One-Pot Synthesis of Silylated Enol Triflates from Silyl Enol Ethers for Cyclohexynes and 1,2-Cyclohexadienes

Article abstract of DOI:10.1002/ejoc.201800353

Regiocontrolled synthesis of precursors for strained cyclohexynes and 1,2-cyclohexadienes is described based on one-pot rearrangement of silyl enol ether followed by formation of enol triflate. Treatment of silyl enol ether with a combination of LDA and tBuOK led to the migration of the silyl group to generate α-silyl enolate, which was treated with Comins' reagent to provide the corresponding enol triflate. The transient α-silylated lithium enolate was smoothly isomerized in the presence of stoichiometric amount of water within one hour at room temperature, providing precursors for cyclohexynes exclusively in one pot. Effects of silyl groups, isomerization of the lithium enolate, and regiocontrolled generation of these precursors for these strained molecules were also investigated.

Full text of DOI:10.1002/ejoc.201800353

A Journal of
Accepted Article
Title: One-Pot Synthesis of Silylated Enol Triflates from Silyl Enol
Ethers for Cyclohexynes and 1,2-Cyclohexadienes
Authors: Kazuki Inoue, Ryo Nakura, Kentaro Okano, and Atsunori Mori
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800353
Link to VoR: http://dx.doi.org/10.1002/ejoc.201800353
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10.1002/ejoc.201800353
European Journal of Organic Chemistry
COMMUNICATION
,
One-Pot Synthesis of Silylated Enol Triflates from Silyl Enol
Ethers for Cyclohexynes and 1,2-Cyclohexadienes
Kazuki Inoue, Ryo Nakura, Kentaro Okano,* and Atsunori Mori
Previous reports
Abstract: Regiocontrolled synthesis of precursors for strained
cyclohexynes and 1,2-cyclohexadienes is described based on one-
pot rearrangement of silyl enol ether followed by formation of enol
triflate. Treatment of silyl enol ether with a combination of LDA and
tBuOK led to the migration of the silyl group to generate α-silyl
enolate, which was treated with Comins’ reagent to provide the
corresponding enol triflate. The transient α-silyl lithium enolate was
smoothly isomerized in the presence of stoichiometric amount of
water within one hour at room temperature, providing precursors for
cyclohexynes exclusively in one pot. Effects of silyl groups,
isomerization of the lithium enolate, and regiocontrolled generation
of these precursors for these strained molecules were also
investigated.
Synthesis of α-silyl enol triflates as precursors for cycloallene/cycloalkyne
O
O
1) Br2, Et3N
nBuLi; R3SiCl;
H3O+
O
2) ethylene glycol
cat. TsOH, heat
Br
4
L-selectride;
PhNTf2
OTf
CsF
O
SiR3
SiR3
1
2
6
3
5
L-selectride
O
LDA;
OTf
CsF
PhNTf2
SiR3
SiR3
Strained cyclic compounds, such as benzyne, cyclohexyne (1),
and 1,2-cyclohexadiene (2), are reactive intermediates for
synthesizing multiply functionalized organic molecules.[1-4]
Despite their synthetic potentials, preparation of the necessary
precursors can present obstacles. Although reactivity and
generation of benzyne are extensively investigated for decades,
reports on the related cycloalkynes and cycloallenes are still
limited. Among various precursors, synthetically useful
compounds for such strained intermediates are α-silyl enol
triflates because of the unambiguously mild generation
conditions (CsF, rt) and broad functional group compatibilities.
Precursors for both compounds were first synthesized by Guitián
and co-workers and transformed to the cycloalkynes and
cycloallenes.[4] However, this method requires multi-step
synthesis of these precursors, and both precursors follow
different synthetic routes (Scheme 1). To shorten the synthetic
route for these strained intermediates 1 and 2, we realized that
the preparation of α-silyl enone 3 requires multi-step sequence
via cyclohexenyl bromide 4. In addition, the synthetic route
toward 1,2-cyclohexadiene (2) includes reduction of the C–C
double bond in enone 3 followed by triflation of the resultant silyl
ketone 5. In 1980s, Kuwajima[5] and Corey[6] independently
reported the synthesis of α-silyl cyclohexanone. Encouraged by
these literatures, we devised a one-pot synthesis of both silyl
enol triflates 6 and 7 from the same silyl enol ether 8. Based on
Corey’s report, the base-mediated migration of the silyl group
gives lithium enolate 9, which is converted to the corresponding
triflate 7 as a precursor for 1,2-cyclohexadiene (2). On the other
hand, we focused on the kinetic stability of the transient lithium
enolate 9. In turn, isomerization of the trisubstituted enolate 9 to
thermodynamically stable tetrasubstituted enolate 10 gives
triflate 6 as a precursor for cyclohexyne (1). Herein, we report
one-pot synthesis of both precursors through rearrangement of
silyl enol ether with/without isomerization of lithium enolate 9.
7
This work
One-pot synthesis of α-silyl enol triflates from the same silyl enol ether
OSiR3
base
OLi
OTf
SiR3
SiR3
7
8
9
isomerization
OLi
OTf
SiR3
SiR3
10
6
Scheme 1. Related previous work, the key objectives of this study and the
associated challenges.
We first examined the effectiveness of the combination of
nBuLi and tBuOK with TES enol ether 8a as a substrate,
according to the report by Corey[6] (Table 1, entry 1). The
progress of the migration of the TES group was monitored by
TLC, and substantial amount of the starting TES enol ether 8a
was consumed within three hours. However, the subsequent
treatment with Comins’ reagent 11[7] did not produce the desired
enol triflate in spite of the extensive optimization of reaction
conditions, including screening of the triflating reagents.[8] In
these cases, we isolated α-silyl cyclohexanone 5a as the major
product, which should be generated through protonation of the
transient lithium enolate 9a. These results indicated that the
strongly basic Schlosser’s conditions[9] might hamper the
triflation, probably due to the undesired nucleophilic addition of
butyl lithium toward the triflating reagent. Therefore, we re-
examined the reaction conditions that were applicable for our
synthetic strategy. We then attempted tBuOK-free conditions
using butyl lithium. The silicon migration, however, was not
facilitated, resulting in 74% recovery of the starting silyl enol
ether 8a (entry 2). The addition of other promoting agents, such
as TMEDA, led to the formation of a simple enol triflate derived
[a]
K. Inoue, R. Nakura, Prof. Dr. K. Okano, and Prof. Dr. A. Mori
Department of Chemical Science and Engineering
Kobe University
1-1 Rokkodai, Nada, Kobe 657-8501 (Japan)
E-mail: okano@harbor.kobe-u.ac.jp
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201800353
European Journal of Organic Chemistry
COMMUNICATION
,
from cyclohexanone in 72% yield,[10] despite the complete
consumption of silyl enol ether 8a (entry 3). Switching nBuLi to
sBuLi gave a complex mixture of unidentified byproducts (entry
4). Finally, we found that the novel combination of LDA and
tBuOK[11] was extremely effective for the one-pot silyl migration
followed by treatment of the transient lithium enolate using
Kinetic isotope effect of this reaction was also investigated
using a 1:1 mixture of 8a and 8a–d9 (Scheme 3). After the
mixture was treated with the combination of LDA and tBuOK at
room temperature for 20 min, the reaction was quenched with
water. Almost all the silyl enol ether 8a was consumed to
provide the corresponding α-silylketone 5a in 66% yield,
whereas α-silylketone 5a–d8 was generated in 26% with 56%
recovery of silyl enol ether 8a–d9. The results indicated that the
initial allylic deprotonation was the rate-determining step.
Comins’ reagent 11 to give
a
precursor 7a for 1,2-
cyclohexadiene (2) (entry 5). The control experiments revealed
that both LDA and tBuOK were essential (entries 6 and 7). Thus,
the reaction did not proceed in the absence of tBuOK or LDA,
resulting in the recovery of the silyl enol ether 8a.
