DBU-catalyzed addition reactions of sulfonylimidates

Article abstract of DOI:10.1055/s-2008-1067251

Sulfonylimidates react with various types of N-protected imines in the presence of a catalytic amount of DBU to afford β-aminosulfonylimidates in high yields and high anti-selectivities. The experimental procedure is described in detail. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1067251

PRACTICAL SYNTHETIC PROCEDURES
3009
DBU-Catalyzed Addition Reactions of Sulfonylimidates
Synthesis of
b-Ayo
Department of Chemistry, School of Science and Graduate School of Pharmaceutical Sciences,
The University of Tokyo, The HFRE Division, ERATO, Japan Science Technology Agency (JST),
Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Fax +81(3)56840634; E-mail: shu_kobayashi@chem.s.u-tokyo.ac.jp
Received 14 July 2008
PSP
No131
Abstract: Sulfonylimidates react with various types of N-protected imines in the presence of a catalytic amount of DBU to afford
b-aminosulfonylimidates in high yields and high anti-selectivities. The experimental procedure is described in detail.
Key words: addition reaction, imine, catalysis, sulfonylimidate, direct reaction
R5
R5
O2S
R2
O2S
NH
R2
R1
N
DBU (5 mol%)
N
N
+
R1
1 (1.5 equiv)
R4
DMF, 0 °C, 24 h
OR3
OR3
2 (1.0 equiv)
R4
3
Scheme 1 Direct Mannich-type reaction of sulfonylimidate
Ar
Ar
The abstraction of an a-proton from a carbonyl compound
and the subsequent nucleophilic addition reaction of the
formed enolate is a fundamental sequence of transforma-
tion in synthetic organic chemistry. Among the carbonyl
compounds, the use of esters or substrates at the oxidation
level of an ester (e.g., thioester or amide) as nucleophiles
is particularly important as the products can be readily
transformed to other functionalities after the addition re-
actions. In general, a stoichiometric amount of base is
necessary in the deprotonation step; however, for the pur-
pose of practical synthesis, an ideal scenario would be to
use only a catalytic amount of base for enolate formation.
Several groups have reported successful catalytic systems
for the a-functionalization of ester oxidation level carbo-
nyl compounds.1
H2SO4
Red-Al
O
O2S
NH
O2S
N
THF, –70 °C, 18 h
i-PrOH–H2O
100 °C, 3 h
R
H
R
O
R
OR'
DBU
DMF–H2O
r.t., 33 h
O
R
OR'
Scheme 2 Transformation of sulfonylimidate to other functional
groups
Sulfonylimidates could be synthesized in two steps from
the corresponding alcohol and nitrile (Scheme 3).3 The
first step was bubbling of HCl gas into a mixture of alco-
hol and nitrile for 10–20 minutes. Although the reaction
was exothermic, it was not explosive even on a one mole
scale. Cooling to 0 °C should be safer, but retarded the re-
action significantly. Evaporation of the solvents,4 fol-
lowed by recrystallization provided a white, hygroscopic
imidate HCl salt in moderate yield. The relatively low
yield could be ascribed to the loss of volatile starting ma-
terials during the exothermic reaction. Sulfonylation was
carried out according to the standard procedure. To a sus-
Recently sulfonylimidates have been reported to function
as an ester oxidation level nucleophile.2 For example, in
the presence of a catalytic amount of DBU (1,8-diazabicy-
clo[5.4.0]undec-7-ene), N-protected imines react with
sulfonylimidates to afford b-aminosulfonylimidates,
which could be further transformed to the corresponding
N-sulfonylamides, aldehydes, and esters in one step
(Scheme 2). In contrast to preactivated carbonyl nucleo-
philes such as metalated enolates, sulfonylimidates are
stable in air and easy to handle. In view of its practical
usefulness and novelty as a nucleophile, we report herein
the detailed reaction protocol of sulfonylimidate synthesis
as well as the subsequent nucleophilic addition reactions.
R5
R5SO2Cl
R3OH
+
R4CH2CN
O2S
NH⋅HCl
HCl (g)
N
R4
R4
OR3
CH2Cl2, Et3N, DMAP
OR3
SYNTHESIS 2008, No. 18, pp 3009–3011
x
x.
x
x
.
2
0
0
8
Advanced online publication: 04.09.2008
DOI: 10.1055/s-2008-1067251; Art ID: Z16308SS
Scheme 3 Preparation of sulfonylimidates
© Georg Thieme Verlag Stuttgart · New York

3010
R. Matsubara, S. Kobayashi
PRACTICAL SYNTHETIC PROCEDURES
pension of the imidate HCl salt in CH2Cl2 were added the crude sulfonylimidate without column chromatogra-
Et3N, a sulfonyl chloride, and a catalytic amount of phy is also possible.
DMAP, successively. The reactions were generally com-
The scope of the direct-type Mannich reactions of sulfo-
plete within 24 hours. Purification by chromatography on
nylimidates was proved to be broad (Scheme 1, Table 1).
silica gel provided the desired sulfonylimidate in high
Aromatic imines as well as aliphatic imines5 gave the
yield. Most of the sulfonylimidates used in this report
products in high yields, and the selectivities were general-
were solid at room temperature, further purification was
ly high. The addition of molecular sieves suppressed the
possible by recrystallization. Direct recrystallization of
Table 1 DBU-Catalyzed Mannich-Type Reaction of Various Imines and Sulfonylimidates
R5
R5
O2S
R2
O2S
NH
R2
R1
N
DBU (5 mol%)
N
N
+
R1
R4
DMF, 0 °C, 24 h
OR3
OR3
1 (1.5 equiv)
2 (1.0 equiv)
R4
3
Entry
1
R1
R2
R3
R4
R5
Yield (%)
95
anti/syna
96:4
3
Ph
Ph
Ph
Ph
Boc
Boc
i-Pr
i-Pr
Me
Et
2,5-xylyl
2,5-xylyl
Ph
3a
3b
3c
3d
3e
3f
2
94
97:3
3b,c,d
4c
EtO2C
Ts
Et
H
79
–
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
Me
i-Pr
Me
i-Pr
Me
i-Pr
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
2,5-xylyl
2,5-xylyl
2,5-xylyl
2,5-xylyl
2,5-xylyl
2,5-xylyl
2,5-xylyl
2,5-xylyl
2,5-xylyl
2,5-xylyl
2,5-xylyl
2,5-xylyl
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
2,5-xylyl
91
96:4
5e
4-MeOC6H4
4-FC6H4
3-MeC6H4
2-MeC6H4
3-vinylC6H4
2-furyl
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Ts
91
95:5
6
87
97:3
7
quant
64
97:3
3g
3h
3i
8e
93:7
9
97
97:3
10
92
95:5
3j
11
2-thienyl
2-pyridyl
PhCH=CH
cyclopropyl
cyclopropyl
c-C6H11
90
98:2
3k
3l
12
91
98:2
13c
14c
15c,d
16c,d,g
17c,d,g
18c,d,g
19c,d,g
20c,h
21c,d
80
98:2
3m
3n
3o
3p
3q
3r
3s
3t
Ts
84
87:13
88:12
83:17
84:16
69:31
87:13
14:86
55:45i
Bocf
Tsf
quant
51
c-C6H11
Tsf
59
i-Pr
Tsf
56
i-Pr
Tsf
54
t-Bu
Ts
51
EtO2C
4-MeOC6H4
80
3u
a Determined by 1H NMR spectroscopy of the crude product or isolated product.
b Compound 2 (5 equiv) and 1 (1 equiv) were used.
c MS 4A (167 g/mol) were added.
d Amount of DBU used: 10 mol%.
e Time: 38 h.
f Amount of 1 used: 3 equiv.
g Room temperature.
h Conditions: 40 °C, 36 h.
i Major/minor.
Synthesis 2008, No. 18, 3009–3011 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Synthesis of b-Aminosulfonylimidates
3011
h and then diluted with Et2O (100 mL). The mixture was filtered
over Celite; the filtrate was washed with H2O (3 × 40 mL) and dried
(Na2SO4). Filtration and removal of solvents afforded the crude
product. The diastereomer ratio was determined to be anti/
hydrolysis of sulfonylimidates (sulfonylimidates are rela-
tively labile under basic conditions) and effectively im-
proved the yield.
1
In conclusion, we have developed a catalytic direct-type,
Mannich-type reactions of sulfonylimidates, which al-
lows straightforward access to b-aminosulfonylimidates
in high yields.
syn = 96:4 by H NMR analysis of the crude product. Purification
of the crude product was conducted by chromatography on silica gel
(hexane–acetone, 10:1) to afford the desired product 3a; yield: 4.86
g (99%); mp 122–123 °C.
