Torquoselective ring opening of fused cyclobutenamides: Evidence for a cis,trans -cyclooctadienone intermediate

Article abstract of DOI:10.1021/ja502252t

Electrocyclic ring opening of 4,6-fused cyclobutenamides 1 under thermal conditions leads to cis,trans-cyclooctadienones 2-E,E as transient intermediates, en route to 5,5-bicyclic products 3. Theoretical calculations predict that 4,5-fused cyclobutenamides should likewise undergo thermal ring opening, giving cis,trans-cycloheptadienones, but in this case conversion to 5,4-bicyclic products is thermodynamically disfavored, and these cyclobutenamides instead rearrange to vinyl cyclopentenones.

Full text of DOI:10.1021/ja502252t

Communication
pubs.acs.org/JACS
Torquoselective Ring Opening of Fused Cyclobutenamides: Evidence
for a Cis,Trans-Cyclooctadienone Intermediate
Xiao-Na Wang,† Elizabeth H. Krenske,*,‡ Ryne C. Johnston,‡,§ K. N. Houk,*,¶ and Richard P. Hsung*,†
†Division of Pharmaceutical Sciences and Department of Chemistry, University of Wisconsin, Madison, Wisconsin 53705, United
States
‡School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, Australia
¶Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, United States
S
* Supporting Information
cyclobutenamides 1 undergo rearrangement to products
ABSTRACT: Electrocyclic ring opening of 4,6-fused
cyclobutenamides 1 under thermal conditions leads to
cis,trans-cyclooctadienones 2-E,E as transient intermedi-
ates, en route to 5,5-bicyclic products 3. Theoretical
calculations predict that 4,5-fused cyclobutenamides
should likewise undergo thermal ring opening, giving
cis,trans-cycloheptadienones, but in this case conversion to
5,4-bicyclic products is thermodynamically disfavored, and
these cyclobutenamides instead rearrange to vinyl cyclo-
pentenones.
whose structures are consistent with the intermediacy of the
cyclooctadienone 2-E,E, containing one cis and one trans olefin,
derived from cyclobutene ring opening. Small-ring trans-
cycloalkenes are expected to be metastable intermediates that
should undergo facile inter- or intramolecular transformations,
and in the case of 2-E,E, this is manifested in a transannular
cyclization leading to the 5,5-bicyclic product 3. This outcome
is surprising as it is in direct contrast to previous studies of the
related 4,6-fused cyclobutenamine 4 (Scheme 2), which showed
Scheme 2. Ficini’s Thermal Rearrangement of a Fused
Cyclobutenamine10
mall trans-cycloalkenes have unique reactivities and
Sstructural features, including inherent planar chirality,
which have been the focus of many elegant experimental and
seminal theoretical studies,1−6 and have recently attracted
increasing interest relating to their applications in bioconjugate
chemistry.1d Accommodating a trans olefin within a ring size of
7, 8, or 9 engenders significant ring strain, which may be
alleviated if the ring contains heteroatoms such as N, O, or S
but is exacerbated when the ring contains additional sp2-
hybridized atoms.3−5 We report here the discovery of a new
entry point into the chemistry of all-carbon trans-cyclo-
alkenones, uncovered during our studies of cyclobutenamides
1 (Scheme 1).7−9 Under thermal conditions, 4,6-fused
no evidence for cycloalkadienone formation. Thermal rear-
rangement of 4 gave instead the dienes 6-cis and 6-trans.9,10
The sole difference is the amino group in 4 versus the amide in
1. Here we report our experimental and theoretical studies of
the generation and fate of cis,trans-cyclooctadienones 2 from
4,6-fused cyclobutenamides 1 and the contrasting behavior of
the corresponding 4,5-fused cyclobutenamides.
Our experiments on the thermal rearrangements of cyclo-
butenamides 1 are summarized in Table 1. When heated at
100−120 °C in toluene, 4,6-fused cyclobutenamides 1
rearranged to the synthetically useful pentalanes 3 in 45−62%
yield. The choice of appropriate conditions was crucial: no
reaction took place either in DMF or chloroform (entries 1 and
2), or in the presence of base or 4 Å molecular sieves (entries 4
and 5). Yields were slightly higher when the reaction was
conducted at 120 °C than at 100 °C (e.g., entry 3 vs 6) and
were higher when lower concentrations of cyclobutenamide
were used (e.g., entries 7, 8, 10), but in no case could the
reaction be driven to completion.
Scheme 1. Ring-Fused Cyclobutenamides as Potential
Precursors to Small Cis,Trans-Cycloalkadienones
The scope and generality of this fascinating cascade are
accentuated in Figure 1. Variation of substituents on the
nitrogen atom and/or the β-carbon of the starting cyclo-
Received: March 4, 2014
Published: July 3, 2014
© 2014 American Chemical Society
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Table 1. Thermal Rearrangements of 4,6-Fused
Cyclobutenamides 1
Scheme 3. Proposed Mechanism for Thermal
Rearrangement of 1 to 3
a
b
c
All are isolated yields. Recovered starting 1. Mbs = para-methoxy-
d
benzene-sulfonyl; Ns = para-nitro-benzene-sulfonyl. Complete
recovery of 1.
Figure 2. Free energy profile for thermal rearrangement of 1 to 3 in
toluene, calculated at the M06-2X/6-311+G(d,p)//B3LYP/6-31G(d)
level of theory with SMD solvent corrections. ΔG in kcal/mol.
Figure 1. Structurally diverse products accessed through thermal
rearrangements of cyclobutenamides 1.
The E,E isomer of 2 is not only kinetically favored but also
the only isomer possessing an appropriate geometry for
cyclization in the 5,5 mode to give 3 (in 2-Z,Z, the carbonyl
group and diene terminus are too far apart to form a bond).
Ring closure of 2-E,E resembles a Nazarov cyclization (cf.
resonance structure 2′-E,E, Scheme 3). Starting from the
neutral cyclooctadienone, 5,5 ring closure leading to epoxide 7
(the result of barrierless collapse of a 5,5-bicyclic zwitterion)
has a very high barrier (TS7, 47.5 kcal/mol), too high to be
feasible at 100−120 °C. However, protonation of the carbonyl
group (Figure 2 inset) lowers the energy of the Nazarov TS
significantly, such that it lies only 6.2 kcal/mol above
protonated 2-E,E.14,15 Based on this result, together with the
lack of reaction in the presence of 4 Å molecular sieves (Table
1, entry 5), we propose that the cyclization step is catalyzed by
adventitious water acting as an acid catalyst.15 Unfortunately,
the yield of 3 could not be improved by deliberate addition of
an acid catalyst; for example, addition of camphorsulfonic acid
(CSA, 0.4 equiv) brought about severe decomposition.16
The 4,5-fused cyclobutenamides 8 behaved differently from
1, instead echoing the behavior of 4 observed by Ficini
(Scheme 2).10 As shown in Table 2, no products were
identified that could be traced to the cis,trans-cycloheptadie-
none intermediate 9-E,E. Instead, 4,5-fused cyclobutenamides 8
rearranged to amido-dienes 12 as cis/trans mixtures.17 The
butenamides led to the pentalanes 3d (Table 1) and 3e−h
(Figure 1). The initially formed hydroxypentalanes could
undergo syn-dehydration to fulvenes, which may be isolated
(3e′ and 3f′) or trapped by an intramolecular [4 + 2]
cycloaddition onto a tethered alkene to give tetracycles (3h″
and 3g″). These last two examples reveal the synthetic potential
of this rearrangement for the rapid assembly of structural
complexity. It is also noteworthy that, in the case of 3e/3e′,
only the Z exocyclic olefin was found.
Having uncovered this novel cascade reaction, we were
intrigued by its mechanism and distinct contrast to Ficini’s
observations on the 4,6-fused cyclobutenamines 4.10 We
propose that the rearrangement of 1 to 3 follows the
mechanism shown in Scheme 3. The details of the mechanism
were established with the aid of density functional theory
calculations,11 performed at the M06-2X/6-311+G(d,p)//
B3LYP/6-31G(d) level of theory (Figure 2).12 The 4π
electrocyclic ring opening of 1 predictably13 favors the
conrotatory mode in which the cyclohexanone alkyl group
rotates outward and the carbonyl rotates inward (direction a)
leading to 2-E,E. This intermediate lies 9.4 kcal/mol above 1.
The computed torquoselectivity (ΔΔG‡) is 9.8 kcal/mol.
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Table 2. Thermal Rearrangements of 4,5-Fused
Cyclobutenamides 8
a
b
c
All are isolated yields. 72% recovered 8a. 16% recovered 8c.
rearrangements involving the 4,5-fused series required much
higher temperatures (195 °C) than those in the 4,6-fused series
(100−120 °C).
The rearrangement of 8 to 12 is proposed to commence with
formation of the conjugated cyclobutenone 11 (syn/anti), as
previously observed by Ficini10c for 4 (Scheme 2). 4π
electrocyclic ring opening of 11 gives 12. Each isomer of 11
undergoes ring opening with complete torquoselectivity,
avoiding unfavorable inward rotation by the cyclopentanone
alkyl group that would lead to a highly strained trans-
cyclopentenone. Thus, 12-cis is derived from 11-anti and 12-
trans from 11-syn.
Why does 8 rearrange to 12, rather than to 10? Theoretical
calculations (Figure 3a) in fact predict that the cis,trans-
cycloheptadienone 9-E,E, which would be the precursor of 10,
can be accessed from 8 with a barrier of 33.1 kcal/mol (TS9).
This value is only 0.8 kcal/mol higher than the barrier for
formation of 2-E,E from 1. It is therefore likely that some 9-E,E
is formed transiently during the course of the reaction at 195
°C. The transient formation of 9-E,E is not reflected in the final
product distribution, however, because the transannular
cyclization product 10 is higher in energy than the starting
cyclobutenamide (ΔG = 10.4 kcal/mol).18 Given the
thermodynamic driving force against the formation of 10, the
cis,trans-cycloheptadienone 9-E,E reverts to 8 which rearranges
by the alternative pathway shown in Figure 3b to 12.
Conversion of 8 to the α,β-unsaturated intermediate 11 is
likely to be acid catalyzed.19 Formation of 12-cis and 12-trans
from 8 has ΔG ≈ −12 kcal/mol.
Figure 3. Free energy profiles for thermal rearrangements of 8 to (a)
10 and (b) 12 in toluene.
leads to monocyclic amido-dienes 12. The differing behavior
between 1 and Ficini’s 4,6-fused cyclobutenamines 4 likely
reflects the lower basicity of 1, which inhibits the isomerization
to a conjugated cyclobutenamide (cf. 5) that would trigger
rearrangement to monocyclic amido-dienes. Further synthetic
and mechanistic studies and development of an asymmetric
variant are underway.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, compound characterizations, NMR
spectra, X-ray data, computational methods and data,
supporting mechanistic discussion, and a complete citation
for ref 11. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Authors
e.krenske@uq.edu.au
houk@chem.ucla.edu
rhsung@wisc.edu
We have documented here the thermal rearrangements of
4,6-fused and 4,5-fused cyclobutenamides 1 and 8 and the
discovery of contrasting mechanistic pathways. Theory predicts
that 1 and 8 undergo electrocyclic ring opening to cis,trans-
cyclooctadienone 2-E,E and cis,trans-cycloheptadienone 9-E,E,
respectively. For 2-E,E, Nazarov-like ring closure leads to 5,5-
bicyclic amido-dienes 3, but for 9-E,E, Nazarov cyclization is
thermodynamically disfavored and an alternative rearrangement
Present Address
§Visiting PhD student from Department of Chemistry, Oregon
State University, 153 Gilbert Hall, Corvallis, Oregon 97331,
United States.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We thank the NIH (GM-66055 to R.P.H.), NSF (CHE-
0548209 to K.N.H.), and Australian Research Council
(FT120100632 to E.H.K.) for generous financial support, and
the NCI NF (Australia) and University of Queensland
Research Computing Centre for computer resources. R.C.J.
thanks Oregon State University for a 2013−2014 Graduate
Internationalization Grant.
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(14) In contrast, H-bonding catalysis by a water molecule lowers the
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(15) O-Protonation of cyclobutenamide 1 (R = Me, X = SO2Ph)
lowers the barrier for cyclobutene ring opening to 21.3 kcal/mol.
(16) When 1a was heated at 100 °C in the presence of 0.4 equiv of
CSA, we obtained a complex mixture due to decomposition of 1a.
However, we were able to identify from the mixture all four products
including those corresponding [see i] to Ficini’s observations.
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