Highly efficient synthesis of isoquinolines via nickel-catalyzed annulation of 2-iodobenzaldimines with alkynes: Evidence for dual pathways of alkyne insertion

Article abstract of DOI:10.1021/ol0519994

(Chemical Equation Presented) A wide range of substituted isoquinolines were synthesized via a highly efficient nickel-catalyzed annulation of the tert-butyl imines of 2-iodobenzaldehydes and various alkynes; examination of the regiochemistry of isoquinol

Full text of DOI:10.1021/ol0519994

ORGANIC
LETTERS
2005
Vol. 7, No. 23
5179-5182
Highly Efficient Synthesis of
Isoquinolines via Nickel-Catalyzed
Annulation of 2-Iodobenzaldimines with
Alkynes: Evidence for Dual Pathways of
Alkyne Insertion
Rajendra Prasad Korivi and Chien-Hong Cheng*
Department of Chemistry, National Tsing Hua UniVersity, Hsinchu 30013, Taiwan
chcheng@mx.nthu.edu.tw
Received August 18, 2005
ABSTRACT
A wide range of substituted isoquinolines were synthesized via a highly efficient nickel-catalyzed annulation of the tert-butyl imines of
2-iodobenzaldehydes and various alkynes; examination of the regiochemistry of isoquinolines synthesized indicates that there are two different
alkyne insertion pathways for the catalytic reactions.
Functionalized isoquinolines are known to show important
pharmacological properties such as antitumor, analgesic,
antihistaminic, and antifertility activity.1 Furthermore, these
compounds are useful ligands in phosphorescent emitters for
organic light-emitting diodes.2 Classical methods for the
synthesis of isoquinolines including the Bischler-Napier-
alski, the Pomeranz-Fritsch, and the Pictet-Spengler
reactions1a,3 generally require either harsh conditions or
tedious reaction procedures. Transition-metal-catalyzed syn-
thesis of isoquinolines from tert-butylimine of 2-iodoben-
zaldehydes and alkynes (or allenes) was a promising method.
Initially, Heck4 first observed a stoichiometric version of this
reaction with palladium complexes and Larock5 developed
the catalytic version of the reaction. Later, some other related
catalytic reactions appeared.6 All of these reactions were
based on palladium catalysis in the presence of base and
suffered from limitation of alkynes due to various competitive
reactions.5 The use of dialkylalkynes is restricted due to the
possible â-hydride elimination after alkyne insertion into the
arylpalladium bond or multiple insertion of the alkynes.4a,5a
Terminal alkynes and trimethylsilyl alkynes underwent
Sonogashira-type coupling easily under the reaction condi-
tions instead of the direct annulation reaction, although these
coupling products can be converted further to the final
isoquinoline products using CuI as the catalyst.5d Other
drawbacks for these palladium-catalyzed reactions were the
higher reaction temperatures, lengthy reaction intervals, and
(1) (a) The Chemistry of Hetrocyclic Compounds: Isoquinolines; Cop-
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Brown, C. J. U.S. Patent 20050123791A1, 2005. (d) Deaton, J. C.; Hatwar,
T. K.; Kondakov, D. Y. U.S. Patent 20050112401A1, 2005.
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1987, 6, 1941. (b) Wu, G.; Rhiengold, A. L.; Geib, S. J.; Heck, R. F. J.
Org. Chem. 1988, 53, 3238.
10.1021/ol0519994 CCC: $30.25
© 2005 American Chemical Society
Published on Web 10/13/2005

requirement of excess alkynes that led to the formation of
naphthalene derivatives.4a Herein, we report an exceedingly
efficient and convenient nickel-catalyzed annulation of tert-
butylimine of 2-iodobenzaldehydes with various alkynes
under milder reaction conditions that eliminates the above-
mentioned problems. In addition, the regioselectivities of
products indicate two different possible alkyne insertion
pathways for this nickel-catalyzed reaction.
Table 1. Results of Ni-Catalyzed Annulation Reactionsa
Our interest in nickel- and cobalt-catalyzed cyclization
reactions7 prompted us to investigate the possibility of
synthesizing isoquinolines from alkynes and 2-iodobenzaldi-
mine. We started the investigation by evaluating the influence
of catalyst and the ligands on the annulation of 2-iodoben-
zaldimine (1a) with diphenylacetylene (2a). The reaction
carried out in the presence of NiBr2(PPh3)2 and zinc powder
in CH3CN at 80 °C afforded 3,4-diphenylisoquinoline (3a)
in 91% yield. Control experiments revealed that in the
absence of nickel complex or zinc powder, no reaction
occurred. Under similar reaction conditions, other nickel(II)
complexes tested including NiBr2(dppe), NiCl2(PPh3)2, and
NiBr2(PPh3)2 were also active, giving 3,4-diphenylisoquino-
line in 98, 80, and 91% yields,8 respectively. Nickel
complexes with bidendate phosphine ligands appear slightly
more effective than those with monodendate ligands, but the
difference is relatively narrow compared to other nickel-
catalyzed reactions7 reported previously. All of the reactions
were very fast and completed in just 20 min. In addition,
Ni(COD)2 and 2 equiv of P(o-tol)3 without zinc powder also
effectively catalyzed the annulation of 1a with 2a to give
3a in essentially quantitative yield. The solvents employed
for the present catalytic reaction are crucial to the product
yield. The reactions of 1a with 2a in the presence of NiBr2-
(dppe) and zinc powder in various solvents were examined.
The yields of 3a in CH3CN, DMF, and THF (at ∼70 °C)
were 98, 94, and 63%, respectively. Only a trace of the
product was observed in o-xylene. These results show that
acetonitrile is the solvent of choice and that polar solvents
are more effective than nonpolar solvent.8 Based on the above
studies, we chose NiBr2(dppe) in the presence of zinc in
acetonitrile at 80 °C as the standard reaction condition for
the following annulation reactions.
Next, the scope of this nickel-catalyzed annulation was
examined, and the results are summarized in Table 1. In
addition to 2-iodobenzaldimine 2a, the corresponding bromo
species also underwent annulation with 1a effectively to yield
3a in 76% (entry 2). It is interesting to note that product 3a
has shown significant biological activities such as stimulation
of cell growth and inhibition of estradiol binding.1b Under
similar reaction conditions, diethylacetylene 2b reacts smoothly
with 1a to give 3,4-diethylisoquinoline in 87% yield.
Several unsymmetrical alkyne substrates were investigated
to understand the regioselectivity of the present catalytic
reaction. 1-Phenyl-1-butyne underwent cyclization success-
fully with 1a to give regioisomers 3c and 3c′ (Table 1, entry
a Unless otherwise stated, all reactions were carried out under nitrogen
atmosphere using 1a-d 0.10 mmol), alkynes (2a-o, 0.10 mmol), NiBr2(dppe)
(0.0050 mmol), and Zn (0.30 mmol) in CH3CN (3.0 mL) at 80 °C for 20
min. b Isolated yields. c Reaction time for entries 8 and 16 was 3 h.
(7) (a) Jeevanandam, A.; Korivi, R. P.; Huang, I. W.; Cheng. C. H. Org.
Lett. 2002, 4, 807. (b) Rayabarapu, D. K.; Sambiah, T.; Cheng, C. H. Angew.
Chem., Int. Ed. 2001, 40, 1286.
(8) The yields were calculated from crude NMR spectra using mesitylene
as internal standard.
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Org. Lett., Vol. 7, No. 23, 2005

4) in 78 and 9% yields, respectively. Phenylpropiolate 2d
also reacts with 1a regioselectively to give the annulation
products 3d and 3d′ in 86 and 6% yields, respectively (entry
5). As shown in entries 4 and 5, both major products 3c and
3d of these two reactions have the phenyl substituent at the
C-3 position. The observations are surprising in view of the
very different polarity of the alkyne carbons where the phenyl
group is attached in 2c and 2d. The regiochemistry of
compound 3c was established by NOE experiments and of
3d was determined by comparing its spectral data with those
reported.6b
iodopiperonaldimine with 2a. The annulation gave the
expected product 3o in excellent yield, but a longer reaction
time of 3 h was required. To see whether the present
methodology can be applied to the preparation of pyridine
derivative. Aldimine 1d10 was treated with 2a under similar
reaction conditions affording the expected product 3q in 86%
yield (entry 18).
There are several intriguing features of the present nickel-
catalytic reaction. (i) Terminal alkynes and alkynes with a
TMS or alkyl group were all successfully used as substrates
for the annulation of 1a to give the corresponding isoquino-
line derivatives. This is in contrast with the previously
reported palladium-catalyzed reactions. In the latter, these
substrates first underwent Sonogashira-type alkynylation with
1a. The presence of CuI is necessary for further annulation
to give product 3. (ii) For alkynes without a strong electron-
withdrawing substituent including 2c,f,g,j,l-n, the regiose-
lectivity of alkyne insertion is similar to that reported for
the nickel-catalyzed carbocyclization of o-iodophenyl ketone
with these alkynes,11 but for alkynes with a strong electron-
withdrawing substituent such as a keto or ester group, the
regiochemistry is entirely different from that of the carbocy-
clization (see eq 1). (iii) For all of the present annulation
reactions, very high regioselectivity and fast reaction rates
were observed. For each of the present nickel-catalyzed
annulation, the regioselectivity is similar, but the reaction
rate is much faster (at least 20 times) compared to the
corresponding palladium-catalyzed reaction.
The observed regiochemistry of products 3c and 3d
prompted us to investigate the annulation of other unsym-
metrical phenyl-substituted alkynes 2e-g. Under the standard
reaction conditions, alkynes 2e and 2o, both with a keto
substituent, reacted smoothly with 1a in a highly regiose-
lective fashion to provide products 3e and 3p exclusively
with the regiochemistry similar to that of 3d. For phenyl-
substituted alkynes 2f,g, in which the phenyl group is slightly
more electron withdrawing than the hydroxymethyl substitu-
ent in 2f and the TMS group in 2g, the annulation of alkynes
2f,g gave highly regioselective products 3f,g (entries 6 and
7), respectively. Due to the presence of the bulkier TMS
substituent in 2g, the annulation of this alkyne with 1a
required a longer reaction time of 3 h. In addition, a minor
regioisomer 3g′ in 5% was also observed. These results
indicate that irrespective of the electron-withdrawing and
electron-donating group bonded to the phenylalkynl moiety,
the phenyl group in the major isoquinoline products is
generally attached to the carbon near to the nitrogen atom.
The scope and utility of this method was further extended
by the reaction with alkylalkynyl derivatives9 2h and 2i
consisting of a keto and ester group, respectively. For alkyne
2h, completely regioselective product 3h was isolated, but
for 2i, a mixture of products 3i and 3i′ in an 82:4 ratio was
found. Driven by curiosity, we treated 1,3-diyne 2j and 3,9-
diyne 2k with 1a under the standard reaction conditions. For
2j, only product 3j with the 1-hexynyl group attached to the
C-3 of the isoquinoline product was isolated. In the case of
2k, the reaction gave two regioisomers in ca. 1:1 ratio due
to the lack of major functionality difference of the two
substituents over the acetylene moiety. There was no further
annulation of the second alkyne group, even for 2k, where
the second alkyne group is at a distance of four carbons apart.
Encouraged by the above results, terminal alkynes were
tested for the present annulation reaction. Under the standard
catalytic conditions, phenylacetylene (2l) reacted successfully
with 1a to give the corresponding annulation product 3l in
excellent yields. In a similar manner, 1-hexyne (2m) and
5-cyanopentyne (2n) afforded isoquinoline derivatives 3m
and 3n in 76 and 84% yields, respectively. In all these cases,
the competitive Sonogashira reaction was efficiently sup-
pressed.5 Also, no cyclotrimerization of the alkyne or minor
regioisomer are observed. Again, the substitutents of the
terminal alkynes are all attached to the C-3 of isoquinolines.
Finally, we evaluated the reaction of electron rich o-
To account for the results of the present catalytic reaction,
we propose the mechanism shown in Scheme 1. The reaction
Scheme 1
likely starts with reduction of Ni(II) to Ni(0) by zinc powder.
The oxidative addition of 2-iodobenzaldimine to Ni(0) leads
to the formation of a five-membered-ring nickelacycle A.
Coordinative insertion of alkyne into the nickelacycle,
(10) Larock, R. C.; Doty, M. J.; Han, X. J. Org. Lett. 1999, 64, 8770.
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(c) Rayabarapu, D. K.; Yang, C. H.; Cheng, C. H. J. Org. Chem. 2003, 17,
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Org. Lett., Vol. 7, No. 23, 2005
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followed by reductive elimination12 gave an iminium cation6c
D and the regeneration of the Ni(0) catalyst. The tertiary
butyl group on the iminium ion was then removed by the
attack of iodide ion produced during the reaction to give the
final product 3.
is via the nickel-carbon bond to give intermediate B. We
thus believe that the main pathway for the insertion of these
alkynes including 2d-e and 2h-i is into the nickel-nitrogen
bond of the nickelacycle. Facile Michael-type addition of
an imine or pyridine group to an electron-deficient carbon-
carbon triple bond is known.13 For the annulation of
propiolates 2d and 2i with 1a (entries 5 and 10), the minor
isomers 3d′ and 3i′ likely via intermediate B were detected,
indicative of competition between the two pathways for
substrate 2.
There are two possible pathways for the insertion of a
coordinated alkyne into nickelacycle A. One is the insertion
into the nickel-carbon bond of A to give intermediate B;
the other is the insertion13,14 into the nickel-nitrogen bond
to give C. For alkynes without a strong electron-withdrawing
substituent, we propose the alkyne insertion is via the nickel-
carbon bond. The observed insertion regiochemistry is
consistent with that reported previously for the nickel-,11b,c
palladium-5 and cobalt-catalyzed11a carbocyclization that
involved insertion of alkyne into carbon-metal bonds with
the carbon atom generally attacked the more positive carbon
of the alkyne substrate. On the other hand, the observed
regiochemistry for the annulation of 1a with alkynes pos-
sessing a strong electron-withdrawing group such as a keto
or ester goup is very different from that reported for the
metal-catalyzed carbocyclization. Examples of the regio-
chemistry of metal-catalyzed carbocyclization are shown in
eq 1.11c Only one regioisomer, similar to a Michael addition
product, was observed. As a result, it is unlikely that the
insertion of electron-deficient alkyne into the nickelacycle
In conclusion, we have demonstrated a very convenient
and highly regioselective synthetic approach for the prepara-
tion of substituted isoquinolines. This nickel-catalyzed an-
nulation is much more efficient than the known palladium-
catalyzed reaction in terms of the catalytic reaction rate and
the scope of the alkyne substrates. The method tolerates a
wide variety of functional groups and utilizes nonexpensive
catalysts. In addition, the unusual regioselectivity indicated
two pathways of the alkyne insertion into the nickelacycle
intermediate. Further studies along this line are in progress.
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M. Tetrahedron Lett. 2004, 45, 1803. (g) Trofimov, B. A.; Andriyankova,
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Acknowledgment. Financial assistance from the Ministry
of Education and National Science Council of Republic of
China (NSC-93-2113-M-0007-033) is greatly acknowledged.
Supporting Information Available: Experimental pro-
cedures, spectral data of new compounds, and NOE data of
selected compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
(14) Ohtaka, M.; Nakamura, H.; Yamamoto, Y. Tetrahedron Lett. 2004,
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