IR (neat): 3060, 3032, 2841, 2936, 2881, 1715, 1588, 1513, 1495,
1456, 1389, 1365, 1299, 1267, 1248, 1225, 1155, 1102, 1066, 1053,
1004, 973, 930, 910, 884, 851, 824, 738, 707, 644, 599, 553, 499,
465 cm–1.
1H NMR (CDCl3): d = 8.19 (s, 1 H), 7.36 (d, J = 6.8 Hz, 2 H), 6.93–
7.05 (m, 4 H), 6.89 (d, J = 7.3 Hz, 1 H), 6.62 (d, J = 9.6 Hz, 1 H),
5.03 (t, J = 10.5 Hz, 1 H), 4.87 (quint, J = 6.2 Hz, 1 H), 4.48 (sext,
J = 5.9 Hz, 1 H), 2.86 (s, 3 H), 1.96 (s, 3 H), 1.34 (s, 9 H), 1.15 (d,
J = 5.7 Hz, 3 H), 0.98 (d, J = 6.2 Hz, 3 H), 0.91 (d, J = 6.2 Hz, 3 H).
1
Melting points are uncorrected. H and 13C NMR spectra were re-
corded on JEOL JNM-ECX-400, JNM-ECX-500 and JNM-ECX-
600 spectrometers in CDCl3 unless otherwise noted. Tetramethylsi-
1
lane (TMS) served as internal standard (d = 0) for H NMR, and
CDCl3 (d = 77.0) was used as internal standard for 13C NMR. IR
spectra were measured on a JASCO FT/IR-610 spectrometer. Col-
umn chromatography was conducted on Silica gel 60 (Merck) and
preparative thin-layer chromatography was carried out using Wako-
gel B-5F. All reactions were carried out under an argon atmosphere
in dried glassware. All solvents were dried and distilled by standard
procedures.
13C NMR (CDCl3): d = 177.5, 154.7, 141.4, 140.5, 136.1, 134.5,
133.4, 132.4, 128.9, 128.3, 127.9, 127.7, 78.6, 72.1, 58.9, 46.0,
28.4, 21.0, 21.0, 20.6, 20.6, 14.9.
HRMS (ESI): m/z calcd for C26H37N2O5S [M + H]+: 489.2423;
Isopropyl Propionimidate HCl Salt; Typical Procedure
HCl gas was bubbled to a mixture of propionitrile (75.65 g, 1.373
mol) and i-PrOH (77.11 g, 1.28 mol) for 10 min (exothermic), after
which the mixture was kept for 2 h under argon. Removal of all the
volatiles by evaporation gave the almost pure imidate HCl salt. Fur-
ther purification was possible by washing the solid with anhyd Et2O
(200 mL); yield: 78.2 g (41%). Imidate HCl salts are hygroscopic,
but can be kept under inert gas atmosphere in the refrigerator
(–20 °C) for at least one year.
found: 489.2417.
Acknowledgment
This work was partially supported by a Grant-in-Aid for Scientific
Research from Japan Society of the Promotion of Sciences (JSPS).
References
Isopropyl N-(2,5-Xylylsulfonyl)propionimidate (2a); Typical
Procedure
(1) (a) Harada, S.; Handa, S.; Matsunaga, S.; Shibasaki, M.
Angew. Chem. Int. Ed. 2005, 44, 4439. (b) Morimoto, H.;
Wiedeman, S. H.; Yamaguchi, A.; Harada, S.; Chien, Z.;
Matsunaga, S.; Shibasaki, M. Angew. Chem. Int. Ed. 2006,
45, 3146. (c) Marigo, M.; Kjarsgaard, K.; Juhl, K.;
Gathergood, N.; Jørgensen, K. A. Chem. Eur. J. 2003, 9,
2359. (d) Hamashima, Y.; Sasamoto, N.; Hotta, D.; Somei,
H.; Umebayashi, N.; Sodeoka, M. Angew. Chem. Int. Ed.
2005, 44, 1549. (e) Bernardi, L.; Gothelf, A. S.; Hazell, R.
G.; Jørgensen, K. A. J. Org. Chem. 2003, 68, 2583. (f) Ooi,
T.; Kameda, M.; Fujii, J. I.; Maruoka, K. Org. Lett. 2004, 6,
2397. (g) Kobayashi, J.; Yamashita, Y.; Kobayashi, S.
Chem. Lett. 2005, 34, 268. (h) Salter, M. M.; Kobayashi, J.;
Shimizu, Y.; Kobayashi, S. Org. Lett. 2006, 8, 3533.
(2) Matsubara, R.; Berthiol, F.; Kobayashi, S. J. Am. Chem. Soc.
2008, 130, 1804.
(3) (a) Kupfer, R.; Nagel, M.; Würthwein, E.-U.; Allmann, R.
Chem. Ber. 1985, 118, 3089. (b) Walter, W.; Krohn, J.
Liebigs Ann. Chem. 1973, 443. (c) Yoo, E. J.; Bae, I.; Cho,
S. H.; Han, H.; Chang, S. Org. Lett. 2006, 8, 1347; and
references cited therein.
(4) Thorough evaporation of the solvents provided the imidate
HCl salt (a solid). The solidification of imidate salt could be
encouraged by keeping it under argon at –20 °C. The
exposure to air should be avoided as this salt readily absorbs
moisture to form a gum-like solid, from which it was found
to be difficult to remove the starting materials.
Et3N (13.8 mL, 98.22 mmol) was added dropwise to a solution of
isopropyl propionimidate HCl salt (5 g, 32.74 mmol) in CH2Cl2 (78
mL) at r.t. DMAP (402.9 mg, 3.27 mmol) and 2,5-xylylsufonyl
chloride (6.7 g, 32.74 mmol) were added to the resultant suspen-
sion. The mixture was stirred until complete consumption of 2,5-xy-
lylsulfonyl chloride (24 h). The mixture was poured into aq
NaHCO3 (100 mL) and extracted with CH2Cl2 (3 × 20 mL). The or-
ganics were dried (Na2SO4). Filtration and evaporation of the sol-
vent afforded the crude product, which was purified by column
chromatography on silica gel to give the title compound; yield: 8.41
g (91%); mp 32–33 °C.
IR (neat): 3055, 2988, 1590, 1458, 1308, 1265, 1154, 1092, 1066,
896, 740, 705, 642, 459, 413 cm–1.
1H NMR (CDCl3): d = 8.20 (s, 1 H), 6.90 (d, J = 7.4 Hz, 1 H), 6.84
(dd, J = 7.4, 1.4 Hz, 1 H), 4.74 (sept, J = 6.3 Hz, 1 H), 2.91 (q, J =
7.4 Hz, 2 H), 2.77 (s, 3 H), 1.94 (s, 3 H), 1.07 (t, J = 7.4 Hz, 3 H),
0.83 (d, J = 6.3 Hz, 6 H).
13C NMR (CDCl3): d =176.2, 141.2, 135.9, 134.4, 133.0, 132.2,
128.9, 71.2, 28.4, 21.1, 20.6, 20.2, 10.4.
HRMS (ESI): m/z calcd for C14H22NO3S [M + H]+: 284.1320;
found: 284.1323.
Isopropyl anti-3-(tert-Butoxycarbonylamino)-2-methyl-3-phe-
nyl-N-(2,5- xylylsulfonyl)propionimidate (anti-3a); Typical
Procedure (Table 1, Entry 1)
DMF (18.5 mL), MS 4A (1.67 g), and isopropyl N-(2,5-xylylsulfo-
nyl)propionimidate (2a; 2.844 g, 10.0 mmol) were added succes-
sively in this order to a solution of tert-butyl benzylidenecarbamate
(benzaldehyde-derived N-Boc-imine, 3.09 g, 15.1 mmol). The mix-
ture was cooled to 0 °C and a solution of DBU (76.4 mg, 0.50
mmol) in DMF (1.5 mL) was added. The mixture was stirred for 24
(5) (a) Kanazawa, A. M.; Denis, J.-N.; Greene, A. E. J. Am.
Chem. Soc. 1994, 59, 1238. (b) Vishwakarma, L. C.;
Stringer, O. D.; Davis, F. A. Org. Synth. 1987, 66, 203.
(c) Love, B. E.; Raje, P. S.; Williams, T. C. II Synlett 1994,
493. (d) Hodous, B. L.; Fu, G. C. J. Am. Chem. Soc. 2002,
124, 1578. (e) Hagiwara, E.; Fujii, A.; Sodeoka, M. J. Am.
Chem. Soc. 1998, 120, 2474.
Synthesis 2008, No. 18, 3009–3011 © Thieme Stuttgart · New York