Highly diastereoselective strecker reaction of enolizable aliphatic sulfinimines

Article abstract of DOI:10.1021/jo034477f

The reaction of chiral sulfinimines 1c-g derived from aliphatic aldehydes with TMSCN in the presence of CsF gave α-amino nitriles in high diastereoselectivity and yield. α,β-Diamino acid derivatives were also obtained in high diastereoselectivity from the reaction of 2-aziridinesulfinimines 1h and 1i followed by ring-opening of the products with thiophenol. The presence ofhydrogen of hydrogen at the α-position of the C=N double bond is crucial in this TMSCN addition reaction.

Full text of DOI:10.1021/jo034477f

High ly Dia ster eoselective Str eck er Rea ction of En oliza ble
Alip h a tic Su lfin im in es
Bin-Feng Li,† Ke Yuan,† Ming-J ie Zhang,† Hao Wu,‡ Li-Xin Dai,† Quan Rui Wang,‡ and
Xue-Long Hou*,†
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China, and Department of Chemistry,
Fudan University, 220 Han Dan Road, Shanghai 200433, China
xlhou@mai.sioc.ac.cn
Received April 15, 2003
The reaction of chiral sulfinimines 1c-g derived from aliphatic aldehydes with TMSCN in the
presence of CsF gave R-amino nitriles in high diastereoselectivity and yield. R,â-Diamino acid
derivatives were also obtained in high diastereoselectivity from the reaction of 2-aziridinesulfin-
imines 1h and 1i followed by ring-opening of the products with thiophenol. The presence of hydrogen
at the R-position of the CdN double bond is crucial in this TMSCN addition reaction.
The growing interest in nonproteinogenic R-amino
acids in a variety of scientific disciplines has prompted
the development of numerous methods for the asym-
metric synthesis of nonnatural R-amino acids.1 The
addition of HCN to imines (Strecker reaction) is one of
the most direct and viable strategies for the asym-
metric synthesis of R-amino acid derivatives.2 Chiral
imines are often used as substrates and cyanotri-
methylsilane (TMSCN) is a promising alternative to HCN
and is a safer source of cyanide anion.3 Many catalyzed
procedures have also recently been developed.4 However,
most of these are only suitable for aryl imine substrates,
and the aliphatic examples give low yields and low
selectivity.4c
There have been numerous reports on enantiopure
sulfinimines in recent years.5 Sulfinimines are stable
compounds. The sulfinyl group is an excellent chiral
auxiliary and activator of the CdN bond for nucleophilic
addition. It is easily removed from the product. Therefore,
the addition of TMSCN to readily available enantiopure
sulfinimines may be a good method for obtaining dia-
stereomerically enriched R-amino nitriles. However, Davis
and co-workers, who pioneered research on sulfinimines,
recently reported that when N-(benzylidene)-p-toluene-
sulfinamide was treated with TMSCN and CsF in THF,
no desired R-amino nitrile was obtained.6 They therefore
used ethylaluminum cyanide and isopropyl alcohol as an
alternative, and found that extreme care was needed with
this reaction, since it is strongly influenced by moisture.7
In the course of our research on the reactions of imines8
and aziridines,9 we discovered that fluoride anion served
as a trigger to initiate the addition of silicon reagents,
such as allyltrimethylsilane, TMSCN, and TMSN3, to
imines8a and aziridines,9a and the corresponding products
were obtained in excellent yields. Upon further study,
we surprisingly found that in the presence of fluoride
(5) For examples, see: (a) Davis, F. A.; Wu, Y.; Yan, H.; McCoull,
W.; Prasad, K. R. J . Org. Chem. 2003, 68, 2410. (b) Davis, F. A.;
Mohanty, P. K. J . Org. Chem. 2002, 67, 1290. (c) Davis, F. A.; Zhang,
Y.; Andemichael, Y.; Fang, T.; Fanelli, D. L.; Zhang, H. J . Org. Chem.
1999, 64, 1403. (d) Davis, F. A.; Chen, B. C. Chem. Soc. Rev. 1998, 27,
13. (e) Dragoli, D. R.; Burdett, M. T.; Ellman, J . A. J . Am. Chem. Soc.
2001, 123, 10127. (f) Tang, T. P.; Volkman, S. K.; Ellman, J . A. J . Org.
Chem. 2001, 66, 8772. (g) Liu, G.; Cogan, D. A.; Owens, T. D.; Tang,
T. D.; Ellman, J . A. J . Org. Chem. 1999, 64, 1278. (h) Cogan, D. A.;
Liu, G.; Kim, K.; Backes, B. J .; Ellman, J . A. J . Am. Chem. Soc. 1998,
120, 8011. (i) Lefebvre, I. M.; Evans, S. A., J r. J . Org. Chem. 1997, 62,
7532.
(6) Davis, F. A.; Reddy, R. E.; Portonovo, P. Tetrahedron Lett. 1994,
35, 9351.
(7) (a) Davis, F. A.; Portonovo, P. S.; Reddy, R. E.; Chiu, Y. H. J .
Org. Chem. 1996, 61, 440. (b) Davis, F. A.; Fanelli, K. L. J . Org. Chem.
1998, 63, 1981. (c) Davis, F. A.; Srirajan, V.; Titus, D. D. J . Org. Chem.
1999, 64, 6931. (d) Davis, F. A.; Srirajan, V. J . Org. Chem. 2000, 65,
3248. (e) Davis, F. A.; Srirajan, V.; Fanelli, D. L.; Portonovo, P. J . Org.
Chem. 2000, 65, 7663. (f) Davis, F. A.; Lee, S.; Zhang, H.; Fanelli, D.
L. J . Org. Chem. 2000, 65, 8704.
† Chinese Academy of Sciences.
‡ Fudan University.
(1) Williams, R. M. Synthesis of Optically Active R-Amino Acids;
Pergamon: Oxford, UK, 1989.
(2) Strecker, A. Ann. Chem. Pharm. 1850, 75, 27.
(3) For representative recent examples, see: (a) Duthaler, O. R.
Tetrahedron 1994, 50, 1539. (b) Kunz, H.; Rick, C. Angew. Chem., Int.
Ed. Engl. 1993, 32, 336. (c) Kobayashi, S.; Ishitani, H.; Ueno, M. Synlett
1997, 115. (d) Meyers, A. G.; Gleason, J . L.; Yoon, T.; Kung, D. W. J .
Am. Chem. Soc. 1997, 119, 656.
(4) For representative recent examples, see: (a) Sigman, M. S.;
J acobsen, E. N. J . Am. Chem. Soc. 1998, 120, 5315. (b) Krueger, C.
A.; Kuntz, K. W.; Dzierba, C. D.; Wirschun, W. G.; Gleason, J . D.;
Snapper, M. L.; Hoveyda, A. H. J . Am. Chem. Soc. 1999, 121, 4284.
(c) Iyer, M. S.; Gigstad, K. M.; Namdev, N. D.; Lipton, M. J . Am. Chem.
Soc. 1996, 118, 4910. (d) Corey, E. J .; Grogan, M. J . Org. Lett. 1999,
1, 157. (e) Ishitani, H.; Komiyama, S.; Hasegawa, Y.; Kobayashi, S. J .
Am. Chem. Soc. 2000, 122, 762.
(8) (a) Wang, D. K.; Zhou, Y. G.; Tang, Y.; Hou, X. L.; Dai, L. X. J .
Org. Chem. 1999, 64, 4233. (b) Li, A. H.; Dai, L. X.; Hou, X. L. Chem.
Commun. 1996, 491. (c) Wang, D. K.; Dai, L. X.; Hou, X. L. Chem.
Commun. 1997, 1231. (d) Hou, X. L.; Yang, X. F.; Dai, L. X.; Chen, X.
F. Chem. Commun. 1998, 747. (e) Hou, X. L.; Zheng, X. L.; Dai, L. X.
Tetrahedron Lett. 1998, 39, 6949. (f) Li, B. F.; Zhang, M. J .; Hou, X.
L.; Dai, L. X. J . Org. Chem. 2002, 67, 2902. (g) Yang, X. F.; Zhang, M.
J .; Hou, X. L.; Dai, L. X. J . Org. Chem. 2002, 67, 8097.
(9) (a) Wu, J .; Hou, X. L.; Dai, L. X. J . Org. Chem. 2000, 65, 1344.
