One-pot asymmetric synthesis of either diastereomer of tert-butanesulfinyl- protected amines from ketones

Article abstract of DOI:10.1021/jo0616512

A one-pot method for the asymmetric synthesis of tert-butanesulfinyl- protected amines is described. Condensation of aryl alkyl and dialkyl ketones with tert-butanesulfinamide followed by in situ reduction with the appropriate reagent provides either dias

Full text of DOI:10.1021/jo0616512

SCHEME 1
One-Pot Asymmetric Synthesis of Either
Diastereomer of tert-Butanesulfinyl-protected
Amines from Ketones
Jessica Tanuwidjaja, Hillary M. Peltier,
and Jonathan A. Ellman*
Department of Chemistry, UniVersity of California,
Berkeley, California 94720
jellman@berkeley.edu
ReceiVed August 8, 2006
of asymmetric reductive amination using L-Selectride to provide
(RS,S) diastereomer 5 as the major product in good yield and
with good to excellent diastereoselectivity. This method provides
a synthetically useful procedure for the preparation of enan-
tioenriched amines4,5 and complements past studies.1,3,6 In
addition, the scope of the one-pot NaBH4 reduction method was
expanded to include biologically relevant cyclic substrates. After
this work had been completed, researchers at Amgen reported
a study on the reduction of both cyclic and acyclic N-tert-
butanesulfinyl imines with both NaBH4 in wet THF and
L-Selectride in dry THF and invoked a cyclic versus an acyclic
transition state, respectively, to explain the opposing stereo-
chemical outcomes.7 The imine reduction results reported by
Amgen are generally consistent with the one-pot reductive
amination results reported here with all significant differences
being noted.
A one-pot method for the asymmetric synthesis of tert-
butanesulfinyl-protected amines is described. Condensation
of aryl alkyl and dialkyl ketones with tert-butanesulfinamide
followed by in situ reduction with the appropriate reagent
provides either diastereomer of the sulfinamide products in
good yields and with diastereomeric ratios of up to 99:1.
Our investigation began with L-selectride-mediated reductive
amination of the aryl alkyl ketone acetophenone (2a). The
sulfinamide product 5a was obtained in 89% yield and with a
diastereomeric ratio of 97:3 (Table 1, entry 2).8 Dialkyl ketones
2b-e also afforded sulfinamide products in good yields and
with good to excellent selectivities. However, to obtain good
yields for the reductive amination of aliphatic ketones, it is
important that the condensation step is performed under
conditions that are not more forcing than is necessary. For
example, in the reductive amination of ketone 2c, a 76% yield
A previous study by the Ellman group showed that tert-
butanesulfinyl-protected amines can be prepared in a one-pot
procedure (Scheme 1).1 The sulfinyl group can then easily be
cleaved under mildly acidic conditions to obtain the amine
product as its hydrochloride salt. tert-Butanesulfinamide (1)2
was condensed with a variety of ketones 2 using Ti(OEt)4 as a
Lewis acid and water scavenger. The N-sulfinyl imine inter-
mediates 3 were then reduced in situ using NaBH4 to afford
sulfinamides in 66-86% yield and with diastereomeric ratios
from 90:10 to 97:3. This procedure gives predominantly the
(RS,R) diastereomer 4 of the sulfinamide product (Table 1).
Surprisingly, in subsequent work it was observed that different
reducing agents such as Superhydride or L-Selectride gave the
opposite sense of induction to provide sulfinamide diastereomers
5.3 The different sense of induction provided by these reagents
presents the opportunity to prepare both amine stereoisomers
from the same sulfinamide reagent. Herein, we report the scope
(4) For leading references on asymmetric reductions of preformed,
isolated imines, see: (a) Nolin, K. A.; Ahn, R. W.; Toste, F. D. J. Am.
