Rhodium-catalyzed annulation of N-benzoylsulfonamide with isocyanide through C-H activation

Article abstract of DOI:10.1002/chem.201102475

The first rhodium-catalyzed annulation of N-benzoylsulfonamide (1) with isocyanide (2) through CiH activation is described. The transformation is broadly compatible with N-benzoylsulfonamides as well as isocyanides with different electronic properties. Fr

Full text of DOI:10.1002/chem.201102475

COMMUNICATION
DOI: 10.1002/chem.201102475
Rhodium-Catalyzed Annulation of N-Benzoylsulfonamide with Isocyanide
À
through C H Activation
Chen Zhu,* Weiqing Xie, and John R. Falck[a]
The use of amides as directing group has notably im-
À
proved the chemistry of C H bond functionalization, be-
cause these compounds do not only lead to good reactivities
[1]
À
and selectivities but are also precursors of C N bonds.
Indeed, much effort has been made to explore the annula-
tion of amides with various partners, albeit mostly focusing
on the chemistry of alkenes and alkynes.[2,3] To extend the
versatility and utility in the construction of complex hetero-
cycles, in addition to the reactions involving alkenes and al-
kynes, new reaction types are extremely sought after. Re-
cently, Chatani, Yu and their co-workers reported successful
examples of annulation of amides with carbon monoxide
employing ruthenium or palladium catalyst, respectively
(Scheme 1).[4] Isocyanide has been considered a unique
source of C1 that enables transformations that could not be
accomplished with carbon monoxide.[5] However, to date,
À
the reaction of amides with isocyanides by means of C H
bond activation has not been developed.
À
We have revealed that the N H acidity of N-benzoylsul-
[6]
À
fonamide shows superiority in the C H olefination. These
results prompted us to investigate the annulation of N-ben-
zoylsulfonamide with isocyanide which would result in 3-
(imino)isoindolinone, a class of amidines from isoindoline
À
Scheme 1. Annulation with C1 source via C H activation
ubiquitously existing as substructures in bioactive com-
pounds.[7] Despite the documented methods,[8] in view of
atom economy, a more straightforward alternative is de-
sired. Herein, we disclose the first rhodium-catalyzed annu-
achieving a suitable condition that promotes the annulation
and simultaneously suppresses the side reaction.
À
lation of N-benzoylsulfonamide with isocyanide through C
H activation.
At the outset, we realized the key challenges that charac-
terize our studies: 1) an undesired background reaction, ob-
À
tained upon insertion of isocyanide into the acidic N H
bond of N-benzoylsulfonamide and leading to unexpected
rearranged product 3 under simply heating the mixture of
two components [Eq. (1)];[9] 2) isocyanides are prone to
polymerize in presence of transition metals.[10] Apparently,
these competitive reactions significantly raise the barrier of
After unsuccessful trials by using other transition-metal
catalysts,[11] we found that rhodium catalyst [RhCl2Cp*]2 led
to the desired transformation.[12] A survey of reaction pa-
rameters is shown in Table 1. With the standard conditions,
the annulated product 4a was formed in satisfactory yield,
and, more importantly, the formation of by-product 3 was
virtually inhibited (Table 1, entry 1). The use of a reoxidiz-
ing agent had critical influence on the reaction. For exam-
ples, molecular oxygen as oxidant was unable to suppress
the competitive reaction and 3 was obtained as major prod-
[a] Dr. C. Zhu, Dr. W. Xie, Prof. Dr. J. R. Falck
Departments of Biochemistry and Pharmacology
University of Texas Southwestern Medical Center
5323 Harry Hines Blvd., Dallas, TX 75390-9038 (USA)
Fax : (+1)214-648-6455
E-mail: chen.zhu@utsouthwestern.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201102475.
Chem. Eur. J. 2011, 17, 12591 – 12595
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
12591

Table 1. Reaction parameters.
chemical yield (Table 2, entry 9). However, phenyl and p-
methoxyphenyl isocyanide did not give the respective prod-
ucts since these simple aryl isocyanides were too reactive
and prone to polymerization under the given reaction condi-
tions. Significantly, the transformation also proceeded readi-
ly with aliphatic isocyanides. All benzylic, primary, and sec-
ondary aliphatic isocyanides provided useful yields (Table 2,
entries 10–12).
An intriguing trend of Z/E ratio affiliated to the imino
subunit of annulated product was also observed in
Table 2.[13] The use of isocyanide 2a predominantly afforded
the E isomer (Table 2, entries 1–7), while the use of isocya-
nide 2b switched the configuration to Z (Table 2, entry 9).
Specifically, the Z isomer was exclusively formed by using
aliphatic isocyanides 2c–e (Table 2, entries 10–12).
Entry
Conditions
standard conditions[a]
Yield
1
2
3
4
5
6
7
8
70% (<5% 3)
<5% (48% 3)
n.d.
68%
32%
10%
<5%
n.d.
Cu
Ag2CO3 and AgOAc as oxidants
Cu(OAc)2 as oxidant
A
E
To understand the possible mechanistic pathway in the
transformation, some isotopic labeling experiment have
toluene as solvent
THF as solvent
Na2CO3 (2 equiv) as additive
HOAc (10 equiv) as additive
AgSbF6 (10 mol%) as additive
5 instead of 1a
been carried out: 1) Cu
ACHTUNGTRENNUNG
equimolar combination of anhydrous CuACHTUNGTRENNNUG
[eqs. (2) and (3)]; 2) intermolecular competitive reactions
[Eq. (4)], were conducted. Equation (2) indicated that with-
9
50%
n.d.
n.d.
10
11
12
6 instead of 1a
7 instead of 1a
n.d.
[a]Standard conditions: 1a (0.1 mmol), 2a (0.15 mmol), [RhCl2Cp*]2
.
(0.002 mmol), and CuACHTUNGTRENNUNG(OAc)2 H2O (0.2 mmol) in 0.8 mL dichloroethane.
N.D =not detected, Ts=4-toluenesulfonyl.
uct (Table 1, entry 2); the use of silver salts as oxidant re-
sulted in no reaction as isocyanide acted as a good ligand to
the silver cation (Table 1, entry 3). Moreover, the replace-
ment of Cu
G
out coupling partner the proton on the ortho-position of
benzoyl or tosyl side is exchangeable. The absence of deut-
eration at the ortho-position [Eq. (3)] suggested that, under
almost to the same output (Table 1, entry 4). Other solvents
such as toluene or THF notably decelerated the reaction
rate (Table 1, entries 5 and 6). Adding extra base, acid, or
silver salt to the reaction was not beneficial for improving
the chemical yield (Table 1, entries 7–9). As it represented
an advantage in our previous work,[6] the N H acidity was
examined herein as well. It was noted that using unprotect-
À
ed benzamide 5 or weaker N H acidic benzamides (6 and
7) instead of 1a, the corresponding annulated products was
not detected (Table 1, entries 10–12).
With the optimized conditions in hand, we investigated
the scope of the reaction (Table 2). Both N-benzoylsulfona-
mides and isocyanides were evaluated. Naphthyl could re-
place phenyl substrate to afford the best yield (Table 2,
entry 2). Both electron-rich and electron-poor substrates
were tolerated in the reaction. Generally, the former tend to
give better results than the latter (Table 2, entries 3 and 4 vs.
entries 5 and 6). Impressively, in the case of meta-substituted
substrate 1g, the reaction led to high regioselectivity (para/
ortho=7:1) as well as good yield (Table 2, entry 7). The pro-
longed time required to produce an acceptable yield for o-
fluoro substrate 1h implied that the substituent at the adja-
cent position hampered the conversion (Table 2, entry 8).
When the steric hindrance at the ortho-position was further
increased through the introduction of a methoxyl group,
only traces of the product were gained. The insertion of a
halogen atom on the isocyanide did not compromise the
À
the reaction conditions, the C H insertion step is irreversi-
ble. The kinetic isotope effect value (kH/kD =1.5) gained
À
from Equation (4) might indicate that the C H cleavage is
fast, and thus does not take part into the rate-determining
step of the reaction.
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Rhodium-Catalyzed Annulation of N-Benzoylsulfonamide with Isocyanide
COMMUNICATION
Table 2. Substrate scope[a]
The postulated mechanism is
depicted in Figure 1. We specu-
late that the cycle originates
from the generation of five-
membered rhodacycle I via
Entry
1
R1
R2
Product
Yield [%][b]
Z/E Ratio[c]
À
rapid C H activation. Subse-
quently, the isocyanide is
bonded to rhodium center to
form complex II, followed by
70
1:3
1,1-insertion of isocyanide into
[14]
À
the Rh C bond (III). Final-
1a
4a
ly, the annulated product 4 is
released through reductive
elimination, and meanwhile,
the rhodium catalyst is regen-
erated by copper oxidation.
2
81
1:7
The factors that affect the
tendency of the Z/E ratio
shown in Table 2 are not clear
at this earlier stage. However,
with the insight gained from
the mechanistic analysis, we
assume that the isomer ratio is
determined at the step of iso-
1b
1c
1d
1e
1 f
4b
4c
4d
4e
4 f
3
4
5
6
70
65
52
40
1:6
1:5
1:3
1:5
À
cyanide insertion into the Rh
C
bond (intermediate III in
Figure 1).
As
shown
in
Figure 2, when the isocyanide
is relatively small (like 2c–e),
the N-substituent is facing the
highest repulsion from the
ortho-hydrogen (A) rather
than tosyl (B), thus the forma-
tion of Z-imine is favorable.
However, in the case of 2a, the
bulky N-aryl substituent suffers
the competitive repulsion from
both sides. Based on the exper-
imental results reported in
Table 2, more likely, turning to
tosyl (D) side may encounter
stronger repulsion than from
ortho-hydrogen (C), so the
generation of E-imine becomes
favorable.[15]
2a
7
72[d]
1:3
2:1
1g
1h
4g
4h
In summary, the unprece-
dented rhodium-catalyzed an-
nulation of N-benzoylsulfon-
amide with isocyanide through
8[e]
46
À
C H activation has been de-
scribed. The transformation
successfully suppresses the
competitive reaction, and is
broadly compatible with N-
benzoylsulfonamides as well as
isocyanides with different elec-
tronic properties. From a prac-
Chem. Eur. J. 2011, 17, 12591 – 12595
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www.chemeurj.org
12593

C. Zhu et al.
Table 2. (Continued)
Experimental Section
Entry
R1
R2
Product
Yield [%][b]
Z/E Ratio[c]
General procedure for rhodium-cata-
lyzed annulation of N-benzoylsulfona-
mide with isocyanide: N-Benzoylsul-
fonamide 1a (27.5 mg, 0.1 mmol),
[RhCl2Cp*]2 (1.2 mg, 0.002 mmol)
9
60
6:1
and
Cu
(OAc)2·H2O
(40.0 mg,
2b
Bn
4i
4j
0.2 mmol) were loaded in a dry vial
which was subjected to evacuation/
flushing with dry argon three times.
A solution of isocyanide 2a (19.6 mg,
0.15 mmol) in anhydrous methylene
chloride (0.8 mL) was syringed into
the mixture that was then stirred at
1308C for 20 h or until the starting
material had been consumed as deter-
mined by TLC. Upon cooling to
room temperature, all volatiles were
evaporated and the residue was puri-
fied by preparative TLC (ethyl ace-
tate/hexane=1:2) to give 3-(imino)-
isoindolinone 4a in 70% yield (E/Z=
3:1). Z and E isomers were further
separated by preparative TLC (meth-
ylene chloride/hexane=10:1).
10
11
12
41
54
50
only Z
only Z
only Z
2c
1a
n-pentyl
2d
4k
c-hexyl
E Isomer, yellow solid: 1H NMR
(500 MHz, CDCl3): d=1.84 (s, 6H),
2.44 (s, 3H), 6.49 (d, J=7.5 Hz, 1H),
7.02 (dd, J=6.5, 8.0 Hz, 1H), 7.07 (d,
J=7.5 Hz, 2H), 7.34 (d, J=8.0 Hz,
2H), 7.38 (dd, J=7.5, 8.0 Hz, 1H),
7.60 (dd, J=7.5, 7.5 Hz, 1H), 7.94 (d,
J=7.5 Hz, 1H), 8.15 ppm (d, J=
8.0 Hz, 2H); 13C NMR (125 MHz,
2e
4l
(0.15 mmol), [RhCl2Cp*]2 (0.002 mmol), and CuACTHNUGRTNEUNG(OAc)2·H2O
[a] Standard conditions:
1
(0.1 mmol),
2
(0.2 mmol) in 0.8 mL dichloroethane at 1308C for 20 h. [b] Yield of isolated product. [c] Z/E configuration of
the imino bond. Except 4h, all other pairs of isomers are separable on preparative TLC. [d] Product ratio
para/ortho=7:1. [e] 48 h. Bn=benzyl.
CDCl3): d=17.9, 22.0, 124.3, 124.9, 125.0, 126.1, 128.6, 129.2, 129.3, 129.7,
130.6, 133.3, 135.3, 136.5, 145.5, 145.6, 147.3, 163.6 ppm; FT-IR (CH2Cl2):
n˜ =2361, 2342, 1762, 1677, 1380, 1267, 1191, 1178, 1057, 694 cmÀ1; HRMS
(ESI): m/z calcd for C23H21N2O3S: 405.1267 [M+H]+; found: 405.1264.
Z Isomer, colorless solid: 1H NMR (500 MHz, CDCl3): d=2.14 (s, 6H),
2.38 (s, 3H), 7.14 (d, J=7.5 Hz, 2H), 7.20 (d, J=8.0 Hz, 2H), 7.25 (dd,
J=7.5, 7.5 Hz, 1H), 7.65 (d, J=8.0 Hz, 2H), 7.84 (dd, J=7.5, 7.5 Hz,
1H), 7.89 (dd, J=7.5, 7.5 Hz, 1H), 8.01 (d, J=7.5 Hz, 1H), 8.98 ppm (d,
J=7.5 Hz, 1H); 13C NMR (125 MHz, CDCl3): d=18.3, 21.8, 124.5, 126.6,
128.5, 129.5, 129.6, 129.7, 130.1, 130.6, 131.2, 134.7, 134.8, 136.9, 139.1,
143.5, 160.1, 166.6 ppm; FT-IR (CH2Cl2): n˜ =2361, 2342, 1762, 1609, 1380,
1316, 1150, 1078, 899, 827, 710, 660 cmÀ1; HRMS (ESI): m/z calcd for
C23H21N2O3S: 405.1267 [M+H]+; found: 405.1258.
Figure 1. Plausible reaction mechanism.
tical point of view, this method provides the most straight-
forward approach to a series of 3-(imino)isoindolinones.
Figure 2. Steric influence of the isocyanide on the isomer ratio.
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Rhodium-Catalyzed Annulation of N-Benzoylsulfonamide with Isocyanide
COMMUNICATION
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Acknowledgements
We thank the NIH (GM31278) and the Robert A. Welch Foundation
(GL625910) for financial support.
À
Keywords: annulations · C H activation · heterocycles ·
isocyanide · rhodium
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À
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1
[15] These presumed interactions are demonstrated in the H NMR spec-
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Received: August 9, 2011
Revised: September 7, 2011
Published online: October 4, 2011
Chem. Eur. J. 2011, 17, 12591 – 12595
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
12595