(b) Wu, J .; Hou, X. L.; Dai, L. X. J . Chem. Soc., Perkin Trans. 1 2001,
1314. (c) Hou, X. L.; Fan, R. H.; Dai, L. X. J . Org. Chem. 2002, 67,
5295. (d) Fan, R. H.; Hou, X. L. J . Org. Chem. 2003, 68, 726. (e) Fan,
R. H.; Hou, X. L. Org. Biomol. Chem. 2003, 1, 1565.
10.1021/jo034477f CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/18/2003
6264
J . Org. Chem. 2003, 68, 6264-6267

Strecker Reaction of Enolizable Aliphatic Sulfinimines
SCHEME 1
SCHEME 2
SCHEME 3
TABLE 1. Resu lts of Rea ction of TMSCN w ith
Su lfin im in esa
entry sulfinimine
solvent
temp (°C) yield of 2 (%) dec
1b
2b
3
4
5
6
7
8
9
1a
1b
1c
1c
1c
1d
1e
1f
THF
THF
THF
n-hexane
n-hexane
n-hexane
n-hexane
n-hexane
n-hexane
25
25
25
86% of 3d
71% of 3
95
96
98
92
97
99
95
18
80
90
82
86
>98
>98
25
-50
-50
-50
-50
-50
1g
a
Reaction conditions: Sulfinimine (0.1 M in solvent), TMSCN
b
(1.05 equiv), CsF (1.05 equiv). TMSCN (2 equiv), CsF (2.05
equiv), 12 h. c The diastereoselectivity was determined by 1H NMR.
d
Reference 6.
SCHEME 4
anion, TMSCN is also successfully added to the CdN
bond of sulfinimines when there is a hydrogen atom at
the R-position of the CdN bond. Herein we would like to
report our results with the Strecker reaction of aliphatic
imines to give high diastereoselectivity and high yield.
The reaction of sulfinimines5a with TMSCN in the
presence of CsF gave rise to R-amino nitrile 2 or p-
toluenethiocyanate (3) (Scheme 1), and the results are
presented in Table 1. When (S)-(+)-N-(p-methoxybenzyl-
idene)-p-toluenesulfinamide (1a ) reacted with TMSCN
and CsF in THF for 12 h, p-toluenethiocyanate (3) was
isolated in 86% yield and no addition product amino-
nitrile 2a was detected (entry 1).6 The reaction of (S)-
(+)-N-(tert-butylidene)-p-toluenesulfinamide (1b) gave
similar results (entry 2). However, R-amino nitrile 2c was
obtained from (S)-(+)-N-(isopropylidene)-p-toluenesulfin-
amide (1c) in almost quantitative yield (95%). The NMR
spectrum of the product showed two peaks at δ 3.97 (dd,
Various enolizable sulfinimines 1c-g were evaluated
in n-hexane at -50 °C. The addition of (S)-(+)-N-
(cyclohexylidene)-p-toluenesulfinamide 1f and (S)-(+)-
N-(hexylidene)-p-toluenesulfinamide 1g gave the best
results (entries 8 and 9). They also give some of the best
results in the Strecker reaction involving aliphatic imines
by means of chiral imines3 or chiral catalysts.4 A similar
diastereoselectivity and yield were achieved (90% de, 93%
yield) even at a 3-g scale for imine 1c. The absolute
configuration of the major diastereomeric R-amino ni-
triles was determined to be (S,Ss) by comparison with
authentic samples.6 There have been many reports on
the hydrolysis of sulfinylamino nitriles to the correspond-
ing R-amino acids without racemization.6,10 Thus, the
R-amino nitrile 2e was converted to the corresponding
L-leucine 4 in 85% yield. Chiral HPLC analysis of product
4 showed that no racemization took place.10b
J 1 ) 7.9 Hz, J 2 ) 5.6 Hz) and 3.75 (dd, J 1) 8.9 Hz, J 2
)
5.6 Hz) with a ratio of 59:41, which corresponds to 18%
de (entry 3).
The solvent had an important impact on the stereo-
chemistry of the reaction, although it can proceed in
almost any aprotic solvent. Among the solvents tested,
the highest diastereoselectivity (80% de) was realized in
n-hexane (entry 4), while it was lower in CH2Cl2 (16%
de), toluene (12% de), CH3CN (14% de, more syn-product),
Et2O (8% de), and Et3N (52% de). When the concentration
of the substrate in n-hexane was lowered from 0.1 to 0.01
M, the diastereoselectivity decreased from 80% de to 12%
de. The reaction at a concentration of 0.25 M gave the
same diastereoselectivity as that at 0.1 M.