Chem. Soc. 2005, 127, 12462. (b) Yang, Q.; Shang, G.; Gao, W.; Deng, J.;
Zhang, X. Angew. Chem., Int. Ed. 2006, 45, 3832. (c) Storer, R. I.; Carrera,
D. E.; Ni, Y.; MacMillan, D. W. C. J. Am. Chem. Soc. 2006, 128, 84. (d)
Hoffmann, S.; Seayad, A. M.; List, N. Angew. Chem., Int. Ed. 2005, 44,
7424. (e) Blaser, H.-U.; Malan, C.; Pugin, B.; Spindler, F.; Steiner, H.;
Studer, M. AdV. Synth. Catal. 2003, 345, 103. (f) Uematsu, N.; Fujii, A.;
Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1996, 118, 4916.
(g) Cobley, C. J.; Henschke, J. P. AdV. Synth. Catal. 2003, 345, 195. (h)
Hansen, M. C.; Buchwald, S. L. Org. Lett. 2000, 2, 713. (i) Qin, J.; Friestad,
G. K. Tetrahedron 2003, 59, 6393.
(5) For the only alternative asymmetric reductive amination method,
see: Nugent, T. C.; Wakchaure, V. N.; Ghosh, A. K.; Mohanty, R. R. Org.
Lett. 2005, 7, 4967.
(6) For diethylzinc reduction of preformed N-sulfinyl imines catalyzed
by Ni(acac)2, see: Xiao, X.; Wang, H.; Huang, Z.; Yang, J.; Bian, X.; Qin,
Y. Org. Lett. 2006, 8, 139.
(1) Borg, G.; Cogan, D. A; Ellman, J. A. Tetrahedron Lett. 1999, 40,
6709.
(2) (a) For a review on applications of tert-butanesulfinamide, see:
Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35, 984.
(b) For a recent general review on the synthesis and applications of
sulfinamides, see: Senanayake, C. H.; Krishnamurthy, D.; Lu, Z.-H.;
Zhengxu, H.; Gallou, I. Aldrichimica Acta 2005, 38, 93. (c) For a recent
review on additions to arenesulfinyl imines, see: Zhou, P.; Chen, B.-C.;
Davis, F. A. Tetrahedon 2004, 60, 8003.
(7) Colyer, J. T.; Anderson, N. G.; Tedrow, J. S.; Soukup, T. S.; Faul,
M. M. J. Org. Chem. 2006, 71, 6859.
(3) (a) Kochi, T.; Tang, T. P.; Ellman, J. A. J. Am. Chem. Soc. 2003,
125, 11276. (b) Peltier, H. M.; Ellman, J. A. J. Org. Chem. 2005, 70, 7342.
(8) Researchers at Amgen reported a 92:8 dr for L-Selectride reduction
of the isolated N-tert-butanesulfinyl imine prepared from acetophenone.7
10.1021/jo0616512 CCC: $37.00 © 2007 American Chemical Society
Published on Web 12/22/2006
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J. Org. Chem. 2007, 72, 626-629

TABLE 1. Reductive Amination of Acyclic Ketones
temp (°C)/
yieldc
(%)
entrya
ketone
R1
R2
Ph
time (h)b
reductant
product
drd
1e
2
2a
2a
2b
2b
2c
2c
2c
2d
2d
2e
2e
2a
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
NaBH4
L-Selectride
NaBH4
L-Selectride
NaBH4
L-Selectride
L-Selectride
NaBH4
L-Selectride
NaBH4
L-Selectride
NaBH4
4a
5a
4b
5b
4c
5c
5c
4d
5d
4e
5e
4a
78
89
82
72
66
76
33
62
83
74
70
93
96:4f
97:3f
83:17
86:14
97:3
96:4
96:4
99:1
96:4
92:8
96:4
96:4
Ph
75/15
60/10
3e
4
nBu
nBu
iPr
iPr
iPr
tBu
tBu
iBu
iBu
Ph
5e
6
60/15
75/15
75/19
75/19
7
8
9
10e
11
12g
60/10
75/15
a All reactions were performed on a 0.5-1.0 mmol scale unless otherwise indicated. All reductions were performed at -48 °C. b Temperature and time
for condensation to go to completion. c Yields of analytically pure material after chromatography. d Unless otherwise noted, diastereomeric ratios were
determined by GC analysis of (R)- and (S)-MTPA derivatives formed after cleavage of the sulfinyl group. e Previously published result.1 f Diastereomeric
ratio determined by HPLC analysis of the crude sulfinamide product. g Reaction performed on a 10-g (45 mmol) scale.
