3568 J. Org. Chem.

1993,58, 3568-3571
A Convenient Reduction of Amino Acids and
Their Derivatives
Marc J. McKennon and A. I. Meyers'
Department of Chemistry, Colorado State University,
Fort Collins, Colorado 80523
Karlheinz Drauz'J and Michael Schwarm
Degussa AG, ZN Wolfgang, Abt. IC-FEO-A, Postfach 1345,
0-6450 Hanau 1, Germany
Received November 13, 1992
The formation of chiral amino alcohols by reduction of
amino acids has been the subject of considerable effort
due to their importance in asymmetric synthesis? peptide
and pharmaceutical chemistry: resolution of racemic
mixtures: synthesis of insecticidal compounds: and
others. From the earliest reports by Karrer in 1921, amino
alcohols were prepared by reduction of the corresponding
amino acid esters with sodium in ethanol.& Subsequently,
lithium aluminum hydride6b and sodium borohydride&
were employed and furthermore, free amino acids were
shown to be reduced directly by sodium bis(2-methoxy-
ethoxy)aluminum hydride? the borane-dimethyl sulfide
complex activated by boron trifluoride-etherate,w lith-
ium aluminum hydride? lithium borohyride with tri-
methylchl~rosilane,~~ sodium borohydride-trimethyl-
~hlorosilane,~g or boron tri fl ~ori deetherate.~~ Very re-
cently, while this manuscript was being prepared, a report
appeared describing an efficient reduction of amino acids
and derivatives using sodium borohydride and sulfuric
~~~~ ~
(1) Amino Acid Transformations. Part 10. For part 9, see: Draw, K.;
Kottanhahn, M.; Klenk, H. J. Prakt. Chem. 1992,334,214.
(2) (a) Coppola, G. M.; Schuster, H. F. Asymmetric Synthesis; J ohn
Wdey& Sons;NewYork, 1987. (b) Nogradi,M. StereoeelectiueSynthesis;
VCH Weinheim, 1987. (c) Bolm, C. Angew. Chem. Int. Ed. Engl. 1991,
30, 542.
(3) (a) TenBrink, R. E. J. Org. Chem. 1987,52,418. (b) Nicolaides,
E. D.; Tinney, F. J.; Kaltenbronn, J. S.; Repine, J. T.; DeJ ohn, D. A.;
Lunney, E. A.; Roark, W. H.; Marriott, J. G.; Dad, R. E.; Voigtman, R.
E. J. Med. Chem. 1986,29,959. (c) Fincham, C. I.; Higginbottom, M.;
Hill, D. R.; Horwell, D. C.; OToole, J. C.; Ratcliffe, G. S.; Reen, D. C.;
Roberts, E. J. Med. Chem. 1992,35,1472. (d) Auvin-Guette, C.; Rebuffat,
S.; Prigent, Y.; Bodo, B. J. Am. Chem. SOC. 1992,114,2170. (e) Iida, A.;
Okuda, M.; Ueaato, S.; Takaishi, Y.; Shingu, T.; Morita, M.; Fujita., T.
J. Chem. SOC. Perkin Trans 1 1990,3249. (f) Kaehima, C.; Harada, K.;
Fujioka, Y.; Maruyama, T.; Omote, Y. J. Chem. SOC. Perkin Tram 1
1988,535. (g) Roemer, D.; Bueacher, H. H.; Hill, R. C.; Plw, J.; Bauer,
W.; Cardinaux, F.; Cloese, A.; Hauser, D.; Huguenin, R.Nature 1977,268,
547. (h) Rubini, E.; Gilon, C.; Selinger, 2.; Chorev, M. Tetrahedron 1986,
42, 6039.
(4) (a) Horiuchi, F.; Mataui, M. Agr. Biol. Chem. 1973,37,1713. (b)
Kawai, M.; Omori, Y.; Yamamura, H.; Butsugan, Y. Tetrahedron Asym.
