AlCl3-catalyzed ring expansion cascades of bicyclic cyclobutenamides involving highly strained cis,trans-cycloheptadienone intermediates

Article abstract of DOI:10.1021/jacs.5b02561

We report the first experimental evidence for the generation of highly strained cis,trans-cycloheptadienones by electrocyclic ring opening of 4,5-fused cyclobutenamides. In the presence of AlCl₃, the cyclobutenamides rearrange to [2.2.1]-bicycl

Full text of DOI:10.1021/jacs.5b02561

Article
pubs.acs.org/JACS
AlCl3‑Catalyzed Ring Expansion Cascades of Bicyclic
Cyclobutenamides Involving Highly Strained Cis,Trans-
Cycloheptadienone Intermediates
Xiao-Na Wang,†,‡ Elizabeth H. Krenske,*,§ Ryne C. Johnston,§,¶ K. N. Houk,*,∥ and Richard P. Hsung*,‡
†School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450001 P. R. China
‡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, Queensland 4072, Australia
∥Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095 United States
S
* Supporting Information
ABSTRACT: We report the first experimental evidence for the
generation of highly strained cis,trans-cycloheptadienones by
electrocyclic ring opening of 4,5-fused cyclobutenamides. In the
presence of AlCl3, the cyclobutenamides rearrange to [2.2.1]-
bicyclic ketones; DFT calculations provide evidence for a
mechanism involving torquoselective 4π-electrocyclic ring
opening to a cis,trans-cycloheptadienone followed by a
Nazarov-like recyclization and a 1,2-alkyl shift. Similarly, 4,6-
fused cyclobutenamides undergo AlCl3-catalyzed rearrangements to [3.2.1]-bicyclic ketones through cis,trans-cyclooctadienone
intermediates. The products can be further elaborated via facile cascade reactions to give complex tri- and tetracyclic molecules.
Scheme 2. Thermal Rearrangements of 4,5-Fused
Cyclobutenamides 2
INTRODUCTION
■
Small-ring trans-cycloalkenes have unique structural properties
and reactivities, arising from the distortion of the double bond
and the associated ring strain.1−6 Among the parent trans-
cycloalkenes, trans-cyclooctene is an isolable compound,2f while
trans-cycloheptene has a lifetime of several minutes at −10 °C,
and trans-cyclohexene is a fleeting intermediate formed by
photolysis of the cis isomer.2d Strain-induced reactivity of trans-
cycloalkenes has found applications in bioconjugate chemistry,
where strain-promoted [4 + 2] cycloadditions of trans-
cyclooctenes with tetrazines have been utilized for protein
labeling and cellular imaging.1d
Recently, we reported7 a new entry point into trans-
cycloalkene chemistry involving rearrangements of readily
prepared8−11 cyclobutenamides 1 and 2 (Schemes 1 and 2).
Under thermal conditions, 4,6-fused cyclobutenamides 1
rearrange to pentalenes 4 via E,E-cyclooctadienones 3, which
contain one cis and one trans double bond. Highly
Scheme 1. Thermal Rearrangements of 4,6-Fused
Cyclobutenamides 1
torquoselective ring opening of 1 to the E,E-isomer of 3,
followed by Nazarov-type recyclization, was supported by
theoretical studies.
Received: March 10, 2015
© XXXX American Chemical Society
A
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In contrast to 1, thermal reactions of 4,5-fused cyclo-
butenamides 2 gave 2-amidodienes 5. These products arise
from isomerization of 2 to 2′ and do not involve formation of
cycloheptadienones 6.10,11 Nevertheless, we sought suitable
conditions to generate the highly strained cycloheptadienones,
because theory predicted7 that ring opening of 2 to 6 has a
similar barrier to the opening of 1 to 3. We now report
evidence for the generation of these highly strained cyclo-
heptadienone intermediates in AlCl3-catalyzed rearrangements
of 2. The Lewis acid-catalyzed rearrangements yield different
products from the corresponding thermal and Brønsted acid-
catalyzed rearrangements and trigger cascade reactions leading
to complex polycyclic molecules.
RESULTS AND DISCUSSION
We first examined the effects of Brønsted acid on the
rearrangements of 2 (Figure 1). In the presence of 0.4 equiv
■
Figure 2. AlCl3-catalyzed rearrangements of 4,5-fused cyclobutena-
mides 2 to [2.2.1]-bicyclic ketones 8 (a, isolated yields b, ratios
1
determined by H NMR spectroscopy).
Scheme 3. Two Possible Pathways for the AlCl3-Catalyzed
Rearrangement of Cyclobutenamides 2 to Ketones 8
Figure 1. Brønsted acid-catalyzed rearrangements of 4,5-fused
cyclobutenamides 2 to 2-amidodienes 5 (a, isolated yields b, ratios
1
determined by H NMR spectroscopy).
camphorsulfonic acid (CSA), cyclobutenamides 2 rearranged to
2-amidodienes 5, the same products as obtained from thermal
rearrangements.7,12−14 The Brønsted acid-mediated rearrange-
ments were higher yielding and faster than the thermal
reactions, presumably because the acid catalyzes the isomer-
ization of 2 to 2′ (which is rate limiting under thermal
conditions).7 In contrast to 2, 4,6-fused cyclobutenamides 1
containing the cyclohexanone instead of cyclopentanone
(Scheme 1) were found to decompose in the presence of 0.4
equiv CSA.
Different reactivity was observed when rearrangements of 2
were conducted in the presence of a Lewis acid (Figure 2).
Treatment of 2a with 0.4 equiv AlCl3 (toluene, 105 °C) gave
[2.2.1]-bicyclic ketone 8a in 68% yield. The structure of 8a was
unambiguously assigned via its single-crystal X-ray structure
(Figure 2), and minor quantities of 2-amidodiene 5a (10%)
were also isolated, exclusively as the Z isomer.15 Similar
products were obtained from AlCl3-catalyzed rearrangements of
cyclobutenamides 2b and 2c, which bear Ts and Mbs groups,
respectively, on nitrogen.
for the thermal and AlCl3-catalyzed rearrangements of 2 in
toluene. Calculations were performed at the M06-2X/6-
311+G(d,p)//B3LYP/6-31G(d) level of theory,17,18 simulating
the solvent with the SMD model.19 All attempts to locate the
first 1,2 shift transition state (TS) in Path A led instead to
electrocyclic ring opening. The conformation required for a 1,2
shift TS, in which C-1 and C-2 must be coplanar, is effectively
the same as that required for ring opening.20 Moreover, ring
opening is thermodynamically favored by the extended
conjugation in pentenyl cation 10 as compared to allyl cation
11.21 The calculations therefore support Path B. Coordination
of the cyclobutenamide to AlCl3 significantly accelerates ring
opening: the barrier for ring opening of 9 (ΔG⧧ = 28.3 kcal/
mol) is 5 kcal/mol lower than that for opening of 2 (33.1 kcal/
mol). The intermediate cycloheptadienone is stabilized by
about 3 kcal/mol by coordination to AlCl3 (10 vs 6). The
torquoselectivity of ring opening, favoring the E,E- rather than
the Z,Z-isomer of 10, is predictable based on the established
effects of donor and acceptor groups on cyclobutene ring
opening.22
Nazarov-like cyclization of cycloheptadienone 10 furnishes
11, which undergoes a 1,2-alkyl shift to give 12. Both of these
steps have barriers that are 4 kcal/mol lower than that for
cyclobutenamide ring opening. The overall transformation of 9
to 12 is thermodynamically favored by 4 kcal/mol.23 In
contrast, uncatalyzed rearrangement of 2 may proceed only as
far as 7, which is uphill by 10.4 kcal/mol. Thus, coordination to
AlCl3 serves both to activate the cyclobutenamide toward
cycloheptadienone formation and to provide a low-energy
pathway for cycloheptadienone rearrangement that is not
We considered two alternative mechanisms for the AlCl3-
catalyzed rearrangement of 2 to 8 (Scheme 3). In Path A, a
sequence of two 1,2-alkyl shifts converts AlCl3-coordinated
cyclobutenamide 9 into [2.2.1]-bicyclic 12 via intermediate 11.
In Path B, the cyclobutenamide undergoes electrocyclic ring
opening to coordinated cycloheptadienone 10, followed by
Nazarov-like recyclization to 11 and then a 1,2-alkyl shift giving
12.
Density functional theory (DFT) calculations16 provided
insights into the rearrangement mechanism and the role of the
Lewis acid. Figure 3 shows the computed free energy profiles
B
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Figure 3. Free energy profiles for (a) thermal7 and (b) AlCl3-catalyzed rearrangements of 4,5-fused cyclobutenamide 2 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 4. Free energy profiles for (a) thermal7 and (b) AlCl3-catalyzed rearrangements of 4,6-fused cyclobutenamide 1 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.
available to the thermal reaction.24,25 The availability of this
downhill pathway explains why cycloheptadienone-derived
products are obtained in the AlCl3-catalyzed rearrangement of
2 but not in the thermal rearrangement.
Other Lewis acids, such as TMSOTf, BF3-OEt2, TiCl4, Ti(i-
PrO)2Cl2, AlMe2Cl, AlEtCl2, CuCl2, Zn(OTf)2, and AgSbF6
were not effective in promoting the rearrangement of 2 to 8.
These Lewis acids gave only 2-amidodienes 5, in very low
yields, together with hydrolysis of the starting cyclobutena-
mide.12 Traces of water are essential: when the reaction was
performed in the presence of 4 Å molecular sieves, cyclo-
butenamide 2 was completely recovered. It is likely that traces
of HCl are formed by hydrolysis, and the strong acid HAlCl4
may play a role.
Calculations on the corresponding rearrangements of 4,6-
fused cyclobutenamides 1 are shown in Figure 4. The AlCl3-
catalyzed rearrangement of 1 displays a qualitatively similar
energy profile to that of 2 but has a smaller barrier (ΔG⧧ = 22.9
kcal/mol) and is more thermodynamically favored (ΔG = −9.0
kcal/mol). The product is a [3.2.1]-bicyclic ketone. Consistent
with these theoretical findings, AlCl3-catalyzed rearrangements
of cyclobutenamides 1a−c (Figure 5) were found experimen-
tally to be cleaner reactions, giving [3.2.1]-bicyclic ketones
17a−c in nearly quantitative yield. No 2-amidodienes
analogous to 5 were obtained. In contrast to 4,5-fused
C
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Figure 6. (a) Formation of tri- and tetracyclic products 21 from 4,6-
fused cyclobutenamides 1. (b) Proposed mechanism for the cascade.
Figure 5. AlCl3-catalyzed rearrangements of 4,6-fused cyclobutena-
mides 1 to [3.2.1]-bicyclic ketones 17.
place with cyclobutenamide 1f, however, where the rearrange-
ment was arrested at ketone 17f. Structurally, 1f differs from 1j
(and 1k and 1l) by having a more electron-rich N-substituent
(Mbs versus Ns or Ts). The cascade leading to aza-tri- and
tetracycles 21 is rapid. For example, when the rearrangement of
1j was performed in toluene-d6 and monitored by NMR, 21j
was found to be formed within 10 min, with no detectable
formation of [3.2.1]-bicyclic ketone 17j.26
cyclobutenamides 2, the rearrangements of 1 could also be
catalyzed by other Lewis acids. Specifically, we found that BF3-
OEt2 and AlMe2Cl were as effective as AlCl3 in catalyzing the
rearrangement of 1c to 17c,12 while TMSOTf, Ti(i-PrO)2Cl2,
Zn(OTf)2, and AgSbF6 afforded low to modest yields of 17c.
Compared with the rearrangements of 2, the more facile
rearrangements of 1 reflect the easier ring opening to the less
strained, eight-membered cyclic dienones, and the lower
energies of the TSs for the ensuing Nazarov-type cyclization
and 1,2-alkyl shift. The generality of this transformation is
exemplified by the high-yielding syntheses of bicyclic ketones
17d−i from cyclobutenamides 1d−i (Figure 5).
The AlCl3-catalyzed rearrangement of 1j, bearing a tethered
alkene on nitrogen, did not give any of the expected bicyclic
ketone 17j but instead gave the complex aza-tetracycle 21j in
87% yield (Figure 6). The structure of 21j was unambiguously
determined from its single-crystal X-ray structure. Calculations
on this skeletal rearrangement (see the Supporting Informa-
tion) mapped out a mechanism involving Prins-like cyclization
of the tethered alkene onto bicyclic intermediate 16j. Due to
geometrical constraints imposed by the tether, the formation of
the C−C bond between the alkene terminus and the
carbocationic center occurs concomitantly with formation of
a C−C bond between the substituted alkene carbon and the
nitrogen-substituted carbon of the enamide [a formal (3 + 2)
cycloaddition]. A 1,2-alkyl shift then gives 19j, which undergoes
retro-aldol ring opening to furnish the tetracyclic skeleton of
21j. This cationic cascade does not apply to all types of
tethered alkenes (see 17f−h in Figure 5) but appears facile for
certain cyclobutenamides containing a homoallyl group. Thus,
aza-tricycles 21k and 21l were obtained in high yields from 1k
and 1l, respectively (Figure 6). The Prins cascade did not take
CONCLUSIONS
■
We have documented here the generation of highly strained
seven- and eight-membered cis,trans-cycloalkadienones by
AlCl3-catalyzed ring opening of fused cyclobutenamides 2 and
1, respectively. While cycloheptadienones had previously been
theoretically predicted to be generated from 2 under thermal
conditions,7 the use of Lewis acidic conditions has allowed their
reactivity to be studied for the first time. The bicyclic ketones
derived from the novel Lewis acid-catalyzed rearrangements of
1 and 2 serve as excellent platforms for the synthesis of
complex targets, as exemplified by the facile cascade syntheses
of tri- and tetracyclic compounds 21. It is noteworthy that such
structural complexity can be generated in a one-pot operation
from simple cyclobutenamides, which are themselves derived
from straightforward [2 + 2] cycloadditions of enones with
readily available ynamides.
EXPERIMENTAL SECTION
■
Rearrangement of 4,6-Fused Cyclobutenamides 1. To a
flamed-dried sealed tube were added cyclobutenamide 1a (58.7 mg,
0.14 mmol), toluene (2.1 mL, cyclobutenamide concn = 0.067 M) and
AlCl3 (1 M in nitrobenzene) (55.1 μL, 0.055 mmol) at rt. The reaction
vessel was then capped and directly heated to 105 °C. After stirring at
105 °C for 1 h, the reaction mixture was cooled to rt slowly. The crude
mixture was purified using silica gel flash column chromatography
D
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(first using hexane to wash toluene away, and then isocratic eluent:
15% EtOAc in Hexane) to afford bicyclic ketone 17a (57.0 mg, 0.13
mmol) in 97% yield.
(2) For earlier studies of trans-cycloalkenes, see: (a) Bach, R. D. J.
Am. Chem. Soc. 2009, 131, 5233. (b) Strickland, A. D.; Caldwell, R. A.
J. Phys. Chem. 1993, 97, 13394. (c) Marshall, J. A.; Konicek, T. R.;
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(e) Cope, A. C.; Moore, W. R.; Bach, R. D.; Winkler, H. J. S. J. Am.
Chem. Soc. 1970, 92, 1243. (f) Cope, A. C.; Bach, R. D. Org. Synth.
1969, 49, 39. (g) Binsch, G.; Roberts, J. D. J. Am. Chem. Soc. 1965, 87,
5157. (h) Cope, A. C.; Ganellin, C. R.; Johnson, H. W., Jr.; Van
Auken, T. V.; Winkler, H. J. S. J. Am. Chem. Soc. 1963, 85, 3276.
(i) Blomquist, A. T.; Liu, L. H.; Bohrer, J. C. J. Am. Chem. Soc. 1952,
74, 3643.
(3) For recent leading examples, see: (a) Ralph, M. J.; Harrowven, D.
C.; Gaulier, S.; Ng, S.; Booker-Milburn, K. I. Angew. Chem., Int. Ed.
2015, 54, 1527. (b) Miura, T.; Nakamuro, T.; Liang, C.-J.; Murakami,
M. J. Am. Chem. Soc. 2014, 136, 15905. (c) Darko, A.; Wallace, S.;
Dmitrenko, O.; Machovina, M. M.; Mehl, R. A.; Chin, J. W.; Fox, J. M.
Chem. Sci. 2014, 5, 3770. (d) Herth, M. M.; Andersen, V. L.; Lehel, S.;
Madsen, J.; Knudsen, G. M.; Kristensen, J. L. Chem. Commun. 2013,
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Rearrangement of 4,5-Fused Cyclobutenamides 2. To a
flamed-dried sealed tube were added cyclobutenamide 2a (82.5 mg,
0.20 mmol), toluene (3.0 mL, cyclobutenamide concn = 0.067 M) and
AlCl3 (1.0 M in nitrobenzene: 80.0 μL, 0.080 mmol) at rt. The
reaction vessel was then capped and directly heated to 105 °C. After
stirring at 105 °C for 3.0 h, the reaction mixture was allowed to cool to
rt slowly. The crude mixture was purified using silica gel flash column
chromatography (first using hexane to wash toluene away, and then
gradient eluent: 15% to 33% EtOAc in Hexane) to afford bicyclic
ketone 8a (56.1 mg, 0.14 mmol) in 68% yield and 2-amidodiene 5a-Z2
(8.6 mg, 0.021 mmol) in 10% yield.
Computational Methods. Geometry optimizations were per-
formed in the gas phase at the B3LYP/6-31G(d) level of theory.17
Vibrational frequency calculations indicated the nature of each
stationary point (local minimum or first-order saddle point), and the
computed frequencies were also used to derive unscaled zero-point
energy and thermochemical corrections. Solvation energies were
computed by means of single-point calculations with B3LYP/6-
31G(d) in implicit toluene using the SMD continuum method.19
Single-point energies were computed at the M06-2X/6-311+G(d,p)
level of theory in the gas phase.18 Free energies in solution were
calculated by adding the B3LYP zero-point energy, thermochemical
corrections, and solvation energy to the M06-2X potential energy. A
standard state of 298.15 K and 1 mol/L was used.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, compound characterizations, NMR
spectra, X-ray structural files, computational methods and
computational data. This material is available free of charge via
the Internet at http://pubs.acs.org.
(4) For examples containing N, O, or S linkages, see: (a) Tomooka,
K.; Uehara, K.; Nishikawa, R.; Suzuki, M.; Igawa, K. J. Am. Chem. Soc.
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(5) For seminal studies of 1,5-cis,trans-cyclooctadiene, see: (a) Cope,
A. C.; Howell, C. F.; Knowles, A. J. Am. Chem. Soc. 1962, 84, 3190.
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AUTHOR INFORMATION
■
Corresponding Authors
*e.krenske@uq.edu.au
*houk@chem.ucla.edu
*rhsung@wisc.edu
(6) For experimental and theoretical studies of the electrocyclic ring
opening of cis-bicyclo[4.2.0]oct-7-ene to cis,trans-1,3-cyclooctadiene,
and subsequent isomerization to cis,cis-1,3-cyclooctadiene, see:
Present Address
¶Visiting Ph.D. student from Department of Chemistry,
Oregon State University, 153 Gilbert Hall, Corvallis, Oregon
97331, United States.
́
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ez, C.; Nieto Faza, O.; de Lera, A. R. Chem.−Eur. J.
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Notes
The authors declare no competing financial interest.
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 National Computational Infrastructure National Facility
(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.
(7) Wang, X.-N.; Krenske, E. H.; Johnston, R. C.; Houk, K. N.;
Hsung, R. P. J. Am. Chem. Soc. 2014, 136, 9802.
(8) For leading reviews on ynamide chemistry, see: (a) Wang, X.-N.;
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R. P. Acc. Chem. Res. 2014, 47, 560. (b) DeKorver, K. A.; Li, H.; Lohse,
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E
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(13) 2-Amidodienes 5-Z and 5-E interconvert under the reaction
conditions but do not fully equilibrate during the time scale of the
synthetic experiments. The Z/E ratios depend on the rates of
isomerization of 2 to 2′-trans/cis, which are believed7 to be rate-
limiting.
(14) In an effort to trap any cycloheptadienone 6 that might be
generated, we attempted an intramolecular Diels−Alder reaction
starting from 2d (see hypothetical DA transition state 6d). However,
only the normal 2-amidodienes 5d (Z/E) were obtained (93%).
(15) DFT calculations predict that ring opening of 2 to 5-Z is favored
by 4 kcal/mol (ΔΔG⧧) over opening to 5-E (see the Supporting
Information).
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(21) It is possible that, due to a relatively flat potential energy surface
in the region of TS2, dynamical effects lead to some direct conversion
of 9 to 11. See: Ess, D. H.; Wheeler, S. E.; Iafe, R. G.; Xu, L.; Çelebi-
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Olcu̧ m, N.; Houk, K. N. Angew. Chem., Int. Ed. 2008, 47, 7592.
̈
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Chem. Res. 1996, 29, 471.
(23) Decomplexation of AlCl3 from 12 is uphill by 29 kcal/mol.
However, in the catalytic cycle, product inhibition is avoided because
complex formation between 2 and AlCl3 is very favorable (−33 kcal/
mol).
(24) It is not possible to quantitatively compare the rates of
formation of 5 and 8, because the step that is likely to be rate-
determining in the formation of 5 (isomerization of 2 to 2′) is
catalyzed by traces of protic acid. However, the computed barriers for
electrocyclic ring opening of 2′-trans to 5-Z and 2′-cis to 5-E (25.3 and
29.3 kcal/mol, respectively) are consistent with the experimentally
observed exclusive Z selectivity in the formation of 5a−c (see the
Supporting Information).
(25) In our previous study7 we concluded that traces of water are
essential for the thermal rearrangement of 1 to 4; specifically, a
molecule of water acts a Brønsted acid catalyst of the Nazarov-like
cyclization of 3 to 4.
(26) Calculations indicate that the conversion of 16 to 20 (as the
AlCl3 complex) has ΔG⧧ = 15.7 kcal/mol and ΔG = −14.2 kcal/mol
(see the Supporting Information).
F
DOI: 10.1021/jacs.5b02561
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX