Three-component reactions of sulfonylimidates, silyl glyoxylates and N - Tert -butanesulfinyl aldimines: An efficient, diastereoselective, and enantioselective synthesis of cyclic N -sulfonylamidines

Article abstract of DOI:10.1021/ol201029b

Three-component coupling reactions of sulfonylimidates, silyl glyoxylates and N-tert-butanesulfinyl aldimines efficiently provide cyclic N-sulfonylamidines containing free endocyclic N-H. The formation of two C-C bonds (contiguous stereogenic carbons), on

Full text of DOI:10.1021/ol201029b

ORGANIC
LETTERS
2011
Vol. 13, No. 10
2782–2785
Three-Component Reactions of
Sulfonylimidates, Silyl Glyoxylates and
N-tert-Butanesulfinyl Aldimines: An
Efficient, Diastereoselective, and
Enantioselective Synthesis of Cyclic
N-Sulfonylamidines
Ming Yao and Chong-Dao Lu*
Xinjiang Technical Institute of Physics & Chemistry, Chinese Academy of Sciences,
Urumqi 830011, China and Graduate University of the Chinese Academy of Sciences
clu@ms.xjb.ac.cn
Received April 18, 2011
ABSTRACT
Three-component coupling reactions of sulfonylimidates, silyl glyoxylates and N-tert-butanesulfinyl aldimines efficiently provide cyclic
N-sulfonylamidines containing free endocyclic NÀH. The formation of two CÀC bonds (contiguous stereogenic carbons), one OÀSi bond,
and one CÀN bond, together with the cleavage of the chiral auxiliary (tert-butanesulfinyl group), occurs with excellent chemoselectivity,
diastereoselectivity, and enantioselectivity in this one-pot cascade transformation.
Amidines have been identified as an important class of
compounds with applications in medicinal chemistry,1
coordination chemistry,2 and supramolecular chemistry3
due to their structural characteristics. Traditional proto-
cols for the synthesis of the amidines rely on transforming
the functional groups of amides, nitriles, aldoximes, and
amines, among others.4 In addition, several methods
involving convergent direct couplings of sulfonyl azides,5
isocyanides,6 or carbodiimides7 with the suitable coupling
partnershavebeendevelopedinrecent years, allowing easy
access to several types of amidines. However, the applic-
ability of these methods is restricted by intrinsic limitations
in the reaction scope and generality.8 Meeting the demand
for the efficient construction of the structurally diverse
group of amidines necessitates further synthetic explora-
tions toward efficient methods for their synthesis.
(1) (a) Boyd, G. V. In The Chemistry of Amidines and Imidates; Patai,
S., Rappoport, Z., Eds.; Wiley: New York, 1991; Vol. 2, Chapter 8. (b)
Greenhill, J. V.; Lue, P. Prog. Med. Chem. 1993, 30, 203.
(2) Barker, J.; Kilner, M. Coord. Chem. Rev. 1994, 133, 219.
(3) Katagiri, H.; Tanaka, Y.; Furusho, Y.; Yashima, E. Angew.
Chem., Int. Ed. 2007, 46, 2435 and references therein.
(4) (a) King, C. J. Org. Chem. 1960, 25, 352. (b) Heck, M.-P.; Vincent,
S.-P.; Murray, B. W.; Bellamy, F.; Wong, C.-H.; Mioskowski, C. J. Am.
Chem. Soc. 2004, 126, 1971. (c) Kumagai, N.; Matsunaga, S.; Shibasaki,
M. Angew. Chem., Int. Ed. 2004, 43, 478. (d) Nazarenko, K. G.;
Shirokaya, T. I.; Tolmachev, A. A. Chem. Heterocycl. Compd. 2005,
41, 195. (e) Takuwa, T.; Minowa, T.; Onishi, J. Y.; Mukaiyama, T. Bull.
Chem. Soc. Jpn. 2004, 77, 1717. (f) Lange, U. E. W.; Schafer, B.; Baucke,
D.; Buschmann, E.; Mack, H. Tetrahedron Lett. 1999, 40, 7067. (g)
Wang, J.; He, Z.; Chen, X.; Song, W.; Lu, P.; Wang, Y. Tetrahedron
2010, 66, 1208 and references therein.
(6) Saluste, C. G.; Whitby, R. J.; Furber, M. Angew. Chem., Int. Ed.
2004, 43, 478.
(7) Yu, R. T.; Rovis, T. J. Am. Chem. Soc. 2008, 130, 1833.
(8) For example, only cyclic N-sulfonylamidines with a protected
nitrogen at the N-amino position can be accessed by the direct-coupling
methods in refs 5b and 5e. The analogues provided in refs 6 and 7 are
N-alkyl amidines.
(5) (a) Bae, I.; Han, H.; Chang, S. J. Am. Chem. Soc. 2005, 127, 2038.
(b) Chang, S.; Lee, M.; Jung, D. Y.; Yoo, E. J.; Han, S. K. J. Am. Chem.
Soc. 2006, 128, 12366. (c) Yoo, E. J.; Chang, S. Curr. Org. Chem. 2009,
13, 1766. (d) Xu, X.; Li, X.; Ma, L.; Ye, N.; Weng, B. J. Am. Chem. Soc.
2008, 130, 14048. (e) Xu, X.; Ge, Z.; Cheng, D.; Ma, L.; Lu, C.; Zhang,
Q.; Yao, N.; Li, X. Org. Lett. 2010, 12, 897. (f) Wang, S.; Wang, Z.;
Zheng, X. Chem. Commun. 2009, 7372.
r
10.1021/ol201029b
Published on Web 04/26/2011
2011 American Chemical Society

Herein, we report a three-component coupling reaction of
sulfonylimidates, silyl glyoxylates9 and N-tert-butanesulfinyl
aldimines for an efficient, convergent, asymmetric synthesis
of substituted cyclic N-sulfonylamidines possessing free
NÀH at the cyclic nitrogen atom (Scheme 1). In this reaction,
the nucleophilic addition of lithium aza-enolates Li-1 to silyl
glyoxylates 2 triggers a Brook rearrangement,10 and the
generated enolates 5 undergo addition to (RS)-N-tert-buta-
nesulfinyl aldimines 3, in which the Ellman imines11 partici-
pate as the second electrophile. The anionic nitrogen-induced
cyclization and subsequent desulfinylation by nucleophilic
attack by the extruding ethoxide give enantioenriched cyclic
N-sulfonylamidines 4. To the best of our knowledge, this is
the first report that explores the use of lithium aza-enolates as
nucleophiles to initiate a Brook rearrangement and the first
report that azomethines serve as the second electrophile in
silyl glyoxylate-mediated cascades.12
2a. The reaction mixture was stirred at À78 °C for 5 h and
warmedgraduallytoÀ5 °C. The three-component product
4a was obtained in 82% isolated yield with excellent
diastereoselectivity and enantioselectivity (Table 1, entry 1).
Table 1. Scope of Cyclic Sulfonyl Amidines 4aÀ4qa
entry 1, 2
imine 3 (R2)
4
yield [%]b
ee [%]c
1f
1a, 2a 3a (Ph)
1a, 2a 3b (4-ClC6H4)
4a
4b
4c
4d
4e
4f
82 (76)d 98 (À99)d
2f
72
72
80
85
89
82
91
69
86
95
94
98
99
97
99
99
97
98
3f
1a, 2a 3c (4-BrC6H4))
1a, 2a 3d (4-MeC6H4)
1a, 2a 3e (4-MeOC6H4)
1a, 2a 3f (3-MeOC6H4
1a, 2a 3g (2-MeOC6H4)
1a, 2a 3h (piperonyl)
1a, 2a 3i (1-naphthyl)
1a, 2a 3j (2-furyl)
4f
5g
Scheme 1. Silyl Glyoxylates-Mediated Cascade Reaction for the
Synthesis of Chiral Cyclic N-Sulfonylamidines
6g
7g
4g
4h
4i
8g
9f
10g
11g
12g
13g
4j
h
1a, 2a 3k (2-thienyl)
1a, 2a 3l (Et)
4k
4l
90 (83)h 99.3 (99)
80
70
76
59
82
86
98
96
99
99
99
99
1a, 2a 3m (PhCH2CH2)
4m
14e,g 1a, 2a 3n (trans-PhCHdCH) 4n
15g
16g
17g
1a, 2b 3k (2-thienyl)
1b, 2a 3k (2-thienyl)
1c, 2a 3k (2-thienyl)
4o
4p
4q
a Imine 3 and silyl glyoxylate 2 were added sequentially to a 0.1 M
enolate solution in THF at À78 °C (see the Supporting Information for
the detailed procedures). The diastereoselectivity (dr) was determined
from 1H NMR spectra of crude reaction mixtures. b Isolated yields
after silica gel chromatography. c Determined by HPLC with a Chiralcel
OD-H column. d Using (SS)-3a as a substrate in place of (RS)-3a.
e Amidines of tert-butanesulfinyl-4n and 4n were obtained in 63 and
13% yields, respectively. f Substrate ratio: sulfonylimidate 1 (2.5 equiv),
silylglyoxylate 2 (2.5 equiv), imine 3 (1.0 equiv). g Substrate ratio:
sulfonylimidate 1 (2.0 equiv), silylglyoxylate 2 (2.0 equiv), imine 3
(1.0 equiv). h One-gram scale reaction.
We beganourinvestigation withthe couplingreaction of
1a (Ar = 4-MeC6H4), 2a (R1 = tBu), and 3a (R2 = Ph) in
the presence of several readily available metal amides.13
After some pilot studies, the optimized reaction conditions
were found to be the metalation of sulfonylimidate 1a with
LHMDS at À78 °C, followed by the sequential addition of
(RS)-tert-butanesulfinyl aldimine 3a and silyl glyoxylate
This high yield suggested that the lithium enamide of
sulfonylimidate 1a reacts as a discriminating nucleophile
with a strong preference for the silylglyoxylate 2a over
N-tert-butanesulfinyl aldimine 3a (Scheme 2). To verify
this, several control experiments were conducted. The
aldimine 3a was added to the solution of the lithium
enamide of sulfonylimidate 1a at À78 °C, and no product
was observed. Even when the reaction mixture was warmed
to room temperature, only the starting materials were
recovered (eq 2). Furthermore, when N-Ts phenyl aldimine
6 was used instead of the sulfinyl aldimine 3a as an elec-
trophile under the standard three-component coupling
conditions, the major product appeared to be the two-
component adduct 7 derived from the sulfonylimidate
1a and the N-Ts imine 6 (eq 3).14 Studies of the nucleophilic
(9) The synthetic applications of silyl glyoxylates are growing in
prominence. For related examples see: (a) Nicewicz, D. A.; Johnson,
J. S. J. Am. Chem. Soc. 2005, 127, 6170. (b) Nicewicz, D. A.; Satterfield,
A. D.; Schmitt, D. S.; Johnson, J. S. J. Am. Chem. Soc. 2008, 130, 17281.
(c) Greszler, S. N.; Johnson, J. S. Org. Lett. 2009, 11, 827. (d) Greszler,
S. N.; Johnson, J. S. Angew. Chem., Int. Ed. 2009, 48, 3689. (e) Greszler,
S. N.; Malinowski, J. T.; Johnson, J. S. J. Am. Chem. Soc. 2010, 132,
17393. (f) Boyce, G. R.; Johnson, J. S. Angew. Chem., Int. Ed. 2010, 49,
8930. (g) Schmitt, D. C.; Johnson, J. S. Org. Lett. 2010, 12, 944.
(10) (a) Brook, A. G. Acc. Chem. Res. 1974, 7, 77. (b) Bulman Page,
P. C.; Klair, S. S.; Rosenthal, S. Chem. Soc. Rev. 1990, 19, 147. (c) Moser,
W. H. Tetrahedron 2001, 57, 2065.
(11) For reviews of tert-butanesulfinamide: (a) Ferreira, F.; Botuha,
C.; Chemla, F.; Perez-Luna, A. Chem. Soc. Rev. 2009, 38, 1162. (b)
Robak, M. T.; Herbage, M. A.; Ellman, J. A. Chem. Rev. 2010, 110,
3600.
(12) For examples of aryl acylsilanes acting as conjunctive reagents
for the union of lithium amide enolates and N-diphenylphosphinyl
imines, see: (a) Lettan, R. B.; Woodward, C. C.; Scheidt, K. A. Angew.
Chem., Int. Ed. 2008, 47, 2294. (b) Lettan, R. B.; Galliford, C. V.;
Woodward, C. C.; Scheidt, K. A. J. Am. Chem. Soc. 2010, 132, 8805. It is
noteworthy that the aryl acylsilanes failed to enable the three-compo-
nent coupling reaction described here; see ref 17.
(13) See the Supporting Information for details.
Org. Lett., Vol. 13, No. 10, 2011
2783

tert-butanesulfinyl-4n. The latter compound was the pro-
duct without cleavage of the sulfinyl auxiliary. Warming
the reaction mixture to À5 °C resulted in an intractable
mixture of products. Notably, the enantioselectivity for 4k
(99.3% ee, entry 11) is consistent with the enantiopurity of
(RS)-tert-butanesulfinamide (99.3% ee) used to prepare
imine 3k.16 This implies that a complete chirality transfer
from the chiral auxiliary occurred in this example. One-
gram scale preparation of 3k gave comparable ee and a
slightly lower yield compared to a small scale process
because the desulfinylation in the larger scale reaction is
slower, and prolonging the reaction time led to partial
decomposition (entry 11). The cyclic arylsulfonyl amidines
incorporating a benzyl ester or other arylsulfonyl groups
(Ar = Ph, PMP) can be prepared using the corresponding
starting materials (Table 1, entries 15À17). Aryl acylsilanes
such as PhCOTBS (10) did not function as useful reagents to
enable the three-component coupling reaction because the
intramolecular electrophilic trapping is more efficient.17
Scheme 2. Control Experiments
behaviors of lithium ester enolates (Li-8a and Li-8b) toward
the mixture of 2a and 3a indicated that the predominant
reaction pathway is addition to sulfinylimine 3a, rather than
the addition to the silylglyoxylate 2a (eq 4). These results
reveal that the three-component reaction described here
exhibits unusual and exquisite chemoselectivity.
The scope and limitations of this method were investigated,
and are summarized in Table 1. The reactions provided the
desired products in good isolated yields (59À91%) with
excellent diastereoselectivity (>20:1 dr) and enantioselectiv-
ity (94À99.3% ee). The enantiomer of the cyclic sulfonyla-
midine 4a could be obtained by employing (SS)-tert-
butanesulfinyl phenyl aldimines (entry 1). The crystalline
compound of the (R)-mandelic acid derivative from 4j was
prepared, which allowed us to determine the absolute stereo-
chemistry of the newly formed contiguous stereogenic car-
bons by single-crystal X-ray diffraction.15
The aryl aldimines bearing electron-donating groups
were more reactive than those bearing electron-withdraw-
ing groups. Higher yields were obtained, and an excess of
more than 2.0 equiv of the sulfonylimidates and silylglyox-
ylates was unnecessary: yields of 80À91% were obtained
with 2.0 equiv, compared to the 72% with 2.5 equiv
(Table 1, entrie 4À8, 10, and 11 vs entries 2À3). Good
yields and excellent enantioselectivities were achieved
using the following compounds: phenyl aldimines with a
methoxy substituent in the ortho, meta, and para positions;
heteroaromatic aldimines; and unbranched aliphatic aldi-
mines (Table 1, entries 5À7, 10À13). Unfortunately, sulfi-
nylimine derived from bulky pivaldehyde was inert. When
the R,β-unsaturated aldimine 3n was used in the reaction
(Table 1, entry 14), two products were observed: the NÀH
sulfonylamidine 4n and the N-sulfinyl sulfonylamidine
Scheme 3. Rationale of Stereochemistry
To rationalize the stereochemistry of this transforma-
tion, a transition state TS-1 was proposed (Scheme 3)
according to Ellman’s six/four-membered bicyclic transi-
tion state with a preferred chair conformation.18 It has
been well established by Johnson and co-workers that
(Z)-glycolate enolates were preferentially formed over
(E)-isomer in the lithium enolate-initiated Brook rearran-
gements of silyl glyoxylates.9g The intermediate glycolate
enolates (Z)-5 approach the imines (E)-(Rs)-3 from the
(16) The enantioselectivity of tert-butanesulfinamide was determined
by HPLC with a Chiralcel OD column. See the Supporting Information
for details.
(17) The cyclopropane derivative 12 was predominantly formed with
excellent diastereoselectivity by intramolecular nucleophilic trapping of
the R-silyloxy carbanion 11 (intermediate of Brook rearrangement). The
stereochemistry of the product 12 was determined from 2D ROESY
spectrum. For details, see the Supporting Information. For similar
reaction behavior in the addition of lithium ketone enolates to acylsi-
lanes, see: Takeda, K.; Nakatani, J.; Nakamura, H.; Sako, K.; Yoshii,
E.; Yamaguchi, K. Synlett 1993, 841.
(14) For studies on the addition of sulfonylimidates to N-Ts imines in
the presence of catalytic amounts of base or alkaline earth metal
complexes, see: (a) Matsubara, R.; Berthiol, F.; Kobayashi, S. J. Am.
Chem. Soc. 2008, 130, 1804. (b) Nguyen, H. V.; Matsubara, R.;
Kobayashi, S. Angew. Chem., Int. Ed. 2009, 48, 5927. (c) Matsubara,
R.; Nguyen, H. V.; Kobayashi, S. Bull. Chem. Soc. Jpn. 2009, 82, 1083.
(15) The absolute stereochemistry of the product 4j was determined
by X-ray crystallography of the (R)-mandelic acid derivative of the
enantiopure 4j, with 4aÀ4i and 4kÀ4q assigned by analogy. Single
crystal structure of racemic 4q were also provided to determine the
relative configuration. See the Supporting Information for details.
(18) For the addition of lithium (or titanium) ester enolates to
sulfinylimines rationalized by a six/four-membered bicyclic transition
state, see: (a) Davis, F. A.; Reddy, R. T.; Reddy, R. E. J. Org. Chem.
1992, 57, 6387. (b) Tang, T. P.; Ellman, J. A. J. Org. Chem. 2002, 67,
7819.
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Org. Lett., Vol. 13, No. 10, 2011

opposite direction of the sterically hindered tert-butyl
group (the Si face of imines 3). Nucleophilic attack by
the Re face of the lithium enolates 5 is facilitated and
favored by the complexation of the lithium and gives the
products with the observed stereochemistry.
In summary, we have devoloped a Brook rearrange-
ment-mediated, three-component coupling reaction of
sulfonylimidates, silyl glyoxylates and N-tert-butanesulfi-
nyl aldimines for efficient asymmetric synthesis of substi-
tuted cyclic sulfonyl amidines. The cascade promotes the
formation of two CÀC bonds (contiguous stereogenic
carbons), one CÀN bond, and one OÀSi bond, together
with cleavage of the chiral auxiliary (tert-butanesulfinyl
group) in a one-pot operation. The reaction occurs with
exquisite chemoselectivity, excellent diastereoselectivity,
and excellent enantioselective induction.
Acknowledgment. This work was partially sup-
ported by the Chinese Academy of Sciences, the
National Natural Science Foundation of China
(20972182), and the “Western Light” program of the
Chinese Academy of Sciences. We are indebted to
Prof. Armen Zakarian at UCSB (U.S.A.) for helpful
comments. We thank Prof. Liu-Zhu Gong’s research
group at USTC (China) for their help in establishing
the conditions for HPLC resolution of the racemic
compound 4a.
Supporting Information Available. Experimental de-
tails, characterization data, and crystal structure data of
the racemic 4q and the (R)-mandelic acid derivative of the
enantiopure 4j. This material is available free of charge
via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 10, 2011
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