Advantage of in situ generation of N-arylsulfonyl imines from α-amide sulfones in the phase-transfer-catalyzed asymmetric Strecker reaction

Article abstract of DOI:10.1016/j.tetlet.2006.12.122

Highly efficient, catalytic enantioselective synthesis of N-arylsulfonyl α-amino nitriles from the corresponding α-amido sulfones has been achieved under toluene-aqueous potassium cyanide biphasic conditions using chiral quaternary ammonium iodide (R,R,R)-1 as an effective phase-transfer catalyst. This Strecker synthesis involving the in situ generation of the reactive N-sulfonyl imines is advantageous for the cyanation of the substrates having primary and secondary alkyl substituents.

Full text of DOI:10.1016/j.tetlet.2006.12.122

Tetrahedron Letters 48 (2007) 1337–1340
Advantage of in situ generation of N-arylsulfonyl imines
from a-amide sulfones in the phase-transfer-catalyzed
asymmetric Strecker reaction
Takashi Ooi,* Yukitaka Uematsu, Jun Fujimoto, Kazuhiro Fukumoto and Keiji Maruoka*
Department of Chemistry, Graduate School of Science, Kyoto University Sakyo, Kyoto 606-8502, Japan
Received 21 November 2006; revised 18 December 2006; accepted 21 December 2006
Available online 23 December 2006
Abstract—Highly efficient, catalytic enantioselective synthesis of N-arylsulfonyl a-amino nitriles from the corresponding a-amido
sulfones has been achieved under toluene–aqueous potassium cyanide biphasic conditions using chiral quaternary ammonium iodide
(R,R,R)-1 as an effective phase-transfer catalyst. This Strecker synthesis involving the in situ generation of the reactive N-sulfonyl
imines is advantageous for the cyanation of the substrates having primary and secondary alkyl substituents.
Ó 2006 Elsevier Ltd. All rights reserved.
Stereochemical control in the Strecker reaction, cyana-
tion of imines, has been the focus of extensive study pri-
marily due to the importance of optically active a-amino
acids, obtained through hydrolysis of a-amino nitriles,
in various fields of science. For the last decade, enor-
mous efforts have been devoted to the development of
chiral catalysts to effect the enantioselective Strecker
reaction of aldimines and ketimines.1–3 In this context,
we have recently devised the phase-transfer-catalyzed
asymmetric cyanation of N-arylsulfonyl aldimines using
aqueous potassium cyanide (KCN) as a cyanide source
through the molecular design of a chiral quaternary
ammonium salt (R,R,R)-1 bearing a stereochemically
defined tetranaphthyl backbone.4 Although this new
asymmetric Strecker protocol nicely accommodates a
wide range of aliphatic aldimines, the chemical yield
and enantioselectivity were still insufficient in the reac-
tions with secondary and, particularly, primary alkyl
aldimines compared to tertiary alkyl ones. This could
be ascribed to the partial imine hydrolysis and uncata-
lyzed cyanation under biphasic conditions. To overcome
these problems associated with the direct use of the reac-
tive imines, we sought to employ N-arylsulfonyl a-
amido sulfones as a suitable starting substrate for the
in situ generation of the imine under similar liquid–
liquid phase-transfer conditions.5–7 Herein, we report
the highly enantioselective synthesis of N-protected a-
amino nitriles from the corresponding a-amido sulfones
with remarkable efficiency, featuring its distinct practi-
cal advantages (Scheme 1).
The requisite N-mesitylenesulfonyl (Mts)8 a-amido
sulfone, a synthetic precursor of the corresponding
PG
PG
CN
(R,R,R)-1 (1 mol%)
2 M aq KCN (1.05 equiv)
HN
HN
R
SO2(
p
-Tol)
R
toluene–H2O
3
2
0 °C
(R = prim-,sec-alkyl)
Ar
Ar
Me
N
I
Me
Ar
Keywords: a-Amido sulfones; a-Amino nitriles; Chiral quaternary
ammonium iodide; Potassium cyanide; Strecker synthesis.
*
Corresponding authors at present address: Department of Applied
Chemistry, Graduate School of Engineering, Nagoya University,
Chikusa, Nagoya, 464-8603 Japan (T.O.). Tel./fax: +81 75 753 4041
(K.M.); e-mail addresses: tooi@apchem.nagoya-u.ac.jp; tooi@
kuchem.kyoto-u.ac.jp; maruoka@kuchem.kyoto-u.ac.jp
Ar
(R,R,R)-1 (Ar = p-CF3-C6H4)
Scheme 1.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.12.122

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T. Ooi et al. / Tetrahedron Letters 48 (2007) 1337–1340
aldimines, can be readily prepared from aldehydes and
mesitylenesulfonamide as we previously reported,4 and
easily purified by recrystallization. With cyclohexane-
carboxaldehyde-derived a-amido sulfone 2a as a repre-
sentative substrate, we first attempted the exposure of
2a to our original biphasic conditions using (R,R,R)-1
as a catalyst. Thus, a mixture of 2a, 1.5 equiv of 2 M
KCN aqueous solution and 1 mol % of 1 in toluene–
H2O (volume ratio = 1:3) was stirred vigorously at
0 °C. Complete consumption of 2a was confirmed after
1.5 h, and the desired N-Mts a-amino nitrile 3a was pro-
duced in a quantitative yield with 97% ee (entry 1 in
Table 1). The considerable improvement of the chemical
yield and the enhanced enantioselectivity compared to
the case with the imine as substrate clearly indicates that
the intervention of imine hydrolysis and background
cyanation is minimized, thereby releasing the full poten-
tial of the chiral phase-transfer catalysis of 1. It should
be emphasized that reducing the amount of KCN to
1.05 equiv did not afford any detrimental effect on the
reaction efficiency, thus solidifying the practical aspect
of the present system (entry 2).
metric synthesis of an a-amino nitrile possessing a
secondary alkyl a-substituent as represented by the
cyanation starting from the substrate with N-benzyloxy-
carbonyl-4-piperidinyl group, where the target product
3d was isolated quantitatively in an essentially enantio-
merically pure form (entry 5).
To strengthen this approach further with respect to the
stereoselectivity in the reactions with a-primary-alkyl
a-amido sulfones, the effect of substituents on the
N-arylsulfonyl moiety was evaluated, fortunately
revealing that the use of the 4-methoxy-2,3,6-
trimethylbenzenesulfonyl (Mtr) group8,9 proved to be
beneficial. The N-Mtr a-amido sulfones was assembled
from aldehydes and Mtr-NH2 (7), which was conve-
niently derivatized from commercially available 2,3,5-
trimethylphenol (4) as illustrated in Scheme 2. After
methylation of 4, the resulting 2,3,5-trimethylanisole
(5) was converted to 4-methoxy-2,3,6-trimethylbenz-
ene-sulfonyl chloride (6, Mtr-Cl) according to the proce-
dure reported by Fujino.9a Subsequent treatment with
aqueous ammonia furnished 7.
Other selected examples are summarized in Table 1.
With a variety of a-amido sulfones derived from a-
branched and a-unbranched aldehydes including a
highly enolizable one, the reaction proceeded rapidly
and cleanly in the presence of 1 mol % of (R,R,R)-1
and 1.05 equiv of aqueous KCN, and the corresponding
a-amino nitriles 3 were obtained in excellent chemical
yields and always with higher enantioselectivities. In
particular, this method is quite effective for the asym-
As included in Table 1, subjection of N-Mtr a-amido
sulfones to the phase-transfer cyanation with 2 M
KCN aqueous solution under the influence of (R,R,R)-
1 led to formation of the corresponding N-Mtr a-amino
nitriles with uniformly improved enantioselectivities
(entries 10–13 vs entries 6–9 in Table 1).10 A notable
enhancement of the selectivity was attained with
unbranched, a-heptyl-substituted a-amido sulfone
(entry 12 vs entry 8). Unfortunately, however, chemical
Table 1. Phase-transfer-catalyzed asymmetric Strecker reaction with a-amido sulfones 2 as a starting substratea
PG
PG
(R,R,R)-1 (1 mol%)
HN
HN
2 M aq KCN (1.05 equiv)
R
SO2(p-Tol)
R
CN
toluene–H2O, 0 °C
2
3
Entry
a-Amido sulfone 2 (R)
PG
Time (h)
Yieldb (%)
eec (%)
Product
1d,e
2
3e
4e
5
c-Hex (2a)
c-Hex (2a)
c-Oct
Mts
Mts
Mts
Mts
Mts
1.5
1.5
2
1.5
1
99 (89)
99
99 (88)
99 (85)
99
97f (95)
97f
98 (97)
97 (93)
99
3a
3a
3b
3c
3d
i-Pr
N
Cbz
6e
7e
8
Ph(CH2)2
Mts
Mts
Mts
Mts
Mtr
Mtr
Mtr
Mtr
1
1
1
1
1
1
1
1
99 (81)
96 (82)
96
93
98
99
96
86
94 (90)
91 (88)
84
85
96
93
89
86
3e
3f
3g
3h
3i
(CH3)2CHCH2
CH3(CH2)5CH2
PhCH2
9
10
11
12
13
Ph(CH2)2
(CH3)2CHCH2
CH3(CH2)5CH2
PhCH2
3j
3k
3l
a Unless otherwise specified, the reaction was conducted with 1.05 equiv of 2 M KCN aqueous solution in the presence of 1 mol % of (R,R,R)-1 in
toluene–H2O (volume ratio = 1:3) at 0 °C for the given reaction time.
b Isolated yield.
c Enantiopurity of 3 was determined by HPLC analysis using a chiral column (DAICEL Chiralpak AD-H or Chiralcel OD-H) with hexane–2-
propanol as solvent. For detail, see the Supplementary data.
d With 1.5 equiv of 2 M KCN.
e The results with the corresponding aldimine as a starting substrate using 1.5 equiv of 2 M KCN are shown in the parenthesis.
f Absolute configuration of 3a was assigned to be S by comparison of the HPLC retention time with the reported value.4

T. Ooi et al. / Tetrahedron Letters 48 (2007) 1337–1340
1339
R'O
MeO
MeO
b
c
SO2Cl
SO2NH2
7 (Mtr-NH2
4 (R' = H)
5 (R' = Me)
6 (Mtr-Cl)
)
a
Scheme 2. Reagents and conditions: (a) NaH, MeI, THF, 0 °C, 92%; (b) chlorosulfonic acid (3 M solution in CH2Cl2), CH2Cl2, 0 °C; (c) 25% NH3
aqueous solution, THF, 0 °C, 71% (two steps).
yield was sacrificed in the reaction involving the genera-
tion of the imine with a-protons of high acidity (entry 13
vs entry 9).
(3 mL) was cooled to 0 °C and a 2 M KCN aqueous
solution (105 lL, 0.210 mmol) was added dropwise.
The reaction mixture was stirred vigorously for 1.5 h
at this temperature. Then, saturated NH4Cl aqueous
solution was added and the mixture was extracted with
CH2Cl2. The combined extracts were dried over
Na2SO4. Evaporation of solvents and purification of
the crude products by flash column chromatography
on silica gel (EtOAc/hexane = 1:4 as eluent) gave N-
(Mts)-a-(cyano)cyclohexylmethylamine (3a, 64.1 mg,
0.2 mmol, >99%); HPLC analysis: DAICEL Chiralpak
AD-H, 2-propanol/hexane = 1:10, flow rate = 0.5 mL/
min, k = 254 nm, retention time; 13.3 min (R) and
In conclusion, highly efficient, enantioselective synthesis
of N-Mts and N-Mtr a-amino nitriles from the corre-
sponding a-amido sulfones has been accomplished
under toluene–aqueous KCN biphasic conditions by the
utilization of phase-transfer catalysis of chiral quater-
nary ammonium iodide (R,R,R)-1. This asymmetric
Strecker synthesis has the following characteristics: (1)
N-arylsulfonyl a-amido sulfones can be used directly
as a starting substrate, thus obviating the preformation
of the reactive N-arylsulfonyl aldimines having primary
or secondary alkyl a-substituents; (2) 1.05 equiv of KCN
are sufficient for the smooth reaction, which is com-
pleted within 2 h at 0 °C; (3) the products are isolated
with excellent levels of chemical yield and enantioselec-
tivity. We believe these salient features should be greatly
appreciated in the large-scale industrial applications,
underscoring the practical advantage of our approach.
1
14.7 min (S); H NMR (400 MHz, CDCl3) d 6.99 (2H,
s, ArH), 5.37 (1H, d, J = 9.1 Hz, NH), 3.92 (1H, dd,
J = 6.7, 9.1 Hz, NHCH), 2.65 (6H, s, ArCH3), 2.31
(3H, s, ArCH3), 1.86–1.67 (6H, m, CH and CH2),
1.29–1.06 (5H, m, CH2) ppm; 13C NMR (100 MHz,
CDCl3) d 143.0, 139.0, 132.7, 132.1, 116.5, 49.5, 41.2,
29.0, 28.4, 25.7, 25.4, 25.3, 23.0, 21.1 ppm; IR (thin film)
3275, 3028, 2930, 2855, 2253, 1602, 1566, 1450, 1330,
1157, 1091, 1057, 904, 852, 731 cmÀ1; HRMS (ESI-
TOF) calcd for C17H24N2O2SNa ([M+Na]+):
343.1454, found: 343.1451.
Synthesis of N-Mts a-amido sulfone [N-(Mts)-a-(p-tolu-
enesulfonyl)cyclohexylmethylamine (2a)]:4 A mixture of
cyclohexanecarboxaldehyde (363 lL, 3.0 mmol), mesit-
ylenesulfonamide (598 mg, 3.0 mmol) and sodium p-tolu-
enesulfinate (481 mg, 3.0 mmol) in HCO2H (4.5 mL)
and H2O (4.5 mL) was stirred for 12 h at room temper-
ature. The resulting white precipitate was filtered off,
washed with H2O and hexane. The precipitate was then
recrystallized from EtOAc/hexane to obtain 2a (301 mg,
2.01 mmol, 67%) as a crystalline material; 1H NMR
(400 MHz, CDCl3) d 7.52 (2H, d, J = 8.3 Hz, ArH),
7.03 (2H, d, J = 8.3 Hz, ArH), 6.81 (2H, s, ArH), 5.27
(1H, d, J = 10.7 Hz, NH), 4.53 (1H, dd, J = 3.0,
10.7 Hz, NHCH), 2.50–2.40 (1H, m, CH(CH2)2), 2.42
(6H, s, ArCH3), 2.34 (3H, s, ArCH3), 2.29 (3H, s,
ArCH3), 2.11 (1H, d, J = 12.3 Hz, CH2), 1.81–1.60
(4H, m, CH2), 1.38–1.28 (2H, m, CH2), 1.19–1.02 (3H,
m, CH2) ppm; 13C NMR (100 MHz, CDCl3) d 144.4,
141.7, 137.5, 135.7, 134.2, 131.6, 129.3, 128.3, 77.5,
37.5, 30.7, 27.2, 26.2, 25.8, 25.7, 22.9, 21.7, 21.0 ppm;
IR (thin film) 3401, 3285, 3028, 2928, 2855, 1599,
1566, 1450, 1331, 1302, 1155, 1123, 1082, 903, 853,
814, 733 cmÀ1; HRMS (ESI-TOF) calcd for C23H31-
NO4S2Na ([M+Na]+): 472.1575, found: 472.1587.
Acknowledgements
This work was partially supported by the Shorai Foun-
dation for Science and Technology and a Grant-in-Aid
for Scientific Research on Priority Areas ‘Advanced
Molecular Transformation of Carbon Resources’ from
the Ministry of Education, Culture, Sports, Science
and Technology, Japan.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2006.12.122.
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T. Ooi et al. / Tetrahedron Letters 48 (2007) 1337–1340
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