Rhodium(III)-catalyzed amidation of aryl ketone o-methyl oximes with isocyanates by C-H activation: Convergent synthesis of 3-methyleneisoindolin-1- ones

Article abstract of DOI:10.1002/chem.201204448

Going green! The rhodium(III)-catalyzed annulation of aryl ketone O-methyl oximes with isocyanates for the synthesis of 3-methyleneisoindolin-1-ones is reported (see scheme). This reaction exhibits high regioselectivity, functional-group tolerance, and broad substrate scope, without the use of additives or production of environmentally hazardous waste. Copyright

Full text of DOI:10.1002/chem.201204448

COMMUNICATION
DOI: 10.1002/chem.201204448
RhodiumACHTUNGTRENNUNG
À
Isocyanates by C H Activation: Convergent Synthesis of
3-Methylene
N
Bing Zhou,* Wei Hou, Yaxi Yang, and Yuanchao Li*[a]
The 3-methyleneisoindolin-1-one structural motif is com-
monly present in a number of bioactive natural products
and designed pharmaceutical molecules,[1] such as fumari-
dine (I),[1a] magallanesine (II),[1b] compound III showing
local anesthetic activity superior to that of procaine,[1c] (E)-
IV exhibiting anesthetic activity,[1d] and (Z)-IV and V show-
ing sedative activity.[1e,f] In addition, 3-methyleneisoindolin-
1-ones are useful intermediates in the synthesis of alkaloids,
such as lennoxamine,[2a–c] fumaridine,[2d] fumaramidine,[2e]
narceine imide,[2f] aristocularines,[2g] and aristolactams.[2hÀj]
of o-(1-alkynyl)benzamides,[4a–g] annulation of 2-(2,2-dihalo-
vinyl)benzonitriles,[4h] CuI/l-proline-catalyzed coupling of 2-
bromobenzamides and terminal alkynes,[4i–j] Heck-Suzuki–
Miyaura domino reactions involving ynamides,[4k] Sonoga-
shira coupling–carbonylation–hydroamination of 2-bromoio-
dobenzene,[4l] a Sonogashira reaction of 2-iodobenzamides
with terminal alkynes followed by NaOEt-mediated cycliza-
tion,[4m] and the one-pot regioselective elimination cycliza-
tion-Suzuki approach.[4n] However, in spite of their potential
utility, these procedures typically suffer from intrinsic draw-
backs, such as tedious and expensive substrate preparation,
poor functional-group tolerance or harsh reaction condi-
tions. In addition, stoichiometric amounts of environmental-
ly hazardous byproducts cannot be avoided from the reagent
and halide salts. Therefore, an efficient, simple, and environ-
mentally friendly protocol under mild conditions is highly
desirable.
Over the past several years, transition-metal-catalyzed ar-
À
omatic C H bond functionalization, one of the hot topics in
current organic chemistry, represents a burgeoning field.
À
While transition-metal-catalyzed addition of C H bonds to
alkene and alkyne derivatives has been extensively investi-
[6]
gated,[5] analogous additions across polarized C O and
À
À
C N[7–8] multiple bonds have seen considerably less progress.
Recently, several studies about RhIII-catalyzed oxidative
coupling of N-aryl benzamides with activated olefins to give
substituted 3-methyleneisoindolin-1-ones have been devel-
oped [Eq. (1)].[9] However, stoichiometric amounts of exter-
nal oxidant are still required and the substitution on the
methylene group is limited to electron-withdrawing groups.
The synthetic utility of 3-methyleneisoindolin-1-ones, to-
gether with their biological activity, makes their synthesis an
attractive task. The classical methods to 3-methyleneisoindo-
lin-1-ones are Wittig reactions with phthalimides or addition
of organometallic reagents to phthalimides, followed by de-
hydration.[3] However, these procedures typically suffer
from poor regioselectivity in the case of unsymmetrical sub-
strates. In addition, several synthetic protocols have been
developed in the last few years,[4] such as heteroannulation
Very recently, RhIII and RuII-catalyzed amidation of aryl and
vinyl C H bonds with isocyanates has been developed.
[10]
À
Herein, we report a new type of rhodium
(III)-catalyzed an-
nulation of aryl ketone O-methyl oximes with isocyanates in
the absence of any additives under mild and neutral reaction
À
conditions, wherein the directing group for C H bond func-
tionalization serves an auxiliary role of capturing the result-
ing amide group to afford synthetically and pharmaceutical-
ly important 3-methyleneisoindolin-1-ones [Eq. (2)]. It is
noteworthy to mention that direct nucleophilic attack of the
[a] Dr. B. Zhou, Dr. W. Hou, Dr. Y. Yang, Prof. Dr. Y. Li
Shanghai Institute of Materia Medica, Chinese Academy of Sciences
555 Zu Chong Zhi Road, Shanghai 201203 (P.R. China)
Fax : (+86)21-50807288
À
À
Rh N moiety to the C N bond is quite rare, although rho-
dium-catalyzed intramolecular nucleophilic cyclizations by
E-mail: zhoubing2012@hotmail.com
[11]
À
C H bond activation have been widely reported.
ycli@mail.shcnc.ac.cn
We started our investigation by testing the RhIII-catalyzed
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201204448.
addition of acetophenone (1a) to p-tolyl isocyanate 3a
Chem. Eur. J. 2013, 00, 0 – 0
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vealed that using 1,2-dichloro-
ethane (DCE) as the reaction
solvent led to a reactivity simi-
lar to that observed with THF
(entries 6–9). Raising the tem-
perature did not result in any
reduction in yield (entry 10)
and lowering the temperature
led to a slightly low conversion
(entry 11). The present annula-
tion reaction can also be carried
out with good efficiency in the
presence of 2.5 mol% of cata-
lyst by simply lengthening the
(Table 1). However, no product was observed, irrespective
of the reaction conditions used (Table 1, entries 1–3), pre-
sumably due to the poor directing ability of the ketone
group. Therefore, acetophenone O-methyl oxime (2a) with
a more strongly metal coordinating functionality was investi-
reaction time to 24 h (entry 12). Finally, we were pleased to
find that this reaction was successfully scaled-up to a
2 mmol substrate level without
a decrease in yield
(entry 13). More importantly, in this annulation reaction
nothing is required except the catalyst and solvent to facili-
tate the addition as desired. In addition, N-phenyl and
-benzyl ketimines were also readily converted to the desired
product 4a in moderate yields (entries 14 and 15).
gated. Although the use of [RhCl
thylcyclopentadienyl) proved unsuccessful in catalyzing this
reaction (entry 4), [RhCl2A(Cp*)]2 (5 mol%) in the presence
of Ag[SbF6] (20 mol%) in THF at 1008C provided the de-
sired product 4a in 84% yield (entry 5). The prepared RhIII
precursor [Rh(CH3CN)3A(Cp*)][SbF6]2 led to a reactivity sim-
ilar to that observed with [RhCl2A(Cp*)]2 and Ag[SbF6]
(entry 6), and [Rh(CH3CN)3A(Cp*)][SbF6]2 was used for all
2ACHTUNGTREN(NNUG Cp*)]2 (Cp*=pentame-
CTHUNGTRENNUNG
T
Under the optimized conditions, the substrate scope with
a range of acetophenone oximes (2) containing different
substitution patterns was investigated (Table 2). It was
found that the electronic nature of the substituents on the
phenyl ring did not play a key role. With either electron-
withdrawing or -donating groups, for example CF3 (4b),
ester (4c), methoxy (4g), and methyl groups (4h), acetophe-
none oximes were readily converted to the corresponding
products in good to excellent yields. Substitutions at the
para (4b–h), meta (4i and 4j), and ortho (4k and 4l) posi-
tions were all well tolerated. Notably, the tolerance of the
halides (4d and 4e) offers the opportunity for further func-
tionalization. To scrutinize further the regioselectivity, the
reaction of meta-substituted acetophenone oximes selective-
ly occurred at the less sterically hindered position (4i and
4j). For example, meta-methyl-substituted oxime gave a
single regioisomer (4i) and meta-chloro-substituted oxime
produced a 10:1 ratio of regioisomers 4j. Steric bulkiness on
the phenyl ring was also tested. To our delight, all the reac-
tions with a methyl group at the ortho, meta, or para posi-
tions of the phenyl ring showed good to excellent reactivi-
ties (4h, 4i, and 4k), thus showing high tolerance for steric
hindrance.
We next explored the possibility of changing the substitu-
ents at the methyl group of acetophenone oximes and were
pleased to find that both alkyl and aryl substitutions were
compatible with these conditions to give the corresponding
products in excellent yields (4m–q). For the stereochemistry
of the present transformation, it was found that alkyl-substi-
tuted acetophenone oximes gave inseparable E and Z iso-
mers (4m and 4n) in a ratio of nearly 1.7:1. Gratifying, in
case of aryl-substituted acetophenone oximes (4o–q) as sub-
strates, E isomers were isolated as the major products in ex-
cellent yields and with good diastereoselectivities. Their ge-
ometry was established through NOE studies.
A
N
ACHTUNGTRENNUNG
C
ACHTUNGTRENNUNG
A
N
ACHTUNGTRENNUNG
subsequent optimization studies. A screen of solvents re-
Table 1. Reaction development.[a]
Entry Substrate Catalyst (5 mol%)
Solvent Yield [%][b]
ACHTNUTRGNEUGN[SbF6]2 THF 0
1
1a
1a
1a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a’
2a’’
[Rh
[RhCl
[RhCl
[RhCl
[RhCl
G
N
2
G
E
U
THF
THF
THF
THF
0
0
0
3
N
CHTUNGTRENNUNG
4
G
U
5
G
E
N
84
6
7
8
9
[Rh
[Rh
[Rh
[Rh
[Rh
[Rh
[Rh
[Rh
[Rh
[Rh
N
G
A
87
A
88
A
<10
A
43 (87)
10[c]
11[d]
12[e]
13[f]
14
15
A
88
A
82 (90)
85
ACHTUNGTRENNUNG
A
85
A
62
A
65
[a] Reaction conditions: 1a or 2a (0.2 mmol), 3a (0.3 mmol), Rh cat.
(0.01 mmol), solvent (1 mL), 1008C, 12 h. [b] Yield of isolated product;
yield in parentheses is based on recovered starting material. [c] The reac-
tion was carried out at 1208C. [d] The reaction was carried out at 908C.
[e] 2.5 mol% of catalyst was used. Reaction time is 24 h. [f] The reaction
was scaled-up to a 2 mmol substrate level.
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Convergent Synthesis of 3-Methyleneisoindolin-1-ones
Table 2. Substrate scope for acetophenone oximes.[a]
COMMUNICATION
tion. In addition, 2-naphthyl isocyanate also gave the corre-
sponding product 4v in 80% yield. Particularly remarkable
is the participation of alkyl isocyanate in this reaction, pro-
viding the corresponding derivative 4w in 60% yield.
To probe the catalytic mechanism, we carried out a com-
petition experiment between equimolar amounts of deuter-
io-2a and 2a with p-tolyl isocyanate 3a under our standard
conditions for 1 h, which results in the intermolecular kinet-
ic isotope effect (kH/kD) of 3.5:1 (Scheme 1A). However,
Scheme 1. Mechanistic studies: a) [Rh
DCE, 1008C, 1 h, kH/kD =3.5:1; b) p-tolyl isocyanate [Rh
(Cp*)][SbF6]2 (5 mol%), DCE, 1008C, 2 h.
ACHTUGNTREN(NUGN CH3CN)3ACHTUNTRGEG(NNUN Cp*)]ACUTHNGTRENNUNG
ACHTUNGTRENNUNG
N
ACHTUNGTRENNUNG
[a] Reaction conditions:
2
(0.2 mmol), 3a (0.3 mmol), Rh cat.
(0.01 mmol), DCE (1 mL), 1008C, 12 h. The yield of isolated product is
given. [b] A mixture of 4j and minor regioisomeric product was deter-
mined in a ratio of 10:1.
