Rh(III)-catalyzed addition of alkenyl C-H bond to isocyanates and intramolecular cyclization: Direct synthesis 5-ylidenepyrrol-2(5 H)-ones

Article abstract of DOI:10.1021/ol4003674

The rhodium-catalyzed addition of an alkenyl C-H bond to isocyanates via sp² C-H bond activation followed by an intramolecular cyclization is described. This atom-economic and catalytic reaction affords a simple and straightforward access to bi

Full text of DOI:10.1021/ol4003674

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Rh(III)-Catalyzed Addition of Alkenyl CꢀH
Bond to Isocyanates and Intramolecular
Cyclization: Direct Synthesis
5‑Ylidenepyrrol-2(5H)‑ones
Wei Hou, Bing Zhou,* Yaxi Yang, Huijin Feng, and Yuanchao Li*
Shanghai Institute of Materia Medica, Chinese Academy of Sciences,
555 Zu Chong Zhi Road, Zhang Jiang Hi-Tech Park, Shanghai 201203, PR China
zhoubing2012@hotmail.com; ycli@mail.shcnc.ac.cn
Received February 7, 2013
ABSTRACT
The rhodium-catalyzed addition of an alkenyl CꢀH bond to isocyanates via sp2 CꢀH bond activation followed by an intramolecular cyclization is
described. This atom-economic and catalytic reaction affords a simple and straightforward access to biologically relevant 5-ylidene pyrrol-2(5H)-
ones and can be carried out under mild and neutral conditions in the absence of any additives and environmentally hazardous waste production.
5-Ylidenepyrrol-2(5H)-ones are found in a number of
bioactive natural products1 as well as designed pharma-
ceutical molecules (Figure 1).2 Despite its importance, only
a few examples are reported for the preparation of 5-yli-
denepyrrol-2(5H)-ones. The classical methods are based
on using maleimides as starting materials, which undergo a
Wittig reaction to give the target molecules.3 However, this
procedure suffers from poor regioselectivity in the cases
of unsymmetrical substrates. Several synthetic protocols
have been developed in the past few years.4 Among
them, Abarbri’s electrophilic cyclization strategy generates
stoichiometric amounts of halide waste.4a,b The transi-
tion-metal-mediated domino reaction requires the harsh
reaction conditions and stoichiometric amounts of transi-
tion metal.4c Yoshimatsu’s method4d is limited to selenium-
stabilized alkynyl amide substrates, and Murakami’s
strategy suffers from harsh acidic reaction conditions.4e
Therefore, the development of simple, effective, and
catalytic methods for synthesis of valuable 5-ylidenepyrrol-
2(5H)-ones under mild and neutral reaction conditions
remains a great goal.
On the other hand, synthetic transformation via transi-
tion-metal-catalyzed CꢀH bond functionalization, one of
the hot topics in current organic chemistry, has consider-
ably improved the field of cross-coupling chemistry in
terms of atom- and step-economical points of view.5
Recently, several investigations revealed that RhIII com-
plexes are promising catalysts for direct addition of
C(sp2)ꢀH to polarized CꢀO6 and CꢀN7 multiple bonds
(1) Selected examples: (a) Celmer, W. D.; Solomons, I. A. J. Am.
Chem. Soc. 1955, 77, 2861. (b) Simmons, C. J.; Marner, F.-J.; Cardellina,
J. H., II; Moore, R. E.; Seff, K. Tetrahedron Lett. 1979, 20, 2003.
(c) Cardellina, J. H., II; Moore, R. E. Tetrahedron Lett. 1979, 20, 2007.
(d) Falk, H.; Grubmayr, K.; Herzig, U.; Hofer, O. Tetrahedron Lett.
1975, 16, 559. (e) Lightner, D. A.; Park, Y.-T. J. Heterocycl. Chem. 1977,
14, 415.
(2) Selected examples: (a) Falk, H. The Chemistry of Linear Oligo-
pyrrole Compounds; Springer Verlag: New York, 1989. (b) Birru, W.;
Fernley, R. T.; Graham, L. D.; Grusovin, J.; Hill, R. J.; Hofmann, A.; Howell,
L.; James, P. J.; Jarvis, K. E.; Johnson, W. M.; Jones, D. A.; Leitner, C.; Liepa,
A. J.; Lovrecz, G. O.; Lu, L.; Nearn, R. H.; O'Driscoll, B. J.; Phan, T.; Pollard,
M.; Turner, K. A.; Winkler, D. A. Bioorg. Med. Chem. 2010, 18, 5647.
(c) Kumar, N.; Iskander, G. WO2007085042. (d) Li, B.; Lyle, M. P. A.;
Chen, G.; Li, J.; Hu, K.; Tang, L.; Alaoui-Jamali, M. A.; Webster, J.
Bioorg. Med. Chem. 2007, 15, 4601.
(4) (a) Cherry, K.; Duchene, A.; Thibonnet, J.; Parrain, J.-L.;
Anselmi, E.; Abarbri, M. Synthesis 2009, 257. (b) Cherry, K.; Thibonnet,
J.; Duchene, A.; Parrain, J.-L.; Abarbri, M. Tetrahedron Lett. 2004, 45,
2063. (c) Wuckelt, J.; Doring, M.; Langer, P.; Beckert, R.; Gorls, H.
J. Org. Chem. 1999, 64, 365. (d) Yoshimatsu, M.; Machida, K.; Fuseya,
T.; Shimizu, H.; Kataoka, T. J. Chem. Soc., Perkins Trans. 1 1996, 1839.
(e) Murakami, M.; Hayashi, M.; Ito, Y. J. Org. Chem. 1994, 59, 7910.
(3) Gill, G. B.; James, G. D.; Oates, K. V.; Pattenden, G. J. Chem.
Soc., Perkin Trans. 1 1993, 23, 2567.
r
10.1021/ol4003674
XXXX American Chemical Society

addition to N-tosylimines and aldehydes using a pyridine
and oxime as directing groups, respectively. Herein we
report the direct RhIII-catalyzed alkenyl CꢀH bond addi-
tion to isocyanates, wherein the directing group for CꢀH
bond functionalization serves an auxiliary role of capturing
the resulting amide group to afford synthetically and phar-
maceutically important 5-ylidene-pyrrol-2(5H)-ones (eq 1).
More importantly, in contrast to previous methods,3,4 this
RhIII-catalyzed annulation reaction9 proceeded in the ab-
sence of any additives and environmentally hazardous waste
production under mild and neutral reaction conditions.
As indicated in Table 1, we initiated our studies by con-
ducting the RhIII-catalyzed addition of R,β-unsaturated
oxime (1a) to p-tolyl isocyanate (2a). Although the use of
5 mol % of (Cp*RhCl2)2 proved unsuccessful in catalyzing
this reaction (entry 1), (Cp*RhCl2)2 (5 mol %) in the
presence of AgSbF6 (20 mol %) in THF at 100 °C provided
the desired product 3a in 60% yield (entry 2). The prepared
RhIII precursor [Cp*Rh(CH3CN)3](SbF6)2 showed super-
ior reactivity compared to that observed with (Cp*RhCl2)2
and AgSbF6 (entry 3). A screen of solvents revealed DCE
tobesuperiortoTHF (entries 3ꢀ6). A longer reaction time
and a higher temperature (120 °C) did not result in any
reduction in yield (entry 7) and lowering the temperature
led to a slightly low conversion (entry 8). A lower catalyst
Figure 1. Structures of some biologically important 5-ylidene-
pyrrol-2(5H)-ones.
via a chelation-assisted electrophilic metalation of the
ortho C(sp2)ꢀH bond. However, applying these directed
arene CꢀH functionalization methods to alkenes is still
challenging due to the increased reactivity and lability of
olefins. Until now, only a few examples have been reported.8
Recently, Bergman and Ellman reported the addition
of alkenyl CꢀH bonds of enamides to isocyanates.8a Very
recently, Shi8b and Ellman8c reported alkenyl CꢀH bond
(5) For selected recent reviews on CꢀH bond functionalization, see:
(a) Song, G.; Wang, F.; Li, X. Chem. Soc. Rev. 2012, 41, 3651. (b)
Patureau, F. W.; Wencel-Delord, J.; Glorius, F. Aldrichimica Acta 2012,
45, 31. (c) Colby, D. A.; Tsai, A. S.; Bergman, R. G.; Ellman, J. A. Acc.
Chem. Res. 2012, 45, 814. (d) Wencel-Delord, J.; Droge, T.; Liu, F.;
Glorius, F. Chem. Soc. Rev. 2011, 40, 4740. (e) Yeung, C. S.; Dong, V. M.
Chem. Rev. 2011, 111, 1215. (f) Cho, S. H.; Kim, J. Y.; Kwak, J.; Chang,
S. Chem. Soc. Rev. 2011, 40, 5068. (g) Ackermann, L. Chem. Rev. 2011,
111, 1315. (h) Liu, C.; Zhang, H.; Shi, W.; Lei, A. Chem. Rev. 2011, 111,
1780. (i) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010,
110, 624. (j) Chen, X.; Engle, K. M.; Wang, D. H.; Yu, J. Q. Angew.
Chem., Int. Ed. 2009, 48, 5094. (k) Lyons, T. W.; Sanford, M. S. Chem.
Rev. 2010, 110, 1147. (l) Mkhalid, I. A. I.; Barnard, J. H.; Marder, T. B.;
Murphy, J. M.; Hartwig, J. F. Chem. Rev. 2010, 110, 890. (m) Satoh, T.;
Miura, M. Chem.;Eur. J. 2010, 16, 11212. (n) Shi, R. B. F.; Engle,
K. M.; Maugel, N.; Yu, J. Q. Chem. Soc. Rev. 2009, 38, 3242. (o) Park,
Y. J.; Park, J. W.; Hun, C. H. Acc. Chem. Res. 2008, 41, 222. (p) Lewis,
J. C.; Bergman, R. G.; Ellman, J. A. Acc. Chem. Res. 2008, 41, 1013.
(q) Godula, K.; Sames, D. Science 2006, 312, 67. For selected recent
examples, see: (r) Yang, L.; Qian, B.; Huang, H. Chem.;Eur. J. 2012,
18, 9511. (s) Qian, B.; Shi, D.; Yang, L.; Huang, H. Adv. Synth. Catal.
2012, 354, 2146. (t) Zhao, P.; Niu, R.; Wang, F.; Han, K.; Li, X. Org.
Lett. 2012, 14, 4166. (u) Zhao, P.; Wang, F.; Han, K.; Li, X. Org. Lett.
2012, 14, 5506. (v) Li, H.; Li, Y.; Zhang, X.-S.; Chen, K.; Wang, X.; Shi,
Z.-J. J. Am. Chem. Soc. 2011, 133, 15244. (w) Zeng, R.; Fu, C.; Ma, S.
J. Am. Chem. Soc. 2012, 134, 9597. (x) Xie, P.; Xie, Y.; Qian, B.; Zhou,
H.; Xia, C.; Huang, H. J. Am. Chem. Soc. 2012, 134, 9902. (y) Jia, X.;
Zhang, S.; Wang, W.; Luo, F.; Cheng, J. Org. Lett. 2009, 11, 3120.
(z) Chan, C.-W.; Zhou, Z.; Yu, W.-Y. Adv. Synth. Catal. 2011, 353, 2999.
(aa) Xiao, F.; Shuai, Q.; Zhao, F.; Basle, O.; Deng, G.; Li, C.-J. Org.
Lett. 2011, 13, 1614.
(7) For the rhodium(III)-catalyzed direct addition of arene CꢀH
bonds to imines, isocyanates, isocyanide, and azides, see: (a) Tsai, A. S.;
Tauchert, M. E.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2011,
133, 1248. (b) Li, Y.; Li, B.-J.; Wang, W.-H.; Huang, W.-P.; Zhang,
X.-S.; Chen, K.; Shi, Z.-J. Angew. Chem., Int. Ed. 2011, 50, 2115. (c)
Tauchert, M. E.; Incarvito, C. D.; Rheingold, A. L.; Bergman, R. G.;
Ellman, J. A. J. Am. Chem. Soc. 2012, 134, 1482. (d) Hesp, K. D.;
Bergman, R. G.; Ellman, J. A. Org. Lett. 2012, 14, 2304. (e) Li, Y.;
Zhang, X.-S.; Li, H.; Wang, W.-H.; Chen, K.; Li, B.-J.; Shi, Z.-J. Chem.
Sci. 2012, 3, 1634. (f) Zhou, B.; Yang, Y.; Lin, S.; Li, Y. Adv. Synth.
Catal. 2013, 355, 360. (g) Zhu, C.; Xie, W.; Falck, J. R. Chem.;Eur. J.
2011, 17, 12591. (h) Kim, J. Y.; Park, S. H.; Ryu, J.; Cho, S. H.; Kim,
S. H.; Chang, S. J. Am. Chem. Soc. 2012, 134, 9110. (i) Shi, J.; Zhou, B.;
Yang, Y.; Li., Y. Org. Biomol. Chem. 2012, 10, 8953. (j) Ryu, J.; Shin, K.;
Park, S. H.; Kim, J. Y.; Chang, S. Angew. Chem., Int. Ed. 2012, 51, 9904.
(k) Zhou, B.; Hou, W.; Yang, Y.; Li, Y. Chem.-Eur. J. 2013, 19, 4701.
(8) (a) Hesp, K. D.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc.
2011, 133, 11430. (b) Li, Y.; Zhang, X.-S.; Zhu, Q.-L.; Shi, Z.-J. Org.
Lett. 2012, 14, 4498. (c) Lian, Y.; Huber, T.; Hesp, K. D.; Bergman,
R. G.; Ellman, J. A. Angew. Chem., Int. Ed. 2013, 52, 629.
(9) Selected rhodium(III)-catalyzed annulation reaction using non-
polar alkynes and alkenes as substrates: (a) Li, B.-J.; Wang, H.-Y.; Zhu,
Q.-L.; Shi, Z.-J. Angew. Chem., Int. Ed. 2012, 51, 3948. (b) Wang, D.;
Wang, F.; Song, G.; Li, X. Angew. Chem., Int. Ed. 2012, 124, 12514. (c)
Pham, M. V.; Ye, B.; Cramer, N. Angew. Chem., Int. Ed. 2012, 51, 10610.
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2011, 133, 2154. (e) Wei, X.; Zhao, M.; Du, Z.; Li, X. Org. Lett. 2011, 13,
4636. (f) Guimond, N.; Gorelsky, S. I.; Fagnou, K. J. Am. Chem. Soc.
2011, 133, 6449. (g) Huestis, M. P.; Chan, L.; Stuart, D. R.; Fagnou, K.
Angew. Chem., Int. Ed. 2011, 50, 1338. (h) Patureau, F. W.; Glorius, F.
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Song, G.; Li, X. Org. Lett. 2010, 12, 5462. (j) Hyster, T. K.; Rovis, T.
J. Am. Chem. Soc. 2010, 132, 10565. (k) Too, P. C.; Wang, Y.-F.; Chiba,
S. Org. Lett. 2010, 12, 5688. (l) Rakshit, S.; Grohmann, C.; Besset, T.;
Glorius, F. J. Am. Chem. Soc. 2011, 133, 2350. (m)Wang, H.; Grohmann,
C.; Nimphius, C.; Glorius, F. J. Am. Chem. Soc. 2012, 134, 19592. (n)
Rakshit, S.; Patureau, F. W.; Glorius, F. J. Am. Chem. Soc. 2010, 132,
9585. (o) Besset, T.; Kuhl, N.; Patureau, F. W.; Glorius, F. Chem.;Eur. J.
2011, 17, 7167. (p) Patureau, F. W.; Nimphius, C.; Glorius, F. Org. Lett.
2011, 13, 6346. (q) Zhang, J.; Loh, T.-P. Chem. Commun. 2012, 48, 11232.
(6) For the rhodium(III)-catalyzed direct addition of arene CꢀH
bonds to aldehydes, see: (a) Yang, L.; Correia, C. A.; Li, C.-J. Adv.
Synth. Catal. 2011, 353, 1269. (b) Li, Y.; Zhang, X.-S.; Chen, K.; He,
K.-H.; Pan, F.; Li, B.-J.; Shi, Z.-J. Org. Lett. 2012, 14, 636. (c) Park, J.;
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3088.
B
Org. Lett., Vol. XX, No. XX, XXXX

loading proved to be effective. At a 2.5 mol % catalyst
loading, complete conversion into product was maintained
by simply lengthening the reaction time to 24 h (entry 9).
Finally, we were pleased to observe that this reaction was
scaled-up without difficulty (entry 10).
Scheme 1. Substrate Scope for Isocyanatesa
Table 1. Reaction Optimizationa
entries
catalysts (5 mol %)
(Cp*RhCl2)2
solvent
yieldb (%)
1
THF
THF
THF
PhMe
DCM
DCE
DCE
DCE
DCE
DCE
0
2
(Cp*RhCl2)2, AgSbF6
60
3
[Cp*Rh(CH3CN)3](SbF6)2
[Cp*Rh(CH3CN)3](SbF6)2
[Cp*Rh(CH3CN)3](SbF6)2
[Cp*Rh(CH3CN)3](SbF6)2
[Cp*Rh(CH3CN)3](SbF6)2
[Cp*Rh(CH3CN)3](SbF6)2
[Cp*Rh(CH3CN)3](SbF6)2
[Cp*Rh(CH3CN)3](SbF6)2
73
4
35
5
44
6
86
7c
8d
9e
10f
86
77 (87)
84
a Reaction conditions: 0.2 mmol of 1a, 0.3 mmol of 2, 0.01 mmol of
catalyst, 1 mL of DCE, 100 °C, 12 h. Yield of isolated product.
80
a Reaction conditions: 0.2 mmol of 1a, 0.3 mmol of 2a, 0.01 mmol of
Rh catalyst, 1 mL of solvent, 100 °C, 12 h. b Yield of isolated product.
Yield in parentheses is based on recovered starting material. c The
reaction was carried out at 120 °C for 20 h. d The reaction was carried
out at 90 °C. 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.
transformation (3r), providing easily separable Z- and
E-isomers in a ratio of 3:1. The R2 substituent is not essential
for the success of the reaction, thereby enabling the pre-
paration of 3-subtituted 5-ylidene-pyrrol-2(5H)-ones (3s).
With the optimal conditions established, we next inves-
tigated the substrate scope of various isocyanates in this
transformation (Scheme 1). The isocyanates 2 allowed
incorporation of a wide range of functionalization in the
products; aromatic groups bearing electron-donating (3a
and 3b) or -withdrawing groups (3cꢀh) were tolerated and
excellent yields were observed, irrespectiveofthe electronic
nature of the substituents on the phenyl ring. Notably, the
tolerance of the ester (3e), bromo (3f), and chloro group
(3g) offers the opportunity for further functionalization. In
addition, 1-naphthyl isocyanate was also readily converted
to the corresponding product (3i) in good yields. In addi-
tion to phenyl isocyanate, primary and secondary alkyl
isocyanate substrates showed good reactivity, providing
the corresponding products 3j and 3k in excellent yields.
To evaluate the scope of the present catalytic reaction,
we next investigated the substrate scope with a range of
R,β-unsaturated oximes (1) having different substitution
patterns (Scheme 2). Inaddition to(E)-1-(cyclohex-1-en-1-
yl)ethanone O-methyl oxime (3a), acyclic oximes were
readily converted to the corresponding fully substituted
5-ylidene-pyrrol-2(5H)-ones (3lꢀr) in good yields. The
variation of R3 in the oximes 1 to alkyl group (3l), phenyl
group with electron-donating and electron-withdrawing
substitution (3mꢀp) as well as to 2-naphthyl group (3q) led
to moderate to good yields. We also explored variation at
R1 and established that ethyl group also work well in this
Scheme 2. Oxime Substrate Scopea
a Reaction conditions: 0.2 mmol of 1, 0.3 mmol of 2a, 0.01 mmol of
catalyst, 1 mL of DCE, 100 °C, 12 H. Yield of isolated product.
Based on the known chemistry of metal-catalyzed CꢀH
bond activation and addition reactions,6,7 we tentatively
Org. Lett., Vol. XX, No. XX, XXXX
C

of intermediate C was observed by carrying out the reac-
tion at 85 °C for 5 h (eq 2). Finally, intramolecular
nucleophilic addition followed by elimination of one
molecule of methoxyamine, provided compound 3a and
regenerated the catalyst.
Scheme 3. Proposed Mechanism (L = CH3CN)
In summary, we described herein a novel method for
synthesis of substituted 5-ylidene pyrrol-2(5H)-ones via
RhIII-catalyzed addition of an alkenyl CꢀH bond to iso-
cyanates with subsequent cyclization. This operationally
simple approach exhibits high regioselectivity and functional
group tolerance and is amenable to a number of different
substituents on the isocyanates and R,β-unsaturated oximes.
Most importantly, this reaction gives a simple and straight-
forward access to biologically relevant 5-ylidene pyrrol-
2(5H)-ones and can be carried out under mild and neutral
conditions in the absence of any additives and environmen-
tally hazardous waste production. Because of the potential
utility of the resulting 5-ylidene pyrrol-2(5H)-ones, we
expect this catalytic method to be widely applied in the
pharmaceutical fields.
propose the following reaction pathway (Scheme 3). The
catalytic annulation reaction is initiated by the oxime-
directed ortho CꢀH bond activation to form a relatively
stable five-membered rhodacycle A and is accompanied
by a release of one equivalent of proton (Hþ). Selective
insertion of isocyanate into the RhꢀC bond of intermedi-
ate A gives the seven membered rhodacycle B, which is
protonated to produce the intermediated C. The existence
Supporting Information Available. Experimental pro-
cedures, characterization of products, and copies of
1H and 13C NMR spectra. The material is available free
of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX