4042
M. D. Middleton, S. T. Diver / Tetrahedron Letters 46(2005) 4039–4043
1)
Fmoc
Fmoc
Fmoc
Pd(OAc)2, LiCl,
p-benzoquinone,
6 (5 mol %)
N
AcO
N
N
CH2Cl2, reflux
Ts
Ts
Ts
Me2CO,LiOAc,
HOAc
2)
CO2H
37%
Cl
32
30
31
53%
DBU,
MeCN
AcO
AcO
HN
Cl
N
Ts
65%
Ts
H
34
33
Scheme 3. Three-step synthesis ofindoline 34.
(Hoveyda complex) also proved effective in this proce-
dure (entry 3). Lowering the loading ofcatalyst 6 to
2.5 mol % proved to be unsuccessful, leading to a failure
ofthe initial tandem enyne/ring-closing metathesis (en-
try 4). The second procedure (B), does not require any
manipulation ofthe mixture of 10, 11: the mixture is di-
rectly treated with excess acrylic acid and additional cata-
lyst (entry 5). Dropping the equivalents of1,5-hexadiene
proved deleterious in the alkyne conversion step (entries
6 and 7), but this could be overcome by running the 1,5-
hexadiene–alkyne cross reaction at higher concentration
(entry 8). Without the addition ofmore catalyst, the tri-
ene 10 was still detected at the end ofthe reaction (entry
9). Catalyst 6 gave a good result (entry 10 vs entry 8)
and significantly, did not require a second charge ofcat-
alyst for the cross alkene metathesis step (entry 11). This
represents a highly efficient catalytic process where
the catalyst 6 has promoted a cross enyne metathesis,
a ring-closing alkene-alkene metathesis and a cross
alkene-alkene metathesis.
diene 31 was then subjected to Ba¨ckvallÕs conditions
for palladium-catalyzed 1,4-chloroacetoxylation to give
32.8 When treated with DBU in acetonitrile, the Fmoc
group was completely removed after 1 h to give amine
33. Chloride displacement occurred in situ to afford indo-
line 34 in 65% isolated yield.9
In summary, a rapid synthesis of1,5-hexadienes rfom
simple alkyne precursors has been developed. The
method is functional group-tolerant and is applicable
to a wide range ofalkynes. Furthermore, use ofthis
procedure enabled the rapid synthesis ofindoline 34 in
only three linear steps from alkyne 30. Current work is
focused on improving the selectivity of the initial cross
enyne metathesis step and in applying this methodology
in target-directed synthesis.
Acknowledgements
The authors thank Brian Peppers for helpful discussions
and Dr. Richard Fisher (Materia, Inc.) for catalyst sup-
port. We gratefully acknowledge the National Cancer
Institute (R01CA090603) for financial support of this
work.
The scope ofthe reaction was demonstrated for a range of
functionalized alkynes (Table 2). The procedure enabled
a variety of2-substituted 1,3-cyclohexadienes to be syn-
thesized and isolated in Ôone-potÕ from terminal alkynes.7
The potentially coordinating propargyl silyl ether 14
worked well (entry 1). Propargylic substitution did not
diminish the effectiveness ofthe procedure (entry 2).
The presence ofhomopropargylic heteroatoms was toler-
ated, but an extra 2.5 mol % catalyst was required in
order to push the second metathesis to completion (entries
4, 5, and 6). In general, nitrogen-containing functionality
has posed difficulties in both the alkyne and alkene reac-
tants, particularly ifthere is an NH bond. 1a It is therefore
noteworthy that homopropargylic amine derivatives
were found to participate in the two-step metathesis with-
out difficulty (entries 5 and 6). In addition to terminal
alkynes, the one-pot procedure worked equally well for
internal alkynes, giving access to 2,3-disubstituted 1,3-
cyclohexadienes (entries 7 and 8). Internal alkynes have
not been used in methylene-free metathesis.4
References and notes
1. For recent reviews see: (a) Diver, S. T.; Giessert, A.
J. Chem. Rev. 2004, 104, 1317–1382; (b) Poulsen, C. S.;
Madsen, R. Synthesis 2003, 1–18.
2. (a) Lee, H.-Y.; Kim, B. G.; Snapper, M. L. Org. Lett. 2003,
5, 1855–1858; (b) Giessert, A. J.; Diver, S. T. J. Org. Chem.
2005, 70, 1046–1049.
3. Smulik, J. A.; Diver, S. T. Tetrahedron Lett. 2001, 42, 171–
174.
4. Kulkarni, A. A.; Diver, S. T. J. Am. Chem. Soc. 2004, 126,
8110–8111.
5. Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R.
H. J. Am. Chem. Soc. 2003, 125, 11360–11370.
6. Dienes are known to react in cross alkene metathesis but
have not been categorized in GrubbsÕ model for selectivity
in cross metathesis. See for example, (a) Royer, F.; Vilain,
C.; Elkaiem, L.; Grimaud, L. Org. Lett. 2003, 5, 2007–2009;
(b) Wang, X.; Porco, J. A. J. Am. Chem. Soc. 2003, 125,
6040–6041; (c) Funk, T. W.; Efskind, J.; Grubbs, R. H.
Org. Lett. 2005, 7, 187–190.
The procedure was applied to the synthesis ofa ufnc-
tionalized tetrahydroquinoline ring system (Scheme 3).
Alkyne 30 was converted to 1,3-cyclohexadiene 31 using
the one-pot metathesis procedure in 37% yield. The