155–2162.
(44.9 mg, 0.35 mmol), a-methylbenzylamine (301 mL, 5 (a) T. Ziegler, Science of Synthesis, ed. S. M. Weinreb, Thieme,
Stuttgart, 2005, vol. 21, pp. 43–76; (b) G. Benz, Comprehensive
2.33 mmol) and fluorobenzene (4.63 mL) were added to the Organic Synthesis, ed. B. M. Trost, I. Fleming, Pergamon, Oxford,
reaction vessel at ambient temperature. After heating to reflux, 1991, vol. 6, pp. 381–417.
benzoic acid (0.285 g, 2.33 mmol) was added to the stirred 6 (a) A. Pelter, T. E. Levitt and P. Nelson, Tetrahedron, 1970, 26,
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interactions are aliased with three factor interactions, and two
Morpholin-4-yl-phenylmethanone:20 yield: 0.04 g (21%). factor interactions are aliased with other two factor interactions.
15 The thermal reaction is not significant in either fluorobenzene or
N-(1-Phenyl)ethylbenzamide:19 yield: 0.16 g (71%). toluene in this case (0% and 5% conversion in 24 h, respectively).
16 T. Hudlicky, D. A. Frey, L. Koroniak, C. D. Claeboe and
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Acknowledgements 18 N. Shangguan, S. Katukojvala, R. Greenberg and L. J. Williams,
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We thank the EPSRC for a research grant and DTA 19 M. Noji, T. Ohno, K. Fuji, N. Futaba, H. Tajima and K. Ishii,
J. Org. Chem., 2003, 68, 9340–9347.
studentship (KA), and GlaxoSmithKline for CASE funding 20 J. D. Moore, R. J. Byrne, P. Vedantham, D. L. Flynn and
(KA) and the National Mass Spectrometry Service at Swansea. P. R. Hanson, Org. Lett., 2003, 5, 4241–4244.

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