when [D5]2a was subjected to the standard reaction condi-
tions, only modest deuterium exchange was observed at the
ortho positions of both the unreacted oxime (25% H) and
the product (13% H) (Scheme 1B). Although elucidation of
the rate law for the annulation reaction is necessary to inter-
pret this result properly, a notable primary kinetic isotope
In addition to 3a, other isocyanates were also investigated
for the reaction (Table 3). It was found that the reactivity of
this reaction was to some degree sensitive to the substitution
patterns (4a, 4r–u) and electronic properties of the phenyl
ring, and benefited from electron-donating groups (4a and
4r). Notably, the tolerance of the bromo (4s) and ester
groups (4u) offers the opportunity for further functionaliza-
À
effect (KIE, kH/kD =3.5) suggests that the C H bond cleav-
age is likely involved in the rate-limiting step.[12]
Although the reaction mechanism remains to be elucidat-
ed, we tentatively propose the following reaction pathway
(Scheme 2). The catalytic annulation reaction should involve
initially the coordination of the oxime nitrogen to the rhodi-
À
um center and subsequent ortho C H bond activation forms
Table 3. Substrate scope for isocyanates 3.[a]
a five-membered rhodacycle A and the release of one equiv-
alent of proton (H+). After the ligand exchange from aceto-
nitrile to isocyanate, the coordinating complex B forms. Se-
À
lective insertion of isocyanate into the Rh C bond of inter-
mediate B gives the seven-membered rhodacycle C, which
undergoes an intramolecular insertion of the oxime group
into the nitrogen–Rh bond to form intermediate D (path a).
This intermediate is protonated by the acid that is generated
in situ at the initiating step, followed by elimination of one
molecule of methoxyamine, thus producing the desired
product 4. This final step is also accompanied by the regen-
eration of the active catalyst. On the other hand, protona-
tion of C affords intermediate E (path b), in which rhodium
could activate the oxime for intramolecular nucleophilic ad-
[a] Reaction conditions: 2a (0.2 mmol),
(0.01 mmol), DCE (1 mL), 1008C, 12 h. The yield of isolated product is
given.
3
(0.3 mmol), Rh cat.
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B. Zhou, Y. Li et al.
Scheme 2. Proposed mechanism (L=CH3CN).
Scheme 4. Conditions: a) NaH, dimethyl carbonate, toluene, reflux for
3 h, 88%; b) MeONH2·HCl, NaOAc, MeOH/H2O, 80 8C for 2 h, 93%;
c) isocyanate, [RhACTHUGNTREN(NGUN CH3CN)3ACHTUNRTGE(NGNUN Cp*)]CATHUNGTREN[UNGN SbF6]2, DCE, 1408C for 16 h, (E)-8
dition by coordination or serving as a Lewis acid. Finally,
elimination of one molecule of methoxyamine affords prod-
uct 4 and regenerates the catalyst.
(73%), (Z)-8 (12%); d) Pd/H2, MeOH, 608C for 4 h; e) 15% K2CO3,
MeOH, 808C for 10 h; f) 1-methylpiperazine, EDC, HOBt, THF, 258C
for 16 h.
We carried out several experiments to probe the reaction
pathway. To our delight, when using 2n as the substrate, the
intermediate 4n’ was obtained in 15% yield by lowering the
reaction temperature to 908C and shortening the reaction
time to 5 h (Scheme 3A). Subjecting intermediate 4n’ to
Reaction of commercially available starting material 5 with
dimethyl carbonate, followed by treatment with O-methyl-
hydroxylamine hydrochloride in MeOH and H2O in the
presence of NaOAc, gave
oxime 7 in 82% yield for the
two steps. Rh-catalyzed annula-
tion of oxime 7 and 4-fluoro-
phenyl isocyanate provided the
key intermediate
8 in 85%
yield as a mixture of E and Z
isomers (6:1). Hydrogenation
and hydrolysis of the ester
group, followed by treatment of
1-methylpiperazine in the pres-
ence of N-(3-dimethylamino-
propyl)-N’-ethylcarbodiimide
hydrochloride (EDC) and 1-hy-
droxybenzotriazole
hydrate
(HOBt), afforded the bioactive
compound V in 83% yield for
Scheme 3. Probing the reaction mechanism: a) [Rh
ACHTUNGNERT(NUGN CH3CN)3ACHTUNRTGEG(NNUN Cp*)]ACHTNGUTERN[NUGN SbF6]2 (5 mol%), DCE, 908C, 5 h, 15%;
b) [Rh(CH3CN)3A(Cp*)][SbF6]2 (5 mol%), DCE, 1008C, 12 h, 95%; c) DCE, 1008C, 12 h, 24%.
A
N
ACHTUNGTRENNUNG
the three steps.[1f] On the other
hand, direct hydrolysis of the
standard reaction conditions gave 4n in 95% yield, whereas
only a 24% yield was observed in the absence of catalyst
[RhACHTUNGTRENNUNG(CH3CN)3ACHTUNGTRENNUNG(Cp*)]ACHTNUGTRNE[NUGN SbF6]2 (Scheme 3B). These results indi-
ester group and subsequent treatment with 1-methylpipera-
zine provided compound (E)-IV in 89% yield over two
steps.[1d]
cate the existence of path b and suggest that the subsequent
intramolecular nucleophilic addition is mainly promoted by
the Rh catalyst.
In summary, we have developed a novel rhodium-cata-
lyzed annulation of aryl ketone O-methyl oximes with iso-
cyanates for the synthesis of 3-methyleneisoindolin-1-ones
À
To further illustrate the synthetic usage of the present
method, we developed an efficient and concise synthesis of
bioactive compounds (E)-IV and V, as depicted in Scheme 4.
by C H bond activation. The reaction can be carried out in
the absence of any additives and environmentally hazardous
waste production, without the requirement of special techni-
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Convergent Synthesis of 3-Methyleneisoindolin-1-ones
COMMUNICATION
À
[5] For selected recent reviews on C H bond functionalization, see:
ques. This reaction is potentially applicable in laboratory
and industrial synthesis. Most importantly, this process gives
a simple and straightforward access to 3-methyleneisoindo-
lin-1-ones and may find applications in the synthesis of com-
plex natural products or designed bioactive compounds.
a) G. Song, F. Wang, X. Li, Chem. Soc. Rev. 2012, 41, 3651; b) D. A.
Colby, A. S. Tsai, R. G. Bergman, J. A. Ellman, Acc. Chem. Res.
2012, 45, 814; c) D. A. Colby, R. G. Bergman, J. A. Ellman, Chem.
Rev. 2010, 110, 624; d) X. Chen, K. M. Engle, D. H. Wang, J. Q. Yu,
Angew. Chem. 2009, 121, 5196; Angew. Chem. Int. Ed. 2009, 48,
5094; e) T. W. Lyons, M. S. Sanford, Chem. Rev. 2010, 110, 1147;
f) I. A. I. Mkhalid, J. H. Barnard, T. B. Marder, J. M. Murphy, J. F.
Hartwig, Chem. Rev. 2010, 110, 890; g) T. Satoh, M. Miura, Chem.
Eur. J. 2010, 16, 11212; h) R. B. F. Shi, K. M. Engle, N. Maugel, J. Q.
Yu, Chem. Soc. Rev. 2009, 38, 3242; i) Y. J. Park, J. W. Park, C. H.
Hun, Acc. Chem. Res. 2008, 41, 222; j) J. C. Lewis, R. G. Bergman,
J. A. Ellman, Acc. Chem. Res. 2008, 41, 1013; k) K. Godula, D.
Sames, Science 2006, 312, 67. For selected recent examples, see: l) L.
Yang, B. Qian, H. Huang, Chem. Eur. J. 2012, 18, 9511; m) B. Qian,
D. Shi, L. Yang, H. Huang, Adv. Synth. Catal. 2012, 354, 2146; n) P.
Zhao, R. Niu, F. Wang, K. Han, X. Li, Org. Lett. 2012, 14, 4166;
o) P. Zhao, F. Wang, K. Han, X. Li, Org. Lett. 2012, 14, 5506; p) P.
Zhao, F. Wang, K. Han, X. Li, Org. Lett. 2012, 14, 3400; q) H. Li,
K.-H. He, J. Liu, B.-Q. Wang, K.-Q. Zhao, P. Hu, Z.-J. Shi, Chem.
Commun. 2012, 48, 7028; r) H. Li, Y. Li, X.-S. Zhang, K. Chen, X.
Wang, Z.-J. Shi, J. Am. Chem. Soc. 2011, 133, 15244; s) R. Zeng, C.
Fu, S. Ma, J. Am. Chem. Soc. 2012, 134, 9597; t) S. Mochida, K.
Hirano, T. Satoh, M. Miura, J. Org. Chem. 2011, 76, 3024; u) S. Mo-
chida, K. Hirano, T. Satoh, M. Miura, Org. Lett. 2010, 12, 5776; v) T.
Ueyama, S. Mochida, T. Fukutani, K. Hirano, T. Satoh, M. Miura,
Org. Lett. 2011, 13, 706.
Experimental Section
General procedure: An oven-dried reaction vessel was charged with
[RhACHTUNGTRENNUNG(CH3CN)3ACHTUNGTRENNUNG(Cp*)]ACHTUNGTRENNUNG[SbF6]2 (8.4 mg, 5 mol%, 0.01 mmol), DCE (1 mL),
substrate 2 (0.2 mmol), and substrate 3 (0.3 mmol). The reaction mixture
was stirred in the sealed tube at 1008C under N2 for 12 h. The resulting
mixture was cooled to room temperature, filtered through a short silica
gel pad, and transferred to a silica gel column directly to give product 4.
À
Keywords: annulation · C H activation · isocyanates ·
ketones · rhodium
[1] a) G. Blaskꢁ, D. J. Gula, M. Shamma, J. Nat. Prod. 1982, 45, 105;
b) E. Valencia, V. Fajardo, A. J. Freyer, M. Shamma, Tetrahedron
Lett. 1985, 26, 993; c) Laboratori Baldacci S. p. A. JP 59046268;
[Chem. Abstr. 1984, 101, 54922]; d) T. Kouhei, O. Osaka, EP
1566378A1; e) B. Hulin, J. C. Parker, D. W. Piotrowski, US
2005234065; f) N. Kanamitsu, T. Osaki, Y. Itsuji, M. Yoshimura, H.
Tsujimoto, M. Soga, Chem. Pharm. Bull. 2007, 55, 1682; g) H. M.
Botero Cid, C. Trankle, K. Baumann, R. Pick, E. Mies-Klomfass, E.
Kostenis, K. Mohr, U. Holzgrabe, J. Med. Chem. 2000, 43, 2155;
h) Y. Kato, M. Takemoto, K. Achiwa, Chem. Pharm. Bull. 1993, 41,
2003; i) K. Toyooka, N. Kanamitsu, M. Yoshimura, H. Kuriyama, T.
Tamura, WO2004048332.
[2] a) A. Couture, E. Deniau, P. Grandclaudon, C. Hoarau, Tetrahedron
2000, 56, 1491; b) S. Couty, B. Liegault, C. Meyer, J. Cossy, Tetrahe-
dron 2006, 62, 3882; c) S. Couty, C. Meyer, J. Cossy, Tetrahedron
Lett. 2006, 47, 767; d) V. Rys, A. Couture, E. Deniau, P. Grandclau-
don, Tetrahedron 2003, 59, 6615; e) M. Lamblin, A. Couture, E.
Deniau, P. Grandclaudon, Tetrahedron 2006, 62, 2917; f) M. Lam-
blin, A. Couture, E. Deniau, P. Grandclaudon, Org. Biomol. Chem.
2007, 5, 1466; g) A. Moreau, A. Couture, E. Deniau, P. Grandclau-
don, J. Org. Chem. 2004, 69, 4527; h) A. Couture, E. Deniau, P.
Grandclaudon, H. R. Rosen, S. Lꢂonce, B. Pfeiffer, P. Renard,
Bioorg. Med. Chem. Lett. 2002, 12, 3557; i) V. Rys, A. Couture, E.
Deniau, S. Lebrun, P. Grandclaudon, Tetrahedron 2005, 61, 665; j) C.
Hoarau, A. Couture, H. Cornet, E. Deniau, P. Grandclaudon, J.
Org. Chem. 2001, 66, 8064.
À
[6] For recent examples of the direct addition of C H bonds to alde-
hydes, see: a) C. W. Chan, Z. Zhou, W.-Y. Yu, Adv. Synth. Catal.
2011, 353, 2999; b) Y. Yuan, D. Chen, X. Wang, Adv. Synth. Catal.
2011, 353, 3373; c) C. Li, L. Wang, P. Li, W. Zhou, Chem. Eur. J.
2011, 17, 10208; d) B. J. Li, Z. J. Shi, Chem. Sci. 2011, 2, 488; e) J.
Park, E. Park, A. Kim, Y. Lee, K. W. Chi, J. H. Kwak, Y. H. Jung,
I. S. Kim, Org. Lett. 2011, 13, 4390; f) L. Yang, C. A. Correia, C. J.
Li, Adv. Synth. Catal. 2011, 353, 1269; g) A. Flores-Gaspar, R.
Martin, Adv. Synth. Catal. 2011, 353, 1223; h) Y. Li, X. S. Zhang, K.
Chen, K. H. He, F. Pan, B. J. Li, Z. J. Shi, Org. Lett. 2012, 14, 636;
i) S. Sharma, E. Park, J. Park, I. S. Kim, Org. Lett. 2012, 14, 906;
j) B. Zhou, Y. Yang, Y. Li, Chem. Commun. 2012, 48, 5163; k) Y.
Lian, R. G. Bergman, J. A. Ellman, Chem. Sci. 2012, 3, 3088; l) Y.
Yang, B. Zhou, Y. Li, Adv. Synth. Catal. 2012, 354, 2916; m) X. Shi,
C.-J. Li, Adv. Synth. Catal. 2012, 354, 2933; n) Y. Lian, T. Huber,
K. D. Hesp, R. G. Bergman, J. A. Ellman, Angew. Chem. Int. Ed.
2012, DOI: 10.1002/anie.201207995.
À
[7] For examples of the direct addition of C H bonds to imines, see:
a) A. S. Tsai, M. E. Tauchert, R. G. Bergman, J. A. Ellman, J. Am.
Chem. Soc. 2011, 133, 1248; b) Y. Li, B.-J. Li, W.-H. Wang, W.-P.
Huang, X.-S. Zhang, K. Chen, Z.-J. Shi, Angew. Chem. 2011, 123,
2163; Angew. Chem. Int. Ed. 2011, 50, 2115; c) K. Gao, N. Yoshikai,
Chem. Commun. 2012, 48, 4305; d) M. E. Tauchert, C. D. Incarvito,
A. L. Rheingold, R. G. Bergman, J. A. Ellman, J. Am. Chem. Soc.
2012, 134, 1482; e) K. D. Hesp, R. G. Bergman, J. A. Ellman, Org.
Lett. 2012, 14, 2304; f) Y. Li, X.-S. Zhang, H. Li, W.-H. Wang, K.
Chen, B.-J. Li, Z.-J. Shi, Chem. Sci. 2012, 3, 1634; g) Y. Li, X.-S.
Zhang, Q.-L. Zhu, Z.-J. Shi, Org. Lett. 2012, 14, 4498.
[3] a) W. Flitsch, H. Peters, Tetrahedron Lett. 1969, 10, 1161; b) A. G.
Griesbeck, K.-D. Warzecha, J.-M. Neudorfl, H. Gorner, Synlett 2004,
13, 2347; c) T. Bousquet, J.-F. Fleury, A. Daich, P. Netchitailo, Tetra-
hedron 2006, 62, 706.
[4] a) G. Bianchi, M. Chiarini, F. Marinelli, L. Rossi, A. Arcadi, Adv.
Synth. Catal. 2010, 352, 136; b) C. Kanazawa, M. Terada, Chem.
Asian J. 2009, 4, 1668; c) M.-J. Wu, L.-J. Chang, L.-M. Wei, C.-F.
Lin, Tetrahedron 1999, 55, 13193; d) W.-D. Lu, C.-F. Lin, C.-J. Wang,
S.-J. Wang, M.-J. Wu, Tetrahedron 2002, 58, 7315; e) C. Koradin, W.
Dohle, A. L. Rodriguez, B. Schmid, P. Knochel, Tetrahedron 2003,
59, 1571; f) N. G. Kundu, M. W. Khan, Tetrahedron Lett. 1997, 38,
6937; g) T. Yao, R. C. Larock, J. Org. Chem. 2005, 70, 1432; h) C.
Wang, C. Sun, F. Weng, M. Gao, B. Liu, B. Xu, Tetrahedron Lett.
2011, 52, 2984; i) L. Li, M. Wang, X. Zhang, Y. Jiang, D. Ma, Org.
Lett. 2009, 11, 1309; j) M. Hellal, G. D. Cuny, Tetrahedron Lett.
2011, 52, 5508; k) S. Couty, B. Liegault, C. Meyer, J. Cossy, Org.
Lett. 2004, 6, 2511; l) H. Cao, L. McNamee, H. Alper, Org. Lett.
2008, 10, 5281; m) N. G. Kundu, M. W. Khan, Tetrahedron 2000, 56,
4777; n) C. Sun, B. Xu, J. Org. Chem. 2008, 73, 7361.
À
[8] For direct addition of C H bonds to isocyanides, see: C. Zhu, W.
Xie, J. R. Falck, Chem. Eur. J. 2011, 17, 12591.
[9] a) F. Wang, G. Song, X. Li, Org. Lett. 2010, 12, 5430; b) F. W. Patur-
eau, T. Besset, F. Glorius, Angew. Chem. 2011, 123, 1096; Angew.
Chem. Int. Ed. 2011, 50, 1064; c) J. W. Wrigglesworth, B. Cox, G. C.
Lloyd-Jones, K. I. Booker-Milburn, Org. Lett. 2011, 13, 5326; d) X.
Wei, F. Wang, G. Song, Z. Du, X. Li, Org. Biomol. Chem. 2012, 10,
5521.
[10] a) K. D. Hesp, R. G. Bergman, J. A. Ellman, J. Am. Chem. Soc.
2011, 133, 11430; b) K. Muralirajan, K. Parthasarathy, C.-H. Cheng,
Org. Lett. 2012, 14, 4262. Rhenium-catalyzed addition of C H
bonds to isocyanates, see: c) Y. Kuninobu, Y. Tokunaga, A. Kawata,
K. Takai, J. Am. Chem. Soc. 2006, 128, 202; d) Y. Kuninobu, Y. To-
kunaga, K. Takai, Chem. Lett. 2007, 36, 872.
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Chem. Eur. J. 2013, 00, 0 – 0
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B. Zhou, Y. Li et al.
[11] For selected recent examples of the rhodium
(III)-catalyzed annula-
Fagnou, Angew. Chem. 2011, 123, 1374; Angew. Chem. Int. Ed. 2011,
50, 1338; h) Y. Su, M. Zhao, K. Han, G. Song, X. Li, Org. Lett. 2010,
12, 5462; i) T. K. Hyster, T. Rovis, J. Am. Chem. Soc. 2010, 132,
10565; j) P. C. Too, Y.-F. Wang, S. Chiba, Org. Lett. 2010, 12, 5688;
k) F. W. Patureau, F. Glorius, Angew. Chem. 2011, 123, 2021; Angew.
Chem. Int. Ed. 2011, 50, 1977.
tion of alkynes and alkenes, see: a) D. Wang, F. Wang, G. Song, X.
Li, Angew. Chem. Int. Ed. 2012, 51, 12348; b) M. V. Pham, B. Ye, N.
Cramer, Angew. Chem. 2012, 124, 10762; Angew. Chem. Int. Ed.
2012, 51, 10610; c) B.-J. Li, H.-Y. Wang, Q.-L. Zhu, Z.-J. Shi, Angew.
Chem. 2012, 124, 4014; Angew. Chem. Int. Ed. 2012, 51, 3948;
d) F. W. Patureau, T. Besset, N. Kuhl, F. Glorius, J. Am. Chem. Soc.
2011, 133, 2154; e) X. Wei, M. Zhao, Z. Du, X. Li, Org. Lett. 2011,
13, 4636; f) N. Guimond, S. I. Gorelsky, K. Fagnou, J. Am. Chem.
Soc. 2011, 133, 6449; g) M. P. Huestis, L. Chan, D. R. Stuart, K.
[12] E. M. Simmons, J. F. Hartwig, Angew. Chem. Int. Ed. 2012, 51, 3066.
Received: December 13, 2012
Published online: && &&, 0000
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Convergent Synthesis of 3-Methyleneisoindolin-1-ones
COMMUNICATION
Annulation
B. Zhou,* W. Hou, Y. Yang,
Y. Li* ........................... &&&& — &&&&
RhodiumACTHNUGTRNEUNG(III)-Catalyzed Amidation of
Aryl Ketone O-Methyl Oximes with
Going green! The rhodium
(III)-cata-
reaction exhibits high regioselectivity,
functional-group tolerance, and broad
substrate scope, without the use of
additives or production of environmen-
tally hazardous waste.
lyzed annulation of aryl ketone O-
methyl oximes with isocyanates for the
synthesis of 3-methyleneisoindolin-1-
ones is reported (see scheme). This
À
Isocyanates by C H Activation:
Convergent Synthesis of 3-Methylene-
AHCTUNGTREGiNNNU soindolin-1-ones
Chem. Eur. J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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These are not the final page numbers!