Generation of cycloalkynes through deprotonation of cyclic enol triflates with magnesium bisamides

Article abstract of DOI:10.1039/c6cc09920c

Deprotonative generation of cyclohexynes, cycloheptynes, and cyclooctynes was achieved by controlling the reactivities of transient anionic species from the corresponding enol triflates with magnesium bis(2,2,6,6-tetramethylpiperidide) as a base. The star

Full text of DOI:10.1039/c6cc09920c

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DOI: 10.1039/C6CC09920C
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Generation of Cycloalkynes through Deprotonation of Cyclic Enol
Triflates with Magnesium Bisamides
Received 00th January 20xx,
Accepted 00th January 20xx
Yuto Hioki, Kentaro Okano,* and Atsunori Mori
DOI: 10.1039/x0xx00000x
www.rsc.org/
Deprotonative generation of cyclohexynes, cycloheptynes, and
cyclooctynes was achieved by controlling the reactivities of
transient anionic species from corresponding enol triflates with
magnesium bis(2,2,6,6-tetramethylpiperidide) as a base. The
starting enol triflates are readily obtained through triflation of the
corresponding ketones, allowing direct access to the cycloalkynes.
Generation of cyclohexyne from difunctionalized cyclohexene
Mg
hν
Br
Br
N
N
N
Wittig (Ref. 4)
Willey (Ref. 5)
NLiTs
2
3
5
N
N
40–60 °C
or hν
Strained organic molecules have high reactivities and various
reaction modes and therefore attract much attention for
synthetic use.1 Representative arynes2 and cycloalkynes3 have
been extensively investigated. There are fewer reports in the
literature of strained cycloalkynes than of eight-membered or
larger cycloalkynes. Several methods have been used for
cycloalkyne generation but the reaction conditions are harsh,
or multi-step substrate preparation is involved (Scheme 1).
Wittig and co-workers accomplished the generation of
cyclohexyne (1) from 1,2-dibromocyclohexene (2) and
magnesium by isolation of the cycloadduct with 1,3-
diphenylisobenzofuran.4 Willey achieved photo-induced
generation of cyclohexyne (1) from aminotriazole 3.5 Guitián
and co-workers generated cyclohexyne from α-trimethylsilyl
enol triflate 4 with CsF under mild conditions.6 Banert and co-
workers developed heat- or photo-induced degradation of
bis(diazirine) 5 to form 1 with evolution of nitrogen gas.7
Rearrangement of vinylidene carbenes also provided strained
cycloalkynes.8 Wittig and Roberts established cyclohexyne
generation from a monofunctionalized cyclohexene; treatment
of 1-chlorocyclohexene (6) with phenyllithium gave adduct 7 in
29% yield.9 Fujita and co-workers employed iodonium salt 8
for the formation of 1 under heating.10 Further examples of
the formation of strained cycloalkynes,11 seven-membered
cycloalkynes,12 and eight-membered or larger cycloalkynes
have been reported.4,13
TMS
OTf
1
F–
N
N
Banert (Ref. 7)
Guitián (Ref. 6)
4
Generation of cyclohexyne from monofunctionalized cyclohexene
Wittig and Roberts (Ref. 9)
Ph
PhLi
Et2O
150 °C
Cl
H
6
1
1
7
9
29%
Fujita (Ref. 10)
OAc
AcONBu4
I+Ph
CHCl3
60 °C
8
50%
Scheme 1 Methods for cyclohexyne formation.
To the best of our knowledge, simple deprotonation of
cyclic enol triflates involving β-elimination of the triflate has
not yet been achieved to generate medium sized-cycloalkynes,
probably due to the undesired side reactions of highly
electrophilic cycloalkyne with transient anion species. Herein
we disclose that magnesium bisamide, derived from
magnesium chloride and two equivalents of lithium amide,
facilitates the formation of strained cycloalkyne from the
corresponding ketone. These features enable direct access to
cycloalkynes from ketones via cyclic enol triflates, which has
been recognized as an unsolved problem in the synthetic
community.
Our study began by exploring effective bases for the
formation of cyclohexyne (1) from enol triflate 10a. We
evaluated their efficacies based on the yields of the
cycloadduct 12a from 1,3-diphenylisobenzofuran (11) and in
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-4 | 1
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situ generated cyclohexyne (1) (Table 1). In an initial the desired cycloadduct 12a (Table 1, Entry 4). VIinewdeArpticelenOdnelinnet
17
18
experiment, the enol triflate 10a was treated with phenyl studies performed in Knochel’s grouDpOI: 1a0n.10d39o/Cu6rCCg0r9o9u2p0C
lithium9 as a base in the presence of isobenzofuran 11 (Table 1, indicated that highly basic magnesium bisamides should
Entry 1). All the starting triflate 10a was consumed; however, promote deprotonation. The reaction was therefore carried
the desired cycloadduct 12a was not detected in the crude out using Mg(Ni-Pr2)2·2LiCl (14),17c,19 and an improved yield of
material, which consisted of several unidentified products due the desired cycloadduct 12a was obtained as we expected
to the strong nucleophilicity of phenyl lithium, although the (Table 1, Entry 5). Unlike the case for LDA, only a small amount
reaction was performed even at –78 °C. We therefore of 12a was isolated, with 68% recovery of the starting triflate
examined lithium amides such as lithium diisopropylamide 10a, when the reaction was conducted at –78 °C. The sterically
(LDA)14 and lithium 2,2,6,6-tetramethylpiperidide (TMP)15 demanding Mg(Ni-Prt-Bu)2·2LiCl (15) gave a lower yield of 12a
(Table 1, Entries 2 and 3). The desired cycloadduct 12a was (Table 1, Entry 6). The sterically hindered amine-based
isolated in both cases, albeit in low yields. Encouraged by the magnesium bisamide Mg(Nt-Amt-Bu)2·2LiCl (16) gave no
results, we then used a milder base, so-called the Knochel– cycloadduct 12a, with 91% recovery of triflate 10a (Table 1,
Hauser base,16 TMPMgCl·LiCl (13), but most of the starting Entry 7). We then examined cyclic amine-based magnesium
triflate 10a was recovered in this case, without formation of
bisamides. Both Mg(cis-2,6-dimethylpiperidide)2·2LiCl (17)20
and Mg(TMP)2·2LiCl (18)17 promoted the formation of
cyclohexyne (1) to give the cycloadduct 12a in 51% and 56%
yields, respectively (Table 1, Entries 8 and 9). We also
examined zinc amides, such as Zn(TMP)2·2LiCl21 or
TMPZnCl·LiCl,22 but these bases did not facilitate cyclohexyne
formation, and substrate 10a was recovered (Table 1, Entries
10 and 11). We also examined the leaving group and found
that the enol nonaflate was also converted to the cycloadduct
12a in comparable yield, while cyclohexenyl chloride and
bromide were recovered under the same conditions.
These results indicate that a magnesium bisamide is
essential for achieving this transformation (Scheme 2). Unlike
the case for phenyllithium,9 the transient anionic species 19
generated through deprotonation by Mg(TMP)2·2LiCl is
unreactive because of steric hindrance by the bulky TMP group
attached to the magnesium ion; this hampers the undesired
reaction with the cyclohexyne (1) yielding dimeric species 20.
The low nucleophilicity of the transient anionic species
facilitates smooth generation of cyclohexyne (1) and
subsequent cycloaddition to provide 12a.
Table 1 Generation of cyclohexyne by deprotonation of enol triflate.
Ph
O
Ph
Ph
Base
11
O
THF
rt, 3 h
OTf
Ph
10a
1
12a
Entry Base
Triflate
10a (%)
<1 (traced)
<1 (traced)
<1 (traced)
84
Cycloadduct
12a (%)
c
1
2
PhLi
LDA
–
18
3
LiTMP
14 (23d)
c
4
TMPMgCl·LiCl
–
5
Mg(Ni-Pr2)2·2LiCl
<1 (68d)
<1
38 (3d)
24
6
Mg(Ni-Prt-Bu)2·2LiCl
c
7
Mg(Nt-Amt-Bu)2·2LiCl 91
–
8
9
10
11
Mg(DMP)2·2LiCl
Mg(TMP)2·2LiCl
Zn(TMP)2·2LiCl
TMPZnCl·LiCl
<1
<1
84
90
51
56
c
–
TMPMg
c
–
Mg(TMP)2
Mg(TMP)
·2LiCl
1
a
The yield was determined by 1H NMR spectrum of the crude material with
THF
rt, 3 h
OTf
OTf
OTf
b
1,1,2,2-tetrachloroethane as an internal standard. Reaction conditions: triflate
Ph
O
10a
19
20
10a (1 equiv; 0.50 mmol), base (3 equiv), 1,3-diphenylisobenzofuran (11) (1.5
equiv), THF, rt, 3 h. Not detected in the crude 1H NMR spectra. Reaction
c
d
Ph
temperature: –78 °C. TMP
dimethylpiperidyl.
=
2,2,6,6-tetramethylpiperidyl. DMP
=
cis-2,6-
Ph
11
O
Ph
12a
1
Scheme 2 Plausible reaction pathway: competing undesired nucleophilic addition of
the transient anionic species.
N
MgCl·LiCl
N
Mg
N
N
Mg
N
TMPMgCl·LiCl (13)
Mg(Ni-Pr2)2·2LiCl (14) Mg(Ni-Prt-Bu)2·2LiCl (15)
Having established the optimum conditions, we
investigated the substrate scope of cyclic enol triflates (Table
2). Use of triflates 10b and 10c resulted in smooth generation
of cycloheptyne and cyclooctyne, to provide the corresponding
cycloadducts 12b and 12c in 58% and 96% yields,
respectively.23 In both cases, the cycloadduct yields were
N
Mg
N
N
Mg
N
N Mg N
Mg(Nt-Amt-Bu)2·2LiCl (16) Mg(DMP)2·2LiCl (17)
Mg(TMP)2·2LiCl (18)
Figure 1 Structure of magnesium amides.
