Recycling the tert-butanesulfinyl group in the synthesis of amines using tert-butanesulfinamide

Article abstract of DOI:10.1021/jo9001883

A practical process for recycling the tert-butanesulfinyl group upon deprotection of N-tert-butanesulfinyl amines has been achieved. Treatment of N-tert-butanesulfinyl amines with HCl in cyclopentyl methyl ether results in complete conversion to tert-butanesulfinyl chloride and the corresponding amine hydrochloride salt, which is isolated by filtration in analytically pure form and in quantitative yield. Treatment of the resulting sulfinyl chloride solution with aqueous ammonia then provides analytically pure tert-butanesulfinamide in 97% yield. Alternatively, the tert-butanesulfinyl chloride solution can be treated with ethanol and catalytic quinidine as a sulfinyl transfer catalyst to provide a cyclopentyl methyl ether solution of ethyl tert-butanesulfinate with 88% ee. Addition of NaNH2 in ammonia followed by simple trituration of the product with octane provides tert-butanesulfinamide with 99% ee and in 67% overall isolated yield based upon the starting N-tert-butanesulfinyl amine.

Full text of DOI:10.1021/jo9001883

Recycling the tert-Butanesulfinyl Group in the Synthesis of Amines
Using tert-Butanesulfinamide
Masakazu Wakayama and Jonathan A. Ellman*
Department of Chemistry, UniVersity of California, Berkeley, California 94720-1460
jellman@berkeley.edu
ReceiVed January 28, 2009
A practical process for recycling the tert-butanesulfinyl group upon deprotection of N-tert-butanesulfinyl
amines has been achieved. Treatment of N-tert-butanesulfinyl amines with HCl in cyclopentyl methyl
ether results in complete conversion to tert-butanesulfinyl chloride and the corresponding amine
hydrochloride salt, which is isolated by filtration in analytically pure form and in quantitative yield.
Treatment of the resulting sulfinyl chloride solution with aqueous ammonia then provides analytically
pure tert-butanesulfinamide in 97% yield. Alternatively, the tert-butanesulfinyl chloride solution can be
treated with ethanol and catalytic quinidine as a sulfinyl transfer catalyst to provide a cyclopentyl methyl
ether solution of ethyl tert-butanesulfinate with 88% ee. Addition of NaNH2 in ammonia followed by
simple trituration of the product with octane provides tert-butanesulfinamide with 99% ee and in 67%
overall isolated yield based upon the starting N-tert-butanesulfinyl amine.
Introduction
acid byproducts (5 as undesired waste. The recovery of the
sulfinyl group with recycling back to the tert-butanesulfinamide
starting material has the potential to significantly enhance the
utility and practicality of sulfinamide chemistry, particularly for
large-scale applications for which it would result in significant
waste reduction and reduced starting material costs. Herein, we
report an extremely straightforward single-step recycling of the
sulfinyl group to provide racemic 1 with near quantitative
recovery, as well as a practical two-step procedure that proceeds
via dynamic kinetic resolution to provide (R)-1 in 99% ee and
67% overall yield.
tert-Butanesulfinamide (1) is an extremely versatile chiral
amine reagent that is now used in a number of the most popular
approaches for the asymmetric synthesis of amine-containing
compounds.1 Key features of these methods include (a) the direct
condensation of 1 with a wide range of aldehydes and ketones
in high yields under mild conditions to give stable N-sulfinyl
imines 2, (b) the electrophilicity of imines 2 that enables diverse
nucleophiles to be added cleanly and, when stereocenters are
introduced, with high diastereoselectivity, and (c) the convenient
and high-yielding cleavage of the N-sulfinyl group to provide
the desired amine products 4 (Scheme 1).
The removal of the sulfinyl group is typically performed with
an acid such as hydrogen chloride in a protic solvent such as
methanol, ethanol, or water2 to produce sulfinate ester or sulfinic
Results and Discussion
Racemic rather than enantiomerically pure tert-butanesulfi-
namide has been used in the synthesis of a large number of
different amines because either the desired amine product is
achiral,3 the racemic rather than enantiomerically pure product
is desired,4 or the sulfinyl group is not the stereocontrolling
element in the addition step.5 For these applications, we
(1) (a) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35,
984. (b) Ellman, J. A. Pure Appl. Chem. 2003, 75, 39. (c) Kochi, T.; Mukade,
T.; Ellman, J. A. J. Syn. Org. Chem. Jpn. 2004, 62, 128. (d) Morton, D.;
Stockman, R. A. Tetrahedron 2006, 62, 8869.
(2) Cogan, D. A.; Liu, G.; Ellman, J. A. Tetrahedron 1999, 55, 8883.
2646 J. Org. Chem. 2009, 74, 2646–2650
10.1021/jo9001883 CCC: $40.75 2009 American Chemical Society
Published on Web 03/04/2009

Recycling the tert-Butanesulfinyl Group
SCHEME 1. Asymmetric Synthesis of Amines Using tert-Butanesulfinamide
SCHEME 2. Recovery of Racemic tert-Butanesulfinamide
SCHEME 3. Recovery of Racemic tert-Butanesulfinamide
envisioned that a highly practical and efficient method for the
recovery of the sulfinyl group with recycling to racemic 1 could
be achieved by performing the HCl-mediated cleavage step in
an aprotic solvent to provide the desired amine hydrochloride
4 and sulfinyl chloride 6, which is not configurationally stable
and rapidly racemizes (Scheme 2). Assuming that sulfinyl
chloride 6 could indeed be formed cleanly and in high yield,
separation from the amine hydrochloride 4 followed by addition
of an ammonia source should then enable the complete recycling
of racemic 1.
SCHEME 4. Recovery of Enantiomerically Pure
tert-Butanesulfinamide
An acid-stable aprotic solvent is required not only to enable
the preparation of the sulfinyl chloride but also to effect efficient
precipitation of the desired amine hydrochloride salt 4 and,
consequently, separation from the sulfinyl chloride solution.
Cyclopentyl methyl ether (CPME) was selected because it is
an inexpensive and safe nonpolar solvent that has seen increasing
use in industrial applications.6 Alternative nonpolar ethereal
solvents that would also efficiently precipitate amine hydro-
chloride 4, such as diethyl ether and tert-butyl methyl ether,
were rejected due to high flammability and instability to HCl,
respectively.
Tertiary carbinamine derivative 7 (Scheme 3) was selected
as a model substrate due to the large number of instances where
pharmaceutical companies have employed racemic 1 for the
preparation of cyclic tertiary carbinamines.3 Sulfinyl group
cleavage from compound 7 was carried out using a slight excess
(2.05 equiv) of hydrogen chloride in CPME for 1 h at 0 °C
followed by 1 h at 23 °C. Simple filtration through a glass filter
using positive nitrogen pressure then provided analytically pure
amine hydrochloride 8 in very high yield along with a solution
of sulfinyl chloride 6 in CPME. Addition of the solution of
sulfinyl chloride to ammonium hydroxide at -10 °C resulted
in the formation of racemic 1, which was isolated with virtually
complete recovery from 7 in analytically pure form simply by
concentration, dilution with 1/9 EtOAc/hexanes, followed by
filtration to remove the NH4Cl byproduct, and reconcentration.
The scale independence of this procedure from 1 to 80 mmol
of 7 indicates that this process should be successful on
considerably larger scales. This straightforward procedure
enables the recovery of the sulfinyl group with conversion back
to tert-butanesulfinamide (1) with almost no material loss.