1992,3,1019. (c) Sawayama, T.; Tnukamoto, M.; Sasagawa, T.; Naruto,
S.; Mataumoto, J .; Uno, H. Chem. Pharm. Bull. 1989, 37, 1382. (d)
Tsukamoto, M.; Sawayama, T.; J pn. Kokai Tokkyo Koho JP 6130,572,
Feb 12, 1986; Chem. Abstr. 1986,105,60626~.
(5) Wu, S.; Takeya, R.; Eto, M.; Tomizawa, C. J. Pestic. Sci. 1987,12,
221.
(6) (a) Karrer, P.; Karrer, W.; Thomann, H.; Horlacher, E.; Miider, W.
Helu. Chim. Acta 1921,4, 76. (b) Karrer, P.; Portmann, P.; Suter, M.
Helu. Chim. Acta 1948, 31, 1617. (c) Seki, H.; Koga, K.; Matsuo, H.;
Ohki, S.; Matsuo, I.; Yamada, S. Chem. Phar. Bull. 196S,13, 995.
(7) (a) Praaad, B.; Saund, A. K.; Bora, J. M.; Mathur, N. K. Indian J.
Chem. 1974,12,290. (b) Lane, C. F.; U.S. Patent 3 935 280, J an 27,1976;
Chem. Abstr. 1976, 84, 135101~. (c) Smith, G. A.; Gawley, R. E. Org.
Synth. 1985,63,136. (d) Gage, J. R.; Evans, D. A. Org. Synth. 1989,?,
77. (e) Dickman, D. A.; Meyern, A. I.; Smith, G. A.; Gawley, R. E. Organrc
Syntheses; Wiley: New York, 1990; Collect Vol. VII, p 630. (0 Giannis,
A.; Sandhoff, K. Angew. Chem. Int. Ed. Engl. 1989, 28, 218. (B)
Dharanipragada, R.; Alarcon, A.; Hruby, V. J. 0rg.Prep. Proc. Int. 1991,
23,396. (h) Boestan, W. H. J .;Schepers,C.H. M.;Roberts,M. J .A.;Eur.
Pat.Appl.EP0 322 982 A2, J uly5,1989,Chem.Abstr. 1989,111,233669a.
(i) Abiko, A.; Masamune, S. Tetrahedron Lett. 1992,33, 5517.
0022-32631931 l95&3568$O4.OO/O
acid.7' One of the examples briefly mentioned the NaBHr
I2 system, a procedure which wehad been already utilizing
and now wish to describe in detail. It had been shown
some 15 years ago that most of the above hydride
reductions proceed without any detectable racemization?
The lithium aluminum hydride procedure is one of the
most commonly used techniques but on large scale (-1
kg) still suffers from the disadvantage of cost, inflamma-
bility, and, in certain cases, laborious isolation procedures
resulting in widely varying yields. Therefore, a cheaper,
safer, and simpler process was sought, especially when
preparations on a larger scale are required.
Reduction of Free a-Amino Acids
Recently, a study appearedodescribing the reduction of
various aliphatic, aromatic, and a,/3-unsaturated carboxylic
acids to the corresponding alcohols using sodium boro-
hydride and iodine in THF. We now report that this was
found to be an excellent process for the direct reduction
of amino acids. The reactions were routinely carried out
on a 10-g scale while the reduction of phenylalanine haa
been successfdy performed on a molar scale. Further-
more, this method proved to beconvenient both from a
safety and cost standpoint, while producing optically pure
materials. Treatment of several amino acids with sodium
borohydride-iodine in THF afforded the corresponding
amino alcohols as crude products which were essentially
colorless and in most cases pure enough by 'H NMR to
be of further synthetic utility (Table I). It is of nota that
reduction of asparagine and glutamine proved difficult
owing to the high water solubility of the products.
