Diels-Alder approach to biaryls (DAB): Importance of the ortho-nitro moiety in the [4 + 2] cycloaddition

Article abstract of DOI:10.1039/b714893c

A series of nitrophenyl acetylenes were evaluated for their utility in a cycloaddition-cycloreversion approach to polysubstituted biaryls. ortho-Nitrophenyl acetylene consistently provided the target biaryls in superior yields as compared to the meta and para nitro substituted variants. This journal is The Royal Society of Chemistry.

Full text of DOI:10.1039/b714893c

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Diels–Alder approach to biaryls (DAB): Importance of the ortho-nitro moiety
in the [4 + 2] cycloaddition†
Bradley O. Ashburn and Rich G. Carter*
Received 27th September 2007, Accepted 16th November 2007
First published as an Advance Article on the web 27th November 2007
DOI: 10.1039/b714893c
A series of nitrophenyl acetylenes were evaluated for their
utility in a cycloaddition–cycloreversion approach to poly-
substituted biaryls. ortho-Nitrophenyl acetylene consistently
provided the target biaryls in superior yields as compared to
the meta and para nitro substituted variants.
with only a trace (<10% yield) of the desired biaryl 12. Dienes
6 and 11 have proven previously effective at undergoing biaryl
formation with 2-chloro-6-nitrophenyl acetylene.2c One possible
rationale for this reactivity difference could be that the chlorine
substituent’s increased electron withdrawing character activates
the alkyne 1 by lowering its LUMO orbitals.
Given the success of the reaction of dienophile 1 with cyclic
dienes 2, 4, 7 and 9, we chose next to explore relocating the nitro
moiety to the meta and para positions (Scheme 1). Alkynes 13 and
14 were synthesized in one step from the corresponding 3-iodo-
nitrobenzene and 4-iodo-nitrobenzene respectively via copperless
Sonogashira coupling9 with trimethylsilylacetylene, [Pd(OAc)2
(3 mol%), DABCO, Cs2CO3, MeCN, 49% 13, 47% 14]. Treatment
of dienophiles 13 and 14 with diene 2 at 140 ◦C in the absence of
solvent provided the resultant biaryl 1510 and 1611 in 29% and 67%
yield respectively. A similar outcome was observed with diene 4 to
provide biaryls 1712 and 1813 in 22% and 40% respectively. While
the ortho and para nitrophenyl alkynes 1 and 14 should have similar
electron withdrawing capabilities due to resonance stabilization,
a pronounced difference in reactivity is observed—82% versus
67% yield with diene 2 and 80% versus 40% yield with diene 4.
This reactivity pattern continued with the bis-oxygenated dienes
2 and 4—86% versus 76% yield with diene 7 and 81% versus 66%
yield with diene 9. We are not certain at this time as to the exact
rationale for the reduced efficiency of the para-nitro compound
14. While we hesitate to draw any firm conclusions without a
more extensive analysis of the transition structures of the reaction
pathways, we have explored a simplistic computational study of the
molecular orbitals of dienophiles 1 and 14.14 Interestingly, alkyne
1, with the nitro moiety in the ortho position, should react through
the LUMO + 1 orbital since there is a node on the a carbon
of the LUMO. While the para nitro compound 14 does have a
lower LUMO energy, this alkyne is not able to undergo concerted
cycloaddition at either the LUMO or LUMO + 1 level. Instead,
only the LUMO + 2 possesses the necessary orbital symmetry to
facilitate a concerted [4 + 2] cycloaddition. Not surprisingly, the
LUMO + 2 of alkyne 14 exists at a significantly higher energy
than the LUMO + 1 of alkyne 1. A more detailed analysis of the
transition state energies and kinetics experiments will be necessary
to further probe this reactivity difference. It is important to note
that while we have previously observed the [2.2.2] bicycle derived
from the initial cycloaddition as a discreet intermediate in other
systems,2 the analogous intermediate was not seen in any of the
reactions with dienophiles 1, 13 or 14. This reactivity pattern will
complicate any kinetics study.
Diels–Alder cycloadditions have proven to be a powerful tool
for the rapid construction of complex systems.1 Our group2
and others3 have demonstrated the utility of this transformation
for the formation of biaryl compounds. We have been particu-
larly interested in employing acetylenic dienophiles possessing
a nitrophenyl moiety as the resultant biaryl can be rapidly
functionalized into the corresponding anilino species.2 While a
wealth of literature examples are present for acetylenic dienophiles
undergoing cycloadditions,3 we are not aware of any attention
being paid to the nitrophenyl substituted alkynes prior to our
work.2 In this communication, we probe the role that the nitro
moiety plays in the cycloadditions with oxygenated, cyclic dienes.
Given our considerable success of cycloadditions with the halo-
genated, ortho-nitro phenyl acetylene, the reactivity of the parent
unhalogenated compound 1 was explored initially (Table 1).4
Reaction of the alkyne 1 with commercially available dienes 2
and 45 nicely provided the anisole derivative 36 and the phenol
57 in excellent yields (82% and 80% respectively). In contrast, the
acyclic diene 6 proved less effective in the cycloaddition process—
yielding the same phenol 5 in modest yield (53%). Other drawbacks
of the acyclic diene include more challenging purification due
to extensive diene decomposition and the need for the addition
of TBAF to induce aromatization. The cyclohexadiene-based
cycloadditions involve initial [4 + 2] Diels–Alder reaction to
yield the [2.2.2] bicyclic intermediate, which undergoes [4 + 2]
cycloreversion to extrude ethylene and yield the aromatic product
3. It is important to note that the oxygen substitution on the
diene is critical to the success of this transformation. To this end,
treatment of alkyne 1 with 1,3-cyclohexadiene at 140 ◦C for 24 h led
to none of the desired biaryl products. Use of cyclic, bis-oxygenated
dienes 7 and 92c cleanly gave the tri-substituted biaryls 8 and 10
respectively. It should be noted that these results represent the
shortest reaction times in any series of mono and bis-substituted
acetylenes that we have employed to date.2 Once again, use of an
acyclic diene (Brassard’s diene 118) resulted in a complex mixture
Department of Chemistry, 153 Gilbert Hall, Oregon State University,
Corvallis, OR, USA. E-mail: rich.carter@oregonstate.edu; Fax: +1 (541)
737-9496; Tel: +1 (541) 737-9486
† Electronic supplementary information (ESI) available: Complete exper-
imental procedures and copies of 1H and 13C NMR spectra. See DOI:
10.1039/b714893c
Not surprisingly, the meta nitro phenyl alkyne 13 proved less
reactive in the cycloadditions—with reaction times increased
by 5–10 fold. Yields for these Diels–Alder reactions were also
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Table 1 Diels–Alder reactions with dienophile 1
Diene
Conditions
Product
% Yield
82%
140 ◦C, neat, 2 h
140 ◦C, neat, 2 h;
K2CO3, MeOH, 10 min
80%
53%
86%
81%
Trace
120 ◦C, neat, 6 h; TBAF,
DCM, 0 ◦C, 15 min
140 ◦C, neat, 30 min;
K2CO3, MeOH, 10 min
140 ◦C, neat, 30 min;
K2CO3, MeOH, 10 min
Scheme 1 Diels–Alder reactions with dienophiles 13 and 14.
noticeably lower—presumably due to decomposition and
side reactions (no starting material was recovered from any of the
cycloadditions with dienophile 13). Of note was the reversal in
selectivity for diene 4—providing the unexpected biaryl 17 with
the phenolic moiety in the meta position in a low yield (22%). The
nitro moiety does impart an increased reactivity profile—even at
the meta position. Treatment of phenyl acetylene with diene 2 at
140 ◦C did not provide any observable product. A modest amount
of the resultant biaryl could be observed at higher temperatures
(160 ◦C, 8 h, 26%). The methoxy diene 7 also did not prove
reactive at 140 ◦C with phenyl acetylene. Again, additional energy
120 ◦C, neat, 4 h; Et3N,
DCM, rt, 1 h
◦
was required to produce the expected biaryl (160 C, 6 h, 38%).
Attempted Diels–Alder reaction of phenyl acetylene with the
dienes 4 and 9 produced no isolable products at 160 ◦C.
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In conclusion, we have systematically explored the reactivity
profile of nitro-phenylsubstituted acetylenes in the cycloaddition–
cycloreversion process with a series of oxygenated dienes. The
importance of the ortho nitro moiety on the phenyl acetylene has
been clearly demonstrated. Further exploration into the use of the
DAB strategy will be reported in due course.
The authors would like to acknowledge the National Science
Foundation for financial support (CHE-0549884). In addition, the
authors would like to thank Professor Kevin P. Gable (OSU) for his
assistance with the computational data, Professor Max Deinzer
(Mass Spectrometry Facility, Environmental Health Sciences
Center, Oregon State University) and Dr Jeff Morre´ (Mass Spec-
trometry Facility, Environmental Health Sciences Center, Oregon
State University) for mass spectra data and Michael R. Naffziger
(OSU) and Dr Roger Hanselmann (Rib-X Pharmaceuticals) for
their helpful discussions.
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14 A table detailing the calculated energies is provided in the ESI.† The
ꢀ
molecular modelling program Spartan 06 was used to carry out the
density functional B3LYP calculations. The 6-31G** basis set was
chosen to better optimize the structures and calculate the molecular
orbital energies and coefficients. Computations were performed using
a Linux workstation running Spartan version ꢀ06.
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 255–257 | 257
©