A catalytic amount of CsF (0.1 equiv) also promoted
the addition of TMSCN to (S)-(+)-N-(isopropylidene)-p-
toluenesulfinamide (1c), although the yield (91%) and
diastereoselectivity (70%) were slightly lower. The best
results were obtained when the reaction temperature was
lowered to -50 °C (entry 5). This addition reaction was
almost suppressed at -78 °C.
2-Aziridinesulfinimines 1h and 1i8f were also suitable
substrates in this reaction and provided the desired
products in excellent diastereoselectivity and yield (Scheme
3). Simple crystallization from CH2Cl2/ethyl acetate
provided optically pure amino nitriles 2h and 2i. The best
solvent in this reaction is THF. Davis reported the
asymmetric Strecker reaction of â-hydroxyl sulfinimines,7f
and the results suggested the influence of a double
stereodifferentiation effect where the chirality of the
resident hydroxyl moiety influences asymmetric induc-
(10) (a) DeWitt, H. D.; Ingersoll, A. W. J . Am. Chem. Soc. 1951, 73,
3359. (b) Wang, M X.; Lin, S. J . J . Org. Chem. 2002, 67, 6542. (c)
Reference 7f and references therein.
J . Org. Chem, Vol. 68, No. 16, 2003 6265

Li et al.
SCHEME 5
SCHEME 6
diastereoselectivity that involves the addition of TMSCN
to chiral enolizable sulfinimines. The combination of the
Strecker reaction and the ring-opening reaction of 2-azir-
idinesulfinimines provides a convenient route to chiral
R,â-diamino acids. This CsF-promoted addition comple-
ments Davis’ protocol and is attractive on several
points: higher yields, better diastereoselectivities, milder
reaction conditions, and no need for strict moisture-free
and oxygen-free conditions. Further studies on the mech-
anism and application of this reaction to asymmetric
synthesis are in progress.
tion. In our case, the stereochemistry was controlled by
the chiral sulfinyl group.
The products 2h and 2i were R,â-diamino nitriles and
also intermediates for the preparation of a variety of R,â-
diamino acids by ring-opening of the aziridine with
various nucleophiles. To explore this point, the ring-
opening reaction of anti-2h with 4-chlorothiophenol
was carried out, and the corresponding product, R-(N-
sulfinylamino)-â-benzylamino nitrile 5, was obtained in
82% yield (Scheme 4). Since the enantiomers of 2h and
2i are conveniently prepared from (R)-(-)-p-toluene-
sulfinamide and 1-benzyl-2-aziridinecarboxaldehyde,8f
the combination of the Strecker reaction of 2-aziridine-
sulfinimines followed by ring-opening of the products
provided a potential facile route to all four diastereo-
isomers of R,â-diamino acid derivatives.11
In the reaction of imines with TMSCN, the presence
of hydrogen at the R-position of the CdN bond was crucial
because the reaction of arylimine 1a and tertiary butyl
imine 1b, which have no R-H, gave p-toluenethiocyanate
(3) as the product while all other substrates 1c-i with a
hydrogen at the R-position of the CdN bond provided
R-amino nitriles 2c-i in high yields. The following
experiment supported our hypothesis. When the reaction
of TMSCN with (S)-(+)-N-(isopropylidene)-p-toluene-
sulfinamide 1c at -50 °C proceeded for 6 h and was then
stopped, a new compound was isolated in 15% yield in
addition to the substrate 1c (21% recovery) and product
2c (54% yield and 88% de). On the basis of IR and 1H
NMR spectra, we deemed it was an enamine 6 (Scheme
5). When the above mixture of 1c, 2c, and 6 was
re-exposed to the reaction conditions, R-amino nitrile 2c
was obtained in almost quantitative yield and 88% de.
The reaction of ketimine 7 provided further evidence to
support our hypothesis. In contrast to the result with
methoxy-phenylimine 1a , the reaction of ketosulfinimine
7 under the above Strecker reaction conditions gave rise
to R-amino nitrile 8 in 90% yield. The NMR spectrum of
the product in benzene-d6 showed two singlet peaks at δ
5.25 and 4.98 with a ratio of 11:89, which corresponds to
78% de. After chromatograph purification, enantiopure
product 8 was obtained in 72% yield (Scheme 6).7f
In summary, we have developed an effective and facile
route to aliphatic R-amino acid derivatives with high
Exp er im en ta l Section
Gen er a l. The commercially available reagents were used
without further purification. The solvents were treated by
using standard methods. Compounds 1c-f,12 1h -i,8f R-amino
acid 4,6,10 and 77f were synthesized according to the literature
procedures. All reactions were performed under a nitrogen
atmosphere.1H NMR spectra were recorded in CDCl3 and the
chemical shifts were referenced to CHCl3 (δ 7.27). Optical
rotations were measured with a thermally jacketed 10-cm cell
at 25 °C (concentration c given as g/100 mL). IR spectra were
measured in cm-1
.
P r ep a r a t ion of (S)-N-H ep t ylid en e-p -t olu en esu lfin -
a m id e (1g). To a solution of heptyl aldehyde (685 mg, 6 mmol)
and (S)-p-toluenesulfinamide (775 mg, 5 mmol) in CH2Cl2 (50
mL) was added Ti(OEt)4 (5.3 mL, 5.76 g, 25 mmol). The
mixture was refluxed and monitored by TLC. After completion,
the reaction mixture was quenched at 0 °C by addition of H2O
(50 mL). The solution was filtered through Celite, and the filter
cake was washed with CH2Cl2 (3 × 30 mL). The aqueous phase
was extracted with CH2Cl2 (2 × 20 mL), and the combined
organic portions were dried over Na2SO4, concentrated, and
purified by column chromatography over silica gel (petroleum
ether:EtOAc 10:1) to give (S)-N-heptylidene-p-toluenesulfin-
amide (1g): 1.155 g, 92% yield. 1H NMR (CDCl3/TMS, 300
MHz) δ 0.86 (t, J ) 6.2 Hz, 3H), 1.27-1.33 (m, 6H), 1.57-
1.62 (m, 2H), 2.38 (s, 3H), 2.44-2.51 (m, 2H), 7.29 (d, J ) 7.9
Hz, 2H), 7.56 (d, J ) 7.9 Hz, 2H), 8.22 (t, J ) 4.8 Hz, 1H). IR
(neat) 1621, 1099 cm-1. EI-MS m/z (%) 139 (100). Anal. Calcd
for C14H21NOS: C, 66.89; H, 8.42; N, 5.57. Found: C, 66.56;
H, 8.11; N, 5.34.
Gen er a l P r oced u r e for th e Ad d ition of TMSCN to
Su lfin im in es 1c-g in th e P r esen ce of CsF . To a solution
of sulfinimine (0.2 mmol) and CsF (32 mg, 0.21 mmol) in
n-hexane (2 mL) at -50 °C was added TMSCN (21 mg, 0.028
mL, 0.21 mmol) dropwise via syringe. The resulting mixture
was stirred at -50 °C and monitored by TLC. After completion,
the reaction mixture was quenched with a saturated solution
of NH4Cl and extracted with ethyl acetate (2 × 5 mL). The
organic phase was dried over Na2SO4. Removal of solvent in a
vacuum afforded the corresponding R-amino nitrile. The
1
diastereoselectivity was determined by H NMR.
(S s,S )-1-(p -Tolu e n e su lfin yla m in o)-2-m e t h ylb u t yr o-
n itr ile (2c): 46 mg, 98% yield, 90% de. 1H NMR (CDCl3/TMS,
(12) Davis, F. A.; Reddy, R. E.; Szewczyk, J . M.; Reddy, G. V.;
Portonovo, P. S.; Zhang, H.; Fanelli, D.; Reddy, R. T.; Zhou, P.; Carroll,
P. J . J . Org. Chem. 1997, 62, 2555.
(11) For example, see: Luo, Y.; Blaskovich, M. A.; Lajoie, G. A. J .
Org. Chem. 1999, 64, 6106 and references therein.
6266 J . Org. Chem., Vol. 68, No. 16, 2003

Strecker Reaction of Enolizable Aliphatic Sulfinimines
300 MHz) (major product) δ 1.06 (d, J ) 6.7 Hz, 3 H), 1.11 (d,
J ) 6.7 Hz, 3 H), 2.06-2.13 (m, 1 H), 2.42 (s, 3 H), 3.97 (dd,
J 1 ) 7.9 Hz, J 2 ) 5.6 Hz, 1 H), 4.76 (d, J ) 7.9 Hz, 1 H), 7.35
(d, J ) 8.2 Hz, 2 H), 7.60 (d, J ) 8.2 Hz, 2 H); (minor product)
δ 1.06 (d, J ) 6.7 Hz, 3 H), 1.11 (d, J ) 6.7 Hz, 3 H), 2.06-
2.13 (m, 1 H), 2.42 (s, 3 H), 3.75 (dd, J 1 ) 8.9 Hz, J 2 ) 5.6 Hz,
1 H), 4.76 (d, J ) 7.9 Hz, 1 H), 7.35 (d, J ) 8.2 Hz, 2 H), 7.60
(d, J ) 8.2 Hz, 2 H). IR (KBr) 3040, 1052 cm-1. EI-MS m/z (%)
236 (M, 1), 139 (100). Anal. Calcd for C12H16N2OS: C, 60.98;
H, 6.82; N, 11.85. Found: C, 61.07; H, 6.78; N, 11.92.
(Ss,S)-1-(p-Tolu en esu lfin yla m in o)p en ta n en itr ile (2d ):6
44 mg, 92% yield, 82% de. 1H NMR (CDCl3/TMS, 300 MHz)
(major product) δ 0.97 (t, J ) 7.3 Hz, 3 H), 1.48-1.57 (m, 2
H), 1.81-1.89 (m, 2 H), 2.43 (s, 3 H), 4.07-4.14 (m, 1 H), 4.87
(d, J ) 7.3 Hz, 1 H), 7.36 (d, J ) 8.0 Hz, 2 H), 7.61 (d, J ) 8.0
Hz, 2 H); (minor product) δ 0.97 (t, J ) 7.3 Hz, 3 H), 1.48-
1.57 (m, 2 H), 1.81-1.89 (m, 2 H), 2.43 (s, 3 H), 3.97-4.03 (m,
1 H), 4.87 (d, J ) 7.3 Hz, 1 H), 7.36 (d, J ) 8.0 Hz, 2 H), 7.61
(d, J ) 8.0 Hz, 2 H).
(Ss,S)-1-(p -Tolu en esu lfin yla m in o)-3-m et h ylp en t a n e-
n itr ile (2e):6 48 mg, 97% yield, 86% de. 1H NMR (CDCl3/TMS,
300 MHz) (major product) δ 0.94 (d, J ) 6.3 Hz, 3 H), 0.98 (d,
J ) 6.3 Hz, 3 H), 1.70-1.88 (m, 3 H), 2.43 (s, 3 H), 4.10-4.17
(m, 1 H), 4.60 (s, br, 1 H), 7.36 (d, J ) 7.8 Hz, 2 H), 7.61 (d, J
) 7.8 Hz, 2 H); (minor product) δ 0.94 (d, J ) 6.3 Hz, 3 H),
0.98 (d, J ) 6.3 Hz, 3 H), 1.70-1.88 (m, 3 H), 2.43 (s, 3 H),
3.96-4.03 (m, 1 H), 4.60 (s, br, 1 H), 7.36 (d, J ) 7.8 Hz, 2 H),
7.61 (d, J ) 7.8 Hz, 2 H).
J 1 ) 7.7 Hz, J 2 ) 4.5 Hz, 1 H), 4.46 (d, J ) 7.7 Hz, 1 H), 7.26-
7.42 (m, 7 H), 7.51-7.54 (m, 2 H). IR (KBr) 3062, 2234, 1736
cm-1. EI-MS m/z (%) 325 (M, 15), 234 (42), 91 (100). Anal.
Calcd for C18H19N3OS: C, 66.43; H, 5.88; N, 12.91. Found: C,
66.23; H, 5.89; N, 12.93.
P r ep a r a tion of (Ss,S)-2-(p-Tolu en esu lfin yla m in o)-2-
p h en ylp r op ion itr ile (8).7f To a solution of sulfinimine 7 (52
mg, 0.2 mmol) and CsF (32 mg, 0.21 mmol) in n-hexane (2
mL) at -50 °C was added TMSCN (21 mg, 0.028 mL, 0.21
mmol) dropwise via syringe. The resulting mixture was stirred
at -50 °C and monitored by TLC. After completion, the
reaction mixture was quenched with a saturated solution of
NH4Cl and extracted with ethyl acetate (2 × 5 mL×). The
organic phase was dried over Na2SO4. Removal of solvent in a
vacuum afforded the corresponding R-amino nitrile 8: 51 mg,
90% yield, 78% de. After flash chromatography (Et2O:CH2Cl2
5:95), 41 mg, 72% yield. [R]20 72.0 (c 0.6, CHCl3). 1H NMR
D
(CDCl3/TMS) δ 2.07 (s, 3H), 2.39 (s, 3H), 4.78 (s, 1H), 7.25-
7.29 (m, 2H), 7.42-7.46 (m, 3H), 7.56 (d, J ) 8.1 Hz, 2H),
7.68-7.72 (m, 2H). EI-MS m/z (%) 284 (M, 1.5), 154 (59) 139
(100).
Rin g-Op en in g Rea ction of a n ti-2h w ith 4-Ch lor oth io-
p h en ol. To a solution of anti-2h (66 mg, 0.2 mmol) in CH2Cl2
(5 mL) was added 4-chlorothiophenol (87 mg, 0.6 mmol); after
being stirred overnight at room temperature, the solvent was
removed by evaporation under vacuum and purified by column
chromatography over silica gel (petroleum ether:EtOAc 3:1)
to give thioether 5: 77 mg, 82% yield. [R]20 +85.7 (c 1.1,
D
1
CHCl3). mp 103-104 °C. H NMR (CDCl3-D2O, 300 MHz) δ
(Ss,S)-r-(p-Tolu en esu lfin yla m in o)-r-cycloh exyla ceto-
n itr ile (2f): 54 mg, 99% yield, >98% de. [R]20 +72.9 (c 1.33,
2.42 (s, 3H), 2.90 (dd, J 1 ) 12.9 Hz, J 2 ) 6.3 Hz, 1H), 2.97-
3.02 (m, 1H), 3.08 (dd, J 1 ) 12.9 Hz, J 2 ) 5.8 Hz, 1H), 3.78,
3.89 (AB, J ) 13.2 Hz, 2H), 4.15 (d, J ) 2.8 Hz, 1H), 7.11-
7.36 (m, 11H), 7.59 (d, J ) 8.3 Hz, 2H). IR (KBr) 3330, 1058
D
CHCl3). mp 98-99 °C. 1H NMR (CDCl3/TMS, 300 MHz) δ
1.10-1.24 (m, 5 H), 1.68-1.90 (m, 6 H), 2.42 (s, 3 H), 3.90-
3.94 (m, 1 H), 4.82 (s, br, 1 H, NH), 7.34 (d, J ) 8.0 Hz, 2 H),
7.60 (d, J ) 8.0 Hz, 2 H). IR (KBr) 3309, 1091 cm-1. EI-MS
m/z (%) 259 (26), 139 (100). Anal. Calcd for C15H20N2OS: C,
65.18; H, 7.29; N, 10.14. Found: C, 65.14; H, 7.28; N, 10.13.
(Ss,S)-1-(p-Tolu en esu lfin yla m in o)octa n en itr ile (2g): 53
cm-1. EI-MS m/z (%) 276 (35), 91 (100). Anal. Calcd for C24H24
-
ClN3OS2: C, 61.33; H, 8.94; N, 5.15. Found: C, 61.18; H, 9.00;
N, 5.17.
Mech a n istic Stu d y: (a ) Th e F or m a tion of En a m in e 6.
To a solution of sulfinimines 1c (209 mg, 1 mmol) and CsF
(160 mg, 1.05 mmol) in hexane (10 mL) was added TMSCN
(0.14 mL, 105 mg, 1.05 mmol) at -50 °C. The mixture was
stirred for 6 h and quenched with a saturated solution of
NH4Cl and extracted with EtOAc (2 × 10 mL×). The organic
phase was dried over Na2SO4. Removal of solvent in a vacuum
and chromatography provided 2c (127 mg, 54% yield, 88% de),
recovered 1c (44 mg, 21% recovery), and enamine 6 (31 mg,
1
mg, 95% yield, >98% de. H NMR (CDCl3/TMS, 300 MHz) δ
0.88 (t, J ) 7.1 Hz, 3H), 1.25-1.34 (m, 6H), 1.44-1.49 (m, 2H),
1.81-1.89 (m, 2H), 2.43 (s, 3H), 4.06-4.13 (m, 1H), 4.54 (d, J
) 7.3 Hz, 1H), 7.36 (d, J ) 7.9 Hz, 2H), 7.61 (d, J ) 7.9 Hz,
2H). IR (KBr) 3044, 1088 cm-1. EI-MS m/z (%) 261 (2), 139
(100). Anal. Calcd for C15H20N2OS: C, 64.71; H, 7.96; N, 10.06.
Found: C, 64.68; H, 7.78; N, 9.99.
Gen er a l P r oced u r e for th e Ad d ition of TMSCN to
Su lfin im in es 1h -i in th e P r esen ce of CsF . To a solution
of sulfinimine (0.2 mmol) and CsF (32 mg, 0.21 mmol) in THF
(2 mL) at -50 °C was added TMSCN (21 mg, 0.028 mL, 0.21
mmol) dropwise via syringe. The resulting mixture was stirred
at -50 °C and monitored by TLC. After completion, the
reaction mixture was quenched with a saturated solution of
NH4Cl and extracted with ethyl acetate (2 × 5 mL). The
organic phase was dried over Na2SO4. Removal of solvent in a
vacuum afforded the corresponding R-amino nitrile. The
1
15% yield). H NMR (CDCl3/TMS) δ 1.30-1.32 (m, 6 H), 2.38
(s, 3 H), 3.46 (s, 1 H, NH), 7.22-7.42 (m, 4 H), 7.70 (s, 1 H).
IR (neat) 3411 (br, S), 1611 cm-1. EI-MS m/z (%) 209 (M+, 27),
166 (100). Anal. Calcd for C11H15NOS: C, 63.12; H, 7.22; N,
6.69. Found: C, 63.23; H, 7.33; N, 6.73.
(b) Rea ction of Su lfin im in es 1c, Am in o Nitr ile 2c, a n d
En a m in e 6 w ith TMSCN in Str eck er Rea ction Con d i-
tion s. The crude product from procedure a was not purified
and dissolved in hexane (10 mL). After the solution cooled to
-50 °C, TMSCN (0.14 mL, 105 mg, 1.05 mmol) was added.
The mixture was stirred for an additional 6 h. After the same
workup procedure, product 2c was isolated in 95% yield and
88% de.
1
diastereoselectivity was determined by H NMR.
(2R,Ss,rR)-r-(p-Tolu en esu lfin ylam in o)-r-(1-ben zylazir i-
d in yl-2)-a ceton itr ile (2h ): 65 mg, 99% yield, 96% de. Crys-
tallization from CH2Cl2/hexane provided pure 2h : 56 mg, 84%
yield. [R]20 -11.8 (c 1.0, CHCl3). mp 135-136 °C. 1H NMR
D
Ack n ow led gm en t. This research was financially
supported by the National Natural Science Foundation
of China, the Major Basic Research Development Pro-
gram (grant No. G2000077506), the National Outstand-
ing Youth Fund, the Chinese Academy of Sciences, and
the Shanghai Committee of Science and Technology.
(CDCl3/TMS, 300 MHz) δ 1.58 (d, J ) 6.2 Hz, 1 H), 1.97-2.01
(m, 1 H), 2.09 (d, J ) 3.0 Hz, 1 H), 2.42 (s, 3 H), 3.51, 3.60
(AB, J ) 13.2 Hz, 2 H), 4.12 (dd, J 1 ) 6.8 Hz, J 2 ) 2.1 Hz, 1
H), 7.26-7.39 (m, 7 H), 7.57 (d, J ) 8.2 Hz, 2 H). IR (KBr)
3188, 2247, 1091, 1069 cm-1. EI-MS m/z (%) 325 (10), 234 (46),
91 (100). Anal. Calcd for C18H19N3OS: C, 66.43; H, 5.88; N,
12.91. Found: C, 66.10; H, 5.75; N, 12.68.
(2S,Ss,rR)-r-(p-Tolu en esu lfin ylam in o)-r-(1-ben zylazir i-
d in yl-2)-a ceton itr ile (2i): 65 mg, 99% yield, 92% de. Crys-
tallization from CH2Cl2/hexane provided pure 2i: 48 mg, 74%
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedure for hydrolysis of R-amino nitrile 2e as well as spectral
and analytical data for reaction product 4. This material is
available free of charge via the Internet at http://pubs.acs.org.
yield. [R]20 +63.1 (c 0.9, CHCl3). mp 89-90 °C. 1H NMR
D
(CDCl3/TMS, 300 MHz) δ 1.66-1.70 (m, 1 H), 2.03-2.12 (m, 2
H), 2.41 (s, 3 H), 3.14, 3.86 (AB, J ) 12.6 Hz, 2 H), 4.23 (dd,
J O034477F
J . Org. Chem, Vol. 68, No. 16, 2003 6267