Cycloadditions of cyclohexynes and cyclopentyne

Article abstract of DOI:10.1021/ja508635v

We report the strategic use of cyclohexyne and the more elusive intermediate, cyclopentyne, as a tool for the synthesis of new heterocyclic compounds. Experimental and computational studies of a 3-substituted cyclohexyne are also described. The observed regioselectivities are explained by the distortion/interaction model.

Full text of DOI:10.1021/ja508635v

Communication
pubs.acs.org/JACS
Cycloadditions of Cyclohexynes and Cyclopentyne
Jose M. Medina,† Travis C. McMahon,† Gonzalo Jimenez-Oses, K. N. Houk,* and Neil K. Garg*
́
́
Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, United States
S
* Supporting Information
drugs, natural products, and other compounds of tremendous
importance.11 Thus, new methods for their synthesis, especially
previously inaccessible compounds, remain highly sought after.
As suggested in Figure 1, cycloadditions involving 3 or 4 would
provide heterocycles 5 or 6, respectively. Despite the simplicity
of this approach, there are no examples of the trapping of
cyclohexyne or cyclopentyne to construct heterocycles with one
or more newly formed C−X bonds (where X = heteroatom). In
addition, we sought to prepare a substituted cyclohexyne 7 and
probe regioselectivities in both nucleophilic trapping and
cycloaddition reactions. We have previously explained regio-
selectivities in reactions of substituted benzynes and hetarynes
using the distortion/interaction model,12 but this model has
not been tested on the non-aromatic cyclohexyne derivatives.
Herein, we demonstrate the synthetic utility of 3 and 4 for the
construction of bicyclic heterocycles, and also explain the
regioselectivities seen in reactions of the first 3-substituted
cyclohexyne using the distortion/interaction model.
ABSTRACT: We report the strategic use of cyclohexyne
and the more elusive intermediate, cyclopentyne, as a tool
for the synthesis of new heterocyclic compounds.
Experimental and computational studies of a 3-substituted
cyclohexyne are also described. The observed regio-
selectivities are explained by the distortion/interaction
model.
he study of small rings containing triple bonds has been a
T
topic of vast interest for over 100 years.1 Following a
provocative report in 1902 suggesting the intermediacy of an
aryne,2 chemists probed the viability of benzyne (1, Figure 1)
To initiate our study, we opted to generate cyclohexyne in
situ from the corresponding silyl triflate, 9 (Table 1). Silyl
triflate 9 was first synthesized in 1998,9a but has seen limited
use, for example, in Diels−Alder reactions and formal C−C
bond insertion reactions.7a,9,13,14 We were delighted to find that
treatment of silyl triflate 9 with CsF in the presence of a variety
of trapping agents delivered heterocyclic products in syntheti-
cally useful yields. Specifically, triazoles and pyrazoles were
obtained by the trapping of azide and diazo coupling partners,
respectively (entries 1−3).15 An N-Ph pyrazole was accessed
using a sydnone cycloaddition (entry 4). We also explored
nitrone and nitrile oxide cycloadditions, which provided
isoxazoline- and isoxazole-containing products, respectively
(entries 5 and 6). Moreover, additional new trapping
experiments to forge 6-membered heterocycles from cyclo-
hexyne are provided in the Supporting Information (SI). It
should be emphasized that in contrast to many common
methods for heterocycle synthesis, particularly benzyne
trapping, the products obtained from cyclohexyne trapping
possess more aliphatic character. Being able to access
compounds possessing significant sp3 character is an important
direction in contemporary drug discovery.16
Figure 1. Well-studied cyclic alkynes 1 and 2, cyclohexyne (3), and
cyclopentyne (4), and objectives of the present study.
and related intermediates. Roberts, in 1953, validated the
existence of benzyne (1),3 which can be used today in a host of
synthetic applications.1 Perhaps the next most well-studied
classes of strained alkynes are cyclooctynes (e.g., 2) and
thiacycloheptynes, which have proven useful in bioorthogonal
reactions by Bertozzi, Boons, and others.4 In contrast,
cyclohexyne (3)5 and cyclopentyne (4)6 have seen only sparse
use in synthetic applications. Breakthroughs in the manipu-
lation of cyclohexyne include formal C−C bond insertions
reported by the laboratories of Stoltz and Carreira,7,8 in
addition to Diels−Alder reactions as shown by the groups of
Encouraged by our success in building heterocycles from
cyclohexyne, we performed trapping experiments of the less
well-studied intermediate, cyclopentyne (4), using silyl triflate
10 (Table 2).17 Although silyl triflate 10 has been synthesized
previously,18 no successful trapping experiments involving 10
have been reported. Thus, 10 was treated with CsF in
acetonitrile in the presence of various trapping agents. Most
Guitian
́
and Du Bois.9 The use of cyclopentyne has been
limited to [2+2] and Diels−Alder cycloadditions.10
Despite the relatively limited use of 3 and 4 in synthetic
applications for the construction of C−C bonds, we envisioned
harnessing these strained intermediates to construct new
bicyclic heterocyclic scaffolds. Heterocycles are prevalent in
Received: August 21, 2014
© XXXX American Chemical Society
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Figure 2 shows the optimized structures of cyclohexyne (3)
and cyclopentyne (4) (see the SI for computational details).21
Table 1. Cycloaddition Reactions of 3 to Construct 5-
Membered Heterocycles
Figure 2. Optimized structures of 3, 4, 11, and 12 obtained using
PCM(THF)/M06‑2X/6‑311+G(2d,p).
The minimum energy conformer of cyclopentyne is slightly
puckered and shows Cs symmetry, in agreement with previous
studies.22 The significant angle-strain of this structure is
revealed by the large deviation of the internal ring angles
(116°) from the ideal linear disposition of alkynes. The strain
has been calculated to be ca. 74 kcal mol−1.22 Such a large strain
distorts the in-plane π bond in a way that cyclopentyne has
∼10% calculated diradical character.23 The more relaxed
internal angle in cyclohexyne (132°) causes a smaller, but still
significant strain, estimated as ca. 44 kcal mol−1.22 Cyclohexyne
(3) possesses a C2-symmetric structure that resembles the well-
known half-chair structure of cyclohexene.22a,24
a
Reported yields are the average of two experiments and are based on
b
We also compared 3-methoxybenzyne (11) to its non-
aromatic counterpart, 3-methoxycyclohexyne (12) (Figure 2).
In the case of 11, as we have previously described,12a,b the
inductively withdrawing methoxy group at C3 distorts the aryne
significantly. Nucleophilic trapping occurs at C1, the more
linear aryne terminus whose reactive orbital possesses more p
character, uniformly with high degrees of regioselectivity.
Interestingly, 3-methoxycyclohexyne (12) bears similar dis-
tortion, with internal angles at C1 and C2 being calculated as
138° and 124°, respectively.25 Much like the distortion seen in
11, the distortion in 12 is attributed to the inductively
withdrawing nature of the C3 methoxy group that causes
rehybridization of C2 (Bent’s rule, see SI for further
discussion).26 Consequently, we predict that nucleophilic
addition to 3-alkoxycycloalkynes should occur with a significant
preference for attack at C1, the more linear alkyne terminus.
To test our prediction, we prepared benzyloxysilyl triflate 13,
the first C3-substituted cyclohexyne precursor, and performed
trapping experiments (Figure 3).27 When silyl triflate 13 was
treated with CsF in the presence of imidazole, adduct 15 was
obtained exclusively, which arises via attack at C1 of
cyclohexyne 14. Similarly, trapping with benzyl azide gave a
5.1 to 1 ratio of cycloadducts 16 and 17, which is consistent
with a preference for initial bond formation occurring between
the more nucleophilic terminus of the azide28 and C1 of 14.
Figure 4 shows the calculated competing transition states,
TS1−TS4, for the reactions shown in Figure 3.29 In agreement
with the observed selectivity, attack by imidazole at C1 is highly
preferred (by ca. 3 kcal mol−1) because 3-methoxycyclohexyne
(12) is pre-distorted toward the preferred transition state, TS1.
Similarly, in the azide cycloaddition, TS3 is favored over TS4,
although the calculated regioselectivity is overestimated. It is
important to note the systematic increase in distortion energy
(ΔEdist), the cost of altering the substrate geometry toward the
the amounts of isolated products. Benzene was used as a cosolvent.
c
Et2O was used as a cosolvent.
Table 2. Trapping Experiments of Cyclopentyne (4)
a
Reported yields are the average of two experiments and are based on
the amounts of isolated products.
trapping agents gave only low yields or none of the desired
products; however, benzyl azide and sydnone partners could be
employed to deliver triazole and pyrazole products, respectively
(entries 1 and 2). Additionally, we found that trapping of 4 with
a cyclic dimethylurea19 generated a unique product possessing a
[5,7]-fused ring system (entry 3).20 Despite the limited scope
of trapping agents that can be used to intercept 4, these studies
validate the notion that cyclopentyne can be used in reactions
beyond [2+2] and Diels−Alder cycloadditions and may react
through non-radical pathways.
B
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Scheme 1. Elaboration of Benzyloxycyclohexyne 16 to
Triazolopyrrole 19
In summary, we have demonstrated that cyclohexyne and the
more elusive intermediate, cyclopentyne, serve as effective tools
for the synthesis of new heterocyclic compounds. We have also
shown that the distortion/interaction model correctly predicts
regioselectivities in reactions of the first 3-substituted cyclo-
hexyne. This validates the distortion/interaction model as a
powerful predictive tool for gauging cycloalkyne regio-
selectivitities, just from the reactant’s structure, while also
providing the impetus for the further exploration of highly
strained cycloalkynes as valuable synthetic building blocks.
Figure 3. Experimental results validate regioselectivity predictions in
reactions of 3-substituted cyclohexyne 14.
ASSOCIATED CONTENT
* Supporting Information
■
S
Detailed experimental and computational procedures, com-
pound characterization, Cartesian coordinates, electronic
energies, entropies, enthalpies, Gibbs free energies, and lowest
frequencies of the calculated structures. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
houk@chem.ucla.edu
■
neilgarg@chem.ucla.edu
Author Contributions
†J.M.M. and T.C.M. contributed equally.
Notes
The authors declare no competing financial interest.
Figure 4. Optimized transition states for nucleophilic addition by
imidazole and cycloaddition with methyl azide to 12 using
PCM(THF)/M06‑2X/6‑311+G(2d,p). Energies are provided in kcal
mol−1.
ACKNOWLEDGMENTS
■
The authors are grateful to the NIH-NIGMS (R01 GM090007
to N.K.G. and GM075962 to K.N.H), Bristol−Myers Squibb,
the S. T. Li Foundation, the A. P. Sloan Foundation, the
Dreyfus Foundation, the UC CRCC, UCLA, and the UCLA
Cota Robles Fellowship Program (J.M.M.) for financial
support. This work used the Extreme Science and Engineering
Discovery Environment (XSEDE), which is supported by the
National Science Foundation (OCI-1053575) along with the
UCLA Institute of Digital Research and Education (IDRE). We
thank Ashley Pournamdari for experimental assistance and the
Garcia-Garibay laboratory (UCLA) for access to instrumenta-
tion. These studies were supported by shared instrumentation
grants from the NSF (CHE-1048804) and the NIH NCRR
(S10RR025631).
transition state, of the 3-methoxycyclohexyne moiety in TS2
and TS4, which accounts for most of the calculated energy
differences between competing transition states. As a common
feature of distortion-controlled reactions, the interaction
energies (ΔEint), or in other words, the stabilization due to
orbital overlap between the reacting fragments in the transition
state, is nearly identical when comparing competing transition
states. It is notable that this trend is observed for both the
imidazole and azide trapping agents, despite their different
electronic properties.
In addition to serving as a probe to assess the distortion/
interaction model, benzyloxycyclohexyne 14 can also be used to
access highly functionalized heterocycles. As shown in Scheme
1, triazole 16, prepared from the benzylazide cycloaddition of
14 (Figure 3), was converted to azide 18 through an
uncommon functionalization of a pseudobenzylic benzyloxy
group.30 Subsequent reduction and pyrrole formation provided
triazolopyrrole 19.
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Journal of the American Chemical Society
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́ ́
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D
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