Heterocyclized carbometalation of alkynes: Unexpected formation of eight-membered oxazirconacycles with an intramolecularly coordinated isoquinoline moiety

Article abstract of DOI:10.1021/om049302q

The isoquinolyl-zirconation of various unactivated alkynes was investigated by a one-pot, three-component reaction of two different alkynes with a nitrile in the presence of 1 equiv of CuCl. The true nature of the resulting products of novel eight-membered oxazirconacycles containing an intramolecular Zr-N coordination was established using X-ray crystallography.

Full text of DOI:10.1021/om049302q

5900
Organometallics 2004, 23, 5900-5902
Heterocyclized Carbometalation of Alkynes: Unexpected
Formation of Eight-Membered Oxazirconacycles with an
Intramolecularly Coordinated Isoquinoline Moiety
Shaolin Zhou, Dongyun Liu, and Yuanhong Liu*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, People’s Republic of China
Received September 8, 2004
Summary: The isoquinolyl-zirconation of various unac-
tivated alkynes was investigated by a one-pot, three-
component reaction of two different alkynes with a nitrile
in the presence of 1 equiv of CuCl. The true nature of
the resulting products of novel eight-membered oxazir-
conacycles containing an intramolecular Zr-N coordi-
nation was established using X-ray crystallography.
shown in eq 1, in which a heterocycle group is directly
introduced into a C-C double-bond unit. Although by
utilization of heteroaryl halides, palladium-catalyzed
heterocyclized carbopalladation of alkynes followed by
trapping with oxygen or nitrogen nucleophilic reagents
has been reported,3 the metal-containing intermediate
of carbometalation has not been examined.
In this paper, we report novel zirconium-mediated
heterocyclized carbometalation of unactivated alkynes
in the presence of CuCl to afford air-stable isoquinolyl-
zirconation products by a one-pot, three-component
reaction of two different alkynes with a nitrile (eq 2).
Reaction processes that can provide a significant
amplification of molecular complexity from simple build-
ing blocks occupy a special place in organic synthesis.
In this sense, carbometalation of alkynes would be a
powerful method for generating alkenyl organometallics,
which represents an important access to stereodefined
CdC double bonds.1 Functionalized carbometalations
such as allyl-, acyl-, dienyl-, vinyl-, and alkynylmeta-
lation2 of alkynes are of particular interest, as they
provide synthetically useful functionalized di-, tri-, and
tetrasubstituted alkenes. There are few reports, how-
ever, of heterocycle-incorporated carbometalation as
(1) For reviews on carbometalation of alkynes, see: (a) Handbook
of Organopalladium Chemistry for Organic Synthesis; Negishi, E. I.,
Ed.; Wiley: New York, 2002; pp 1123-1651. (b) Knochel, P. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: Oxford, U.K., 1991; Vol. 4, pp 865-911. (c) Normant,
J. F.; Alexakis, A. Synthesis 1981, 841-870. (d) Marek, I.; Normant,
J. F. In Metal-Catalyzed Cross-Coupling Reactions; Diederich, F.,
Stang, P. J., Eds.; Wiley-VCH: Weinheim, Germany, 1998; pp 271-
337. (e) Lipshutz, B. H.; Sengupta, S. Org. React. 1992, 41, 135-631.
See also: (f) Liu, Y. H.; Shen, B. H.; Kotora, M.; Takahashi, T. Angew.
Chem., Int. Ed. 1999, 38, 949-952. (g) Xi, C.; Kotora, M.; Nakajima,
K.; Takahashi, T. J. Org. Chem. 2000, 65, 945-950. (h) Barluenga, J.;
Sanz, R.; Granados, A.; Fan˜ana´s, F. J. J. Am. Chem. Soc. 1998, 120,
4865.
(2) For allyl-metalation of alkynes, see: (a) Eisch, J. J.; Merkley, J.
H.; Galle, J. E. J. Org. Chem. 1979, 44, 587. (b) Bernardou, F.; Miginiac,
L. J. Organomet. Chem. 1977, 125, 23. (c) Suzuki, N.; Kondakov, D.
Y.; Kageyama, M.; Kotora, M.; Hara, R.; Takahashi, T. Tetrahedron
1995, 51, 4519-4540. (d) Yamanoi, S.; Imai, T.; Matsumoto, T.; Suzuki,
K. Tetrahedron Lett. 1997, 38, 3031-3034. (e) Shirakawa, E.;
Yamasaki, K.; Yoshida, H.; Hiyama, T. J. Am. Chem. Soc. 1999, 121,
10221-10222. For acyl-metalation of alkynes, see: (f) Hoberg, H.;
Schaefer, D.; Burkhart, G.; Kru¨ger, C.; Romao, M. J. J. Organomet.
Chem. 1984, 266, 203 and references therein. (g) DeShong, P.; Sidler,
D. R.; Rybczynski, P. J.; Slough, G. A.; Rheingold, A. L. J. Am. Chem.
Soc. 1988, 110, 2575. (h) DeShong, P.; Sidler, D. R. J. Org. Chem. 1988,
53, 4892. (i) Takai, K.; Kataoka, Y.; Yoshizumi, K.; Oguchi, Y.; Utimoto,
K. Chem. Lett. 1991, 1479-1482. For alkenyl- or dienyl-metalation
of alkynes: (j) Furber, M.; Taylor, R. J. K.; Burford, S. C. J. Chem.
Soc., Perkin Trans. 1 1986, 1809-1815. (k) Takahashi, T.; Kondakov,
D. Y.; Xi, Z.; Suzuki, N. J. Am. Chem. Soc. 1995, 117, 5871-5872.
(l) Chinkov, N.; Majumbar, S.; Marek, I. J. Am. Chem. Soc. 2003,
125, 13258-13264. For alkynyl-metalation, see: (m) Shirakawa, E.;
Yoshida, H.; Kurahashi, T.; Nakao, Y.; Hiyama, T. J. Am. Chem. Soc.
1998, 120, 2975-2976. (n) Liu, Y. H.; Zhong, Z.; Nakajima, K.;
Takahashi, T. J. Org. Chem. 2002, 67, 7451-7456. For haloamidation,
see: (o) Li, Y.; Matsumura, H.; Yamanaka, M.; Takahashi, T. Tetra-
hedron 2004, 60, 1393-1400. For metalloesterification, see: (p)
Takahashi, T.; Xi, C.; Ura, Y.; Nakajima, K. J. Am. Chem. Soc. 2000,
122, 3228-3229.
This reaction provides a versatile procedure for the
synthesis of functionalized isoquinoline derivatives after
hydrolysis. We also report the unique X-ray structure
of the zirconium-containing complex.
The synthesis of isoquinoline ring systems has re-
ceived considerable attention, since they widely occur
in natural alkaloids and have pharmacological activi-
ties.4 During our studies of new processes for heterocycle
formation, we found that azazirconacyclopentadienes5
derived from highly selective coupling of an alkyne and
o-halobenzonitrile reacted with DMAD (dimethyl acety-
lenedicarboxylate) in the presence of 1 equiv of CuCl to
afford the novel eight-membered oxazirconacycles 2 with
(3) (a) Wensbo, D.; Eriksson, A.; Jeschke, T.; Annby, U.; Gronowitz,
S.; Cohen, L. A. Tetrahedron Lett. 1993, 34, 2823. (b) Kartens, W. F.
J.; Stol, M.; Rutjes, F. P. J. T.; Kooijman, H.; Spek, A. L.; Hiemstra,
H. J. Organomet. Chem. 2001, 624, 244. (c) Finch, H.; Pegg, N. A.;
Evans, B. Tetrahedron Lett. 1993, 34, 8353.
(4) (a) Bentley, K. W. The Isoquinoline Alkaloids; Harwood Aca-
demic: Amsterdam, 1998; Vol. 1. (b) Croisy-Delcey, M.; Croisy, A.;
Carrez, D.; Huel, C.; Chiaroni, A.; Ducrot, P.; Bisagni, E.; Jin, L.;
Leclercq, G. Bioorg. Med. Chem. 2000, 8, 2629.
(5) For the formation of azazirconacyclopentadienes, see: (a)
Takahashi, T.; Xi, C. J.; Xi, Z. F.; Kageyama, M.; Fischer, R.; Nakajima,
K.; Negishi, E. J. Org. Chem. 1998, 63, 6802-6808. (b) Negishi, E.;
Holms, S. J.; Tour, J. M.; Miller, J. A.; Cederbaum, F. E.; Swanson, D.
R.; Takahashi, T. J. Am. Chem. Soc. 1989, 111, 3336-3346. (c) Fagan,
P. J.; Nugent, W. A. J. Am. Chem. Soc. 1988, 110, 2310-2312. (d)
Quntar, A. A.; Melman, A.; Srebnik, M. J. Org. Chem. 2002, 67, 3769-
3772.
10.1021/om049302q CCC: $27.50 © 2004 American Chemical Society
Publication on Web 11/06/2004

Communications
Organometallics, Vol. 23, No. 25, 2004 5901
Table 1. Isoquinolyl-Zirconation of Alkynes:
Formation of Eight-Membered Oxazirconacycles
first
alkyne
second
alkyne
yield of
entry
ArCN
2 (%)a
1
2
3
4
5
6
7
8
9
PrCtCPr
PrCtCPr
PhCtCBu
PrCtCPr
PrCtCPr
PhCtCPh
PhCtCPh
BuCtCBu
PrCtCPr
2-BrC6H4CN
DMAD
DEAD
DMAD
DMAD
DEAD
DMAD
DMAD
DMAD
DEAD
50 (2c)
61 (2d)
44b (2e)
56 (2f)
61 (2g)
60 (2h)
30 (2b)
67 (2a)
63c (2i)
2-BrC6H4CN
2-BrC6H4CN
2,6-Cl2-C6H3CN
2,6-Cl2-C6H3CN
2,6-Cl2-C6H3CN
2-Cl-C6H4CN
2-F-C6H4CN
2,6-F2-C6H3CN
a Isolated yields. Unless noted, all the reactions were carried
out using CuCl at room temperature for 1 h and 50 °C for 12 h.
b Two isomers were obtained in a ratio of 1:1. c Reaction was done
at room temperature for 12 h.
an intramolecular Zr-N coordination (eq 3). Remark-
Figure 1. Structure of one of the two crystallographically
independent 2b. Selected bond lengths (Å): Zr(1)-O(1) )
2.152(4), Zr(1)-N(1) ) 2.336(4), Zr(1)-C(22) ) 2.365(5),
O(1)-C(11) ) 1.261(6), O(2)-C(11) ) 1.225(6); C(11)-C(12)
) 1.518(8).
C-Cl and C-F bonds during the reaction. It is note-
worthy that employing DEAD (diethyl acetylenedicar-
boxylate) also works well in this reaction (entries 2, 5,
and 9). However, using other activated alkynes such as
phenyl- or alkyl-substituted alkynyl esters or ketones
resulted in the formation of a complicated reaction
mixture. On the other hand, hydrolysis of 2c afforded
the 3-isoquinolyl acid 3 in 93% isolated yield. Bromi-
ably, 2 proved to be stable to air and water in its solid
state, surviving an aqueous alkali-hydrolysis workup
and allowing a convenient separation through column
chromatography on silica gel. It is noteworthy that air-
stable, C-Zr σ-bond-containing complexes are rare.6
A typical procedure for the preparation of 2 is as
follows: to a solution of azazirconacyclopentadiene 1a
(1 mmol), prepared by cross-coupling of 1 mmol of
alkyne and 1 mmol of 2-bromobenzonitrile assisted by
a low-valent zirconocene-ethylene complex in THF,
were added DMAD (2 mmol) and CuCl (1 mmol)
sequentially at 0 °C. The reaction mixture was warmed
to room temperature for 1 h and kept at 50 °C for 12 h,
quenched with 20% NaHCO3 solution. Purification by
column chromatography on silica gel afforded 2a in 67%
isolated yield. The representative reactions of various
o-halonitriles with alkynes are listed in Table 1. To
investigate the generality of this reaction, chloro-
substituted nitriles such as o-chlorobenzonitrile and 2,6-
dichlorobenzonitrile were used in the reaction; the
corresponding products were obtained in 30-61% iso-
lated yields (entries 4∼7). Selective C-F bond activation
is of current interest in organometallic chemistry.7 Very
surprisingly, here even the fluoro-substituted nitriles,
namely o-fluorobenzonitrile and 2,6-difluorobenzonitrile,
worked well in this chemistry and afforded oxazircona-
cycles 2a and 2i in 67% and 63% yield, respectively.
These results indicated the ease of cleavage of stronger
nation of 2g or iodination of 2b with 1 equiv of bromine
or iodine afforded the corresponding halogenated prod-
ucts 4 and 5 in 84% and 67% yields, respectively.
The 1H NMR spectrum of 2a in CDCl3 showed a
singlet peak at 6.0 ppm assigned to Cp protons. Integra-
tion of a singlet at 4.1 ppm (methyl protons of the -CO2-
Me moiety) indicated only one ester group existed and
the C-O bond of the other ester group was cleaved
during the reaction. Additionally, the 13C NMR spec-
trum of 2a showed peaks at 109.86 and 230.58 ppm
assignable to the Cp and dCZr moieties, respectively.8
To confirm spectroscopic assignments and to have a
deep insight into the molecular structure of 2, an X-ray
diffraction study was carried out and shown in Figure
1. The ORTEP plot clearly shows the eight-membered
oxametallacyclic structure of the product. The Zr-C
distance of 2.365(5) Å is comparable to that found for
other ZrIV-C(sp2)-containing oxametallacycles,8 while
the Zr-N(1) distance of 2.336(4) Å9 suggests a dative
interaction between the isoquinolyl nitrogen and the
(6) (a) Luker, T.; Whitby, R. J.; Webster, M. J. Organomet. Chem.
1995, 492, 53-57. (b) Mohamadi, F.; Spees, M. M. Organometallics
1992, 11, 1398-1400.
(7) Deck, P. A.; Konate, M. M.; Kelly, B. V.; Slebodnick, C. Organo-
metallics 2004, 23, 1089-1097 and references therein.
(8) Sun, H.; Burlakov, V. V.; Spannenberg, A.; Baumann, W.; Arndt,
P.; Rosenthal, U. Organometallics 2002, 21, 3360-3366.
(9) Kempe, R. Brenner, S.; Arndt, P. Organometallics 1996, 15,
1071-1074.

5902 Organometallics, Vol. 23, No. 25, 2004
Communications
metal. The O(CdO) group was found to assume the
expected ester-type structure, where one oxygen atom,
O(1), links to the metal while the other is bent away
from the metal. This orientation causes the metal center
to be pentacoordinate and results in an 18-electron
complex. The bite angle (136.68°) defined by O(1)-
Zr(1)-C(22) is the largest among the oxazirconacycle
family: for example, 121.2° for the seven-membered σ,
and formation of a Zr-O bond. A similar demethylation
was observed in o-MeO-containing benzyl-substituted
cyclopentadienyltitanium complexes.12
In summary, a novel isoquinolyl-zirconation of unac-
tivated alkynes to produce new air-stable oxazircona-
cycles has been described. This method enhances the
synthetic utility of five-membered azazirconacycles by
providing products of highly functionalized isoquinoline
derivatives. Clarification of the reaction mechanism and
further application of this chemistry are in progress.
syn-η3-allyl-type species Cp*2Zr[C4H6C(dO)O],10 and
96.85° for rac-(ebthi)ZrOCMedCHCH2C(SiMe3)dC-
(SiMe3).9
Acknowledgment. We thank the National Natural
Science Foundation of China, the Chinese Academy of
Science, and the Science and Technology Commission
of Shanghai Municipality for financial support. We also
thank Prof. X. Lu in our institute for his helpful
discussions.
Recently, Takahashi et al. reported a novel coupling
reaction of azazirconacyclopentadienes with alkynes to
form pyridines in the presence of NiCl2(PPh3)2, in which
transmetalation of azazirconacycles to give azanickela-
cycles is suggested.11 Although the mechanism of the
reaction presented here is not clear yet, one plausible
reaction pathway may involve the following steps:
selective transmetalation of the Zr-N bond to a Cu-N
bond since the Zr-C(sp2) bond of azazirconacyclopen-
tadienes remains intact, subsequent conjugate addition/
cyclization concomitant with demethylation of DMAD,
Supporting Information Available: Text and figures
giving experimental details and spectroscopic characterization
data for all isolated compounds and a CIF file giving crystal-
lographic data for 2b. This material is available free of charge
via the Internet at http://pubs.acs.org.
(10) Yasuda, H.; Okamoto, T.; Matsuoka, Y.; Nakamura, A.; Kai,
Y.; Kanehisa, N.; Kasai, N. Organometallics 1989, 8, 1139-1152.
(11) (a) Takahashi, T.; Tsai, F.; Kotora, M. J. Am. Chem. Soc. 2000,
122, 4994. (b) Takahashi, T.; Tsai, F.; Li, Y. Z.; Wang, H.; Kondo, Y.;
Yamanaka, M.; Nakajima, K.; Kotora, M. J. Am. Chem. Soc. 2002, 124,
5059-5067.
OM049302Q
(12) Qian, Y. L.; Huang, J. L.; Yang, J. M.; Chan, A. S. C.; Chen,
W. H.; Chen, X. P.; Li, G. S.; Li, B. H.; Jin, X. L.; Yang, Q. C. J.
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