Tandem Diels-Alder and retro-ene reactions of 1-sulfenyl- and 1-sulfonyl-1,3-dienes as a traceless route to cyclohexenes

Article abstract of DOI:10.1021/ja505721v

A pericyclic approach for the synthesis of six-membered ring structures is described. The method employs 1,3-dienes with a 1-sulfur substituent in a tandem sequence of Diels-Alder and retro-ene reactions. In this pairing of [4 + 2] cycloaddition and 1,5-sigmatropic rearrangement, 1-sulfenyl-1,3-dienes engage in Diels-Alder reactions with electron-deficient dienophiles. Subsequently, the sulfenyl group of the cycloadducts is oxidized and unmasked to form allylic sulfinic acids, which undergo sterospecific reductive transposition via sulfur dioxide extrusion. The sequence can also include an inverse electron demand Diels-Alder reaction by using a 1-sulfonyl-1,3-diene. This combination of two pericyclic events offers novel stereocontrolled access to cyclohexenes that are inaccessible via a direct [4 + 2] cycloaddition route.

Full text of DOI:10.1021/ja505721v

Communication
pubs.acs.org/JACS
Tandem Diels−Alder and Retro-Ene Reactions of 1‑Sulfenyl- and
1
‑Sulfonyl-1,3-dienes as a Traceless Route to Cyclohexenes
†
†
†
‡
,‡
,†
Jin Choi, Hoyoon Park, Hyun Jung Yoo, Sinae Kim, Erik J. Sorensen,* and Chulbom Lee*
†
Department of Chemistry, Seoul National University, Seoul 151-747, South Korea
‡
Department of Chemistry, Princeton University, Princeton, New Jersey 08544, United States
*
S Supporting Information
cyclohexene systems, we envisioned that the concept could
be brought further to bear on the formulation of a unique
annulation strategy of broad utility. In particular, we were
intrigued by the prospect of exploiting a sulfur substituent as an
enabling functional handle, which could facilitate the cyclo-
ABSTRACT: A pericyclic approach for the synthesis of
six-membered ring structures is described. The method
employs 1,3-dienes with a 1-sulfur substituent in a tandem
sequence of Diels−Alder and retro-ene reactions. In this
pairing of [4 + 2] cycloaddition and 1,5-sigmatropic
rearrangement, 1-sulfenyl-1,3-dienes engage in Diels−
Alder reactions with electron-deficient dienophiles. Sub-
sequently, the sulfenyl group of the cycloadducts is
oxidized and unmasked to form allylic sulfinic acids,
which undergo sterospecific reductive transposition via
sulfur dioxide extrusion. The sequence can also include an
inverse electron demand Diels−Alder reaction by using a
addition and in turn render an allylic sulfinic acid poised for the
5
postcycloaddition retro-ene reaction (Scheme 1, Z = SO H). It
2
was anticipated that our design plan to utilize two aspects of
sulfur chemistry in interwoven contexts could offer a traceless
route to cyclohexenes defying a usual Diels−Alder retro-
6
synthetic analysis. Along with the suprafacial nature of the
sulfur extrusion process that would allow for the alkene
7
transposition to occur in a stereospecific manner, this
1
-sulfonyl-1,3-diene. This combination of two pericyclic
approach was deemed to be potentially more versatile, since
various oxidation states of sulfur (e.g., sulfenyl, sufinyl and
sulfonyl) could be tapped into varying settings of the Diels−
events offers novel stereocontrolled access to cyclohexenes
that are inaccessible via a direct [4 + 2] cycloaddition
route.
8
Alder reaction with stereo- and electronic control.
For the evaluation of our proposition, 1-sulfenyldiene 1a was
9
prepared from methacrolein and probed for its potential in the
he Diels−Alder reaction is a powerful method for the
Diels−Alder reaction with N-phenylmaleimide (2) (Scheme 2).
T
construction of six-membered ring structures that has
1
The sulfenyl (TBSOCH S) group was expected to accelerate
2
impacted profoundly on complex chemical synthesis. Among
the cycloaddition due to its donor capacity and could, in turn,
the most notable developments in this reaction is the
employment of functionalized dienes for enhanced reactivity
be converted to the requisite sulfinic acid through a simple
10
2
oxidation−deprotection sequence under mild conditions. In
and selectivity. In addition to facilitating the cycloaddition,
the event, heating a 1:1 mixture of 1a and 2 at 40 °C for 2 h
engineered dienes may also enable structural reorganization
subsequent to a Diels−Alder event giving rise to cyclohexenes
3
Scheme 2. Diels−Alder and Retro-Ene Sequence for
Cyclohexene Synthesis Using 1-Sulfenyl-1,3-diene
that are inaccessible via the direct [4 + 2] route. In this
context, one of us has reported 1-hydrazino-1,3-dienes for use4
in a tandem sequence of Diels−Alder and retro-ene reactions.
Through this pairing of two pericyclic processes, the initial
cycloadduct undergoes a reductive alkene transposition with a
1,3-transfer of stereochemistry while the hydrazino group is
removed via an allylic diazene rearrangement accompanying
loss of molecular nitrogen (Scheme 1, Z = N H). In light of the
2
efficiency of channeling [4 + 2] cycloaddition with 1,5-
sigmatropic rearrangement for the synthesis of unusual
Scheme 1. Cyclohexene Synthesis via Tandem [4 + 2]
Cycloaddition and 1,5-Sigmatropic Rearrangement
Received: June 6, 2014
©
XXXX American Chemical Society
A
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Journal of the American Chemical Society
Communication
gave rise to cycloadduct 3a as a single diastereomer in 89%
yield. This finding attested to the markedly enhanced reactivity
of the diene imparted by the sulfenyl group, forming a contrast
to the cases of hydrazinodienes in which the cycloaddition did
Table 1. Tandem Diels−Alder and Retro-Ene Reaction
4
not occur under simple thermal conditions. To set the stage
for the second pericyclic event, the allylic sulfinic acid
rearrangement, sulfide 3a was subjected to an unmasking
sequence. It was found that the oxidation of sulfide 3a to
sulfone 4a could be most efficiently achieved using hydrogen
11
peroxide under paramolybdate catalysis. Subsequently, treat-
ment of sulfone 4a with methanolic HCl at 50 °C for 12 h led
to smooth removal of the TBSOCH SO group to generate
2
2
cyclohexene 5a as a single isomer in 72% yield (2 steps). When
DCl−CD OD was instead employed for this reaction, deuterio-
3
5
a was produced in 66% yield (D incorporation >95%) again as
a single diastereomer, indicating the reductive alkene trans-
position to be the consequence of the stereospecific 1,5-
sigmatropic rearrangement of a putative allylic sulfinic acid
1
2
intermediate.
Having established conditions for the cyclohexene synthesis,
we examined the scope of the protocol with an assortment of
substrates (Table 1). The one-pot pericyclic sequence of [4 +
2] cycloaddition and 1,5-sigmatropic rearrangement proved to
be viable with a broad range of sulfenyldiene and dienophile
pairs, affording the corresponding cyclohexene products. In
addition to the methyl-substituted diene 1a (entries 1−4),
sulfenyldienes possessing a phenyl group (entry 5), a ring
fusion (entries 6−7), and 3,4-disubstitution (entry 8) all
participated well in the process to furnish deconjugated
cyclohexene 5i, trans-decalins 5j and 5k, and highly substituted
cyclohexene 5l, respectively. The dienophiles could also be
varied to include both acyclic and cyclic enones as well as
enoates. In general, simple thermal conditions (40−110 °C in
toluene) were sufficient for the Diels−Alder reaction to yield
endoadducts as the major products. In the presence of a Lewis
acid, the reaction temperatures and times could be significantly
decreased (entries 3 and 7), while preference for the formation
of an endo product increased (e.g., entry 1, 3b, 3:1 to 20:1).
The standard oxidation−deprotection conditions were found to
be uniformly effective for facile reductive alkene transposition
of the cycloadducts, with the exception of tricyclic 3j which
gave a low yield of 5j presumably due to the rigid ring system
that might render the conformation required for an allylic
3
h,i
sulfinic acid rearrangement less accessible. In all cases, the
retro-ene reaction took place with complete 1,3-chirality
transfer, manifesting high stereospecificity of the 1,5-sigma-
tropic rearrangement. It is noteworthy that the cyclohexenyl
ring structures contained within products 5 would not be easily
constructed with comparable efficiency by means of other
annulation methods.
The cycloaddition−sigmatropic rearrangement sequence
could also be practiced with an enal dienophile (Scheme 3).
When methacrolein (6) was exposed to diene 1a in DCM at
−
78 °C in the presence of catalytic Sc(OTf) , a rapid Diels−
3
Alder reaction occurred to generate only the endo adduct,
which upon oxidation furnished allylic sulfone 7a in 80% yield
(2 steps). The unmasking of the allylic sulfinic acid under the
methanolic HCl conditions, however, did not induce the
a
Standard reaction conditions. diene (0.4 mmol), dienophile (1.2
removal of SO , but instead resulted in the formation of acetal
b
2
mmol), toluene, 40−110 °C. Sc(OTf) (10 mol %), 3 Å MS, CH Cl ,
3
2
2
8
a as a 1:1 mixture of diastereomers. Hence, the cyclic mixed
c
−
78 to 0 °C. Dienophile (0.5 mmol), Et AlCl (100 mol %), CH Cl ,
2 2 2
d
acetal 8a was further treated with ethylene glycol to bring about
transacetalization. Indeed, the acetal exchange process led to
the formation of the desired alkene product 10a as a single
−
78 °C. H O (5 equiv), (NH ) Mo O (10 mol %), MeOH, 25 °C.
2 2 4 6 7 24
f
e
HCl (1 N in MeOH, 2 equiv), DCE, 50 °C. Isolated yield of both
g
1
diastereomers. The diasteromeric ratio was determined by H NMR.
B
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Journal of the American Chemical Society
Communication
Scheme 3. Diels−Alder Reaction with Methacrolein and
Subsequent Allylic Sulfinic Acid Rearrangement
Scheme 4. Inverse Electron Demand Diels−Alder Reaction
of Sulfonyldiene and Retro-Ene Reaction
illustrate the potential utility of the protocol in the expeditious
access to diverse cyclohexene systems.
In summary, a new approach for the stereoselective synthesis
of six-membered ring structures has been developed. The
method employs 1-sulfenyl-1,3-dienes in the tandem sequence
of [4 + 2] cycloaddition and 1,5-sigmatropic rearrangement to
produce cyclohexenes that are unavailable directly through a
cycloaddition route. The dienes equipped with a TBSOCH2S
group are highly reactive toward electron-deficient dienophiles,
readily engaging in Diels−Alder reactions under simple thermal
conditions or mild Lewis acid catalysis. The allylic sulfide
arising from the initial cycloaddition process is then subjected
to a mild oxidation-deprotection sequence to form an allylic
sulfinic acid, which undergoes a facile retro-ene reaction
effecting stereospecific alkene transposition with removal of
isomer in 68% yield. Although 7a could not enter into a retro-
ene process with the aldehyde group intact, the observation of
the formation of 8a and its conversion to 10a provided support
for the intermediacy of an allylic sulfinic acid (e.g., 9a).
The reactivity of the new sulfenyldiene was assessed by
further competition experiments where 1a was directly
compared with hydrazinodiene 11 and Danishefsky’s diene
1
3, respectively. As expected, the reaction of maleimide 2 with a
mixture containing equimolar amounts of two dienes 1a and 11
at 40 °C gave rise exclusively to 3a (eq 1). On the other hand,
SO and transfer of chirality. The protocol can also be practiced
2
via an inverse electron demand Diels−Alder reaction using an
electron-rich dienophile and a sulfonyldiene derived from
oxidation of a sulfenyldiene. This pairing of two pericyclic
events constitutes a unique and efficient means of stereo-
controlled cyclohexene synthesis that can be permuted in many
ways in the application to complex synthesis. Further efforts to
extend the utility of this chemistry are continuing.
ASSOCIATED CONTENT
Supporting Information
Experimental procedures and compound characterization data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
■
*
S
cycloadducts 3a and 14 arose in a 1:2 ratio from a similar
2c
reaction performed with a 1:1 mixture of 1a and 13 (eq 2),
suggesting the reactivity of diene 1a possessing the sulfenyl
group to be comparable to that of synergistic diene 13.
Having verified the high reactivity of the new sulfenyldiene
toward various electron-deficient dienophiles, we probed the
feasibility of altering the electronic nature of the diene by
changing the sulfur oxidation state. Indeed, 1-sulfonyldiene 15
AUTHOR INFORMATION
■
13
Corresponding Authors
chulbom@snu.ac.kr
ejs@princeton.edu
Notes
The authors declare no competing financial interest.
(
Scheme 4), an oxidized variant of the phenyl-substituted
14
sulfenyldiene (cf. Table 1, entry 5), proved to be capable of
ACKNOWLEDGMENTS
This research was supported by the Basic Research Program
through the National Research Foundation (NRF) of Korea
■
undergoing an inverse electron demand Diels−Alder reaction
(
6
IEDDA) with butyl vinyl ether (16), giving cyclohexene 17 in
9% yield as a 3:1 mixture of endo and exo isomers.
15
(
0409-20120064).
Subsequently, removal of the TBSOCH SO group was
2
2
accomplished by heating a solution of the major diastereomer
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