Reversal of diastereofacial selectivity in hydride reductions of N-tert-butanesulfinyl imines

Article abstract of DOI:10.1021/jo0609834

A variety of N-tert-butanesulfinyl imines were reduced with NaBH ₄ in THF containing 2% water to provide the corresponding secondary sulfinamides in high yield and diastereoselectivity. By using the same sulfinyl imine starting materials and changing the reductant to L-Selectride, the stereoselectivity could be efficiently reversed to afford the opposite product diastereomer in high yield and selectivity.

Full text of DOI:10.1021/jo0609834

Reversal of Diastereofacial Selectivity in Hydride Reductions of
N-tert-Butanesulfinyl Imines
John T. Colyer, Neil G. Andersen,* Jason S. Tedrow, Troy S. Soukup, and
Margaret M. Faul
Chemistry Process Research and DeVelopment, Amgen Inc., Thousand Oaks, California 91320-1799
neila@amgen.com
ReceiVed May 11, 2006
A variety of N-tert-butanesulfinyl imines were reduced with NaBH4 in THF containing 2% water to
provide the corresponding secondary sulfinamides in high yield and diastereoselectivity. By using the
same sulfinyl imine starting materials and changing the reductant to L-Selectride, the stereoselectivity
could be efficiently reversed to afford the opposite product diastereomer in high yield and selectivity.
In support of a recent medicinal chemistry SAR study, we
required an efficient route to chiral secondary amines that would
allow access to both product antipodes in high stereoselectivity
and would be suitably flexible to work with a variety of
functional groups. The reduction of N-sulfinyl imines, first
reported by Cozzi1 and later studied by Ellman,2 attracted our
attention in part as a result of the increasing commercial
availability of both (R)- and (S)-2-methyl-2-propanesulfin-
amide.3,4 Although the synthesis of amines via addition of carbon
nucleophiles to various N-sulfinyl imines has been widely
investigated5 and exploited in the pharmaceutical industry,6 we
were surprised to find that the corresponding hydride addition
reactions have not been thoroughly studied. Whereas it was clear
from the work of Ellman2 that NaBH4 reduction of tert-butane-
sulfinyl imines provided high levels of diastereofacial control,
it was unclear how other reducing agents would effect the
stereochemical course of the reaction. Although reversals of
diastereofacial selectivity had been reported for addition of
carbon nucleophiles to sulfinyl imines,7 this observation had
not been clearly documented for the corresponding hydride
additions.8,9 We herein disclose our investigations into the
reduction of various N-tert-butanesulfinyl imines and show that
high levels of diastereofacial control can be obtained to provide
(6) (a) Lu, B. Z.; Senanayake, C.; Li, N.; Han, Z.; Bakale, R. P.; Wald,
S. A. Org. Lett. 2005, 7, 2599. (b) Kennedy, A.; Nelson, A.; Perry, A.
Synlett 2004, 6, 967. (c) Kuduk, S. D.; DiPardo, R. M.; Chang, R. K.; Ng,
C.; Bock, M. G. Tetrahedron Lett. 2004, 45, 6641. (d) DeSolms, S. J.;
Ciccarone, T. M.; MacTough, S. C.; Shaw, A. W.; Buser, C. A.; Ellis-
Hutchings, M.; Fernandes, C.; Hamilton, K. A.; Huber, H. E.; Kohl, N. E.;
Lobell, R. B.; Robinson, R. G.; Tsou, N. N.; Walsh, E. S.; Graham, S. L.;
Beese, L. S.; Taylor, J. S. J. Med. Chem. 2003, 46, 2973. (e) DeGoey, D.
A.; Chen, H.-J.; Flosi, W. J.; Grampovnik, D. J.; Yeung, C. M.; Klein, L.
L.; Kempf, D. J. J. Org. Chem. 2002, 67, 2002. (f) Han, Z.; Krishnamurthy,
D.; Grover, P.; Fang, Q. K.; Senanayake, C. H. J. Am. Chem. Soc. 2002,
124, 7880. (g) Lu, Z.-H.; Bhongle, N.; Su, X.; Ribe, S.; Senanayake, C. H.
