Catalytic Asymmetric Carbonylation of Prochiral Sulfonamides via C-H Desymmetrization

Article abstract of DOI:10.1021/acscatal.8b04725

An enantioselective oxidative C-H/N-H carbonylation process was developed in this work. A bimetallic Pd/Cu-based catalyst system was found to catalyze enantioselective C(sp²)-H carbonylation of prochiral arylsulfonamides via desymmetrization pr

Full text of DOI:10.1021/acscatal.8b04725

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Letter
Catalytic Asymmetric Carbonylation of Prochiral
Sulfonamides via C-H Desymmetrization
Xing-Feng Bai, Qiu-Chao Mu, Zheng Xu, Ke-Fang Yang, Li Li, Zhan-Jiang Zheng, Chungu Xia, and Li-Wen Xu
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Catalytic Asymmetric Carbonylation of Prochiral Sulfonamides via
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C−H Desymmetrization
‡
§
Xing-Feng Bai,†, , Qiu-Chao Mu,†, § Zheng Xu,‡ Ke-Fang Yang,‡ Li Li,‡ Zhan-Jiang Zheng,‡ Chun-Gu
Xia,† and Li-Wen Xu*,†,‡
†State Key Laboratory for Oxo Synthesis and Selective Oxidation, Suzhou Research Institute (SRI) of Lanzhou Institute of
Chemical Physics (LICP), Chinese Academy of Sciences and University of Chinese Academy of Sciences (UCAS), Lanzhou
730000, P. R. China
‡Key Laboratory of Organosilicon Chemistry and Material Technology of Ministry of Education, Hangzhou Normal Univer-
sity, Hangzhou 311121, P. R. China
ABSTRACT: An enantioselective oxidative C−H/N−H carbonylation process was developed in this work. A bimetallic Pd/Cu-
based catalyst systems were found to catalyze enantioselective C(sp2)−H carbonylation of prochiral arylsulfonamides via desymme-
trization process in the presence of mono-N-protected amino acid ligands. This reaction provides a facile strategy to the
stereoselective construction of the lactam-type products, such as isoindoline-1-ones and isoquinoline-1-ones, in good yields and
enantioselectivities under balloon pressure with the mixture of CO/O2. The reaction mechanism was rationalized by using density
functional theory (DFT) study.
KEYWORDS: C−H activation; enantioselective carbonylation; lactam; desymmetrization; palladium; DFT.
Catalytic carbonylation is one of the most straightforward
processes for oxo-synthesis and its asymmetric versions have
been a great interest of synthetic chemists. 1 Although many
studys on enantioselective carbonylation have been reported
over the past decades, most of the them fall into the category
of asymmetric carbonylation of alkenes under the promotion
of specified chiral ligands, which was usually difficult to syn-
thesize,2 and more model reactions thereby in the context of
enantioselective carbonylation are highly desired. In this re-
gard, the thriving of C−H carbonylation3 strategy and the tre-
mendous success of enantioselective C−H functionalization4
provided a new potential protocol for enantioselective car-
bonylation. For instance, Baudoin and co-workers have suc-
ceeded in an asymmetric palladium(0)-catalyzed intramolecu-
lar C(sp3)−H carbamoylation of TMB-protected carbamoyl
chloride in the presence of TADDOL-derived phosphine, with
75% yield of chiral β-lactam and 84% ee.5 However, to the
extent of our knowledge, this is the only study related to enan-
tioselective C−H carbonylation reported up to now.
study on the construction of chiral isoindolinone and
isoquinolinone cores through the enantioselective carbonyla-
tion strategy. Herein, we report an enantioselective C−H/N−H
carbonylation of prochiral sulfonamides, providing a new ex-
ample for enantioselective carbonylation and an easily access
to chiral isoindolinone and isoquinolinone cores. Gaunt’s
group has reported a series of pioneering work on the C−H
Scheme 1. C−H carbonylation of amines and design of
asymmetric version.
Lactams bearing medium rings, such as isoindolinone and
isoquinolinone cores, are privileged structural unit in many
natural products and bioactive compounds.6 Furthermore, cata-
lytic asymmetric synthesis of these valuable structures has
been almost widely recognized as a challenge work and thus
gained broad attentions.7 Since Orito’s pioneer work,8 Pd-
catalyzed C−H carbonylation of amines has been proved to be
a highly powerful strategy for the construction of lactam;
However, to the best of our knowledge, there is no reported
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Table 1. Investigation of reaction parameters for asym-
Scheme 2. Effect of ligands on the reactivity and enantiose-
lectivity.
metric C(sp2)−H carbonylation.
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5
6
7
8
9
Yield (%)[b]
1a 2a
trace >95(91) 94
Variation from standard
condition
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Entry
ee
1[a]
2
none
Without Pd(OAc)2
Without CuCl2
PdCl2 instead of Pd(OAc)2
>99
>95
77
N.R.[c]
Trace
23
N.D.[d]
N.D.
95
3
4
(PPh3)2PdCl2 instead of
Pd(OAc)2
5
>99
N.R.
N.D.
2.0 equivalent CuCl2 instead
6
of oxygen under 1/5 mixture >95
of CO/N2
trace
N.D.
standard condition was 0.1 M 1a in i-PrOH with 10 mol %
Pd(OAc)2, 10 mol % CuCl2, 30 mol % Boc-L-Val-OH and
30mol % Cs2CO3 at 80 ºC under a balloon atmospheric of CO/
O2(1/5 in v/v) mixture. 91% isolated yield and 94% ee of 2a
was obtained after refluxing for 24 hours under this standard
condition (Table 1, entry 1). Table 1 showed representative
results for the enantioslective C−H carbonylation of prochiral
arylsulfonamide 1a to isoindolinone 2a. For example, the reac-
tion almost didn’t work in the absence of either Pd(OAc)2,
CuCl2, or Cs2CO3 (Table 1, entry 2-3 and 8). Replacing
Pd(OAc)2 with PdCl2 diminished the yield of 2a to 23%, while
the ee value slightly increased to 95% (Table 1, entry 4).
[(PPh3)2PdCl2] showed no catalytic activity in this reaction
(Table 1, entry 5). A trace amount of product was detected
when using 2.0 equivalents of CuCl2 as the oxidant under a
balloon atmospheric of CO/N2(1:5 in v/v) gas mixture (Table 1,
entry 6). Replacing carbon monoxide with 10 equivalents of
paraformaldehyde also leaded to trace amount of yiel. When it
comes to using other bases, K2CO3 or Na2CO3, the yield was
decreased to 37% and 6% respectively, while the ee values
maintained at 93-94%. Notably, 95% ee was acquired in the
sacrifice of reaction efficiency (50% yield) when the reaction
temperature was decreased to 60 ºC. Gas mixture of CO/O2
proved to be more efficient than CO/Air. A suitable partial
pressure ratio of CO/O2 range from 1/3 to 1/10, the conversion
of 1a suffered from any change either increase or decrease, of
the ration of CO/O2. (Table 1, entry 13-15; Supporting Infor-
mation, Table S4). Based on our experimental observations,
increasing the ratio of CO lead to black dust quickly during
the reaction, that is the result of the strong reducing effect of
CO against Pd(II). In addition, lowering the concentration of
CO would slow down the carbonyl insertion step of the reac-
tion.
10 equivalent (CH2O)n in-
stead of carbon monoxide >95
under oxygen atmosphere
7
trace
N.D.
8
9
Without Cs2CO3
>99
N.R.
N.R.
N.D.
N.D.
i-Pr2NEt or 2,6-lutidine
instead of Cs2CO3
>99
10
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12
13
14
15
60 mol% Cs2CO3 was used
Carried out at 60 °C
Carried out at 40 °C
CO/Air = 1/1
54
49
>95
80
69
52
Trace
50
N.D.
95
Trace
16
N.D.
N.D.
N.D.
N.D.
CO/Air = 1/5
31
CO/O2 = 1/2
45
[a] The standard reaction was carried out at 0.1 mmol scale
with 10 mol% Pd(OAc)2, 10 mol% CuCl2, 30 mol% Boc-L-Val-
OH and Cs2CO3 in 1 mL i-PrOH, the partial pressure ratio of
CO/O2 was 1/5 and the reaction was refluxed at 80 °C for 24
hours. [b] Determined by H NMR analysis with CH2Br2 as an
internal standard, the value in parentheses shows the isolated
yield. [c] N.R.= no reaction. [d] N.D.= not determined.
1
carbonylation of simple amines,9 and proposed a plausible
model that both the carboxylate ion and another amine mole-
cule play key role in the reaction. We questioned whether it is
feasible to use amino acid derived ligands instead of both
amine and carboxylate ion moieties in their model to design an
enantioselective C−H carbonylation protocol (Scheme 1). In
fact, mono-N-protected amino acids (MPAA) has been fre-
quently used as magic ligands in Pd-catalyzed enantioselective
desymmetric functionalization of C−H bonds since the pio-
neering works of Yu’s group.10 Meanwhile, the MPAA also
proved to be effective ligands in promoting palladium-
catalyzed C(sp2)−H carbonylation.11 However, enantioselec-
tive version of C(sp2)−H carbonylation that promoted by
MPAA ligands has not been reported yet. To test our hypothe-
sis, we initiated our study using tosyl-protected diarylmethyl-
amine (1a) as the substrate and evaluated a series of conditions
(Table S1-S6 of Supporting Information), The optimized
The influence of electronic and substituent effect of mono-N-
protected amino acid on the reactivity and enantioselectivity
was studied under the optimized condition (Scheme 2). Gener-
ally, most of the commercial mono-N-protected amino acids
evaluated in this reaction showed improvement on the Pd/Cu
co-catalyzed enantioselective desymmetric C−H carbonylation
of diarylsulfonamide, resulting up to 91% isolated yield and
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Scheme 3. Scope of diarylsulfonamides for the enantiose-
Scheme 4. Scope of diarylmethylsulfonamides for the enan-
lective C(sp2)−H carbonylation.
tioselective C(sp2)−H carbonylation.
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[a] Unless otherwise specify, the reaction was carried out at 0.3
mmol scale with 10 mol% Pd(OAc)2, 10 mol% CuCl2, 30 mol%
Boc-L-Val-OH and 30 mol% Cs2CO3 in 3 mL i-PrOH, the partial
pressure ratio of CO/O2 was 1/5 and the reaction was refluxed at
80 °C for 24 hours. [b] CO/O2 = 1/7, reflux at 80 °C for 24 hours.
[a] Unless otherwise specified, the reaction was carried out at
0.3 mmol scale with 10 mol% Pd(OAc)2, 10 mol% CuCl2, 30
mol% Boc-L-Val-OH and 30 mol% Cs2CO3 in 3 mL i-PrOH, the
partial pressure ratio of CO/O2 was 1/5 and the reaction was re-
fluxed at 80 °C for 24 hours. [b] CO/O2 = 1/7, reflux at 80 °C for
48 hours. [c]: reflux for 72 hours.
Scheme 5. Enantioselective carbonylation of Ts-protected
2,2-diphenylethylsulfonamide 5.
94% ee of 2a, except Boc-L-Phe-OH and Cbz-L-Phe-OH,
which decreased the ee of 2a to 83% and 50% ee respectively.
These results indicated that both the substituents on the
backbone and the protecting group of amino acid ligands in-
volved in the enantiocontrol state. Boc-L-His-OH showed no
activation on the reactivity, that might be due to the competi-
tive coordination of imidazolyl toward metal center. When
using unprotected amino acid L10 or replacing the carboxyl
with an N-methoxyamide group (L8), the carbonylation almost
did not take place. Methyl instead of hydrogen on the nitrogen
of ligand (L9) was detrimental to both the yield (5%) and ee
(19%). Other commercial chiral azo ligands such as Ph-Box
(L11) and L12 showed no improvements on this C−H car-
bonylation reaction. These experimental results indicated that
both the mono-N-protected amino and acid moieties are essen-
tial to the reactivity of this C−H carbonylation approach.
substituted product 2j also obtained in 94% yield and 95% ee
in the same way as 2i did. For Ts-protected di(2-naphthyl)-
methylsulfonamide 1k, unsatisfactory site selectivity compro-
mised the yield of 2k to 69% at 89% ee. In addition, 2l, with a
chiral quaternary carbon stereo center, acquired in 70% yield
and 82% ee.
To further test the application of our catalytic enantioselective
C−H carbonylation system, we next applied the standard reac-
tion condition to the carbonylation of Ts-protected
dibenzylmethylsulfonamides.12 As the results shown in
Scheme 4, isoquinolinones 4a-4e were obtained in moderate to
good yields under the optimized condition mentioned above,
the corresponding ee values distributed from 83% to 89%. Ts-
protected 2,2-diphenylethan-1-sulfonamide 5 converted to 4-
phenyl substituted isoquinolinones 6 in 87% yield and even
low to 72% ee. These results indicated that the bigger cyclic
transient state in the C−H activation step for isoquinolinones
formation prejudiced the stereo control and resulted to poor
enantioselectivity. Fortunately, we obtained the single crystal
diffraction data of 2e, 2k, 4a and 6 from the corresponding
enantiopure samples (>99% ee obtained through a recrystalli-
zation from i-PrOH). It should be noted that the phenyl on the
C4 position of 6 stretched toward to the up side of the isoquin-
olinone plane as shown in Scheme 5, while the phenyl on the
C3 position of isoquinolinone 4a-4e pointed to the down side.
With the optimized condition in hand, we next investigated the
scope and limitations of the Pd/Cu co-catalyzed enantioselec-
tive carbonylation reaction. As demonstrated in Scheme 3, The
carbonylation reactivity was obviously affected by the protect-
ing group of nitrogen and substituents on the phenyl of sub-
strates.
For
instance,
Ms-
or
Tf-
protected
diphenylmethylsulfonamide provided enantiomer enriched
isoindolinones with slightly lower ee values and yields. Meta-
substituted (Me-, MeO- for example) substrates exerted exclu-
sive site selectivity, giving 2d and 2e in 87% and 83% ee
respectively with good yields. Para-substituted substrates
afforded corresponding carbonylated products 2f-2h in high
yields (74-88%) and good enantioselectivities (> 91% ee). For
a strong electric-donating and sterically hindered group, t-
butyl for instance, providing 2i in 96% ee but only giving 50%
yield. When changed the partial pressure ratio of CO/O2 to 1/7
and extended the reaction time to 48 hours, the yield of 2i
increased to 93% and ee value matained at 96%. 3,5-Dimethyl
For the reaction mechanism, there are two possible pathways
for the asymmetric C−H activation of sulfonamide to chiral
lactams according to references: A) carbamoyl directed C−H
activation or B) amine directed C−H activation (Scheme 6).
Yu and co-workers proposed a reasonable transient state
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Scheme 6. Free energy profiles for enantioselective C−H
sure. This enantioselective process has the potential to be used
in the asymmetric synthesis and pharmaceutical fields because
of its mild reaction conditions. In addition, a plausible enanti-
oselective carbamoyl-Pd oriented C−H activation mechanism
was proposed based on the computational study.
activation of sufulamide 1a. [a]
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website. At DOI: 10.1021/acscatal.xxxx.
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Experimental procedures, characterization of products and spec-
troscopic data (PDF); Crystallographic data for 2e (CIF); Crystal-
lographic data for 2k (CIF); Crystallographic data for 4a (CIF);
Crystallographic data for 6 (CIF)
AUTHOR INFORMATION
Corresponding Author
*liwenxu@hznu.edu.cn.
[a] Activation free energies are given in kcal/mol. The Gibbs
energy of intA-III and intB-I were set to zero for each protocol
respectively.
Author Contributions
§(X.-F. Bai, Q.-C. Mu) These authors contributed equally.
model for the mono-N-protected amino acid promoted enanti-
oselective desymmetric C−H functionalization before, com-
bining experiments and DFT calculations.13 Herein, we con-
ducted a DFT study to compare the activation free energy of
the C−H activation step between these two different protocols.
As shown in Scheme 6, the lowest activation energy of car-
bamoyl directed C−H activation was calculated to be 14.2
kcal/mol (TS-A(D-R)), while the amine directed C−H activa-
tion calculated to 16.2 kcal/mol (TS-B(D-R); that is, 2.0
kcal/mol higher than TA-A(D-R)). This result supported a
carbamoyl directed C−H activation protocol. A complete cata-
lytic cycle was proposed based on it (the Supporting infor-
mation, Scheme S1). For the driving force of enantioselectivi-
ty, four different transition states were simulated for the transi-
tion from carbamoyl-Pd species (int-III) to Pd tether bicycle
species (int-IV). In the transition state TS-A(D-R) and TS-
A(D-S), activating C−H bond was oriented blow the Pd coor-
dination plane, whereas in TS-A(U-S) and TS-A(U-R), the
activating C−H bond was oriented upward. The lower energy
state for S-enantiomer (TS-A(U-S)) was calculated to be 15.7
kcal/mol, which is 1.5 kcal/mol higher than TS-A(D-R). The
energy difference elucidated the origin of R-enantiomer selec-
tive carbamoyl directed C−H carbonylation protocol. Transi-
tion state models of carbamoyl-Pd oriented C−H activation for
sulfonamide 4a and 6 also simulated and optimized under the
same theoretical model and basis set (see Supporting Infor-
mation, Figure S2(B, C)). The free Gibbs energy of TS-4a(D-
S) was calculated to be 1.8 kcal/mol higher than TS-4a(D-R);
TS-6-R calculated to 2.5 kcal/mol higher than TS-6-S. These
were consistent with the experiment results.
Funding Sources
We thank National Natural Science Foundation of China (NSFC
201702211, 21703051, and 21773051), Natural Science Founda-
tion of Jiangsu Province (BK20170421), and Zhejiang Provincial
Natural Science Foundation of China (LZ18B020001) for finan-
cial support of this work.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We thank Yildiz Tasdan (Ms.) and Chan Wai Lun (Mr.) for their
kindly help of the improvement of the language.
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