β-selective C-H arylation of pyrroles leading to concise syntheses of lamellarins C and I

Article abstract of DOI:10.1021/ja508449y

The first general β-selective C-H arylation of pyrroles has been developed by using a rhodium catalyst. This C-H arylation reaction, which is retrosynthetically straightforward but results in unusual regioselectivity, could result in de novo syntheses of

Full text of DOI:10.1021/ja508449y

Article
pubs.acs.org/JACS
β‑Selective C−H Arylation of Pyrroles Leading to Concise Syntheses
of Lamellarins C and I
Kirika Ueda,† Kazuma Amaike,† Richard M. Maceiczyk,† Kenichiro Itami,*,†,‡ and Junichiro Yamaguchi*,†
†Institute of Transformative Bio-Molecules (WPI-ITbM) and Graduate School of Science, Nagoya University, Chikusa, Nagoya
464-8602, Japan
‡JST, ERATO, Itami Molecular Nanocarbon Project, Nagoya University, Chikusa, Nagoya 464-8602, Japan
S
* Supporting Information
ABSTRACT: The first general β-selective C−H arylation of
pyrroles has been developed by using a rhodium catalyst. This
C−H arylation reaction, which is retrosynthetically straightfor-
ward but results in unusual regioselectivity, could result in de
novo syntheses of pyrrole-derived natural products and
pharmaceuticals. As such, we have successfully synthesized
polycyclic marine pyrrole alkaloids, lamellarins C and I, by
using this β-selective arylation of pyrroles with aryl iodides
(C−H/C−I coupling) and a new double C−H/C−H coupling
as key steps.
reactions of five-membered heteroarenes, such as pyrroles,
thiophenes, and furans, typically proceed preferentially at the α-
positions when both α- and β-positions are available. However,
we have shown in several cases in the C−H arylation of
thiophenes that otherwise-difficult β-selective arylation can be
achieved by catalyst control. Thus, we began by examining
some of our unique catalysts with a hope to identify conditions
for β-selective arylation of pyrroles (Table 1). When PdCl2 (5
mol %) and an electron-deficient phosphite ligand P[OCH-
(CF3)2]3 (L, 10 mol %), which were effective for the β-selective
arylation of thiophenes,10 were used, N-phenylpyrrole (1A) was
coupled with iodobenzene (2a) using Ag2CO3 in m-xylene at
140 °C to unfortunately give arylated product 3(α) with
complete α-selectivity (entry 1).
Next, we performed the C−H arylation of pyrrole 1A with 2a
under Ir catalysis (entries 2−4). We have also reported that
Crabtree’s catalyst, [Ir(cod)(py)PCy3]PF6 (cod = 1,5-cyclo-
octadiene, py = pyridine), is effective for the C−H arylation of
thiophenes and furans with virtually complete α-selectivity.11
When the coupling of 1A and 2a was performed using the
reported conditions (Ag2CO3 in m-xylene), surprisingly, the β-
arylated product 3(β) was obtained, albeit in a very low yield
(6%, entry 2). Encouraged by this result, we then screened
several Ir catalysts,12 and we found that [Ir(cod)2]BF4 (5 mol
%) and PCy3 (10 mol %) were effective for the C−H arylation
of pyrrole, providing the β-arylated product in 39% yield (entry
3). Moreover, an increase in catalyst loading allowed for the
corresponding coupling product to be formed in 64% yield
(entry 4). Although we achieved a β-selective arylation of N-
phenylpyrrole (1A), this iridium-based catalytic system was not
INTRODUCTION
■
De novo construction of natural products and pharmaceutically
relevant building blocks has always been a significant goal in
organic synthesis. Arylpyrroles, particularly β-aryl-substituted
pyrroles, form a set of structures that have been sought after by
many synthetic chemists (representative compounds are
showcased in Figure 1).1 Classically, β-arylpyrroles have been
synthesized by the Paal−Knorr pyrrole synthesis,2 but the 1,4-
diketone starting material (or its equivalent) is not necessarily
easy to synthesize depending on the number and type of
substituents (Figure 2). Furthermore, despite the development
of many methods in heterocyclic chemistry and cross-coupling
reactions for the synthesis of β-arylpyrroles,3 the current state-
of-the-art method involves catalytic C−H borylation of
pyrroles, followed by Pd-catalyzed Suzuki−Miyaura cross-
coupling.1e
Meanwhile, transition-metal-catalyzed C−H functionalization
of organic molecules has emerged as an enabling synthetic tool
for natural products and pharmaceuticals.4,5 Particularly, the
construction of C−C bonds between (hetero)arenes and arenes
by C−H arylation has attracted much attention from organic
chemists because it is an ideal method for the synthesis of
(hetero)biaryls.6 However, in terms of arylated pyrrole
synthesis, β-selective arylation of unsubstituted pyrroles is
rare compared to α-arylation7 and a general protocol has not
been reported thus far.8,9 Herein, we report the first general β-
selective C−H arylation of pyrroles by using a Rh catalyst as
well as its application to the total synthesis of polycyclic pyrrole
alkaloids, lamellarins C and I.