2 | J. Name., 2012, 00, 1-4
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significantly lower with LDA. We then investigatVeiedw oArtthicleerOnsliinxe-
membered cyclic enol triflates, 10d–10f; these are readily
Table 2 Substrate scope of cycloalkynes.
DOI: 10.1039/C6CC09920C
Ph
O
obtained by triflation of the corresponding ketones. Treatment
of enol triflate 10d under the established conditions led to the
formation of cyclohexyne bearing an ethyl group, which was
converted to the desired cycloadduct 12d in 62% yield
[diastereomer ratio (dr) = 1:1, estimated using 1H NMR
spectroscopy]. Similarly, a cyclohexyne bearing a benzyl group
adjacent to the alkyne moiety was converted to the
corresponding adduct 12e in 65% yield (dr = 9:4, estimated
Ph
Mg(TMP)2
·2LiCl
Ph
11
O
R
R
R
THF
rt, 3 h
( )n
( )n
( )n
OTf
Ph
Substrate
Product
Yield (%)a
1
Ph
O
55% (14%b,c)
58% (7%c)
using H NMR spectroscopy). The more congested substrate
10f was also transformed to the corresponding product 12f in
75% yield. Gratifyingly, enol triflate 10g bearing an ester
moiety was also converted to the corresponding cycloadduct
( )n
OTf
( )n
10a
n = 1
Ph
96% (56%b,c)
1
10b
10c
n = 2
n = 3
12g in satisfactory yield (dr = 3:2, estimated using H NMR
12a–12c
spectroscopy). Spirocyclic enol triflate 10h, which was
prepared from the corresponding diol over two steps, was
converted to the desired product 12h in 81% yield. This
method can be used to generate benzo-fused cyclohexyne as
well as simple cyclohexynes. Enol triflate 10i, which was
derived from α-tetralone, was converted to benzo-fused
cycloadduct 12i in 91% yield.
Ph
O
Et
Et
62%d
(dr = 1:1e)
OTf
Ph
10d
12d
Ph
O
These encouraging results prompted us to examine other
reactions of cycloalkynes; however, trapping agents such as
nitrones and diazo compounds gave low yields or none of the
rdesired products.24 Among the reactions we tested, strain-
promoted [3+2] cycloaddition25 of cycloalkynes and aryl azide
2126 proceeded smoothly (Scheme 3). The six-membered cyclic
enol triflate 10a was converted to the triazole 22a in 31% yield.
The same reaction of enol triflates 10b and 10c provided the
corresponding product 22b and 22c in 37% and 85% yields,
respectively.27 The method was also effective for rapid access
to a triazole from a complex cyclic ketone such as 5α-
cholestan-3-one. Its triflate 10j was also converted to triazole-
fused cholestane derivative 22j and 22j’ in 39% combined yield.
65%f
OTf
Bn
(dr = 9:4e)
Bn Ph
10e
12e
Ph
O
75%d
OTf
Me Me
Me Me
Ph
10f
12f
Ph
O
i-Pr
60%
OTf
N3
(dr = 3:2e)
EtO2C Me
EtO2C Me
Ph
12g
21
N
N
i-Pr
10g
N
Mg(TMP)2·2LiCl
( )n
i-Pr
i-Pr
22a n = 1
22b n = 2
22c n = 3
31%
37%
85%
Ph
THF
rt, 18–23 h
( )n
OTf
i-Pr
10a–10c
O
OTf
81%g
Ph
N3
i-Pr
H
10h
12h
21
H
Mg(TMP)2·2LiCl
THF, rt, 10 h
39%
H
H
Ph
O
TfO
10j
H
91%
OTf
H
H
i-Pr
Ph
H
H
i-Pr
N
N
N
N
N
10i
+
12i
N
H
H
H
H
i-Pr
H
H
a
b
c
Isolated yield. LDA was used as a base instead of Mg(TMP)2·2LiCl. The yield
i-Pr
was determined by 1H NMR spectrum of the crude material with 1,1,2,2-
13%
22j'
22j
26%
d
e
tetrachloroethane as an internal standard.
Five hours.
The ratio of
Scheme 3 Trapping of cycloalkynes with aryl azide.
diastereomers was determined by 1H NMR. f Seven hours. g Four hours.
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10 (a) M. Fujita, Y. Sakanishi, W. H. Kim, T. OkuyamVaie,wCAhreticmle.Online
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In summary, deprotonative generation of cyclohexynes,
cycloheptynes, and cyclooctynes from the corresponding enol
triflates was achieved by controlling the reactivities of
transient anionic species with magnesium bis(2,2,6,6-
tetramethylpiperidide) as a mild base. The starting enol
triflates were readily obtained by triflation of the
corresponding ketones. Extension of scope and its synthetic
application are currently under investigation and will be
reported in due course.
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. Jun
Onodera (JEOL Ltd.) for mass spectrometric analysis.
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Chem. Soc., 1965, 87, 1917.
27 For the detail of structure determination of the two isomers
22j and 22j’, see the Electronic Supplementary Information.
9
4 | J. Name., 2012, 00, 1-4
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