Silyl Tosylate Precursors to Cyclohexyne, 1,2-Cyclohexadiene, and 1,2-Cycloheptadiene

Article abstract of DOI:10.1021/acs.orglett.0c01510

Transient strained cyclic intermediates have become valuable intermediates in modern synthetic chemistry. Although silyl triflate precursors to strained intermediates are most often employed, the instability of some silyl triflates warrants the developmen

Full text of DOI:10.1021/acs.orglett.0c01510

pubs.acs.org/OrgLett
Letter
Silyl Tosylate Precursors to Cyclohexyne, 1,2-Cyclohexadiene, and
1,2-Cycloheptadiene
Matthew S. McVeigh, Andrew V. Kelleghan, Michael M. Yamano, Rachel R. Knapp, and Neil K. Garg*
Cite This: https://dx.doi.org/10.1021/acs.orglett.0c01510
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: Transient strained cyclic intermediates have become valuable intermediates
in modern synthetic chemistry. Although silyl triflate precursors to strained intermediates
are most often employed, the instability of some silyl triflates warrants the development of
alternative precursors. We report the syntheses of silyl tosylate precursors to cyclohexyne,
1,2-cyclohexadiene, and 1,2-cycloheptadiene. The resultant strained intermediates undergo
trapping in situ to give cycloaddition products. Additionally, the results of competition
experiments between silyl triflates and silyl tosylates are reported.
he chemistry of transient strained cyclic intermediates has
been a popular topic of study for over a century.1 Early
instability of the corresponding silyl triflates. This instability
can be attributed to the ease of triflate dissociation and cation
formation in related systems.11,12
With the aim of circumventing silyl triflate instability and
accessing a wider range of strained intermediates under
Kobayashi-type conditions, we sought to develop new
precursors to cyclic alkynes and allenes (i.e., 2 and 3, Figure
2). As mentioned above, the most common means to access 2
T
efforts in the field established the existence of benzyne (1),2
cyclohexyne (2),3 and 1,2-cyclohexadiene (3)4 through
pioneering studies conducted by Roberts and Wittig in the
1950s and 1960s (Figure 1). Since their discovery, these
Figure 2. Silyl triflate (previous) and silyl tosylate (current)
precursors to 2 and 3.
Figure 1. Strained cyclic intermediates and selected synthetic
applications.
and 3 is via the corresponding silyl triflates (e.g., 8 and 10,
respectively) using fluoride-induced elimination. Encouraged
by the success of silyl tosylates as aryne precursors,13 we
sought to develop silyl tosylate cyclic alkyne and allene
precursors 9 and 11, respectively.14 We hypothesized that the
diminished leaving group ability of a tosylate anion relative to a
triflate15 could alleviate difficulties associated with vinyl triflate
species, along with their heterocyclic derivatives (e.g., 4), have
been employed in a host of synthetic applications spanning
natural product synthesis,1c,d,i,5 heterocycle construction,1e,g,h,6
and materials chemistry,1e,7 as exemplified by the syntheses of
5−7.
Many of the advanced synthetic applications of strained
cyclic intermediates have been enabled by the use of silyl
triflates as precursors. Initially developed by Kobayashi as
precursors to benzyne (1),8 silyl triflates have since become the
most commonly employed precursors for accessing arynes,
nonaromatic cyclic alkynes, and cyclic allenes.1,9,10 However,
we have encountered difficulties in preparing certain function-
alized strained cyclic allene and alkyne precursors due to the
Received: May 1, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01510
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

Organic Letters
pubs.acs.org/OrgLett
Letter
a
instability, while retaining sufficient reactivity to form the
desired strained intermediates.13 These alternative precursors
could also allow for new synthetic methods that leverage the
differences in reactivity between tosylates and triflates.16
Furthermore, we hoped that silyl tosylates 2 and 3 would be
crystalline,17 in contrast to silyl triflates, which are often oils.
This characteristic could facilitate their purification and use in
process chemistry. Herein, we describe the preparation,
validation, and synthetic application of the desired silyl
tosylates as strained intermediate precursors.
Table 1. Silyl Tosylate 9 as a Precursor to Cyclohexyne (2)
Our first objective was to develop synthetic routes to the
requisite silyl tosylates, which led to the preparation of 9 and
11 as shown in Figure 3. Following literature procedures,18
a
General conditions: silyl tosylate 9 (1.0 equiv, 0.14 mmol), trapping
agent (1.5−3.0 equiv), TBAF (5.0 equiv), and THF (0.07 M) heated
b
in a sealed vial under an atmosphere of N2. Yields reflect the average
of two isolation experiments. Literature isolated yields under
c
comparable reaction conditions when using 8 (R = Me or Et).
Figure 3. Syntheses of silyl tosylates 9 and 11.
Table 2. Silyl Tosylate 11 as a Precursor to 1,2-
Cyclohexadiene (3)
a
cyclohexanone (12) was converted to silyl ketone 14 in good
yield through a sequence involving silyl enol ether formation
(12 → 13) and allylic deprotonation/retro-Brook rearrange-
ment (13 → 14). From common intermediate 14,
deprotonation under either thermodynamic or kinetic control,
followed by quenching with p-toluenesulfonic anhydride,
generated silyl tosylates 9 and 11, respectively. Gratifyingly,
both alkyne precursor 9 and allene precursor 11 were obtained
as crystalline solids and could be prepared on gram-scale.
As shown in Table 1, we found that silyl tosylate 9 serves as
a viable precursor to generate cyclohexyne (2) with in situ
trapping. It should be noted that our initial attempts to
generate 2 from 9 using CsF (based on literature conditions
for the corresponding trimethylsilyl triflate6b) led to the
recovery of unreacted 9. However, the use of the more soluble
fluoride source tetrabutylammonium fluoride (TBAF) proved
fruitful and enabled the generation of 2 in situ. Trapping with
diene 16 furnished oxabicycle 17 via a (4 + 2) cycloaddition
(entry 1). Similarly, the use of nitrone 18 as the trapping agent
gave rise to isoxazolidine 19 by way of a (3 + 2) cycloaddition
(entry 2). In both cases, yields were comparable to those
observed using a silyl triflate precursor.6b,18b Lastly, nucleo-
philic trapping of 2 with imidazole (20) proved successful,
generating vinyl imidazole 21 in moderate yield.19 These
trapping experiments demonstrate that silyl tosylate 9 serves as
an effective precursor to 2, rendering 9 a useful intermediate
for the synthesis of heterocyclic products.
a
General conditions: silyl tosylate 11 (1.0 equiv, 0.14 mmol),
trapping agent (1.0−5.0 equiv), CsF (5.0 equiv), and MeCN (0.1 M)
heated in a sealed vial under an atmosphere of N2. Yields reflect the
average of two isolation experiments. Literature isolated yields and
diastereomeric ratios under comparable reaction conditions when
b
c
d
1
using 10 (R = Et). Diastereomeric ratios determined by H NMR
e
analysis of the crude reaction mixture. Yield determined by 1H NMR
f
analysis using an external standard. Cyclic allene generated from 6,6-
dibromobicyclo[3.1.0]hexane.
We also investigated silyl tosylate 11 as a precursor to
strained cyclic allene 3 (Table 2). In contrast to our
observations in reactions of alkyne precursor 9, CsF could
be utilized to induce strained intermediate formation from silyl
tosylate 11 under the same conditions reported in the
literature for the corresponding silyl triflate 10 (R = Et).6a
We were delighted to find that silyl tosylate 11 could be
employed in (4 + 2), (3 + 2), and (2 + 2) cycloadditions to
deliver 23, 24, and 26, respectively (entries 1−3). In all cases,
yields and diastereomeric ratios were consistent with those
reported in the literature for reactions employing silyl triflate
10 (R = Et).6a,18b,20 The synthesis of isoxazolidine 24 was also
carried out on mmol-scale to demonstrate scalability of the
reaction.
B
https://dx.doi.org/10.1021/acs.orglett.0c01510
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Having established silyl tosylates as effective substitutes for
silyl triflates, we sought to extend this alternative method of
strained intermediate generation to address a particular
shortcoming in silyl triflate chemistry. As mentioned earlier,
silyl triflates can sometimes be unstable due to their
pronounced leaving group ability.11,12 We have observed this
type of instability when attempting to synthesize a silyl triflate
precursor to 1,2-cycloheptadiene (29) (Figure 4).21 Alter-
triflate and tosylate anions.15 This observed selectivity should
prove useful in synthetic applications, analogous to prior
studies in which multiple strained intermediates have been
generated sequentially to synthesize complex polycyclic
products.7
In summary, we have developed scalable syntheses of silyl
tosylate precursors to the transient strained intermediates
cyclohexyne (2), 1,2-cyclohexadiene (3), and 1,2-cyclo-
heptadiene (29). Our synthetic routes to these precursors
generate crystalline silyl tosylates, an attribute that could prove
useful to process chemists. The silyl tosylate strained
intermediate precursors not only replicate the chemistry
attained using silyl triflates but also can allow access to
strained intermediates inaccessible using known silyl triflate
chemistry, as exemplified by silyl tosylate 28. Furthermore,
competition experiments demonstrate that silyl triflate
precursors to 2 and 3 react chemoselectively in the presence
of their silyl tosylate counterparts. This selectivity should prove
useful in synthetic design. Collectively, these studies
demonstrate the synthetic utility of silyl tosylates as precursors
to transient strained intermediates.
Figure 4. Silyl tosylate 28 to access 1,2-cycloheptadiene (29).
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01510.
■
natively, silyl tosylate 28, accessible in three steps from 27 (see
the Supporting Information for details), could be obtained as a
crystalline solid. Treatment of 28 with isobenzofuran 16 under
standard conditions for cyclic allene generation and trapping
afforded oxabicycle 30 in excellent yield via the intermediacy of
cyclic allene 29. This example demonstrates that silyl tosylates
can be used to expand the scope of strained intermediates
accessible under mild fluoride-based conditions.22
sı
Experimental details, compound characterization data,
and NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Finally, two key experiments were performed to compare the
relative reactivity of our silyl tosylates to the corresponding
silyl triflates (Figure 5). In the first, equimolar amounts of silyl
Neil K. Garg − Department of Chemistry and Biochemistry,
University of California, Los Angeles, California 90095-1569,
United States; orcid.org/0000-0002-7793-2629;
Email: neilgarg@chem.ucla.edu
Authors
Matthew S. McVeigh − Department of Chemistry and
Biochemistry, University of California, Los Angeles, California
90095-1569, United States
Andrew V. Kelleghan − Department of Chemistry and
Biochemistry, University of California, Los Angeles, California
90095-1569, United States
Michael M. Yamano − Department of Chemistry and
Biochemistry, University of California, Los Angeles, California
90095-1569, United States
Rachel R. Knapp − Department of Chemistry and Biochemistry,
University of California, Los Angeles, California 90095-1569,
United States
Figure 5. Competition experiments between silyl triflate and silyl
tosylate strained intermediate precursors. Yields determined by H
NMR analysis with external standard.
1
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01510
triflate 8a and silyl tosylate 9, both precursors to cyclohexyne
(2), were treated with nitrone 18 under CsF-based reaction
conditions. We observed that silyl triflate 8a reacted selectively
over silyl tosylate 9 to generate cycloadduct 19. Silyl tosylate 9
did not react under these conditions. An analogous
competition experiment was performed using silyl triflate 10a
and silyl tosylate 11, both of which serve as precursors to 1,2-
cyclohexadiene (3). This led to the efficient formation of 24
and the nearly quantitative retention of silyl tosylate 11. The
preferential reactivity of the silyl triflate in both cases can be
rationalized based on the relative leaving group abilities of the
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are grateful to the University of California, Los
Angeles, NIH-NIGMS (R01-GM123299 and R01-GM132432
for N.K.G., T32-GM067555 for A.V.K., and F31-GM134625
for R.R.K.), the National Science Foundation (DGE-1144087
for M.M.Y.), the Foote Family (for M.S.M.), and the
C
https://dx.doi.org/10.1021/acs.orglett.0c01510
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
oxygen-containing strained alkynes. J. Am. Chem. Soc. 2016, 138,
4948−4954. (f) Barber, J. S.; Yamano, M. M.; Ramirez, M.; Darzi, E.
R.; Knapp, R. R.; Liu, F.; Houk, K. N.; Garg, N. K. Diels−Alder
cycloadditions of strained azacyclic allenes. Nat. Chem. 2018, 10,
953−960. (g) Nendel, M.; Tolbert, L. M.; Herring, L. E.; Islam, M.
N.; Houk, K. N. Strained allenes as dienophiles in the Diels−Alder
reaction: an experimental and computational study. J. Org. Chem.
1999, 64, 976−983. (h) Lofstrand, V. A.; West, F. G. Efficient
trapping of 1,2-cyclohexadienes with 1,3-dipoles. Chem. - Eur. J. 2016,
22, 10763−10767. (i) Yamano, M. M.; Knapp, R. R.; Ngamnithiporn,
A.; Ramirez, M.; Houk, K. N.; Stoltz, B. M.; Garg, N. K.
Cycloadditions of oxacyclic allenes and a catalytic asymmetric
entryway to enantioenriched cyclic allenes. Angew. Chem., Int. Ed.
2019, 58, 5653−5657.
Trueblood Family (N.K.G.) for financial support. These
studies were supported by shared instrumentation grants
from the NSF (CHE-1048804) and the NIH-NCRR
(S10RR025631).
REFERENCES
■
(1) For reviews of transient strained cyclic intermediates, see:
(a) Wenk, H. H.; Winkler, M.; Sander, W. One century of aryne
chemistry. Angew. Chem., Int. Ed. 2003, 42, 502−528. (b) Bronner, S.
M.; Goetz, A. E.; Garg, N. K. Understanding and modulating indolyne
regioselectivities. Synlett 2011, 18, 2599−2604. (c) Tadross, P. M.;
Stoltz, B. M. A comprehensive history of arynes in natural product
total synthesis. Chem. Rev. 2012, 112, 3550−3577. (d) Gampe, C. M.;
Carreira, E. M. Arynes and cyclohexyne in natural product synthesis.
Angew. Chem., Int. Ed. 2012, 51, 3766−3778. (e) Dubrovskiy, A. V.;
Markina, N. A.; Larock, R. C. Use of benzynes for the synthesis of
heterocycles. Org. Biomol. Chem. 2013, 11, 191−218. (f) Hoffmann,
R. W.; Suzuki, K. A “hot, energized” benzyne. Angew. Chem., Int. Ed.
2013, 52, 2655−2656. (g) Goetz, A. E.; Garg, N. K. Enabling the use
of heterocyclic arynes in chemical synthesis. J. Org. Chem. 2014, 79,
846−851. (h) Yoshida, S.; Hosoya, T. The renaissance and bright
future of synthetic aryne chemistry. Chem. Lett. 2015, 44, 1450−1460.
(i) Takikawa, H.; Nishii, A.; Sakai, T.; Suzuki, K. Aryne-based strategy
in the total synthesis of naturally occurring polycyclic compounds.
Chem. Soc. Rev. 2018, 47, 8030−8056. (j) Dhokale, R. A.; Mhaske, S.
B. Transition-metal-catalyzed reactions involving arynes. Synthesis
2018, 50, 1−16.
(7) (a) Darzi, E. R.; Barber, J. S.; Garg, N. K. Cyclic alkyne approach
to heteroatom-containing polycyclic aromatic hydrocarbon scaffolds.
́
Angew. Chem., Int. Ed. 2019, 58, 9419−9424. (b) Perez, D.; Pena, D.;
̃
́
Guitian, E. Aryne cycloaddition reactions in the synthesis of large
polycyclic aromatic compounds. Eur. J. Org. Chem. 2013, 2013,
5981−6013. (c) Xiao, X.; Hoye, T. R. The domino hexadehydro-
Diels−Alder reaction transforms polyynes to benzynes to naphthynes
to anthracynes to tetracynes (and beyond?). Nat. Chem. 2018, 10,
838−844. (d) Suh, S.-E.; Barros, S. A.; Chenoweth, D. M. Triple
aryne−tetrazine reaction enabling rapid access to a new class of
polyaromatic heterocycles. Chem. Sci. 2015, 6, 5128−5132.
(e) Mizukoshi, Y.; Mikami, K.; Uchiyama, M. Aryne polymerization
enabling straightforward synthesis of elusive poly(ortho-arylene)s. J.
Am. Chem. Soc. 2015, 137, 74−77.
(8) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Fluoride-induced 1,2-
elimination of o-trimethylsilylphenyl triflate to benzyne under mild
conditions. Chem. Lett. 1983, 12, 1211−1214.
(2) (a) Wittig, G. Phenyl-lithium, der Schlussel zu einer neuen
̈
Chemie metallorganischer Verbindungen. Naturwissenschaften 1942,
30, 696−703. (b) Roberts, J. D.; Simmons, H. E.; Carlsmith, L. A.;
Vaughan, C. W. Rearrangement in the reaction of chlorobenzene-1-
C14 with potassium amide. J. Am. Chem. Soc. 1953, 75, 3290−3291.
(3) Scardiglia, F.; Roberts, J. D. Evidence for cyclohexyne as an
intermediate in the coupling of phenyllithium with 1-chlorocyclohex-
ene. Tetrahedron 1957, 1, 343−344.
́
́
(9) Atanes, N.; Escudero, S.; Perez, D.; Guitian, E.; Castedo, L.
Generation of cyclohexyne and its Diels−Alder reaction with α-
pyrones. Tetrahedron Lett. 1998, 39, 3039−3040.
́ ́
(10) Quintana, I.; Pena, D.; Perez, D.; Guitian, E. Generation and
̃
reactivity of 1,2-cyclohexadiene under mild reaction conditions. Eur. J.
Org. Chem. 2009, 2009, 5519−5524.
(4) Wittig, G.; Fritze, P. On the intermediate occurrence of 1,2-
cyclohexadiene. Angew. Chem., Int. Ed. Engl. 1966, 5, 846.
(11) For a review related to vinyl triflate dissociation, see: Stang, P. J.
Vinyl triflate chemistry: unsaturated cations and carbenes. Acc. Chem.
Res. 1978, 11, 107−114.
(5) (a) Gampe, C. M.; Carreira, E. M. Total syntheses of
guanacastepenes N and O. Angew. Chem., Int. Ed. 2011, 50, 2962−
2965. (b) Kou, K. G. M.; Pflueger, J. J.; Kiho, T.; Morrill, L. C.;
Fisher, E. L.; Clagg, K.; Lebold, T. P.; Kisunzu, J. K.; Sarpong, R. A
benzyne insertion approach to hetisine-type diterpenoid alkaloids:
synthesis of cossonidine (davisine). J. Am. Chem. Soc. 2018, 140,
8105−8109. (c) Goetz, A. E.; Silberstein, A. L.; Corsello, M. A.; Garg,
N. K. Concise enantiospecific total synthesis of tubingensin A. J. Am.
Chem. Soc. 2014, 136, 3036−3039. (d) Neog, K.; Borah, A.; Gogoi, P.
Palladium(II)-catalyzed C−H bond activation/C−C and C−O bond
formation reaction cascade: Direct synthesis of coumestans. J. Org.
Chem. 2016, 81, 11971−11977. (e) Neumeyer, M.; Kopp, J.;
(12) For references related to β-silyl stabilized vinyl cations, see:
(a) Siehl, H.-U.; Kaufmann, F. P. Carbon-13 NMR spectroscopic
determination of the magnitude of the β-silyl stabilization effect in 1-
mesitylvinyl cations. J. Am. Chem. Soc. 1992, 114, 4937−4939.
(b) Muller, T.; Meyer, R.; Lennartz, D.; Siehl, H.-U. Unusually stable
̈
vinyl cations. Angew. Chem., Int. Ed. 2000, 39, 3074−3077.
(c) McGibbon, G. A.; Brook, M. A.; Terlouw, J. K. Stabilization
energies for α- and β-silyl substituents on vinyl cations determined
using mass spectrometric techniques. J. Chem. Soc., Chem. Commun.
1992, 4, 360−362.
(13) (a) Cunico, R. F.; Dexheimer, E. M. Generation of 1,2-
dehydrobenzene from the dehalosilylation of (o-halophenyl)-
trimethylsilanes. J. Organomet. Chem. 1973, 59, 153−160. (b) Lv,
C.; Wan, C.; Liu, S.; Lan, Y.; Li, Y. Aryne trifunctionalization enabled
by 3-silylaryne as a 1,2-benzdiyne equivalent. Org. Lett. 2018, 20,
1919−1923.
(14) Although silyl triflates 8 and 10 do not suffer from instability,
their known reactivity provides a useful point of comparison for
developing the complementary precursors 9 and 11, respectively.
(15) (a) Streitwieser, A., Jr.; Wilkins, C.; Kiehlmann, E. Kinetics and
isotope effects in solvolyses of ethyl trifluoromethanesulfonate. J. Am.
Chem. Soc. 1968, 90, 1598−1601. (b) Noyce, D. S.; Virgilio, J. A. The
synthesis and solvolysis of 1-phenylethyl disubstituted phosphinates. J.
Org. Chem. 1972, 37, 2643−2647.
Bruckner, R. Controlling the substitution pattern of hexasubstituted
̈
naphthalenes by aryne/siloxyfuran Diels−Alder additions: regio and
stereocontrolled synthesis of arizonin C1 analogs. Eur. J. Org. Chem.
2017, 2017, 2883−2915. (f) Corsello, M. A.; Kim, J.; Garg, N. K.
Total synthesis of (−)-tubingensin B enabled by the strategic use of
an aryne cyclization. Nat. Chem. 2017, 9, 944−949.
(6) (a) Barber, J. S.; Styduhar, E. D.; Pham, H. V.; McMahon, T. C.;
Houk, K. N.; Garg, N. K. Nitrone cycloadditions of 1,2-cyclo-
hexadiene. J. Am. Chem. Soc. 2016, 138, 2512−2515. (b) Medina, J.
́
́
M.; McMahon, T. C.; Jimenez-Oses, G.; Houk, K. N.; Garg, N. K.
Cycloadditions of cyclohexynes and cyclopentyne. J. Am. Chem. Soc.
2014, 136, 14706−14709. (c) McMahon, T. C.; Medina, J. M.; Yang,
Y.-F.; Simmons, B. J.; Houk, K. N.; Garg, N. K. Generation and
regioselective trapping of a 3,4-piperidyne for the synthesis of
functionalized heterocycles. J. Am. Chem. Soc. 2015, 137, 4082−4085.
(d) Tlais, S. F.; Danheiser, R. L. N-Tosyl-3-azacyclohexyne. Synthesis
and chemistry of a strained cyclic ynamide. J. Am. Chem. Soc. 2014,
136, 15489−15492. (e) Shah, T. K.; Medina, J. M.; Garg, N. K.
Expanding the strained alkyne toolbox: generation and utility of
(16) For methods that leverage the reactivity differences between
triflates and tosylates to achieve selective, sequential functionalization
of arynes, see: (a) Hamura, T.; Arisawa, T.; Matsumoto, T.; Suzuki, K.
Two-directional annelation: dual benzyne cycloadditions starting
from bis(sulfonyloxy)diiodobenzene. Angew. Chem., Int. Ed. 2006, 45,
D
https://dx.doi.org/10.1021/acs.orglett.0c01510
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
6842−6844. (b) Xu, H.; He, J.; Shi, J.; Tan, L.; Qiu, D.; Luo, X.; Li, Y.
Domino aryne annulation via a nucleophilic-ene process. J. Am. Chem.
Soc. 2018, 140, 3555−3559.
(17) The introduction of tosyl groups is known to impart
crystallinity; for examples, see: (a) Kazemi, F.; Massah, A. R.;
Javaherian, M. Chemoselective and scalable preparation of alkyl
tosylates under solvent-free conditions. Tetrahedron 2007, 63, 5083−
5087. (b) Jiang, X.; Li, J.; Zhang, R.; Zhu, Y.; Shen, J. An improved
preparation process for gemcitabine. Org. Process Res. Dev. 2008, 12,
888−891.
(18) (a) Corey, E. J.; Rucker, C. The 1,3 O→C silyl rearrangement
̈
of silyl enol ether anions − synthesis of α-silyl ketones. Tetrahedron
Lett. 1984, 25, 4345−4348. (b) Inoue, K.; Nakura, R.; Okano, K.;
Mori, A. One-pot synthesis of silylated enol triflates from silyl enol
ethers for cyclohexynes and 1,2-cyclohexadienes. Eur. J. Org. Chem.
2018, 2018, 3343−3347.
(19) The yield of 21 from 9 is lower than when using the analogous
trimethylsilyl triflate (see ref 6b). This may be attributed to an
empirically observed inhibitory effect of excess imidazole on the
consumption of 9.
(20) Christl, M.; Schreck, M. 7-Arylbicyclo[4.2.0]oct-1-ene −
Synthese durch [2 + 2]-Cycloadditionen von 1,2-Cyclohexadien
̈
sowie 1-Methyl-1,2-cyclohexadien und thermische Aquilibrierung der
exo/endo-Isomeren. Chem. Ber. 1987, 120, 915−920.
(21) Attempts to synthesize the corresponding silyl triflate precursor
to 1,2-cycloheptadiene (29) were unsuccessful due to rapid
degradation of the desired vinyl triflate upon attempted purification.
(22) For methods to access 29 under harsher reaction conditions,
see: (a) Bottini, A. T.; Hilton, L. L. Relative reactivities of
bicyclo[3.2.1]octa-2,3-diene and 1,2-cycloheptadiene with conjugated
dienes and styrene. Tetrahedron 1975, 31, 2003−2006. (b) Sutbeyaz,
Y.; Ceylan, M.; Secen, H. A novel synthesis of transient 1,2-
cyclohexadiene and 1,2-cycloheptadiene via β-halosilanes. J. Chem.
Res. (M) 1993, 8, 2189−2196.
E
https://dx.doi.org/10.1021/acs.orglett.0c01510
Org. Lett. XXXX, XXX, XXX−XXX