OSiEt3
O
SiEt3
5a 66%
LDA
tBuOK
8a
8a
<1%
56%
Cl
D
D
H
Base
Additive
D
D
D
D
N
NTf2
hexane
RT, 20 min;
H2O
OSiEt3
D
O
OSiEt3
OLi
OTf
D
D
D
D
11
SiEt3
D
RT, 1 h
hexane
RT, Time
D
SiEt3
SiEt3
D
D
D
5a-d8
D
8a
9a
7a
26%
8a-d9
8a-d9
Table 1. Screening of bases for one-pot silyl group migration/triflation[a]
Scheme 3. Kinetic isotope effect of the rearrangement of silyl enol ether.
Entry
Base
nBuLi
nBuLi
nBuLi
sBuLi
LDA
LDA
–
Additive
tBuOK
–
Time
3 h
3 h
3 h
3 h
1 h
3 h
3 h
8a [%][b]
15
7a [%][b]
With the optimal conditions in hand, scope and limitation of
this method were investigated (Table 2). The established
reaction conditions can be applied to the multi-gram scale
synthesis, i.e., 1.3 g of 7a was isolated in 74% yield. TBS, TIPS,
and TBDPS enol ethers 8c–8e were converted to the
corresponding α-silyl enol triflates 7c–7e in low to moderate
yields. Silyl enol ethers 8c–8e smoothly underwent migration of
the silyl group, which was monitored by TLC analysis. In the
case of TIPS enol ether 8a, subsequent triflation of the resulting
lithium enolate was slower, probably due to the steric hindrance
of the TIPS group. Trimethylsilyl enol ether 8f was converted to
cyclohexanone, through nucleophilic attack to the less hindered
silicon atom, causing the cleavage of the Si–O bond. Silyl enol
ether 8g was converted to silyl enol triflates 7g.
1
2
3
4
5
6
7
<2
[c]
74
–
[c]
[c]
TMEDA
tBuOK
tBuOK
–
–
–
67
12
93
[c]
–
[c]
98
89
–
[c]
tBuOK
–
[a] Reaction conditions: silyl enol ether 8a (1 equiv; 0.50 mmol), base (2.5
equiv), additive (2.5 equiv), hexane, RT, then Comins reagent 11 (2.0 equiv).
[b] The yield was determined by 1H NMR spectrum of the crude material with
1,1,2,2-tetrachloroethane as an internal standard. [c] Not detected in the 1H
Cl
NMR spectrum of the crude material. TMEDA
tetramethylethylenediamine. LDA = lithium diisopropylamide.
=
N,N,N’,N’-
N
NTf2
LDA
tBuOK
OSi
OLi
OTf
11
R
R
R
LDA
tBuOK
THF
RT, 1 h
OSiEt3
hexane
RT, 1 h
Si
Si
(1)
94% recovery of 8b
8
9
7
hexane
RT, 3 h
Table 2. Scope of the preparation of precursors for 1,2-cyclohexadiene[a]
8b
Silyl enol ether 8b without an allylic α-proton was inert under
the conditions (eq 1), which supports that the reaction
proceeded through deprotonation of allylic proton rather than
olefinic proton.[6] Thus, the generation of allylic anion 12 led to
the formation of thermodynamically more favored α-silyl lithium
enolate 9. Subsequent trapping with Comins’ reagent provided 7
as a precursor for 1,2-cyclohexadinene (2) (Scheme 2).
Silyl enol ether
Product
OTf
Yield [%][b]
74[c]
68
38
Si = TES
TBS
7a
7c
7d
OSi
TIPS
TBDPS
TMS
Si
7e 56
8a, 8c–8f
7a, 7c–7f
7f
–
OSiEt3
OTf
SiEt3
LDA
tBuOK
70
(dr = 9:1)
OSiR3
OSiR3
Li
OLi
OTf
tBu
tBu
hexane
RT, 1 h
8g
7g
SiR3
SiR3
7
8
12
9
[a] Reaction conditions: silyl enol ether 8a (1 equiv; 0.50 mmol), LDA (2.5
equiv), tBuOK (2.5 equiv), hexane, RT, then THF, Comins’ reagent 11 (2.0
equiv). [b] Isolated yield. [c] 5 mmol scale.
Scheme 2. Plausible reaction pathway: favored initial allylic deprotonation.
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10.1002/ejoc.201800353
European Journal of Organic Chemistry
COMMUNICATION
,
After the establishment of the one-pot synthesis of
precursors for 1,2-cyclohexadiene, we then turned our attention
to parallel synthesis of precursors for cyclohexynes through
isomerization of the transient anion 9a (Scheme 4). To promote
isomerization of lithium enolate 9a to 10a, silyl enol ether 8a was
subjected to the same reaction conditions in a prolonged period
(20 h), which provided the desired product 6a in 6% yield
associated with 7a in 80%.
Additive
Time;
LDA
tBuOK
OSiEt3
OTf
OTf
+
hexane
RT, 1 h;
THF;
Cl
SiEt3
SiEt3
8a
6a
7a
N
NTf2
11
Table 3. Screening of reaction conditions for isomerization of enolate[a]
LDA
OSiEt3 tBuOK
Entry
1
Additive
–
Equiv
–
Time
20 h
20 h
20 h
20 h
20 h
3 h
6a [%][b]
6
7a [%][b]
80
OLi
OLi
hexane
RT, Time;
SiEt3
Cl
SiEt3
10a
9a
8a
2
iPr2NH
Ph3CH
MeOH
H2O
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
0.5
1.0
3.0
5.0
28
54
3
73
10
N
NTf2
11
[c]
4
68
–
Time 7a
1 h 93%
20 h
6a
OTf
OTf
+
–
[c]
5
77
–
SiEt3
SiEt3
80% 6%
[c]
7a
6a
6
H2O
81
–
[c]
7
H2O
1 h
91
–
Scheme 4. Effect of reaction time for isomerization of the transient enolate.
[c]
8
H2O
10 min
1 h
95
–
9[d]
10
11
12
13
H2O
13
71
68
34
Encouraged by the promising results, we then focused on
the isomerization of the transient α-silyl enolate to
thermodynamically favored enolate (Table 3). The prolonged
reaction time was insufficient for isomerization (Scheme 4 and
Table 3, entry 1); however, these results indicated that
diisopropylamine, the conjugate acid LDA, should work as an
acid in the reaction. We then examined a suitable proton donor
that could function as an acid to promote the isomerization of the
resulting enolate. Based on the hypothesis, the reaction mixture
was treated with diisopropylamine as an additive and was stirred
for 20 h at room temperature. The isomerization, however, was
not effectively promoted (entry 2). We then investigated other
H2O
1 h
17
H2O
1 h
54
[c]
H2O
1 h
76
–
[c]
H2O
1 h
43
–
[a] Reaction conditions: silyl enol ether 8a (1 equiv; 0.50 mmol), LDA (2.5
equiv), tBuOK (2.5 equiv), hexane, RT, 1 h, then THF, additive (1.5 equiv),
RT, then Comins’ reagent 11 (2.0 equiv). [b] The yield was determined by
1H NMR spectrum of the crude material with 1,1,2,2-tetrachloroethane as an
internal standard. [c] Not detected in the 1H NMR spectrum of the crude
material. [d] No additional THF.
proton
sources
for
the
smooth
isomerization.
Triphenylmethane[13] was effective, and methanol was proved
superior for the reaction (entries 3 and 4). Finally, we found that
the subsequent addition of THF and 1.5 equivalents of water
provided complete isomerization to give the desired compound
exclusively (entry 5). The isomerization was found to complete in
a shorter reaction period, even in 10 min with reproducibility
(entries 5–8). The isomerization was hampered in the absence
of additional THF that was added after the migration of the silyl
group (entry 9), probably due to the insufficient solvation of
water. Finally, we examined the effect of equivalents of water on
the isomerization. When the reaction was run with 0.5 and 1.0
equivalents of water, the desired silyl triflate 6a was formed in
17% and 54% yields with concomitant generation of silyl triflate
7a in 68% and 34%, respectively (entries 10 and 11). On the
other hand, increased amount of water (3.0 equiv) provided the
desired compound 6a in slightly reduced yield with none of silyl
triflate 7a (entry 12). The yield of the silyl triflate 6a was
evidently reduced to 43% with 5 equivalents of water, and the α-
silylated cyclohexanone 6a was recovered in 57% 1H NMR yield
(entry 13). These results indicated that generated lithium enolate
was protonated by the excess water, providing the α-silylated
cyclohexanone 6a.
After establishing the isomerization conditions of the
double bond in the transient enolate, we then investigated scope
and limitation of the transformation (Table 4). Silyl enol ethers 8a
and 8c–8e, which gave satisfactory results in the synthesis of
the precursor for 1,2-cyclohexadiene (2), were subjected to the
established reaction conditions to provide the corresponding α-
silyl enol triflates. In the case of TES enol ether 8a, the reaction
could be performed to provide 6a in 85% in a 1.4-gram scale.
For the synthesis of substituted cyclohexynes, the
stereochemical problem should be considered. We then
examined TES enol ether 8g and isolated the corresponding
product 6g in 44% yield as a sole regioisomer. TES enol ether
8h was also converted to the desired product 6h in 61% yield.
With these α-silyl enol triflates in hand, we then
investigated the rate for generation of 1,2-cyclohexadiene (2)
(Table 5). According to previous reports,[4b,4c] TES enol triflate 7a
was treated with tetrabutylammonium fluoride (TBAF) in the
presence of 1,3-diphenylisobenzofuran (12) at room temperature.
The starting TES enol triflate 7a was consumed within one hour
and the cycloadducts 13 was isolated in 83% yield as a mixture
of 71:29 endo/exo adducts (Entry 1). On the other hand, TBS
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10.1002/ejoc.201800353
European Journal of Organic Chemistry
COMMUNICATION
,
Cl
α-Silyl enol triflates 6 were found to generate cyclohexyne
(1) in the presence of fluoride ion (Table 6). Similarly, among
these α-silyl enol triflates 6, TES enol triflates 6a was smoothly
converted to the corresponding cycloadduct 14 in 94% yield
(Entry 1). TBS and TIPS enol triflates 6c and 6d were also
converted to 14 in good to excellent yields for 24 h (Entries 2
and 3). The reaction of TBDPS enol triflates 6e furnished to
provide cycloadduct 14 for 4 h (Entry 4).
N
NTf2
LDA
tBuOK
OSi
OTf
11
R
R
hexane
RT, 1 h;
H2O;
THF
RT, 1 h
Si
8
6
Table 4. Scope of the preparation of precursors for cyclohexyne[a]
Silyl enol ether
Product
Yield [%][b]
Ph
O
6a 85[c]
6c 65
6d 46
6e 16
OTf
Si = TES
TBS
OSi
Ph
Ph
TIPS
TBDPS
Si
OTf
TBAF
12
O
8a, 8c–8e
6a, 6c–6e
THF
RT, Time
Si
Ph
OSiEt3
OTf
61
44
6
1
14
tBu
tBu
tBu
SiEt3
6g
Table 6. Generation of cyclohexyne[a]
8g
8h
OTf
tBu
OSiEt3
Entry
Si
Time [h]
6 [%][b]
14 [%][b]
[c]
[c]
[c]
[c]
1
2
3
4
TES
TBS
TIPS
TBDPS
1
24
24
4
–
–
–
–
94 (78[d]
87
)
SiEt3
6h
[a] Reaction conditions: silyl enol ether 8a (1 equiv; 0.50 mmol), LDA (2.5
equiv), tBuOK (2.5 equiv), hexane, RT, then THF, H2O (1.5 equiv), RT, then
Comins’ reagent 11 (2.0 equiv). [b] Isolated yield. [c] 5 mmol scale.
73
86
[a] Reaction conditions: silyl enol triflate
6 (1 equiv; 0.20 mmol), 1,3-
and TIPS enol triflates 7c and 7d required a prolonged reaction
time (24 h) for consumption to provide 13 in 97% and 98% yields,
respectively (Entries 2 and 3). TBDPS enol triflate 7e was also
converted to 13 in 4 h to give 13 in quantitative yield (Entry 4).
diphenylisobenzofuran (12) (1.5 equiv), THF, RT, then TBAF (1.5 equiv). [b]
The yield was determined by 1H NMR spectrum of the crude material with
1,1,2,2-tetrachloroethane as an internal standard. [c] Not detected in the 1H
NMR spectrum of the crude material. [d] Isolated yield. TBAF
tetrabutylammonium fluoride.
=
Ph
O
In conclusion, we developed the synthesis of precursors
for 1,2-cyclohexadienes based on one-pot rearrangement of silyl
enol ether followed by the formation of enol triflate. The transient
α-silylated lithium enolate was smoothly isomerized in the
presence of stoichiometric water at room temperature to give
precursors for cyclohexynes. In addition, we investigated the
effects of silyl groups on the reaction rates for generating 1,2-
cyclohexadiene and cyclohexyne. Further application of these
findings will be reported in due course.
Ph
Ph
OTf
TBAF
12
O
THF
RT, Time
Si
H
Ph
7
2
13
Table 5. Generation of 1,2-cyclohexadiene[a]
Entry
Si
Time [h]
7 [%][b]
13 [%][b]
quant (83[d]
97
endo/exo
71:29 (78:22[d]
72:28
[c]
1
2
3
4
TES
TBS
TIPS
TBDPS
1
24
24
4
–
)
)
Acknowledgements
1
This work was financially supported by JSPS KAKENHI Grant
Numbers JP16K05774 in Scientific Research (C), JP16H01153
in the Middle Molecular Strategy, Creation of Innovation Centers
for Advanced Interdisciplinary Research Areas (Innovative
Bioproduction Kobe), and Kawanishi Memorial ShinMaywa
Education Foundation. We thank Dr. Takashi Niwa (The
“Compass to Healthy Life” Research Complex program, RIKEN)
for mass spectrometric analysis.
[c]
–
98
71:29
[c]
–
quant
72:28
[a] Reaction conditions: silyl enol triflate
7 (1 equiv; 0.20 mmol), 1,3-
diphenylisobenzofuran (12) (1.5 equiv), THF, RT, then TBAF (1.5 equiv). [b]
The yield was determined by 1H NMR spectrum of the crude material with
1,1,2,2-tetrachloroethane as an internal standard. [c] Not detected in the 1H
NMR spectrum of the crude material. [d] Isolated yield. TBAF
tetrabutylammonium fluoride.
=
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European Journal of Organic Chemistry
COMMUNICATION
,
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Conflict of interest
The authors declare no conflict of interest.
Keywords: strained molecules • reactive intermediates •
[3]
cycloalkyne • cycloallene • migration
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10.1002/ejoc.201800353
European Journal of Organic Chemistry
COMMUNICATION
,
Entry for the Table of Contents
COMMUNICATION
Kazuki Inoue, Ryo Nakura, Kentaro
Okano,* and Atsunori Mori
Page No. – Page No.
One-pot Synthesis of Silylated Enol
Triflates from Silyl Enol Ethers for
Cyclohexynes and 1,2-
Regiocontrolled synthesis of precursors for strained cyclohexynes and 1,2-
cyclohexadienes is described based on one-pot rearrangement of a silyl group
followed by the formation of enol triflates. The transient α-silylated lithium enolate
was smoothly isomerized in the presence of stoichiometric amount of water within
one hour at room temperature to provide precursors for cyclohexyne.
Cyclohexadienes
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