With the successful recovery of the sulfinyl group with
recycling to racemic 1 achieved, we next directed our efforts
to the more challenging recovery of highly enantiomerically
enriched material.7 As illustrated in Scheme 4, we envisioned
that this could be accomplished by dynamic kinetic resolution
of 6 to provide enantiomerically enriched sulfinate ester 9
followed by conversion back to sulfinamide (R)-1.8
Several quite selective methods for the dynamic kinetic
resolution of configurationally unstable tert-butanesulfinyl chlo-
(3) (a) Velazquez, F.; Bogen, S. L.; Arasappan, A.; Venkatraman, S.; Njoroge,
F. G.; Shih, N.-Y. PCT Patent Appl. WO 2008124148, 2008. (b) Baeschlin,
D. K.; Sedrani, R.; Flohr, S.; Namoto, K.; Sirockin, F.; Gessier, F.; Fenton, G.;
Beswik, M. C.; Clark, D. E.; Waszkowycz, B. PCT Int. Appl. WO 2008077597,
2008. (c) Plettenburg, O.; Lorenz, K.; Goerlitzer, J.; Loehn, M.; Biscarrat, S.;
Jeannot, F.; Duclot, O. PCT Int. Appl. WO 2008077556, 2008. (d) John, V.;
Maillard, M.; Tucker, J.; Aquino, J.; Hom, R.; Tung, J.; Dressen, D.; Shah, N.;
Neitz, R. J. PCT Int. Appl. WO 2005087215, 2005. (e) Fujii, H.; Nishimura,
Y.; Nitta, A.; Sakami, S.; Nakaki, J.; Kozono, H. PCT Int. Appl. WO
2007063928, 2007. (f) John, V.; Maillard, M.; Tucker, J. PCT Int. Appl. WO
2005087752, 2005. (g) Davies, T. G.; Garrett, M. D.; Boyle, R. G.; Collins, I.
PCT Int. Appl. WO 2007125321, 2007. (h) Caldwell, J. J.; Collins, I. Synlett
2006, 2565. (i) Nitta, A.; Fujii, H.; Sakami, S.; Nishimura, Y.; Ohyama, T.;
Satoh, M.; Nakaki, J.; Satoh, S.; Inada, C.; Kozono, H.; Kumagai, H.; Shimamura,
M.; Fukazawa, T.; Kawai, H. Bioorg. Med. Chem. Lett. 2008, 18, 5435.
(4) Naskar, D.; Roy, A.; Seibel, W. L.; Portlock, D. E. Tetrahedron Lett.
2003, 44, 8865.
(5) McMahon, J. P.; Ellman, J. A. Org. Lett. 2004, 6, 1645.
(6) Watanabe, K.; Yamigiwa, N.; Torisawa, Y. Org. Process Res. DeV. 2007,
11, 251.
(7) We also tried the direct conversion of tert-butanesulfinyl chloride to
tert-butanesulfinamide by using ammonia or ammonium hydroxide with
sulfinyl transfer catalysts, but so far, this procedure has not been rendered
enantioselective.
(8) For leading references demonstrating complete inversion of stereochem-
istry in the addition of amide anions as well as carbanions to tert-butanesulfinate
esters, see: (a) Han, Z.; Krishnamurthy, D.; Grover, P.; Fang, Q. K.; Senanayake,
C. H. J. Am. Chem. Soc. 2002, 124, 7880. (b) Khiar, N.; Fernandez, I.; Alcudia,
F. Tetrahedron Lett. 1994, 35, 5719. (c) Drabowicz, J.; Dudzinski, B.;
Mikolajczyk, M.; Wieczorek, M. W.; Majzner, W. R. Tetrahedron: Asymmetry
1998, 9, 1171.
J. Org. Chem. Vol. 74, No. 7, 2009 2647

Wakayama and Ellman
TABLE 1. Solvent Screen Using Ethanol and Quinidine
TABLE 2. Alcohol Screen Using Quinidine at Various
Temperatures
entry
solvent
yield (%)a
57
-
23
ee (%)b
temperature sulfinate
1
2
3
4
5
CH2Cl2
AcOEt
toluene
THF
26
70
77
entry
alcohol
(°C)
ester
yield (%)a ee (%)b
c
1
2
3
4
5
6
7
8
EtOH
PrOH
BuOH
-50
-40
-20
-50
-40
-20
-50
-40
-20
-50
-50
-50
-50
-50
9a
9a
9a
9b
9b
9b
9c
9c
9c
9e
9e
9f
>99
>99
>99
98
97
99
95
97
91
<85
<2
87
87
79
89
86
76
88
85
66
88
70
2
30
79
CPME
36 (69)d
91 (90)d
a Yields determined by NMR with 2,6-dimethoxytoluene as an inter-
nal standard. b Enantiomeric excess determined by chiral HPLC. c Yield
could not be determined due to overlapping of ethyl acetate and ethyl
sulfinate NMR peaks. d Reaction time was 40 h.
9
10
11
12
13
14
i-BuOH
i-PrOH
(CF3)2CHOH
FCH2CH2OH
CF3CH2OH
ride using an alcohol nucleophile and a chiral sulfinyl transfer
catalyst have been reported.9 However, these procedures are
not practical and cost-effective from an industrial standpoint
due to the necessity of relatively high molecular weight alcohols
or multistep catalyst preparation. We consequently focused on
quinidine as a commercially available and inexpensive sulfinyl
transfer catalyst and ethanol as a practical and low molecular
weight nucleophile (Table 1). Proton sponge (1,8-bis(dimethy-
lamino)naphthalene) was employed as the HCl scavenger
because we had previously determined that other common amine
bases catalyze nonselective sulfinate ester formation.9a We began
by examining various solvents at -78 °C (Table 1). Using
dichloromethane resulted in a moderate yield and low enantio-
meric purity of the ethyl sulfinate 9a (entry 1), with the low
selectivity due to a competitive background reaction. Ethyl
acetate, toluene, and THF resulted in slightly lower yields but
improved selectivities (entries 2-4). By using cyclopentyl
methyl ether (CPME) as the solvent, the sulfinate ester 9a was
obtained with high enantiomeric purity (entry 5). Longer reaction
times resulted in increased yields; however, the reaction did
not proceed to completion even after 40 h (entry 5).
>99
>99
98
9g
9h
89
79
a Yields determined by NMR with 2,6-dimethoxytoluene as an inter-
nal standard. b Enantiomeric excess determined by chiral HPLC.
TABLE 3. Optimization of Reaction Conditions
base
catalyst
EtOH
yield
ee
entry
base
(equiv) (mol %) (equiv) (%)a (%)b
1
2
3
4
5
6
7
8
9
NaHCO3
K2CO3
Na2CO3
proton sponge
proton sponge
proton sponge
proton sponge
proton sponge
proton sponge
2.5
2.5
2.5
2.5
2.5
2.5
2.5
1.5
1.2
10
10
10
10
20
5
1
10
10
5
5
5
5
5
5
5
5
2
19
18
17
>99
>99
>99
84
>99
45
58
70
74
87
87
86
84
88
87
We next evaluated higher reaction temperatures using several
simple alcohol nucleophiles with CPME as solvent in order to
improve the yield while maintaining high product enantiomeric
purity (Table 2). When EtOH was employed, the temperature
could be raised to -50 and even -40 °C to provide the ethyl
sulfinate 9a in a quantitative yield with only minimal reduction
in selectivity (entries 1 and 2). The reaction performed at -20
°C also resulted in an excellent yield, but a more significant
drop in selectivity was observed (entry 3). Use of PrOH and
BuOH at -50 °C (entries 4 and 7) provided slightly higher
selectivity (88-89% ee) than was observed for EtOH (entry
1), but the yields were a bit lower. Moreover, when these longer
chain alcohols were employed at or above -40 °C, a more
significant drop in the enantiomeric purity of the sulfinate ester
products was observed (entries 5, 6, 8, and 9). Thus, we chose
-50 °C as the optimal reaction temperature and evaluated
additional alcohol nucleophiles with varying steric properties
and acidities. Increasing the steric bulk of the alcohol resulted
in lower yields and did not increase the enantiomeric purity of
a Yields determined by NMR with 2,6-dimethoxytoluene as an inter-
nal standard. b Enantiomeric excess determined by chiral HPLC.
the sulfinate ester products (entries 10 and 11). More acidic
alcohols provided excellent reaction conversion (entries 12-14),
and 2-fluoroethanol (entry 13) gave comparable selectivity to
the sterically similar primary unbranched alcohols ethanol,
propanol, and butanol (entries 1, 4, and 7).
To further optimize the reaction, a final evaluation of the
reaction parameters was performed (Table 3). As anticipated,
inorganic bases were not beneficial for this reaction (entries
1-3). Increasing the catalyst loading to 20 mol % or decreasing
to 5 mol % did not result in any change in the yield or
enantiomeric purity of the product. However, the use of 1 mol
% of catalyst resulted in a slight reduction in selectivity and a
lower yield (entries 4-7). The stoichiometry of proton sponge
could be reduced to 1.5 equiv without any detrimental effects
(entry 8), but when the stoichiometry of the alcohol was dropped
to 2 equiv, a significant reduction in yield was observed (entry
9). A variety of cinchona-derived catalysts were also evaluated
with EtOH as the nucleophile and CPME as the solvent at -50
°C, but none provided comparable selectivity to quinidine.
Notably, quinine provided the opposite sense of induction (72%
(9) (a) Evans, J. W.; Fierman, M. B.; Miller, S. J.; Ellman, J. A. J. Am.
Chem. Soc. 2004, 126, 8134. (b) Shibata, N.; Matsunaga, M.; Nakagawa, M.;
Fukuzumi, T.; Nakamura, S.; Toru, T. J. Am. Chem. Soc. 2005, 127, 1374. (c)
Peltier, H. M.; Evans, J. W.; Ellman, J. A. Org. Lett. 2005, 7, 1733. (d) Shibata,
N.; Matsunaga, M.; Fukuzumi, T.; Nakamura, S.; Toru, T. Synlett 2005, 11,
1699.
2648 J. Org. Chem. Vol. 74, No. 7, 2009

Recycling the tert-Butanesulfinyl Group
TABLE 4. Recovery and Recycling of Enantiomerically Pure tert-Butanesulfinamide
11
9a
ee (%)a
1 (crude)
ee (%)a
1
1 (mother liquors)
yield (%)
ee (%)a
entry
scale of 10
yield (%)
yield (%)
ee (%)a
1
0.9 g
18 g
0.9 g
98
98
99
87
87
86
86
86
85
63
67
65
98 (R)
99 (R)
98 (R)
17
19
21
33 (R)
19 (R)
40 (R)
2
3b
a Enantiomeric excess determined by chiral HPLC. b Recycled proton sponge and quinidine were used.
ee), indicating that this method could potentially access both
enantiomers of tert-butanesulfinamide (see Supporting Informa-
tion).
overall recovery to (R)-1 can be expected upon identification
of an even more highly selective sulfinyl transfer catalyst.
Reuse of the quinidine and proton sponge mixture obtained
upon extraction during the dynamic kinetic resolution step was
also investigated. When the reaction was performed using
recovered quinidine and proton sponge on gram scale, the same
yield and % ee were observed (entry 3, Table 4) when compared
to the reaction performed with new quinidine and proton sponge
(entry 1). Therefore, not only has a procedure been established
for the recovery of the tert-butanesulfinyl group to provide tert-
butanesulfinamide (1) with high enantiomeric purity, but
recovery and reuse of the sulfinyl transfer catalyst and acid
scavenger employed in the dynamic resolution step can also be
accomplished by simple extractive isolation.
Enantiomerically pure N-sulfinyl-protected R-branched amine
1010 was selected as a model substrate for developing appropri-
ate conditions for the recovery of the sulfinyl group to provide
1 with high enantiomeric purity (Table 4). Initially, the reaction
was conducted on gram scale (entry 1). Treatment of N-sulfinyl
amine 10 with 2.05 equiv of hydrogen chloride in CPME at
room temperature resulted in complete sulfinyl group removal
to provide the benzyl amine hydrochloride 11, which was
removed by pressure filtration through a glass filter under an
inert atmosphere. The filtered tert-butanesulfinyl chloride solu-
tion was used directly for dynamic kinetic resolution under the
optimized conditions. An extractive workup then provided
the CPME solution of ethyl tert-butanesulfinate (9a) with 87%
ee. Notably, the extractive workup in addition to removing the
excess ethanol enables the recovery of the quinidine and proton
sponge mixture (vide infra). The CPME solution of tert-
butanesulfinate ester 9a was then directly added to 5 equiv of
sodium amide in NH3 at -48 °C.11 Simply removing the
ammonia gas by gradual warming to ambient temperature under
a gentle nitrogen flush followed by filtration provided a CPME
solution of tert-butanesulfinamide (1) with 86% ee. The enan-
tiomeric purity of the tert-butanesulfinamide product could easily
be enhanced by stirring the product in hydrocarbon solvents,
and thus, after solvent replacement from CPME to octane, the
analytically pure tert-butanesulfinamide (1) was obtained by
stirring the resulting suspension and filtration in 63% yield and
98% ee. Increasing the reaction scale 20-fold resulted in an
improved 67% overall yield of 1, which was obtained with 99%
ee (entry 2). The high yield and enantiomeric purity of 1
obtained upon increasing the scale over an order of magnitude
bodes well for effectively performing the reaction at even larger
scales. Moreover, concentration of the mother liquors provided
1 in approximately 19% yield and with 19% ee. The good
overall mass recovery of 1 (86%) suggests that an even higher
Conclusions
In conclusion, a practical process for recycling the tert-
butanesulfinyl group upon deprotection of N-tert-butanesulfinyl
amines 3 has been achieved. Treatment of N-tert-butanesulfinyl
amines 3 with HCl in cyclopentyl methyl ether results in
complete conversion to tert-butanesulfinyl chloride 6 and the
corresponding amine hydrochloride salt 4, which is isolated by
filtration in analytically pure form and in quantitative yield.
Treatment of the sulfinyl chloride solution with aqueous
ammonia then provides analytically pure tert-butanesulfinamide
with virtually complete recovery (97% yield). Alternatively, the
tert-butanesulfinyl chloride solution can be treated with ethanol
and catalytic quinidine as a sulfinyl transfer catalyst to provide
a cyclopentyl methyl ether solution of ethyl tert-butanesulfinate
(9a) in 88% ee. Addition of NaNH2 in ammonia followed by
simple trituration of the product with octane provides analyti-
cally pure tert-butanesulfinamide (1) with 99% ee and in 67%
overall isolated yield based upon the starting N-tert-butane-
sulfinyl amine 3. The reported protocols should greatly enhance
the practicality and utility of large-scale applications of tert-
butanesulfinamide-based amine synthesis methods.
(10) tert-Butanesulfinamide derivative 10 was prepared from (R)-tert-
butanesulfinamide (1) in good yield according to literature procedures. (a) Liu,
G.; Cogan, D. A.; Owens, T. D.; Ellman, J. A. J. Org. Chem. 1999, 64, 1278.
(b) Reference 2. (c) Reference 5.
(11) The use of sodium amide eliminated the troublesome multi-extractive
workup when using lithium amide. Weix, D. J.; Ellman, J. A. Org. Synth. 2005,
82, 157.
Experimental Section
Large-Scale Procedure for the Recovery of Racemic tert-
Butanesulfinamide 1. To a solution of 7 (17.39 g, 80.00 mmol) in
CPME (156 mL) was added 43.9 mL of 3.74 M HCl in CPME
(0.164 mol, 2.05 equiv) at 5 °C, the first 8.60 mL over a period of
J. Org. Chem. Vol. 74, No. 7, 2009 2649

Wakayama and Ellman
5 min, and then after 10 min, the remaining 35.3 mL over a period
of 25 min. After 1 h at 5 °C, the reaction mixture was allowed to
warm to 23 °C. After 1 h at 23 °C, crystals were removed by
pressure filtration through a glass filter and were washed with
CPME (100 mL) under an inert atmosphere to provide 8 (11.75 g,
98%) as a white solid and the CPME solution of 6.
added Fe(NO3)3 ·9H2O (162 mg, 0.400 mmol, 0.005 equiv) followed
by addition of small pieces of sodium (9.20 g, 0.400 mol, 5 equiv)
over 3 h. After the solution turned into a dark gray suspension, the
reaction mixture was cooled to -48 °C. The CPME solution of 9a
was slowly added to the freshly prepared sodium amide in NH3 to
keep the internal temperature at -48 °C (ca. 1 h). After 1 h, solid
ammonium chloride (23.5 g, 0.440 mol) was added in eight portions
over 8 min, and the mixture was allowed to slowly warm to room
temperature overnight under a gentle stream of nitrogen. CPME
(100 mL) was added to the resulting mixture, and the mixture was
concentrated under a reduced pressure until the total volume was
ca. 300 mL. After stirring at room temperature for 30 min, the
resulting inorganic salt was removed by filtration and was washed
with CPME (30 mL) to give the CPME solution of 1 with 86% ee.
The filtered solution was concentrated until the total volume was
ca. 80 mL. Octane (200 mL) was added to the resulting solution,
and the mixture was concentrated until the total volume was ca.
80 mL. More octane (200 mL) was added, and the same operation
was repeated. The resulting suspension was stirred at room
temperature for 20 h and then at 0 °C for 4 h. The crystals were
collected by filtration and washed with cold hexanes (60 mL,
precooled to 0 °C) and suction-dried to provide (R)-1 (6.47 g, 67%,
99% ee) as a white solid.
The filtered solution of 6 was slowly added to 14.8 M ammonium
hydroxide (27 mL, 0.40 mol, 5 equiv) to keep the internal
temperature at -10 °C (ca. 35 min), and the reaction mixture was
stirred for 30 min at -10 °C and then for 1.5 h at 23 °C. The
solvent was removed, and EtOAc/hexanes (1/9, 350 mL) was added.
After 3 h, the resulting inorganic salt was removed by filtration
and washed with EtOAc/hexanes (1/9, 50 mL). The solvent was
removed in vacuo, and hexanes (200 mL) was added. Concentration
then provided 1 (9.37 g, 97%) as a white solid.
8:12 mp 270-275 °C (decomp.); H NMR (D2O, 400 MHz) δ
1
1.29 (s, 3H), 1.23-1.35 (m, 1H), 1.40-1.70 (m, 9H); 13C NMR
(D2O, 100 MHz) δ 21.2, 22.7, 24.3, 35.3, 54.5; MS (ESI) m/z 114
(MH+). The data corresponded to that reported in the literature.
1: mp 98-102 °C; 1H NMR (400 MHz) δ 1.23 (s, 9H), 3.82 (br
s, 2H); 13C NMR (100 MHz) δ 22.1, 55.3; MS (ESI) m/z 122
(MH+). Anal. Calcd for C4H11NOS: C, 39.64; H, 9.15; N, 11.56;
S, 26.46. Found: C, 39.30; H, 9.51; N, 11.48; S, 26.56.
Large-Scale Procedure for the Recovery of tert-Butanesulfi-
namide (R)-1. To a solution of 10 (18.03 g, 80.00 mmol) in CPME
(181.9 mL) was added 38.1 mL of 4.30 M HCl in CPME (0.164
mol, 2.05 equiv) at 23 °C, 6.50 mL over a period of 4 min, and
after 10 min,13 the remaining 31.6 mL over a period of 35 min.
After 1 h, the crystals were removed by pressure filtration through
a glass filter and washed with CPME (140 mL) under an inert
atmosphere to provide 11 (12.37 g, 98%, 99% ee) as a white solid
and the CPME solution of 6.
