Direct enantioselective: C -acylation for the construction of a quaternary stereocenter catalyzed by a chiral bicyclic imidazole

Article abstract of DOI:10.1039/c6cc09451a

A direct enantioselective C-acylation of 3-substituted benzofuran-2(3H)-ones (with up to 97% ee) was developed using a chiral bicyclic imidazole catalyst OAc-DPI and an achiral tertiary amine additive DIPEA. The reaction mechanism for the direct C-acylation has been investigated using both experimental and theoretical studies.

Full text of DOI:10.1039/c6cc09451a

View Article Online
View Journal
ChemComm
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: M. Wang, X.
Zhang, Z. Ling, Z. Zhang and W. Zhang, Chem. Commun., 2017, DOI: 10.1039/C6CC09451A.
This is an Accepted Manuscript, which has been through the
Volume 52 Number
1 4 January 2016 Pages 1–216
Royal Society of Chemistry peer review process and has been
accepted for publication.
ChemComm
Accepted Manuscripts are published online shortly after
Chemical Communications
www.rsc.org/chemcomm
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
ISSN 1359-7345
COMMUNICATION
Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
first methanofullerene derivatives of Sc N@D5h-C80
=
3
rsc.li/chemcomm

Please do not adjust margins
Page 1 of 4
ChemComm
View Article Online
DOI: 10.1039/C6CC09451A
Journal Name
COMMUNICATION
Direct Enantioselective C-Acylation for the Construction of a
Quaternary Stereocenter Catalyzed by a Chiral Bicyclic Imidazole
Mo Wang,a Xiao Zhang,a Zheng Ling,a Zhenfeng Zhang,*b and Wanbin Zhang*a,b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A direct enantioselective C-acylation of 3-substituted benzofuran-
2(3H)-ones (with up to 97% ee) was developed using a chiral
bicyclic imidazole catalyst OAc-DPI and an achiral tertiary amine
additive DIPEA. The reaction mechanism for the direct C-acylation
has been investigated using both experimental and theoretical
studies.
Enantioselective acylation, one of the most commonly used
methodologies, has been widely studied using numerous
organocatalysts,
enzymes,
and
metal
complexes.1
Enantioselectivity is often controlled during esterification and
amidation via (dynamic) kinetic resolution of carboxylic
derivatives, alcohols, thiols, amines, and amides.2 C-acylation
differs from O-acylation, S-acylation and N-acylation, in that it
allows for: 1. the construction of challenging and valuable
quaternary stereocenters; 2. the formation of a new C-C bond; Scheme 1 Enantioselective acylation.
3. the utilization of a wide range of C-nucleophiles with diverse
molecular skeletons (Scheme 1). So far, indirect
catalysts to several indirect C-acylations.3g,6c The target
enantioselective C-acylations such as Steglich and Black
rearrangements of enol esters,3 and related transformations
using silyl enol ethers,4 have been well studied. However, the
additional step needed for the preparation of enol
intermediates and the extra energy required to break the O-
acyl or O-silyl bond will probably result in a relatively low
reaction efficiency. Therefore, a one-step economical, direct
enantioselective C-acylation of readily available starting
materials is greatly desired but still remains challenging.5
In continuation of our research involving the construction
of quaternary stereocenters,3g,6 a structural motif prevalent in
numerous natural products and pharmaceutical compounds,7
we have applied a series of chiral bicyclic imidazole Lewis base
compounds were obtained by acyl rearrangement of the O-
acyl enol esters, which were prepared from O-acylation of the
corresponding lactones. However, a dramatic decrease in
reactivity was observed when we attempted to increase
enantioselectivity by using lower reaction temperatures.
Furthermore, some other enol esters were also prepared but
failed to undergo rearrangement under similar reaction
conditions. In order to solve these problems, we have
developed a direct C-acylation process that avoids breaking
the strong O-acyl bond. Herein we describe our preliminary
results concerning the direct enantioselective C-acylation of 3-
substituted benzofuran-2(3H)-ones catalyzed by the chiral
bicyclic imidazole OAc-DPI and assisted by an achiral tertiary
amine such as DIPEA.
We hypothesized that for such an approach to be
successful, an additional Brønsted base would be needed as a
H-abstracting agent and/or an acid-binding agent. Several
organic bases and inorganic bases were screened in the direct
C-acylation of 3-methylbenzofuran-2(3H)-one (1a) to give
phenyl 3-methyl-2-oxo-2,3-dihydrobenzofuran-3-carboxylate
(Table 1). OAc-DPI, which has been shown to be an excellent
a.School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800
Dongchuan Road, Shanghai 200240, P. R. China. E-mail: wanbin@sjtu.edu.cn
b.School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road,
Shanghai 200240, P. R. China. E-mail: zhenfeng@sjtu.edu.cn
Electronic Supplementary Information (ESI) available: experimental details and
analytical data. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 2 of 4
COMMUNICATION
Journal Name
Table 1 Reaction condition optimization.a
Table 2 The influence of reaction temperature.a
View Article Online
DOI: 10.1039/C6CC09451A
entry
1
2
3
4
base
-
TEA
TEA
TEA
DIPEA
DIPEA
DIPEA
DIPEA
loading (eq)
conv (%)b
ee (%)c
-
79
79
78
78
78
88
entry
1
2
temp. (°C)
25
2a (%)b
85
79
65
82
0
51
13
84
85
88
74
91
93
2a' (%)b
13
18
31
11
100
4
ee (%)c
87
91
94
96
-
96
96
96
96
96
96
96
96
-
<5
42
63
81
93
94
92
85
1.2
1.6
2.4
2.4
3.0
2.4
2.4
0
3
-20
-40
-40
-60
-78
-40
-40
-40
-40
-40
-40
4
5d
6
5
6
7d
8d,e
7
1
8e
9f
13
14
7
19
9
87
a 1a (0.05 M), ClCOOPh (1.2 eq), OAc-DPI (10 mol %), Brønsted
base, t-amyl alcohol (2 mL), 25 °C, 24 h, unless otherwise
10g
11h
12i
13j
b
1
c
noted. Conversions were calculated from H NMR spectra.
The ee values were determined by HPLC. d ClCOOallyl was used
e
instead of ClCOOPh. Toluene was used instead of t-amyl
alcohol.
7
a
1a (0.05 M), ClCOOallyl (1.2 eq), OAc-DPI (10 mol %), DIPEA
(2.4 eq), toluene (2 mL), 24 h, unless otherwise noted.
b
catalyst for use in asymmetric Black rearrangements due to a
cation/π–π interaction between the imidazolium ring and the
carbonyl group,6c was chosen as the catalyst. At first, one of
the most commonly used organic bases, triethylamine (TEA),
was added to the reaction system and an obvious promoting
effect was detected (entry 2 vs 1). The desired product was
obtained with 42% conversion and with 79% ee (the same as
that obtained by Black rearrangement of 3-methylbenzofuran-
2-yl phenyl carbonate6c). Increasing the loading of TEA from
1.2 eq to 2.4 eq significantly improved the conversion from 42%
to 81% with similar enantioselectivity (entries 2-4). Use of the
organic base di(isopropyl)ethylamine (DIPEA) afforded a higher
conversion of 93% (entry 5). Further increasing the amount of
base had little effect on conversion (entry 6). Other organic
and inorganic bases were also examined but provided poorer
conversions and enantioselectivities. Using the reaction
conditions described in entry 5, a variety of acylating agents
RCOX were examined.8 Allyl chloroformate proved to be the
most suitable giving the desired product with 88% ee and 92%
conversion (entry 7). The solvent effect was also studied and it
was found that less polar solvents such as toluene, dioxane
and t-amyl alcohol gave relatively high enantioselectivities.8
Toluene was chosen as the optimal solvent due to its low
melting-point (entry 8).
The reaction temperature was reduced in order to improve
the enantioselectivity (Table 2). At a reaction temperature of
25 °C, 2a (by C-acylation) and 2a' (by O-acylation) were
obtained with 85% and 13% conversions, respectively (entry 1).
When the reaction temperature was reduced to 0 °C and
subsequently to -20 °C, the conversion of 2a was reduced to 65%
while the enantioselectivity increased to 94% (entries 2 and 3).
To our surprise, further lowering the reaction temperature to -
40 °C resulted in an increase in enantioselectivity to 96% and
an increase in conversion to 82% (entry 4). This unexpected
1
c
Conversions were calculated from H NMR spectra. The ee
values were determined by HPLC. d 2a' was used as the starting
e
f
g
material. ClCOOallyl (1.5 eq) toluene (1 mL). OAc-DPI (20
mol %). OAc-DPI (5 mol %). -40 °C, 24 h; then 0 °C, 12 h. -
40 °C, 24 h; then 25 °C, 12 h.
