Practical Synthesis of Precursors of Cyclohexyne and 1,2-Cyclohexadiene

DOI: 10.1055/s-0037-1610356

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Synthesis p. 1561 - 1564 (2019)

Update date:2022-08-31

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Authors:

Nakura, Ryo

Inoue, Kazuki

Okano, Kentaro

Mori, Atsunori

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Article abstract of DOI:10.1055/s-0037-1610356

This study investigated a practical method for regiocontrolled synthesis of precursors of strained cyclohexynes and 1,2-cyclohexadienes, which is a one-pot procedure consisting of a rearrangement of silyl enol ether and subsequent formation of the enol triflates. Triethylsilyl enol ether, derived from cyclohexanone, was treated with a combination of LDA and t -BuOK in n -hexane/THF to encourage the migration of the silyl group to generate an α-silyl enolate. Subsequently, the α-silyl enolate was reacted with Comins' reagent to yield the corresponding enol triflate. Finally, the α-silylated trisubstituted lithium enolate for the synthesis of 1,2-cyclohexadiene precursor was isomerized in the presence of a stoichiometric amount of water for one hour at room temperature to exclusively provide tetrasubstituted lithium enolate for the synthesis of cyclohexyne precursor in one pot.

Full text of DOI:10.1055/s-0037-1610356

SYNTHESIS

2019, 51, A–D

psp

R. Nakura et al.

PSP

Synthesis

Practical Synthesis of Precursors of Cyclohexyne and

1,2-Cyclohexadiene

Ryo Nakura

n-BuLi

diisopropylamine

t-BuOK

Kazuki Inoue

Kentaro Okano*

Atsunori Mori

OSiEt₃

OLi

OTf

NTf₂

TBAF

0-0

9-8

n-hexane/

THF (95:5)

r.t., 1 h

–78 °C to r.t.

1 h

SiEt₃

gram-scale

no SEC-HPLC

isomerization

with H₂O

Department of Chemical Science and Engineering, Kobe

University, 1-1 Rokkodai, Nada, Kobe 657-8501, Japan

okano@harbor.kobe-u.ac.jp

OLi

OTf

NTf₂

–78 °C to r.t.

1 h

SiEt₃

gram-scale

no SEC-HPLC

Received: 16.10.2018

Accepted after revision: 14.11.2018

Published online: 11.01.2019

ether.¹²However, this method involves tedious purification

process that employs SEC (size-exclusion chromatography)-

HPLC to separate the desired products from low polarity

compounds. Herein, we describe a detailed modification of

reaction conditions and achieve a gram-scale synthesis of

silyl enol triflates 1 and 2 without using SEC-HPLC separa-

tion (Scheme 1).

DOI: 10.1055/s-0037-1610356; Art ID: ss-2018-f0697-psp

Abstract This study investigated a practical method for regiocon-

trolled synthesis of precursors of strained cyclohexynes and 1,2-cyclo-

hexadienes, which is a one-pot procedure consisting of a rearrange-

ment of silyl enol ether and subsequent formation of the enol triflates.

Triethylsilyl enol ether, derived from cyclohexanone, was treated with a

combination of LDA and t-BuOK in n-hexane/THF to encourage the mi-

gration of the silyl group to generate an α-silyl enolate. Subsequently,

the α-silyl enolate was reacted with Comins’ reagent to yield the corre-

sponding enol triflate. Finally, the α-silylated trisubstituted lithium eno-

late for the synthesis of 1,2-cyclohexadiene precursor was isomerized in

the presence of a stoichiometric amount of water for one hour at room

temperature to exclusively provide tetrasubstituted lithium enolate for

the synthesis of cyclohexyne precursor in one pot.

n-BuLi

diisopropylamine

t-BuOK

OSiEt₃

OLi

OTf

NTf₂

n-hexane/THF (95:5)

r.t., 1 h

–78 °C to r.t.

1 h

SiEt₃

Procedure 1

H₂O

r.t., 1 h

Key words strained molecules, allenes, alkynes, enolate, isomeriza-

tion, lithiation, rearrangement, solvent effects

OLi

NTf₂

OTf

–78 °C to r.t.

1 h

SiEt₃

Strained cycloalkynes and cycloallenes have attracted

attention as reactive intermediates in a variety of reactions

such as cycloaddition and nucleophilic addition.¹However,

synthetic application of cyclohexynes²and 1,2-cyclohexa-

dienes³lag far behind those of cyclooctynes,⁴dibenzocy-

clooctyne derivatives,⁵and 4,8-diazacyclononynes,⁶be-

cause the latter can be isolated as stable organic com-

pounds. Therefore, various methods to generate

cyclohexyne and 1,2-cyclohexadiene in situ have been re-

ported.⁷Roberts⁸and Wittig⁹reported seminal work on the

generation of cyclohexyne and 1,2-cyclohexadiene, respec-

tively. In addition, Guitián and co-workers reported a fluo-

ride ion-promoted generation of cyclohexynes and 1,2-cy-

clohexadienes from silyl enol triflates.¹⁰Recently, we re-

ported a short-step synthesis of the silyl enol triflates from

cyclohexanone using a two-pot process based on a modifi-

cation of Corey’s rearrangement reaction¹¹of silyl enol

Procedure 2

Scheme 1 Preparation of triflates 1 and 2

In our previous study,¹²a combination of t-BuOK and

commercially available lithium diisopropylamide (LDA) in

tetrahydrofuran/ethylbenzene/heptane (purchased from

Tokyo Chemical Industries (TCI): Product Number L0171)

was used for the migration of a silyl group. It was found to

be difficult to separate the desired compounds 1 and 2 from

low polarity compounds by silica gel column chromatogra-

phy. One compound that was obtained by SEC-HPLC separa-

tion was identified to be 1,4-diphenylbutane (3) after care-

ful analysis (Figure 1). At first, it was assumed that this

compound was generated under the basic conditions from

ethylbenzene that was involved in the commercial LDA

solution.¹³However, it was found that the LDA solution it-

R. Nakura et al.

PSP

Synthesis

self contained compound 3, because treatment of the LDA

solution with water and the extraction of the mixture pro-

vided compound 3.

Table 1 Effects of Solvent on the Migration of Silyl Group

n-BuLi

diisopropylamine

t-BuOK

OSiEt₃

OLi

H₂O

n-hexane/THF

r.t., 1 h

SiEt₃

Entry

n-hexane/THF

(v:v)

Recovered silyl Silyl ketone 5 Cyclohexanone

enol ether 4 (%) (%) (%)

Figure 1 Identified compound obtained by SEC-HPLC separation

100:0

95:5

93^a

7^a

–

99^a(84)^c

85^a

In order to avoid the tedious SEC-HPLC separation, a

readily prepared LDA that did not contain the low polar

compound 3 was used. In preliminary experiments, we

found that the migration of a silyl group was significantly

affected by the solvent ratio. We first examined the solvent

ratio between n-hexane/THF to establish a robust proce-

dure (Table 1). When only n-hexane was used as a solvent,

the desired α-silyl ketone 5 was obtained with a 93% recov-

ery of the starting silyl enol ether 4 (Table 1, entry 1). The

reaction was then repeated with an n-hexane/THF ratio of

95:5, which is close to the ratio used with the commercially

available LDA in the authors’ previous work.¹²In this case,

the migration of the silyl group smoothly took place to give

α-silyl ketone 5 in 84% isolated yield (entry 2). The yield of 5

slightly decreased in n-hexane/THF (90:10) (entry 3). The

α-silyl ketone 5 was not obtained in n-hexane/THF (85:15)

with detection of 4% cyclohexanone (entry 4). These results

indicated that the silyl group was removed by the nucleop-

hilic attack of LDA. By increasing the solvent ratio, the re-

covery of the starting silyl enol ether 4 decreased and the

formation of cyclohexanone became preferable (entries 5–

7). These drastic solvent effects suggest that the aggrega-

tion state of LDA is important for the selective formation of

α-silyl ketone 5 over cyclohexanone.¹⁴

90:10

85:15

80:20

70:30

17:83

15^a

71^a

76^a

67^a

27^a

–

4^a

–

11^a

2^a

–

65^a

^aThe yield was determined by ¹H NMR spectrum of the crude material with

1,1,2,2-tetrachloroethane as an internal standard.

^bNot detected in the ¹H NMR spectrum of the crude material.

^cIsolated yield.

n-BuLi

diisopropylamine

t-BuOK

OSiEt₃

OLi

OTf

NTf₂

n-hexane/THF (95:5)

r.t., 1 h

–78 °C to r.t.

1 h

SiEt₃

2.49 g, 73%

n-BuLi

diisopropylamine

t-BuOK

OSiEt₃

OLi

NTf₂

OTf

n-hexane/THF (95:5)

r.t., 1 h

then H₂O, r.t., 1 h

–78 °C to r.t.

1 h

SiEt₃

1.81 g, 53%

Having established the optimal conditions for the mi-

gration of the silyl group, we then focused on investigating

the one-pot rearrangement of silyl enol ether, followed by

triflation without/with isomerization, giving precursors of

1,2-cyclohexadiene and cyclohexyne on multi-gram scales

without SEC-HPLC separation (Scheme 2). Thus, the migra-

tion proceeded smoothly with in situ generated LDA in n-

hexane/THF (95:5) at room temperature. The resulting eno-

late was then trapped with Comins’ reagent¹⁵to provide si-

lyl enol triflate 1 in 73% yield. The trisubstituted enolate

was isomerized with water, and the resulting tetrasubsti-

tuted enolate was subjected to triflation to give silyl enol

triflate 2 in 53% yield.

Scheme 2 One-pot gram-scale syntheses of precursors of cyclohexyne

and 1,2-cyclohexadiene

sults would promote the research on using these reactive

and strained synthetic intermediates for bioactive natural

products, drugs, and functional organic molecules.

Analytical TLC was performed on Merck 60 F254 aluminum sheets

precoated with a 0.25 mm thickness of silica gel. IR spectra were re-

corded on a Bruker Alpha with an ATR attachment (Ge) and are re-

ported in wave numbers (cm^–1). ¹H NMR (400 MHz) and ¹³C NMR

(100 MHz) spectra were measured on a JEOL ECZ400 spectrometer.

Chemical shifts for ¹H NMR are reported in parts per million (ppm)

downfield from TMS with the solvent resonance as the internal stan-

dard (CHCl₃: δ = 7.26) and coupling constants are in hertz (Hz). Stan-

dard abbreviations are used for spin multiplicity. Chemical shifts for

¹³C NMR are reported in ppm from TMS with the solvent resonance as

the internal standard (CDCl₃: δ = 77.16). All workup and purification

procedures were carried out with reagent-grade solvents in air. Un-

In summary, we have achieved one-pot gram-scale syn-

theses of precursors of cyclohexyne and 1,2-cyclohexadiene

from the same silyl enol ether. The synthetic method devel-

oped in this work could be applied to the synthesis of both

cycloalkyne precursor and cycloallene precursor. These re-

R. Nakura et al.

PSP

Synthesis

less otherwise noted, materials were obtained from commercial sup-

pliers and used without further purification. Flash column chroma-

tography was performed on Wakogel^®C-300 (45–75 μm, Wako Pure

Chemical Industries, Ltd.). Recycling preparative SEC-HPLC was per-

formed with LC-9201 (Japan Analytical Industry Co., Ltd.) equipped

with preparative SEC columns (JAI-GEL-1H and JAI-GEL-2H). Anhyd

umn chromatography (n-hexane) followed by preparative SEC-HPLC

to provide 6-(triethylsilyl)cyclohex-1-en-1-yl trifluoromethanesul-

fonate (1)¹²(2.24 g, 6.50 mmol, 65%) as a colorless oil and 1,4-diphen-

ylbutane (3)¹⁶(62.0 mg, 0.316 mmol) as a colorless oil, whose spec-

troscopic data were identical to those reported in the literature.

¹H NMR (CDCl₃, 400 MHz): δ = 7.31–7.23 (m, 4 H), 7.21–7.11 (m, 6 H),

2.68–2.57 (m, 4 H), 1.74–1.61 (m, 4 H).

THF and n-BuLi (1.6

M in n-hexane) were purchased from

Kanto Chemical Co., Inc. THF was further dried by passing through a

solvent purification system (Grass Contour) prior to use. Anhyd n-

hexane (H₂O content <30 ppm) was purchased from Nacalai Tesque,

Inc. LDA (ca. 1.5 M in THF/ethylbenzene/heptane) and t-BuOK

(>95.0%) was purchased from Tokyo Chemical Industry Co., Ltd. i-

Pr₂NH was purchased from FUJIFILM Wako Pure Chemical Co., Ltd.

and distilled over CaH₂prior to use.

¹³C NMR (CDCl₃, 100 MHz): δ = 142.7, 128.5, 128.4, 125.8, 35.9, 31.2.

6-(Triethylsilyl)cyclohex-1-en-1-yl Trifluoromethanesulfonate (1)

A flame-dried 500 mL two-necked flask equipped with a Teflon-coat-

ed magnetic stirring bar, a rubber septum, and a three-way stopcock

was charged with i-Pr₂NH (3.52 mL, 25.0 mmol, 2.5 equiv) and anhyd

THF (4.0 mL). After the resulting solution was cooled to –78 °C, n-BuLi

(1.57 M in n-hexane, 15.9 mL, 25.0 mmol, 2.5 equiv) was added to the

flask. The mixture was then warmed to 0 °C and stirred for 30 min.

The resulting LDA solution was warmed to r.t. To the solution were

added anhyd n-hexane (62.2 mL) and t-BuOK (2.80 g, 25.0 mmol, 2.5

equiv). After stirring at r.t. for 30 min, the reaction mixture was treat-

ed with silyl enol ether 4 (2.11 g, 9.93 mmol, 1.0 equiv), and the re-

sulting mixture was stirred at r.t. for 1 h, at which time TLC (n-hex-

ane/MeOAc 9:1) indicated complete consumption of the starting silyl

enol ether. To the mixture was added anhyd THF (40 mL). After cool-

ing to –78 °C, the resulting mixture was treated with Comins’ reagent

(7.86 g, 20.0 mmol, 2.0 equiv) in THF (30 mL) dropwise and the mix-

ture was warmed to r.t. After stirring at r.t. for 1 h, the resulting mix-

ture was treated with H₂O (60 mL). After partition of the layers, the

aqueous layer was extracted with n-hexane (3 × 40 mL). The com-

bined organic extracts were washed with brine (80 mL), dried (Na₂-

SO₄), and filtered. The filtrate was concentrated under reduced pres-

sure to give a crude material, which was purified by silica gel column

chromatography (n-hexane) to provide the title compound (2.49 g,

7.24 mmol, 73%) as a colorless oil, whose spectroscopic data were

identical to those reported in the literature.¹²

2-(Triethylsilyl)cyclohexan-1-one (5)

A flame-dried 20 mL Schlenk tube equipped with a Teflon-coated

magnetic stirring bar and a rubber septum was charged with i-Pr₂NH

(0.176 mL, 1.25 mmol, 2.5 equiv) and anhyd THF (0.20 mL). After the

resulting solution was cooled to –78 °C, n-BuLi (1.57 M in n-hexane,

0.796 mL, 1.25 mmol, 2.5 equiv) was added to the Schlenk tube. The

mixture was then warmed to 0 °C and stirred for 30 min. The result-

ing LDA solution was warmed to r.t. To the solution were added anhyd

n-hexane (3.11 mL) and t-BuOK (0.139 g, 1.24 mmol, 2.5 equiv). After

stirring at r.t. for 30 min, the reaction mixture was treated with silyl

enol ether 4 (0.107 g, 0.504 mmol, 1.0 equiv), and the resulting mix-

ture was stirred at r.t. for 1 h, at which time TLC (n-hexane/MeOAc

9:1) indicated complete consumption of the starting silyl enol ether.

The resulting mixture was treated with H₂O (3 mL). After partition of

the layers, the aqueous layer was extracted with Et₂O (3 × 2 mL). The

combined organic extracts were washed with brine (4 mL), dried

(Na₂SO₄), and filtered. The filtrate was concentrated under reduced

pressure to give a crude material, which was purified by silica gel col-

umn chromatography (n-hexane/MeOAc 20:1) to provide the title

compound (90.1 mg, 0.424 mmol, 84%) as a colorless oil, whose spec-

troscopic data were identical to those reported in the literature.¹²

¹H NMR (CDCl₃, 400 MHz): δ = 5.68–5.60 (m, 1 H), 2.27–2.16 (m, 1 H),

2.15–2.01 (m, 2 H), 2.00–1.90 (m, 1 H), 1.72–1.60 (m, 2 H), 1.56–1.41

(m, 1 H), 0.97 (t, J = 7.8 Hz, 9 H), 0.66 (q, J = 7.8 Hz, 6 H).

¹H NMR (CDCl₃, 400 MHz): δ = 2.40–2.30 (m, 2 H), 2.28–2.16 (m, 1 H),

2.00–1.86 (m, 3 H), 1.79–1.62 (m, 3 H), 0.96 (t, J = 7.8 Hz, 9 H), 0.65 (q,

J = 7.9 Hz, 6 H).

¹³C NMR (CDCl₃, 100 MHz): δ = 153.2, 118.7 (q, ¹J_C,F= 319 Hz), 115.2,

26.1, 25.6, 24.3, 21.4, 7.5, 3.0.

¹³C NMR (CDCl₃, 100 MHz): δ = 213.0, 42.0, 41.5, 26.6, 25.2, 23.8, 7.4,

3.3.

2-(Triethylsilyl)cyclohex-1-en-1-yl Trifluoromethanesulfonate (2)