Microwave assisted synthesis of bridgehead alkenes

Article abstract of DOI:10.1021/ol200244p

A new, concise method to synthesize triene precursors for the type 2 intramolecular Diels-Alder reaction has been developed. Microwave irradiation of the trienes provides a convenient method for the synthesis of bridgehead alkenes. Higher yields, shorter

Full text of DOI:10.1021/ol200244p

ORGANIC
LETTERS
2011
Vol. 13, No. 7
1781–1783
Microwave Assisted Synthesis of
Bridgehead Alkenes
Leah Cleary, Hoseong Yoo, and Kenneth J. Shea*
Department of Chemistry, University of California, Irvine, 1102 Natural Sciences 2,
Irvine, California 92697-2025, United States
kjshea@uci.edu
Received January 25, 2011
ABSTRACT
A new, concise method to synthesize triene precursors for the type 2 intramolecular Diels-Alder reaction has been developed. Microwave
irradiation of the trienes provides a convenient method for the synthesis of bridgehead alkenes. Higher yields, shorter reaction times, and lower
reaction temperatures provide a general and efficient route to this interesting class of molecules.
The type 2 intramolecular Diels-Alder (IMDA) reaction
is a powerful tool for the construction of polycyclic com-
pounds containing bridgehead alkenes.1 Highly strained
bicyclo[n.3.1],2-11 five-seven fused,12 azobicyclo[n.3.1],13
and caprolactam ring systems14 can all be synthesized with
high regio- and stereoselectivity utilizing this reaction.
Application as a key carbon-carbon bond forming step in
the syntheses of complex molecules aptly displays the
synthetic significance of the reaction.15,16
Compared to the type 1 IMDA variant, the type 2
IMDA reaction has an elevated activation free energy.
This difference is due to the formation of a strained
bridgehead alkene and the cumulative nonbonding inter-
actions that develop in the transition state leading to the
bridged bicyclic product. Experimental values of the acti-
vation free energy (ΔG‡) for the reaction range from
approximately 37 to 41 kcal/mol (210 °C).8 This energy
barrier is overcome with either elevated reaction tempera-
tures for extended periods of time3,4 or by the use of Lewis
acid catalysis.6 In a complex molecule setting, Lewis acid
activation is often prohibited due to the presence of more
sensitive functional groups.16 Solution phasethermolysis is
then necessary to induce cycloaddition of highly functio-
nalized trienes; however, this often requires temperatures
(1) Bear, B. R.; Sparks, S. M.; Shea, K. J. Angew. Chem., Int. Ed.
2001, 40, 820–849.
(2) Shea, K. J.; Wise, S. J. Am. Chem. Soc. 1978, 100, 6519–6521.
(3) Wise, S.; Shea, K. J. Tetrahedron Lett. 1979, 12, 1011–1014.
(4) Shea, K. J.; Beauchamp, P. S.; Lind, R. S. J. Am. Chem. Soc. 1980,
102, 4544–4546.
(5) Shea, K. J.; Wise, S.; Burke, L. D.; Davis, P. D.; Gilman, J. W.;
Greeley, A. C. J. Am. Chem. Soc. 1982, 104, 5708–5715.
(6) Shea, K. J.; Wada, E. J. Am. Chem. Soc. 1982, 104, 5715–5719.
(7) Shea, K. J.; Gilman, J. W. Tetrahedron Lett. 1983, 24, 657–660.
(8) Shea, K. J.; Fruscella, W. M.; Carr, R. C.; Burke, L. D.; Cooper,
D. K. J. Am. Chem. Soc. 1987, 109, 447–452.
(9) Shea, K. J.; Burke, L. D.; England, W. P. J. Am. Chem. Soc. 1988,
110, 860–864.
(10) Shea, K. J.; Zandi, K. S.; Staab, A. J.; Carr, R. Tetrahedron Lett.
1990, 31, 5885–5888.
(11) Shea, K. J.; Staab, A. J.; Zandi, K. S. Tetrahedron Lett. 1991, 32,
2715–2718.
(12) Gwaltney, S. L.; Sakata, S. T.; Shea, K. J. Tetrahedron Lett.
1995, 36, 7177–7180.
(13) (a) Shea, K. J.; Lease, T. G.; Ziller, J. W. J. Am. Chem. Soc. 1990,
112, 8627–8629. (b) Shea, K. J.; Lease, T. G. J. Am. Chem. Soc. 1993,
115, 248–2260.
(14) (a) Sparks, S. M.; Chow, C. P.; Zhu, L.; Shea, K. J. J. Org. Chem.
2004, 69, 3025–3035. (b) Chow, C. P.; Shea, K. J. J. Org. Chem. 2005,
127, 3678–3679. (c) Molina, C. L.; Chow, C. P.; Shea, K. J. J. Org. Chem.
2007, 72, 6816–6823.
(15) Examplary synthetic efforts include: (a) Shea, K. J.; Davis, P. D.
Angew. Chem., Int. Ed. Engl. 1983, 22, 419–420. (b) Schreiber, S. L;
Kiessling, L. L. J. Am. Chem. Soc. 1988, 110, 631–633. (c) Dzierba, C. D;
Zandi, K. S.; Mollers, T.; Shea, K. J. J. Am. Chem. Soc. 1996, 118, 4711–
4712. (d) Nicolaou, K. C.; Baran, P. S.; Zhong, Y. L.; Choi, H. S.; Yoon,
He, Y; Fong, K. C. Angew. Chem., Int. Ed. 1999, 38, 1669–1675.
(e) Nicolaou, K. C.; Baran, P. S.; Zhong, Y. L; Fong, K. C.; He, Y.;
Yoon, W. H.; Choi, H. S. Angew. Chem., Int. Ed. 1999, 38, 1676–1678.
(f) Waizumi, J.; Itoh, T.; Fukuyama, T. J. Am. Chem. Soc. 2000, 122,
7825–7826. (g) Baran, P. S.; Burns, N. Z. J. Am. Chem. Soc. 2006, 128,
3908–3909. (h) Zhu, L.; Lauchli, R.; Loo, M.; Shea, K. J. Org. Lett. 2007,
9, 2269–2271. (i) Brailsford, J. A.; Lauchli, R.; Shea, K. J. Org. Lett.
2009, 11, 5330–5333.
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r
10.1021/ol200244p
2011 American Chemical Society
Published on Web 03/08/2011

inexcessof 200 °C withreactiontimesofseveral hours. The
yields of these reactions are often compromised by com-
peting decomposition of the diene under these harsh and
Triene 5 was chosen as a standard substrate for optimi-
zation of the microwave conditions (Table 1). Cinnamyl-
Table 1. Optimization of the Type 2 IMDA Reaction Condi-
tions
Scheme 1. Expediant Triene Synthesis
temp
time
(h)
yield
(%)
entry
solvent
(°C)
base
1
toluene
o-DCB
o-DCB
o-DCB
o-DCB
o-DCB
o-DCB
o-DCB
o-DCB
160
220
180
160
140
140
160
160
240
1
1
-
-
-
-
-
-
0
47
66
73
65
prolonged conditions. Alternately, use of microwave ra-
diation has been known to decrease reaction times and
lower temperatures for reactions carried out under thermal
conditions.17,18 A microwave reactor also provides a more
convenient, safer method for heating reactions to the
temperatures necessary for the type 2 IMDA reaction to
occur. We thus set out to develop a straightforward
method using microwave irradiation to accomplish the
cycloadditions with Diels-Alder reaction precursors that
incorporate a range of substitution patterns.
2
3
1
4
1
5
1.5
1
a
6
-
b
7
1
DTBP
-
8c
9c
10
4
-
-
0
45
a Reaction was incomplete, and product could not be separated from
starting material. b An inseperable mixture of products was formed.
c Conventional heating was employed.
A succinct method to synthesize these triene substrates
was designed (Scheme 1). Utilizing enyne metathesis, alkynes
can be viewed as protected dienes. Under 300 psi of ethylene,
iodoalkyne 119 was converted to diene 2. Iododiene 2 was
then coupled with acid chloride 3 or 4 to furnish trienes 5 or
6, respectively. Similarly diester 13 can be synthesized from
pentynol 7 (Scheme 2). Silyl protection of the alcohol
followed by alkyne metathesis gave diene 9. After deprotec-
tion of the silyl group and condensation of the resulting
alcohol with acid chloride 4,20 triene 13 was obtained. Triene
14 was synthesized analogously starting from pentynol 8.
derived dienophiles are less reactive substrates for the
Diels-Alder reaction and thus provide a more useful
platform for optimization of the reaction conditions.
Because of the high temperatures necessary to induce
cycloaddition when thermal conditions are employed, we
chose aromatic solvents with high boiling points for the
reactions. We initially found that heating in toluene was
ineffective for conversion to the cycloadduct, likely due to
starting material decomposition during the ramp time for
the reaction to reach 200 °C. Switching solvents to o-
dichlorobenzeneandheatingto220°C resultedinamodest
yield of 47%. By incrementally decreasing the temperature
we found that at a temperature of 160 °C the product yield
increased to 73%. We were surprised to find that the
reaction proceeded at temperatures as low as 140 °C;
however, this required longer reaction times and the yield
was reduced to 65%. The addition of base to buffer any
adventitious acid did not improve the yield. Lastly, for
direct comparison of the optimized microwave conditions
to thermal conditions we heated triene 5 in a sealed tube.
No cycloaddition occurred under thermal conditions at
160 °C after 10 h. Full conversion of the starting material
occurred only after heating to 240 °C for 4 h, providing a
modest 45% yield.
Scheme 2. Synthesis of Trienes with Diester Dienophiles
Conditions for substrates in which a carbonyl group is
not part of the diene-dienophile tether differ from the
cinnamyl derived substrate (Table 2). Triene 16 decom-
posed under microwave irradiation in o-dichlorobenzene.
As was found when optimizing the cycloaddition of triene
€
(17) (a) Tierney, J. P.; Lidstrom, P. Microwave Assisted Organic
Synthesis: Blackwell Publishing: Boca Raton, FL, 2005. (b) Hoz, A.;
Díaz-Ortis, A.; Moreno, A.; Langa, F. Eur. J. Org. Chem. 2000, 3659–3673.
(18) Lidstrom, P.; Tierney, J.; Wathey, B.; Westman, J. Tetrahedron
€
2001, 57, 9225–9283.
(19) Mancini, I.; Cavazza, M.; Guella, G.; Pietra, F. J. Chem. Soc.,
Perkin Trans. 1 1994, 2181–2185.
(20) Acheson, R. M.; Feinberg, R. S.; Hands, A. R. J. Chem. Soc.
1964, 508–544.
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Org. Lett., Vol. 13, No. 7, 2011

Table 2. Alternate Conditions of the Type 2 IMDA
5, the use of o-xylene as the solvent also lead to extensive
decomposition of the starting material. It was hypothe-
sized that the extended ramp time necessary to heat the
nonpolar solvents permitted the gradual decomposition of
the starting material. We hoped to exploit the fact that the
addition of ions or polar solvent facilitates the rapid
heating of a nonpolar solvent.18 When the reaction was
run in o-xylene “doped” with DMSO, the ramp time to 200
°C was reduced to under 4 min and a 75% yield of
cycloadduct 21 was obtained. Under thermal conditions,
triene 17 requires heating to 240 °C for 4 h to obtain a 64%
yield. Again, the triene decomposed in o-dichlorobenzene,
but using o-xylene and DMSO as solvent for the micro-
wave assisted reaction gave cycloadduct 17 in 75% yield in
an abbreviated 6 h reaction time.
A series of trienes were subjected to optimized micro-
wave conditions. These specific trienes were chosen because
thermal conditions resulted in yields ranging from 40 to
60%.4 Under microwave conditions, triene 14 underwent
cycloaddition to provide a 90% yield of cycloadduct 22 in
toluene under microwave conditions. The cycloadditions
of diesters 6 and 13 were also performed in toluene and
resulted in 89% and 92% yields, respectively. The ramp time
for the toluene reactions is approximately 25 min; however,
the yields are excellent as compared to the cycloaddition of
trienes 165 and 173 in o-xylene. This discrepancy may be
attributed to trienes 6-14 possessing a less polarized die-
nophile reducing any nucleophilic attack or polymeriza-
tion. We also note that, under these conditions, yields are
independent of steric constrains that arise from shortening
the tether length from 6 to 4 atoms. Furthermore, the
cycloaddition of triene 14 with a tether length of six
atoms does not yield any of the [6.2.2] cycloadduct, the
regioisomer that is formed under Lewis acid catalyzed
conditions.
The more concise synthesis of requisite trienes rapidly
affords substrates for the type 2 IMDA reaction. Microwave
reactors provide optimal conditions for the subsequent
cycloaddition to afford bridgehead alkenes. We found that
all substrates require less reaction time and lower tempera-
tures to provide cycloadducts in higher yields. In many
cases, the cycloaddition reaction times are similar to those
of catalyzed reactions without the necessity of stoichio-
metric quantities of Lewis acid. Microwave conditions are
also safer than traditional thermolysis because the reactor
is built to handle the increased pressures caused by high
temperatures necessaryfor cycloaddition to occur. Finally,
regioselectivity to form the 1,3-regioisomer was conserved
even for longer tether lengths.
Acknowledgment. The authors would like to thank Dr.
John Greaves (UC Irvine) for assistance with GC-MS
analysis and Drs. Katy Bridgwood and Grant Shibuya
(UC Irvine) for helpful advice. This research was sup-
ported in part by the National Institutes of Health.
Supporting Information Available. Experimental pro-
cedures, spectroscopic data (1H NMR, 13C NMR, IR,
HR-MS) for all new compounds. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 7, 2011
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