Rhodium(III)-Catalyzed Ortho-Alkenylation of Anilines Directed by a Removable Boc-Protecting Group

Article abstract of DOI:10.1021/acs.orglett.7b00569

The rhodium(III)-catalyzed ortho-alkenylation of N-Boc-anilines with alkenes such as acrylate ester and styrene proceeds smoothly through C-H bond cleavage. Obtained o-alkenylanilines can be readily transformed to nitrogen-containing fused heteroaromatic compounds including indoles and quinolines.

Full text of DOI:10.1021/acs.orglett.7b00569

Letter
pubs.acs.org/OrgLett
Rhodium(III)-Catalyzed Ortho-Alkenylation of Anilines Directed by a
Removable Boc-Protecting Group
Tomohiro Morita,† Tetsuya Satoh,*,†,‡ and Masahiro Miura*,†
†Department of Applied Chemistry, Graduate School of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
‡Department of Chemistry, Graduate School of Science, Osaka City University, 3-3-138 Sugimoto, Sumiyoshi-ku, Osaka 558-8585,
Japan
S
* Supporting Information
ABSTRACT: The rhodium(III)-catalyzed ortho-alkenylation of N-
Boc-anilines with alkenes such as acrylate ester and styrene proceeds
smoothly through C−H bond cleavage. Obtained o-alkenylanilines
can be readily transformed to nitrogen-containing fused hetero-
aromatic compounds including indoles and quinolines.
ransition-metal-catalyzed direct C−H bond functionaliza-
tion reactions have been significantly developed as
Scheme 1. Synthesis and Further Functionalization of o-
Alkenylanilines
T
powerful synthetic tools in modern organic synthesis. The
direct transformations provide straightforward synthetic
approaches to complex target molecules from relatively simple
starting materials. Among them, the reactions utilizing a
directing group are particularly useful because the directing
group leads to regioselective functionalization of ubiquitous C−
H bonds in organic molecules at the neighboring position.1,2
For example, N-acylanilines undergo ortho-selective alkenyla-
tion upon treatment with alkenes under palladium,3 rhodium,4
or ruthenium5 catalysis. In contrast to the acylamino directing
group,3−5 the utilization of carbamate moieties including the
tert-butoxycarbonyl (Boc) function has been less explored.6
The Boc function is one of the most widely employed
protecting groups for amino groups in organic synthesis. Since
this can be added and removed on and from amines more
readily compared to acyl protecting groups, there is high
potential for it to be utilizable as a traceless directing group.7
During our continuous studies on rhodium-catalyzed ortho-
selective C−H bond functionalization reactions,2v,w,8 we have
found that N-Boc-anilines react with alkenes such as acrylate
esters and styrene efficiently in the presence of a rhodium(III)
catalyst and a copper salt oxidant through Boc-directed C−H
bond cleavage to produce ortho-alkenylated aniline derivatives
(Scheme 1). Products obtained in this way can be converted to
N-unprotected 2-alkenylanilines by a conventional deprotection
procedure9 and undergo further functionalization that leads to
valuable nitrogen-containing fused heteroaromatic compounds.
These new findings are described herein.
phenyl]acrylate (3aa), was obtained in 68% yield (Table 1,
entry 1). Besides ortho-alkenylated 3aa, no ortho-alkylated and
annulation products were detected. The reaction could be
conducted in the presence of a catalytic amount of Cu(OAc)2·
H2O (0.04 mmol) under air, in spite of its somewhat lower
efficiency (entry 2). The use of neutral [Cp*RhCl2]2 as a
catalyst did not give 3aa at all (entry 3). While the yield of 3aa
was slightly increased in ButOH (entry 4), the reaction was
sluggish in other solvents such as EtOH, PhCl, and THF
(entries 5−7). Decreasing the reaction temperature to 60 °C
enhanced the 3aa yield up to 82% (entry 8), although a further
decrease to 50 °C reduced the yield to 68% (entry 9). The use
of anhydrous Cu(OAc)2 in place of Cu(OAc)2·H2O gave a
somewhat better result (entry 10). The amount of the rhodium
catalyst could be cut down to 4 mol % without a significant
change of reaction efficiency (entry 11), although a further
decrease reduced the product yield (entry 12). The gram-scale
synthesis of 3aa (1.29 g) could be accomplished by a simple
scale-up using 1a (5.2 mmol), 2a (10.4 mmol), [Cp*Rh-
In an initial attempt, N-Boc-aniline (1a) (0.2 mmol) was
treated with n-butyl acrylate (2a) (0.4 mmol) in the presence of
[Cp*Rh(MeCN)3][SbF6]2 (0.01 mmol, 5 mol %) and
Cu(OAc)2·H2O (0.4 mmol) in AmtOH (tert-amyl alcohol)
under N2 at 80 °C for 6 h. As a result, an ortho-alkenylated
product, n-butyl (E)-3-[2-[(tert-butoxycarbonyl)amino]-
Received: February 23, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00569
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Reaction of N-Boc-aniline (1a) with n-Butyl
Acrylate (2a)
Table 2. Reaction of N-Boc-anilines 1 with Alkenes 2
a
b
entry
1
Cu salt
solvent
temp (°C)
yield (%)
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2
AmtOH
AmtOH
AmtOH
ButOH
EtOH
80
80
80
80
80
80
80
60
50
60
60
60
60
68
43
0
c
2
d
3
4
70
29
36
53
82
68
86
87
78
78
5
6
PhCl
7
THF
8
ButOH
ButOH
ButOH
ButOH
ButOH
ButOH
9
10
e
11
Cu(OAc)2
f
12
g
Cu(OAc)2
13
Cu(OAc)2
a
Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), [Cp*Rh-
(MeCN)3][SbF6]2 (0.01 mmol), and Cu salt (0.4 mmol) in solvent (2
mL) under N2 for 6 h, unless otherwise noted. Isolated yield based on
the amount of 1a used. Cu(OAc)2·H2O (0.04 mmol) was employed
under air. [Cp*RhCl2]2 (0.005 mmol) was employed in place of
[Cp*Rh(MeCN)3][SbF6]2. [Cp*Rh(MeCN)3][SbF6]2 (0.008 mmol)
was employed. [Cp*Rh(MeCN)3][SbF6]2 (0.004 mmol) was
employed. The reaction was conducted using 1a (5.2 mmol), 2a
b
c
d
e
f
g
(10.4 mmol), [Cp*Rh(MeCN)3][SbF6]2 (0.16 mmol, 3 mol %), and
Cu(OAc)2 (10.4 mmol) in ButOH (25 mL) under N2 at 60 °C for 24
h.
(MeCN)3][SbF6]2 (0.16 mmol, 3 mol %), and Cu(OAc)2·H2O
(10.4 mmol) (entry 13).
With the optimized conditions in hand (Table 1, entry 10),
the ortho-alkenylation of 1a with various alkenes 2b−f was
examined (Table 2). A series of acrylates 2b−e reacted with 1a
smoothly to produce the corresponding o-alkenylaniline
derivatives 3ab−ae in 83−87% yields (entries 1−4). Besides
acrylates, acrylamides such as N,N-dimethylacrylamide and N-
(tert-butyl)acrylamide and acrylonitrile did not react with 1a at
all under standard conditions. In the case using styrene (2f), o-
styrylaniline derivative 3af could be obtained in 60% yield by
increasing the catalyst loading and reaction temperature (entry
6). Next, the reactions of variously substituted N-Boc-anilines
1b−g with 2a were examined. A series of 4-substituted N-Boc-
anilines possessing methyl, methoxy, bromo, and butoxycar-
bonyl groups underwent ortho-alkenylation to afford 3ba−ea
(entries 7−10). In the case with N-Boc-3-methylaniline (1f),
the alkenylation took place exclusively at the less hindered
position (entry 11). The reaction of N-Boc-2-methylaniline
(1g) was found to be sluggish, probably due to steric reasons
(entry 12). Interestingly, the reaction of tert-butyl (9-ethyl-9H-
carbazol-3-yl)carbamate (1h) with 2a proceeded efficiently and
regioselectively to give C2-alkenylated carbazole derivative 3ha
as a sole product in an excellent yield (entry 13).
a
Reaction conditions: 1 (0.2 mmol), 2 (0.4 mmol), [Cp*Rh-
(MeCN)3][SbF6]2 (0.008 mmol), Cu(OAc)2 (0.4 mmol) in ButOH
(2 mL) under N2 at 60 °C for 6 h, unless otherwise noted. Isolated
yield based on the amount of 1 used. [Cp*Rh(MeCN)3][SbF6]2
(0.01 mmol) was employed. At 80 °C.
b
c
d
Scheme 2. Plausible Mechanism for the Reaction of 1 with 2
On the basis of the literature information,4,6 a plausible
mechanism for the ortho-alkenylation of 1 with 2 is illustrated
in Scheme 2. Coordination of the Boc group of 1 to the
rhodium center triggers C−H bond cleavage at the ortho-
position to form a rhodacycle intermediate A. Then, alkene
insertion to form B and subsequent β-hydrogen elimination
may take place to give 3. The rhodium(I) species generated by
releasing HX at the last step can be reoxidized by a copper salt
to regenerate a rhodium(III) active species.
B
DOI: 10.1021/acs.orglett.7b00569
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Organic Letters
Letter
It was confirmed that the Boc moiety of ortho-alkenylated
products 3 can be readily removed by a conventional method
under acidic conditions.8 For example, treatment of 3aa with
CF3CO2H at rt for 12 h gave deprotected n-butyl (E)-2-
aminocinnamate (3aa′) quantitatively (Scheme S1).10 Next, we
examined further derivatization of thus-obtained N-unprotected
2-alkenylanilines 3′. First, 3ha′ was treated with benzaldehyde
using MgSO4/Na2SO4 as dehydrative condensation reagents in
THF at room temperature for 12 h. Without isolation, the
crude aldimine intermediate was subjected to a Stetter-type
reaction.11 Thus, the imine was successively treated with a
catalytic amount of KCN and molecular sieves 4 Å (MS4A) in
DMF at 60 °C for 12 h to produce a pyrrolo[3,2-b]carbazole
derivative 4a in 85% yield (Scheme 3a). In a similar manner, 2-
also other nitrogen-containing fused heterocyclic compounds
including indoloquinoline, isoquinolonoquinazoline, chrome-
noquinoline, and benzoimidazothiazine derivatives.15
In summary, we have demonstrated that N-Boc-anilines
readily undergo ortho-alkenylation upon treatment with alkenes
in the presence of a rhodium(III) catalyst and a copper salt
oxidant. In this reaction, the Boc function acts as a removable
directing group. Further derivatization of the produced o-
alkenylanilines to nitrogen-containing multicyclic aromatic
compounds has also been achieved.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00569.
Scheme 3. Transformation of Compound 3ha′ to Indole and
Quinoline Derivatives
Experimental procedures, results for additional experi-
ments, and characterization data of products (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: satoh@sci.osaka-cu.ac.jp.
*E-mail: miura@chem.eng.osaka-u.ac.jp.
ORCID
Tetsuya Satoh: 0000-0002-1792-140X
Masahiro Miura: 0000-0001-8288-6439
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was partly supported by Grants-in-Aid from MEXT,
JSPS KAKENHI (Grant No. JP16H01037, in Precisely
Designed Catalysts with Customized Scaffolding), and JST
(ACT-C), Japan, to T.S. and JSPS KAKENHI (Grant No. JP
24225002, Grant-in-Aid for Scientific Research (S)) to M.M.
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