In order to further evaluate the scope of the reaction,
westudied the reduction of phenylalanine under various
conditions. When gaseous chlorine was used as the
activating agent instead of the iodine solution, the reaction
proceeded in a similar fashion producing L-phenylalaninol
in -60% yield aftar crystallization. Activation of the
borohydride with bromine in tetrahydrofuran proved
unsuccessful, affording poor mass recovery and extensive
decomposition. It is note that a vigorous exotherm
occurred upon addition of bromine to tetrahydrofuran at
25 OC. Lithium borohydride was also shown to be an
equally suitable reducing agent. The reduction could also
be carried out in dimethoxyethane (monoglyme, DME)
while essentially no conversion was observed in methyl
tert-butyl ether (MTBE). The poor solubility of the
reactants in this solvent was probably responsible.
Reduction of N-Acyl-a-amino Acids
Since the earlier report using NaBH4-12 indicated that
carboxylic acids could be reduced to alcohols in the
presence of ester groups,9 weanticipated that the reduction
of N-acylamino acids would lead to the formation of
N-acylamino alcohols. Surprisingly, the N-acyl group was
completely reduced affording N-alkylamino alcohols as
the only products. A similar observation was made in the
analogous NaBH4-H2SO4 system.7i Decrease in temper-
ature, time, and reducing agent resulted in lower yields of
product and the N-acylamino alcohols were never observed.
This was confi i ed by a subsequent study of the NaBHr
(8) Poindextar, G. S.; Meyers, A. I. Tetrahedron Lett. 1977,3527.
(9) Bhaskar Kanth, J. V.; Periasamy, M. J. Org. Chem. 1991,66,5964.
(9 1993 American Chemical Society
Notes J. Org. Chem., Vol. 58, No. 13, 1993 3669
. Me Me
Table I. Reduction of a-Amino Acids with NaBH4-Iodine
.*' - NaBH4-I2
, " F O H
1 a-h 2a-h
THF, reflux NH2
Rrco2H
NH2
yield, [almp,
e nt w config structure %b deg (ht.)
84 +37 (+3719
+m2H (1, EtOH)
a
NH2
94 +17 (+1711)
(10, EtOH)
2
67 -32 (-31.7")
H! !
b~
PhYC02H (0.75,l M HC1)
C
NHZ
72 -22 (-22.8")
PhCH2YCozH (1.2,l M HCl)c
NH2
e L 58 +30 (+31")
QCO2H (1.6, toluene)
f L 75 +3.5 (+5.4," -3.6")
(1, EtOH)
8 L 65 -14 (-12.711)
(1, EtOH)
MeS
45 -13.6
H0-2H (2, H20)
h~
i H2
Compounds 2a, 2b, 20, W, and 2g were distilled bulb-to-bulb; 2c
and 2d were recrystallized from toluene. 2h was isolated as
hydroiodide and recrystallized from ethanol. Isolated, purified
yields. [a]D in EtOH (c =1) gave -24.1O.
Table 11. Reduction of N-Acyl-a-amino Acids to
N-Alkylamino Alcohols
RYCo2H - NaBH4-I2 RYCH20H
N R "
RI'
R, " THF, 24h
0
3a-d 4a-d
entry" confii R R' R" yield ( %) b
a L PhCH2 H H 73
b D PhCH2 H Me 83
C L -(CH2)s- Me 57
d H H Ph 64
,I Compound 4a was recrystallized from toluene and ethyl acetate,
respectively, and 4b from n-hexane. 4c and 4d were bulb-to-bulb
distilled. Isolated, purified yields.
I 2 system describing the reduction of carboxylic acids,
esters, amides, and nitriles.12
The results of reduction of several N-acylamino acids
to N-alkylamino alcohols are given in Table 11.
In assessing further the efficacy of the NaBH4-I2 system,
weobserved that glycine derivative 5 was smoothly reduced
to the N-t-Boc-imidazolidine 6 in 61 % yield. The latter
is known to be a useful template in asymmetric routes to
2,3-diaminopropanoic acids.13
(10) Niahiyama, H.; Sakaguchi, H.; N b u r a, T.; Horihata, M.; Kondo,
(11) Aldrich Chemical Catalog, 1990-1991.
(12) Bhanu Praaad, A. S.; Bhaekar Kanth, J. V.; Periasamy, M.
M.; Itoh, K. Organometallics 1989,8, 846.
Tetrahedron 1992, 48, 4623.
.____)
THF, 48 h
5 6
It is noteworthy that the Boc group in 5 was resistant
to reduction. This fact may hold true for other urethane
protecting groups since it was already shown for other
reducing agenta.7iQ4
The reduction of N-acylamino acids (3) is probably due
to the presence of a proton in the free carboxylic acid
which results in the formation of an (acy1oxy)borohy-
dride,16 previously shown to be suitable for the reduction
of amides to amines.16 The reduction of esters of N-(ary-
1oxy)- or N-(alkoxycarbony1)-protected amino acid esters
to the corresponding alcohols has also been described.'"
Experimental Section
General Procedures. 'H NMR spectra were recorded
at 250 or 500 MHz and 13C NMR spectra at 62.9 MHz,
respectively. Polarimetric measurements were taken on
an automatic polarimeter. Melting points are not cor-
rected. All chemicals and solvents were of technical or
ACS reagent grade and used as received unless otherwise
stated.
L- tert-Leucinol(2a). A 1-L three-neck round-bottom
flask was fittedwith amagnetic stirbar, a reflux condenser,
and an addition funnel. The flask was charged with 6.92
g (183 mmol) sodium borohydride and 200 mL of THF
(predried over sodium). L-tert-Leucine (la) (10.00 g, 76
mmol) was added in one portion. The remaining neck
was sealed with a septum and an argon line attached, and
the flask was cooled to 0 "C in an ice bath. A solution of
19.30 g (76 mmol of iodine dissolved in 50 mL of THF was
poured into the addition funnel and added slowly and
dropwise over 30 min resulting in vigorous evolution of
hydrogen. After addition of the iodine was complete and
gas evolution had ceased, the flask was heated to reflux
for 18 h and then cooled to roomtemperature, and
methanol was added cautiously until the mixture became
clear. After stirring 30 min, the solvent was removed by
rotary evaporation leaving a white paste which was
dissolved by addition of 150 mL of 20% aqueous KOH.
The solution was stirred for 4 h and extracted with 3 X
150 mL of methylene chloride. The organic extracts were
dried over sodium sulfate and concentrated in vacuo,
affording a white semisolid (100%) which was bulb-to-
bulb distilled to yield 7.53 g (84% of 2a as a white solid:
mp 30 OC, bp 90 "C/0.2 mm(lit.lo 117-120 OC/57mm).
L-Valinol (2b). Prepared from L-valine (lb) by the
same procedure in 94% yield as a colorless solid: mp 32
OC, bp 75 OC/6mm(1it.ll 8 OC/8 mm).
(13) Pfammatter, E.; Seebach, D. Liebigs Ann. Chem. 1991,1323.
(14) (a) Rodriguez, M.; Llinarea, M.; Doulut, 5.; Heitz, A.; Martinez,
J. TetMhedrOn Lett. 1991,32,923. (b) Kokotos, G. Synthesis 1990,299.
(c) Soucek, M.; Urban, J.; Saman, D. Collect. Czech. Chem. Commun.
1990,56,761. (d) Freeman Stanfield, C.; Parker, J. E.; Kanellie, P. J. Org.
Chem. 1981,46,4797.
(16) Brown, H. C.; Subba Rao, B. C. J. Am. Chem. SOC. 1960,82,681.
(16) Umino, N.; Iwakuma, T.; Itoh, N. Tetrahedron Lett. 1976, 763.
3670 J. Org. Chem., Vol. 68, No. 13, 1993
D-Phenylglycinol (2c) was prepared from D-phenyl-
glycine (lc) by the same procedure, with the exception
that the amino acid was added after addition of the iodine
was completed. The crude material (91 % ) was recrys-
tallized from toluene to afford 67% 2c as colorless
crystals: mp 69-71 OC (lite1' 75-77 OC).
L-Phenylalaninol (2d). Iodine Procedure. 2d was
prepared from 82.60 g (500 "01) L-phenylalanine (ld)
by the same procedure. The crude material was recrys-
tallized from toluene to yield 72% of 2d as colorless
crystals: mp 90-92 OC (lit.ll 92-94 OC).
Chlorine Procedure. A 500-mL three-neck round-
bottom flask equipped with a magnetic stirbar, reflux
condenser, thermometer, and gas inlet was flushed with
argon and charged with 250mL of THF, 16.52 g (100 "01)
of Id, and 9.10 g (240 "01) of NaBK. Then, 7.09 g (100
mmol) of chlorine,17 diluted with argon, was bubbled into
the suspension over a period of 1 h with external cooling
with an ice bath. Vigorous gas evolution and a strongly
exothermic reaction were observed. Afterwards, the flask
was heated to reflux overnight. The reaction mixture was
then hydrolyzed by dropwise addition of 30 mL of MeOH
at room temperature. The solvent was removed in vacuo,
the residue taken up in 150 mL of 20% aqueous KOH,
and the product extracted three times with 150 mL of
methyl-tert-butyl ether (MTBE), respectively. The or-
ganic extracts were dried (Na2SO4) and evaporated to
dryness yielding 14.92 g (99 % ) of a colorless solid. Double
recrystallization from toluene afforded 8.36 g (55 % ) 2d as
colorless crystals: mp 91-92 OC (1it.ll 92-94 OC).
Lithium Borohydride Procedure. This procedure is
identical to the NaBH4-I2 procedure with the exception
of the substitution of LiBK for NaBK on a molar basis.
Phenylalaninol was obtained in 70% yield as colorless
crystals. mp 92-94 OC (lit." 92-94 "C).
L-Prolinol (28) was prepared from L-proline (le) by
the NaBH4-I2 procedure and obtained in 58% yield as
colorless liquid: bp 80 OC/1 mm (lit.ll 74-76 OC/2mm).
L-Isoleucinol(2f) was prepared from L-isoleucine (If)
by the NaBH4-I2 procedure to afford, after double
distillation, 75% of 2f as a colorless solid bp 100-101
OC/S mm (lit'l 97 OC/14mm); mp 38-40 OC(lit.ll30 "C).
L-Methioninol(2g) was prepared from L-methionine
(lg) by the NaBH4-I2 procedure to afford 65% of 2g as
a colorless oil: bp 140 OC/1 mm. The oil obtained from
a second experiment spontaneously solidified to give
colorless crystals: mp 34-35 OC.
