Concise Approach to Cyclohexyne and 1,2-Cyclohexadiene Precursors

Article abstract of DOI:10.1021/acs.joc.8b03223

Silyl triflate precursors to cyclic alkynes and allenes serve as valuable synthetic building blocks. We report a concise and scalable synthetic approach to prepare the silyl triflate precursors to cyclohexyne and 1,2-cyclohexadiene. The strategy involves a retro-Brook rearrangement of an easily accessible cyclohexanone derivative, followed by triflation protocols. This simple, yet controlled, method should enable the further study of strained alkynes and allenes in chemical synthesis.

Full text of DOI:10.1021/acs.joc.8b03223

Note
Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
pubs.acs.org/joc
Concise Approach to Cyclohexyne and 1,2-Cyclohexadiene
Precursors
†
†
Jason V. Chari, Francesca M. Ippoliti, and Neil K. Garg*
Department of Biochemistry and Chemistry, University of California, Los Angeles, California 90095, United States
*
S Supporting Information
ABSTRACT: Silyl triflate precursors to cyclic alkynes and allenes serve as valuable
synthetic building blocks. We report a concise and scalable synthetic approach to
prepare the silyl triflate precursors to cyclohexyne and 1,2-cyclohexadiene. The
strategy involves a retro-Brook rearrangement of an easily accessible cyclohexanone
derivative, followed by triflation protocols. This simple, yet controlled, method should
enable the further study of strained alkynes and allenes in chemical synthesis.
he existence of arynes, cyclic alkynes, and cyclic allenes
1
T
was once considered scientific conjecture. However,
following a series of seminal studies in the 1950s and 1960s by
Roberts and Wittig, strained intermediates such as benzyne (1),
cyclohexyne (2), and 1,2-cyclohexadiene (3) were experimen-
2
tally validated (Figure 1). In the modern era, these
intermediates and their derivatives, such as heterocycles 4
and 5, have become valuable synthetic building blocks. Indeed,
these strained intermediates have been used to synthesize
3
4
5
important ligands, agrochemicals, medicinal agents, natural
6
7
products, and materials. Studies of 1−5 have also led to new
insights regarding reactivities and selectivities,
8
−10
particularly
as a result of the distortion/interaction model investigated by
1
1
Houk.
Figure 2. Cycloadditions of cyclohexyne (2) and 1,2-cyclohexadiene
(
3).
substituted variants of 3, it has been shown that regioselectiv-
ities, relative stereochemistry, and even absolute stereo-
chemistry can be controlled in reactions of cyclic allenes, thus
Figure 1. Strained cyclic alkynes and allenes.
9
,10,13
boding well for future synthetic applications.
In comparison to arynes, strained cyclic alkynes and allenes
are less well studied. However, as exemplified in Figure 2 in the
context of 2 and 3, cyclic alkynes and allenes can be trapped in
an array of cycloadditions to give a diverse range of
Given the synthetic utility of 2 and 3 (and derivatives
thereof), chemists have sought to design practical synthetic
precursors to these strained intermediates. Kobayashi’s break-
14
6
,9,10
through in the context of benzyne has unveiled silyl triflates as
ideal precursors to strained intermediates by enabling mild
reaction conditions, as will be highlighted later. In seminal
products.
For example, cycloadducts 7, 9, and 11 have
been obtained by (3 + 2) and (4 + 2) cycloadditions of
9
c,15
cyclohexyne (2).
Analogously, 13, 15, and 16 have been
studies, Guitian
precursors to 2 and 3 could be synthesized from cyclohexenone
́
and co-workers demonstrated that silyl triflate
prepared using (3 + 2), (2 + 2), and (4 + 2) cycloaddition
9b,d,12,15
reactions of 1,2-cyclohexadiene (3).
In all cases, the
9a,b
(
17) (Figure 3).
As depicted, Guitian’s approach initially
́
reactions proceed by the controlled formation of two new
bonds, which may be either carbon−carbon bonds or carbon−
heteroatom bonds. By virtue of using heteroatom-containing
trapping agents, the carbocyclic strained intermediates can be
used to access heterocyclic products (e.g., 7, 9, 11, 13, 16) that
are of value to the pharmaceutical community. Lastly, it should
be noted that the cycloadducts can bear one or more
stereocenters, as seen in 11, 13, 15, and 16. In the case of
utilized trimethylsilyl groups. The sequence involves α-
bromination of 17, ketone protection and silylation, followed
by deprotection to give 18. 1,4-Reduction of 18 furnishes
intermediate 19a, which can undergo direct triflation to give
Received: December 19, 2018
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.8b03223
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Figure 4. Retro-Brook approach to silyl triflates 20b and 21b.
chromatographic separations. Furthermore, all steps can be
performed on gram-scale.
To illustrate the mildness and simplicity of strained cyclic
alkyne and allene chemistry using silyl triflate precursors, two
known examples from the literature are depicted (Figure 5). In
Figure 3. Synthetic approaches to cyclohexyne precursors 20a and 20b
and 1,2-cyclohexadiene precursors 21a and 21b.
cyclohexyne precursor 20a. Alternatively, protonation of 19a,
followed by kinetic enolate formation and triflation, delivers
1
,2-cyclohexadiene precursor 21a. Our laboratory questioned if
intermediates reminiscent of 19a could be more rapidly
accessed by another means. However, it should be emphasized
that during our efforts, Mori disclosed an elegant method to
15
prepare triethylsilyl derivatives 20b and 21b. Silyl enol ether
2 was treated with LDA and t-BuOK. This led to allylic
2
deprotonation, followed by in situ silyl migration, to afford 23.
Triflation of 23 provided 1,2-cyclohexadiene precursor 21b. On
the other hand, the authors found that 23 could isomerize to
1
9b under modified reaction conditions, which, in turn,
underwent triflation to give cyclohexyne precursor 20b. It
should be noted that silyl triflates 20b and 21b required
purification by conventional chromatography, followed by size-
exclusion chromatography/HPLC. Nonetheless, Mori’s use of
Figure 5. Examples of cycloadditions using silyl triflates 20b and 21b.
the first, silyl triflate 20b is treated with 10 in the presence of
2
2 as the key building block offers a clever strategy.
15
We have developed an alternative means to access 20b and
1b, which is depicted in Figure 4. Our route begins with α-
TBAF in THF. This presumably leads to the formation of 2 in
situ, which undergoes cycloaddition to give Diels−Alder adduct
11. In the second example, silyl triflate 21b is treated with CsF
2
bromocyclohexanone (24), which is commercially available or
16
9d
can be easily prepared from cyclohexanone. Treatment of 24
with DABCO and triethylsilyl chloride in DMF at 0 °C gives
silyl enol ether 25 as a single constitutional isomer. Next, we
perform halogen−metal exchange using sec-BuLi. This proceeds
with retro-Brook rearrangement to intercept anionic inter-
mediate 19b in a highly controlled and concise manner. This
strategy was conceived based on the well-established retro-
using nitrone 27 as the trapping agent. Interception of 1,2-
cyclohexadiene (3) gives 28. The reactions proceed without the
rigorous exclusion of water or oxygen, with 1.5−2.0 equiv of the
trapping agents, and with minimal byproduct formation. As
such, silyl triflates 20b and 21b can be transformed to value-
added products using simple reaction conditions.
In summary, we have developed a concise approach to silyl
triflate precursors to cyclohexyne (2) and 1,2-cyclohexadiene
(3). Our strategy relies on a retro-Brook rearrangement of a
readily available silyl enol ether. The resulting enolate
intermediate can be diverted through two different sequences.
Direct triflation gives cyclohexyne precursor 20b, whereas
protonation, followed kinetic enolization and triflation, affords
1,2-cyclohexadiene precursor 21b. We expect this concise and
controlled strategy to access silyl triflate precursors will
ultimately enable further studies involving strained alkynes
and allenes in chemical synthesis.
17
Brook approach to aryne precursors. Following rearrange-
ment, simply quenching 19b with PhNTf provides cyclo-
2
hexyne precursor 20b in 97% yield. Alternatively, 19b can be
quenched by the addition of aqueous sodium bicarbonate to
furnish α-silyl ketone 26 in 95% yield. Our laboratory has
previously reported the final step, wherein 26 can be converted
to 21b by kinetic enolate formation, followed by triflation. This
earlier result is depicted based on the literature yield. The
routes to silyl triflates 20b and 21b are only two and three steps
from 24, respectively, and notably do not require challenging
9d
B
DOI: 10.1021/acs.joc.8b03223
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
α-Silyl Ketone 26: To a solution of silyl enol ether 25 (1.00 g, 3.43
mmol, 1.00 equiv) in THF (40 mL, 0.085 M) at −78 °C was added sec-
BuLi (0.84 M in cyclohexane, 10 mL, 8.6 mmol, 2.5 equiv) dropwise
over 13 min. The solution was stirred for 2 h at −78 °C, and then the
EXPERIMENTAL SECTION
■
Materials and Methods. Unless stated otherwise, reactions were
conducted in flame-dried glassware under an atmosphere of nitrogen
using anhydrous solvents (either freshly distilled or passed through
activated alumina columns). All commercially obtained reagents were
used as received unless otherwise specified. 1,4-Diazabicyclo[2.2.2]-
octane (DABCO) was purchased from Acros Organics. sec-
Butyllithium 1.4 M solution in cyclohexane (sec-BuLi) and cyclo-
hexanone were obtained from Sigma-Aldrich. N-Phenylbis(trifluoro-
methanesulfonimide) and triethylsilyl chloride (TESCl) were
purchased from Oakwood Chemical. Cyclohexanone and TESCl
were distilled over CaH2 prior to use. Unless stated otherwise,
reactions were performed at 23 °C. Thin-layer chromatography was
conducted with EMD gel 60 F254 precoated plates (0.25 mm) and
visualized using anisaldehyde or potassium permanganate staining.
Silicycle Siliaflash P60 (particle size 0.040−0.063 mm) was used for
reaction was quenched with saturated aqueous NaHCO (15 mL) and
3
allowed to warm to 23 °C. The reaction mixture was then diluted with
EtOAc (15 mL) and H O (15 mL). The layers were then separated
2
and the aqueous layer was extracted with EtOAc (3 × 25 mL). The
combined organic layers were dried over MgSO , filtered, and
4
concentrated under reduced pressure. The resulting crude oil was
purified by flash chromatography (100% hexanes → 9:1 hexanes/
EtOAc) to afford silyl ketone 26 (691 mg, 95% yield) as a light yellow
oil: R 0.39 (9:1 hexanes/EtOAc); spectral data match those previously
f
15
reported.
ASSOCIATED CONTENT
Supporting Information
■
1
*
S
flash column chromatography. H NMR spectra were recorded on
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.8b03223.
Bruker spectrometers (at 500 MHz) and are reported relative to the
1
residual solvent signal. Data for H NMR spectra are reported as
follows: chemical shift (δ ppm), multiplicity, coupling constant (Hz),
1H NMR spectra for compounds 25, 20b, and 26; 13
C
1
3
and integration. C NMR spectra were recorded on Bruker
spectrometers (at 100 MHz) and are reported relative to the residual
NMR spectrum for compound 25 (PDF)
1
3
solvent signal. Data for C NMR spectra are reported in terms of
chemical shift (δ ppm). IR spectra were obtained on a PerkinElmer
UATR Two FT-IR spectrometer and are reported in terms of
AUTHOR INFORMATION
Corresponding Author
E-mail: neilgarg@chem.ucla.edu.
■
−
1
frequency of absorption (cm ). DART-MS spectra were collected on
a Thermo Exactive Plus MSD (Thermo Scientific) equipped with an
ID-CUBE ion source, a Vapur Interface (IonSense Inc.), and an
Orbitrap mass analyzer. Both the source and MSD were controlled by
Excalibur software v. 3.0. The analyte was spotted onto OpenSpot
*
ORCID
Neil K. Garg: 0000-0002-7793-2629
Author Contributions
†
sampling cards (IonSense Inc.) using CDCl as the solvent. Ionization
3
J.V.C. and F.M.I. contributed equally.
was accomplished using UHP He (Airgas Inc.) plasma with no
additional ionization agents. The mass calibration was carried out
using Pierce LTQ Velos ESI (+) and (−) ion calibration solutions
Notes
The authors declare no competing financial interest.
(
Thermo Fisher Scientific).
ACKNOWLEDGMENTS
Silyl Enol Ether 25: To a stirred solution of known bromo ketone
(2.01 g, 11.3 mmol, 1.00 equiv) in DMF (10.3 mL, 1.10 M) at 0
C were added DABCO (2.93 g, 26.1 mmol, 2.30 equiv) and TESCl
3.1 mL, 18 mmol, 1.6 equiv) sequentially. The reaction mixture was
■
1
6
24
The authors are grateful to the University of California, Los
Angeles, NIH-NIGMS (R01 GM123299), the Trueblood
Family (N.K.G.), and the Foote Family (J.V.C. and F.M.I.)
for financial support. These studies were supported by shared
instrumentation grants from the NSF (CHE-1048804) and the
NIH NCRR (S10RR025631). The authors thank Michael M.
Yamano (UCLA) for insightful discussions and suggestions.
°
(
stirred for 45 min before being quenched with deionized H O (5 mL).
2
The reaction was then allowed to warm to 23 °C before being diluted
with hexanes (20 mL) and H O (20 mL). The layers were separated
2
and the aqueous layer was extracted with hexanes (3 × 25 mL). The
combined organic layers were dried over MgSO , filtered, and
4
concentrated under reduced pressure. The resultant crude oil was
purified via flash chromatography (100% hexanes) to afford silyl enol
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(
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C
DOI: 10.1021/acs.joc.8b03223
J. Org. Chem. XXXX, XXX, XXX−XXX

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DOI: 10.1021/acs.joc.8b03223
J. Org. Chem. XXXX, XXX, XXX−XXX