Facile β-alkyl and β-hydride elimination in the nickel-catalyzed annulation of o-iodophenyl ketones and aldehydes with bicyclic alkenes

Article abstract of DOI:10.1021/ol061051p

o-Iodoaryl aldehydes react with bicyclic alkenes in the presence of NiBr₂(dppe) and Zn powder in acetonitrile at 80 °C undergoing annulation to give polycyclic ketone derivatives. Surprisingly, o-iodoaryl alkyl ketones also react with bicyclic

Full text of DOI:10.1021/ol061051p

ORGANIC
LETTERS
2006
Vol. 8, No. 13
2867-2869
Facile
â-Alkyl and â-Hydride Elimination
in the Nickel-Catalyzed Annulation of
o-Iodophenyl Ketones and Aldehydes
with Bicyclic Alkenes
Paritosh Shukla and Chien Hong Cheng*
Department of Chemistry, National Tsing Hua UniVersity, Hsinchu 30013, Taiwan
chcheng@mx.nthu.edu.tw
Received May 1, 2006
ABSTRACT
o-Iodoaryl aldehydes react with bicyclic alkenes in the presence of NiBr2(dppe) and Zn powder in acetonitrile at 80
°
C undergoing annulation
to give polycyclic ketone derivatives. Surprisingly, o-iodoaryl alkyl ketones also react with bicyclic alkenes to form polycyclic ketones with
structures the same as those from the corresponding o-iodoaryl aldehydes.
Selective C-C bond formation employing transition-metal
complexes as catalysts is at the core of modern synthetic
chemistry.1 Carbocyclization being an excellent method to
accomplish desired C-C bond formation, reports abound in
this field.2 Conversely, reports pertaining to transition-metal-
catalyzed C-C bond cleavage leading to â-alkyl elimination
are few.3 However, some reports regarding catalytic â-alkyl
eliminations in strained4 and other5 systems are worth noting.
Our long interest in nickel-promoted cyclizations6 prompted
us to investigate the reaction of ortho-iodophenyl carbonyl
compounds with norbornene derivatives. Recently, Larock
and co-workers reported a palladium-catalyzed annulation
of o-iodobenzonitriles with norbornene to give polycyclic
ketones.7 While extending our reaction of aldehydes to
ketones, we discovered an unprecedented â-alkyl elimination.
Amazingly, the products of reaction of aldehydes or ketones
with the same bicyclic alkene were the same, i.e., ketones
(Scheme 1). To the best of our knowledge, such â-alkyl
Scheme 1
(1) Hegedus, L. S. In ComprehensiVe Organometallic Chemistry II; Abel,
E. W., Stone, F. G. A., Wilkinson, G., Eds.; Pergamon: Oxford, U.K., 1995;
Vol. 12. Davies, S. G. In Organotransition Metal Chemistry-Application
to Organic Synthesis; Pergamon: Oxford, U.K., 1982.
(2) (a) Tsuji, J. In Palladium Reagents and Catalysts: InnoVations in
Organic Synthesis; John Wiley & Sons: New York, 1995. (b) Heck, R. F.
In Palladium Reagents in Organic Synthesis; Academic Press: New York,
1985. (c) Negishi, E.; Cope´ret, C.; Ma, S.; Liou, S.-Y.; Liu, F. Chem. ReV.
1996, 96, 365-393. (d) Li, J. J.; Gribble, G. W. In Palladium in Heterocyclic
Chemistry; Pergamon: Oxford, 2000. (e) Ba¨ckvall, J.-E. Pure Appl. Chem.
1992, 64, 429-437.
(3) For a recent review on catalytic cleavage of a C-C bond including
â-alkyl eliminations, see: Jun, C.-H. Chem. Soc. ReV. 2004, 33, 610-618
and references therein.
eliminations are unknown in the case of nickel-catalyzed
reactions.
We first set out to examine the products obtained from
the nickel-catalyzed reaction of various o-iodobenzaldehydes
with a variety of bicyclic alkenes; the results are summarized
in Table 1. Thus, treatment of 2-iodobenzaldehyde (1a) with
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6-iodopiperonal 1b also underwent annulation with bicyclic
alkene 2b to furnish the expected ketone product 3d in 70%
yield. The reaction of 1a with bicyclic alkene 2d, where n
) 2 (Scheme 1), also proceeded smoothly resulting in the
formation of product 3e in 68% yield. Likewise, treatment
of 1a with naphthonorbornadiene 2e resulted in the formation
of 3f in 74% isolated yield.
Table 1. Results of Nickel-Catalyzed Annulation of
o-Iodobenzaldehydes and o-Iodophenyl Alkyl Ketones with
Bicyclic Alkenesa
Encouraged by these results, we extended the present
catalytic annulation to include o-iodophenyl alkyl ketones
as substrates. To our surprise, the reaction of these ketones
with norbornene derivatives under similar catalytic conditions
gave the same keto products as those from the corresponding
o-iodobenzaldehydes. Thus, 2-iodoacetophenone (4a) reacted
with norbornene (2a) in the presence of Ni(dppe)Br2 and
Zn powder in acetonitrile at 80 °C to form keto product 3a
(entry 1, Table 2), which is the same as that from the reaction
of o-iodobenzaldehyde (1a) with norbornene, in 70% yield.
The expected annulated indenol derivative8 was not observed.
Similarly, the reaction of 4a with norbornadiene (2b)
afforded keto product 3b in 61% yield. In the same vein,
benzonorbornadiene 2c underwent annulation with 4a to
provide multicyclic keto product 3c in 52% yield. In all of
these cyclization reactions, a dealkylation step presumably
occurred during the process of catalysis prior to the formation
of the final product (Table 2, entries 1-3).
To further understand the nature and scope of the above
annulation reactions, we prepared several different alkyl
o-iodo-p-anisyl ketones, 4b-d, for the cyclization with
norbornene derivatives. The reaction of n-butyl o-iodo-p-
anisyl ketone (4b) with 2a-c proceeded smoothly under
similar catalytic conditions to give the corresponding ketones
3h-j in 71∼63% yields (entries 10-12), respectively.
Clearly, the butyl group bonded to the carbonyl in 4b was
cleaved during these catalytic reactions. In a similar manner,
(4) (a) Nishimura, T.; Uemura, S. J. Am. Chem. Soc. 2000, 122, 12049-
12050. (b) Nishimura, T.; Uemura, S. J. Am. Chem. Soc. 1999, 121, 11010-
11011. (c) Nishimura, T.; Ohe, K.; Uemura, S. J. Am. Chem. Soc. 2000,
122, 12049-12050. (d) Murakami, M.; Takahashi, K.; Amii, H.; Ito, Y. J.
Am. Chem. Soc. 1997, 119, 9307-9308 and references therein. (e) Matsuda,
T.; Makino, M.; Murakami, M. Org. Lett. 2004, 6, 1257-1259. (f)
Murakami, M.; Ashida, S.; Matsuda, T. J. Am. Chem. Soc. 2006, 128, 6932-
6933.
(5) (a) Kondo, T.; Kodoi, K.; Nishinaga, E.; Okada, T.; Morisaki, Y.;
Watanabe, Y.; Mitsudo, T. J. Am. Chem. Soc. 1998, 120, 5587-5588. (b)
Terao, Y.; Wakui, H.; Satoh, T.; Miura, M.; Nomura, M. J. Am. Chem.
Soc. 2001, 123, 10407-10408. (c) Nishimura, T.; Araki, H.; Maeda, Y.;
Uemura, S. Org. Lett. 2003, 5, 2997-2999. (d) Jun, C.-H.; Lee, H.; Lim,
S. G. J. Am. Chem. Soc. 2001, 123, 751-752. (e) Terao, Y.; Wakui, H.;
Kawasaki, S.; Satoh, T.; Miura, M.; Nomura, M. J. Am. Chem. Soc. 2004,
126, 8658-8659. (f) Harayama, H.; Kuroki, T.; Kimura, M.; Tanaka, S.;
Tamaru, Y. Angew. Chem., Int. Ed. Engl. 1997, 36, 2352 and references
therein.
(6) (a) Rayabarapu, D. K.; Cheng, C.-H. J. Am. Chem. Soc. 2002, 124,
5630-5631. (b) Rayabarapu, D. K.; Shukla, P.; Cheng, C. H. Org. Lett.
2003, 5, 4903-4906. (c) Jeevanandam, A.; Korivi, R. P.; Huang, I.-W.;
Cheng, C.-H. Org. Lett. 2002, 4, 807-810. (d) Shanmugasundaram, M.;
Wu, M.-S.; Cheng, C.-H. Org. Lett. 2001, 3, 4233-4236. (e) Hsiao, T.-Y.;
Santhosh, K. C.; Liou, K.-F.; Cheng, C.-H. J. Am. Chem. Soc. 1998, 120,
12232-12236. (f) Rayabarapu, D. K.; Cheng, C.-H. Chem.-Eur. J. 2003,
9, 3164. (g) Rayabarapu, D. K.; Chiou, C.-F.; Cheng, C.-H. Org. Lett. 2002,
4, 1679-1682. (h) Huang, D.-J.; Rayabarapu, D. K.; Li, L.-P.; Sambaiah,
T.; Cheng, C.-H. Chem.-Eur. J. 2000, 6, 3706-3713.
a Unless stated otherwise, all reactions were conducted using iodo
compound 1 or 4 (1.0 mmol), alkene 2 (3.0 mmol), NiBr2(dppe) (0.10
mmol), and zinc powder (2.0 mmol), in CH3CN at 80 °C for 12 h. b Isolated
yields.
norbornene (2a) in the presence of Ni(dppe)Br2 catalyst and
Zn powder, in acetonitrile at 80 °C, gave annulated product
3a in 80% isolated yield. Norbornadiene (2b) also reacted
similarly with 1a to furnish 3b in 77% yield. When
benzonorbornadiene (2c) was treated with 1a, polycyclic
ketone 3c was obtained in 75% yield. Electron-donating
(7) (a) Larock, R. C.; Tian, Q.; Pletnev, A. A. J. Am. Chem. Soc. 1999,
121, 3238-3239. (b) Pletnev, A. A.; Tian, Q.; Larock, R. C. J. Org. Chem.
2002, 67, 9276-9287.
(8) (a) Rayabarapu, D. K.; Cheng, C. H. Chem. Commun. 2002, 942-
944. (b) Rayabarapu, D. K.; Yang, C.-H.; Cheng, C.-H. J. Org. Chem. 2003,
68, 6726-6731.
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Org. Lett., Vol. 8, No. 13, 2006

the very long-chain ketone, 1-(o-iodo-p-anisyl)hexadecan-
1-one (4c), underwent dealkylative annulation with 2a and
2b successfully, giving rise to cyclic ketones 3h and 3i,
respectively (entries 13 and 14), in decent yields. Finally,
the reaction of o-iodoanisyl ketone 4d consisting of a benzyl
moiety, with 2a and 2b, also furnished the same annulated
ketones 3h and 3i, respectively (entries 15 and 16), in
moderate yields. To see the fate of the benzyl group in 4d
after reaction, the reaction mixture of 4d with 2a was
carefully analyzed leading to the isolation of product 5d in
37% yield, in addition to product 3h. It should be noted that
the catalytic reaction does not work for the reaction of
o-iodobenzophenone and o-iodophenyl 2-thienyl ketone with
2a, indicating that the annulation is limited to alkyl o-iodoaryl
ketones.
Figure 1. Structure of compound 5d.
tion of long-chain alkyl ketones 4b or 4c with norborn-
ene derivative 2, we did not observe the corresponding
product 5. In these reactions, the NiII alkyl species 9 likely
undergoes the facile â-hydrogen elimination to give the
corresponding olefin. However, attempts to isolate the
expected olefin failed.
On the basis of the foregoing observations and the
established nickel chemistry, we propose the mechanistic
pathway shown in Scheme 2 to account for the present
The present dealkylative annulation is interesting in view
of the fact that most â-alkyl eliminations occur with
cyclobutanols leading to a C-C bond cleavage in the butanol
rings. In the present nickel-catalyzed reactions, 1-alkylcy-
clopentenol is involved as a key intermediate and the C-C
bond between the alkyl and the R-carbon is cleaved in the
catalytic reaction. To the best of our knowledge, this is the
first time that such alkyl elimination was observed. A
possible driving force for the present alkyl elimination is
the large repulsion of the three bulky substituents on the
tertiary alkoxide 8. A â-alkyl elimination of this intermediate
to give the final ketone product can greatly reduce the
repulsion.
Scheme 2
Scheme 2 can also be used to account for the reaction of
o-iodoaryl aldehydes with norbornene derivatives catalyzed
by nickel complexes. The major difference is that intermedi-
ate 8 undergoes â-hydride elimination to give ketone 3
instead of the â-alkyl elimination for the reaction of
o-iodoaryl ketones with norbornene derivatives.
We have demonstrated a novel nickel-mediated carbocy-
clization involving o-iodoaryl ketones and aldehydes with a
variety of bicyclic alkene derivatives to yield the same
annulated ketone products. The reaction exhibits unique C-C
bond cleavage such that the alkyl group attached to the
starting ketone compound undergoes â-alkyl elimination.
Further studies to pinpoint the mechanistic aberrations and
to broaden the scope of this interesting reaction are currently
underway.
dealkylative annulation reaction. The catalytic reaction is
likely initiated by the reduction of Ni(II) to Ni(0). Oxidative
addition of the o-iodoaryl ketone to Ni(0) to give intermediate
6, coordination, and insertion of a norbornene molecule lead
to the formation of 7. Intramolecular addition of the
norbornenyl group to the keto moiety gives a cyclized alkoxy
intermediate 8.6 After this step, â-alkyl elimination occurs
to yield the observed ketone product 3 and a NiII alkyl species
9. The details of the fate of the alkyl group in the NiII alkyl
species are not entirely clear. For the alkyl species without
a â-hydrogen, a possible route is the transfer of the alkyl
group in 9 to another molecule of intermediate 6 to afford
10. Reductive elimination of 10 leads to product 5. Similar
pathways were proposed previously for the palladium-
catalyzed arylation of t-butylcyclobutanols by aryl bromide
that involved a â-alkyl elimination as the key step.4b Strong
evidence of the formation of 5 is the isolation of 5d (Figure
1) in 37% yield from the reaction of 4d with 2a. The
formation of 5 explains at least in part the low yields of
products 3 from 4. For the dealkylative annulation reac-
Acknowledgment. We thank the National Science Coun-
cil of the Republic of China (NSC 93-2113-M-007-033) for
the support of this research. P.S. would also like to thank
St. Xavier’s College, Ranchi, India, for providing study leave
for the project.
Supporting Information Available: General experimen-
tal procedures, spectral data, and spectra for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
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