Formal Lossen Rearrangement/Alkenylation or Annulation Cascade of Heterole Carboxamides with Alkynes Catalyzed by CpRhIII Complexes with Pendant Amides

Article abstract of DOI:10.1002/chem.201904156

It has been established that a cyclopentadienyl (Cp) Rh^III complex with two aryl groups and a pendant amide moiety catalyzes the formal Lossen rearrangement/alkenylation cascade of N-pivaloyl heterole carboxamides with internal alkynes, leading to alkenylheteroles. Interestingly, the use of sterically demanding internal alkynes afforded not the alkenylation but the [3+2] annulation products ([5,5]-fused heteroles). In these reactions, the pendant amide moiety of the CpRh^III complex may accelerate the formal Lossen rearrangement. The use of five-membered heteroles may deter reductive elimination to form strained [5,5]-fused heteroles; instead, protonation proceeds to give the alkenylation products. Bulky alkyne substituents accelerate the reductive elimination to allow the formation of the [5,5]-fused heteroles.

Full text of DOI:10.1002/chem.201904156

A Journal of
Accepted Article
Title: Formal Lossen Rearrangement/Alkenylation or Annulation
Cascade of Heterole Carboxamides with Alkynes Catalyzed by
CpRhIII Complexes with Pendant Amides
Authors: Takayuki Yamada, Yu Shibata, and Ken Tanaka
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content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201904156
Link to VoR: http://dx.doi.org/10.1002/chem.201904156
Supported by

Chemistry - A European Journal
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FULL PAPER
Formal Lossen Rearrangement/Alkenylation or Annulation
Cascade of Heterole Carboxamides with Alkynes Catalyzed by
III
CpRh Complexes with Pendant Amides
[
a]
[a]
,[a]
Takayuki Yamada, Yu Shibata, and Ken Tanaka*
III
Abstract: It has been established that a cyclopentadienyl (Cp) Rh
(a)
Ph
O
O
O
CpiPrRhCl
TFE, 21 °C
[
2
]
2
, CsOAc
R
2
iPr
CpiPr
complex with two aryl groups and a pendant amide moiety catalyzes
the formal Lossen rearrangement/alkenylation cascade of N-pivaloyl
heterole carboxamides with internal alkynes, leading to
alkenylheteroles. Interestingly, the use of sterically demanding
internal alkynes afforded not the alkenylation but the [3+2]
annulation products ([5,5]-fused heteroles). In these reactions, the
Ph
Ph
N
O
R1
R1
O
[
1
Cp*tBuRh(CH
-AdCO Cs
3
CN)
3
](SbF
6
)
2
Me
+
R2
Me
Me
tBu
2
R1
Me
Cp*tBu
R2
MeOH, RT
then toluene, 60 °C
N
O
O
III
pendant amide moiety of the CpRh complex may accelerate the
formal Lossen rearrangement. The use of five-membered heteroles
may deter reductive elimination to form strained [5,5]-fused
heteroles; instead, protonation proceeds to give the alkenylation
products. Whereas, bulky alkyne substituents accelerate the
reductive elimination to allow the formation of the [5,5]-fused
heteroles.
(b)
O
Cp*CyRhCl
O
HO
Me
[
2
]
2
Me
OPiv
CsOAc
O
Me
Me
Cy
Me
N
H
N
CH CN, RT
3
Me
Cp*Cy
+
Ph
O
O
O
Me
Me
E
Me
[
Cp RhCl
2
]
2
NH
EtO C
CO Et
2
2
CsOAc
O
Me
Me
Ph
Me
Me
Ph
CH CN, 60 °C
3
CpE
Introduction
O
Transition-metal-catalyzed C-H bond functionalization has been
actively studied because of its step and atom economical
Scheme 1. Ligand-controlled changes of reaction pathways in rhodium(III)-
catalyzed C-H bond functionalization. EWG = electron withdrawing group.
[1]
nature.
Especially,
a
commercially
available
(a)
O
III
pentamethylcyclopentadienyl rhodium(III) (Cp*Rh ) complex is
one of the most frequently used catalysts for the C-H bond
functionalization, and numerous efficient transformations have
OPiv
N
H
O
R2
R2
NH
R1
[
Cp*RhCl
CsOAc
2
]
2
3
0°C
0°C
[
2]
R1
been reported to date. To improve catalytic activity and
selectivity, several research groups have been developed
MeOH
O
[3]
rhodium(III) complexes with modified Cp ligands, and many
X
NH
6
[
4–6]
successful applications have been reported.
Interestingly,
R3
O
examples in which the reaction pathways are changed by
modification of the Cp ligands have also been reported. For
example, the Rovis group reported that the [2+1] annulation and
OPiv
X
R1
N
H
R3
X = O, S
carboamination of N-enoxyphthalimides with alkenes are
(b)
O
O
iPr
catalyzed
by
isopropylcyclopentadienyl
(Cp*
(Cp Cy)
and
R = OMe
R
tBu
OMe
[
Cp*RhCl
AgSbF
Cu(OAc)
2 2
]
tetramethyl(tert-butyl)cycopentadienyl
)
ligands,
N
6
[
7a,b]
respectively (Scheme 1a).
The Chang group reported that
2
·H
2
O
Ac
the [4+2] and [4+1] annulations of N-acyloxybenzamides with
tAmOH, 120 °C
Cl
O
enynones are catalyzed by rhodium(III) complexes with
NHAc
tetramethyl(cyclohexyl)cyclopentadienyl
trimethyl(diethoxycarbonyl)cyclopentadienyl
(Cp*Cy)
and
R = Cl
E
NH
Ac
(Cp )
ligands,
[
7c]
respectively (Scheme 1b).
(c)
O
O
R = OMe
R1
N
OMe
R
R1
N
H
R3
[Cp*RhCl
base
2 2
]
R2
[a]
T. Yamada, Dr. Y. Shibata, Prof. Dr. K. Tanaka
Department of Chemical Science and Engineering, Tokyo Institute
of Technology
O-okayama, Meguro-ku, Tokyo 152-8550 (Japan)
E-mail: ktanaka@apc.titech.ac.jp
+
ROH, RT–40°C
O
OR
NH
F
F
R3
R1
R2
R3
R = OPiv
R2
http://www.apc.titech.ac.jp/~ktanaka/
Supporting information for this article is given via a link at the end
of the document
F F
Scheme 2. Substrate-controlled changes of reaction pathways in rhodium(III)-
catalyzed C-H bond functionalization.
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Chemistry - A European Journal
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FULL PAPER
(a) [4+2] annulation vs. formal Lossen rearrangement/[3+2] annulation (previous work)
CO2R4
O
modified CpRh(III) catalyst
our previous work)
R1
O
(
Cp*Rh(III) catalyst (Fagnou, Rovis)
H (LG)
N
N
R3
R1
LG
+
R3
R3
N
H
formal Lossen rearrangement/
3+2] annulation
[4+2] annulation
R1
R3
[
H
R2
R3
ligand control
b) formal Lossen rearrangement/alkenylation vs. [3+2] annulation (this work)
(
CO2R3
NH
substrate control
modified CpRh(III) catalyst
Het
CO2R3
NH
R1
alkenylation
no precedent)
formal Lossen rearrangement/
O
H
R1
R2
R1
(
alkenylation
R2
1
(R , R2 = compact substituents)
LG
+
N
H
+
Het
Het
R2
CO2R3
H
modified CpRh(III) catalyst
N
R1
Het
[
3+2] annulation
no precedent)
formal Lossen rearrangement/
[3+2] annulation
(
R2
(R , R2 = bulky substituents)
1
Scheme 3. Rhodium(III)-catalyzed annulation and alkenylation reactions. LG = leaving group.
[
15]
Not only the ligand structure but also the substrate structure
3a, right),
but the formal Lossen rearrangement/oxidative
[8]
[16,17]
changes the reaction pathways. For example, the Cui group
reported that the reactions of methylenecyclopropanes with
benzamides afford the [4+2] annulation products, but those with
heterole carboxamides afford the [4+3] annulation products via
β-carbon elimination followed by reductive elimination (Scheme
[3+2] annulation cascade (Scheme 3a, left).
In this paper, we have established that the substrate
A
III
structure changes the reaction pathways in the Cp Rh
complex-catalyzed reactions. The use of N-pivaloyl heterole
carboxamides in place of N-pivaloylbenzamides afforded not the
formal Lossen rearrangement/oxidative [3+2] annulation
[
8a]
2
a). The Xu and Liu groups reported that in the intramolecular
reactions of anilides with alkynes, reductive elimination proceeds
to give an annulation product when using an electron-rich alkyne, products ([5,5]-fused heteroles) but the formal Lossen
but protonation proceeds to give an alkenylation product when
rearrangement/oxidative alkenylation products (alkenylated
[
8b]
[18]
using an electron-deficient alkyne (Scheme 2b). The Loh and
Feng groups reported that in the [4+2] annulation of N-
acyloxybenzamides with internal alkynes, not reductive
elimination but β-fluorine elimination or protonation proceeds to
heteroles) (Scheme 3b, top right). On the contrary, the use of
bulky internal alkynes afforded not the alkenylated heteroles but
[5,5]-fused heteroles (Scheme 3b, bottom right). Importantly, the
above alkenylation and annulation products have not been
prepared from the corresponding N-carbonyl aminoheteroles
[8c]
[8d]
give [4+1] annulation
or alkenylation
products when using
III
[19]
difluorinated internal alkynes (Scheme 2c). In these Cp*Rh -
catalyzed C-H bond functionalization reactions, substrate
structures deter direct reductive elimination from rhodacycle
intermediates.
(Scheme 3b, left) due to their low stability and availability.
R1 R2
HF
H
N
2
C
3
F C
H
N
N
N
N
N
N
Me
Me
O
N
O
Cl
O
Cl
Ph
S
S
In 2011, our research group reported the synthesis of an
bis(ethoxycarbonyl)-substituted cyclopentadienyl rhodium(III)
R
R
2
HO C
R
R
S
Cy
inhibitors of
Hepatitis C virus
E
III
agricultural fungicides
(Mitsui Chemicals, Bayer)
complex (Cp Rh ) via the rhodium(I)-catalyzed [2+2+1]
cycloaddition of two ethyl 2-butynoates with
triisopropylsilylacetylene, leading to a substituted silylfulvene,
(
a)
3 4
pTsOH or H PO
[9a]
O
NH
2
followed by its reductive complexation with RhCl
3
in ethanol.
NH2
NH2
NH
2
E
III
S
Pleasingly, this Cp Rh complex showed significantly higher
+
+
S
S
III
S
catalytic activity than the Cp*Rh complex in the oxidative [3+2]
toluene solution
b)
[
9–11]
annulation of anilides with internal alkynes.
Subsequently in
(
III
2
017, we reported the synthesis of CpRh complexes bearing a
HNO
Ac
3
O
A
III
NO
2
NO
2
pendant amide moiety (Cp Rh ) via the rhodium(I)-catalyzed
2+2+1] cycloaddition of 1,6-diynes with
cyclopropylideneacetamides, leading to substituted fulvenes,
2
PhCHO
HO
2
C
2
MeO C
MeO
2
C
[
S
Me
then
SO
S
S
Ph
Me
H
2
4
2 5 3
P(OC H )
[
12]
1
2
180 °C
followed by their reductive complexation with RhCl
3
in ethanol.
R
R
N
A
III
Some of these Cp Rh complexes also showed high catalytic
activity in the oxidative [3+2] annulation of anilides with internal
H
N
O
6 steps
MeO
2
C
Ph
N
Ph
Cy
[
12–14]
A
III
S
alkynes.
Interestingly, the use of the Cp Rh complex in
2
HO C
III
S
place of the Cp*Rh complex changed the reaction pathways in
the reactions of N-pivaloylbenzamides with internal alkynes. The
A
III
Figure 1. Structures and syntheses of biologically active alkenylated and [5,5]-
Cp Rh complex catalyzed not the previously reported [4+2]
fused thiophene derivatives.
III
annulation, which is catalyzed by the Cp*Rh complex (Scheme
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Furthermore, alkenylated and [5,5]-fused thiophene
derivatives are found in biologically active compounds (e.g.
afforded formal Lossen rearrangement/[3+2] annulation product
7aa in low yield along with a trace amount of the non-rearranged
[
20]
[21]
[16]
agricultural fungicides and inhibitors of the Hepatitis C virus
,
[4+2] annulation product 8aa (Scheme 4a). Subsequently, we
Figure 1, top), the syntheses of which are problematic. For
example, the synthesis of the former compounds suffered from
instability of the starting material (3-aminothiophene) and low
tested the reaction of N-(pivaloyloxy)thiophene-2-carboxamide
(4b) and 4-octyne (5b) under the same reaction conditions.
Unexpectedly, not [5,5]-fused heterole 7bb but alkenylated
thiophene 6bb was generated in 32% yield along with non-
rearranged [4+2] annulation product 8bb in 47% yield (Scheme
4b). The use of N-(pivaloyloxy)thiophene-3-carboxamide (4c)
instead of 4b improved the yield of alkenylated thiophene 6cb
and decreased the yield of [4+2] annulation product 8cb
(Scheme 4c).
[
20c]
regio- and stereoselectivities (Figure 1a),
and the synthesis
of the latter compounds suffered from the high-temperature
[
21c]
[21c,d]
reaction
and long reaction steps
(Figure 1b). Thus, the
present cascade reactions involving the formal Lossen
rearrangement of the stable N-pivaloyl heterole carboxamides
might be synthetically useful.
(a, ref 16)
CO2Me
NH
CO2Me
S
S
N
O
Results and Discussion
Ph
OPiv
S
+
N
H
Ph
2.5 mol %
[Cp RhCl2]2
30 mol % CsOPiv
Ph
A1
Ph
As mentioned in the introduction, recent interests in the
6
aa / 0%
7aa / 14%
III
CpRh complex-catalyzed C-H functionalization are focused on
4a
(1.1 equiv)
MeOH, RT, 16 h
under air
O
modification of Cp ligands because this modification affects the
S
III
+
NH
Ph
catalytic activity and selectivity of their Rh complexes. The
Ph
Ph
III
structures of the modified CpRh complexes, used in this
5a
Ph
8aa / 2%
A
III
research, are summarized in Figure 2. Newly developed Cp Rh
A4
A6
A7
complexes [Cp RhCl
2
]
2
, [Cp RhCl
2
]
2
, and [Cp RhCl
2
]
2
were
and
(b)
CO2Me
NH
[12]
[12]
CO2Me
N
prepared from the corresponding fulvenes 3aa,
3ba,
S
S
S
O
+
3
cb, respectively, derived from 1,6-diynes 1a–c and
cyclopropylideneacetamides 2a,b, by our previously reported
nPr
OPiv
S
nPr
N
H
2.5 mol %
A1
nPr
7bb / 0%
[Cp RhCl2]2
nPr
6bb / 32%
[
12]
protocol in good yields.
30 mol % CsOPiv
4b
(1.1 equiv)
MeOH, RT, 16 h
under air
O
Cp RhCl2]2 (R1 = R2 = Ph, R3 = R4 = Me, ref 12)
A1
+
[
NH
R3
N
[Cp RhCl2]2 (R1 = R = Me, R3 = R = Me, ref 17a)
A2
2
4
nPr
nPr
R1
A3
1
2
3
4
[
Cp RhCl2]2 (R = R = 3,5-Me2C6H3, R = R = Me, ref 16)
5b
nPr
R4
[Cp RhCl2]2 [R = R = 4-(CF3)C6H4, R3 = R = Me]
A4
1
2
4
O
R2
nPr
8bb / 47%
O
[Cp RhCl2]2 [R1 = R = 3,5-(CF3)2C6H3, R = R4 = Me, ref 16]
A5
2
3
Rh
Cl
Cl
[Cp RhCl2]2 (R = CO2Me, R2 = Ph, R3 = R = Me)
A6
1
4
Cp RhCl2]2 [R1 = R = 3,5-(CF3)2C6H3, R = Ph, R = H)
A7
2
3
4
(c)
2
[
CO2Me
NH
A
[Cp RhCl2]2 (R1 = CO Me, R2 = Ph, R3 = Ph, R4 = H, ref 17b)
2
A8
CO2Me
[
Cp RhCl2]2
N
O
+
nPr
Me
Ph
Me
Me
EtO2C
Cl
CO2Et
Me
Me
Me
Cl
R1
R2
OPiv
S
nPr
S
N
H
2.5 mol %
A1
nPr
6cb / 50%
nPr
7cb / 0%
Ph
[Cp RhCl2]2
0 mol % CsOPiv
S
Rh
Cl
Rh
Rh
Cl
3
Cl
Cl
4c
2
2
2
(1.1 equiv)
MeOH, RT, 16 h
under air
O
E
[CpCyPh2RhCl2]2
(ref 3b)
[Cp* RhCl2]2 (R1 = R2 = Ph, ref 3b)
Ph2
+
[
Cp RhCl2]2
ref 9a)
(
[Cp* RhCl2]2 (R = Ph, R2 = Me, ref 22)
Ph
1
nPr
nPr
NH
[
Cp*RhCl2]2 (R1 = R2 = Me)
S
5b
nPr
nPr
1
0 mol %
R1
O
[Rh(cod)2]BF4/
segphos
8cb / 41%
R1
R2
R3
R4
O
+
N
R4
O
CD2Cl2, 40 °C
A1
III
N
R3
Scheme 4. Cp Rh complex-catalyzed reactions of N-(pivaloyloxy)thiophene-
24 h
R2
O
carboxamides with internal alkynes.
a [R1 = R = 4-(CF3)C6H4]
2
2a (R3 = R = Me)
4
3aa / 83% (ref 12)
3ba / 58% (ref 12)
3cb / 68%
1
1
1
b (R = CO2Me, R2 = Ph)
1
2b (R3 = Ph, R4 = H)
c [R1 = R = 3,5-(CF3)2C6H3) (1.1 equiv)
2
Thus, the optimization of the reaction conditions to produce
alkenylated thiophene 6cb from 4c and 5b was studied
systematically as shown in Table 1. With respect to the
substituents on the Cp ring, the use of electron-rich Me
RhCl3•nH2O EtOH
O
O
(1 equiv)
60 °C, 16 h
PPh2
PPh2
R1
R3
N
O
O
A2 [17a]
A3 [16]
A4
[
Cp RhCl2]2 / 75%
R4
(Cp
)
and 3,5-MeC
6
H
3
(Cp
)
derivatives decreased the
O
A6
R2
[Cp RhCl2]2 / 65%
O
yield of 6cb and increased the yield of 8cb (Table 1, entries 2
A7
Rh
Cl
segphos
[Cp RhCl2]2 / 62%
Cl
A1
[12]
and 3), compared with the reaction using the Cp ligand
2
(
entry 1). On the contrary, the use of an electron-deficient 4-
III
A4
Figure 2. Structures and synthesis of modified CpRh complexes. cod = 1,5-
cyclooctadiene.
CF
3
C
6
H
4
(Cp ) derivatives increased the yield of 6cb (entry 4).
A5 [16]
The use of more electron-deficient 3,5-(CF
3
)C
6
H
3
(Cp
)
and
A6
CO
2
Me/Ph (Cp ) derivatives dramatically increased the yield of
In
our
previous
report,
the
reaction
(4a)
of
N-
6
cb (entries 5 and 6). With respect to the amide substituents on
(
pivaloyloxy)benzo[b]thiophene-2-carboxamide
and
A7
,
A1
III
[12]
the Cp ring, the use of Cp
bearing the (N-
diphenylacetylene (5a) using a Cp Rh complex as a catalyst
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Chemistry - A European Journal
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FULL PAPER
A7
phenyl)carbamoylmethyl moiety, gave 6cb in the highest yield
11
[Cp RhCl2]2
4f
CsOPiv
0
55
10
(
(
entry 7), although the use of the corresponding ester derivative
A7
12
13
14
[Cp RhCl
2
]
]
2
4c
4c
4c
4c
4c
4c
4c
4c
Cs OC Ps Oi vA( c0 .3)
Cs OK PO i vA (c 0.3)
Cs ON aP Oi vA( c0 .3)
Cs ON aP Oi vA( c0 .3)
Cs ON aP Oi vA( c0 .3)
Cs ON aP Oi vA( c0 .3)
Cs ON aP Oi vA( c0 .3)
Cs ON aP Oi vA( c0 .3)
CsOPiv (0.3)
84
87
93
86
26
18
4
A8 [17b]
Cp
)
decreased the yield of 6cb (entry 8). Screening of the
A7
[Cp RhCl
2
2
9
leaving groups (4d–f, entries 9–11) and bases (entries 12–14)
A7
[Cp RhCl
2
]
2
6
revealed that the use of OPiv and NaOAc further improves the
E
III
E
yield of 6cb (entry 14). The electron-deficient Cp Rh complex
was also effective for the formation of 6cb (entry 15), but the
15
[Cp RhCl
2
]
2
8
Cy-Ph2
1
6
7
[Cp
RhCl
2
]
2
70
A7
III
yield did not exceed that using the Cp Rh complex (entry 14).
Ph2
1
[Cp* RhCl
2
]
2
71
Cy-Ph2
III
[3b]
Importantly, the use of a Cp
Rh complex, the structure of
Ph
A1
III
18
19
[Cp* RhCl2]2
88
which corresponds to the Cp Rh complex without the pendant
[
c]
amide moiety (entry 1), significantly lowered the yield of 6cb
[Cp*RhCl
2
]
2
0
98 (76 )
(
entry 16), Thus, not only the electron-deficient nature but also
[
a] [Rh] (0.0025 mmol), base (0.030 mmol), 4 (0.11 mmol), 5b (0.10 mmol),
2
the presence of the pendant amide moiety may facilitate the
1
and solvent (0.5 mL) were used. [b] DC se Ot e Pr mi vi n( 0e .d3 )by H NMR using 1,1,2,2-
tetrachloroethane as an internal standard. [c] Isolated yield.
CsOPiv (0.3)
Ph2
III
formal Lossen rearrangement. The use of Cp* Rh and
Ph
III
[3b,22]
Cp* Rh complexes
further decreased the yields of 6cb
With the optimized reaction conditions in hand, we
CsOPiv (0.3)
(
entries 17 and 18), and the use of Cp* ligand afforded 8cb
investigated the scope of the alkenylheterole synthesis, as
exclusively (entry 19). It is worthy of noting that formal Lossen
rearrangement/[3+2] annulation product 7cb was not generated
at all in all entries.
CsOPiv (0.3)
shown in Scheme 5. With respect to the N-pivaloyl heterole
carboxamides, the use of thiophene-3-carboxamide 4c afforded
the corresponding 2-alkenylthiophene 6cb in high yield (entry 1).
The reaction of furan-3-carboxamide 4g afforded the desired 2-
alkenylfuran 6gb in moderate yield along with the non-
rearranged [4+2] annulation product 8gb (entry 2). Unfortunately,
the reaction of 1H-pyrrole-3-carboxamide 4h with 5b was
sluggish, and no coupling products were generated (entry 3).
The bromo group on the thiophene ring (4i) was intact, and the
desired product 6ib was obtained in high yield (entry 4). The
reaction of benzothiophene-3-carboxamide 4j also afforded 2-
alkenylbenzothiophen 6jb in high yield along with formal Lossen
rearrangement/[3+2] annulation product 7jb in low yield (entry 5).
Thiophene-2-carboxamide 4b also reacted with 5b to give the
corresponding 3-alkenylthiophene 6bb in moderate yield along
with the non-rearranged [4+2] annulation product 8bb, by using
[a]
Table 1. Optimization of reaction conditions.
CO
NH
2
Me
S
nPr
nPr
CO
2
Me
O
nPr
2.5 mol % [Rh]
30 mol % base
2
N
6
cb
R
nPr
N
H
+
+
S
MeOH, RT, 16 h
under air
O
nPr
cb
not detected
S
nPr
4
4
4
4
c (R = OPiv)
d (R = OBz)
e (R = OBoc)
f (R = OMe)
5b
NH
nPr
7
S
nPr
cb
8
(
1.1 equiv)
[
b]
Entry
2
[Rh ]
4
Base
Yield [%]
A8
III
the Cp Rh complex (entry 6). Under the optimized conditions,
6cb
8cb
the reaction of N-(pivaloyloxy)benzo[b]thiophene-2-carboxamide
A1
1
2
3
4
5
6
7
8
9
[Cp RhCl
2
]
]
]
]
]
]
]
]
]
]
2
4c
CsOPiv
50
<2
32
63
84
84
87
81
87
82
41
84
64
26
11
11
7
(
4a) was reinvestigated, but the alkenylation reaction did not
A2
[Cp RhCl
2
2
4c
4c
4c
4c
4c
4c
4c
4d
4e
Cs CO sP Oi vP(i 0v .3)
Cs CO sP Oi vP(i 0v .3)
Cs CO sP Oi vP(i 0v .3)
Cs CO sP Oi vP(i 0v .3)
Cs CO sP Oi vP(i 0v .3)
Cs CO sP Oi vP(i 0v .3)
Cs CO sP Oi vP(i 0v .3)
Cs CO sP Oi vP(i 0v .3)
Cs CO sP Oi vP(i 0v .3)
CsOPiv (0.3)
CsOPiv (0.3)
CsOPiv (0.3)
CsOPiv (0.3)
CsOPiv (0.3)
CsOPiv (0.3)
CsOPiv (0.3)
CsOPiv (0.3)
CsOPiv (0.3)
CsOPiv (0.3)
CsOPiv (0.3)
CsOPiv (0.3)
CsOPiv (0.3)
proceed, and the yields of annulation products decreased (entry
7). With respect of the internal alkynes, not only 4-octyne (5b)
but also 6-dodecyne (5c) and diphenylacetylene (5a) could
equally be employed (entries 8 and 9). Alkyl and phenyl-
substituted unsymmetric internal alkynes 5d–f were able to react
with 4c with good yields and regioselectivities (entries 10–12).
A3
[Cp RhCl
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
A4
[Cp RhCl
A5
[Cp RhCl
A6
[Cp RhCl
A7
[Cp RhCl
A8
This cascade reaction could be carried out on a preparative
scale, as shown in Scheme 6. The 1 mmol scale reaction with a
[Cp RhCl
14
8
A7
[Cp RhCl
2
low catalyst loading (1.5 mol % [Rh ]) smoothly proceeded to
A7
10
[Cp RhCl
9
give 6cb in high yield of 93%.
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Chemistry - A European Journal
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FULL PAPER
Ar
H
N
2.5 mol % [CpA7
3
CO2Me
NH
R1
RhCl2]2
0 mol % NaOAc
O
O
Ph
OPiv
Ar
N
H
+
Het
O
Het
Rh
Cl
MeOH, RT, 16 h
under air
R1
Cl
R2
R2
2
[
Ar = 3,5-(CF3)2C6H3]
4
5
6
A7
[
Cp RhCl2]2
(
1.1 equiv)
Entry
4
5
Product / Yield
Entry
4
5
Product / Yield
CO2Me
NH
CO2Me
nPr
nPr
CO2Me
O
O
NH
S
S
N
OPiv
OPiv
1
N
H
S
nPr
N
H
S
nPr
nPr
S
nPr
nPr
nPr
nPr
7ab / 8%
nPr
4
c
5b
6cb / 89%
7
4a
5b
6ab / 0%
O
S
NH
nPr
CO2Me
NH
O
O
nPr
OPiv
NH
2
N
H
nPr
O
O
nPr
nPr
nPr
O
nPr
8ab / 6%
nPr
CO2Me
NH
4
g
5b
6gb / 47%
8gb / 9%
O
nC5H11
OPiv
8
9
N
H
CO2Me
NH
S
nC5H11
nC5H11
O
nPr
S
S
S
nC5H11
OPiv
N
H
3
4
c
5c
6cc / 80%
N
H
N
H
nPr
nPr
CO2Me
NH
nPr
O
Ph
4h
5b
6hb / 0%
OPiv
OPiv
N
H
S
Ph
Ph
CO2Me
Ph
O
nPr
NH
4c
5a
6ca / 88%
4
OPiv
N
H
Br
Br
CO2Me
NH
S
Ph
nPr
O
S
nPr
nPr
10
N
H
4i
5b
6ib / 77%
S
Ph (Me)
Me (Ph)
Me
4c
5d
6cd (6cd') / 85%
CO2Me
(6cd/6cd' = 89:11)
CO2Me
O
nPr
NH
N
nPr
OPiv
CO2Me
NH
5
N
H
O
Ph
S
S
nPr
OPiv
S
nPr
11
N
H
nPr
nPr
S
Ph (nBu)
nBu (Ph)
6ce (6ce') / 77%
S
nBu
4
j
5b
6jb / 76%
7jb / 10%
4
c
5e
(6ce/6ce' = 89:11)
CO2Me
NH
O
CO2Me
NH
nPr
Ph
O
O
S
S
6[a]
OPiv
NH
OPiv
S
12
N
H
N
H
nPr
nPr
nPr
S
Ph [(CH2)3Cl]
CH2)3Cl (Ph)
6cf (6cf') / 60%
6cf/6cf' = 87:13)
nPr
S
nPr
Cl
(
4b
5b
6bb / 58%
8bb / 22%
4c
5f
(
A7
Scheme 5. Scope of alkenylheterole synthesis. [Cp RhCl ] (0.0050 mmol), 4 (0.22 mmol), 5 (0.20 mmol), NaOAc (0.060 mmol), and MeOH (1.0 mL) were used.
2 2
A8
A7
Cited yields were of the isolated products. [a] [Cp RhCl
2
]
2
2 2
was used instead of [Cp RhCl ] .
1.5 mol % [CpA7RhCl2]2
CO2Me
O
nPr
rearrangement/oxidative [3+2] annulation of 4c with 5g (Table 2).
NH
30 mol % NaOAc
A8
III
OPiv
N
H
+
The use of the Cp Rh complex that is more electron-deficient
MeOH, RT, 16 h
under air
S
A7
III
nPr
S
nPr
than the Cp Rh complex increased the yield of reductive
elimination product 8cg, and decreased the yield of formal
Lossen rearrangement/protonation product 6cg. However, the
yield of formal Lossen rearrangement/reductive elimination
product 7cg was not changed (entry 2 vs entry 1). The more
nPr
4
c
5b
6cb / 93%
(250 mg, 0.934 mmol)
(
1.1 equiv)
(110 mg, 1.00 mmol)
Scheme 6 Preparative scale reaction.
E
III
electron-deficient Cp Rh complex was also tested, but the
yields of 7cg and 8cg decreased simultaneously (entry 3). We
anticipated that increasing the coordination ability of the pendant
amide moiety would accelerate both the formal Lossen
rearrangement and reductive elimination, which increase the
Unexpectedly, the reaction of 4c and bulky (cyclohexyl-
ethynyl)benzene (5g) gave strained [5,5]-fused heterole 7cg as
a major product along with alkenylated thiophene 6cg and non-
rearranged [4+2] annulation product 8cg (entry 1, Table 2). Thus,
we reinvestigated the catalysts for this formal Lossen
A6
III
yield of 7cg. Pleasingly, the use of the Cp Rh complex
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Chemistry - A European Journal
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FULL PAPER
bearing the highly coordinative dimethylcarbamoyl group
carboxamide 4g and 5g failed to afford the corresponding 5-5
fused heterole 7gg, and non-rearranged [4+2] annulation
product 8gg was generated as a major product (entry 2). 2-
Bromothiophene-4-carboxamide 4i and benzothiophen-3-
carboxamide 4j reacted with 5g to give the corresponding fused
heteroles 7ig and 7jg, although the product yields were lower
than that of 7cg (entries 3 and 4). The reaction of thiophene-2-
carboxamide 4b and 5g was also tested, while the yield of the
corresponding [5,5]-fused heterole 7bg was low and non-
rearranged [4+2] annulation product 8bg was generated as a
major product (entry 5). With respect to the alkynes, not only
cyclohexyl-substituted phenylacetylene 5g but also sterically
increased the yield of 7cg to 55% (entry 4). As with the reaction
A2
III
of 4c and 5b, the use of the electron-rich Cp Rh complex
predominantly afforded non-rearranged [4+2] annulation product
8cg (entry 5).
[a]
Table 2. Screening of catalysts.
CO Me
2
CO
2
Me
O
NH
N
OPiv
N
H
+
Ph
S
Ph (Cy)
S
2.5 mol %
X
S
Cy
7cg
[
Cp RhCl
2
]
2
Cy (Ph)
less
demanding cyclopentyl- and isopropyl-substituted
4
c
30 mol % NaOAc
6
cg (6cg')
(
1.1 equiv)
phenylacetylenes 5h and 5i could be employed to give the
corresponding [5,5]-fused heteroles 7ch and 7ci, although their
MeOH, RT, 16 h
under air
+
O
Ph
NH
yields were lower than that of 7cg (entries
6 and 7).
S
Ph
Trimethylsilyl-substituted phenylacetylene 5j could also react
with 4c, while the corresponding [5,5]-fused heterole 7cj was
obtained in low yield, and non-rearranged [4+2] annulation
product 8cj was generated as a major product (entry 8).
Substituents on the phenyl group were also examined. When the
Cy
Cy
5g
8cg
X
[b]
Entry
[Cp RhCl
2
]
2
Yield [%]
[
c]
6
cg+6cg’ (6cg/6cg’)
29 (71:29)
9 (71:29)
7cg
45
45
35
55
2
8cg
A7
III
A6
III
A7
Cp Rh complex was used instead of the Cp Rh complex,
electron-rich methoxyphenyl-substituted alkynes 5k and 5l
smoothly reacted with 4c to give the corresponding [5,5]-fused
heteroles 7ck and 7cl in good yields (entries 9 and 10). On the
contrary, the reaction of 4c and electron-deficient
trifluoromethylphenyl-substituted alkyne 5m afforded the
corresponding [5,5]-fused heterole 7cm in lower yield than that
of 7ck due to the formation of alkenylated product 6cm (entry
1
2
3
4
5
[Cp RhCl
2
]
2
2
17
29
20
22
A8
[Cp RhCl
2
]
E
[Cp RhCl
2
]
2
9 (72:28)
A6
[Cp RhCl
2
]
2
11 (64:36)
0
A2
[d]
[Cp RhCl
2
]
2
72 (65 )
X
[
a] [Cp RhCl
2
]
2
(0.0025 mmol), NaOAc (0.030 mmol), 4c (0.11 mmol), 5g (0.10
1
mmol), and MeOH (0.5 mL) were used. [b] Determined by H NMR using
,1,2,2-tetrachloroethane as an internal standard. [c] These compounds could
11). These results indicate that not only steric but also electronic
1
1
nature of substituents affects the selectivity between protonation
and reductive elimination from rhodacycle intermediates. That is,
the use of the electron-rich alkyne facilitates reductive
elimination from the rhodacycle intermediate giving the [5,5]-
fused heterole product, on the contrary, the use of the electron-
deficient alkyne facilitates protonation giving the alkenylated
not be isolated in pure forms. The yield and ratio were determined by H NMR
using 1,1,2,2-tetrachloroethane as an internal standard. [d] Isolated yield. The
product was isolated as a 94:6 mixture of regioisomers. See the Supporting
Information.
The scope of the formal Lossen rearrangement/[3+2]
annulation reaction is summarized in Scheme 7. Thiophene-3-
carboxamide 4c reacted 5g to give 5-5 fused heterole 7cg in
moderate isolated yield (entry 1), but the reaction of furan-3-
III
product, as with the previously reported Cp*Rh complex-
[8b]
catalyzed intramolecular reactions of anilides with alkynes.
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10.1002/chem.201904156
FULL PAPER
CO
2
Me
Me
N
R1
2.5 mol % [CpA6RhCl
2 2
]
CO
2
Me
O
O
Me
30 mol % NaOAc
N
Ph
OPiv
R1
N
H
+
Het
Rh
O
Het
Cl
Cl
MeOH, RT, 16 h
under air
R2
R2
2
[CpA6RhCl2]2
4
5
7
(1.1 equiv)
Entry
1
4
5
Product / Yield
Entry
7
4
5
Product / Yield
CO Me
Ph
CO
2
Me
2
O
Ph
O
Ph
N
N
OPiv
OPiv
OPiv
OPiv
N
H
Ph
N
H
S
S
S
Cy
S
S
iPr
Cy
7cg / 53%
iPr
4c
5g
4c
5i
7ci / 48%
O
CO
2
Me
O
CO
2
Me
Ph
O
Ph
O
N
N
NH
NH
2
N
H
Ph
8
N
H
Ph
O
O
S
S
Ph
SiMe3
Ph (Cy)
Cy (Ph)
O
Cy
SiMe
3
Cy
SiMe
3
4
g
5g
7gg / 0%
8gg (8gg') / 47%
8gg/8gg' = 60:40)
4c
5j
7cj / 12%
8cj (8cj') / 23%
(8cj/8cj' = 67:33)
(
OMe
CO
2
Me
O
Ph
N
2
CO Me
OPiv
OPiv
O
3
4
5
N
H
Br
Ph
N
Br
9[a]
OPiv
OPiv
OPiv
S
N
H
OMe
S
S
Cy
Cy
S
S
S
S
Cy
4
i
5g
7ig / 26%
Cy
CO
2
Me
O
Ph
4c
5k
7ck / 62%
N
N
H
Ph
OMe
S
2
CO Me
Cy
O
Cy
N
10[a]
N
H
4
j
5g
7jg / 37%
OMe
S
O
iPr
CO
2
Me
Ph
O
S
N
S
NH
iPr
OPiv
S
Ph
N
H
4c
5l
7cl / 47%
Ph
Cy
Cy
Cy
CF3
CO Me
2
4
b
5g
7bg / 6%
8bg / 21%
2
CO Me
O
NH
N
CO
N
2
Me
11
N
H
CF
3
Ph
S
S
Ar (Cy)
Cy (Ar)
Ph
Cy
6
4c
S
Cy
4c
5m
7cm / 34%
6cm (6cm') / 29%
Ar = 4-F CC
(6cm/6cm' = 90:10)
(
3
6 4
H )
5h
7ch / 33%
A6
Scheme 7. Scope of 5,5-fused heterole synthesis. [Cp RhCl
2
]
2
(0.0050 mmol), 4 (0.022 mmol), 5 (0.20 mmol), NaOAc (0.060 mmol), and MeOH (1.0 mL) were
A7
A6
used. Cited yields were of the isolated products. [a] [Cp RhCl
2
]
2
was used instead of [Cp RhCl
2 2
] .
(
a)
The synthetic transformation of the [5,5]-fused heterole
products is shown in Scheme 8. Hydrolysis of 7cg smoothly
proceeded to give the corresponding N-H compound 7cg-H in
2.5 mol % [CpA7RhCl2]2
30 mol % NaOAc
O
H
N
OPiv
OPiv
OMe
N
H
MeOH, RT, 16 h
under air
(condition A)
O
S
S
S
6
9% yield. The subsequent methylation afforded the
4c
9c / 6%
[23]
corresponding N-Me compound 7cg-Me in 66% yield.
(
b)
O
condition A
(in CD3OD)
O
H
N
Similarly, 7ck and 7cm were transformed into the corresponding
N-Me compounds 7ck-Me and 7cm-Me in 73% and 48% yields,
OMe
OPiv
N
H
N
H
+
O
S
[23]
H
S
H/D
H
respectively.
4c
4c
9c
CO
2
Me
H
Me
92% recovery (12% D)
7% (0% D)
N
NaOH
EtOH / H O, RT
N
MeI, NaH
DMF, RT
N
(c)
Ar
Ar
Ar
H
N
CO Me
2
S
2
S
S
CO2Me
condition A
N
Cy
cg (Ar = Ph)
ck (Ar = 4-MeOC
cm (Ar = 4-F CC
Cy
Cy
Ph
S
S
Ph (Cy)
Cy (Ph)
6cg (6cg')
7
7
7
7cg-H / 69%
7cg-Me / 66%
7ck-Me / 73% (2 steps)
7cm-Me / 48% (2 steps)
Cy
6
H
4
)
)
3
6
H
4
7cg / 0%
Scheme 8. Transformations of [5,5]-fused heterole products.
Scheme 9. Mechanistic studies.
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Chemistry - A European Journal
10.1002/chem.201904156
FULL PAPER
Lossen rearrangement
MeOH addition
O
cat.
III
H
N
[
Rh]
X
2
N
OMe
OPiv
C
MeOH
N
H
O
–PivOH
S
S
O
S
H
H
4
c
9c
[Rh]IIIX2
[
Rh]III
2HX
X
2
–2HX
–
C-H
cleavage
O
O
OMe
[Rh]
O
N
tBu
N
S
[Rh]
O
S
A
A
E
[
Rh] = Cp Rh
R2
R3
R2
R3
alkyne
insertion
5
5
O
O
tBu
O
•
tBu
O
OMe
O
N
N
O
N
O
MeOH
[Rh]
R2
[Rh]
R2
[Rh]
S
S
–PivOH
S
R2
R3
R3
R3
B
C
D
R3 = compact group
R3 = bulky group
–RhI
CO Me
RhI
H+
H+
–
–
RhIII
O
O
CO
NH
2
Me
2
OPiv
R2
N
H
N
NH
R2
R2
S
S
R2
S
S
R3
R3
R3
R
6
3
7
8
10
Scheme 10. Possible mechanisms for formation of 6–8 from 4c and 5.
To clarify the mechanism of this cascade process, the
following experiments were conducted (Scheme 9). The reaction
sluggish progress of the normal Lossen rearrangement shown in
Scheme 9a may exclude the formation of 6 from possible non-
A7
III
[25]
of 4c with the Cp Rh complex under the present reaction
rearranged protonation product 10. The formation of 7 from 6
conditions (condition A) gave the normal Lossen rearrangement
can also be considered, but the conversion of 6 to 7 did not
proceed under the present reaction conditions, as shown in
Scheme 9c.
