An elusive thermal [2 + 2] cycloaddition driven by visible light photocatalysis: Tapping into strain to access C 2-symmetric tricyclic rings

Article abstract of DOI:10.1039/c8ob01273c

A mild and operationally simple methodology is reported for the synthesis of cyclobutane rings imbedded within a C2-symmetric tricyclic framework. The method uses visible light and an iridium-based photocatalyst to drive the oft-stated "forbidden" thermal

Full text of DOI:10.1039/c8ob01273c

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DOI: 10.1039/C8OB01273C
Organic & Biomolecular Chemistry
ARTICLE
An elusive thermal [2+2] cycloaddition driven by visible light
photocatalysis: Tapping into strain to access C2-symmetric
tricyclic rings
Received 00th January 20xx,
Accepted 00th January 20xx
Kamaljeet Singh, Winston Trinh, and Jimmie D. Weaver III*
DOI: 10.1039/x0xx00000x
A mild and operationally simple methodology is reported for the synthesis of cyclobutane rings imbedded within a C2-
symmetric tricyclic framework. The method uses visible light and an iridium-based photocatalyst to drive the oft-stated
“forbidden” thermal [2+2] cycloaddition of cycloheptenes and analogs. Importantly, it generates cyclobutane with four new
stereocenters with excellent stereoselectivity, and perfect regioselectivity. The reaction is propelled forward when the
photocatalyst absorbs a visible light photon, which transfers this energy to the cycloheptene. Key to success is, upon
excitation to the triplet via sensitization from the photocatalyst, the double bond isomerizes to give the transient, highly
strained, trans-cycloheptene. The trans-cycloheptene undergoes a strain relieving thermal, intermolecular [π2s+π2a]
cycloaddition with another cis-cycloheptene. X-ray analysis reveals that the major product is the head-to-head, C2-
symmetric all trans-cyclobutane. Additionally, a dramatic display structural complexity enhancement is observed with the
use of chiral cycloheptenols possesing one stereocenter, which result in the formation of cyclobutanes with six contiguous
stereocenters with good to excellent diastereocontrol, and can be used to isolate single stereoisomers of stereochemically
complex cyclobutanes in good yield.
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Introduction
Cyclobutane rings are found in naturally occurring alkaloids and
biologically relevant molecules,1, 2 and the [2+2] cycloaddition
of olefins represents a powerful strategy for the synthesis of
such cyclobutane rings. Although thermal [2+2] cycloadditions
are energetically favorable (ΔGo
= -18.0 kcal/mol for
dimerization of ethene),3, they are generally considered
“forbidden” because the suprafacial approach of pi-orbitals of
the alkenes does not give the necessary overlap. While
generally kinetically much less feasible because of steric
inhibition, the orbital symmetry requirements can be met via an
antara- / supra-facial approach of the alkenes.5 The common
exception is the [π2s+π2a] of ketenes with alkenes, which is made
possible because of the minimal steric hindrance of the ketene
partner. Transition metal catalysis offers alternative pathways
to promote [2+2] cycloaddition reactions,6-9 with Ti, Mn, Fe, and
Ni having been employed.10, 11 The presence of d-orbitals in the
transition metals allows the [2+2] reaction between alkenes by
virtue of low energy pathways to metallacycle intermediates.
Another way to overcome the orbital symmetry constraint is to
proceed through the photochemical [2+2], in which a higher
4
energy orbital is utilized and allows the more facile suprafacial
approach of both alkenes in the cycloaddition.12 Unfortunately,
the direct irradiation of cycloalkenes with a high energy UV light
source often produces a mixture of rearranged products (path
13-15
a, Scheme 1).
One alternative to direct irradiation is sensitization.
However, again the sensitization of the cycloalkenes, when UV
light is used, generally produces mixture of various
cyclobutane stereoisomers (path b Scheme 1), as well as other
sensitizer-alkene adducts. These are formed from different
mechanisms originating on the excited state alkene surface.
Another strategy which has been investigated is the formation
a
107 Physical Science, Department of Chemistry, Oklahoma State University,
Stillwater OK 74078.
* Email: jimmie.weaver@okstate.edu
Electronic Supplementary Information (ESI) available: Experimental procedures,
characterization, and spectral data. CCDC: 1581327, 1814020, and 1840823. See
DOI: 10.1039/x0xx00000x
,
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and subsequent trapping of the ground state trans- expected to be relatively diminished. The decreVaieswedArtricelelaOtnilvinee
DOI: 10.1039/C8OB01273C
cycloheptene, which can result upon relaxation from the energy barriers of the transition states might make it possible
excited state.16, 17 One such attempt employed is the use of for otherwise difficult thermal [π2s+π2a] cycloadditions to take
copper triflate (4 mol%) under UV light irradiation. In this place for ground state alkenes. For cyclic alkenes, isomerization
method, Cu+ redshifts the absorption and coordinates to the leads to trans-cycloalkenes, which are known to increase in
strained, ground state trans-cycloheptene sterically restricting strain energy with decreasing ring size.40 Key to success, would
the number of available approaches to the cis-cycloheptene, be controlling the concentration of both the excited alkene, and
thereby minimizing the number of diastereomers formed. In a strained trans-cycloalkene. Based on our previous work,38, 41, 42
direct comparison, the acetone sensitized UV irradiation of we anticipated that the use of visible light photocatalysis would
cyclohexene produced the trans-anti-trans dimer in 1%, allow us to carefully control the concentration of transient,
whereas when catalytic Cu and UV light18-21 were employed, the highly strained, trans-phenylcycloheptene, which we
trans-anti-trans dimer was formed in 49% yield.17, 22-24 While anticipated would either undergo the desired thermal [π2s+π2a]
Cu+ enhanced the stereoselectivity, the reaction still produced reaction with the more abundant cis-phenylcycloheptene, or
multiple stereoisomers and products. Similarly, Corey and alternatively simply revert back to the relaxed isomer with the
Eaton25 have demonstrated the ability to generate trans- evolution of heat. Moving out of the UV and into the visible
cycloheptenones via direct UV irradiation, and Bunce26 and spectrum would ensure that competitive photochemical [2+2]
Margaretha27 have studied their dimerization as cyclobutanes. does not occur, and might make it possible to selectively
Consequently, despite promising results, essentially no scope perform a thermal [π2s+π2a] cycloaddition.
was demonstrated.28 While there are some clear shortcomings,
this strategy becomes much more attractive if visible light can Results and discussion
be used for excitation, because of the lower energy
irradiation.29
Starting with similar conditions to our previous work,43 we
performed a reaction with Ir catalyst
A (0.3 mol%) in MeCN, at
In this context, Yoon has showcased elegant examples of 30 oC, under an atmosphere of argon, with 0.05
M
visible light mediated [2+2] cycloaddition reactions of styrenyl concentration of 1a, using blue LEDs. We were pleased to see
80% conversion to the desired product 2a after 24 h of
irradiation, as observed by 19F NMR (entry 1, Table 1).
Screening revealed that the reaction progressed in a number of
solvents, which is consistent with a reaction that does not
generate polar intermediates.
However, the solvent
dimethylformamide (DMF) provided full conversion within 24 h
of irradiation (entry 3). Next, we examined the role of the
catalyst structure in the reaction. For these experiments, lower
catalyst loadings (0.08 mol%) were used to slow the reactions,
and exaggerate the differences in reactivity, making it easier to
discern the effects on the rates of the reactions.
We anticipated that the catalyst structure would be
important, having previously observed that the catalyst volume,
in addition to its emissive energy, played a significant role in the
rate of isomerization of styrene derivatives; rates slowed as the
photocatalyst became larger.44 Indeed, we found that Cat A 45
,
derivatives either by electron transfer30-33 or energy transfer
which is significantly smaller46 than the other catalysts, gave
higher conversion in the same time period than sterically larger
35
mechanisms34,
initiating from the excited state of
photocatalyst (Scheme 2A). Reiser has recently shown the [2+2]
dimerization of chalcones, cinnamates, and styrene motifs to
access substituted cyclobutanes in moderate to good
diastereoselectivities.36 Recently, Lu has also shown the
synthesis of cyclobutane rings by [2+2] cycloaddition reactions
between 1,4-dihydropyridines and styrenes via energy
transfer.37 Common to each of these reactions was the use of a
visible light photocatalyst, which interacts with the alkene to
directly excite a ground state alkene to its triplet. The triplet
then reacts with a ground state singlet alkene via [π2s+π2s]
mechanisms (i.e. photochemical [2+2]), yielding substituted
cyclobutanes in moderate to good diastereoselectivities.
Cat B
Cat C and Cat D are substantially higher than that of catalyst Cat
, confirming that the exergonicity of the sensitization is not the
, Cat C, and Cat D (entries 6-9). The emissive energies of
B
only important feature. Thus, we used Cat A for further
optimization. Next, the effect of catalyst loading was evaluated.
With higher catalyst loadings, greater conversion to the product
2a was observed within the same time period (entries 10-12).
The photocatalyst is an 18-electron complex that is
coordinatively saturated with three chelating ligands, making it
very robust. This is evidenced by the high catalyst turnover
number (1563 in entry 10), and likely represents a minimum
since this was suboptimal conditions, and that the reaction had
not yet reached completion.
A
conceptually different approach to synthesizing
cyclobutanes is to initially capture the energy in the form of ring
strain. Owing to the immense ring strain (ca. 27-36 kcal/mol for
trans-cycloheptene),16, 24, 38, 39 subsequent energy barriers are
Given that the lifetime of the strained trans-cycloheptene
was anticipated to decrease with increasing temperature, we
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Specifically, it showed that the dimerization resulted in the
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formation of the head-to-head regioisoDmOeI:r1,0a.1n0d39t/hCa8tObB0o1t2h737C-
membered rings were trans-fused onto the cyclobutane and
trans to the other 7-membered ring. Both rings adopted a
chair conformation (Fig. 1).
This stereochemical outcome is best explained by the
involvement of the ground state trans-cycloheptene and a cis-
cycloheptene, operating under orbital symmetry conservation
restrictions, which dictates that the olefins approach one
another orthogonally.12 Within this restriction, there are
several potential ways in which such an orthogonal approach
could occur. At the outset, the involvement of two cis-
phenylcycloheptenes can be ruled out, because these do not
dimerize on their own.48
Likewise, other unobserved
stereochemical possibilities A3 and A4 could stem from the
cycloaddition of two trans-phenyl cyloheptenes. This scenario
is both statistically unlikely, due to the short half-life of the
strained cycloalkene, and furthermore, is expected to be
higher in energy because of severe interactions between the
phenyl rings, as well as the methylene bridges of the
cycloheptene rings. A more likely scenario involves one
isomerized trans-phenylcycloheptene and one cis-
phenylcycloheptene,22 of which there are two possible
approaches (Fig. 2).
evaluated the effect of temperature on the reaction outcome.
To our surprise, the rate of reaction was found to be relatively
impervious across a range of temperatures (-30 to 15 oC)
o
(entries 13-16), however, upon increase to 30 C an increase in
the reaction rate was observed.47 Finally, control experiments
revealed that both light and photocatalyst are necessary
components for the desired [π2s+π2a] cycloaddition reaction.
Having determined optimal conditions, we next assessed
the stereochemical outcome of the reaction. When allylic
alcohol 1a was dimerized, X-ray analysis revealed that the major
The major isomer, A1 (as confirmed by x-ray analysis of 2a),
most probably results from the orthogonal approach of the cis-
and trans-phenylcycloheptenes. This approach occurs in such a
way that both the phenyl groups point away from one another
diastereomer was the C2-symmetric cylclobutandiol, 2a
.
(
TS1
Alternatively, if the phenyl groups approach on the same side
TS2), this leads to cyclobutane A2, in which both the phenyl
, Fig. 2) in order to minimize the steric interaction.
(
groups will be cis to each other. It was anticipated that there
would be considerable steric interactions between the phenyl
groups in this transition state, which also lead to a higher energy
product (vide infra). Thus, while up to 128 regio- and
stereoisomers are possible, the reaction takes place
Fig. 1 X-ray crystal structure of major diastereomer 2a
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predominantly through TS1, and gives primarily a cyclobutane direction. Thus, we became curious to learn more about the
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DOI: 10.1039/C8OB01273C
energetics of the reaction. When we looked into the literature,
of type A1
.
The possibility of a stepwise mechanism involving the we found that although the dimerization of ethylene to
excited state biradical can be ruled out for several reasons. cyclobutane was exergonic in nature, that the dimerization of
First, when the reaction was run in presence of TEMPO (a radical more substituted alkenes became progressively more
scavenger), no TEMPO adduct was formed, nor was the rate or endergonic. In fact, Burford has calculated that the reaction is
yield reduced. TEMPO and other radical traps have been shown expected to be slightly endergonic with 1,2-mesityl substitution
to inhibit stepwise radial additions.37 Further, we did not and when the methyl groups of mesitylenes were replaced with
observe any dicycloheptanes arising from failure to complete iPr groups, the dimerization became endergonic by 5-16
the cyclization which is often seen when such step-wise kcal/mol. In general, the endergonicity of the dimerization
additions occur18 (see path b, Scheme 1). Finally, we found that reaction increases further with increase in the steric bulk
the electronics of the phenyl ring did not substantially impact around the cyclobutane.50 This sensitivity to the sterics is
the rate of the reaction which would be expected to affect both expected. First, substitution of alkenes stabilizes the starting
the rate and selectivity of the reaction.36, 49
material, ethelyene being the least substituted and stable.
As we were capturing a portion of the photochemical energy Additionally, the cyclobutane ring dramatically exaggerates
38
in the form of strain energy (i.e. ca 36 kcal/mol) this raised steric interactions when compared to their cyclohexane
the possibility that we could be formally performing uphill magnitudes. To probe this question, we performed the
catalysis, by driving the reaction in the contra thermodynamic computational analysis of the thermodynamics of several [2+2]
Fig. 3 The energies of the various diastereomers reported are relative to the phenyl cycloheptene as calculated using B3LYP/6-31
4 | J. Name., 2012, 00, 1-3
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cycloadducts. Density functional theory calculations were and resulted in good yields of the cyclobutane product (2a, 2b,
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performed (geometry/energy) on 1a and 2a, which indicated 2d
,
2f,
and 2h), as well as good to
DOI: 10.1039/C8eOxBc0e1l2l7e3nCt
that this particular [π2s+π2a] cycloaddition reaction is indeed net diastereoselectivities.
In most cases, only one major
endothermic in nature. B3LYP/6-31 G(d) calculations of the diastereomer was isolated after purification. It is interesting
minimized energy structures of 1a and 2a revealed that the that despite the numerous possible stereoisomers (16 in the
[π2s+π2a] cycloadduct 2a is higher in energy as compared to 1a case of R = H and 64 if R = OH) only two to four stereoisomers
(ΔH = +5.0 kcal/mol),49 highlighting the ability of photocatalysis are ever observed in the crude reaction mixture. The [π2s+π2a]
to facilitate contra-thermodynamic catalysis.51-53
We next looked at several diastereomers of the head-to- occurs in a highly diastereoselective fashion.
cycloaddition appears to be the primary reaction pathway and
head dimerization products of phenylcycloheptene, devoid of
When the alcohol in 1f was protected with a pivalate group,
the OH group. The geometries of the diastereomers were 2f was obtained in high yields, and good diastereoselectivity.
minimized using the aforementioned conditions, and the results The reaction also worked very well when there was no alcohol
are shown in Fig. 3
.
In all cases, the [2+2] cycloaddition group present in 1. It was interesting to see that the 4-
reactions were found to be endergonic in nature, but ranged fluorophenylcycloheptene 1g produced only one diastereomer
from +8.4 to +28.2 kcal/mol. The major diastereomer formed 2g and the reaction completed within 6 hours of irradiation.
in this reaction (D1) was found to be +12.6 kcal/mol, and closely Substrates 1, devoid of an OH group, were reacted in MeCN in
matched the X-ray structure. This diversity of energies of the order to take advantage of the low solubility of the product
diastereomers could be in part due to the different cyclobutane in MeCN. After the reaction, the cyclobutanes
conformations of the cycloheptane rings. Hendrickson has could be easily filtered to obtain the analytically pure product
found that the most stable twist chair conformation is around 3 as a colorless solid, making the reaction and isolation extremely
kcal/mol lower in energy than the highest energy boat simple to carry out. The compound 1h which contains three
conformation of cycloheptane.54 With two cycloheptane rings fluorine atoms on the phenyl ring was found to be highly
in our structures, variation of roughly 6 kcal/mol energy diastereoselective, yielding the desired cyclobutane product 2h
difference could exist within different conformers of each in 80% yield with d.r. >99:1. Similarly, 1i which contained
diastereomer. By analysis of the structures, we hoped to be electron withdrawing trifluoromethyl groups, also produced the
able to provide some guidelines that would allow prediction of desired cyclobutane product 2i in 85% yield, and high
the relative stability of such tricyclic systems.
The least stable diastereomer, D6, which was subjected to
multiple geometry optimization calculations, was found to be
substantially higher in energy (+28.2 kcal/mol) than all the
other structures (average D1-D5 +10.8 kcal/mol). Chair, boat,
and twist chair cycloheptane conformers were all observed.
High energy D6 displayed two chair conformers, as did the
relatively more stable D5 (+9.0 kcal/mol), indicating that
cycloheptane conformer analysis is not a reliable predictor of
the overall strain energy. D6 places both phenyl groups syn and
could cause substantial strain, but this is also true with D5 and
D2 which are not as strained (+9.0 and +12.9 kcal/mol,
respectively). D6 is unique in that it is the least puckered of the
cyclobutanes 6.6o dihedral angle,19 whereas D1
-D5 range from
14.7-25.6o which likely serves to relieve the torsional strain
caused by the cyclobutane substituents.
Importantly, while all of these cyclobutanes are expected to
be net endergonic, they are exergonic when compared to the
trans-cycloheptene (+36 kcal/mol)38 and therefore are
energetically accessible. Furthermore, while we are using
highly strained molecules, the reaction exhibits a significant
and synthetically useful difference in transition state energies
that lead to each diastereomeric cyclobutane. Cycloheptene
dimer product 2a, whose calculated and crystal structure were
well matched, was found to be of lower energy as compared to
the dimer D1 (5.0 vs. 12.1 kcal/mol). This difference is likely
due to the H atoms of both the OH groups on the cycloheptane
rings point directly towards the π-electron cloud of the phenyl
rings which stabilizes 2a compared to D1 55
.
We next explored the scope of the reaction (Table 2). A
variety of functional groups were tolerated on the phenyl ring
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diastereoselectivity (>99:1) after isolation. Cyclocheptenone 1j energetically inaccessible. We anticipate that this reaction will
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also underwent the dimerization reaction smoothly to yield the spur other strategic uses of visible lDigOhIt: 10e.1n0e3r9g/yC8OtoB01d2r7i3vCe
desired [π2s+π2a] adduct in 70% yield as a single diastereomer endergonic chemical synthesis.
after isolation. An optically active chiral allylic alcohol 1k (96%
ee) was synthesized, and exposed to reaction conditions. 2k
Conflicts of interest
There are no conflicts to declare.
was formed with high enantioselectivity (97% ee)56 and
diastereoselectivity (11.5:1) with 58% isolated yield. Allylic
alcohol (1l) with the OH group transposed to the tail carbon also
produced the [π2s+π2a] cycloadduct 2l in moderate yield and
Acknowledgements
high d.r. (>99:1) after isolation.
The research results discussed in this publication were made
In order to see whether an intramolecular cycloaddition
possible in total or in part by funding through the award for
could outcompete the intermolecular [π2s+π2a] cycloaddition,
project number HR-14-072, from the Oklahoma Center for the
the OH group in 1m was substituted with an allyl group. In this
Advancement of Science and Technology, and NSF (CHE-
case, no intramolecular [π2s+π2a] occurred, rather only
1453891).
intermolecular [π2s+π2a] reaction occurred to yield 2m in 73%
yield, albeit with moderate d.r. of 1.3:1.3:1. Aside from the
stereochemistry, the fact that a tethered alkene does not
undergo preferential photochemical [2+2] highlights the
Notes and references
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benefits of moving to the visible region, which allows alkenyl
functional groups to survive the reaction which would not likely
be possible using UV irradiation.57 Interestingly, replacing the
allyl with
a cinnamyl ether (1n) completely halts the
intermolecular cycloaddition, and instead gives rise exclusively
to the intramolecular cycloaddition product. After isolation, the
product 2n was obtained in moderate yield (58%) as an
exclusive diastereomer.58 It may be possible that stacking of the
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lived excited state intermediates are rapidly intercepted, or
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cycloheptene ring, which we found were also well tolerated.
For instance, cycloheptene ring containing an N-Ts group (1o
)
was synthesized and exposed to reaction conditions. The
desired cycloadduct 2o was obtained in good yields (78%) as a
single diastereomer both before and after purification.
While the reaction requires the presence of an aryl group
attached to the cycloheptene ring to make the triplet state
energetically accessible, it does not necessarily have to be a
phenyl derivative. A substrate containing a pyridine ring instead
of phenyl ring was synthesized (1p) and was exposed to reaction
conditions. The desired [π2s+π2a] cyclobutane product was
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formed in 65% yield with d.r. >99:1.
The relative
stereochemistry was confirmed via X-ray analysis.49
Conclusions
In conclusion, we have developed a method which is very
mild and operationally straightforward, and requires only
visible light and very low concentrations of the Ir photocatalyst
and easy to access alkenes, and results in the formation of
valuable cyclobutanes. The use of visible light photocatalysis
makes it possible to access the highly strained trans-
cycloheptene and avoid reaction on the excited state surface.
Consequently, this work demonstrates the ability to convert
photochemical energy into useable forms, i.e. ring strain, which
can be used to drive the synthesis of cyclobutanes and to open
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