Carbozincation of enynes catalyzed by titanium(IV) alkoxides and alkylmagnesium Derivatives [16]

Full text of DOI:10.1021/ja973841n

J. Am. Chem. Soc. 1998, 120, 5345-5346
5345
Scheme 1
Carbozincation of Enynes Catalyzed by Titanium(IV)
Alkoxides and Alkylmagnesium Derivatives†
Jean-Luc Montchamp and Ei-ichi Negishi*
Department of Chemistry, Purdue UniVersity
West Lafayette, Indiana 47907
ReceiVed NoVember 10, 1997
We report herein that a novel trimetallic reagent system
consisting of Et2Zn (Aldrich or Strem) XTi(OPri)3 (0.1 equiv),
where X is Cl or OPri, and an alkylmagnesium halide (0.2 equiv),
e.g., EtMgBr and PriMgCl, reacts with various enynes (1) to
produce the corresponding cyclic organozinc derivatives 2.
Protonolysis, deuteriolysis, and iodinolysis of 2 provide the
corresponding derivatives 3-5, while treatment of 2 with CH3-
OCH2Br (1.1 equiv relative to an enyne) provides in good yields
the corresponding 1-alkenylbicyclo[n.1.0]alkanes 6, where n is 3
or 4 (Scheme 1).1 The potential generality of the reaction is
indicated by the results summarized in Table 1.
found that the same enyne could be cyclized to give the
corresponding aluminabicycle in a moderate yield using Et3Al
and 10 mol % of Cp2ZrCl2,4 but its scope appears to be much
more limited. Very recently, a Ni-catalyzed organozinc-promoted
carbocyclization of electron-deficient enynes was reported,5 but
it is clearly distinct from that reported herein.
Although 2.5 equiv of Et2Zn was used in most cases, it appears
that only 1 equiv of Et2Zn per enyne is necessary as indicated by
entry 3 in Table 1. The results also indicate that there is only
one Zn atom per enyne, although the exact structures of the
organozinc products remain unclear beyond those represented by
2. The need for an alkylmagnesium derivative strongly suggests
Ti(II) derivatives, presumably alkene-Ti(II) complexes, as the
active species, as in the stoichiometric versions.2 Once they are
generated, catalytic cycles must be sustained with enynes and
Et2Zn. Despite some ambiguities, the mechanism shown in
Scheme 2 may be suggested.
Monoynes do undergo a related cyclization reaction, but it is
a much slower reaction that needs to be further developed.
Specifically, the reaction of 5-decyne with the standard reagent
system consisting of 2.5 equiv of Et2Zn, 10 mol % of Ti(OPri)4,
and 20 mol % of EtMgBr in Et2O-hexanes slowly proceeded at
23 °C. After 24 h, the same quantity of Ti(OPri)4 was added to
drive the reaction to completion. After 4 d, the desired (Z)-5-
ethyl-5-decene was obtained in 64% yield after protonolysis.
Attempts to convert 1-phenyl-8-nonen-1-yne and 1-phenyl-5-
hexen-1-yne into the desired seven- and four-membered ring
products under the standard Ti-Mg-catalyzed carbozincation
conditions resulted in mere ethylzincation as described above.
Evidently, these enynes functioned as ordinary alkynes.
Although carbonylation of organozinc products has not been
successful,6 treatment with 1 equiv of CH3OCH2Br per enyne
converted the organozinc derivatives to 1-alkenylbicyclo[n.1.0]-
alkanes, where n is 3 or 4. The results may be interpreted as
shown in Scheme 3. Thus, CH3OCH2Br must selectively react
with the alkenyl-Zn bond to generate 8, which must then undergo
homoallyl-cyclopropylcarbinyl rearrangement and deoxyzinca-
tion to produce 6.
Despite a recent surge of publications on Ti(II)-promoted
carbon-carbon bond formation involving alkenes, alkynes, and
related heteroatom containing π-compounds,2 those that are
catalytic in Ti are rare, and such reactions appear to be limited
to the enyne3a,b and alkenone3c bicyclization-isocyanide or CO
insertion tandem process and the alkenone bicyclization-silane
reduction tandem process3d,e catalyzed by titanocene derivatives.
However, our attempts to cyclize 1-phenyl-6-hepten-1-yne with
either EtMgBr in the presence of 10 mol % of Cp2TiCl2 or Et2Zn
in the presence of 10 mol % of Cp2TiCl2 and 20 mol % of BunLi
or EtMgBr led mostly to the formation of (Z)-1-phenyl-1,6-
heptadiene after protonolysis. Thus, alkoxytitanium derivatives,
i.e., XTi(OPri)3, where X is Cl or OPri, appear to be especially
suited for the observed cyclic carbozincation reaction. Other
variations of the presently reported reaction have led to inferior
results. Thus, replacement of Et2Zn with 2.5 equiv of EtMgBr
or PriMgBr in the reaction of 1-(trimethylsilyl)-6-hepten-1-yne
led to its consumption, but only complex mixtures resulted.
Similarly, replacement of Et2Zn with Et3Al led to complex
mixtures, even though a significant amount of the starting enyne
remained unreacted. The use of EtZnI in place of Et2Zn did not
induce the desired cyclization, with the starting enynes remaining
unreacted. Thus, Et2Zn has thus far been essential to observing
the desired clean cyclization in high yields. An alkylmagnesium
derivative is also critically needed. Without it, the starting enyne
remains unreacted. The use of BunLi in place of EtMgBr led to
low yields (20-30%) of the desired cyclization products with
the balance of the starting enyne remaining unreacted. We earlier
† Most of the results were presented at the 9th IUPAC meeting on
Organometallic Chemistry Directed toward Organic Synthesis (OMCOS 9),
Go¨ttingen, Germany, July 20-25, 1997.
(1) For some representative reviews on transition-metal-promoted and
-catalyzed cyclization reactions of enynes and related compounds, see: (a)
Schore, N. E. In ComprehensiVe Organic Synthesis; Paquette, L. A., Ed.;
Pergamon Press: New York, 1991; Vol. 5, Chapter 9.1, p 1037. (b) Negishi,
E. In ComprehensiVe Organic Synthesis; Paquette, L. A., Ed.; Pergamon
Press: New York, 1991; Vol. 5, Chapter 9.5, p 1163. (c) Ojima, I.;
Tzamarioudaki, M.; Li, Z.; Donovan, R. J. Chem. ReV. 1996, 96, 635.
(2) (a) Harada, K.; Urabe, H.; Sato, F. Tetrahedron Lett. 1995, 36, 3203.
(b) Urabe, H.; Hata, T.; Sato, F. Tetrahedron Lett. 1995, 36, 4261. (c) Gao,
Y.; Harada, K.; Sato, F. Tetrahedron Lett. 1995, 36, 5913. (d) Gao, Y.; Harada,
K.; Sato, F. Chem. Commun. 1996, 533. (e) Urabe, H.; Sato, F. J. Org. Chem.
1996, 61, 6756. (f) Gao, Y.; Shirai, M.; Sato, F. Tetrahedron Lett. 1996, 37,
7787.
The operational simplicity of the catalytic cyclization method
herein reported can be seen in the following representative
procedure for the conversion of 1 (Y ) CH2; Z ) Ph) into the
(4) (a) Choueiry, D. Ph.D. Dissertation, Purdue University, 1995. (b)
Negishi, E.; Montchamp, J. L.; Anastasia, L.; Elizarov, A.; Choueiry, D.
Tetrahedron Lett. In press.
(5) Montgomery, J.; Oblinger, E.; Sawchenko, A. V. J. Am. Chem. Soc.
1997, 119, 4911.
(6) Rathke, M. W.; Yu, H. J. Org. Chem. 1972, 37, 1732. For a recent
cocatalyzed carbonylation of organozincs, see: Devasagayaraj, A.; Knochel,
P. Tetrahedron Lett. 1995, 36, 8411.
(3) (a) Berk, S. C.; Grossman, R. B.; Buchwald, S. L. J. Am. Chem. Soc.
1993, 115, 4912; 1994, 116, 8593. (b) Hicks, F. A.; Buchwald, S. L. J. Am.
Chem. Soc. 1996, 118, 11688. (c) Kabalaoui, N. M.; Hicks, F. A.; Buchwald,
S. L. J. Am. Chem. Soc. 1996, 118, 5818; 1997, 119, 4424. (d) Kabalaoui, N.
M.; Buchwald, S. L. J. Am. Chem. Soc. 1995, 117, 6785; 1996, 118, 3182.
(e) Crowe, W. E.; Rachita, M. J. J. Am. Chem. Soc. 1995, 117, 6787.
S0002-7863(97)03841-9 CCC: $15.00 © 1998 American Chemical Society
Published on Web 05/13/1998

5346 J. Am. Chem. Soc., Vol. 120, No. 21, 1998
Communications to the Editor
Carbozincation of Enynes Catalyzed by Titanium(IV) Alkoxides and Alkylmagnesium Derivativesa
enyne (1)
product yield,b %
Table 1.
entry
Y
Z
X of XTi(OPri)3
RMgX
time, h
3
4
5
6
1
2
3
4
5
6
7
8
9
CH2
CH2
CH2
CH2
SiMe3
SiMe3
Ph
Me
Ph
Cl
EtMgBr
PriMgCl
EtMgBrd
EtMgBr
EtMgBr
PriMgCl
EtMgBr
PriMgCl
EtMgBr
EtMgBr
EtMgBr
3
42
3
85
84
53c
99
80 (61)c
OPri
Cl
93 (90)c
60
90e
61 (59)c
50
95
Cl
3
O
Clf
Cl
48
18
18
48
24
24
18
95
80
75
89
83
86
65
(CH2)2
(CH2)2
(CH2)2
(CH2)2
(CH2)2
CH2Oh
SiMe3
SiMe3
SiMe3
Ph
Cl
OPri
Cl
79g
56c
62
10
11
Bun
Me
Cl
Cl
a Unless otherwise mentioned, enynes were treated at 23 °C with 2.5 equiv of Et2Zn, 10 mol % of XTi(OPri)3, where X ) Cl or OPri, and 20
mol % of an alkylmagnesium halide, EtMgBr and PriMgBr, in Et2O-hexanes. b Unless otherwise mentioned, the yields were determined by either
GLC or NMR using appropriate internal standards. c Isolated yield. d Only 1 equiv of Et2Zn was used. e The extents of D incorporation in the
methyl and benzylidene groups were g99 and >86%, respectively. f After the reaction was run with 10 mol % of ClTi(OPri)3 and 20 mol % of
g
EtMgBr, for 24 h, an additional 10 mol % of Ti(OPri)4 was added to complete the reaction. The extents of D incorporation in the two labeled
positions were g97%. h MeCtC(CH2)2OCH2CHdCH2.
Scheme 2
mmol) in THF (10 mL) was added. The reaction mixture was
warmed to 23 °C and stirred overnight. The mixture was then
partitioned between 3 N aqueous HCl and ether. The organic
layer was washed with water and aqueous Na2S2O3. Drying over
MgSO4, concentration, and purification on silica gel (pentane)
provided 5 (0.491 g, 1.15 mmol, 59%). The organozinc product
2 obtained as above was cooled to -78 °C, and freshly distilled
MeOCH2Br (90%, 0.20 mL, 2.2 mmol) was added neat. The
reaction mixture was warmed to 23 °C, stirred overnight, and
poured into 3 N aqueous HCl and ether. The organic layer was
washed with brine, dried over MgSO4, and concentrated to a
yellow oil. Purification by chromatography on silica gel (pentane)
provided 6 (0.219 g, 1.19 mmol, 61%).
In summary, the novel trimetallic Zn-Ti-Mg reagent systems
provide a means of devising cyclization of enynes (and simple
alkynes) with catalytic quantities of Ti and Mg reagents, which
is potentially attractive for use in conjunction with chiral ligands,
and such studies are currently underway. In a more general sense,
the catalytic reaction reported herein promises to represent a
breakthrough for converting a large number of known stoichio-
metric reactions with Ti-Mg reagent systems2 into catalytic
processes.
Scheme 3
Acknowledgment. We thank the National Science Foundation (CHE
9704994) for support of this research.
corresponding 5 and 6. To a solution of 1-phenyl-6-hepten-1-
yne (0.335 g, 2 mmol) and Et2Zn (1 M in hexanes, 2 mL, 2 mmol)
in ether (5 mL) and hexanes (3 mL) was added ClTi(OPri)3 (0.5
M in hexanes, 0.4 mL, 0.2 mmol) followed by EtMgBr (3 M in
Et2O, 0.13 mL, 0.4 mmol). After 3.5 h at 23 °C, the reaction
mixture was cooled to -78 °C, and a solution of I2 (1.26 g, 5
Supporting Information Available: Spectral data and elemental
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JA973841N