RESULTS AND DISCUSSION
■
β-Selective C−H Arylation of Pyrroles with Iodoar-
enes. It has been well documented that the C−H arylation
Received: February 8, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja508449y | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
microwave irradiation.13 In these reports, only one example
demonstrated the β-arylation of heteroarenes, when N-
phenylpyrrole (1A) was coupled with 4-acetylaryl iodide (2b)
in 58% yield (entry 6).13a When the reaction temperature was
decreased to 150 °C, the yield of the corresponding coupling
product increased to 84% without any change in regioselectiv-
ity, and microwave irradiation was no longer needed (entry 7).
With the use of these reaction conditions, even when the
pyrrole substrate was changed from 1A to N-methylpyrrole
(1B), the corresponding coupling product was obtained in 74%
yield (entry 8, β/α = 93:7).
On the basis of this promising result, we further optimized
the reaction conditions using N-methylpyrrole (1B) and
iodobenzene (2a) as substrates.12 Other Rh sources decreased
the yields as well as β-selectivities (entries 9−11). When AgO
was used instead of Ag2CO3, the decrease in yield and
regioselectivity was observed (entry 12), while Ag2O gave
similar results (entry 13). The use of other bases such as
K2CO3 completely shut down the reaction (entry 14). The use
of DME (1,2-dimethoxyethane) as an additive was slightly
effective for preventing double C−H arylation of pyrrole 1B
(entry 15), and 1,4-dioxane was slightly better than DME
(entry 16). Finally, the amount of Ag2CO3 can be reduced from
1.0 to 0.5 equiv (entry 17) and the solvent system was changed
to 1,4-dioxane/m-xylene (1:1) to allow for a greater solubility
of a wider range of substrates. Under these optimized
conditions, 1B was coupled with 2a in the presence of the
same Rh catalyst to give N-methyl-3-pheynlpyrrole (3Ba) in
73% yield with 91% β-selectivity (entry 18).
Figure 1. Arylpyrrole-derived natural products and pharmaceuticals.
On the basis of these findings, we then examined the scope
of present C−H arylation by employing various pyrrole and
aryl iodide substrates (Scheme 1). N-Methylpyrrole (1B) was
successfully coupled with phenyl (2a), 3-methoxyphenyl (2c),
4-nitrophenyl (2d) and 4-trifluoromethylphenyl iodide (2e) to
afford the corresponding coupling products 3Ba, 3Bc, 3Bd, and
3Be in moderate to good yields with high β-selectivity (β/α >
91:9). The coupling reaction of 1B with 4-bromo-1-
iodobenzene (2f) proceeded at the carbon−iodine bond
selectively to give the resulting coupling product 3Bf in
excellent yield and excellent β-selectivity. Iodoheteroarenes
such as 3-iodothiophene (2g) were also tolerated to give the
resulting product (3Bg) in 72% yield. To our delight, the N-
substituent on the pyrrole portion can be changed from methyl
to ethyl (3Ca), benzyl (3Dd), phenyl (3Ad, 3Ab, 3Ah) and
triisopropylsilyl (TIPS) (3Ei, 3Ed). For example, when N-ethyl
(1C), N-phenyl (1A), N-TIPS (1E), and N-alkyl (1F: R =
CH2CH2C6H4OMe) pyrroles were used instead of 1B, the
coupling reaction proceeded well to give the corresponding β-
arylpyrroles.
Moreover, substituted pyrroles with C2-substituents such as
benzyl (1G), ethylpropanoate (1H), and ethyl acrylate (1I)
also gave β-arylated (C4-arylated) pyrroles (3Gd, 3Hd, 3Id) in
good to moderate yields. The regioselectivity was not only
maintained for 2,3-disubstituted pyrrole (1J), but also for 3-
substituted pyrrole (1K), thus affording the corresponding
coupling products (3Jd and 3Kd) in moderate yields. Even
when a more sterically demanding 2,5-disubstituted pyrrole
(1L) was reacted with iodoarene, the resulting coupling
product (3Ld) was obtained in 51% yield. It should be noted
that complete or greater than 90% regioselectivities of β-C−H
arylation were achieved, and the regioisomers can be readily
separated by column chromatography in all cases.
Figure 2. Synthetic methods for β-arylpyrroles.
general in terms of pyrrole substrate. For example, when N-
methylpyrrole (1B) was subjected under otherwise identical
conditions, the corresponding product was obtained in only
26% yield (entry 5). To gain more reactivity, we then examined
other transition-metal catalysts.
Our group previously reported a direct C−H arylation of
(hetero)arenes, with mainly thiophenes and furans reacting
with aryl iodides in the presence of RhCl(CO){P[OCH-
(CF3)2]3}2 and Ag2CO3 in m-xylene at 200 °C under
B
dx.doi.org/10.1021/ja508449y | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
a
Table 1. C−H Arylation of Pyrroles with Iodoarenes Using Transition-Metal Catalysts
b
entry
pyrrole
aryl iodide
catalyst (mol %)
PdCl2 (5), L (10)
base (equiv)
additive
temp (°C)
yield of 3 (%)
β/α
1
1A
1A
1A
1A
1B
1A
1A
1B
1B
1B
1B
1B
1B
1B
1B
1B
1B
1B
2a
2a
2a
2a
2a
2b
2b
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
Ag2CO3 (1)
Ag2CO3 (1)
Ag2CO3 (1)
Ag2CO3 (1)
Ag2CO3 (1)
Ag2CO3 (1)
Ag2CO3 (1)
Ag2CO3 (1)
Ag2CO3 (1)
Ag2CO3 (1)
Ag2CO3 (1)
AgO (1)
−
−
−
−
−
140
160
160
160
150
200
150
150
150
150
150
150
150
150
150
150
150
150
63
6
1:>99
96:4
2
[Ir(cod)(py)PCy3]PF6 (5)
[Ir(cod)2]BF4 (5), PCy3 (10)
[Ir(cod)2]BF4 (10), PCy3 (20)
[Ir(cod)2]BF4 (10), PCy3 (20)
RhCl(CO)L2 (3)
3
39
64
26
58
84
74
29
52
24
37
73
0
98:2
4
>99:1
>99:1
>99:1
>99:1
93:7
50:50
79:21
64:36
85:15
92:8
5
6
DME
7
RhCl(CO)L2 (3)
DME
8
RhCl(CO)L2 (3)
DME
9
[Rh(nbd)2]BF4 (3), L (6)
[Rh(nbd)2Cl]2 (1.5), L (6)
Rh(acac)(C2H4)2 (3), L (6)
RhCl(CO)L2 (3)
DME
10
11
12
13
14
15
16
17
DME
DME
DME
RhCl(CO)L2 (3)
Ag2O (1)
DME
RhCl(CO)L2 (3)
K2CO3 (1)
Ag2CO3 (1)
Ag2CO3 (1)
Ag2CO3 (0.5)
Ag2CO3 (0.5)
DME
−
89:11
RhCl(CO)L2 (3)
−
66
78
77
RhCl(CO)L2 (3)
1,4-dioxane
1,4-dioxane
1,4-dioxane
93:7
RhCl(CO)L2 (3)
87:13
91:9
c
18
RhCl(CO)L2 (3)
73
a
b
Reaction conditions: 1 (0.75 mmol), 2 (0.5 mmol), catalyst, base, additive (0.5 mmol), and m-xylene (2.5 mL), temp, 12−19 h. Isolated yield. L =
c
P[OCH(CF3)2]3 1,4-Dioxane/m-xylene (1:1) was used as a solvent.
Mechanistic Considerations. Through extensive inves-
tigations, we were able to identify synthetically useful
conditions affecting β-selective C−H arylation of pyrroles
through the agency of rhodium catalysis. Before describing our
synthetic campaign toward biologically active natural products,
here we provide some mechanistic considerations we have
gained through these studies. One of the most interesting
findings from mechanistic point of view is the observation of
“seemingly” reverse regioselectivity in pyrroles (β-selective;
present study) and thiophenes/furans (α-selective; our
previous study)13a,b using the same rhodium catalyst (Figure
3a).
Previously we uncovered that RhCl(CO){P[OCH(CF3)2]3}2
catalysis works best for electron-rich heteroarenes and benzene
derivatives and the reaction sites for these substrate match
nicely to those of classical electrophilic substitution reactions;
α-selective for thiophenes/furans and ortho−para selective for
anisole. This was achieved based on our catalyst design
employing a strongly π-accepting ligand on rhodium.13a,b In
addition to such electronic factor, however, we noticed that
steric factor also contributes in determining the reaction sites of
aromatic substrates. For example, in the reaction of anisole and
iodoarenes, the C−H arylation took place preferentially at the
para position over the ortho position (ortho/para = 29:71),
indicating that the steric repulsion of an arene substituent
(methoxy group in anisole) and catalyst is another controlling
element in regioselectivity. We assume that the emergence of
such steric factor led to the β-selective C−H arylation in
pyrroles.
aryl-RhIII species B. The π-complexation of a pyrrole followed
by C−H rhodation of thus-formed C leads to the key diaryl-
RhIII intermediates D. The reductive elimination from D
releases an arylpyrrole product, with the regeneration of A. We
assume that the steric repulsion of N-substituent of pyrrole
substrate and bulky catalyst framework (particularly our
phosphite ligand) in the key π-complexation and C−H
rhodation steps facilitates the preferential generation of
intermediate D(β), leading to the production a β-arylpyrrole.
In the case of thiophenes and furans, there are no such
substituents on heteroatoms. We assume that the lack of such
steric factor led these substrates to follow the typical
electrophilic substitution regioselectivity (α-selective).
The importance of N-substituents of pyrrole substrates was
seen in our substrate scope study shown in Scheme 1. For
example, we observed a trend that the β-selectivity increases as
the N-substituent on the pyrrole gets larger (Me (3Ba) < Et
(3Ca) < Bn (3Dd) = TIPS (3Ei)). To further check this
tendency using the same arylating agent, we investigated this
coupling reaction using various pyrroles and iodobenzene (2a)
as shown in Figure 4a. As a result, the experiments clearly
showed that the bigger N-substituent on the pyrroles increased
the β-selectivity (Me, 91%; Et, 96%; Bn, >99%; and TIPS,
>99%) and decreased the yield (Me, 73%; Et, 53%; Bn, 32%;
and TIPS, 12%). Unfortunately, pyrroles without a N-
substituent (N−H pyrroles) did not react at all. Additionally,
when one of the β-positions is blocked as with 1K, the
selectivity was decreased (β/α = 92:8) even when using TIPS
as an N-substituent (Scheme 1). Moreover, we found that the
steric factor (N-substituent effect) overrides the electronic
factors exerted by a C-substituent on pyrrole ring (Figure 4b).
For example, the C2-substitution with electron-donating benzyl
group, which should electronically facilitate the electrophilic
Shown in Figure 3b is our currently assumed mechanistic
pathway for β-selective C−H arylation of pyrroles. The neutral
RhI complex A first undergoes oxidative addition with an
iodoarene and halide removal with Ag2CO3 to generate cationic
C
dx.doi.org/10.1021/ja508449y | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Scheme 1. Substrate Scope for the β-Selective Arylation of
a
Pyrroles
Figure 3. Arene C−H regioselectivity and a possible mechanism of
pyrrole C−H arylation under RhCl(CO){P[OCH(CF3)2]3}2.
a
Reaction conditions: 1 (0.75 mmol), 2 (0.5 mmol), RhCl(CO){P-
[OCH(CF3)2]3}2 (3 mol %), Ag2CO3 (0.25 mmol), 1,4-dioxane/m-
b
xylene =1:1 (1.7 mL), 150 °C, 19 h. 1 (0.75 mmol), 2 (0.5 mmol),
Figure 4. Importance of steric effect in pyrrole C−H arylation under
RhCl(CO){P[OCH(CF3)2]3}2.
RhCl(CO){P[OCH(CF3)2]3}2 (1.5 mol %), Ag2CO3 (0.25 mmol),
DME (0.5 mmol), m-xylene (2.5 mL), 150 °C, 24 h. All product yields
are isolated yields (single isomer).
settings was demonstrated through the total synthesis of
lamellarins. Lamellarins are a family of marine natural products
isolated from the prosobranch mollusc Lamellaria sp.14,15 This
series of compounds inhibit the proliferation of cancer cells and
therefore are promising candidates for anticancer drugs. In
particular, in 1993, Bowden et al. reported six new lamellarin
substitution at the C5 position (α position), did not decrease
the β-selectivity of parent system.
