[4+2] cycloaddition reaction of cyclic alkyne-{Co2(CO) 6} complexes with dienes

Article abstract of DOI:10.1002/anie.201002683

A general protocol for the title transformation has been achieved and is applicable to a wide range of acyclic 1,3-dienes and cyclicalkyne-{Co ₂(CO)₆} complexes leading to various types of benzannulated medium-sized cyclic compounds after oxidative work up (see scheme; DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone). Interestingly, the [4+2] cycloaddition proceeded preferentially over the Pauson-Khand reaction.

Full text of DOI:10.1002/anie.201002683

Communications
DOI: 10.1002/anie.201002683
Cycloaddition Reactions
[4+2] Cycloaddition Reaction of Cyclic Alkyne–{Co2(CO)6}
Complexes with Dienes**
Nobuharu Iwasawa,* Isao Ooi, Kennichi Inaba, and Jun Takaya
Table 1: Optimization of reaction conditions.[a]
Utility of alkyne—{Co2(CO)6} complexes in synthetic organic
chemistry is widely recognized, however, it is mostly limited
to the Pauson–Khand reaction[1] and the Nicholas reaction.[2]
There have been few reported examples of [4+2] cycloaddi-
tion reaction of alkyne—{Co2(CO)6} complexes,[3,4] partly
because the Pauson–Khand reaction proceeds even when
dienes were employed as a reactant.[5] Such a reaction would
make it possible to annulate a six-membered ring onto
cycloalkynes such as cycloheptynes or cyclooctynes, which are
usually inaccessible owing to their highly strained bond
angles. Herein, we report a general protocol for the
Entry
Reaction conditions
Yield [%]
[4+2] cycloaddition reaction of cyclic alkyne—{Co2(CO)6}
complexes[6] with dienes to give benzene derivatives after
oxidation. This approach is another utilization of alkyne—
{Co2(CO)6} complexes for carbocycle formation.
3
4
1[b]
2[d]
3[d]
4[d]
5[d]
toluene, 608C, 62 h
608C, 21 h
CH3CN (10 equiv), toluene, 608C, 11 h
NMO (10 equiv), toluene, RT, 1 h
47[c]
56
6
ca. 6
n.d.
74
17
The reaction conditions were optimized for the reaction of
cycloheptynone—{Co2(CO)6} 1 and 2,3-dimethyl-1,3-buta-
diene (Table 1). Heating a mixture of these reactants in
toluene at 608C for 62 hours gave 47% yield of a mixture of
the dihydrobenzene derivative 2 and its oxidized, benzene
derivative 3 along with 6% yield of the Pauson–Khand
product 4 (Table 1, entry 1). Direct treatment of the reaction
mixture with DDQ cleanly converted the products into the
benzene derivative 3 in good yield (Table 1, entry 2). Use of
dimethylbutadiene as the solvent somewhat improved the
yield of the product, and furthermore, addition of about
10 equivalents of CH3CN to the reaction in toluene shortened
the reaction time and increased the yield of the product
considerably (Table 1, entry 3).[7] On the other hand, com-
monly employed promoters for the Pauson–Khand reaction
such as NMO and O = PPh3 were not effective (Table 1,
entries 4 and 5). Thus, 3 was obtained in 74% yield by heating
a mixture of 1 and an excess amount of dimethylbutadiene in
toluene in the presence of 10 equivalents of CH3CN at 608C
for 11 hours followed by oxidation of the crude products with
DDQ. In all cases, formation of a small amount (ca. 5%) of
Pauson–Khand product was observed.
2[e]
O PPh3 (10 equiv), toluene, 608C, 10 h
46[e]
ca. 7
=
[a] All reactions were performed with 60 equivalents of dimethylbuta-
diene. [b] Work-up was done under air. [c] Obtained as a mixture of 2 and
3 (2/3=1:2). [d] Oxidized with 3 equivalents of DDQ in toluene at room
temperature for 3 h. [e] Based on 1H NMR spectroscopy. n.d.=not
determined, NMO=4-methylmorpholine N-oxide.
consumption of 1 in toluene at 608C. For example, after
10 hours of heating at 608C, the amount of complex 1
recovered was as follows: 87% (without the diene in toluene),
65% (with the diene in toluene), 27% (without the diene in
toluene/CH3CN (20:1); 10 equiv of CH3CN based on 1), 0%
(with the diene in toluene/CH3CN (20:1); 10 equiv of CH3CN
based on 1).[8] We believe that CH3CN would facilitate
liberation of CO as a Lewis base,[9] and p complexation of the
diene with the coordinatively unsaturated alkyne–Co(CO)5
complex generated under the reaction conditions plays an
important role in promoting the reaction. From these results
along with the reversal of regioselectivity of the reaction with
siloxydiene (as will be described in Table 2, entry 6),[10] it is
likely that liberation of a noncomplexed cycloheptynone
derivative through decomposition of the cyclic alkyne—
{Co2(CO)6} complex 1 did not occur as the major reaction
pathway under the reaction conditions, and the reaction
proceeded through the Pauson–Khand-like pathway as shown
in Scheme 1. Thus, by heating the complex at 608C, a
coordinatively unsaturated cobalt species was generated and
the diene coordinated to the cobalt (B), followed by insertion
Notably, not only the addition of CH3CN but also the
presence of the diene considerably accelerated the rate of
[*] Prof. Dr. N. Iwasawa, I. Ooi, Dr. K. Inaba, Dr. J. Takaya
Department of Chemistry, Tokyo Institute of Technology
2-12-1 E1-2, O-okayama, Meguro-ku, Tokyo 152-8551 (Japan)
Fax: (+81) 3-5734-2931
À
of the diene into the Co C bond to give metallacyclic
E-mail: niwasawa@chem.titech.ac.jp
intermediate C. Instead of undergoing CO insertion leading
to a cyclopentenone derivative (Pauson–Khand product), this
intermediate undergoes a 1,3-allylic shift to give another
metallacyclic intermediate D,[11] which finally underwent
reductive elimination to give the product E.
[**] This research was supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports, Science,
and Technology of Japan.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201002683.
7534
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 7534 –7537

Angewandte
Chemie
this reaction and gave nonsubstituted benzan-
nulated product in reasonable yield (Table 2,
entry 4). Other acyclic dienes such as 1,3-disub-
stituted diene was employed for this reaction,
although the yield decreased (Table 2, entry 5).
Importantly a siloxy diene also reacted and gave
a phenol derivative in a regioselective manner
with acceptable yield (Table 2, entry 6). Inter-
estingly, the regioselectivity of the reaction was
contrary to the one expected for the Diels–
Alder-type reaction employing a,b-unsaturated
ketones and 2-siloxydienes. The selectivity could
be explained by assuming that the terminally
nonsubstituted side of the diene first inserts into
Scheme 1. Proposed reaction mechanism.
À
the C Co bond neighboring the carbonyl
group.[12,13]
Next, we examined the generality of the reaction and we
first examined various diene derivatives. As shown in Table 2,
the reaction is applicable to acyclic dienes, in particular, 2-
substituted or 2,3-disubstituted dienes and gave the corre-
sponding fused benzene derivatives in good yields after DDQ
oxidation. Isoprene gave a 3:2 mixture of the regioisomers
(Table 2, entry 1). Exocyclic dienes 8 and 10 gave the
corresponding tricyclic products 9 and 11 in good yields
(Table 2, entries 2 and 3). Butadiene itself was employed for
Then we examined the generality of cyclic alkyne—
{Co2(CO)6} complexes employing 2,3-dimethylbutadiene as
the diene component. As summarized in Table 3, this reaction
is general for a wide variety of cyclic alkyne—{Co2(CO)6}
complexes. Seven- to nine-membered alkyne—{Co2(CO)6}
complexes reacted smoothly and the corresponding benzan-
nulated products were obtained in good yields (Table 3,
entries 1–3). With respect to the functional groups neighbor-
ing the alkyne—{Co2(CO)6} moiety, somewhat higher reac-
tivity was observed for the carbon-
Table 2: Generality of diene derivatives (OR=OSiiPr3).[a,b]
yl group (Table 3, entry 4) and the
reaction proceeded without prob-
lem for the acetoxy group, silyloxy
group (Table 3, entries 5 and 6),
and even the simple methylene
group (Table 3, entry 10). Cyclic
lactones 30 and 32 could also be
employed for this reaction
(Table 3, entries 7 and 8). The
reaction of 34 gave a product
related to taxol. (Table 3, entry 9).
Notably, cycloheptynes or cyclo-
octynes are usually unstable, and
thus, the present reaction would be
an appropriate substitute for the
Diels–Alder of cycloalkynes, which
are not available under the stan-
dard conditions.[14]
In summary, we have suc-
ceeded in realizing a [4+2] cyclo-
addition reaction of cyclic alkyne—
{Co2(CO)6} complexes with acyclic
dienes. As this reaction is applica-
ble to cyclic alkyne—{Co2(CO)6}
complexes in general and various
methods for the preparation of
cyclic alkyne—{Co2(CO)6} com-
plexes are now available, this
approach should afford a concise
method for the preparation of a
variety of benzannulated polycyc-
lic compounds.
Entry
Diene
T [8C]
t [h]
Products
Yield [%]
1[c]
5 (30 equiv)
60
10.4
6
7
65
2
3
8 (10 equiv), n=1
10 (30 equiv), n=2
110
60
3
12
9, n=1
11, n=2
70
71
4[c]
5[c]
6[c]
12 (370 equiv)
14 (10 equiv)
16 (5 equiv)
60
110
110
9.3
13
15
17
47
41
49
2
5
[a] All reactions were performed at 0.1m in toluene with substrate 1 and 10 equivalents of CH3CN.
[b] R=TIPS. [c] The crude product was oxidized with 3 equivalents of DDQ in toluene for 3 hours.
[d] Obtained as a mixture of 6 and 7 (6/7=3:2). DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone,
TIPS=triisopropylsilyl.
Angew. Chem. Int. Ed. 2010, 49, 7534 –7537
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
7535

Communications
Table 3: Generality of cyclic alkyne—{Co2(CO)6} complexes.[a]
Castells, Chem. Soc. Rev. 2004, 33,
32 – 42; g) S. E. Gibson, N. Main-
olfi, Angew. Chem. 2005, 117,
3082 – 3097; Angew. Chem. Int.
Ed. 2005, 44, 3022 – 3037.
Entry
1
Substrate
T [8C] t [h]
Product
Yield [%]
45
18
60
23
19
[2] a) K. M. Nicholas, Acc. Chem. Res.
1987, 20, 207 – 214; b) B. J. Teobald,
Tetrahedron 2002, 58, 4133 – 4170.
[3] To our knowledge, two papers
describe [4+2] cycloaddition reac-
tion of alkyne—{Co2(CO)6} com-
plexes with dienes. The first one by
Khand, Pauson, et al. describes the
reaction of alkyne—{Co2(CO)6}
complexes and 1,3-cyclohexadiene
to give consecutive [4+2] and
[2+2+1] cycloadducts. The second
one by Chung and co-workers
2
3
20
22
60
60
27
32
21
23
81
86
4
24
110
3.5 25
77
5
6
26, R=Ac
28, R=TBS
60
60
14
20
27
29
85
52
describes
a
{Co2(CO)8}-catalyzed
Pauson–Khand
intramolecular
reaction of diene-ynes that accom-
panied [4+2] cycloadditions, how-
ever, it seems that the reaction
7
8
30, n=1
32, n=2
110
60
2
15
31
33
75
76
proceeded
thermally;
a) I. U.
Khand, P. L. Pauson, M. J. A.
Habib, J. Chem. Res. Synop. 1978,
346 – 347; b) K. H. Park, S. Y. Choi,
S. Y. Kim, Y. K. Chung, Synlett
2006, 527 – 532.
9
34
36
60
60
23
25
35
37
60
88
10
[4] For [2+2+2] cycloaddition reac-
tions
including
alkyne—
[a] All reactions were performed at 0.1m in toluene with 30 equivalents of dimethylbutadiene and
10 equivalents of CH3CN. The crude product was oxidized with 3 equivalents of DDQ in toluene for
3 hours. TBS=tert-butyldimethylsilyl. Bz=benzoyl.
{Co2(CO)6} complexes as a compo-
nent, see: a) A. Goswami, C.-J.
Maier, H. Pritzkow, W. Siebert,
Eur. J. Inorg. Chem. 2004, 2635 –
2645; b) V. Gandon, D. Leca, T.
Aechtner, K. P. C. Vollhardt, M. Malacria, C. Aubert, Org. Lett.
2004, 6, 3405 – 3407.
[5] I. U. Khand, P. L. Pauson, M. J. A. Habib, J. Chem. Res.
Miniprint 1978, 4401 – 4417.
Experimental Section
Typical procedure (synthesis of 3): A dried two-necked flask with a
magnetic stirring bar was charged with alkyne—{Co2(CO)6} complex
1 (38.2 mg, 0.064 mmol), toluene (640 mL), 2,3-dimethylbutadiene
(436 mL, 3.86 mmol), acetonitrile (33.6 mL, 0.643 mmol) and the
mixture was heated at 608C for 11 h. The reaction mixture was
[6] Our reports on the preparation of cyclic alkyne—{Co2(CO)6}
complexes: a) N. Iwasawa, K. Inaba, S. Nakayama, M. Aoki,
Angew. Chem. 2005, 117, 7613 – 7616; Angew. Chem. Int. Ed.
2005, 44, 7447 – 7450; b) K. Inaba, J. Takaya, N. Iwasawa, Chem.
Lett. 2007, 36, 474 – 475.
[7] For examples of promoters of the Pauson–Khand reaction, see:
a) D. C. Billington, I. M. Helps, P. L. Pauson, W. Thomson, D.
Willison, J. Organomet. Chem. 1988, 354, 233 – 242; b) S.
Shambayai, W. E. Crowe, S. L. Schreiber, Tetrahedron Lett.
1990, 31, 5289 – 5292; c) T. Sugihara, M. Yamada, H. Ban, M.
Yamaguchi, C. Kaneko, Angew. Chem. 1997, 109, 2884 – 2886;
Angew. Chem. Int. Ed. Engl. 1997, 36, 2801 – 2804; d) C.
Perez del Valle, A. Milet, Y. Gimbert, A. E. Greene, Angew.
Chem. 2005, 117, 5863 – 5865; Angew. Chem. Int. Ed. 2005, 44,
5717 – 5719, and references therein.
[8] For the use of CH3CN as an additive in the Pauson–Khand
reaction, see: a) Y. K. Chung, B. Y. Lee, N. Jeong, M. Hudecek,
P. L. Pauson, Organometallics 1993, 12, 220 – 223; for the Lewis
base promoted Pauson–Khand reaction, see: b) T. Sugihara, M.
Yamaguchi, M. Nishizawa, Chem. Eur. J. 2001, 7, 1589 – 1595.
[9] For details, see the Supporting Information. We have not been
successful in obtaining any obvious decomposition products
derived from 1 when the reaction was carried out in the absence
of the diene.
filtered through
a column of silica gel, and the filtrate was
concentrated under reduced pressure. To the residue in toluene
(2 mL) was added DDQ (43.8 mg, 0.193 mmol) and the mixture was
stirred for 3 h at RT. Then the reaction mixture was concentrated
under reduced pressure, and the residue was purified by PTLC (ethyl
acetate/hexanes = 1:9) to give the compound 3 (18.4 mg, 0.047 mmol)
in 74% yield.
Received: May 4, 2010
Revised: July 11, 2010
Published online: September 3, 2010
Keywords: alkynes · cobalt · cycloaddition · 1,3-dienes ·
.
medium-sized rings
[1] a) I. U. Khand, G. R. Knox, P. L. Pauson, W. E. Watts, M. I.
Foreman, J. Chem. Soc. Perkin Trans. 1 1973, 977 – 981; b) N. E.
Schore, Org. React. 1991, 40, 1; c) K. M. Brummond, J. L. Kent,
Tetrahedron 2000, 56, 3263 – 3283; d) S. E. Gibson (nꢀe Tho-
mas), A. Stevenazzi, Angew. Chem. 2003, 115, 1844 – 1854;
Angew. Chem. Int. Ed. 2003, 42, 1800 – 1810; e) L. V. R. Bonaga,
M. E. Krafft, Tetrahedron 2004, 60, 9795 – 9833; f) J. Blanco-
Urgoiti, L. Aꢁorbe, L. Pꢀrez-Serrano, G. Domꢂnguez, J. Pꢀrez-
[10] The similar activity of a-oxy and a-methylene substrates
(Table 3, entries 5, 6; and 10) compared to that of the a-keto
substrate also supports this mechanism.
7536
www.angewandte.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 7534 –7537

Angewandte
Chemie
[11] It is likely that a p-allyl intermediate actually exists and retards
insertion of CO.
[12] The regioselectivity of the Pauson–Khand reaction using alky-
nones or alkynoates as an alkyne component has been examined
both experimentally and theoretically to reveal that insertion
the reaction did not proceed efficiently and the yield was not
very good. For example, the following reaction did not proceed
even at 1008C without complexation, but the corresponding
alkyne—{Co2(CO)6} complex gave benzene derivative in mod-
erate yield.
À
reaction occurs at the C Co bond adjacent to the carbonyl group
first, see: a) T. J. M. de Bruin, C. Michel, K. Vekey, A. E.
Greene, Y. Gimbert, A. Milet, J. Organomet. Chem. 2006, 691,
4281; b) F. Robert, A. Milet, Y. Gimbert, D. Konya, A. E.
Greene, J. Am. Chem. Soc. 2001, 123, 5396 – 5400; c) M. E.
Krafft, R. H. Romero, J. L. Scott, J. Org. Chem. 1992, 57, 5277 –
5278; d) T. R. Hoye, A. J. Suriano, J. Org. Chem. 1993, 58, 1659 –
1660.
[13] This reversal of regioselectivity was also observed in the reaction
of acyclic alkyne—{Co2(CO)6} complex although the yield was
low.
[14] This [4+2] cycloaddition reaction of alkyne—{Co2(CO)6} com-
plexes with dienes is applicable to acyclic substrates, however,
Angew. Chem. Int. Ed. 2010, 49, 7534 –7537
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
7537