Asymmetric michael addition of N-tert-butanesulfinyl imidate with α,β-unsaturated diesters: Scope and application to the synthesis of indanone derivatives

Article abstract of DOI:10.1021/ol400277h

An additive-free and highly diastereoselective Michael addition reaction of an N-tert-butanesulfinyl imidate to α,β-unsaturated diesters has been developed using LDA as a base with good to excellent yields. The utility of this chemistry is further demonstrated by the asymmetric synthesis of 3-substituted indanone derivatives 8a, 8d, 8e, and 8i with high enantiomeric excess, which are potential building blocks for preparing biologically active lead compounds.

Full text of DOI:10.1021/ol400277h

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Asymmetric Michael Addition of
N-tert-Butanesulfinyl Imidate with
r,β-Unsaturated Diesters: Scope and
Application to the Synthesis of Indanone
Derivatives
Jinfang Wang, Yu Zhou,* Lei Zhang, Zeng Li, Xianjie Chen, and Hong Liu*
State Key Laboratory of Drug Research, CAS Key Laboratory of Receptor Research,
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi
Road, Shanghai 201203, P. R. China
zhouyu@mail.shcnc.ac.cn; hliu@mail.shcnc.ac.cn
Received January 30, 2013
ABSTRACT
An additive-free and highly diastereoselective Michael addition reaction of an N-tert-butanesulfinyl imidate to r,β-unsaturated diesters has been
developed using LDA as a base with good to excellent yields. The utility of this chemistry is further demonstrated by the asymmetric synthesis of
3-substituted indanone derivatives 8a, 8d, 8e, and 8i with high enantiomeric excess, which are potential building blocks for preparing biologically
active lead compounds.
The addition of metalloenamines to electrophiles is
one of the most important strategies in the preparation
of diverse amine-containing derivatives.1 Recently, the
highly diastereoselective addition of metalloenamines de-
rived from N-tert-butanesulfinyl imines to aldehydes,2,3
trifluoromethyl ketones,4 alkyl halides,5 and imines6 has
been developed for the asymmetric synthesis of 1,3-amino
alcohols, β-hydroxy-β-trifluoromethyl imines, R-alkyl im-
idates, and R-chloro-β-amino-N-sulfinylimidates, respec-
tively. However, the asymmetric addition of N-tert-
butanesulfinyl metalloenamines to other electrophiles,
especially Michael addition of the metalloenamines to
R,β-unsaturated ketones or esters, is still a challenging area
of organic chemistry.7 This is in part attributed to the
strong electron-withdrawing character of the sulfinyl
group, which attenuates the nucleophilicity of the metal-
loenamines, the low electrophilicity and the competitive
deprotonation7 of simple R,β-unsaturated ketones or
esters. In 2005, Ellman et al. reported the first Michael
conjugate addition of N-tert-butanesulfinyl metallo-
enamines to R,β-unsaturated ketones,7 LDA was used as
a base and only moderate yields were obtained. ZnBr2
was used as an additive to overcome the competitive
(1) (a) Mangelinckx, S.; Giubellina, N.; De Kimpe, N. Chem. Rev.
2004, 104, 2353. (b) Job, A.; Janeck, C. F.; Bettray, W.; Peters, R.;
Enders, D. Tetrahedron. 2002, 58, 2253. (c) Lanter, J. C.; Chen, H. F.;
Zhang, X. Q.; Sui, Z. H. Org. Lett. 2005, 7, 5905. (d) Colpaert, F.;
Mangelinckx, S.; De Kimpe, N. Org. Lett. 2010, 12, 1904. (e) Schenkel,
L. B.; Ellman, J. A. Org. Lett. 2004, 6, 3621. (f) Zhao, C. H.; Liu, L.;
Wang, D.; Chen, Y. J. Eur. J. Org. Chem. 2006, 13, 2977. (g) Dessole, G.;
Bernardi, L.; Bonini, B. F.; Capito, E.; Fochi, M.; Herrera, R. P.; Ricci,
A.; Cahiez, G. J. Org. Chem. 2004, 69, 8525.
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11276.
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(5) (a) Kochi, T.; Ellman, J. A. J. Am. Chem. Soc. 2004, 126, 15652.
(b) Colpaert, F.; Mangelinckx, S.; De Kimpe, N. J. Org. Chem. 2011, 76,
234. (c) Colpaert, F.; Mangelinckx, S.; Verniest, G.; De Kimpe, N.
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J. Org. Chem. 2011, 76, 2204.
(7) Peltier, H. M.; Ellman, J. A. J. Org. Chem. 2005, 70, 7342.
r
10.1021/ol400277h
XXXX American Chemical Society

deprotonation of the Michael acceptor and to give im-
proved yields and diastereoselectivities (Scheme 1, eq 1).
Therefore, we envisioned that more nucleophilic metallo-
enamines derived from N-sulfinyl imidates and more
electrophilic R,β-unsaturated diesters derived from diethyl
arylidenemalonates would more effectively facilitate the
Michael addition reaction (Scheme 1, eq 2).
2-(3-((R)-tert-butylsulfinylimino)-3-methoxy-1-arylpropyl)-
malonates. The application of this chemistry was further
demonstrated through the efficient synthesis of 3-substi-
tuted 1-indanone derivatives with high enantiomeric ex-
cess, which are potential building blocks of biologically
active lead compounds.
Table 1. Optimization of the Reaction Conditions of Synthesis
of 3aa
Scheme 1. Michael Additions to R,β-Unsaturated Compounds
entry
base (equiv)
time (h)
yield (%)
dr
1b
2c
3d
4
NaHMDS (1.5)
KHMDS (1.5)
LiHMDS (1.5)
LDA (1.5)
2
2
95
93
94
90
90
73
89
87
85
85
94
84
85:15
87:13
90:10
93:7
95:5
96:4
88:12
96:4
95:5
96:4
98:2
97:3
2
2
5
LDA (1.2)
2
6
LDA (1.0)
2
Successful Michael additions to R,β-unsaturated dies-
ters 2 would be of particular interest because the addition
products 3 could potentially be converted to chiral 3-sub-
stituted-1-indanones 8 by simple deprotection, decarbox-
ylation, and cyclization reactions (Scheme 4). Substituted
indanone rings are well-known privileged structures which
are widely distributed in natural products and biologically
synthetic compounds.8 They exhibit a wide spectrum of
biological activities, such as smooth muscle relaxant, anti-
cancer, anti-inflammatory activity, and acetylcholinesterase
(AChE) inhibition.9 Although some advances have been
achieved for the asymmetric synthesis of 3-substituted-1-
indanones, most of them suffered from the use of precious
metal catalysts and unreadily available ligands.10
In our ongoing efforts to develop efficient methods
to construct potential bioactive chiral heterocyclic
compounds,11 we herein describe an additive-free
and highly diastereoselective Michael addition reac-
tion of N-tert-butanesulfinyl imidate to diethyl aryl-
idenemalonates using LDA as a base to generate diethyl
7
LDA (1.8)
2
8
LDA (1.2)
5
9
LDA (1.2)
12
2
10e
11f
12g
LDA (1.2)
LDA (1.2)
2
LDA (1.2)
2
a Unless otherwise stated, all reactions were carried out using 1
(1.0 equiv, 0.2 mmol), 2a (1.5 equiv, 0.3 mmol), and 0.5 mol/L of LDA
as base at À78 °C in 5 mL of THF. b 1.0 mol/L of NaHMDS was used as
base. c 1.0 mol/L of KHMDS was used as base. d 1.0 mol/L of LiHMDS
was used as base. e 10 mL of THF was used as solvent. f 0.5 mol/L of LDA
was diluted to 0.25 mol/L. g 1.1 equiv of 2a was used.
N-tert-Butanesulfinyl imidate 1 and 2a were chosen as
model substrates for exploring the optimum reaction con-
ditions for the synthesis of optically pure diethyl 2-(3-((R)-
tert-butylsulfinylimino)-3-methoxy-1-arylpropyl)malonate
(3a) via asymmetric Michael addition (Table 1). First,
N-tert-butanesulfinyl imidate 1 was synthesized through
condensation of (R)-tert-butanesulfinamide with the cor-
responding ortho ester in the presence of a catalytic
amount of p-TsOH without solvent.5c Subsequently, the
Michael addition reaction of 1 and 2a was systematically
optimized by changing the reaction conditions (Table 1).
Commercially available NaHMDS was initially used as
the base, and full conversion of 1 was observed after 2 h
at À78 °C (95%) (Table 1, entry 1). However, the diaste-
reoselectivity (dr = 85:15) was not satisfactory. Replace-
ment of NaHMDS with KHMDS also resulted in a
disappointing diastereoselectivity (Table 1, entry 2). How-
ever, using LiHMDS as base gave an improved diastereo-
selectivity (dr = 90:10) (Table 1, entry 3). To further in-
crease the diastereoselectivity, 0.5 mol/L of LDA in THF
was freshly prepared. To our delight, the use of LDA
greatly improved the diastereoselectivity (Table 1, entries
4À12). When 1.5 equiv of LDA was used, 3a was obtained
(8) (a) Satake, T.; Murakami, T.; Yokote, N.; Saiki, Y.; Chen, C. M.
Chem. Pharm. Bull. 1985, 33, 4175. (b) Saito, M.; Umeda, M.; Enomoto,
M.; Hatanaka, Y.; Natori, S. Experientia 1975, 31, 829.
(9) (a) Sheridan, H.; Frankish, N.; Farrell, R. Eur. J. Med. Chem.
1999, 34, 953. (b) Nagle, D. G.; Zhou, Y. D.; Park, P. U.; Paul, V. J.;
Rajbhandari, I.; Duncan, C. J. G.; Pasco, D. S. J. Nat. Prod. 2000, 63,
1431. (c) Tumiatti, V.; Vincenza, A.; Banzi, R.; Bartolini, M.; Minarini,
A.; Rosini, M.; Melchiorre, C. J. Med. Chem. 2004, 47, 6490. (d)
Ssaravanan, V. S.; Selvan, P. S.; Gopal, N.; Gupat, J. K. Asian J. Chem.
2006, 18, 2597.
(10) (a) Shintani, R.; Takatsu, K.; Hayashi, T. Angew. Chem., Int. Ed.
2007, 46, 3735. (b) Shintani, R.; Yashio, K.; Nakamura, T.; Okamoto,
K.; Shimada, T.; Hayashi, T. J. Am. Chem. Soc. 2006, 128, 2772. (c) Arp,
F. O.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 10482. (d) Kundu, K.;
McCullagh, J. V.; Morehead, A. T., Jr. J. Am. Chem. Soc. 2005, 127,
16042. (e) Matsuda, T.; Shigeno, M.; Makino, M.; Murakami, M. Org.
Lett. 2006, 8, 3379.
(11) Chen, X. J.; Zhu, W.; Qian, W. K.; Feng, E. G.; Zhou, Y.; Wang,
J. F.; Jiang, H. L.; Yao, Z. J.; Liu, H. Adv. Synth. Catal. 2012, 354, 2151.
B
Org. Lett., Vol. XX, No. XX, XXXX

diastereoselectivity (dr = 98:2) and excellent yield (94%)
(Table1, entry 11). Besides, we screened the amount of
substrate 2a and excellent diastereoselectivity (dr = 97:3)
was obtained when 1.1 equiv of 2a was used but with mod-
erate yield (84%) (Table1, entry 12). Altogether, the opti-
mum result (dr = 98:2;94% yield) wasobtained by treating
N-tert-butanesulfinyl imidate 1 (0.2 mmol) in 5 mL of THF
with 1.2 equiv of LDA (0.25 mol/L) at À78 °C for 45 min
followed by reaction with 2a (0.3 mmol) for another 2 h.
Under the aforementioned optimized reaction condi-
tions, we examined the substrate scope of this Michael
reaction by various substituted diethyl 2-arylidenemalo-
nates (Scheme 2). A variety of novel diethyl 2-(3-((R)-tert-
butylsulfinylimino)-3-methoxy-1-arylpropyl)malonates
3bÀo were prepared with good to excellent reaction yields
(88%-95%) and excellent diastereoselectivities (dr = 97:3
to 98:2). A range of substituted diethyl arylidenemalonates
with electron-withdrawing or -donating groups were all
successfully transformed into the corresponding Michael
adducts, with high dr values and good to excellent yields
(3bÀl). These results indicated that the electronic property
of the substituents and the substituted-positions on
the benzene ring of diethyl arylidenemalonates have no
Scheme 2. Asymmetric Michael Addition of N-tert-Butanesul-
finyl Imidate with Diethyl Arylidenemalonatesa
Scheme 3. Determination of the Absolute Stereochemistry of 3a
significant influence on the yields and diastereoselectivities
of these Michael adducts. Some heterocyclic systems, such as
N-methylindole, furan, or thiofuran, were also introduced
to the Michael reaction acceptors (2mÀo),andhighyieldsand
excellent diastereoselectivities were also obtained (3mÀo). In
addition, when 2-cyclohexylmethylenemalonate was used as
the Michael acceptor, high yield (93%) and excellent
diastereoselectivity of 3p (dr >99:1) were obtained.
In order todetermine the absolute stereochemistry of the
Michael adducts, 2-phenylpropane-1,1,3-tricarboxylate 5a
was synthesized from 3a according to the literature proce-
dures (Scheme 3).5c First, compound 3a was treated with
saturated HCl in dioxane to afford the corresponding
imidate hydrochloride 4a, which was stirred in water at
room temperature for 24 h to generate the desired com-
pound 5a at high yield (85%). 2-Phenylpropane-1,1,3-
tricarboxylate 5a has been characterized by Jørgensen’s
group.12 Therefore, we compared optical rotation of 5a
([R]2D5 À31.3 (c 1.0, CHCl3)) to those published in the
literature (R-5a, [R]2D5 À29 (c 1.0, CHCl3)), and confirmed
that the absolute stereochemistry of compounds 3aÀp are
R-configuration.
a All reactions were carried out using 1 (1.0 equiv, 0.2 mmol), 2bÀp
(1.5 equiv, 0.3 mmol), and 0.25 mol/L of LDA as base at À78 °C in 5 mL
of THF for 2 h. The dr value was determined by LC/MS.
with good diastereoselectivity (dr = 93:7) and high yield
(90%) (Table 1, entry 4). Further studies demonstrated
that better diasteroselectivity could be obtained when 1.0
equiv of LDA was used, but the yield of 3a was decreased
dramatically (73%) (Table 1, entry 6), which indicated that
a small excessive base was necessary for the reaction to go
on smoothly. However, increasing the amount of LDA to
1.8 equiv led to decreased diastereoselectivity (Table 1,
entry 7). Overall, 1.2 equiv of LDA could give a higher
yield and better diastereoselectivity (Table 1, entry 5). The
yields decreased slightly when the reaction time was pro-
longed to 5 and 12 h, respectively (Table 1, entries 8 and 9).
Inaddition, the concentrationofthe substratealsoaffected
the reaction, the yield of 3a was slightly decreased after
dilution of the substrate (Table 1, entry 10). Similarly, the
concentration of base was also crucial to this Michael
reaction, diluting LDA to 0.25 mol/L provided the best
The stereoselectivity of the Michael addition of N-tert-
butanesulfinyl imidate with diethyl arylidenemalonates
(12) Brandau, S.; Landa, A.; Franzen, J.; Marigo, M.; Jørgensen,
K. A. Angew. Chem., Int. Ed. 2006, 45, 4305.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 4. Synthesis of Chiral Indanones 8 from 3
Figure 1. Proposed transition-state model.
could be explained with a proposed transition-state model
that is shown in Figure 1. Chelation of the metal with the
nitrogen and sulfinyl oxygen occurredupon deprotonation
of imidate 1. The steric repulsion between the tert-butyl
group of 1 and the R-group of the diethyl arylidenemalo-
nates in the transition state B led to the diastereomers
formed via transition state A as major products.
Furthermore, we demonstrated the utility of this meth-
odology by transforming the addition products into 3-sub-
stituted indanone derivatives 8a, 8d, 8e, and 8i. As shown
in Scheme 4, treatment of 3a, 3d, 3e, and 3i with HCl/
dioxane resulted in the cleavage of the sulfinyl group and
formed the imidate hydrochlorides which were excellent
intermediates for an easy transformation to 6a, 6d, 6e,
and 6i via heating at reflux temperature in CHCl3 for 16 h.
Then, the resulting amides were heated with Triton-B
(benzyltrimethyl ammonium hydroxide in methanol
solution) in DMSO at 80 °C for 3 h13 afforded the de-
ethoxycarbonylation products 7a, 7d, 7e, and 7i which
were further hydrolyzed by KOH (5%) and followed by
FriedelÀCrafts reactions toprepare the target products 8a,
8d, 8e, and 8i with good yields (75%, 77%, 85%, and 82%,
respectively) and enantiomeric excesses (ee = 94% for 8a,
8e, and 8i and ee = 95% for 8d).
groups, heterocyclic substituents and alicyclic groups.
By comparing optical rotation with known compound,
the absolute stereochemistry of the Michael adducts
was confirmed as R-configuration. As evidenced by
the asymmetric synthesis of 3-substituted indanone de-
rivatives, our method could be readily extended to an
efficient asymmetric synthesis of a wide variety of 3-sub-
stituted indanone derivatives, which are valuable build-
ing blocks for preparing potential biologically active
compounds.
Acknowledgment. We gratefully acknowledge financial
support from the National Natural Science Foundation
of China (Grant Nos. 21021063, 91229204, 81102307, and
81025017), National S&T Major Projects (2012ZX09103-
101-072), and the China-EU Science and Technology
Cooperation Project (1109).
In summary, we have developed an efficient methodology
for a highly diastereoselective Michael addition reaction of
N-tert-butanesulfinyl imidate with diethyl arylidenemalo-
nate derivatives. This strategy was proved to be tolerant to
the diversified diethyl arylidenemalonates containing aryl
Supporting Information Available. Detailed experimen-
tal procedures including spectroscopic and analytical
data. This material is available free of charge via the
Internet at http://pubs.acs.org.
(13) Melo, J. O. F.; Pereir, E. H. T.; Donnici, C. L.; Wladislaw, B.;
Marzorati, L. Synth. Commun. 1998, 28, 4179.
The authors declare no competing financial interest.
D
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