of sulfinamide 5c was obtained upon imine reduction when the
condensation step was performed at 60 °C for 15 h (entry 6).
In contrast, when the condensation step was performed under
more forcing conditions (75 °C for 15 h), 5c was obtained in a
significantly lower overall yield (entry 7). For dialkyl ketone
substrates, the highest diastereomeric ratios were obtained for
R-branched ketones 2c and 2d (entries 6 and 9),9 although a
â-branched ketone also gave product with high selectivity (entry
11). Presumably, substitution at the R- and â-positions of dialkyl
ketones provides additional steric discrimination leading to
higher selectivity than for unbranched dialkyl ketones (entry
4). This trend was also observed for the previously reported
method using NaBH4 as the reducing agent (entries 3, 5, 8, and
10). In the study by Amgen, a pronounced scale dependence
was observed for the reduction of N-tert-butanesulfinyl imines
with NaBH4 in wet THF, with considerable reduction in dr being
observed at 20 mmol versus 0.2 mmol scale.7 We therefore
chose to evaluate scale dependence for our one-pot reductive
amination procedure when using NaBH4 as the reductant. As
shown in entry 12, when the NaBH4-mediated reductive
amination was performed on a 10-g scale (45 mmol), no drop
in yield or dr was observed, thereby clearly demonstrating that
the one-pot NaBH4 reductive amination procedure does not show
scale dependence.
The scope of the one-pot condensation and reduction proce-
dures was explored further by employing cyclic ketones 2f-j
(Table 2). Reductive amination of ketone 2f with either NaBH4
or L-Selectride provided sulfinamides 4f and 5f with excellent
diastereomeric ratios of 99:1 and >98:2, respectively (entries
1 and 2). However, the yields for these transformations are
modest due to competing side reactions that occur during the
imine condensation step. Reductive amination of the six-
membered ring system 2g proceeded in dramatically increased
yields (entries 3 and 4). Using NaBH4 resulted in amine 4g in
80% yield and with 84:16 dr. When L-Selectride was used as
the reductant, 5g was obtained in 83% yield and with 99:1 dr.
To explore the electronic effects of various substituents on the
aryl ring, the reductive amination conditions were applied to
both electron-rich and electron-poor six-membered ring systems
2h,i, respectively. Use of NaBH4 resulted in amine 4h in 89%
yield and with 91:9 dr (entry 5). Amine 5h was obtained in
80% yield and with 97:3 dr when L-Selectride was employed
as the reducing agent (entry 6). Amines 4i and 5i were also
produced in good yield with use of either NaBH4 or L-Selectride,
73 and 72%, and with high selectivity, 90:10 and 98:2 dr,
respectively (entries 7 and 8). Notably, entries 5-8 demonstrate
that the one-pot reductive amination conditions are general for
six-membered ring substrates with electron-donating or electron-
withdrawing substituents. When the method was applied to the
seven-membered ring system 2j, depending on the conditions
utilized, the amines were produced either in good yield or with
good selectivity, but not both. Specifically, use of NaBH4
produced 4j in quantitative yield, but with a diastereoselectivity
(9) Researchers at Amgen reported a much lower dr for L-Selectride
reduction of the isolated N-tert-butanesulfinyl imine prepared from methyl
tert-butyl ketone (88:12).7 In our hands, L-Selectride reduction of this
isolated imine gave 96:4 dr, which is the same dr observed for the one-pot
reductive amination sequence (Table 1, entry 9).