Tetrahedron Lett. 2002, 43, 8617. (h) Pflum, D. A.; Krishnamurthy, D.;
Han, Z.; Wald, S. A.; Senanayake, C. H. Tetrahedron Lett. 2002, 43, 923.
(i) Plobeck, N.; Powell, D. Tetrahedron: Asymmetry 2002, 13, 303. (j)
Staas, D. D.; Savage, K. L.; Homnick, C. F.; Tsou, N. N.; Ball, R. G. J.
Org. Chem. 2002, 67, 8276. (k) Adamczyk, M.; Reddy, R. E. Tetrahe-
dron: Asymmetry 2001, 12, 1047. (l) Barrow, J. C.; Ngo, P. L.; Pellicore,
J. M.; Selnick, H. G.; Nantermet, P. G. Tetrahedron Lett. 2001, 42, 2051.
(m) Shaw, A. W.; DeSolms, S. J. Tetrahedron Lett. 2001, 42, 7173.
(7) For reversals of diastereofacial selectivity using p-toluenesulfinyl
imines, see: (a) Koriyama, Y.; Nozawa, A.; Hayakawa, R.; Shimizu, M.
Tetrahedron 2002, 58, 9621. (b) Fujisawa, T.; Kooriyama, Y.; Shimizu,
M. Tetrahedron Lett. 1996, 37, 3881. For reversals of diastereofacial
selectivity using tert-butanesulfinyl imines, see: refs 6a and 6i.
* To whom correspondence should be addressed. Tel: 805 447 0597.
(1) (a) Annunziata, R.; Cinquini, M.; Cozzi, F. J. Chem. Soc., Perkin
Trans. 1 1982, 1, 339. (b) Cinquini, M,; Cozzi, F. J. Chem. Soc., Chem.
Commun. 1977, 723.
(2) (a) Kochi, T.; Tang, T. P.; Ellman, J. A. J. Am. Chem. Soc. 2003,
125, 11276. (b) Kochi, T.; Tang, T. P.; Ellman, J. A. J. Am. Chem. Soc.
2002, 124, 6518. (c) Borg, G.; Cogan, D. A.; Ellman, J. A. Tetrahedron
Lett. 1999, 40, 6709.
(3) Both (R)- and (S)-2-methyl-2-propanesulfinamide are readily available
from AstaTech, Inc. in kilogram quantities for $9.90/g and $6.90/g,
respectively.
(4) The sulfinamide starting material may be prepared in two steps via
catalytic asymmetric oxidation of tert-butyl disulfide. See: (a) Weix, D.
J.; Ellman, J. A. Org. Lett. 2003, 5, 1317. (b) Cogan, D. A.; Liu, G.; Kim,
K.; Backes, B. J.; Ellman, J. A. J. Am. Chem. Soc. 1998, 120, 8011.
(5) For recent reviews, see: (a) Zhou, P.; Chen, B.-C.; Davis, F. A.
Tetrahedron 2004, 60, 8003. (b) Zhou, P.; Chen, B.-C.; Davis, F. A.
AdVances in Sulfur Chemistry; Rayner, C. M., Ed.; JAL Press: Greenwich,
CT, 2000; Vol. 2, p 249. (c) Cogan, D. A.; Liu, G.; Ellman, J. A.
Tetrahedron 1999, 55, 8883. (d) Davis, F. A.; Zhou, P.; Chen, B.-C. Chem.
Soc. ReV. 1998, 27, 13.
10.1021/jo0609834 CCC: $33.50 © 2006 American Chemical Society
Published on Web 08/11/2006
J. Org. Chem. 2006, 71, 6859-6862
6859

Colyer et al.
