Rh(III)-catalyzed C-H activation/cyclization of benzamides and diazo compounds to form isocoumarins and α-pyrones

Article abstract of DOI:10.1039/c4cc09314c

Rhodium-catalyzed intermolecular cyclization of benzamides and diazo compounds via C-H activation has been achieved to construct C-C/C-O bonds for the first time. The process provides a facile approach for the construction of isocoumarins and α-pyrones wi

Full text of DOI:10.1039/c4cc09314c

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DOI: 10.1039/C4CC09314C
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Rh(III)-catalyzed C–H activation/cyclization of
benzamides and diazo compounds to form
isocoumarins and α-pyrones
Cite this: DOI: 10.1039/x0xx00000x
Xing Guang Li,a Min Sun,a Kai Liu,a Qiao Jina and Pei Nian Liua,*
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
www.rsc.org/
with diazo compounds via C–C/C–O bonds formation (Scheme 1, eq.
3).
Rhodium-catalyzed intermolecular cyclization of benzamides
and diazo compounds via C–H activation has been achieved
to construct C–C/C–O bonds for the first time. The process
provides
isocoumarins and
a
facile approach for the construction of
-pyrones without the need of high
α
temperature or adding oxidant.
Rhodium-catalyzed C–H activation/cyclization has emerged as a
powerful and promising tool for the construction of diversified
heterocyclic systems in organic synthesis.1 As good partners for C–H
activation coupling or cyclization, diazo compounds are easily
prepared, stable and reactive and therefore widely used in synthetic
organic chemistry.2 In 2012, Yu developed the first example of
Rh(III)-catalyzed intermolecular cross-coupling of diazomalonates
with arene C–H bonds.3 After this pioneering work, Li, 4a Wang,4b
Yi,4c Chang4d and Zhou4e reported studies on Rh(III)-catalyzed
cross-coupling of diazomalonates with arene C–H. Notably, Rovis
and co-workers uncovered the cyclization of benzamides and diazo
compounds to construct γ-lactams via Rh(III)-catalyzed C–C/C–N
bonds formation (Scheme 1, eq. 1).5 Even more recent examples of
Rh(III)-catalyzed cyclization using diazo compounds as
coupling/cyclization partners have come from the groups of
Glorius,6 Cui,7 Cramer,8 Wang,9 Yu10 and Yi,11 but all these elegant
transformations are restricted to C–C/C–N bonds formation to
generate N-heterocycles such as isoindolinones, isoquinoline N-
oxides, azepinones and 1-aminoindoles (Scheme 1, eq. 2).6-11 To the
best of our knowledge, C–C/C–O bonds formation via Rh(III)-
catalyzed C–H activation/cyclization of aromatics with diazo
compounds has not been reported yet.
Isocoumarin and α-pyrone are important structural motifs in many
pharmaceuticals because of their various biological and medicinal
activities.12 However, their synthesis frequently requires specific
pre-activated C–X or C–M reagents as substrates.13 Oxidative
annulations of aryl carboxylic acids and alkynes can be achieved in
the presence of Rh,14 Ru15 or Ir16 catalyst, but these reactions
require stoichiometric oxidants and high temperatures above 100 oC.
As part of our continuing efforts in heterocycle construction,17 we
report here a mild procedure for generating various isocoumarins
and α-pyrones. The process involves Rh(III)-catalyzed C–H
activation of benzamides and subsequent intermolecular cyclization
Scheme 1 Rh(III)-catalyzed C–H activation/cyclization using diazo
compounds as cyclization partners.
Initially,
N,N-dimethylbenzamide was treated with tert-butyl
2-diazo-3-oxobutanoate (2a) in the presence of [Cp*RhCl2]2
(2.5 mol%), AgSbF6 (10 mol%) and AcOH (2.0 equiv.) in DCE
o
at 100 C for 12 h. We were pleased to obtain the unexpected
isocoumarin derivative 3a in 8% yield, and its structure was
fully characterized and confirmed by the single crystal X-ray
analysis (see ESI, CCDC: 1035334). Then we screened various
amido groups to determine whether they played a significant
role in this novel cyclization reaction (Table 1, entries 2-7). The
pyrrolidinyl group performed much better than any other
groups we tested. The catalysts [Cp*Rh(CH3CN)3](SbF6)2 and
[Cp*RhCl2]2 showed similar activity, whereas Cp*Rh(OAc)2,
Pd(OAc)2 or [RuCl2(p-cymene)]2 showed little or even no
activity in this transformation (entries 8-11). Therefore we
selected [Cp*RhCl2]2 as the catalyst and investigated various
additives (entries 12-18). AcOH promoted the reaction to 54%
yield, while Ac2O led to better 66% yield. Using a 4:1 mixture
of Ac2O/AcOH improved the yield to 77%. Lowering the
temperature further increased the yield to 87% (entry 20). The
further result demonstrated that the reaction could also be
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conducted under air atmosphere with 3a giving 72% yield afforded the corresponding products 3o-s in 74-81% yields, except
(entry 22). Once conditions had been optimized, scaling up the low yield of 34% for 3q. Similarly, aryl-substituted substrates
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reaction proved straightforward to afford product 3a in 74% reacted under the optimal conditions to provide products 3t and 3u
isolated yield (0.58 g, entry 23).
Table 1 Optimization of reaction conditionsa
in excellent yields. Interestingly, the reactDioOnI: 1o0f.110a39/wCi4thCC20-9d3i1a4zCo
substituted 1,3-dione substrates also proceeded to afford the
corresponding products 3v and 3w in 38% and 93% yield,
respectively.
.
Notably, the annulation reaction with 2a tolerated the alkenyl
substrate, producing α-pyrone 4a in 76% yield. Employing 2-
methyl-1-(pyrrolidin-1-yl)prop-2-en-1-one as the substrate to
explore with different diazo compounds provided various α-pyrones
4b-4g in moderate to good yields. However, other alkenyl substrates
such as ethenyl, (E)-(2-methyl)-ethenyl, (E)-(2-phenyl)-ethenyl and
cyclohexenyl substrates showed much less or even no reactivity with
2a in the reaction.
Entry
R
NMe2
NEt2
NHOMe
piperidinyl
morpholinyl
N(OMe)Me
pyrrolidinyl
pyrrolidinyl
Catalyst
Additive (equiv)
Yield (%)b
8
1
2
3
4
5
6
7
8c
[Cp*RhCl2]2 AcOH (2.0)
[Cp*RhCl2]2 AcOH (2.0)
[Cp*RhCl2]2 AcOH (2.0)
[Cp*RhCl2]2 AcOH (2.0)
[Cp*RhCl2]2 AcOH (2.0)
[Cp*RhCl2]2 AcOH (2.0)
[Cp*RhCl2]2 AcOH (2.0)
[Cp*Rh(CH3C AcOH (2.0)
N)3](SbF6)2
0
Trace
6
7
9
52
49
Table 2 Rh(III)-catalyzed C–H activation/cyclization of benzamides
1 and diazo compounds 2.
O
[Cp*RhCl2]2 (2.5 mol%)
AgSbF6 (10 mol%)
O
O
O
O
R1
N
9
10
11
pyrrolidinyl
pyrrolidinyl
pyrrolidinyl
Cp*Rh(OAc)2 AcOH (2.0)
Trace
0
Trace
+
R2
R3
R1
(Ac)2O, AcOH
DCE, 60 oC, 12 h
R2
Pd(OAc)2
[RuCl2(p-
cymene)]2
AcOH (2.0)
AcOH (2.0)
N2
R3
1
2
3 or 4
12
13
14
15
pyrrolidinyl
pyrrolidinyl
pyrrolidinyl
pyrrolidinyl
pyrrolidinyl
pyrrolidinyl
pyrrolidinyl
pyrrolidinyl
pyrrolidinyl
pyrrolidinyl
[Cp*RhCl2]2 TFA (2.0)
[Cp*RhCl2]2 AgOAc (2.0)
[Cp*RhCl2]2 NaOAc (2.0)
[Cp*RhCl2]2 KOAc (2.0)
[Cp*RhCl2]2 AcOH (2.0)
[Cp*RhCl2]2 (Ac)2O (2.0)
[Cp*RhCl2]2 (Ac)2O (1.6), AcOH (0.4)
[Cp*RhCl2]2 (Ac)2O (1.6), AcOH (0.4)
[Cp*RhCl2]2 (Ac)2O (1.6), AcOH (0.4)
[Cp*RhCl2]2 (Ac)2O (1.6), AcOH (0.4)
[Cp*RhCl2]2 (Ac)2O (1.6), AcOH (0.4)
[Cp*RhCl2]2 (Ac)2O (1.6), AcOH (0.4)
Trace
0
24
21
54
66
77
81
87
25
72
74
16d
17d
18d
19d,e
20d,f
21d,g
22d,f,h pyrrolidinyl
23d,f,i pyrrolidinyl
a
Reaction conditions:
1 (0.3 mmol), 2a (0.6 mmol), catalyst (2.5 mol%),
AgSbF6 (10 mol%), DCE (2 mL), 100 oC, 12 h, under N2. b Yields based on
1H NMR analysis using phenyltrimethylsilane as the internal standard. c 5.0
mol% catalyst was used. d 1a (0.6 mmol) and 2a (0.3 mmol) were used. e At
80 oC. f At 60 oC. g At 40 oC. h Under air atomosphere. i Performed on a 3.0
mmol scale; isolated yield was shown.
After optimizing reaction conditions, we explored the scope of the
substrates for this Rh(III)-catalyzed C–H activation/cyclization
reaction of benzamides and diazo compounds (Table 2). Various 1-
benzoylpyrrolidines 1 substituted at the para-position with electron-
donating substituents (-Me, -OMe, -NMe2) reacted smoothly to
afford the desired products 3b-d in excellent 83-93% yields. In
contrast, substrates with strong electron-withdrawing groups (-CF3, -
NO2) at the same position inhibited the reaction, affording products
3h and 3i in lower respective yields of 64% and 63%. Nevertheless,
substrates with halo-substituents (-F, -Cl, -Br) at the same position
reacted smoothly with 2a to afford the corresponding products 3e-g
in 78-90% yields. Ortho-methyl-substituted benzamide also
participated in the reaction, providing the desired product 3j in good
yield. Interestingly, coupling-cyclization of meta-fluoro-substituted
benzamide and 2a occurred exclusively at the less sterically hindered
position of the benzamide, generating 3k in 68% yield. Moreover,
C–H annulation involving 3,4-dichloro-substituted benzamide
occurred at the less hindered position, generating 3l as the single
isomer in low yield. Naphthalene and heterocyclic derivatives were
also well tolerated in this transformation, and moderate to good
yields of the corresponding products 3m and 3n were obtained.
To further evaluate the scope of the C–H activation/cyclization
process, a range of diazo compounds 2 were reacted with 1a to form
various isocoumarin products. Diazo substrates bearing alkyl groups
such as methyl, n-propyl, chloromethyl, i-propyl and cyclopropyl
a
Reaction conditions: 1 (0.6 mmol), 2 (0.3 mmol), [Cp*RhCl2]2 (2.5 mol%),
AgSbF6 (10 mol%), DCE (2 mL), 60 oC, 12 h, under N2.
To gain insight into the mechanism of this transformation, we
conducted several control experiments. The competition experiment
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of C–H activation/cyclization to construct heterocycles in a variety
between differently 4-substituted (4-OMe and 4-CF3) benzamides
was carried out under standard conditions and gave the products 3c
in 77% yield and 3h 10% yield. The results showed the electron-
donating substituent of the benzamide is beneficial for this
transformation (Scheme 2, eq. 1). Then the reaction of 2a with the
same amounts of both 1a and 1a-d5 was explored under standard
conditions for 30 min. A significant KIE value of 3.5 was measured
of future applications.
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DOI: 10.1039/C4CC09314C
[Cp*RhCl2]2
AgSbF6
AcOH
NH +
3 or 4
1
Cp*RhX2
HOAc
HOAc
O
1
based on H NMR analysis (Scheme 2, eq. 5). Moreover, separate
N
reactions of 2a with either 1a or 1a-d5 were performed in parallel,
and a similar KIE value of 2.7 was obtained (Scheme 2, eq. 6).
These results suggest that C–H cleavage may be involved in the rate-
determining step. Moreover, when we mixed diethyl 2-
diazomalonate 2b with 1a under standard conditions, the reaction did
not proceed (Scheme 2, eq. 7). This suggests that the final
lactonization of ketone plays a vital role in the coupling/cyclization
cascade transformation.
N
R1
R1
O
O
Cp*RhOAc
Rh
OAc
R3
R2
*Cp
A
D
2
N
O
N
OAc-
R1
R1
O
Rh
Rh+
Cp*
OAc
Cp*
R2
R3
O
R3
2HX
R2
O
C
OAc-
B
Cp*RhX2
O
O
N
N
R1
R1
3 or 4
OH
R2
O
R3
R3
R2
N
E
F
H
Scheme
3
Plausible reaction mechanism for the C–H
activation/cyclization of benzamides and diazo compounds.
This work was supported by the National Natural Science
Foundation of China (Project Nos. 21172069, 21372072 and
21190033), the Science Fund for Creative Research Groups
(21421004), NCET (NCET-13-0798), the Basic Research Program
of the Shanghai Committee of Sci.
& Tech. (Project No.
13NM1400802) and the Fundamental Research Funds for the
Central Universities.
Notes and references
a
Shanghai Key Laboratory of Functional Materials Chemistry, Key Lab
for Advanced Materials and Institute of Fine Chemicals, East China
University of Science and Technology, Meilong Road 130, Shanghai
200237, China, Fax: (+) 86-21-64250552, E-mail: liupn@ecust.edu.cn
Scheme 2 Mechanistic studies for the C–H activation/cyclization of
benzamides and diazo compounds.
†
Electronic Supplementary Information (ESI) available: [Experimental
On the basis of these observations and literature precedents,1, 3-11 a
plausible mechanism is proposed (Scheme 3). Firstly, the o- C–H of
1a is cleaved directly by the Cp*RhX2 species to afford intermediate
A,18 followed by the formation of the Rh(III)-carbene species B.
Then, migration insertion of the carbene into the Rh–C bond gives
the six-membered rhodacyclic intermediate C, which can
tautomerize to intermediate D. Finally, Rh- or Ag-assisted
lactonization via addition-elimination furnishes the product 3 or 4
with the release of pyrrolidine (detected by GC-MS). However,
another possible process where the intermediate C can be protonated
by acetic acid along with the regeneration of the Rh catalyst and E.9
Then product 3 or 4 could be produced through the enolization and
esterification.
In summary, we have developed the first Rh(III)-catalyzed C–H
activation/cyclization of benzamides with diazo compounds to form
C–C/C–O bonds, generating useful isocoumarins and α-pyrones
under mild conditions. In this strategy, the amide functions
efficiently as the directing group in C–H activation, constraining the
substrates to undergo formation of an intermolecular C–C bond and
an intramolecular C–O bond. Diverse substrates were applied in this
transformation to produce various isocoumarins and α-pyrones in
moderate to good yields. We believe the results will inspire the use
procedures, analysis data of the products, and crystallographic data of 3a].
See DOI: 10.1039/c000000x/
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