J. Org. Chem, Vol. 72, No. 2, 2007 627

TABLE 2. Reductive Amination of Cyclic Ketones
a Temperature and time for condensation to go to completion. b Yields of analytically pure material after chromatography. c Diastereomeric ratios were
determined by GC analysis of (R)- and (S)-MTPA derivatives formed after cleavage of the sulfinyl group. d Diastereomeric ratio determined by HPLC
analysis of the crude sulfinamide product. e Because L-Selectride efficiently reduces nitro groups, only 1.1 equiv of L-Selectride was used, and the reaction
was quenched at -78 °C.
TABLE 3. Effect of Ti(OEt)4 on L-Selectride Reductions
of 58:42 (entry 9). Use of L-Selectride produced 5j in 49% yield
and with 88:12 dr (entry 10). The generally successful reductive
amination of these cyclic substrates is significant because the
amine products are prevalent substructures in drugs and drug
candidates.10
Ti(OEt)4 serves as both a desiccant and a Lewis acid for the
entry
additive
ketone
R1
R2
product
yield
dr
imine synthesis step.11 When using NaBH4 as the reducing
agent, the yield and diastereoselectivity of the reduction are also
improved by employing Ti(OEt)4 as an additive.1 However,
when using L-Selectride as the reducing agent, Ti(OEt)4 has
minimal effect on the yield or the selectivity of the reduction
step (Table 3).12 Reduction of N-sulfinyl imines 3a and 3c in
the absence of Ti(OEt)4 gave sulfinamides 5a and 5c with
comparable yields and diastereomeric ratios as those obtained
1
2
3
4
none
Ti(OEt)4
none
3a
3a
3c
3c
Me
Me
Me
Me
Ph
Ph
iPr
iPr
5a
5a
5c
5c
82
89
86
76
96:4a
97:3
95:5b
96:4
Ti(OEt)4
a Diastereomeric ratio determined by HPLC analysis of the crude
sulfinamide product. b Diastereomeric ratio determined by GC analysis of
(R)- and (S)-MTPA derivatives formed after cleavage of the sulfinyl group.
(10) For examples, see: (a) Uiterweerd, P. G. H.; van der Sluis, M.;
Kaptein, B.; de Lange, B.; Kellogg, R. M.; Broxterman, Q. B. Tetrahedron:
Asymmetry 2003, 14, 3479. (b) Rover, S.; Adam, G.; Cesura, A. M.; Galley,
G.; Jenck, F.; Monsma, F. J., Jr.; Wichmann, J.; Dautzenberg, F. M.
J. Med. Chem. 2000, 43, 1329. (c) Coe, B. K.; Weissman, A.; Welch,
W. M.; Broune, R. G. J. Pharmacol. Exp. Ther. 1983, 226, 686. (d) Welch,
W. M.; Kraska, A. R.; Sarges, R.; Coe, K. B. J. Med. Chem. 1984, 27,
1508. (e) Hurd, Y. L.; Ungerstedt, U. Eur. J. Pharmacol. 1989, 166, 251.
(11) Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J. A.
J. Org. Chem. 1999, 64, 1278.
in the one-pot condensation and reduction procedure (Table 3,
entries 1 and 3).
In conclusion, an efficient one-pot procedure for the asym-
metric reductive amination of ketones is reported. The sulfin-
(12) In the L-Selectride-mediated reduction of isolated N-tert-butane-
sulfinyl imines, Amgen also observed that Ti(OEt)4 as an additive had
minimal effect on reaction dr.7
628 J. Org. Chem., Vol. 72, No. 2, 2007

(60:40 EtOAc/hexanes) afforded 76.4 mg (76%) of 5c as a pale
yellow oil. The diastereomeric ratio was determined by GC analysis
of (R)- and (S)-MTPA derivatives of the amine hydrochloride salts
of crude 5c (Ultra II column, 100-250 °C, 2 °C/min, 20 psi; (R)-
MTPA derivative of 4c tR ) 29.7 min (minor diastereomer), 5c
amide products are easily accessed in good yields and with good
to excellent diastereoselectivities of up to 99:1. This method
complements previously described asymmetric reductions of
N-sulfinyl ketimines and expands the scope of these methods.