h
i
j
result can be explained by a direct C-acylation mechanism. At
high temperature, the desired product 2a was obtained by
direct C-acylation of 1a and Black rearrangement of O-acylated
2a'. However, the rearrangement from 2a' to 2a is strongly
suppressed when the reaction temperature is reduced. No
rearrangement of 2a' was observed under the same conditions
at -40 °C (entry 5). This result suggested that the desired
product 2a can only be obtained by direct C-acylation of 1a at -
40 °C. Because the production of inactive by-product 2a' was
also strongly suppressed at -40 °C, the conversion of the
desired product 2a increased instead (mechanistic studies
using DFT calculations are described in detail later). Further
decreasing the temperature to -60 °C and -78 °C reduced the
conversions of both 2a and 2a' (entries 6 and 7). In order to
improve the conversion of 2a, loadings of allyl chloroformate
and catalyst were increased in addition to reaction system
concentration. Using higher quantity of allyl chloroformate
(1.5 eq) had little effect on reactivity; the desired product 2a
was obtained in 84% conversion with 96% ee (entry 8).
Reducing the amount of solvent from 2 mL to 1 mL showed a
similar result (85% conversion and 96% ee) (entry 9). Altering
the catalyst loading had a clear influence on conversion
(entries 10 and 11). Finally, a sequential process was used to
obtain the desired product with a higher conversion and same
enantioselectivity. Thus the reaction was first conducted at -
40 °C for 24 h and then the temperature was gradually raised
to 0 °C or 25 °C for another 12 h affording the desired product
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 3 of 4
ChemComm
Please do not adjust margins
Journal Name
COMMUNICATION
View Article Online
DOI: 10.1039/C6CC09451A
Scheme 3 Acylation in the absence of catalyst.
Scheme 2 Substrate scope.
2a with 91-93% conversions and 96% ee (entries 12 and 13).
Having established the optimized reaction conditions, we
then tested the acylation of allyl chloroformate with various
substrates (Scheme 2). Substrates with alkyl R1 groups such as
Me, Et, nPr and Bn showed good yields and enantioselectivities
Scheme 4 Acylation in the presence of catalyst.
barrier from to TS-II is higher than that to TS-III. These
(2a-d). The absolute configurations of the products were
3
speculated to be the same as 2d whose configuration was
assigned by X-ray single crystal diffraction.8 A challenging
substrate in which R1 is a phenyl group6c was also subjected to
the reaction conditions and the corresponding product 2e was
obtained in 96% yield but with only 45% ee. Substrates bearing
a methyl substituent at the 5-, 6- or 7-position of the phenyl
ring were acylated to the corresponding products 2f-h with
94%, 92% and 96% ee, respectively. Other products 2i-r
bearing Et, iPr, tBu, OMe and Ph substituents at the 5- or 6-
position of the phenyl ring were also obtained with good yields
(83-93%) and excellent enantioselectivities (91-96% ee).
Substrates possessing naphthyl groups gave their acylated
products 2s and 2t with similar enantioselectivities (92% and
94% ee). A gram-scale experiment was also conducted using 1a
giving the desired product 2a in 91% yield and with the same
96% ee.8
results explain the formation of 2a' as the main product in the
first step of the indirect C-acylation which was promoted by a
Brønsted base but without a Lewis base. During our
preparation for the starting material of entry 5 in Table 2, the
reaction was performed in the absence of catalyst to obtain
only O-acylated 2a' in a yield of 62% and without any C-
acylated 2a
.
In the presence of catalyst, the C-acylated product 2a is
obtained as the main product (Scheme 4). The energy barrier
from 4/5 (set as base level) to transition state TS-IV was
calculated to be 13.7 Kcal/mol. The formed chlorine salt
converted to by changing the anion. The intermediate
6
7
was
has
7
a choice of two reaction pathways: the O-acylated by-product
2a' can be formed via the transition state TS-V or it can be
converted to product 2a via the favored TS-VI and disfavored
TS-VII. In the Black rearrangement, the starting reaction
In order to explore the mechanism of the direct C-acylation,
a series of DFT calculations were carried out. Scheme 3 shows
the reaction pathway for the acylation in the absence of
catalyst. A mixture of 1a and DIPEA was set as the base level.
mixture 2a'/5 is converted to
energy barrier was calculated to be 19.6 Kcal/mol which is
higher than that of O-acylation in the presence of catalyst
7 via transition state TS-V. The
(11.5 Kcal/mol from
catalyst (17.6 Kcal/mol from
7
to TS-V) and even in the absence of
to TS-III). Therefore, the Black
The H-abstracted species
3 is formed via TS-I with an energy
3
barrier of 18.7 Kcal/mol. C-acylation or O-acylation can occur
via transition states TS-II and TS-III, respectively. The energy
rearrangement is suppressed before O-acylation at low
reaction temperatures. Finally, the desired product bearing the
(S)-configuration is obtained selectively because of the low
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 4 of 4
COMMUNICATION
Journal Name
Uraguchi, K. Koshimoto, T. Ooi, J. Am. Chem. Soc., 2012, 134,
energy barrier from
determining step is the formation of
barrier of 13.7 Kcal/mol.
In conclusion, a direct enantioselective C-acylation of 3-
substituted benzofuran-2(3H)-ones has been developed for
7 to TS-VI (10.7 Kcal/mol). The rate
View Article Online
6972; (k) E. Gould, D. M. Walden, K. Kasten, R. C. Johnston, J.
DOI: 10.1039/C6CC09451A
6 which has an energy
Wu, A. M. Z. Slawin, T. J. L. Mustard, B. Johnston, T. Davies, P.
H.-Y. Cheong, A. D. Smith, Chem. Sci., 2014, 5, 3651; (l) H.
Mandai, K. Fujii, H. Yasuhara, K. Abe, K. Mitsudo, T. Korenaga, S.
Suga, Nat. Commun., 2016, 7, 11297.
4
(a) A. H. Mermerian, G. C. Fu, J. Am. Chem. Soc., 2003, 125, 4050;
(b) A. H. Mermerian, G. C. Fu, J. Am. Chem. Soc., 2005, 127,
5604; (c) A. H. Mermerian, G. C. Fu, Angew. Chem., Int. Ed.,
2005, 44, 949; (d) E. Bappert, P. Müller, G. C. Fu, Chem.
Commun., 2006, 2604; (e) P. A. Woods, L. C. Morrill, R. A. Bragg,
A. D. Smith, Chem. Eur. J., 2011, 17, 11060; (f) J. A. Birrell, J.-N.
Desrosiers, E. N. Jacobsen, J. Am. Chem. Soc., 2011, 133, 13872.
Until now, only a few examples have been reported: (a) J. E.
Delorbe, S. Y. Jabri, S. M. Mennen, L. E. Overman, F.-L. Zhang, J.
Am. Chem. Soc., 2011, 133, 6549; (b) M. Hayashi, S. Bachman, S.
Hashimoto, C. C. Eichman, B. M. Stoltz, J. Am. Chem. Soc., 2016,
138, 8997; (c) B. F. Rahemtulla, H. F. Clark, M. D. Smith, Angew.
Chem., Int. Ed., 2016, 55, 13180.
(a) G. Yang, C. Shen, W. Zhang, Angew. Chem., Int. Ed., 2012, 51,
9141; (b) Yang, G.; Zhang, W. Angew. Chem., Int. Ed., 2013, 52,
7540; (c) M. Wang, Z. Zhang, S. Liu, F. Xie, W. Zhang, Chem.
Commun., 2014, 50, 1227; (d) M. Quan, G. Yang, F. Xie, I. D.
Gridnev, W. Zhang, Org. Chem. Front., 2015, 2, 398; (e) X. Wei, D.
Liu, Q. An, W. Zhang, Org. Lett., 2015, 17, 5768; (f) Q. He, L. Wu,
X. Kou, N. Butt, G. Yang, W. Zhang, Org. Lett., 2016, 18, 288.
For recent representative reviews: (a) B. Wang, Y. Q. Tu, Acc.
Chem. Res., 2011, 44, 1207; (b) P. J. Das, I. Marek, Chem.
Commun., 2011, 47, 4593; (c) K. W. Quasdorf, L. E Overman,.
Nature, 2014, 516, 181; (d) Y. Liu, S.-J. Han, W.-B. Liu, B. M.
Stoltz, Acc. Chem. Res., 2015, 48, 740; (e) M. Büschleb, S. Dorich,
S. Hanessian, D. Tao, K. B. Schenthal, L. E. Overman, Angew.
Chem., Int. Ed., 2016, 55, 4156; (f) X.-P. Zeng, Z.-Y. Cao, Y.-H.
Wang, F. Zhou, J. Zhou, Chem. Rev., 2016, 116, 7330.
the first time.
A
wide range of 3,3-disubstituted
benzofuranones possessing a quaternary stereocenter were
synthesized with excellent enantioselectivities (up to 97% ee)
using a chiral bicyclic imidazole OAc-DPI catalyst and an achiral
tertiary amine DIPEA. The reaction mechanism for the direct C-
acylation has been investigated using both experimental
studies and DFT computations. The direct enantioselective
acylation for the synthesis of other chiral compounds
possessing a quaternary stereocenter, especially the ones that
cannot be obtained by acyl rearrangement, is under study in
our lab.
This work was partially supported by the National Natural
Science Foundation of China (No. 21232004 and 21572131)
and Science and Technology Commission of Shanghai
Municipality (No. 14XD1402300 and 15Z111220016). We
gratefully acknowledge Prof. Ilya D. Gridnev from Tohoku
University for helpful discussion. We also thank the
Instrumental Analysis Center and the High Performance
Computing Center of Shanghai Jiao Tong University.
5
6
7
8
Notes and references
1
For review: C. E. Müller, P. R. Schreiner, Angew. Chem., Int. Ed.,
2011, 50, 6012.
See Supporting Information for details. The experimental
data for optimization of the reaction conditions using other
bases, acylating reagents, and solvents are presented in
pages S9-S10. The procedure for the gram-scale experiment
can be found on page S20. The X-ray single crystal structure
of (S)-2d (CCDC 1508727) can be found on page S62.
2
For recent representative papers: (a) C. K. De, D. Seidel, J. Am.
Chem. Soc., 2011, 133, 14538; (b) M. Binanzer, S.-Y. Hsieh, J. W.
Bode, J. Am. Chem. Soc., 2011, 133, 19698; (c) X. Yang, V. B.
Birman, Angew. Chem., Int. Ed., 2011, 50, 5553; (d) E. Larionov,
M. Mahesh, A. C. Spivey, Y. Wei, H. Zipse, J. Am. Chem. Soc.,
2012, 134, 9390; (e) S. Y. Lee, J. M. Murphy, A. Ukai, G. C. Fu, J.
Am. Chem. Soc., 2012, 134, 15149; (f) X. Yang, V. D. Bumbu, P.
Liu, X. Li, H. Jiang, E. W. Uffman, L. Guo, W. Zhang, X. Jiang, K. N.
Houk, V. B. Birman, J. Am. Chem. Soc., 2012, 134, 17605; (g) S.
Lu, S. B. Poh, W.-Y. Siau, Y. Zhao, Angew. Chem., Int. Ed., 2013,
52, 1731; (h) S. Kuwano, S. Harada, B. Kang, R. Oriez, Y. Yamaoka,
K. Takasu, K. Yamada, J. Am. Chem. Soc., 2013, 135, 11485; (i) S.
Lu, S. B. Poh, Y. Zhao, Angew. Chem., Int. Ed., 2014, 53, 11041; (j)
G. Ma, J. Deng, M. P. Sibi, Angew. Chem., Int. Ed., 2014, 53,
11818; (k) O. Verho, J.-E. Bäckvall, J. Am. Chem. Soc., 2015, 137,
3996; (l) S. Tallon, F. Manoni, S. J. Connon, Angew. Chem., Int.
Ed., 2015, 54, 813; (m) S. Dong, M. Frings, H. Cheng, J. Wen, D.
Zhang, G. Raabe, C. Bolm, J. Am. Chem. Soc., 2016, 138, 2166; (n)
D. W. Piotrowski, A. S. Kamlet, A.-M. R. Dechert-Schmitt, J. Yan,
T. A. Brandt, J. Xiao, L. Wei, M. T. Barrila, J. Am. Chem. Soc.,
2016, 138, 4818; (o) C. Yu, H. Huang, X. Li, Y. Zhang, W. Wang, J.
Am. Chem. Soc., 2016, 138, 6956.
For representative papers: (a) J. C. Ruble, G. C. Fu, J. Am. Chem.
Soc., 1998, 120, 11532; (b) S. A. Shaw, P. Aleman, E. Vedejs, J.
Am. Chem. Soc., 2003, 125, 13368; (c) I. D. Hills, G. C. Fu, Angew.
Chem., Int. Ed., 2003, 42, 3921; (d) S. A. Shaw, P. Aleman, J.
Christy, J. W. Kampf, P. Va, E. Vedejs, J. Am. Chem. Soc., 2006,
128, 925; (e) T. A. Duffey, S. A. Shaw, E. Vedejs, J. Am. Chem.
Soc., 2009, 131, 14; (f) C. Joannesse, C. P. Johnston, C. Concellón,
C. Simal, D. Philp, A. D. Smith, Angew. Chem., Int. Ed., 2009, 48,
8914; (g) Z. Zhang, F. Xie, J. Jia, W. Zhang, J. Am. Chem. Soc.,
2010, 132, 15939; (h) D. Uraguchi, K. Koshimoto, S. Miyake, T.
Ooi, Angew. Chem., Int. Ed., 2010, 49, 5567; (i) C. K. De, N.
Mittal, D. Seidel, J. Am. Chem. Soc., 2011, 133, 16802; (j) D.
3
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins