Stereoselective nickel-catalyzed [2+2+2] cycloaddition of enynes and arynes

Article abstract of DOI:10.1055/s-0030-1261171

Examples of stereoselective reactions of aryne intermediates are rare in the literature. A stereoselective nickel-catalyzed [2+2+2] cycloaddition of 1,6-enynes with aryne intermediates is reported. Excellent stereoselectivities were observed when a substi

Full text of DOI:10.1055/s-0030-1261171

LETTER
1987
Stereoselective Nickel-Catalyzed [2+2+2] Cycloaddition of Enynes and Arynes
[
2+2+2] Cycloadd
a
ition of Eny
v
ne
s
and
A
ry
i
nes d A. Candito, Mark Lautens*
Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario M5S 3H6, Canada
E-mail: mlautens@chem.utoronto.ca
Received 30 May 2011
success of 1,6-enynes in other metal-catalyzed cyclo-
Abstract: Examples of stereoselective reactions of aryne interme-
diates are rare in the literature. A stereoselective nickel-catalyzed
[2+2+2] cycloaddition of 1,6-enynes with aryne intermediates is re-
ported. Excellent stereoselectivities were observed when a substitu-
isomerizations such as Pauson–Khand-type reactions,
where predictable diastereoselectivity has been displayed
and enantioselective variants have been reported. We hy-
ent is adjacent to the olefin moiety resulting in trans- pothesized that the reaction course would proceed similar-
stereochemistry in the products. This reaction is capable of generat-
ly to other cycloisomerizations of enynes making this
ing much complexity from simple and readily available starting ma-
reaction an ideal candidate for the development of a
terials. Furthermore, the products possess a synthetic handle which
stereoselective reaction with an aryne because the stereo-
poises them for further modifications.
chemistry of the products would be set prior to reaction
with the aryne intermediate.
Key words: nickel-catalyzed, arynes, diastereoselective, 1,6-
enynes, [2+2+2] cycloaddition
We began by investigating the reaction of enyne 1a with
aryne precursor 2a (Table 1, entry 1). Optimization stud-
ies revealed that the amount of enyne relative to the aryne
The coordination and stabilization of aryne intermediates
precursor was a critical parameter. An excess of enyne
by transition metals has been known for some time and
was necessary in order to achieve higher yields. Alterna-
their complexes with titanium and zirconium have been
tively, an excess of the aryne precursor could be utilized,
utilized in synthesis as stoichiometric reagents.1
however, the yields were reduced due to competing side
With the advent of mild conditions for the formation of
reactions. It was also found that the use of various phos-
arynes there has been an increase in the number of reports
phine and NHC-based ligands slowed the desired reaction
in which aryne intermediates are participants in catalytic
leading to reduced yields. Common byproducts in these
manifolds.2 The most common transition metals utilized
in these cases have been nickel and palladium.
cases arose from dimerization and trimerization of the
aryne intermediate. Thus, ‘ligand-free conditions’ were
found to be optimal. A rather high catalyst loading was
found to be necessary in order to strike a balance between
the rate of aryne generation and the rate of catalytic turn-
over, otherwise side reactions of the aryne with itself and
with the enyne begin to compete with the desired path-
way. In an attempt to lower the concentration of the aryne
intermediate in solution, slow addition of the aryne was
attempted, and the use of more nonpolar co-solvents such
as THF were employed, however, these changes did not
provide any improvements.
We have had a longstanding interest in the chemistry of
arynes, particularly stereoselective reactions using arynes.
We have previously reported the diastereoselective aryne
Diels–Alder reactions of cyclic and acyclic dienes where
excellent selectivities could be obtained by utilizing a
chiral auxiliary based upon camphorsultam.3 In general,
reports of the use of arynes in stereoselective reactions
have been sparse. We became interested in the idea of a
stereoselective metal-catalyzed process involving arynes
as this would provide the potential for asymmetric cataly-
sis. We outline our efforts towards the development of a
stereoselective [2+2+2] cycloaddition of an enyne with an
aryne intermediate to generate interesting tricyclic scaf-
folds.
With optimal conditions in hand, a substrate study was un-
dertaken. Malonate-derived enynes reacted well under the
optimized conditions (Table 1, entries 1 and 2). Steric
bulk present on the olefin or alkyne slows the reaction
leading to poor conversions and none of the desired cy-
cloadducts (Table 1, entries 5 and 6).
The metal-catalyzed [2+2+2] cycloaddition of aryne in-
termediates has received considerable attention.4 In a
noteworthy contribution from Sato and co-workers it was
reported that when the [2+2+2] cycloaddition of a 1,6-di-
ene and an aryne was attempted, none of the desired cy-
cloadducts was formed; instead products arising from the
reaction of two aryne units and one olefin were ob-
served.4c We elected to investigate the analogous cycliza-
tion of a 1,6-enyne substrate. We were aware of the
The reaction of enyne 1c with a nitrogen heteroatom pro-
ceeded in excellent yield to provide 3c. This encouraging
result prompted us to reduce the catalyst loading to 10
mol%, however, a dramatic decrease in yield was ob-
served (Table 1, entry 4). We then went on to investigate
the reactivity of different aryne precursors. Many silyl tri-
flate precursors are now commercially available or can be
prepared in a straightforward manner. Unfortunately, the
aryne precursors which were investigated provide inferior
results relative to 2a.
SYNLETT 2011, No. 14, pp 1987–1992
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x
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Advanced online publication: 10.08.2011
DOI: 10.1055/s-0030-1261171; Art ID: S04911ST
© Georg Thieme Verlag Stuttgart · New York

1988
D. A. Candito, M. Lautens
LETTER
Table 1 Scope of Nickel-Catalyzed [2+2+2] Cycloadditiona
R2
R1
R2
R1
Ni(cod)2 (20 mol%)
CsF (3 equiv)
R3
R4
R3
TMS
+
X
X
R5
MeCN (0.05 M), 24 h
R4
TfO
R5
1
2
3
Entry
1
Enyne
Precursor
Product
Yield (%)b
Et
Et
TMS
EtO2C
EtO2C
73
TfO
EtO2C
EtO2C
2a
1a
3a
TMS
TMS
EtO2C
EtO2C
2
2a
50
EtO2C
EtO2C
1b
3b
Et
Et
3
4
2a
2a
89
TsN
TsN
1c
1c
3c
3c
47c
Ph
Et
Ph
EtO2C
EtO2C
d
5
6
2a
–
EtO2C
EtO2C
1d
3d
Et
EtO2C
EtO2C
EtO2C
EtO2C
d,e
2a
–
Me
H
Me
1e
3e
Et
TMS
7
8
1c
38
TsN
TfO
2b
3f
OMe
Et
Et
OMe
39f
(1.5:1)
TMS
1c
1c
TsN
TfO
3g
2c
TMS
F
F
F
F
9
36
TsN
TfO
2d
3h
Synlett 2011, No. 14, 1987–1992 © Thieme Stuttgart · New York

LETTER
[2+2+2] Cycloaddition of Enynes and Arynes
1989
Table 1 Scope of Nickel-Catalyzed [2+2+2] Cycloadditiona (continued)
R2
R1
R2
R1
R5
Ni(cod)2 (20 mol%)
R3
R4
CsF (3 equiv)
R3
R4
TMS
TfO
+
X
X
MeCN (0.05 M), 24 h
R5
1
2
3
Entry
10
Enyne
Precursor
Product
Yield (%)b
63
Et
TMS
O
O
O
1c
TsN
TfO
O
2e
3i
Et
TMS
TfO
Cl
d
TsN
11
1c
–
N
N
Cl
2f
3j
a Silyl triflate (1 equiv, 0.1 mmol), enyne (2 equiv), Ni(cod)2 (20 mol%), CsF (3 equiv), MeCN (0.05 M), 60 °C, 24 h.
b Isolated yields.
c Ni(cod)2 (10 mol%).
d Cycloadduct not detected.
e Silyl triflate (2 equiv), enyne (1 equiv, 0.1 mmol).
f Combined yield, measured by NMR of the crude reaction mixture, major isomer shown.
In the cases of 2b, 2d, and 2e the aryne intermediates are temperature to room temperature. In this case there was a
symmetrical and the substituents are located at distances slight preference for the methoxy group to be on the same
which should not dramatically affect the nature of the in- side as the ethyl group. The reaction of silyl triflate 2f did
plane aryne triple bond, thus one would predict similar be- not proceed as desired instead complete consumption of
havior as 2a. It is known that substituents on arynes have the aryne precursor was observed without the formation of
an effect on their stability and lifetime and these subtle the cycloadduct.
changes may be responsible for the discrepency in behav-
ior.5 In the case of aryne precursor 2c poor regioselectivity
was observed which did not improve upon lowering the
Table 2 Stereoselective Nickel-Catalyzed [2+2+2] Cycloadditiona
R1
R3
R3
R1
Ni(cod)2 (20 mol%)
CsF (3 equiv)
TMS
TfO
X
+
X
MeCN (0.05 M), 24 h
R2
R2
3
1
2a
Entry
Enyne
Product
Yield (%)b
drc
Et
Et
O
O
1
58
>20:1
H
MeO
MeO
1f
3k
Synlett 2011, No. 14, 1987–1992 © Thieme Stuttgart · New York

1990
D. A. Candito, M. Lautens
LETTER
Table 2 Stereoselective Nickel-Catalyzed [2+2+2] Cycloadditiona (continued)
R1
R3
R3
R1
Ni(cod)2 (20 mol%)
TMS
CsF (3 equiv)
X
+
X
MeCN (0.05 M), 24 h
TfO
R2
R2
3
1
2a
Entry
2
Enyne
Product
Yield (%)b
drc
Et
Et
O
61
>20:1
O
H
i-Pr
i-Pr
1g
3l
Et
Et
O
O
3
35
>20:1
H
6
6
1h
3m
Et
Et
TsN
TsN
4
37d
>20:1
H
MeO
MeO
1i
3n
Et
O
MeO
52e,f
–
O
Et
5
MeO
1j
3o
n-Bu
n-Bu
100d
3:1
H
6
O
O
H
1k
3p
a Silyl triflate (2 equiv), enyne (1 equiv, 0.1 mmol), Ni(cod)2 (20 mol%), CsF (3 equiv), MeCN (0.05 M), r.t., 24 h.
b Isolated yields.
c Combined yield, ratio taken by crude NMR, major isomer shown.
d Silyl triflate (1 equiv, 0.1 mmol), enyne (2 equiv), 60 °C, 24 h.
e Silyl triflate (1 equiv, 0.1 mmol), enyne (2 equiv), r.t., 24 h.
f Cycloadduct not detected.
We then wanted to address whether substrate control determined to be trans for substrate 3n using ROESY 2D
could be exerted (Table 2) and found that when a substit- NMR and 3k–m were assigned by analogy. This stereo-
uent is present near the olefin excellent diastereoselectiv- chemistry is in line with that reported for the Pauson–
ities could be obtained. The stereochemistry was Khand-type reaction of 1,6-enynes.6
Synlett 2011, No. 14, 1987–1992 © Thieme Stuttgart · New York

LETTER
[2+2+2] Cycloaddition of Enynes and Arynes
1991
higher-energy path
In the case of enyne 1j we wanted to evaluate the effect of
the distance of the stereocenter from olefin, however, it
was found that cyclization to form the desired adduct did
not take place, rather, cyclization took place with two
aryne units and the alkyne. This maybe due to a slower ox-
idative cyclization of the enyne due to the greater entropic
barrier, vide infra. In the case of enyne 1k, cyclization
proceeded in excellent yield but poor stereoselectivity
was observed (Table 2, entry 6).
Me
Me
NiLn
Ph
Ph
NiLn
H
H
H
H
Me
Ph
+
Me
NiLn
H
Me
NiLn
H
Ph
NiLn
Ph
In order to explain the formation of the observed products
we propose a mechanism involving initial coordination of
the enyne to give a nickel(0) complex such as 1 then oxi-
dative cyclization can take place to give metallacycle 2.
At this point coordination of the aryne intermediate and
insertion into one of the carbon–metal bonds can take
place generating 4 which reductively eliminates to pro-
vide the final product (Scheme 1).
H
lower-energy path
H
Scheme 2 Stereochemical model
readily available starting materials. Furthermore, the
products posses an olefin which can be a useful synthetic
handle for further transformations. Future work will focus
on improving this useful reaction and exploring other
strategies for stereoselective synthesis using arynes.
R1
R1
X
R2
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
X
H
R2
NiLn
Acknowledgment
R1
We thank NSERC (Canada), Merck-Frosst (IRC), and the Univer-
sity of Toronto for support of these studies. D. A. C. would like to
thank Dr. Robert Webster for providing inspiration for this study.
R1
X
X
NiLn
NiLn
H
X
R2
1
R2
4
References
R1
NiLn
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2
H
R2
CsF
TMS
TfO
TMSF + CsOTf
Scheme 1 Proposed mechanism
The stereochemistry is set at the stage of intermediate 2.
This trans stereochemistry is common in the metal-
catalyzed cycloisomerization of 1,6-enynes and can be ra-
tionalized by the model illustrated in Scheme 2.6 Com-
plexation yields two diastereomeric complexes which can
go on to cyclize in an irreversible step. The transition state
leading to the trans product minimizes 1,3-allylic strain
making the trans product favored.
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Lautens, M. J. Am. Chem. Soc. 2005, 127, 15028.
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selectivities can be obtained. It is noteworthy that com-
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LETTER
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Synlett 2011, No. 14, 1987–1992 © Thieme Stuttgart · New York

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