Annulation of α,β-unsaturated imines and alkynes via cobalt-catalyzed olefinic C-H activation

Article abstract of DOI:10.1021/ol303259m

A cobalt-triarylphosphine catalyst promotes an annulation reaction of an α,β-unsaturated imine and an internal alkyne to afford a polysubstituted dihydropyridine derivative in good yield under mild conditions. The reaction likely involves alkenylation of the olefinic C-H bond via cobalt-mediated nitrogen-assisted C-H activation followed by facile 6π electrocyclization of the resulting azatriene intermediate.

Full text of DOI:10.1021/ol303259m

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Annulation of r,β-Unsaturated Imines and
Alkynes via Cobalt-Catalyzed Olefinic
CꢀH Activation
Takeshi Yamakawa and Naohiko Yoshikai*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical
Sciences, Nanyang Technological University, Singapore 637371, Singapore
nyoshikai@ntu.edu.sg
Received November 27, 2012
ABSTRACT
A cobaltꢀtriarylphosphine catalyst promotes an annulation reaction of an R,β-unsaturated imine and an internal alkyne to afford a poly-
substituted dihydropyridine derivative in good yield under mild conditions. The reaction likely involves alkenylation of the olefinic CꢀH bond via
cobalt-mediated nitrogen-assisted CꢀH activation followed by facile 6π electrocyclization of the resulting azatriene intermediate.
Over the past two decades, chelation-assisted CꢀH
bond activation has emerged as a powerful strategy for
the direct conversion of aromatic and heteroaromatic
CꢀH bonds to new CꢀC bonds.1 While not as extensive
as the arene functionalization, this strategy has also been
frequently practiced in the direct functionalization of
olefins, with particular focus on the stereocontrolled synthe-
sis of multisubstituted olefins via CꢀH alkylation2 and
arylation3 reactions as well as the regiocontrolled synthesis
of multisubstituted heterocycles via CꢀH alkenylation/
cyclization cascades.4ꢀ6 As an elegant example of the latter
type of reaction, the group of Bergman and Ellman
recently reported a cascade reaction comprising the
rhodium(I)-catalyzed olefinic CꢀH alkenylation of an
R,β-unsaturated imine with an alkyne and 6π-electrocycli-
zation of the resulting azatriene intermediate.4a,b The
dihydropyridine products are not readily accessible by
othersyntheticmethodsand are useful precursors tohighly
substituted pyridines and tetrahydropyridines. On the
other hand, undesirable features of the reaction include
the requirement of the noble metal catalyst with a tailored
phosphine ligand and high reaction temperatures. We
report here that a simple and inexpensive cobaltꢀtriaryl-
phosphine catalyst promotes the same type of cascade
(1) For selected reviews, see: (a) Arockiam, P. B.; Bruneau, C.;
Dixneuf, P. H. Chem. Rev. 2012, 112, 5879. (b) Ackermann, L. Chem.
Rev. 2011, 111, 1315. (c) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010,
110, 1147. (d) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev.
2010, 110, 624. (e) Kakiuchi, F.; Kochi, T. Synthesis 2008, 3013.
(2) For selected examples, see:(a) Kakiuchi, F.; Tanaka, Y.; Sato, T.;
Chatani, N.; Murai, S. Chem. Lett. 1995, 679. (b) Trost, B. M.; Imi, K.;
Davies, I. W. J. Am. Chem. Soc. 1995, 117, 5371. (c) Lim, Y.-G.; Kang,
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Moon, C. W.; Kim, Y.-M.; Lee, H.; Lee, J. H. Tetrahedron. Lett. 2002,
43, 4233. (f) Colby, D. A.; Bergman, R. G.; Ellman, J. A. J. Am. Chem.
Soc. 2006, 128, 5604. (g) Tsai, A. S.; Bergman, R. G.; Ellman, J. A. J. Am.
Chem. Soc. 2008, 130, 6316. (h) Kuninobu, Y.; Fujii, Y.; Matsuki, T.;
Nishina, Y.; Takai, K. Org. Lett. 2009, 11, 2711.
(3) For selected examples, see: (a) Oi, S.; Sakai, K.; Inoue, Y. Org.
Lett. 2005, 7, 4009. (b) Ackermann, L.; Born, R.; Alvarez-Bercedo, P.
Angew. Chem., Int. Ed. 2007, 46, 6364. (c) Zhou, H.; Xu, Y.-H.; Chung,
W.-J.; Loh, T.-P. Angew. Chem., Int. Ed. 2009, 48, 5355. (d) Ilies, L.;
Asako, S.; Nakamura, E. J. Am. Chem. Soc. 2011, 133, 7672. (e) Wencel-
Delord, J.; Nimphius, C.; Patureau, F. W.; Glorius, F. Chem.;Asian J.
2012, 7, 1208. (f) Pankajakshan, S.; Xu, Y.-H.; Cheng, J. K.; Low, M. T.;
Loh, T.-P. Angew. Chem., Int. Ed. 2012, 51, 5701.
(4) For rhodium(I) catalysis, see: (a) Colby, D. A.; Bergman, R. G.;
Ellman, J. A. J. Am. Chem. Soc. 2008, 130, 3645. (b) Duttwyler, S.; Lu,
C.; Rheingold, A. L.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc.
2012, 134, 4064. (c) Parthasarathy, K.; Jeganmohan, M.; Cheng, C.-H.
Org. Lett. 2008, 10, 325. (d) Yotphan, S.; Bergman, R. G.; Ellman, J. A.
J. Am. Chem. Soc. 2008, 130, 2452.
(5) For rhodium(III) catalysis, see: (a) Stuart, D. R.; Alsabeh, P.;
Kuhn, M.; Fagnou, K. J. Am. Chem. Soc. 2010, 132, 18326. (b) Su, Y.;
Zhao, M.; Han, K.; Song, G.; Li, X. Org. Lett. 2010, 12, 5462. (c)
Rakshit, S.; Patureau, F. W.; Glorius, F. J. Am. Chem. Soc. 2010, 132,
9585. (d) Hyster, T. K.; Rovis, T. Chem. Sci. 2011, 2, 1606. (e) Hyster,
T. K.; Rovis, T. Chem. Commun. 2011, 47, 11846. (f) Too, P. C.; Noji, T.;
Lim, Y. J.; Li, X.; Chiba, S. Synlett 2011, 2789.
(6) For ruthenium catalysis, see: Ackermann, L.; Lygin, A. V.;
Hofmann, N. Org. Lett. 2011, 13, 3278.
r
10.1021/ol303259m
XXXX American Chemical Society

process, affordinga seriesofdihydropyridinederivatives in
moderate to good yields. The reaction represents a rare
example of olefinic CꢀH functionalization reactions cat-
alyzed by first-row transition metal complexes3d,7 and
features mild reaction conditions.
Table 1. Screening of Reaction Conditionsa
We recently developed an ortho-alkenylation reaction of
aromatic imines with alkynes promoted by a quaternary
catalytic system consisting of a cobalt(II) salt, triarylpho-
sphine, Grignard reagent, and pyridine.8 The present study
began with an attempt to apply this catalytic system to the
reaction of benzylideneacetone imine 1a and 4-octyne 2a,
which met with only limited success. Thus, the reaction
with CoBr2 (10 mol %), P(3-ClC6H4)3 (20 mol %), and
tBuCH2MgBr (100 mol %) at 40 °C for 3 h afforded the
annulation product, dihydropyridine 3aa, in ca. 30% yield
regardless of the presence (80 mol %) or absence of
pyridine (Table 1, entries 1 and 2).
Subsequent screening of reaction conditions revealed a
signifincant influence of the Grignard reagent. While
Me3SiCH2MgCl and MeMgCl, which we have frequently
used as the most effective reducing agents for cobalt-
catalyzed CꢀH functionalization,8,9 exhibited poor per-
formances (entries 3 and 4), the use of nBuMgBr or a
secondary alkyl Grignard reagent such as iPrMgBr and
CyMgBr significantly improved the reaction (entries
5ꢀ7).10,11 However, the reaction with these Grignard
reagents was accompanied by a nonnegligible amount of a
tertiary amine 4a arising from Grignard addition to the
CdN bond. Other chlorinated or fluorinated triarylpho-
sphines gave rise to moderate or comparable catalytic
activities (entries 8ꢀ10), while the reaction became rather
sluggish with PPh3 (entry 11). In either case, the adduct 4a
was obtained in 6ꢀ8% yield. Suppression of the formation
of 4a was achieved by reducing the loading of iPrMgBr
from 60 mol % to 45 mol % without loss of the catalytic
activity (entry 12). Thus, 3aa was obtained in 87% yield
(1H NMR) and isolated in 59% yield due to partial
decomposition during purification.
yield (%)b
3aa 4a
30
entry
PAr3
RMgX (x)
1c
2
P(3-ClC6H4)3
P(3-ClC6H4)3
P(3-ClC6H4)3
P(3-ClC6H4)3
P(3-ClC6H4)3
P(3-ClC6H4)3
P(3-ClC6H4)3
P(4-ClC6H4)3
P(3-FC6H4)3
P(4-FC6H4)3
PPh3
tBuCH2MgBr (100)
tBuCH2MgBr (100)
Me3SiCH2MgCl (100)
MeMgCl (100)
nBuMgBr (60)
iPrMgBr (60)
0
0
0
0
6
8
7
6
7
7
7
2
29
3
8
4
22
5
67
6
80
7
CyMgBr (60)
72
8
iPrMgBr (60)
45
9
iPrMgBr (60)
71
10
11
12
iPrMgBr (60)
75
iPrMgBr (60)
22
87 (59)d
P(3-ClC6H4)3
iPrMgBr (45)
a The reaction was performed on a 0.2 mmol scale. PMP =
4-MeOC6H4. b Determined by GC or 1H NMR. c Pyridine (80 mol %)
was added. d Isolated yield.
afford the adducts 3abꢀ3eb, 3gb, and 3hb in good to
excellent yields exhibiting tolerance for functional groups
such as chloro, bromo, and cyano groups. Even the
iodinated substrate afforded the annulation product 3fb
albeit in a low yield. The scalability of the reaction was
demonstrated by the reaction of 1a on a 5 mmol scale,
which afforded the adduct 3ab in 91% yield. Imines
derived from other β-substituted and R,β-disubstituted
enones also underwent annulation with diphenylacetylene,
affording the products 3ibꢀ3mb in good yields. Note that,
while most of the unsaturated ketimines existed as mix-
tures of E/Z isomers with respect to the CdN bond (ca. 9:1
to 3:2; see the Supporting Information), the dihydropyr-
idine products were obtained near quantitatively in some
cases (e.g., 3ib and 3jb). Considering that only the E-isomer
is suitable for chelation-assisted olefinic C;H activation,
isomerization of the CdN bond would have taken place
readily under the reaction conditions. A cinnamaldehyde-
derived imine was also amenable to the present reaction
(see 3nb).
With the optimized catalytic system in hand, we ex-
plored the scope of the present annulation reaction
(Scheme 1). First, various R,β-unsaturated imines were
subjected to the reaction with diphenylacetylene. A variety
of benzylideneacetone imines, except the one bearing an
iodine atom, smoothly participated in the reaction to
(7) (a) Kulkarni, A. A.; Daugulis, O. Synthesis 2009, 4087. (b)
Nakamura, E.; Yoshikai, N. J. Org. Chem. 2010, 75, 6061. (c) Sun,
C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Rev. 2011, 111, 1293.
(8) (a) Lee, P.-S.; Fujita, T.; Yoshikai, N. J. Am. Chem. Soc. 2011,
133, 17283. (b) Gao, K.; Lee, P.-S.; Fujita, T.; Yoshikai, N. J. Am. Chem.
Soc. 2010, 132, 12249.
Next, the reaction of 1a with different alkynes was
examined. With 1-phenyl-1-propyne, the reaction took
place through preferential CꢀC bond formation on the
2-position to afford the adduct 3ac as a major regioisomer
with a regioisomer ratio of 85:15. On the other hand, the
reaction of 1-phenyl-1-butyne resulted in a ca. 1:1 mixture
of two regioisomers (see 3ad). Such a trend in the regio-
selectivity is the same as the one observed in the cobalt-
catalyzed aromatic CꢀH alkenylation.8a,9e Symmetrical
diarylalkynes bearing para-methoxy and meta-bromo
(9) (a) Ding, Z.; Yoshikai, N. Org. Lett. 2010, 12, 4180. (b) Gao, K.;
Yoshikai, N. J. Am. Chem. Soc. 2011, 133, 400. (c) Gao, K.; Yoshikai, N.
Angew. Chem., Int. Ed. 2011, 50, 6888. (d) Gao, K.; Yoshikai, N. Chem.
Commun. 2012, 48, 4305. (e) Ding, Z.; Yoshikai, N. Angew. Chem., Int.
Ed. 2012, 51, 4698. (f) Gao, K.; Lee, P.-S.; Long, C.; Yoshikai, N. Org.
Lett. 2012, 14, 4234.
(10) (a) Chen, Q.; Ilies, L.; Nakamura, E. J. Am. Chem. Soc. 2011,
133, 428. (b) Ilies, L.; Chen, Q.; Zeng, X.; Nakamura, E. J. Am. Chem.
Soc. 2011, 133, 5221. (c) Song, W.; Ackermann, L. Angew. Chem., Int.
Ed. 2012, 51, 8251.
(11) Such a significant effect of the Grignard reagent may indicate the
formation of an alkylcobalt(0)ate species as a catalytically active species,
while no evidence is available at this time (cf. ref 8a).
B
Org. Lett., Vol. XX, No. XX, XXXX

time of 5 min, formation of a trace amount (<1%) of the
corresponding dienone was observed by GCMS. These
observations suggest that the present annulation reaction
proceeds in two steps, that is, cobalt-catalyzed olefinic
CꢀH alkenylation and subsequent 6π-electrocyclization
of the resulting azatriene derivative (vide infra). Note also
that the reaction of 1a and 2b, when quenched with water
with a reaction time of 5 min, afforded only 3ab but no
detectable amounts of the corresponding azatriene and
dienone. This and the above results may further suggest
that electrocyclization of the putative azatriene intermedi-
ate does not require the presence of the low-valent cobalt
catalyst.
Scheme 1. Scope of R,β-Unsaturated Imines and Alkynesa
Scheme 2. Vinylic CꢀH Alkenylation of Imine 1o
To gain insight into the relative reactivity of R,β-
unsaturated imines, a competition experiment was performed
(Scheme 3a). Thus, the reaction of an equimolar mixture of
benzylideneacetone imine 1a and cinnamaldehyde imine
1n with diphenylacetylene 2b (1.2 equiv) afforded the
adducts 3ab and 3nb in 80% and 11% yields, respectively.
This observation may be rationalized in terms of the
conformational preference of the unsaturated imines.
The ketimine 1a would prefer to take the s-cis conforma-
tion, which is suited for the olefinic CꢀH activation,
because of the allylic strain in the s-trans conformation
(see the inset).2a On the other hand, there is no such allylic
strain in the s-trans conformer of the aldimine 1n. Next, the
reaction of 1a with a mixture of 4-octyne 2a and dipheny-
lacetylene 2b exclusively afforded the adduct of the latter
alkyne, 3ab, in 64% yield (Scheme 3b). The same chemos-
electivity was previously observed for the alkenylation of
an aryl ketimine.8a
A proposed catalytic cycle of the present reaction is
shown in Scheme 4. A low-valent cobalt species generated
from the precatalyts undergoes nitrogen-assisted oxidative
addition of the olefinic CꢀH bond to form a five-mem-
bered cobaltacycle intermediate.12 As we proposed for the
alkenylation of aryl ketimines,8a precoordination of the
alkyne might be involved prior to the oxidative addition.
Subsequent migratory insertionofofthe alkyne isfollowed
by reductive elimination to afford an azatriene intermedi-
ate, which readily undergoes 6π electrocyclization to fur-
nish the dihydropyridine product. Considering that
electrocyclization of azatriene often requires high tempera-
tures,13 it is notable that the present azatriene intermediate
was not obtained under the mild conditions except for the
a Unless otherwise noted, the reaction was performed on a 0.2 mmol
scale using 5 mol % of CoBr2, 10 mol % of P(3-ClC6H4)3, and 22.5 mol %
of iPrMgBr. b 5mmolscale. c Thereactionwasperformedwith10mol%of
CoBr2, 20 mol % of P(3-ClC6H4)3, and 45 mol % of iPrMgBr. d Obtained
as a mixture with a double bond isomer (5:1, see the Supporting
Information). e r.r. = regioisomer ratio. The major isomer is shown.
groups afforded the adducts 3ae and 3af in 83% and 60%
yields, respectively. An unsymmetrical diarylalkyneelectro-
nically biased by para-trifluoromethyl and para-methoxy
groups preferentially afforded the regioisomer 3ag, where
the new CꢀC bond formed on the acetylenic carbon pro-
ximal to the para-trifluoromethylphenyl group. Origins
of the regioselectivities for the unsymmetrical alkynes are
discussed later.
When we subjected the imine 1o bearing the 1-naphthyl
group to the reaction with diphenylacetylene under the
standard conditions, we obtained a dienone 5ob rather
than a dihydropyridine derivative (Scheme 2). Further-
more, when the reaction of 1a and 2b was subjected to
acidic hydrolysis conditions (aqueous HCl) with a reaction
€
(12) Klein, H.-F.; Camadanli, S.; Beck, R.; Leukel, D.; Florke, U.
Angew. Chem., Int. Ed. 2005, 44, 975.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 3. Competition Experiments
Scheme 4. Proposed Reaction Mechanism
during the alkyne insertion, while the regioselectivity for
the unsymmetrical diarylalkyne (3ag) may be ascribed to
the electrostatic nature of the putative alkenyl(hydrido)-
cobalt species (i.e., Co(δþ)ꢀH(δꢀ)).15
In summary, we have developed a cobalt-catalyzed
annulation reaction of an R,β-unsaturated imine and an
internal alkyne that affords a dihydropyridine derivative
in good yield under mild conditions. The reaction likely
involves alkenylation of the olefinic CꢀH bond via
cobalt-mediated CꢀH bond activation followed by 6π
electrocyclization of the resulting azatriene intermediate.
Further efforts to expand the scope of cobalt-catalyzed
olefinic CꢀH bond functionalization are currently
underway.
case shown in Scheme 2.14 For this exceptional case, we
speculate that steric repulsion between the 1-naphthyl
and its neighboring phenyl groups has prevented the
azatriene intermediate from taking on a cyclic confor-
mation suitable for the electrocyclization. The regio-
selectivities observed for 1-phenyl-1-propyne (3ac) and
1-phenyl-1-butyne (3ad) are rationalized in terms of the
propensity of the cobalt center to avoid steric repulsion
Acknowledgment. This work was supported by the Na-
tional Research Foundation Singapore (NRF-RF2009-05
to N.Y.), Nanyang Technological University, and JST,
CREST.
(13) (a) Tanaka, K.; Mori, H.; Yamamoto, M.; Katsumura, S. J. Org.
Chem. 2001, 66, 3099. (b) Tanaka, K.; Fukase, K.; Katsumura, S. Synlett
2011, 2115 and references cited therein.
(14) A possibility that the cobalt catalyst has assisted the cyclization
step may not be fully excluded.
(15) NPA charges of the acetylenic carbon atoms of 1-methoxy-
4-((4-(trifluoromethyl)phenyl)ethynyl)benzene were calculated to be
þ0.027 (proximal to 4-methoxyphenyl) and ꢀ0.014 (proximal to
4-(trifluoromethyl)phenyl) at the B3LYP/6-31G* level.
Supporting Information Available. Experimental pro-
cedures and characterization of new compounds. This
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