The procedure provides facile and efficient access to either
stereoisomer of the sulfinamide product from a common
N-sulfinyl imine intermediate simply by appropriate choice of
the reductant. Considering the convenience and generality of
the method and the abundance of natural products and biologi-
cally active molecules that contain the amine functionality, this
method should find wide use in both academics and industry.
1
tR ) 30.4 min (major diastereomer). H NMR (400 MHz) δ 0.77
(d, 3H, J ) 6.0 Hz), 0.79 (d, 3H, J ) 6.8 Hz), 1.11 (d, 3H, J ) 6.8
Hz), 1.11 (s, 9H), 1.57-1.65 (m, 1H), 2.76 (br d, 1H, J ) 7.2 Hz),
3.05-3.15 (m, 1H); 13C (100 MHz) δ 18.1, 18.2, 19.7, 22.7, 33.8,
55.8, 57.7. All analytical data agree with the literature data.1
(RS,R)-N-(1,2,2-Trimethylpropyl)-2-methylpropylsulfin-
amide (4d). General procedure B was followed with a 0.5 M
solution of (R)-1 (118 mg, 0.974 mmol, 1 equiv), Ti(OEt)4 (0.472
mL, 1.95 mmol, 2 equiv), pinacolone (0.150 mL, 1.17 mmol, 1.2
equiv), and NaBH4 (147 mg, 3.90 mmol, 4 equiv). Chromatography
(60:40 EtOAc/hexanes) afforded 124 mg (62%) of 4d as a white
crystalline solid. The diastereomeric ratio was determined by GC
analysis of (R)- and (S)-MTPA derivatives of the amine hydro-
chloride salts of crude 4d (Ultra II column, 100-250 °C, 2 °C/
min, 20 psi; (R)-MTPA derivative of 4d tR ) 31.8 min (major
diastereomer), 5d tR ) 32.8 min (minor diastereomer). mp 55-58
°C; [R]23 D -2.3° (c 1.0, MeOH, for amine hydrochloride); IR 1057,
1364, 1474, 1653, 2870, 2958, 3251 cm-1; 1H NMR (400 MHz) δ
0.88 (s, 9H), 1.09 (d, 3H, J ) 6.8 Hz), 1.16 (s, 9H), 3.05-3.11
(m, 1H), 3.21 (br s, 1H); 13C (100 MHz) δ 16.0, 22.8, 26.3, 34.5,
55.5, 59.0; MS (FAB): m/z [M + H]+ 206. Anal. Calcd for C10H23-
NOS: C, 58.49; H, 11.29; N, 6.82. Found: C, 58.14; H, 11.39; N,
7.00.
Experimental Section
General Procedure A for L-Selectride Reductions. Ketone was
added to a solution of (R)-1 and Ti(OEt)4 in THF at room
temperature (rt). The reaction mixture was heated to the temperature
indicated in Table 1, and the reaction conversion was followed by
TLC. Once the reaction was determined to be complete by TLC,
the mixture was cooled to room temperature and then to -48 °C.
L-Selectride (1 M solution in THF) was added dropwise. The
reaction mixture was allowed to warm to rt. Once the reduction
was determined to be complete by TLC, the reaction mixture was
cooled to 0 °C and MeOH was added dropwise until gas evolution
was no longer observed. The crude reaction mixture was poured
into an equal volume of brine while being rapidly stirred. The
resulting suspension was filtered through a plug of celite, and the
filter cake was washed with EtOAc. The filtrate was washed with
brine, and the brine layer was extracted with EtOAc (3×). The
combined organic portions were dried (Na2SO4), filtered, and
concentrated. Sulfinamides 5a-j were purified by silica gel
chromatography (hexanes/EtOAc).
General Procedure B for NaBH4 Reductions. Ketone was
added to a solution of (R)-1 and Ti(OEt)4 in THF at rt. The reaction
mixture was heated to the temperature indicated in Table 1, and
the reaction conversion was followed by TLC. Once the reaction
was determined to be complete by TLC, the mixture was cooled to
room temperature and then to -48 °C. The reaction mixture was
added dropwise via cannula to a -48 °C suspension of NaBH4 in
a minimum amount of THF. The vessel was then rinsed with THF
(2×). The reaction mixture was allowed to warm to rt. Once the
reduction was determined to be complete by TLC, the reaction
mixture was cooled to 0 °C and MeOH was added dropwise until
gas evolution was no longer observed. The crude reaction mixture
was poured into an equal volume of brine while being rapidly
stirred. The resulting suspension was filtered through a plug of
celite, and the filter cake was washed with EtOAc. The filtrate was
washed with brine, and the brine layer was extracted with EtOAc
(3×). The combined organic portions were dried (Na2SO4), filtered,
and concentrated. Sulfinamides 4d and 4f-j were purified by silica
gel chromatography (hexanes/EtOAc).
(RS,S)-N-(1,2,2-Trimethylpropyl)-2-methylpropylsulfin-
amide (5d). General procedure A was followed with a 0.5 M
solution of (R)-1 (59.0 mg, 0.487 mmol, 1 equiv), Ti(OEt)4 (0.236
mL, 0.974 mmol, 2 equiv), pinacolone (0.0745 mL, 0.584 mmol,
1.2 equiv), and L-Selectride (1.46 mL, 1.46 mmol, 3 equiv).
Chromatography (60:40 EtOAc/hexanes) afforded 83.0 mg (83%)
of 5d as a white crystalline solid. The diastereomeric ratio was
determined by GC analysis of (R)- and (S)-MTPA derivatives of
the amine hydrochloride salts of crude 5d (Ultra II column, 100-
250 °C, 2 °C/min, 20 psi; (R)-MTPA derivative of 4d tR ) 31.8
min (minor diastereomer), 5d tR ) 32.8 min (major diastereomer).
mp 72-75 °C; [R]23D +2.3° (c 1.0, MeOH); IR 1016, 1055, 1377,
1
1652, 2958, 2978, 3128, 3249 cm-1; H NMR (400 MHz) δ 0.89
(s, 9H), 1.23 (s, 9H), 1.25 (d, 3H, J ) 6.8 Hz), 2.76 (br d, 1H,
J ) 9.2 Hz), 3.02-3.09 (m, 1H); 13C (100 MHz) δ 18.9, 23.0,
26.4, 35.5, 56.4, 62.3; MS (FAB): m/z [M + H]+ 206. Anal. Calcd
for C10H23NOS: C, 58.49; H, 11.29; N, 6.82. Found: C, 58.71; H,
11.56; N, 6.81.
Acknowledgment. This work was supported by the National
Science Foundation (CHE-0446173). J.T. thanks the Department
of Chemistry at the University of California at Berkeley for a
Summer Research Award, and H.M.P. thanks Eli Lilly for a
graduate student fellowship.
(RS,S)-N-(1,2-Dimethylpropyl)-2-methylpropylsulfinamide (5c).
General procedure A was followed with a 0.5 M solution of (R)-1
(63.3 mg, 0.523 mmol, 1 equiv), Ti(OEt)4 (0.254 mL, 1.05 mmol,
2 equiv), 3-methyl-2-butanone (0.0672 mL, 0.628 mmol, 1.2 equiv),
and L-Selectride (1.46 mL, 1.46 mmol, 3 equiv). Chromatography
Supporting Information Available: Full experimental details,
spectral data, and characterization for all new compounds. This
materialisavailablefreeofchargeviatheInternetathttp://pubs.acs.org.
JO0616512
J. Org. Chem, Vol. 72, No. 2, 2007 629