Application to the Concise Synthesis of Lamellarins C
and I. Next, the utility of this reaction in complex molecular
D
dx.doi.org/10.1021/ja508449y | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Our blueprint for the synthesis of lamellarins C and I is
shown in Scheme 2. Aiming to apply the β-selective arylation of
pyrroles for the synthesis of lamellarins, we planned to connect
its building blocks using direct C−H couplings. As the first step,
the present C−H arylation method would couple an N-
substituted pyrrole at the β-position (C3-position) with an
iodoarene. Then, a carbonyl moiety would be introduced onto
the pyrrole ring at the C5-position. Lastly, the connection
between the C2- and C4-positions of the pyrrole with arene
units would be accomplished by intramolecular double C−H/
C−H couplings.
Scheme 2. Strategy for the Synthesis of Lamellarins via
Direct C−H Couplings
The synthesis of lamellarins C and I commenced with
aldehyde 4, a commercially available compound, which was
readily converted to a pyrrole by a three-step sequence
(nitroaldol reaction, reduction of the nitro group, followed by
pyrrole synthesis) to afford pyrrole 5 (Scheme 3).16,17 Under
our standard conditions, 5 smoothly underwent β-selective
arylation with aryl iodides 6a and 6b to give the corresponding
coupling products 7a and 7b in 49% and 40% yields,
respectively. The synthesis of 7a was feasible on 1.0 g scale
without showing a decrease in yield. Treatment of 7a and 7b
with trichloroacetyl chloride (Friedel−Crafts acylation),
followed by hydrolysis of the trichloroacetyl group, produced
the corresponding carboxylic acids.18,19 These carboxylic acids
were then condensed with phenol derivative 8 to afford esters
9a and 9b in 57% and 99% yield, respectively, over 2 steps.
With the core framework of the lamellarins in hand, we set out
to connect two C−C bonds between the pyrrole unit and the
peripheral aryl groups. Exposure of 9a and 9b with various
oxidants such as phenyliodonium diacetate (PIDA), phenyl-
iodonium ditrifluoroacetate (PIFA), DDQ, ceric ammonium
nitrate (CAN), and K2S2O8 did not yield the desired
cyclodehydrogenation products. Finally, we discovered that an
exceedingly simple construction of these C−C bonds was
alkaloids, including lamellarin I obtained from the Australian
colonial ascidian Didemnum sp.,14c which showed sensitizing
effects in multidrug-resistant P388/Schabel cells to doxorubicin.
Lamellarin C also demonstrates potent cytotoxicity against 10
human tumor cell lines.14d Although the syntheses of
lamellarins were already reported by several research groups,
these syntheses all required more than 10 steps (all steps, not
just longest linear ones, are included in this count).16
a
Scheme 3. Synthesis of Lamellarins C and I
a
Reagents and conditions: (a) CH3NO2 (15 equiv), piperidine (6 mol %), 4 Å MS, toluene, 110 °C, 20 h, 92%; (b) LiAlH4 (3.0 equiv), THF, 0 °C
to reflux, 1.5 h, 83%; (c) 2,5-dimethoxytetrahydrofuran (1.2 equiv), AcOH/EtOH = 1:1, 90 °C, 18 h, 56%; (d) for 7a: 5 (1.4 equiv), 6a (1.0 equiv),
[RhCl(CO)2]2 (1.4 mol %), P[OCH(CF3)2]3 (5.8 mol %), Ag2CO3 (0.94 equiv), DME (1.0 equiv), m-xylene, 150 °C, 25 h, 49%; for 7b: 5 (1.5
equiv), 6b (1.0 equiv), RhCl(CO){P[OCH(CF3)2]3} (3 mol %), Ag2CO3 (1.0 equiv), 1,4-dioxane/m-xylene = 2:3, 150 °C, 24 h, 40%; (e)
trichloroacetyl chloride (1.8 equiv), pyridine (1.8 equiv), THF, 23 °C, 20 h; K2CO3(aq) (30 equiv), acetone, 23 °C, 13 h; (f) 8 (1.5 equiv), EDC
HCl (1.5 equiv), DMAP (1.5 equiv), benzene, 23 °C, 14 h, 57% (2 steps for 9a), 99% (2 steps for 9b); (g) for 10a: Pd(OAc)2 (1.0 equiv),
Cu(OAc)2 (6.0 equiv), K2CO3 (2.0 equiv), DMAc, 80 °C, 27 h, 39%; for 10b: Pd(OAc)2 (2.0 equiv), Cu(OAc)2 (6.0 equiv), K2CO3 (2.0 equiv),
DMAc, 80 °C, 27 h, 46%; (h) BCl3 (6.0 equiv), CH2Cl2, −78 to 23 °C, 71% (for lamellarin I), 39% (for lamellarin C).
E
dx.doi.org/10.1021/ja508449y | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
(2) Paal, C. Ber. Dtsch. Chem. Ges. 1885, 18, 367.
possible by palladium mediation. Thus, 9a and 9b were treated
with stoichiometric Pd(OAc)2, Cu(OAc)2 and K2CO3 (for
which catalytic conditions were reported by Greaney and co-
workers20) to successfully furnish products 10a and 10b in 39%
and 43% yields, respectively. Finally, after removal of the i-Pr
group selectively by treatment with BCl3, the synthesis of
lamellarins C and I was accomplished (8 steps from
commercially available starting materials).
(3) For recent examples, see: (a) Ayats, C.; Soley, R.; Albericio, F.;
́
Alvarez, M. Org. Biomol. Chem. 2009, 7, 860. (b) Gu, Z.; Zakarian, A.
Org. Lett. 2010, 12, 4224. (c) Ni, L.; Li, Z.; Wu, F.; Xu, J.; Wu, X.;
Kong, L.; Yao, H. Tetrahedron Lett. 2012, 53, 1271. (d) Schwalm, C.
S.; de Castro, I.; Ferrari, J.; de Oliveira, F. L. Tetrahedron Lett. 2012,
53, 1660. (e) Zhang, M.; Neumann, H.; Beller, M. Angew. Chem., Int.
Ed. 2013, 52, 597.
(4) (a) Godula, K.; Sames, D. Science 2006, 312, 67. (b) McMurray,
L.; O’Hara, F.; Gaunt, M. J. Chem. Soc. Rev. 2011, 40, 1885.
(c) Gutekunst, W. R.; Baran, P. S. Chem. Soc. Rev. 2011, 40, 1976.
(d) Chen, D. Y.-K.; Youn, S. W. Chem.Eur. J. 2012, 18, 9452.
(e) Yamaguchi, J.; Yamaguchi, A. D.; Itami, K. Angew. Chem., Int. Ed.
2012, 51, 8960.
(5) For recent examples in the total synthesis of natural products via
C−H functionalization, see: (a) Wang, D. H.; Yu, J.-Q. J. Am. Chem.
Soc. 2011, 133, 5767. (b) Gutekunst, W. R.; Baran, P. S. J. Am. Chem.
Soc. 2011, 133, 19076. (c) Mandal, D.; Yamaguchi, A. D.; Yamaguchi,
J.; Itami, K. J. Am. Chem. Soc. 2011, 133, 19660. (d) Zhao, L.;
Tsukano, C.; Kwon, E.; Takemoto, Y.; Hirama, M. Angew. Chem., Int.
Ed. 2012, 52, 1722. (e) Amaike, K.; Muto, K.; Yamaguchi, J.; Itami, K.
J. Am. Chem. Soc. 2012, 134, 13573. (f) Wang, H.; Li, G.; Engle, K. M.;
Yu, J.-Q.; Davies, H. M. L. J. Am. Chem. Soc. 2013, 135, 6774.
(g) Rosen, B. R.; Simke, L. R.; Thuy-Boun, P. S.; Dixon, D. D.; Yu, J.-
Q.; Baran, P. S. Angew. Chem., Int. Ed. 2013, 52, 7317.
(6) For reviews, see: (a) Ackermann, L.; Vicente, R.; Kapdi, A. R.
Angew. Chem., Int. Ed. 2009, 48, 9792. (b) Chen, X.; Engle, K. M.;
Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094.
(c) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174.
(d) Wencel-Delord, J.; Glorius, F. Nat. Chem. 2013, 5, 369.
(7) For a review on the direct α-arylation of pyrroles, see: (a) Beck,
E. M.; Gaunt, M. J. Top. Curr. Chem. 2010, 292, 85. For selected
examples of direct α-arylation of pyrroles, see: (b) Blaszykowski, C.;
Aktoudianakis, E.; Bressy, C.; Alberico, D.; Lautens, M. Org. Lett.
CONCLUSIONS
■
In summary, we have developed a general method for the β-
selective C−H arylation of pyrroles by using a rhodium catalyst.
This β-selective C−H/C−I coupling followed by intra-
molecular double C−H/C−H coupling was applied to a
concise synthesis of lamellarins C and I. Although tremendous
advances in C−H arylation have been achieved, to continue
pushing the boundaries of this field involves not only efficient
ways to generate known compounds, but also a strategy to
construct new motifs that are difficult to make using classical
methods. In this regard, “regiodivergent” C−H arylation has
garnered interest from the synthetic community since it is
retrosynthetically straightforward and provides divergent
regioselectivities in the given products.21 We believe that this
C−H coupling technology would allow for a re-examination of
previous syntheses and a development of de novo syntheses of
biologically active molecules.
ASSOCIATED CONTENT
■
S
* Supporting Information
Detailed experimental procedures and spectral data for all
compounds, including scanned image of H and 13C NMR
1
́
2006, 8, 2043. (c) Toure, B. B.; Lane, B. S.; Sames, D. Org. Lett. 2006,
spectra. This material is available free of charge via the Internet
at http://pubs.acs.org.
8, 1979. (d) Deprez, N. R.; Kalyani, D.; Krause, A.; Sanford, M. S. J.
Am. Chem. Soc. 2006, 128, 4972. (e) Satoh, T.; Miura, M. Chem. Lett.
2007, 36, 200. (f) Wang, X.; Gribkov, D. V.; Sames, D. J. Org. Chem.
2007, 72, 1476. (g) Stuart, D. R.; Villemure, E.; Fagnou, K. J. Am.
Chem. Soc. 2007, 129, 12072. (h) Yang, S.-D.; Sun, C.-L.; Fang, Z.; Li,
B.-J.; Li, Y.-Z.; Shi, Z.-J. Angew. Chem., Int. Ed. 2008, 47, 1473.
(i) Rogera, J.; Doucet, H. Adv. Synth. Catal. 2009, 351, 1977.
(j) Nadres, E. T.; Lazareva, A.; Daugulis, O. J. Org. Chem. 2011, 76,
471.
AUTHOR INFORMATION
■
Corresponding Authors
itami@chem.nagoya-u.ac.jp
junichiro@chem.nagoya-u.ac.jp
Notes
The authors declare no competing financial interest.
(8) For methods in the synthesis of β-arylated pyrroles by oxidative
C−H coupling of pyrroles and heteroarenes, see: (a) Yamaguchi, A.
D.; Mandal, D.; Yamaguchi, J.; Itami, K. Chem. Lett. 2011, 40, 555.
(b) Kuhl, N.; Hopkinson, M. N.; Glorius, F. Angew. Chem., Int. Ed.
2012, 51, 8230.
(9) For intramolecular C−H coupling of pyrroles at the β-position,
see: (a) Bowie, A. L.; Hughes, C. C.; Trauner, D. Org. Lett. 2005, 7,
5207. (b) Bowie, A. L., Jr.; Trauner, D. J. Org. Chem. 2009, 74, 1581.
(10) (a) Yanagisawa, S.; Ueda, K.; Sekizawa, H.; Itami, K. J. Am.
Chem. Soc. 2009, 131, 14622. (b) Ueda, K.; Yanagisawa, S.; Yamaguchi,
J.; Itami, K. Angew. Chem., Int. Ed. 2010, 49, 8946.
ACKNOWLEDGMENTS
■
This work was supported by the Funding Program for Next
Generation World-Leading Researchers from JSPS (220GR049
to K.I.), Grants-in-Aid for Scientific Research on Innovative
Areas “Molecular Activation Directed toward Straightforward
Synthesis” (25105720 to J.Y.) and KAKENHI (25708005 to
J.Y.) from MEXT. K.U. and K.A. thank JSPS for a predoctoral
fellowship. ITbM is supported by the World Premier
International Research Center (WPI) Initiative, Japan.
(11) (a) Join, B.; Yamamoto, T.; Itami, K. Angew. Chem., Int. Ed.
2009, 48, 3644. (b) Junker, A.; Yamaguchi, J.; Itami, K.; Wunsch, B. J.
Org. Chem. 2013, 78, 5579.
̈
REFERENCES
■
(12) See the Supporting Information for further details.
(13) (a) Yanagisawa, S.; Sudo, T.; Noyori, R.; Itami, K. J. Am. Chem.
Soc. 2006, 128, 11748. (b) Yanagisawa, S.; Sudo, T.; Noyori, R.; Itami,
K. Tetrahedron 2008, 64, 6073. One example of β-arylation of N-
methylpyrrole was also reported by Sames. (c) Wang, X.; Lane, B. S.;
Sames, D. J. Am. Chem. Soc. 2005, 127, 4996.
(14) (a) Fan, H.; Peng, J.; Hamann, M. T.; Hu, J.-F. Chem. Rev. 2008,
108, 264. (b) Menna, M.; Fattorusso, E.; Imperatore, C. Molecules
2011, 16, 8694. (c) Carroll, A. R.; Bowden, B. F.; Coll, J. C. Aust. J.
Chem. 1993, 46, 489. (d) Cantrell, C. L.; Groweiss, A.; Gustafson, K.
R.; Boyd, M. R. Nat. Prod. Lett. 1999, 14, 39.
(1) For reviews, see: (a) Young, I. S.; Thornton, P. D.; Thompson, A.
Nat. Prod. Rep. 2010, 27, 1801. For selected examples, see: (b) Roth,
B. D. Prog. Med. Chem. 2002, 40, 1. (c) Furstner, A.; Domostoj, M. M.;
̈
Scheiper, B. J. Am. Chem. Soc. 2005, 127, 11620. (d) Zhang, W.; Liu,
Z.; Li, S.; Yang, T.; Zhang, Q.; Ma, L.; Tian, X.; Zhang, H.; Huang, C.;
Zhang, S.; Ju, J.; Shen, Y.; Zhang, C. Org. Lett. 2012, 14, 3364.
(e) Beck, E. M.; Hatley, R.; Gaunt, M. J. Angew. Chem., Int. Ed. 2008,
47, 3004. (f) Davis, R. A.; Buchanan, M. S.; Duffy, S.; Avery, V. M.;
Charman, S. A.; Charman, W. N.; White, K. L.; Shackleford, D. M.;
Edstein, M. D.; Andrews, K. T.; Camp, D.; Quinn, R. J. J. Med. Chem.
2012, 55, 5851.
F
dx.doi.org/10.1021/ja508449y | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
(15) Andersen, R. J.; Faulkner, D. J.; He, C.-H.; Van Duyne, G. D.;
Clardy, J. J. Am. Chem. Soc. 1985, 107, 5492.
(16) (a) Díaz, M.; Guitian, E.; Castedo, E. Synlett 2001, 1164.
́
(b) Ploypradith, P.; Petchmance, T.; Sahakitpichan, P.; Litvinas, N. D.;
Ruchirawat, S. J. Org. Chem. 2006, 71, 9440. (c) Fujikawa, N.; Ohta,
T.; Yamaguchi, T.; Fukuda, T.; Ishibashi, F.; Iwao, M. Tetrahedron
2006, 62, 594. (d) Ohta, T.; Fukuda, T.; Ishibashi, F.; Iwao, M. J. Org.
Chem. 2009, 74, 8143.
(17) Fioravanti, S.; Pellacani, L.; Tardella, P. A.; Vergari, M. C. Org.
Lett. 2008, 10, 1449.
(18) Richards, J. J.; Reed, C. S.; Melander, C. Bioorg. Med. Chem. Lett.
2008, 18, 4325.
(19) Koriatopoulou, K.; Karousis, N.; Varvounis, G. Tetrahedron
2008, 64, 10009.
(20) Pintori, D. G.; Greaney, M. F. J. Am. Chem. Soc. 2011, 133,
1209.
(21) For a review, see: (a) Roger, J.; Gottumukkala, A. L.; Doucet, H.
ChemCatChem 2010, 2, 20. For thiophenes, see: (b) Kirchberg, S.;
Tani, S.; Ueda, K.; Yamaguchi, J.; Studer, A.; Itami, K. Angew. Chem.,
Int. Ed. 2011, 50, 2387. (c) Yamaguchi, K.; Yamaguchi, J.; Studer, A.;
Itami, K. Chem. Sci. 2012, 3, 2165. (d) Funaki, K.; Sato, T.; Oi, S. Org.
Lett. 2012, 14, 6186. (e) Yamaguchi, K.; Kondo, H.; Yamaguchi, J.;
Itami, K. Chem. Sci. 2013, 4, 3753. (f) Yuan, K.; Doucet, H. Chem. Sci.
2013, 5, 3495. (g) Tang, D.-T. D.; Collins, K. D.; Glorius, F. J. Am.
Chem. Soc. 2013, 135, 7450. For thiazoles, see: (h) Tani, S.; Uehara,
T. N.; Yamaguchi, J.; Itami, K. Chem. Sci. 2014, 5, 123. (i) Uehara, T.
N.; Yamaguchi, J.; Itami, K. Asian. J. Org. Chem. 2013, 2, 938. For
indoles, see: (j) Stuart, D. R.; Villemure, E.; Fagnou, K. J. Am. Chem.
Soc. 2007, 129, 12072. For pyridines, see: (k) Ye, M.; Gao, G.-L.;
Edmunds, A. J. F.; Worthington, P. A.; Morris, J. A.; Yu, J.-Q. J. Am.
Chem. Soc. 2011, 133, 19090.
G
dx.doi.org/10.1021/ja508449y | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX