Cobalt(I)-catalyzed neutral Diels-Alder reactions of oxygen-functionalized acyclic 1,3-dienes with alkynes

Article abstract of DOI:10.1055/s-2002-32592

The cobalt-catalyzed Diels-Alder reaction of alkoxy-substituted 1,3-butadienes with terminal and internal alkynes is described. While the reaction of 1-alkoxy derivatives gave the aromatic hydrocarbons upon elimination of alcohol from the alkoxy-substituted dihydroaromatic intermediates, the reactions with 2-alkoxy derivatives generated stable dihydroaromatic enol ethers in good to excellent chemical yields and good to high regioselectivities for unsymmetrical starting materials. The enol ethers can be easily hydrolysed to the corresponding β,γ-unsaturated ketones in a one pot reaction sequence or used in cyclopropanation or other subsequent chemical transformations.

Full text of DOI:10.1055/s-2002-32592

LETTER
1081
Cobalt(I)-catalyzed Neutral Diels–Alder Reactions of Oxygen-functionalized
Acyclic 1,3-Dienes with Alkynes
C
obalt(I)-catalyze
e
d
N
eutral
D
r
iels–Ald
h
er Reactionsard Hilt,* Konstantin I. Smolko, Bettina V. Lotsch
Department Chemie, Ludwig-Maximilians-Universität München, Butenandtstrasse 5-13, 81377 München, Germany
E-mail: gerhard.hilt@cup.uni-muenchen.de
Received 18 April 2002
Abstract: The cobalt-catalyzed Diels–Alder reaction of alkoxy-
substituted 1,3-butadienes with terminal and internal alkynes is de-
scribed. While the reaction of 1-alkoxy derivatives gave the aromat-
ic hydrocarbons upon elimination of alcohol from the alkoxy-
substituted dihydroaromatic intermediates, the reactions with 2-
alkoxy derivatives generated stable dihydroaromatic enol ethers in
good to excellent chemical yields and good to high regioselectivi-
ties for unsymmetrical starting materials. The enol ethers can be
easily hydrolysed to the corresponding , -unsaturated ketones in a
one pot reaction sequence or used in cyclopropanation or other sub-
sequent chemical transformations.
R1
R1
R2
R1
R2
CoI
- R3OH
OR3
R2
OR3
Scheme 1
detected and isolated in good chemical yields (see
Scheme 1).
Key words: cobalt, neutral Diels–Alder reaction, alkyne, 1,3-di-
Since the synthesis of the 1-trimethylsilyl derivative is
easier than the corresponding methyl enol ether and the
yields for the generation of biphenyl (Table 1, entries 1, 2)
were not significantly lower, subsequent reactions were
conducted with the TMS derivative.5 Besides terminal
alkynes, internal alkynes and 1,3-diynes could also be re-
acted with the silyloxy-substituted butadiene derivative
under mild conditions (generally 5–10 mol% Co-catalyst,
CH2Cl2, r.t., 0.5–16 h)6 to yield the corresponding mono-
and disubstituted aromatic compounds. We also found
that for the reaction with a diyne substrate (entry 5), even
with an excess of the diene and at elevated temperatures
(60 °C in a sealed tube) no conversion to the desired tet-
raphenyl derivative could be detected.
ene, enol ether
Transition metal catalyzed cycloadditions have been in-
vestigated for a long time and important contributions
have been made in the field of Lewis-acid promoted cy-
cloaddition reactions.1 Especially successful are applica-
tions of Lewis-acids in the Diels–Alder reaction with
normal electronic demand, while in Diels–Alder reactions
with neutral electronic demand only few contributions can
be found in the literature.2 In particular, the use of low va-
lent cobalt-complexes for such neutral Diels–Alder reac-
tion has been described by us and other research groups in
the past.2,3
Herein we describe our investigations into the use of oxy-
gen-functionalized 1,3-dienes as substrates for the co-
balt(I)-catalyzed Diels–Alder type reaction with terminal
and internal alkynes. For the present investigation, we
used a mixture of CoBr2(dppe)/ZnI2/Bu4NBH4 as catalyst
system.4
Table 1 Cobalt(I)-catalyzed Neutral Diels–Alder Reactions of 1-
Alkoxy-substituted Butadienes with Various Alkynes
Entry R1 R2
R3
Product
Yield (%)
73
1
H
Ph
Me
Ph
Ph
1-Alkoxy-functionalized 1,3-Butadienes
2
H
Ph
TMS
63
63
When 1-methoxy-1,3-butadiene (R3 = Me) or 1-trime-
thylsilyloxy-1,3-butadiene (R3 = SiMe3) was used as di-
ene in the cobalt(I)-catalyzed neutral Diels–Alder reaction
with alkynes, the 1:1 adduct was formed in quantitative
conversion (GC) under mild reaction conditions. Howev-
er, the dihydroaromatic intermediates could not be ob-
served, and instead the corresponding aromatic products,
which are formed upon in situ elimination of R3OH, were
3
H
C(CH3)=CH2 TMS
4
5
Et Et
TMS
TMS
72
91
Et
Et
Ph –C C–Ph
Ph
Synlett 2002, No. 7, 01 07 2002. Article Identifier:
1437-2096,E;2002,0,07,1081,1084,ftx,en;G10302ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214
Ph

1082
G. Hilt et al.
LETTER
It should be noted that terminal alkynes can easily be Table 2 Cobalt(I)-catalyzed Neutral Diels–Alder Reactions of 2-
Alkoxy-substituted Butadienes with Various Alkynes7
deprotonated and converted to the corresponding 1-deute-
ro compounds, which will in turn generate the regioselec-
En- R1
try
R2
H
R3
Product
Yield
(%)
tively labelled arene derivative in a one step reaction.
These and other isotope labelled starting materials might
be useful for mechanistic investigations where regioselec-
tively labelled phenyl derivatives are required.
Ph
1
Ph
Me
43
MeO
2
Ph
H
H
TMS
TMS
94
Ph
2-Alkoxy-functionalized 1,3-Butadienes
TMSO
The cobalt-catalyzed Diels–Alder reaction of the regioi-
someric 2-alkoxy-substituted 1,3-butadienes generates
1,4-cyclohexadiene enol ether derivatives, which are
much more stable towards elimination of R3OH than the
1-alkoxy-substituted products described above. Further-
more, from terminal alkynes (R2 = H) and 2-alkoxy-buta-
dienes, the products with the substituents R1 and OR3 in a
para-relation are formed predominantly (generally
>95:<5). While for 2-methoxy-1,3-butadiene (R3 = Me)
the reactions are somewhat slower compared to corre-
sponding transformations with the 2-trimethylsilyloxy de-
rivative (R3 = TMS), the regioselectivity in favour of the
para-product is enhanced when the more bulky TMS
ether is used (Table 2, entries 1, 2). In the reactions with
the TMS derivative, the para-products are formed regi-
oselectively with only traces of the second regioisomer
(see Scheme 2).
3
4
C(CH3)
=CH2
92
83
TMSO
cyclo-
hexenyl
H
TMS
TMS
TMSO
TMSO
TMSO
5
6
Et
Et
87
91
Et
Et
CH2OMe CH2OMe TMS
CH2OMe
CH2OMe
7
8
9
Ph
CH3
CH3
Me
57
91
Ph
R1
OR3
R1
R2
R1
R2
MeO
CH3
Ph
CoI
OR3
+
Ph
TMS
OR3
R2
TMSO
CH3
TMS
Ph
TMS
TMS
TMS
87a
92
94
TMS
Scheme 2
TMSO
TMSO
Ph
For symmetrical internal alkynes (entries 5, 6), the reac-
tion generates tri-substituted dihydroaromatic compounds
in good yields. However, in the case of 3-hexyne as dieno-
phile, 12% of 1,2-diethylbenzene was also detected, gen-
erated by elimination of TMSOH from the dihydro-
aromatic compound, whereas in the reaction with 1,4-
dimethoxy-2-butyne as dienophile a similar elimination
was not observed.
10 TMS
11 TMS
n-Bu
TMS
TMS
–C C–
TMS
TMSO
TMS
a The reaction was performed using 10 mol% of cobalt-catalyst at 40
°C for 16 h.
The regioselectivity for unsymmetrical internal alkynes
depends to a great degree on the steric demand of the sub-
stituents R1 and R2 as well as on the steric demand of R3.
A regioisomeric mixture is formed with 1-phenylpropyne
(entry 7) in a 70:30 ratio when the 2-methoxy-butadiene
derivative is used, whereas in the case of the more steri-
cally hindered 2-silyloxybutadiene derivative an 85:15 ra-
tio is observed. When the steric demand in R1 was
increased (entry 9), the regioselectivity dropped to an
80:20 ratio, with the sterically more bulky TMS-group
placed in a para-relation to the enol ether. When the steric
demand of R2 was then diminished to an alkyl chain (entry
10) or an alkyne substituent (entry 11), the given products
were formed exclusively with only traces of the other re-
gioisomer. These findings for the regioselectivity are in
agreement with other results described previously for this
catalyst system.3b,c
The reaction products can be isolated in good chemical
yields, but are, as expected, somewhat sensitive towards
hydrolysis and oxidative conditions. Therefore, when hy-
drolysed in situ (Scheme 3), the , -unsaturated ketones
can be isolated in a one pot procedure. Some examples are
given in Table 3.
Synlett 2002, No. 7, 1081–1084 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Cobalt(I)-catalyzed Neutral Diels–Alder Reactions
1083
Thereby, a whole range of interesting building blocks can
be generated from easily accessible starting materials un-
der mild reaction conditions in an easy predictable regio-
chemical fashion in good chemical yields.
R1
R1
R2
OR3
1. CoI
2. H+
O
R2
Scheme 3
Dialkoxy-functionalized 1,3-Butadienes
Table 3 Cobalt(I)-catalyzed Diels–Alder Reactions of 2-Alkoxy-
substituted Butadienes with Alkynes Followed by Hydrolysis
When higher oxygenated butadienes were used as starting
materials, such as 2,3-dimethoxy-1,3-butadiene, 1,4-
dimethoxy-1,3-butadiene and Danishefsky’s diene, only
traces of the desired products could be detected by GC
and GC/MS analysis. The electronic demands of the start-
ing materials seem to be the reason for the low reactivity
of such substrates more likely than conformational re-
strictions, since reactions with the cisoidal oriented start-
ing material 2,2-dimethyl-4,5-dimethylene-1,3-dioxolane
also gave only traces of the cycloaddition product. How-
ever, our investigations to incorporate these starting mate-
rials into the arsenal of usable starting materials for the
cobalt-catalyzed Diels–Alder reactions with alkynes are
still underway.
Entry R1
R2 R3
Product
Yield (%)
43
Ph
Ph
1
Ph
H
Me
O
O
2
Ph
H
TMS
TMS
93
78
3
C(CH3)=CH2
H
O
O
O
4
5
Et
Et TMS
Ph TMS
83
80
Et
Acknowledgement
Et
We thank the German science foundation DFG for the financial
support.
TMS
TMS
Ph
References
(1) (a) Carruthers, W. Cycloaddition Reactions in Organic
Synthesis; Pergamon Press: Oxford, 1990. (b) Kobayashi,
S.; Jørgensen, K. A. Cycloaddition Reactions in Organic
Synthesis; Wiley-VCH: Weinheim, 2002.
In addition, the dihydroaromatic products can also be used
for several other follow-up chemical transformations, of
which only a few are given in Scheme 4.8 Besides cyclo-
propanation,9 epoxidation and ring opening to the corre-
sponding -hydroxy ketone,10 the bis-acetoxylated
products can also be generated by a hydroboration-oxida-
tion-acetylation protocol following standard procedures.11
(2) For a review see: (a) Lautens, M.; Klute, W.; Tam, W.
Chem. Rev. 1996, 96, 49; and references cited therein.
(b) Dolor, Z. R.; Vogel, P. J. Mol. Catal. 1990, 60, 59.
(c) tom Dieck, H.; Diercks, R. Angew. Chem. 1983, 95, 801.
(d) Lautens, M.; Tam, W.; Lautens, J. C.; Edwards, L. G.;
Crudden, C. M.; Smith, A. C. J. Am. Chem. Soc. 1995, 117,
6863. (e) Paik, S.-J.; Son, S. U.; Chung, Y. K. Org. Lett.
1999, 1, 2045. (f) Gilbertson, S. R.; Hoge, G. S.; Genov, D.
G. J. Org. Chem. 1998, 63, 10077. (g) Duan, I.-F.; Cheng,
C.-H.; Shaw, J.-S.; Cheng, S.-S.; Liou, K. F. Chem.
Commun. 1991, 1347. (h) Brunner, H.; Reimer, A. Bull.
Chem. Soc. Fr. 1997, 134, 307. (i) Pardigon, O.; Buono, G.
Tetrahedron: Asymmetry 1993, 4, 1977. (j) Pardigon, O.;
Tenaglia, A.; Buono, G. J. Org. Chem. 1995, 60, 1868.
(3) (a) Hilt, G.; du Mesnil, F.-X. Tetrahedron Lett. 2000, 41,
6757. (b) Hilt, G.; Korn, T. J. Tetrahedron Lett. 2001, 42,
2783. (c) Hilt, G.; Smolko, K. I. Synthesis 2002, 686. (d)
Hilt, G.; Lüers, S.; Polborn K. Isr. J. Chem. 2002, in press.
(4) The active catalyst (presumably [(dppe)Co+]) is generated in
situ upon one electron reduction of (dppe)CoBr2 towards the
corresponding Co(I)Br-complex and further abstraction of
the remaining halide by the ZnI2 to form the reactive species
and ZnI2Br–.
OTMS
OTMS
Zn / CH2I2
84%
Ph
O
Ph
OTMS
OH
1. MPCBA
2. HF py
42%
Ph
Ph
OTMS
OAc
1. BH3
(5) Makin, S. M.; Kruglikova, R. I.; Shavrygina, O. A.;
Chernyshev, A. I.; Popova, T. P.; Nguen, P. T. Zh. Org.
Khim. 1982, 18, 287.
(6) Reactions of terminal alkynes were complete within 0.5 h,
reactions of internal alkynes needed 2–4 h, while for steri-
cally hindered substrates, such as 1-trimethylsilyl-2-phenyl-
OAc
2. H2O2
3. Ac2O
63%
Ph
Ph
Scheme 4
Synlett 2002, No. 7, 1081–1084 ISSN 0936-5214 © Thieme Stuttgart · New York

1084
G. Hilt et al.
LETTER
acetylene (Table 2, entry 9) the reaction were complete after
16 h (40 °C) with higher catalyst loadings (10 mol%).
(7) Synthesis of 4-Phenyl-1,4-cyclohexadien-1-yl
Trimethylsilyl Ether: (Table 2, entry 2):
4.90–4.96 (m, 1 H, =CH), 5.82–5.88 (m, 1 H, =CH), 7.05–
7.30 (m, 5 H, HAr).
13C NMR (75 MHz, C6D6): = 0.4, 29.2, 32.1, 100.8, 121.3,
125.5, 127.2, 128.5, 134.4, 141.5, 148.1.
To a suspension of CoBr2(dppe) (32 mg, 0.05 mmol, 5
mol%) and ZnI2 (100 mg, 0.3 mmol) in dry dichloromethane
(3 mL) under a nitrogen atmosphere, phenylacetylene (102
mg, 1 mmol), 2-trimethylsilyloxy-1,3-butadiene (170 mg,
1.2 mmol) and Bu4NBH4 (20 mg) were added. The mixture
immediately turned dark brown. In the case of larger scale
preparation (more than 5 mmol) it is advisable to cool the
reaction mixture with a water bath. After 30 min, the mixture
was diluted with pentane (70 mL) and filtered through
Kieselgur. Evaporation of the solvent in vacuo gave 229 mg
(94%) of a yellow-brown material (>95% purity by GC and
1H NMR), which was suitable for the further transformation.
Analytically pure samples were obtained by purification by
column chromatography on silica gel (pentane:diethyl ether
100:1).
IR (KBr): 2959(m), 1494(m), 1444(m), 1348(m), 1251(s),
1197(s), 747(m), 689(m) cm–1.
MS (EI): m/z (%) = 244(100) [M+], 227(18), 211(17),
153(34), 128(11), 73(48).
HRMS: Calcd for C15H20OSi: 244.1283. Found: 244.1264.
(8) For reviews on the chemistry of silyl enol ethers see:
(a) Brownbridge, P. Synthesis 1983, 1. (b) Brownbridge, P.
Synthesis 1983, 85.
(9) Murai, S.; Aya, T.; Sonoda, N. J. Org. Chem. 1973, 38,
4354.
(10) (a) Rubbotom, G. M.; Gruber, J. M.; Juve, H. D.; Charleson,
D. A. In Organic Syntheses, Coll. Vol. 7; Wiley and Sons:
New York, 1990, 282. (b) Rubbotom, G. M.; Gruber, J. M.
J. Org. Chem. 1978, 43, 1599.
(11) Larson, G.; Hernandez, D.; Hernandez, A. J. Organomet.
Chem. 1974, 76, 9.
1H NMR (300 MHz, C6D6): = 0.17 [s, 9 H, Si(CH3)3],
2.77–2.89 (m, 2 H, CH2,CHD), 3.00–3.10 (m, 2 H, CH2,CHD),
Synlett 2002, No. 7, 1081–1084 ISSN 0936-5214 © Thieme Stuttgart · New York