Improved dienophilicity of nitrocycloalkenes: Prospects for the development of a trans-Diels-Alder paradigm

Article abstract of DOI:10.1021/ja9058926

(Chemical Equation Presented) The development of an efficient and stereoselective trans-Diels-Alder paradigm is described. A central element of this transformation is the introduction of a temporary dienophilic functionality (A), which serves both to acti

Full text of DOI:10.1021/ja9058926

Published on Web 08/17/2009
Improved Dienophilicity of Nitrocycloalkenes: Prospects for the Development
of a trans-Diels-Alder Paradigm
Woo Han Kim,† Jun Hee Lee,‡ and Samuel J. Danishefsky*,†,‡
Laboratory for Bioorganic Chemistry, Sloan-Kettering Institute for Cancer Research, 1275 York AVenue, New York,
New York 10065, and Department of Chemistry, Columbia UniVersity, HaVemeyer Hall, 3000 Broadway,
New York, New York 10027
Received July 15, 2009; E-mail: s-danishefsky@ski.mskcc.org
The importance of the Diels-Alder reaction can hardly be
exaggerated. Its many features have been widely discussed.1 The
ability to reach cis-fused bicyclic systems by a Diels-Alder
pathway has been a bulwark of complex target-oriented synthesis.2
We well recognize that strategy in chemical synthesis is primarily
beholden to capabilities arising from advances in methodology. This
said, strategy also involves an intrinsic cognitive element. It
connects a particular target to the huge database of organic
chemistry, seeking to apply its most relevant and salient features
to the challenge at hand. Central in this regard has been the logic
of retrosynthetic analysis, which prioritizes various bond discon-
nections in an inverse sequential manner.3 The attainments resulting
from strategic bond retrosynthetic analysis are legion.
Complementary to the powerful thought process of bond discon-
nections, we have been entertaining a different approach which we
term “pattern analysis.”4 Although these approaches have some
commonality, pattern analysis emphasizes a holistic view of the
target structure, seeking connectivity between its key substructural
characteristics (sometimes obvious but sometimes quite subtle) and
established or prospectively implementable pathways. For instance,
in pattern analysis, the possibility of a Diels-Alder (DA) application
is provoked by the recognition of a cis junction. By contrast, trans
junctions tend to teach away5 from a Diels-Alder universe.
It goes without saying that the scope of pattern analysis would
be dramatically expanded if targets containing trans junctions could
also be encompassed in the general Diels-Alder logic. The simplest
scenario would contemplate an antarafacial cycloaddition.6 Not
having any constructive suggestions in this regard, we turned to
the next best thing. As outlined in Scheme 1, we envisioned
(1) through excision of the activating moiety and its controlled
replacement. The traceless function (A) would first serve the
purpose of activating the dienophile for cycloaddition, thereby
affording a cis junction. Subsequent chemistry would provide entry
to the trans-fused series. We selected a nitro group as (A), based
on its dienophile activating properties,7 its known success in
controlling DA regioselectivity,8 and its ability to generate free
radical intermediates.9 We describe herein the use of nitrocycloalk-
enes as dienophiles, pointing toward an emerging trans-Diels-Alder
paradigm.
We began by studying the dienophilicity of compound 3. At the
outset, there had been only one evaluation of it as a dienophile in
a Diels-Alder reaction.10 In the event, exploitation of its reactivity
in cycloadditions with hydrocarbon dienes (see entries 1-4, Table
1) proved to be a particularly challenging problem. At temperatures
below ∼120-130 °C, there was little or no indication of cycload-
dition. At temperatures above 140 °C there seemed to be a very
serious deterioration of the dienophile, resulting in extremely low
yields of cycloadduct. We were, however, able to identify a narrow
temperature range in which marginally useful cycloaddition could
be achieved. Still, in hydrocarbon solvents such as toluene or on
THF, the yields of isolated cycloadducts were quite low, apparently
Table 1. Diels-Alder Reaction of Nitrocycloalkenes
T
(°C)
t
(h)
yield
(%)a
entry
5
n
diene
solvent
Scheme 1. Trans-Diels-Alder Paradigm
1
2
3
4
a
a
a
a
1
1
1
1
R1 ) R2 ) CH3
R1 ) R2 ) CH3
R1 ) R2 ) CH3
R1 ) R2 ) CH3
tolueneb
tolueneb
tolueneb
THF
110
140
150
130
MWc
12 trace
36 18
36 trace
12 17
5
a
1
R1 ) R2 ) CH3
CH3CH2OH 130
14 36
MWc
6
7
a
a
1
1
R1 ) R2 ) CH3
R1 ) R2 ) CH3
CF3CH2OH 130
CF3CH2OH 130
24 70
12 78
MWc
,
8
9
b
c
1
1
R1 ) H, R2 ) CH3 CF3CH2OH 125
14 57d e
MWc
R1 ) R2 ) (CH2)4
CF3CH2OH 130
10 75
MWc
150
,
10
11
12
d
e
f
1
0
0
R1 ) R2 ) Ph
tolueneb f
48 45
12 78
12 77g
equipping an otherwise unreactive dienophile (such as cyclohexene)
with a temporary, readily removable activating group (A). Following
cycloaddition, a product of the type 2 would be obtained. The
resultant cis-fused substructure would be diverted to the trans series
R1 ) R2 ) CH3
CF3CH2OH 100
R1 ) H, R2 ) CH3 CF3CH2OH 110
a Isolated yield. b In the presence of 2,6-di-tert-butylcresol (5 mol %).
c MW ) microwave. d p-directed/m-directed ) 15:1. e The reaction in
toluene gave a 1:1mixture of regioisomers as a 5% yield. f The diene
was insoluble in CF3CH2OH. g p-directed/m-directed ) 11:1.
† Sloan-Kettering Institute for Cancer Research.
‡ Columbia University.
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10.1021/ja9058926 CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
reflecting competition between the innate destruction of 3, versus
its cycloaddition.
During the course of these studies, we did note some improve-
ment of cycloaddition yield in alcoholic solvents11 (see entry 5,
Table 1). Fortunately a more substantial increase in yield was
realized when we turned to 2,2,2-trifluoroethanol as solvent,
particularly when thermolysis was conducted under microwave
conditions (entry 7). We emphasize, however, that the hydroxylic
solvent effect, including 2,2,2-trifluoroethanol, apparently does not
arise from catalysis (through hydrogen bonding or via other means).
Thus, we see no indication that cycloaddition occurs at lower
temperatures with 2,2,2-trifluoroethanol. Rather, the differences in
yield seem to reflect a more favorable distribution of cycloaddition
relative to decomposition. While the basis of this effect remains to
be explored, it was very helpful to our program. Reasonable yields
of cycloaddition from compound 3 could now be achieved. Happily,
the protocol which was worked out for 2,3-dimethyl-1,3-butadiene
was extendable to several other dienes (see Table 1). Moreover,
we prepared 1-nitrocyclopentene (4)10 and evaluated its dienophi-
licity with the same dienes. Yields for these reactions are also
included in Table 1. Here, we note that the temperatures required
for cycloaddition were substantially lower (ca. 100-110 °C) for 4
than for 3, though, for the moment, the isolated yields tend to be
similar. Table 1 summarizes yields for various conditions under
which cycloaddition of dienophiles 3 and 4 with various acyclic
dienes could be achieved.
Figure 1. Structures of the tertiary bridge head radical.
the hydrindene series, the ratio of the denitration products, was
much closer to unity, presumably reflecting altered trans/cis
preferences.
In the next step in our exploration, we evaluated the consequences
of using a more functionalized diene. In that way, additional
exploitable functionality would be delivered to the eventual
denitration product. We began by studying the cycloaddition
reaction of compound 3 with diene 8.14 Fortunately, our conditions
described above for cycloaddition with acyclic hydrocarbon dienes
work quite well with diene 8. In 2,2,2-trifluoroethanol at 80 °C, a
61% yield of adduct 9 was obtained.15 With 1-nitrocyclopentene
(4), cycloaddition under comparable conditions afforded adduct 12
(Scheme 2).
Scheme 2a
Having substantially advanced the practicality of cycloadditions
with nitrocycloalkene dienophiles, we next faced the central issue
of denitration. We well recognized that if reductive denitration
would lead to a cis junction, the nitrocycloalkene dienophile would
have functioned as an equivalent of otherwise unreactive cyclo-
hexene or cyclopentene.12 However, if the excision-replacement
sequence would afford a trans junction, an overall trans-
Diels-Alder type paradigm would have been demonstrated.
In the event, we began by treating compound 5a with tri-n-butyltin
hydride in the presence of AIBN. We noted an 8:1 ratio of trans-6a
to cis-7a, as established by comparison with authentic reference
compounds prepared in multistep sequences.13 In a similar way, the
isoprene adduct 5b also gave rise to an 8:1 ratio of trans-6b to cis-7b.
Other examples are shown in Table 2. Thus, while one could hope
for an even stronger stereoselectivity, these data encourage application
of Diels-Alder logic to the synthesis of trans octalins.
a Key: (a) CF3CH2OH, 80 °C, MW, 12 h, 61%. (b) HF, CH3CN, rt, 30
min. (c) nBu3SnH, AIBN, benzene, reflux, 2 h. (d) CF3CH2OH, 80 °C, MW,
6 h, 72%.
We then turned to denitration reactions. For each compound,
this process was studied in two different sequences. In one arm,
the silyl enol ethers were hydrolyzed and the subsequent ketones
were denitrated. In this case, a 5:1 ratio of trans compound 10 to
cis compound 11 was obtained. A very similar result pertained when
we reversed the order of steps, wherein denitration was carried out
at the stage of adduct 9 and followed by hydrolysis of the silyl
enol ether, to provide a 6:1 ratio of trans-10/cis-11.16
Table 2. Radical Denitration
We applied the same methodology to adduct 12, which arose
from 4. Once again, both denitration sequences were pursued. When
denitration was conducted at the stage of the silyl enol ether,
followed by hydrolysis, a 1.4:1 ratio of trans-1417 to cis-1318 was
obtained. By contrast, when denitration was conducted at the ketone
stage (i.e., after hydrolysis), a 15:1 ratio of cis-13 to trans-14 was
produced. Thus, once again, in the octalin series a stereoselective
route to trans-fused ketone 10 has been established. By contrast,
in the hydrindane series, a stereoselective route to the cis fusion
has been realized. Unfortunately, no corresponding protocol now
available to us provides a trans hydrindanone junction with useful
levels of stereoselection (Vide infra).
yield
(%)a
entry
6,7
n
diene
6:7b
1
2
a
b
c
d
e
f
1
1
1
1
0
0
R1 ) R2 ) CH3
R1 ) H, R2 ) CH3
R1 ) R2 ) (CH2)4
R1 ) R2 ) Ph
67
53
81
83
61
35d
8:1
8:1
3
12:1c
7:1
4d
5
R1 ) R2 ) CH3
R1 ) H, R2 ) CH3
1.3:1
1.9:1
6
a Isolated yield. b Determined by 1H NMR. c Determined by GC.
d The compound is volatile.
Perhaps, this selectivity pattern represents a preference for
conformer type A relative to conformer B thereby accounting for
the selective formation of trans product (Figure 1). However, in
Finally, we turned our attention to the cycloaddition reaction of
diene 1519 with 1-nitrocyclohexene (3). As it turned out, this
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C O M M U N I C A T I O N S
Scheme 3a
Spectral Core Facility, Columbia University) for mass spectral and
NMR spectroscopic analysis.
Supporting Information Available: Experimental procedures,
copies of spectral data, and characterization. This material is available
free of charge via the Internet at http://pubs.acs.org.
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Acknowledgment. Support was provided by the NIH (HL25848
and CA103823 to SJD). WHK is grateful for a Korea Research
Foundation Grant funded by the Korean government (KRF-2007-
357-c00060). We thank Rebecca Wilson and Dana Ryan for
assistance with the preparation of the manuscript and Prof. W. F.
Berkowitz and Dr. Pavel Nagorny for helpful discussions. We also
thank Dr. George Sukenick, Ms. Hui Fang, Sylvi Rusli (NMR Core
Facility, Sloan-Kettering Institute) and Dr. Yasuhiro Itagaki (Mass
JA9058926
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