Synthetic studies and mechanistic insight in nickel-catalyzed [4+2+1] cycloadditions

Article abstract of DOI:10.1021/ja057741q

A new nickel-catalyzed procedure for the [4+2+1] cycloaddition of (trimethylsilyl)diazomethane with alkynes tethered to dienes has been developed, A broad range of unsaturated substrates participate in the sequence, and stereoselectivities are generally e

Full text of DOI:10.1021/ja057741q

Published on Web 02/03/2006
Synthetic Studies and Mechanistic Insight in Nickel-Catalyzed
[4+2+1] Cycloadditions
Yike Ni and John Montgomery*
Contribution from the Department of Chemistry, Wayne State UniVersity,
Detroit, Michigan 48202-3489, and Department of Chemistry, UniVersity of Michigan,
930 North UniVersity, Ann Arbor, Michigan 48109-1055
Received November 14, 2005; E-mail: jmontg@umich.edu
Abstract: A new nickel-catalyzed procedure for the [4+2+1] cycloaddition of (trimethylsilyl)diazomethane
with alkynes tethered to dienes has been developed. A broad range of unsaturated substrates participate
in the sequence, and stereoselectivities are generally excellent. Stereochemical studies provided evidence
for a mechanism that involves the [3,3] sigmatropic rearrangement of divinylcyclopropanes.
from Padwa.4 Although the developments involving rhodium
catalysis provided elegant access to structurally complex seven-
Introduction
Transition-metal-catalyzed multicomponent cycloadditions
have emerged as a powerful strategy for preparing complex ring
systems. Particular utility in the construction of medium rings
has been demonstrated because the corresponding thermal
counterparts are often either inaccessible or inefficient. In recent
years, the repertoire of available metal-catalyzed cycloaddition
entries to medium rings has grown to include [4+4], [5+2],
[6+2], [6+4], [4+2+2], [5+2+1], [2+2+2+1], and [5+1+2+1]
processes.1 The development of an efficient [4+2+1] process
has been the focus of a number of studies. In early work from
Harvey, a molybdenum carbene-mediated process was devel-
oped in which dienynes underwent addition to the carbene unit
in a [4+2+1] sense to afford seven-membered ring products.2
The mechanism for that class of reactions was proposed to
involve an alkyne metathesis cascade to generate a divinyl-
cyclopropane, which then underwent facile Cope rearrangement
to afford the seven-membered ring adduct. Although those
studies were limited to stoichiometric processes, a related [4+3]
cycloaddition process was extensively developed by Davies
involving the rhodium-catalyzed addition of unsaturated diazo
species with dienes.3 Two isolated examples of the correspond-
ing fully intramolecular [4+2+1] cycloaddition of a diazo-
alkane/alkyne/diene cycloaddition were also reported in studies
membered rings, access to simpler seven-membered ring
systems by catalytic, partially intermolecular [4+2+1] processes
had remained elusive. Prior to our original report in the area,5
the only examples of partially intermolecular, catalytic [4+2+1]
cycloadditions were from Wender.6 In their studies of [2+2+1]
carbonylative cycloadditions of dienynes, the [4+2+1] cyclo-
addition product was observed as a minor component of the
reaction mixture.
In surveying the literature on nickel carbene complexes, it
became apparent that the involvement of nickel carbene species
in synthetic applications was considerably underdeveloped.
Although a number of nickel carbene species had been
characterized7 and nickel complexes of N-heterocyclic carbenes
had been widely used in catalytic applications,8 the development
of procedures in which the carbene unit was incorporated into
an organic product structure had been little studied.9 An
interesting report from Barluenga suggested that nickel catalyzes
carbene transfer from a chromium carbene complex to an
(3) (a) Davies, H. M. L.; McAfee, M. J.; Oldenburg, C. E. M. J. Org. Chem.
1989, 54, 930. (b) Davies, H. M. L.; Doan, B. D. J. Org. Chem. 1999, 64,
8501. (c) Davies, H. M. L.; Calvo, R. L.; Townsend, R. J.; Ren, P.;
Churchill, R. M. J. Org. Chem. 2000, 65, 4261. (d) Davies, H. M. L.;
Stafford, D. G.; Doan, B. D.; Houser, J. H. J. Am. Chem. Soc. 1998, 120,
3326. (e) Deng, L.; Giessert, A. J.; Gerlitz, O. O.; Dai, X.; Diver, S. T.;
Davies, H. M. L. J. Am. Chem. Soc. 2005, 127, 1342.