L-Tyrosinol Hydriodide (2h). A l-L three-neck round-
bottom flask equipped with a magnetic stirbar, reflux
condenser, thermometer, and addition funnel was flushed
with argon and charged with 500 mL of THF, 9.10 g (240
"01) NaBH4, and 18.10 g (100 mmo) L-tyrosine (la). A
solution of 25.40 g (100 mmol) 12 in 75 mL of THF was
added dropwise over a period of 1 h at a temperature of
8-10 OC. After the addition was complete, the flask was
heated to reflux overnight. The reaction mixture was
cooled down to room temperature, and 60 mL of MeOH
was added dropwise. The solvent was evaporated and the
residue dissolved in 100 mL of 2 M HC1. After removal
of the solvent in vacuo, the residue was twice suspended
in 300 mL of EtOH which was again distilled in vacuo to
remove traces of water and HC1. The residue was then
Notee
suspended in 300 mL of EtOH at 40 OCand the suspension
filtered. The filtrate was concentrated until crystallization
beganI8 and was kept at 5 O C overnight. The crystals were
filtered, washed with EtOH, dried, and taken up in 43 mL
of EtOH. After hot filtration to remove some insoluble
material, 20 mL of EtOH was distilled away and the
solution left at 5 OCovernight. The resulting crystals were
isolated by filtration, washed with EtOH, and dried in
vacuo to yield 45% of 2h as colorless crystals: mp 214-
216 OC, 'H NMR (d6-DMSO) S 9.3 (br, 8, lH), 7.8 (br 8,
3H), 7.1 (d, 2H), 6.7 (d, 2H), 5.2 (br a, lH), 3.5 (m, lH),
3.3 (m, lH), 3.2 (m, lH), 2.7 (ABX-system, 2H); IR (KBr),
3480,3270,3100,1610,1575,1513,1475,1433,1255,1200,
1050,818 cm-l. Anal. Calcd for CgH14IN02: C, 36.63; H,
4.78; N, 4.57; I, 43.00. Found C, 36.79; H, 4.82; N, 4.69;
I, 42.40.
L-N-Methylphenylalaninol (4a). a 500-mL three-
neck round-bottom flask equipped with a magnetic stirbar,
reflux condenser, thermometer, and addition funnel was
flushed with argon and charged with 250 mL of THF,
19.32 g (100 mmol) of N-formyl-L-phenylalanine (3a), and
9.10 g (240 "01) of NaBH4 whereupon a vigorous gas
evolution was observed. Then, a solution of 25.40 g (100
"01) of I2in 100 mL of THF was added slowly and
dropwise at atemperature of 25-40 OC. After the addition
was complete, the flask was heated to reflux overnight.
Excess reducing agent was cautiously destroyed by drop-
wise addition of 30 mL of MeOH at roomtemperature.
The solvents were then removed in vacuo, and the residue
was taken up in 100 mL of 20% aqueous KOH and the
product extracted three times with 150 mL of MTBE.
After drying (NazSOr), the extract was evaporated to a
pale-yellow oil which was crystallized by the addition of
200 mL of hot n-hexane. Filtration and drying gave 84%
colorless crystals which were recrystallized from 20 mL of
toluene. Evaporation of both mother liquors and recrys-
tallization of the residue from 5 mL of ethyl acetate yielded
a second crop of crystals which was added to the first one
to give a total yield of 73 % of 4a as colorless crystals: mp
71-74 OC (lit.Ig 68 OC); [a]D =+21.8' (1, EtOH) (lit.la
+17.1 (2, CHCb)).
D-N-Ethylphenylalaninol (4b) was prepared from
D-N-acetylphenylalanine (ab) by the same procedure as
4a. 4b was obtained, after recrystallization from 200 mL
of n-hexane, in 83 % yield as colorless crystals: mp 82-84
"C; lH NMR (d6-DMSO)) 6 7.3-7.1 (m, 6H), 4.4(br 8, lH),
3.2 (ABX-system, 2H), 2.7 (m, lH), 2.6 (m, 2H), 2.5 (9,
2H), 1.4 (br a, lH), 1.0 (t, 3H); 13C NMR (da-DMSO) 6
139.8,129.2,128.0,125.7,62.3,60.8,37.6,15.5; IR (KBr),
3280,3025,2970,2880,1600,1490,1478,1450,1380,1350,
1110,1028,940,863,790,745,700 cm-'; [alD =-11.6O (1,
EtOH). Anal. Calcd for CIIHI~NO: C, 73.70; H, 9.56; N,
7.81. Found C, 73.54; H, 9.69; N, 7.91.
L-N-Ethylprolinol (4c) was prepared by the same
procedure as 4a from N-acetyl-L-proline (3c) with the
modification that the residue from the organic extract
was dissolved in 50 mL of water, the resulting solution
stirred for 30 min and, after the addition of 50 mL of 5 9%
hydrochloric acid, stirred for another 90 min in order to
destroy stable boron complexes. The solution was then
made alkaline with 50 mL of 20% aqueous KOH and
(17) Procedure from Houben-Weyk Methoden der Organiechen
Chemie; Miiller, E., Ed.; Georg Thieme Verlag: Stuttgart, 1962; Vol. V/3,
p 617.
(18) The hydriodide waa formed excluively due to the preaence of
iodide formed during the borane generation. Prwumably, the HI dt is
leas soluble than the HC1 salt and crystallizes preferentially.
(19) Karim, A.; Mortreux, A.; Petit, F.; Buono, G.; Peiffer, 0.; Siv, C.
J. Organomet. Chem. 1986,317, 93.
Notes
extracted with CHzClz (4 X 150 mL). After the solution
was dried (NazSOr), the solvent was evaporated and the
residue bulb-to-bulb distilled to give 57 % of 4c as colorless
liquid: bp 80-85 OC/O.4 mm; [(YID =- 8 4 . 8 O (1, EtOH)
(lit.zo -110.4O (1.9, MeOH)).
N-Benzyl-2-aminoethanol(4d) wss prepared by the
same procedure as 4a from hippuric acid (3d) with the
modification that the residue of the reaction mixture which
had been quenched with MeOH was taken up in diluted
hydrochloric acid, stirred for 30 min, and made alkaline
by addition of aqueous KOH. Extraction with methyl
tert-butyl ether, drying, and evaporation of the extract
and two bulb-to-bulb distillations of the residue afforded
4d in 64% yield as colorless oil: bp 86-88OC/0.4mm(lit."
153-156 OC/12mm); nD =1.544 (1it.l1 1.5435).
(S')-l-( tert-Butoxycarbonyl)-2-tert-butyl-3-methyl-
lf-imidazolidine (6). A 500-mL three-neck round-
bottom flask equipped with a magnetic stirbar, reflux
condenser, thermometer, and addition funnel was flushed
with argon and charged with 150 mL of THF, 25.6 g (100
"01) of (s)-l-(tert-buto~~~ny1)-2-tert-butyl-~me~yl-
1,3-imidazolidin-4-one (S), and 7.56 g (200 mmol) of
NaBH4. After 15 min a solution of 12.70 g (50 mmol) IZ
in 50 mL of THF was added over 1 h at a temperature at
J. Org. Chem., Vol. 58, No. 13, 1993 3671
5 "C. The flask was then heated to reflux for 44 h. After
the reaction mixture had been cooled down to 5 OC, 260
mL of a saturated aqueous ammonium chloride solution
were added cautiously and the mixture was stirred at 50
O C until hydrogen evolution had ceased. The precipitate
was dissolved by addition of sufficient aqueous NaOH,
the organic layer separated, and the water phase extracted
four times with 150 mL of methyl-tert-butyl ether. The
extracts were dried (Na2S04) and evaporated to a colorless
oil which slowly crystallized. This was taken up in 150
mL of n-hexane, insoluble components were filtered off,
and the solution was concentrated to 42 g and placed into
a refrigerator. Large, colorless crystals were obtained thi s
way and by further concentrations of the mother liquors,
which were filtered, washed with n-hexane and dried in
vacuo at 30-40 OCto give 6 in 61% yield: mp 50-52 O C
(lit.13 47-48 "C for the (R)-enantiomer); [ ( Y I ~ ~ D =+22.5O
(1, CHC4) (lit. -22.8O (1.22, CHCld for the (R)-enanti-
omer).
(20) Hammer, C. F.; Weber, J. D. Tetrahedron 1981,37,2173.
Acknowledgment. The authors are indebted to the
National Science Foundation and the National Institutes
of Health for financial support of this research. They
would also like to thank W. Jahn, M. Kraft, and D. Pfeifle
for their skillful technical assistance.