Solvent-controlled switchable C-H alkenylation of 4-aryl-1H-pyrrole-3-carboxylates: Application to the total synthesis of (±)-rhazinilam

Article abstract of DOI:10.1021/ol5023933

A solvent-controlled switchable C-H alkenylation of 4-aryl-1H-pyrrole-3-carboxylates via a Pd(OAc)₂ catalyzed oxidative Heck reaction was first realized. The corresponding C2 and C5 alkenylation products were obtained in good yields with high regioselectivities, respectively. The selective C5-alkenylation was successfully applied to the total synthesis of (±)-rhazinilam.

Full text of DOI:10.1021/ol5023933

Letter
pubs.acs.org/OrgLett
Solvent-Controlled Switchable C−H Alkenylation of
4‑Aryl‑1H‑pyrrole-3-carboxylates: Application to the Total Synthesis
of ( )-Rhazinilam
Youla Su, Haipin Zhou, Jiaxuan Chen, Jinyi Xu, Xiaoming Wu, Aijun Lin,* and Hequan Yao*
State Key Laboratory of Natural Medicines (SKLNM) and Department of Medicinal Chemistry, School of Pharmacy, China
Pharmaceutical University, Nanjing, 210009, P. R. China
S
* Supporting Information
ABSTRACT: A solvent-controlled switchable C−H alkenylation of 4-aryl-1H-pyrrole-3-carboxylates via a Pd(OAc)2 catalyzed
oxidative Heck reaction was first realized. The corresponding C2 and C5 alkenylation products were obtained in good yields with
high regioselectivities, respectively. The selective C5-alkenylation was successfully applied to the total synthesis of
( )-rhazinilam.
Scheme 1. Strategies for Controlling Regioselectivity in
C−H Bond Functionalizations
ver the past decades, transition-metal catalyzed direct C−
H activation has emerged as a powerful and reliable tool
O
in natural products synthesis, medicinal chemistry, and material
sciences.1 Despite the tremendous advances, the widespread
application of C−H functionalization was still hampered by
some long-standing challenges.2 In particular, the control of
regioselectivity is one of the most intriguing problems due to
the multitude of C−H bonds existing in one molecule with
subtle differences in intrinsic reactivity.3,4 Common solutions
for this problem involved directing groups,5 ligands,6 catalysts,7
and electronic/steric8 controlled regioselectivity. The Yu
group9 reported a highly efficient distal C−H bonds activation
approach via an end-on nitrile template (Scheme 1a), which
provided a groundbreaking route for meta-selectivity compared
to the conventional ortho-directing mode. Itami et al. produced
β-selective arylation of thiophenes using a phosphine ligand and
α-selective arylation products with 2,2′-bipyridyl (Scheme
1b).6d,e In 2013, Sanford7b disclosed a complete reversal in
selectivity of naphthalene arylation under the catalysis of
Na2PtCl4 instead of Na2PdCl4 (Scheme 1c). In 2006, Gaunt
developed a switchable 2 or 3 alkenylation of simple pyrroles
via N-protecting groups differentiating in steric and electronic
properties. N-Boc pyrroles offered 2-alkenylation products,
while N-TIPS pyrroles gave 3-alkenylation products (Scheme
1d).8a
Recently, the central theme in C−H bond functionalization is
the development of a convenient method to install the reaction
partner at a specific position and to achieve the target
compounds from simple materials efficiently. However, the
directing groups are not always desirable in the target
molecules, thus the inevitable removal issue obviously limited
their further synthetic utility. Moreover, the implication of
relatively expensive catalysts or ligands does not meet the atom-
economic and operationally simple request. Compared to
Gaunt’s work on pyrrole 2- or 3-alkenylation,8a differentiation
between 2- and 5-positions should be more challenging. Herein,
we will describe a direct solvent-controlled10 switchable
Received: August 12, 2014
© XXXX American Chemical Society
A
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Letter
a
alkenylation of 3,4-substituted pyrroles and the application of
C5-alkenylation to the total synthesis of ( )-rhazinilam
(Scheme 1e).
Table 2. Substrate Scope of C2-Alkenylation
We commenced our research by screening the reaction
between tert-butyl N-methyl-4-phenyl-1H-pyrrole-3-carboxylate
1a and n-butyl acrylate in the presence of 10 mol % of
Pd(OAc)2 and 2 equiv of AgOAc; the results are shown in
Table 1. Reactions in acetone, dioxane, 1,2-dichloroethane, and
a
Table 1. Optimization of the Reaction Conditions
b
b
entry
R
solvent
acetone
total yield (%) ratio (2:3)
1
COOtBu
COOtBu
COOtBu
COOtBu
COOtBu
COOtBu
COOtBu
COOtBu
COOtBu
COOtBu
COOtBu
COOEt
73
66
74
79
90:10
91:9
94:6
>95:5
>95:5
4:1
2
1,4-dioxane
DCE
3
4
mesitylene
toluene
DMF
c
5
92(89 )
53
6
7
DMA
41
3:1
8
NMP
50
3:1
9
HMPA
41
1:1
10
11
12
13
DMSO
68
1:5
d
d
d
c
DMF/DMSO
DMF/DMSO
81(68 )
1:6
c
80(68 )
1:7
c
COOMe
DMF/DMSO
85(73 )
1:8
a
a
Unless otherwise mentioned, all reactions were carried out using 1
Reaction conditions: 1 (0.5 mmol), Pd(OAc)2 (10 mol %), acrylate
(1.0 mmol), and AgOAc (1.0 mmol) in solvent (2.0 mL), 80 °C, 20 h.
(0.5 mmol), Pd(OAc)2 (10 mol %), AgOAc (1.0 mmol), and alkenes
(1.0 mmol) in toluene (2.0 mL), 80 °C, 20 h. Isolated yields of major
products. Ratio and E/Z were determined by H NMR. 120 °C, 36
h. 100 °C. 120 °C, E/Z = 1.6:1. E/Z = 14:1. E/Z = 8:1.
b
b
Yield and ratio were determined by 1H NMR using dibromomethane
c
d
1
c
d
as the internal standard. Isolated yields of the major products. DMF/
DMSO (2.0 mL, v/v = 4:1).
e
f
g
h
mesitylene favorably produced the C2-alkenylated product 2a
with excellent regioselectivities (Table 1, entries 1−4), and
toluene gave the best performance (entry 5). Further screening
of solvents indicated that the C5-selectivity was slightly
improved when aprotic polar solvents were employed (entries
6−9). Surprisingly, the regioselectivity was reversed when
DMSO was employed as solvent, offering C5-alkenylated
product 3a (C5:C2 = 5:1) as the major product (entry 10).
Subtle optimization revealed that the combination of DMF/
DMSO (4:1) could slightly improve the C5-selectivity (C5:C2
= 6:1) (entry 11). Finally, we found that the ratio of C5 to C2
isomer could be further increased to 8:1 when 1c was employed
as the substrate (entry 13).
The substrate scope and generality of C2-alkenylation was
investigated under the optimized conditions as illustrated in
Table 2. tert-Butyl, ethyl, and methyl acrylates reacted with 1a
smoothly to form 2aa−2ac in 75−86% yields with excellent
regioselectivities (C2:C5 > 95:5). Acrylamides and acrylonitrile
gave 2ad−2ag in moderate yields under a prolonged reaction
time and higher temperature. For substrates bearing tert-butyl,
ethyl, and methyl ester at the C3 position (1a−1c), the
reactions afforded the corresponding products 2a−2c in 89%,
70%, and 83% yield. In addition, substitutions at the C4-phenyl
ring with electron-donating and -withdrawing groups were all
compatible with this process. For example, 4-OMe substituted
1f provided 2f in 75% yield, and the 4-Cl substituted 1d and 4-
CF3 substituted 1g furnished 2d and 2g in 74% and 71% yield.
Further studies revealed that 1h with the NO2 group on the
phenyl ring could also convert into the desired product 2h in
62% yield with excellent regioselectivity (C2:C5 > 95:5). When
N-ethyl and N-benzyl substituted 1i and 1j were tested, 2i and
2j were achieved in 75% and 53% yield.
Next, we turned our attention to the investigation of C5-
alkenylation (Table 3). Similar to the C2-alkenylation
procedure, a series of alkenes worked well and C5-alkenylation
products 3ca−3cg were obtained in 57−74% yields. It was
noteworthy that the regioselectivities of the reactions with
acrylamides (i.e., 3cd in 13:1 and 3ce in 13:1) were higher than
those with acrylates (i.e., 3ca in 9:1 and 3cb in 8:1). Moreover,
a variety of substituents on the phenyl ring, regardless of the
electron-deficient to -rich nature, all successfully produced C5-
alkenylated products 3d−3h in 64−75% yields with good
regioselectivities (6:1−9:1). N-Ethyl and N-benzyl substituted
substrates 1i and 1j offered the corresponding 3i and 3j in 65%
and 71% yields.
To better understand the reaction, we proposed a plausible
mechanism for our regioselective alkenylation process, which is
shown in Scheme 2. The palladation could preferentially occur
at the C2 position via a carboxylate assisted chelation11 to form
intermediate I in toluene. A subsequent Heck-type reaction
offers the C2-alkenylation pyrroles 2. However, a strong
coordinating solvent (DMSO)12,10b overrides the chelation
effect of the carboxylate group, promoting the palladation at the
more electron-rich C5 position through an electrophilic C−H
B
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Letter
of ( )-rhazinilam,15 which showed moderate antitumor
activity. As illustrated in Scheme 3, pyrrole 6 was first
a
Table 3. Substrate Scope of C5-Alkenylation
Scheme 3. Total Synthesis of ( )-Rhazinilam
a
Unless otherwise mentioned, all reactions were carried out using 1
(0.5 mmol), Pd(OAc)2 (10 mol %), AgOAc (1.0 mmol), and alkenes
(1.0 mmol) in DMF/DMSO (2.0 mL, v/v = 4:1), 80 °C, 20 h.
b
c
Isolated yields of major products. Ratio was determined by 1H
synthesized from phenyl acrylate 4 and TosMIC 5 through a
van Leusen reaction.16 Treatment of 6 and iodoolefin 715e with
NaH in DMF provided alkyl pyrrole 8. With the full carbon
skeleton in hand, we set out to attempt the key intramolecular
oxidative Heck reaction to build the architecture of
( )-rhazinilam. Gratifyingly, when 8 was subjected to the
regioselective C5-alkenylation conditions, the desired product 9
was achieved in 56% yield (C5:C2 = 12:1). Notably, due to the
existence of the C3-carboxylate group, compound 9 contains
two pairs of separable stereoisomers (9a:9b = 7:4). The relative
configurations of 9a and 9b were determined by X-ray
structural analysis.17 Hydrogenation of 9a with Wilkinson’s
catalyst18 gave intermediate 10a in quantitative yield.
Subsequent decarboxylation, hydrogenation, and macrolactam-
ization fulfilled the total synthesis of ( )-rhazinilam. For-
tunately, we found that 9b was also able to transform to
( )-rhazinilam through the same sequential reactions as 9a,
since the biaryl axis can rotate after decarboxylation.15h
In conclusion, we have developed a solvent-controlled
switchable alkenylation of 3,4-disubstituted pyrroles in
moderate to good yields with excellent regioselectivities for
the first time. Toluene favored the selective C2-alkenylations,
while DMSO led to the C5-alkenylation products. Further-
more, the application of selective C5-alkenylation to the total
synthesis of ( )-rhazinilam highlighted the potential utility of
our method in complex natural products synthesis. Research on
a detailed reaction mechanism and application to other natural
products synthesis are underway in our laboratory.
d
e
NMR. 100 °C. E/Z = 1.6:1.
Scheme 2. Proposed Mechanism of the Regioselective C−H
Alkenylations
activation pathway to produce intermediate II, followed by
rearomatization and a Heck-type reaction to afford the C5-
alkenylated products 3. In additional studies,13 we realized that
the ratios of 3c are closely related to the equivalents of DMSO;
40 mol % of DMSO could reverse the ratio (2c:3c) from 1.5:1
to 1:1.5. Further research showed that methyl 2-(4-(methyl-
thio)phenyl) acetate, which contains a methylthio group, could
also offer 3c in good yield and regioselectivity.
Since pyrrole structural motifs were present in diverse
pharmaceutical agents and bioactive natural products,14 we then
focused on the application of our method to the total synthesis
C
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Organic Letters
Letter
Sanford, M. S. Org. Lett. 2013, 15, 5428. (c) Chen, C.; Hartwig, J. F.
Science 2014, 343, 853.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures, analytical data, and 1H and 13C NMR
spectra for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
■
S
(9) (a) Tang, R.; Li, G.; Yu, J.-Q. Nature 2014, 507, 215. (b) Yang,
Y.-F.; Cheng, G.-J.; Liu, P.; Leow, D.; Sun, T.-Y.; Chen, P.; Zhang, X.;
Yu, J.-Q.; Wu, Y.-D.; Houk, K. N. J. Am. Chem. Soc. 2014, 136, 344.
(c) Wan, L.; Dastbaravardeh, N.; Li, G.; Yu, J.-Q. J. Am. Chem. Soc.
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(10) For selected examples of solvent-controlled regioselectivity, see:
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Shan, G.; Sun, Y.; Rao, Y. Angew. Chem., Int. Ed. 2013, 52, 4440 and
references therein.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: hyao@cpu.edu.cn.
*E-mail: ajlin@cpu.edu.cn.
Notes
The authors declare no competing financial interest.
(12) For selected examples on using DMSO as a coordinating ligand,
see: (a) Diao, T.; White, P.; Guzei, I.; Stahl, S. S. Inorg. Chem. 2012,
51, 11898. (b) McDonald, R. I.; Stahl, S. S. Angew. Chem., Int. Ed.
2010, 49, 5529. (c) Chen, M. S.; White, M. C. J. Am. Chem. Soc. 2004,
126, 1346.
(13) See Table S3 in the Supporting Information for details.
(14) (a) Chong, P. H.; Seeger, J. D. Pharmacotherapy 1997, 17, 1157.
(b) Wilkerson, W. W.; Copeland, R. A.; Covington, M.; Trzaskos, J.
M. J. Med. Chem. 1995, 38, 3895. (c) Fan, H.; Peng, J.; Hamann, M.
ACKNOWLEDGMENTS
■
We acknowledge the generous financial support by the NSFC
(21272276), the SKLNM (JKGZ201110, ZZJQ201306), and
the Ministry of Education of China (PSCIRT-1193). We also
thank Wei Cong in this group for reproducing the results for
2ac in Table 2 and 3cd in Table 3.
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