(1) (a) For [4+4] reactions: Wender, P. A.; Ihle, N. C. J. Am. Chem. Soc.
1986, 108, 4678. (b) For [5+2] reactions: Wender, P. A.; Takahashi, H.;
Witulski, B. J. Am. Chem. Soc. 1995, 117, 4720. (c) For [6+2] reactions:
Rigby, J. H.; Henshilwood, J. A. J. Am. Chem. Soc. 1991, 113, 5122. (d)
For [6+4] reactions: Rigby, J. H.; Ateeq, H. S.; Charles, N. R.; Cuisiat,
S. V.; Ferguson, M. D.; Henshilwood, J. A.; Krueger, A. C.; Ogbu, C. O.;
Short, K. M.; Heeg, M. J. J. Am. Chem. Soc. 1993, 115, 1382. (e) For
[4+2+2] reactions: Evans, P. A.; Robinson, J. E.; Baum, E. W.; Fazal, A.
N. J. Am. Chem. Soc. 2002, 124, 8782. (f) Gilbertson, S. R.; DeBoef, B.
J. Am. Chem. Soc. 2002, 124, 8784. (g) For [5+2+1] reactions: Wender,
P. A.; Gamber, G. G.; Hubbard, R. D.; Zhang, L. J. Am. Chem. Soc. 2002,
124, 2876. (h) For [2+2+2+1] reactions: Ojima, I.; Lee, S.-Y. J. Am.
Chem. Soc. 2000, 122, 2385. (i) For [5+1+2+1] reactions: Wender, P.
A.; Gamber, G. G.; Hubbard, R. D.; Pham, S. M.; Zhang, L. J. Am. Chem.
Soc. 2005, 127, 2836.
(4) Padwa, A.; Krumpe, K. E.; Gareau, Y.; Chiacchio, U. J. Org. Chem. 1991,
56, 2523.
(5) For a preliminary communication of this work, see: Ni, Y.; Montgomery,
J. J. Am. Chem. Soc. 2004, 126, 11162.
(6) Wender, P. A.; Deschamps, N. M.; Gamber, G. G. Angew. Chem., Int. Ed.
2003, 42, 1853.
(7) (a) Mindiola, D. J.; Hillhouse, G. L. J. Am. Chem. Soc. 2002, 124, 9976.
(b) Gabor, B.; Kru¨ger, C.; Marczinke, B.; Mynott, R.; Wilke, G. Angew.
Chem., Int. Ed. Engl. 1991, 30, 1666. (c) Arduengo, A. J.; Gamper, S. F.;
Calabrese, J. C.; Davidson, F. J. Am. Chem. Soc. 1994, 116, 4391. (d)
Hou, H.; Gantzel, P. K.; Kubiak, C. P. Organometallics 2003, 22, 2817.
(8) (a) Herrmann, W. A. Angew. Chem., Int. Ed. 2002, 41, 1290. (b) Mahandru,
G. M.; Liu, G.; Montgomery, J. J. Am. Chem. Soc. 2004, 126, 3698. (c)
Zuo, G.; Louie, J. Angew. Chem., Int. Ed. 2004, 43, 2277. (d) Louie, J.;
Gibby, J. E.; Farnworth, M. V.; Tekavec, T. N. J. Am. Chem. Soc. 2002,
124, 15188. (e) Sato, Y.; Sawaki, R.; Mori, M. Organometallics 2001, 20,
5510. (f) Dible, B. R.; Sigman, M. S. J. Am. Chem. Soc. 2003, 125, 872.
(g) Blakey, S. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2003, 125,
6046.
(2) (a) Harvey, D. F.; Lund, K. P. J. Am. Chem. Soc. 1991, 113, 5066. (b)
Harvey, D. F.; Grenzer, E. M.; Gantzel, P. K. J. Am. Chem. Soc. 1994,
116, 6719. (c) See also: Herndon, J. W.; Chatterjee, G.; Patel, P. P.; Matasi,
J. J.; Tumer, S. U.; Harp, J. J.; Reid, M. D. J. Am. Chem. Soc. 1991, 113,
7808.
9
10.1021/ja057741q CCC: $33.50 © 2006 American Chemical Society
J. AM. CHEM. SOC. 2006, 128, 2609-2614
2609

A R T I C L E S
Ni and Montgomery
Table 1. Reaction Optimizationa
Table 2. Reaction Scope
temp
C)
time
% yield
(dr)
entry
ligand
solvent
(
°
(min)
1
2
3
4
5
6
7
8
dppe
THF
THF
THF
THF
dioxane
toluene
THF
60
60
25
0
90
60
25
60
30
30
10
10
30
5
42
20
35
PCy3
P(t-Bu)3
none
none
none
64 (4.8:1)
54 (3.5:1)
45 (>19:1)
72 (5.3:1)
68 (>19:1)
none
none
5
5
THF
a Entries 1-4: 1a (1.0 equiv) was added to a premixed solution of
TMSCHN2 (2.0 equiv) and Ni(COD)2 (10 mol %). Entries 5-8: Ni(COD)2
(10 mol %) was added to a premixed solution of 1a (1.0 equiv) and
TMSCHN2 (2.0 equiv).
organic substrate,9a and a few studies involving olefin cyclo-
propanation with lithiated sulfones or diazoalkanes as the
carbene precursor had appeared.9b-d Studies from Hillhouse had
elegantly illustrated that reactive nickel carbene species could
be generated from diazoalkanes by a pathway involving η2
coordination of the diazo unit prior to the extrusion of dinitrogen
in the presence of Sm(OTf)3.7a,9d With this backdrop, it appeared
to us that the development of new synthetic procedures involving
the catalytic generation of nickel carbene intermediates from
diazoalkane precursors was an area worthy of study. Considering
the void in catalytic [4+2+1] cycloadditions and the void in
synthetic applications of nickel carbene species, we chose the
nickel-catalyzed [4+2+1] cycloaddition of (trimethylsilyl)-
diazomethane with dienynes as the initial target of our studies.
Herein, we report a full account of our work including the
reaction scope and mechanistic insight.
Results and Discussion
Development of a Catalytic [4+2+1] Cycloaddition Pro-
cess. Our initial studies focused on the [4+2+1] cycloaddition
of nitrogen-tethered substrate 1a (Table 1). A brief screen of
conditions using Ni(COD)2 as the catalyst and a 2:1 stoichi-
ometry of (trimethylsilyl)diazomethane/substrate 1a illustrated
that the desired cycloaddition was most effective in the absence
of phosphine ligands. Both reaction rates and overall yields were
lower in the presence of either monodentate or bidentate ligands
(Table 1, entries 1-4). Variations in order of reagent addition
were tolerated, and yields were highest in THF, although
dioxane and toluene were also effective solvents (entries 5 and
6). Interestingly, diastereoselectivities improved as temperatures
increased, with 60 °C being the optimum temperature to
maximize both yield and diastereoselectivity (entries 7 and 8).
The optimized procedure used throughout most of this study
involved premixing the diazoalkane and dienyne (2:1) in THF,
followed by addition of 10 mol % Ni(COD)2, and stirring at 60
°C for 10-30 min (entry 8).
Following the optimized general procedure, a number of
examples were carried out to illustrate the reaction scope (Table
2). In addition to the nitrogen-tethered substrate described
previously in our optimization studies (entry 1), we examined
the preparation of carbocyclic and oxacyclic structures. Mal-
onate-derived substrate 1b generated product 2b in 76% yield
in 13:1 dr (entry 2), and oxygen-containing substrate 1c
generated product 2c in 65% yield as a 10:1 ratio of diastere-
omers (entry 3). Internal alkynes were also effective participants,
as evidenced by the generation of products 2d, 2e, 2g, and 2h
(entries 4, 5, 7, and 8). Substitution on either the diene terminus
(entries 6 and 7) or an internal position of the diene (entry 8)
was acceptable. Substitution within the tether chain was also
tolerated with excellent resulting diastereoselectivity (entry 8).
Notably, this latter example allowed the rapid preparation of
densely functionalized product 2h with two rings, two sites of
unsaturation, and three chiral centers in a 1,2,5 relationship in
excellent yield and diastereoselectivity from relatively simple
precursor 1h.
(9) (a) Barluenga, J.; Barrio, P.; Lo´pez, L. A.; Toma´s, M.; Garc´ıa-Granda, S.;
Alvarez-Ru´a, C. Angew. Chem., Int. Ed. 2003, 42, 3008. (b) Nakamura,
A.; Yoshida, T.; Cowie, M.; Otsuka, S.; Ibers, J. A. J. Am. Chem. Soc.
1977, 99, 2108. (c) Gai, Y.; Julia, M.; Verpeaux, J.-N. Synlett 1991, 269.
(d) Waterman, R.; Hillhouse, G. L. J. Am. Chem. Soc. 2003, 125, 13350.
9
2610 J. AM. CHEM. SOC. VOL. 128, NO. 8, 2006

Nickel-Catalyzed [4+2+
1] Cycloadditions
A R T I C L E S
Scheme 1. Possible Mechanisms
The allyl silane handle installed in the cycloaddition process
is potentially useful in a variety of post-cycloaddition manipula-
tions. However, in this study, we only examined simple
desilylation. Interestingly, n-Bu4NF-mediated desilylation of 2b
proceeds without alkene migration to generate product 3,10a
whereas protodesilylation of 2b with BF3/HOAc proceeds with
allylic transposition to generate product 4 (eq 1).10b Thus,
metathesis to generate R,â-unsaturated carbene 7. Conversion
of 7 to 8 and reductive elimination of 8 to produce 9, followed
by [3,3] rearrangement, would afford product 2.11 As a second
alternative (mechanism B, Scheme 1), ring expansion of 8 to
10a would allow direct production of 2 upon reductive elimina-
tion.12 In completely distinct mechanism C (Scheme 1), oxida-
tive cyclization of nickel(0) with dienyne 1 could allow
production of metallacycloheptadiene 11.13 Carbene insertion
into either metal carbon bond of 11 to generate metallacycle
10a or 10b, followed by reductive elimination, would afford
product 2. This type of oxidative cyclization, migratory insertion
sequence is commonly invoked in carbonylative cycloadditions,
and the insertion of a metal carbene ligand into a metal-carbon
bond is well precedented in other contexts.14 Finally, a fourth
alternative (mechanism D, Scheme 1) could involve ring
contraction of metallacycle 11 to nickel biscarbene 12. Car-
bene-carbene coupling of 12 could then generate divinylcy-
clopropane 9, which rearranges to 2 as previously described.
The ring contraction of a metallacycle to a cyclopropane has
been demonstrated in a number of contexts.15 Although mech-
anisms C and D have been depicted with the trimethylsilyl
carbene unit present in the intermediate structures 11 and 12,
the analogous structures that lack the trimethylsilyl carbene unit
could also be involved, with diazoalkane incorporation occurring
at a late stage of the reaction pathway. In this study, we have
focused largely on the key question of involvement of divinyl-
cyclopropanes (mechanisms A or D) vs the direct kinetic
production of a seven-membered ring (mechanisms B or C). A
systematic examination of chemical reactivity and stereochem-
desilylated products 3 and 4 may be selectively prepared
according to the reaction conditions chosen, although product
4 was prepared as a 3:1 ratio of isomers favoring the cis isomer.
Unfortunately, readily available alkyl diazoacetates are un-
reactive in the protocol optimized for TMS diazomethane,
although our studies to expand the scope of diazoacetates that
participate are ongoing.
Possible Mechanisms. On the basis of a simple product
analysis, we envisioned several mechanisms that may be
operative in this new catalytic cycloaddition process (Scheme
1). As noted above, the stoichiometric behavior of molybdenum
carbene complexes in [4+2+1] cycloadditions2 as well as the
related rhodium-catalyzed [4+2+1] processes3,4 were proposed
to follow an alkyne metathesis/cyclopropanation/[3,3] rear-
rangement sequence. In analogy to these proposals, the nickel-
catalyzed process, via mechanism A (Scheme 1), could involve
formation of a nickel carbene intermediate 5, followed by alkyne
(11) For a discussion of cyclopropanation and metathesis pathways of enynes,
see: Peppers, B. P.; Diver, S. T. J. Am. Chem. Soc. 2005, 126, 9524.
(12) Involvement of ring-expanded nickel metallacycles in medium ring synthesis
has precedent in Wender’s [4+4] cycloaddition reactions. See ref 1a.
(13) Structure 11 has direct precedent in Wender’s [4+2] alkyne/diene cycload-
ditions. See references: (a) Wender, P. A.; Jenkins, T. E. J. Am. Chem.
Soc. 1989, 111, 6432. (b) Wender, P. A.; Smith, T. E. Tetrahedron 1998,
54, 1255.
(10) (a) Hulme, A. N.; Henry, S. S.; Meyers, A. I. J. Org. Chem. 1995, 60,
1265. (b) Kno¨lker, H.-J.; Baum, E.; Graf, R.; Jones, P. G.; Spiess, O. Angew.
Chem., Int. Ed. Engl. 1999, 38, 2583. (c) For a discussion of the
intermediacy of silanols in protodesilylations of C(sp3)-SiMe2Ph derivatives,
see: Heitzman, C. L.; Lambert, W. T.; Mertz, E.; Shotwell, B.; Tinsley, J.
M.; Va, P.; Roush, W. R. Org. Lett. 2005, 7, 2405.
(14) (a) Greenman, K. L.; Van Vranken, D. L. Tetrahedron 2005, 61, 6438. (b)
Sole´, D.; Vallverdu´, L.; Solans, X.; Font-Bardia, M.; Bonjoch, J. Orga-
nometallics 2004, 23, 1438.
(15) (a) Chowdhury, S. K.; Amarasinghe, K. K. D.; Heeg, M. J.; Montgomery,
J. J. Am. Chem. Soc. 2000, 122, 6775. (b) Urabe, H.; Suzuki, K.; Sato, F.
J. Am. Chem. Soc. 1997, 119, 10014.
9
J. AM. CHEM. SOC. VOL. 128, NO. 8, 2006 2611

A R T I C L E S
Ni and Montgomery
Scheme 2. Stereochemical Analysis: Mechanism A
Table 3. Enyne Cyclizations
entry
(substrate)
X
R1
R2
product, % yield (dr, E/Z)
1 (13a)
2 (13b)
3 (13c)
4 (13d)
C(CO2Me)2
NTs
O
H
H
Et
H
H
H
H
Et
14a, 70 (E only)
14b, 60 (10:1 E/Z)
14c, 36 (>95:5 dr, E only)
14d, 25 (>95:5 dr, 9:1 E/Z)
O
istry and a qualitative comparison of relative rates have provided
significant insight into these intriguing mechanistic questions,
as described below.
Evidence for the Involvement of Cyclopropane Intermedi-
ates. A key feature of mechanisms A and D is the formation of
divinylcyclopropane 9 followed by its thermal conversion to 2.
To gain evidence for the involvement of structures such as 9,
we sought evidence that the nickel adduct generated from Ni-
(COD)2 and TMS diazomethane could directly add to a simple
enyne. This observation would serve as a direct model for the
portions of mechanisms A and D that correspond to the 1 to 9
conversion while avoiding the subsequent sigmatropic rear-
rangement. Notably, Hoye had previously demonstrated this
mode of reactivity upon treatment of enynes to molybdenum
carbene species,16 and the corresponding catalytic reaction was
recently developed by Dixneuf upon exposure of enynes and
TMS diazomethane to Cp*RuCl(COD).17 Both malonate-derived
substrate 13a and nitrogen-tethered substrate 13b were examined
in the catalytic reaction with TMS diazomethane and Ni(COD)2
(Table 3, entries 1 and 2). In both cases, the reactions proceeded
smoothly at 60 °C to afford [3.1.0]-bicyclohexane ring systems
14a,b in analogy to the studies from Hoye and Dixneuf. An
important observation is that the E-vinyl silane was preferentially
generated in both cases. In contrast, the ruthenium-catalyzed
method of Dixneuf, involving the same diazoalkane, favored
the Z-isomer.17 Examination of substrates 13c and 13d clearly
illustrated that this addition step is stereospecific (Table 3, entries
3 and 4). Although the chemical yields were low with 1,2-
disubstituted alkenes, substrate 13c afforded the cyclopropane
14c, whereas 13d afforded cyclopropane 14d. Diastereoselec-
tivities were excellent and opposite for these two cases, and
the E-vinyl silane was produced in both instances with high
selectivity. Knowledge about the stereochemistry of the vinyl
silane produced and about the relationship of starting material
olefin stereochemistry to product cyclopropane stereochemistry
proved to be important features in our stereochemical analysis
of the [4+2+1] process (vide infra).
Scheme 3. Stereochemical Analysis: Mechanism D
and the reaction rate.18 In particular, the development of A1,3
strain in conformation 15 (eq 2), via substitution of R1 or R3,
results in a significant retardation of reaction rates.18f,g
Because the enyne cyclizations described above (Table 3)
provide a clear predictor of the stereochemistry of the vinyl
silane and cyclopropane stereocenters, it is useful to consider
how these stereochemical features would be expected to impact
the stereoselectivity and reaction rates of dienyne cyclizations.
Accordingly, if dienyne 1 participates in mechanism A described
above (Scheme 1), then the initially formed intermediate 7
should possess the E-vinyl silane configuration (Scheme 2).
Addition of the nickel carbene of 7 to the proximal E-alkene of
the tethered diene should proceed in a stereospecific sense to
afford compound 9 with the stereochemistry shown (Scheme
2). A similar analysis of mechanism D also predicts the observed
stereochemistry of product 2 if one assumes that the E-vinyl
silane of 9 is generated from 12 (Scheme 3). The key features
of 9 to note are the E-stereochemistry of the vinyl silane, the
Further Evidence for the Involvement of a [3,3] Rear-
rangement of Divinylcyclopropanes. A considerable amount
is known about the mechanism of [3,3] rearrangements of
divinylcyclopropanes. The reaction proceeds through a boat
transition state, and the alkene stereochemistry controls both
the relative stereochemistry of the newly formed chiral centers
(18) (a) Wender, P. A.; Filosa, M. P. J. Org. Chem. 1976, 41, 3490. (b) Marino,
J. P.; Browne, L. J. Tetrahedron Lett. 1976, 3245. (c) Piers, E.; Nagakura,
I. Tetrahedron Lett. 1976, 3237. (d) Lee, J.; Kim, H.; Cha, J. K. J. Am.
Chem. Soc. 1995, 117, 9919. (e) Hudlicky, T.; Fan, R.; Reed, J. W.;
Gadamesetti, K. G. Org. React. 1992, 41, 1. (f) Rhoads, S. J.; Raulins, N.
R. Org. React. 1975, 22, 1. (g) Ohloff, G.; Pickenhagen, W. HelV. Chim.
Acta 1969, 52, 880.
(16) (a) Korkowski, P. F.; Hoye, T. R.; Rydberg, D. B. J. Am. Chem. Soc. 1988,
110, 2676. (b) Hoye, T. R.; Rehberg, G. M. J. Am. Chem. Soc. 1990, 112,
2841.
(17) Monnier, F.; Castillo, D.; De´rien, S.; Toupet, L.; Dixneuf, P. H. Angew.
Chem., Int. Ed. 2003, 42, 5474.
9
2612 J. AM. CHEM. SOC. VOL. 128, NO. 8, 2006

Nickel-Catalyzed [4
+
2
+
1] Cycloadditions
A R T I C L E S
Scheme 5. Isolation of a Divinylcyclopropane without
Scheme 4. Isolation of a Divinylcyclopropane via Quaternization
Quaternization
cis orientation of the two alkenes with respect to the cyclopro-
pane, and the lack of a bridgehead substituent. All three of these
features combine to provide a divinylcyclopropane structure that
would be expected to undergo rapid [3,3] rearrangement to
product 2, which is exactly the product stereochemistry observed
in catalytic [4+2+1] cycloadditions. Failure to detect the
unrearranged divinylcyclopropane in cyclizations of dienynes
and observation of the stereochemical outcome predicted by the
above analysis are thus consistent with mechanism A or D.
To further probe the mechanistic features following this
stereochemical analysis, we next installed functional groups into
the starting dienyne that would introduce A1,3 strain in the
intermediate divinylcyclopropanes produced via mechanism A
or D. We reasoned that mechanisms B and C would not be
selectively and significantly impacted by these precise structural
modifications. Installation of a bridgehead methyl in the
intermediate divinylcyclopropane required the use of substrate
16 (Scheme 4). Treatment of 16 to the standard conditions at
60 °C in THF led to the selective formation of divinylcyclo-
propane 17 with the expected stereochemistry as shown.
Significantly, the introduction of a bridgehead methyl substituent
prevents the direct formation of a cycloheptadiene and instead
allows divinylcyclopropane 17 to be isolated. Heating 17 to 110
°C in toluene led to a slow rearrangement of 17 to product 19,
and conformation 18 depicts the A1,3 strain that slows the rate
of this [3,3] sigmatropic rearrangement. Alternatively, carrying
out the nickel-catalyzed reaction of 16 in toluene at 110 °C
provided direct access to 19 in 50% yield without requiring
isolation of cyclopropane 17. The rate of [3,3] rearrangement
of 17 was unaffected by the presence of Ni(COD)2, suggesting
that the rearrangement is a purely thermal, uncatalyzed process.
On the basis of this experiment, the suggested involvement of
mechanism A or D via a divinylcyclopropane rearrangement
appears to be more secure.
22a, whereas E,Z-diene 20 will generate divinylcyclopropane
21, which possesses the A1,3 strain that will slow the [3,3]
rearrangement as depicted in confomation 22b. Indeed, these
two stereoisomers 1g and 20 afforded completely different
reaction outcomes at 60 °C in THF, with 1g exclusively
producing rearrangement product 2g and 20 exclusively produc-
ing divinylcyclopropane 21. Heating compound 21 at 105 °C
in toluene resulted in the smooth conversion to cycloheptadiene
23, whereas carrying out the nickel-catalyzed reaction of
substrate 20 in toluene at 110 °C provided direct access to 23
in 60% yield without requiring isolation of cyclopropane 21.
The divergent behavior of these two stereoisomeric starting
materials provides compelling evidence that a mechanism
involving divinylcyclopropane formation and rearrangement is
the operative pathway in [4+2+1] cycloadditions.
Mechanisms A and D (Scheme 1) cannot be distinguished
by the above experiments. However, failure to observe [4+2]
cycloaddition products seems unlikely if a structure related to
11 is involved in the reaction pathway.13 Furthermore, Wender
has previously demonstrated that phosphine promotion is
required to induce nickel-catalyzed [4+2] cycloadditions of
dienyne substrates. Additionally, 1,1-disubstituted dienes with
an E-internal alkene (related to structure 16, Scheme 4) failed
to undergo cyclization in the Wender study. These observations
suggest that fundamental differences exist between the [4+2]
and [4+2+1] cycloaddition pathways. Finally, our prior dem-
onstrations of ring contractions of nickel metallacycles related
to the 11 to 12 conversion (Scheme 1) required oxidative
promotion with molecular oxygen.15a On the basis of these
issues, mechanism A (alkyne metathesis, divinylcyclopropane
formation, [3,3] rearrangement) is perhaps most consistent with
the reactivity trends noted. The current study strongly suggests
that divinylcyclopropanes, irrespective of the precise mechanism
by which they are formed, are key intermediates in the nickel-
catalyzed [4+2+1] reaction.
A caveat in the above analysis is that installation of a
quaternary center could potentially result in a change of
mechanism. To avoid this significant structural change, we
prepared both E,E-diene 1g and E,Z-diene 20 (Scheme 5). This
comparison now allows two stereoisomers to be directly
analyzed. By the proposed mechanism A, E,E-diene 1g will
generate a divinylcyclopropane that lacks the A1,3 strain that
will slow the [3,3] rearrangement as depicted in conformation
9
J. AM. CHEM. SOC. VOL. 128, NO. 8, 2006 2613

A R T I C L E S
Ni and Montgomery
Conclusions
Acknowledgment. We acknowledge support for this research
from NIH grant GM57014. Professor Jin Cha is thanked for
many helpful discussions.
In summary, a new catalytic [4+2+1] cycloaddition of
dienynes and (trimethylsilyl)diazomethane has been developed.
A variety of carbocyclic and heterocyclic bicycles may be
produced in a stereospecific fashion. Through a stereochemical
analysis, strong evidence in favor of a mechanism involving
formation and [3,3] rearrangement of divinylcyclopropanes was
presented.
Supporting Information Available: Full experimental details
1
and copies of H NMR spectra of all new compounds (PDF).
This material is available free of charge via the Internet at
http://pubs.acs.org.
JA057741Q
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2614 J. AM. CHEM. SOC. VOL. 128, NO. 8, 2006