SCHEME 1a
TABLE 1. Reduction of Sulfinyl Imine (RS)-1a Using Various
Metal Hydrides
entrya
hydride
conversion (%)b % ds (major product)c
1
2
3
4
5
6
7
8
LiBH4
NaBH4
100
100
100
100
33
32 (2a)
90 (2a)
98 (2a)
79 (2a)
23 (2a)
70 (2a)
80 (2a)
26 (2a)
75 (2a)
69 (2a)
97 (3a)
95 (3a)
d
NaBH4/Ti(OEt)4
KBH4
Me4NBH4
NaBH3CN
BH3‚THF
LiAlH4
DIBAL-H
Red-Al
L-Selectride
31
100
100
97
100
100
100
a Isolated yields after column chromatography.
9
access to either product diastereomer from a single sulfinimine
enantiomer by appropriate selection of reducing agent and
solvent.
10
11
12
d
L-Selectride/Ti(OEt)4
a All reactions performed using 3.0 equiv of reducing agent in dry THF
Sulfinyl imines 1a-1n were prepared by condensation of the
appropriate ketone with 1.1 equiv of (RS)-2-methyl-2-propane-
sulfinamide using Ti(OEt)4 (2.0 equiv) in THF according to the
procedure developed by Ellman and co-workers2c (Scheme 1).
In all cases, the products were isolated in analytically pure form
1
(-50 °C f rt). b Conversion based on crude H NMR analysis. c Diaste-
reoselectivity based on HPLC analysis. d 20 mol % Lewis acid added.
TABLE 2. Solvent Screen for Sulfinyl Imine (RS)-1a Reduction
entrya
solvent
conversion (%)b
% ds (major product)c
1
by extractive workup followed by flash chromatography. H
NMR analysis revealed that sulfinyl imines 1a-1n existed solely
as the (E)-isomers and the corresponding sulfinyl enamides were
never observed. Sulfinyl imine (RS)-1a was subjected to a screen
of various metal hydrides in dry THF10 (Table 1). In accordance
with Ellman’s findings,2c NaBH4 proved to be optimal among
1
2
3
4
5
6
7
8
toluene
CH2Cl2
CH3CN
THFd
2-BuOH
IPA
100
100
100
100
100
100
100
37
58 (2a)
72 (2a)
10 (2a)
97 (2a)
82 (2a)
52 (2a)
18 (2a)
79 (3a)
the BH4 species examined, giving sulfinamide (RS,R)-2a11 in
-
EtOH
MeOH
quantitative conversion and 90% diastereoselectivity.12 Addition
of 20 mol % Ti(OEt)4 to the reaction mixture significantly
increased the diastereoselectivity in favor of the same product
stereoisomer (entry 3). Me4NBH4 and NaBH3CN were found
to be poorly reactive, furnishing sulfinamide 2a in 23% and
70% diastereoselectivity, respectively. Aluminum hydride re-
agents such as LiAlH4, DIBAL-H, and Red-Al exhibited poor
to modest levels of diastereoselection in favor of isomer 2a
(entries 8-10). We were gratified to find that subjection of
sulfinyl imine 1a to L-Selectride in dry THF provided the
opposite product stereoisomer (RS,S)-3a in 97% diastereo-
selectivity (entry 11). Addition of 20 mol % Ti(OEt)4 to the
reaction mixture slightly diminished the selectivity for product
3a to 95% diastereoselectivity (entry 12).
a All reactions performed using NaBH4 (3.0 equiv) in the appropriate
solvent (-50 °C to rt). b Conversion based on crude 1H NMR analysis after
24 h reaction period. c Diastereoselectivity based on HPLC analysis. d 2%
H2O added.
We subsequently studied the role of solvent on the reaction
using substrate (RS)-1a with 3.0 equiv of NaBH4 as the reductant
(Table 2). Toluene and CH2Cl2 furnished sulfinamide (RS,R)-
2a in good yield but modest selectivity (entries 1 and 2).
Employing acetonitrile as the solvent led to full conversion but
extremely low selectivity.
Performing the reduction in THF containing 2% water re-
sulted in a moderate, reproducible gain in selectivity for product
2a relative to using dry THF (cf. Table 1, entry 2).13 Utilization
of alcoholic solvents had a profound effect on the product
diastereoselectivity, with 2-butanol furnishing the best result for
product 2a (82% diastereoselectivity, entry 5). Employing IPA
also resulted in full conversion but with a diminished selectivity
(52% diastereoselectivity). Ethanol provided diastereomer 2a
with poor selectivity (18% diastereoselectivity), and MeOH gave
incomplete conversion (37%) toward the opposite stereoisomer
3a (79% diastereoselectivity, entry 8).
(8) Reversal of diastereofacial selectivity has been observed in the
reduction of tert-butanesulfinyl imines bearing a hydroxyl group in the
â-position. To explain this observation, Ellman and co-workers have
proposed that coordination of catecholborane to the hydroxyl group leads
to an (E)- to (Z)-imine isomerization. See refs 2a and 2b.
(9) To our knowledge only a single example of reversal in selectivity
has been reported for the reduction of unfunctionalized sulfinyl imines.
See: Kochi, T.; Ellman, J. A. J. Am. Chem. Soc. 2004, 126, 15652.
(10) The sulfinyl imine (0.2 mmol) was weighed into a reaction vessel
and dissolved in 5.0 mL of dry THF. The mixture was cooled to -50 °C
and treated with 3.0 equiv of the appropriate reducing agent. The resulting
mixture was allowed to warm to ambient temperature over a 3 h period
and subsequently subjected to a standard aqueous workup. The crude product
To test if the reversal in diastereofacial selectivity upon
using NaBH4 versus L-Selectride was general, sulfinyl imines
1b-1n were subjected to both reaction conditions (Table 3).
In all cases, reduction with NaBH4 in wet THF provided the
(RS,R)-diastereomer,14 whereas utilization of L-Selectride gave
1
mixtures were analyzed by H NMR and HPLC.
(11) The absolute configuration of product 2a was unequivocally assigned
by cleaving the sulfinamide with HCl and examining the optical rotation
of the known salt.
(12) Although the product % diastereoselectivity could be ascertained
by H NMR analysis, all data reported herein is based on HPLC analysis.
See Supporting Information for details.
1
(13) The explanation why water increases the selectivity of the reduction
is unclear. Further investigation of this effect is ongoing in our laboratories.
6860 J. Org. Chem., Vol. 71, No. 18, 2006

Hydride Reductions of N-tert-Butanesulfinyl Imines
TABLE 3. Reduction of Sulfinyl Imines 1b-1n Using NaBH4
versus L-Selectride
TABLE 4. Gram Scale Reduction of Sulfinyl Imines 1a and 1b
reduction
product,
isolated
% dsb
isolated
yield
imine
conditionsa
crude % dsb
1a
1a
1e
1e
NaBH4
L-Selectride
NaBH4
75
96
74
84
>99c
>99d
94c
84
90
80
82
L-Selectride
>99d
a All reactions were carried out on a 20 mmol scale using the general
conditions described in Table 3. b Based on HPLC analysis. c Isolated by
crystallization from hexanes. d Isolated by flash chromatography
TABLE 5. Cleavage of the Sulfinyl Moiety with HCl
sulfinamidea
yieldb,c
sulfinamidea
yieldb,c
2a
2b
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
94
77
87
95
78
87
88
89
81
84
59
79
55
3a
3b
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
98
96
93
98
92
90
93
81
91
86
84
83
84
a Pure sulfinamide diastereomer obtained by column chromatography.
b Isolated yield. c All salts exhibited >97% chemical purity by HPLC
analysis.
was easily ascertained by analysis of the crude 1H NMR spectra,
we elected to verify the results by means of HPLC analysis.
All reductions were carried out to full conversion, and the
selectivities shown in Table 3 are unoptimized for each imine
substrate.15,16 In general, increasing the scale of the NaBH4
reductions resulted in diminished selectivity, whereas no adverse
effect was observed in the corresponding L-Selectride reductions
(Table 4). However, we were gratified to find that many of the
reduction products could be isolated by crystallization with
considerable upgrade in diastereomeric purity.
In our hands, treatment of the reduction products with HCl
in dioxane (3.0 equiv) at room temperature cleanly provided
the desired amine salts without erosion of the carbon stereo-
chemistry. In all cases, the products were easily isolated via
filtration upon addition of diethyl ether to the reaction mixture
(Table 5).
To explain the origin of the reversal in diastereofacial
selectivity upon changing reducing agents from NaBH4 to
L-Selectride, we propose that the former reactions proceed via
a closed transition state wherein the sulfinyl oxygen participates
in the delivery of the hydride17 (Scheme 2). Under these
circumstances (RS-E)-sulfinyl imines would furnish the observed
(RS,R)-2 sulfinamide products. Alternatively, poorly coordinating
metal hydrides such as L-Selectride would attack the electro-
philic carbon atom in a sterically controlled fashion via an open
a All reactions were carried out on a 0.2 mmol scale using 3.0 equiv of
NaBH4 in THF containing 2% H2O (-50 °C to rt, 3 h). b All reactions
carried out on a 0.2 mmol scale using 3.0 equiv of L-Selectride in dry THF
(0 °C to rt, 3 h). c Average result obtained from two experiments unless
noted otherwise. d Diastereoselectivity based on HPLC analysis. e Result
obtained from a single experiment.
the corresponding (RS,S)-diastereomer. In general, moderate to
excellent selectivities for either product stereoisomer were
observed with the major exception being sulfinyl imine 1n. For
this substrate, the steric bias between the two substituents on
the imine carbon atom is not great enough to impart high levels
of diastereoselection. Although the selectivity of the reductions
(15) The general reaction conditions shown in Table 3 were chosen for
the purposes of screening. Further optimization study is ongoing in our
laboratories.
(16) All reduction products shown in Table 3 were isolated by flash
chromatography and fully characterized. See Supporting Information section
for details.
(14) The absolute configuration of the acetophenone ketimine series was
established by cleaving the sulfinamide and comparing the resulting product
to known samples of sec-phenethylamine. In addition, sulfinamide 3e has
been previously prepared by addition of MeMgBr to (RS)-N-tert-butane-
(17) It must be noted that in the presence of protic solvents the transition
state likely involves an activation of the borohydride reagent by hydrogen
bonding. For a discussion see: (a) Gatling, S. C.; Jackson, J. E. J. Am.
Chem. Soc. 1999, 121, 8655. (b) Wigfield, D. C.; Gowland, F. W. J. Org.
Chem. 1977, 42, 1108.
1
sulfinyl benzaldimine and characterized by H NMR. See ref 2c.
J. Org. Chem, Vol. 71, No. 18, 2006 6861

Colyer et al.
SCHEME 2. Mechanistic Proposal for Origin of
Stereoselectivity Reversal for Sulfinyl Imine Reduction
consumption of imine 1a to provide a product mixture favoring
sulfinamide 2a (75% diastereoselectivity). The solvent was then
removed in vacuo, and the resulting residue was triturated with
CH2Cl2. The solution was dried (MgSO4), filtered, and concentrated
to furnish a yellow oil. The crude product was dissolved in a
minimum volume of hexanes at reflux and subsequently allowed
to cool to ambient temperature. Product 2a was isolated as an off-
white crystalline solid (4.22 g, 84% yield) and determined to be
>99% diastereoselectivity by HPLC analysis. Rf (50% EtOAc/
1
hexanes) ) 0.51; H NMR (400 MHz, CDCl3) δ 7.46 (dd, J )
5.3, 3.7 Hz, 1H), 7.23-7.17 (m, 2H), 7.10 (dd, J ) 5.1, 3.7 Hz,
1H), 4.58 (dd, J ) 7.7, 3.8 Hz, 1H), 3.22 (d, J ) 2.5 Hz, 1H),
2.85-2.69 (m, 2H), 2.04-1.85 (m, 3H), 1.79-1.73 (m, 1H), 1.22
(s, 9H); 13C NMR (100 MHz, CDCl3) δ 137.7, 136.9, 129.6, 129.2,
127.5, 126.5, 55.4, 52.7, 30.5, 29.1, 22.6, 18.1; IR (neat) 3187,
1041, 1027 cm-1. HRMS calcd for C14H21NOS 252.1417 [M +
H]+; found 252.1429 [M + H]+.
(RS)-2-Methyl-N-((S)-1,2,3,4-tetrahydronaphthalen-1-yl)pro-
pane-2-sulfinamide (3a). Imine 1a (5.00 g, 20.1 mmol) was
dissolved in THF (50 mL) and cooled to 0 °C. To the vessel was
then added L-Selectride (60.0 mL, 1.0 M in THF, 60.0 mmol), and
the resulting solution was allowed to warm to room temperature
over a 3 h period. Analysis of the reaction mixture by HPLC showed
complete consumption of the starting imine to give sulfinamide 3a
in 96% diastereoselectivity. The solution was then concentrated
under vacuum to furnish an orange oil. The crude product was
subjected to column chromatography (50% EtOAc/hexanes) to
provide analytically pure product 3a (4.54 g, 90% yield). Rf (50%
transition state. Hence, delivery of the hydride would occur from
the same face as the sulfur lone pair to give sulfinamide products
in the (RS,S)-stereochemical series. This model may also explain
why NaBH4 reductions conducted in alcoholic solvents tend to
give poorer selectivity. Under these conditions the hydrogen
bonding ability of the solvent would be expected to disrupt
sulfinyl oxygen mediated delivery of the hydride reagent. In
the case of MeOH (Table 2, entry 8), the solvent disrupts the
closed transition state to the extent that the opposite stereoisomer
3 is produced.
1
EtOAc/hexanes) ) 0.31; H NMR (400 MHz, CDCl3) δ 7.41 (m,
In conclusion, we have demonstrated that N-tert-butanesulfi-
nyl imines can be reduced with metal hydride reagents to
provide either product stereoisomer selectively in a predictable
fashion. It appears that the sulfinyl oxygen atom plays a key
1H), 7.17 (m, 2H), 7.08 (m, 1H), 4.46 (ddd, J ) 10.0, 6.6, 5.9 Hz,
1H), 3.42 (d, J ) 10.0 Hz, 1H), 2.85-2.69 (m, 2H), 2.35-2.28
(m, 1H), 2.10-1.88 (m, 2H), 1.8501.75 (m, 1H), 1.26 (s, 9H); 13
C
NMR (100 MHz, CDCl3) δ 137.4, 137.3, 129.0, 128.7, 127.1, 125.8,
-
56.2, 55.7, 33.0, 29.0, 22.7, 19.8; IR (neat) 3200, 1050, 1036 cm-1
.
role in the delivery of BH4 reagents to give products derived
HRMS calcd for C14H21NOS 252.1417 [M + H]+; found 252.1423
[M + H]+.
from a closed transition state. Reductions of sulfinyl imines
using L-Selectride provide products derived from an open
transition state.
Acknowledgment. The authors thank Prof. David W.C.
MacMillan for providing helpful suggestions and encourage-
ment.
Experimental Section
(RS)-2-Methyl-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)pro-
pane-2-sulfinamide (2a). Imine 1a (5.00 g, 20.1 mmol) was
dissolved in 98:2 THF/H2O (50 mL) and cooled to -50 °C. To the
mixture was then added NaBH4 (2.28 g, 60.2 mmol), and the
resulting solution was warmed to room temperature over a 3 h
period. HPLC analysis of the reaction mixture showed complete
Supporting Information Available: General methods, char-
acterization data, NMR spectra, and analytical methods. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO0609834
6862 J. Org. Chem., Vol. 71, No. 18, 2006