11:14 [R]20 -4.3 (c 0.37, MeOH); mp 168-171 °C; H NMR
1
D
(CD3OD, 400 MHz) δ 1.63 (d, 3H, J ) 6.9 Hz), 4.46 (q, 1H, J )
6.9 Hz), 7.36-7.49 (m, 5H); 13C NMR (CD3OD, 100 MHz) δ 19.3,
50.9, 126.3, 128.7, 128.8, 138.2; MS (ESI) m/z 122 (MH+). The
enantiomeric ratio of 11 was determined by conversion to N-ben-
zoyl-1-phenylethylamine followed by HPLC analysis (Diacel
Chiralpak IB column, 90:10 hexanes/IPA; 1.0 mL/min), t1 ) 15.5
min, t2 ) 18.9 min. The data corresponded to that reported in the
literature.14
(R)-1: [R]20 +4.7 (c 0.81, CHCl3); mp 104-106 °C; H NMR
(a) Preparation of Ethyl Sulfinate 9a: To the filtered solution
of 6 was added proton sponge (25.71 g, 0.1200 mol, 1.5 equiv) at
-50 °C, and then a solution of quinidine (2.60 g, 8.00 mmol, 0.10
equiv) and EtOH (23.4 mL, 0.400 mol, 5.0 equiv) in CPME (40
mL) was slowly added to keep the internal temperature at -50 °C
(ca. 45 min). After 20 h at -50 °C, the reaction mixture was allowed
to warm to 10 °C over 20 min. The reaction mixture was washed
with 1 M HCl twice (160 mL, 80 mL), saturated NaHCO3 (80 mL),
and brine (80 mL) to provide the CPME solution of 9a with 87%
ee.
(b) Recovery of Proton Sponge and Quinidine: The separated
acidic water layers were combined (ca. 250 mL), and sufficient 5
M NaOH was added to make alkaline (pH 14). The aqueous phase
was then extracted three times with 30 mL of ether. The combined
organic layers were dried over sodium sulfate, filtered, and
concentrated to recover the mixture of quinidine and proton sponge
as a pale pink solid (28.19 g, 100%).
1
D
(400 MHz) δ 1.23 (s, 9H), 3.75 (br s, 2H); 13C NMR (100 MHz)
δ 22.2, 55.3; MS (ESI) m/z 122 (MH+). Anal. Calcd for C4H11NOS:
C, 39.64; H, 9.15; N, 11.56; S, 26.46. Found: C, 39.61; H, 9.33;
N, 11.48; S, 26.08. The enantiomeric ratio of (R)-1 was determined
by HPLC analysis (Diacel Chiralpak AS column, 90:10 hexanes/
EtOH; 1.2 mL/min; 220 nm; (R) rt ) 7.8 min, (S) rt ) 11.0 min).
Acknowledgment. This work was supported by the NSF
(CHE-0742565) and the American Chemical Society Green
Chemistry Institute (GCI-PRF# 48130-GCI). M.W. gratefully
acknowledges support from DAIICHI SANKYO Co., LTD. We
are grateful to Allychem for supplying tert-butanesulfinamide.
Supporting Information Available: Complete experimental
details and spectral data for all compounds described. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(c) Conversion of Ethyl Sulfinate 9a to tert-Butanesulfina-
mide (R)-1: To an ammonia solution (ca. 400 mL) at -40 °C was
JO9001883
(12) Koziara, A.; Osowska-Pacewicka, K.; Zawadzki, S.; Zwierzak, A.
Synthesis 1987, 487.
(13) A separate addition of the HCl solution enabled stirring of the reaction
mixture to be easily performed. If all of the HCl solution is added continuously,
the stirring becomes difficult due to the high viscosity of the slurry.
(14) Nakamura, S.; Nakashima, H.; Sugimoto, H.; Sano, H.; Hattori, M.;
Shibata, N.; Toru, T. Chem.sEur. J. 2008, 14, 2145.
2650 J. Org. Chem. Vol. 74, No. 7, 2009