[
24]
product 9c in low yield (Scheme 9a). In the reaction of 4c in
CD OD under condition A, partial deuterium incorporation was
3
observed only in the recovered substrate 4c (Scheme 9b).
These results indicate that 9c may not be involved in the
A7
III
catalytic cycle. The reaction of 6cg with the Cp Rh complex
did not afford 7cg, thus excluding the intermediacy of 6 for the
formation of 7 (Scheme 9c).
Conclusions
In conclusion, we have established that the substrate structure
A
III
changes the reaction pathways in the Cp Rh complex-
catalyzed reactions of heterole carboxamides with alkynes. A
Based on the above mechanistic studies, possible
III
mechanisms for the formation of 6–8 are proposed, as shown in
cyclopentadienyl (Cp) Rh complex, bearing two aryl groups and
A
III
Scheme 10. First, cleavage of C–H bond of 4c with Cp Rh
a pendant amide moiety, catalyzed the formal Lossen
rearrangement/alkenylation cascade of N-pivaloyl heterole
carboxamides with internal alkynes, leading to substituted
alkenylheteroles. Interestingly, the use of sterically demanding
internal alkynes afforded not the alkenylation but the [3+2]
annulation products ([5,5]-fused heteroles). In these reactions,
followed by insertion of 5 furnishes rhodacycle B via rhodacycle
A. Direct reductive elimination from B affords non-rearranged
[
4+2] annulation product 8. The formal Lossen rearrangement
furnishes isocyanate C, and the addition of MeOH furnishes
[
16]
rhodacycle D. When using a sterically less demanding internal
alkyne, protonation of D proceeds to give alkenylheterole 6 and
III
the pendant amide moiety of the CpRh complex may
A
III
accelerate the formal Lossen rearrangement. The use of five-
membered heteroles may deter reductive elimination to form
strained [5,5]-fused heteroles; instead, protonation proceeds to
give the alkenylation products. Whereas, bulky alkyne
substituents accelerate the reductive elimination to allow the
formation of the [5,5]-fused heteroles. Mechanistic studies
revealed that the present transformations involve the rhodium-
regenerates the Cp Rh complex. On the contrary, the use of a
sterically demanding internal alkyne facilitates reductive
elimination from D to give [5,5]-fused heterole 7. The thus
A
I
liberated Cp Rh complex is oxidized by air to regenerate the
A
III
Cp Rh complex. Although the formation of D via 9c and E can
be considered, this pathway may be excluded according to the
experiments shown in Schemes 9a and 9b. Furthermore,
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Chemistry - A European Journal
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FULL PAPER
mediated formal Lossen rearrangement, not the base-mediated
normal Lossen rearrangement.
Hyster, T. Rovis, Chem. Sci. 2011, 2, 1606; c) T. K. Hyster, T. Rovis,
Chem. Commun. 2011, 47, 11846; d) R. Zeng, J. Ye, C. Fu, S. Ma, Adv.
Synth. Catal. 2013, 355, 1963; e) M. D. Wodrich, B. Ye, J. F. Gonthier,
C. Corminboeuf, N. Cramer, Chem. Eur. J. 2014, 20, 15409; f) T. K.
Hyster, D. M. Dalton, T. Rovis, Chem. Sci. 2015, 6, 254; g) B. Li, J.
Yang, H. Xu, H. Song, B. Wang, J. Org. Chem. 2015, 80, 12397; h) N.
Semakul, K. E. Jackson, R. S. Paton, T. Rovis, Chem. Sci. 2017, 8,
Acknowledgements
1
015; i) T. Piou, F. Romanov-Michailidis, M. A. Ashley, M. Romanova-
This work was supported partly by a Grant-in-Aid for Scientific
Research for Young Scientists (No. 17K14481) from JSPS
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(
Japan). T.Y. thanks JSPS research fellowship for young
scientists (No. 18J13654). We thank Umicore for generous
support in supplying RhCl ·nH O.
3
2
5689.
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Keywords: Alkenylation • Cyclopentadienyl Complexes • C-H
Bond Functionalization • Lossen Rearrangement • Rhodium
1
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E
III
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See the Supporting Information.
A7
14] Our research group reported rhodium(III) complexes with
ethoxycarbonyl-substituted electron-deficient indenyl ligands that show
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2 2 3 2 2 2
[24] The use of [Cp*RhCl ] or RhCl •nH O instead of [Cp RhCl ] , and the
absence of the rhodium(III) complex did not afford 9c at all.
[25] Non-rearranged protonation products 10 were not detected at all in any
combination of substrates 4 and 5.
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FULL PAPER
Takayuki Yamada, Yu Shibata, and Ken
Tanaka*
formal Lossen rearrangement/
alkenylation
CO2R3
NH
Ar
H
N
O
O
Ph
1
2
(R , R = compact substituents)
Ar
O
Het
Het
Rh
Cl
R1
R1
O
H
Cl
[Ar = 3,5-(CF3)2C6H3]
amide-pendant
bulky and electron-deficient
CpRh(III) catalysts
R2
2
OPiv
N
H
+
Het
Page No. – Page No.
R2
CO2R3
CO2Me
Me
N
N
Me
R1
Formal Lossen
Ph
formal Lossen rearrangement/
3+2] annulation
O
Rh
Cl
[
Cl
Rearrangement/Alkenylation or
Annulation Cascade of Heterole
Carboxamides with Alkynes
1
2
R2
(
R , R = bulky substituents)
2
III
It has been established that a cyclopentadienyl (Cp) Rh complex with two aryl groups
and a pendant amide moiety catalyzes the formal Lossen rearrangement/alkenylation
cascade of N-pivaloyl heterole carboxamides with internal alkynes leading to substituted
alkenylheteroarenes. Interestingly, the use of sterically demanding internal alkynes
afforded not the alkenylation but the [3+2] annulation products ([5,5]-fused heteroles).
III
Catalyzed by CpRh Complexes with
Pendant Amides
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