Triflic acid catalyzed synthesis of spirocycles via acetylene cations

Article abstract of DOI:10.1002/anie.200901771

Rings of various shapes and sizes: Spirocyclic hydrocarbons 2 were obtained in good to excellent yield through the triflic acid (TfOH) catalyzed cyclization of alkynyl-substituted cyclic tertiary alcohols 1 under mild conditions with good control of ring

Full text of DOI:10.1002/anie.200901771

Angewandte
Chemie
DOI: 10.1002/anie.200901771
Spirocyclization
Triflic Acid Catalyzed Synthesis of Spirocycles via Acetylene Cations**
Tienan Jin,* Masafumi Himuro, and Yoshinori Yamamoto*
Spirocyclic hydrocarbon frameworks are found in many
natural products with a wide range of biological activities.
Such compounds often become candidates for medicines,
perfumes, and agricultural chemicals.[1] Therefore, many
synthetic methodologies for constructing functionalized spi-
rocycles have been developed, such as intramolecular alkyl-
ation, transition-metal-based cyclization, cycloaddition, and
rearrangement methods.[1] Recently, new preparative meth-
ods have been reported.[2] However, the development of a
catalytic, efficient method for the synthesis of spirocycles with
control over ring size would be highly desirable.
Table 1: Optimization of the Brønsted acid catalyst and the solvent for
the formation of spirocycle 2a.[a]
Entry
Catalyst
Solvent
t [h]
Yield of
Yield of
2a [%][b]
3a [%][b]
1
2
3
4
5
6
7
8
9
p-TsOH·H2O
HBF4
HNTf2
HSbF6·H2O
TfOH
TfOH
TfOH
TfOH
TfOH
DCE
DCE
DCE
DCE
24
24
1
1.5
1
0
84
(75)
85
(90)
82
47
8
90
3
0
0
0
The Brønsted acid mediated cyclization of acetylene
cations is an attractive method for the synthesis of polycycles
DCE
with quaternary carbon centers,[3] because new C C and C O
bonds can be constructed simultaneously in an efficient and
atom-economic manner. To our knowledge, the use of this
method for the construction of spirocyclic frameworks has
never been reported. Herein, we report that a trifluorome-
thanesulfonic acid (TfOH) catalyzed cyclization of alkynyl
cyclic tertiary alcohols 1 via an acetylene cation produces
spirocyclic compounds 2 with rings of various sizes in good to
high yields under mild conditions [Eq. (1)].
À
À
CH2Cl2
CH3CN
toluene
THF
1
0
24
24
24
29
82
90
2
[a] Reaction conditions: 1a (0.4 mmol), catalyst (10 mol%), solvent
(2 mL, 0.2m), 508C. [b] The yield was determined by 1H NMR spectros-
copy by using CH2Br2 as an internal standard. Yields in parentheses are
the yield of the isolated product. Ts=toluenesulfonyl, Tf=trifluorome-
thanesulfonyl, DCE=dichloroethane.
HSbF6, were also effective (Table 1, entries 2–4), although the
use of p-TsOH gave the dehydrated 1,6-enyne 3a in 90%
yield without the formation of 2a (Table 1, entry 1). The
investigation of various solvents in the presence of the TfOH
catalyst revealed that dichloromethane was also effective; the
use of CH3CN led to a mixture of 2a and 3a (Table 1, entries 6
and 7). Interestingly, the use of toluene and THF afforded the
enyne 3a in high yield along with a small amount of 2a
(Table 1, entries 8 and 9).
These results suggest that the spirocycle 2a is formed via
the 1,6-enyne 3a with an appropriate p-electrophilic acid.
Hence, we tested the reaction of enyne 3a with TfOH
(10 mol%) in DCE at 508C. As expected, the reaction
proceeded to completion within 30 min in the presence of
H2O (1 equiv) to give the spirocycle 2a in 96% yield
[Eq. (2)]; in the absence of H2O, only a trace amount of 2a
was produced. This result indicates clearly that a strong
Brønsted acid, such as TfOH, activates the alkene moiety of
1,6-enynes to promote a subsequent nucleophilic carbocy-
cloaddition. Recently, TfOH-catalyzed hydroamination and
hydroalkoxylation reactions of unactivated alkenes were
In preliminary studies, we screened reaction conditions
for the formation of the spirocycle 2a from 1a. We
investigated the use of a series of Brønsted acid catalysts
and various solvents at 508C (Table 1). Among the Brønsted
acids tested in dichloroethane (DCE), TfOH exhibited the
highest catalytic activity to produce 2a in 90% yield (Table 1,
entry 5). Other Brønsted acids, such as HBF4, HNTf2, and
[*] Dr. T. Jin, M. Himuro, Prof. Dr. Y. Yamamoto
Department of Chemistry, Graduate School of Science
Tohoku University, Sendai 980-8578 (Japan)
Fax: (+81)22-795-6784
E-mail: tjin@mail.tains.tohoku.ac.jp
yoshi@mail.tains.tohoku.ac.jp
Homepage: http://hanyu.chem.tohoku.ac.jp/~web/lab/
index.shtml
[**] We thank the faculty members of the Instrumental Analysis Center
at Tohoku University for the measurement of NMR and mass
spectra.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200901771.
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Table 2: TfOH-catalyzed synthesis of various spirocycles 2.[a]
reported independently by the research groups of Hartwig
and He.[4] However, Brønsted acid catalyzed carbocyclization
reactions of enynes have rarely been described.[5] Kozmin and
Zhang reported the first HNTf2-mediated carbocyclization of
siloxy 1,5-enynes, in which the Brønsted acid was proposed to
activate the alkyne moiety.[6]
The TfOH-catalyzed synthesis of spirocycles with rings of
various sizes is summarized in Table 2. The reactions of
alkynes substituted with an electron-donating or electron-
withdrawing aromatic ring, a naphthyl group, or a conjugated
olefin moiety produced the corresponding spiro[4.4]nonanes
2b–e in good to excellent yield (Table 2, entries 1–4). Other
cyclic tertiary alcohols with a cyclobutyl, cyclohex(en)yl, or
cycloheptyl ring were transformed into the expected spiro-
[3.4]octane 2 f, spiro[5.4]decanes 2g–i, and spiro-
[6.4]undecane 2j in good yield (Table 2, entries 5–9). In the
case of the isopropyl-substituted tertiary cyclic alcohol 1h and
the tertiary cyclohexenyl alcohol 1i, the product was formed
as a nearly 1:1 mixture of two diastereomers (Table 2,
entries 7 and 8).
When the number of methylene carbon atoms in the
tether between the ring and the alkyne was increased, the
reaction still proceeded smoothly. Thus, compounds 1k and 1l
were converted into the corresponding spiro[4.5]decane 2k
and spiro[3.5]nonane 2l in 64 and 71% yield, respectively, at
808C (Table 2, entries 10 and 11).
Entry
1
t [h]
2
Yield [%][b]
1
1b: R=4-MeC6H4
1c: R=4-ClC6H4
1d: R=1-naphthyl
1e: R=1-cyclohexenyl
1
1
1
1
2b
2c
2d
2e
79
96
93
55
2[c]
3[c]
4
5
6
10
4
71
75
64[d]
(1:1)
7
5
Substrates 1m and 1n, which contain a benzyl or methyl
ether group on one of the tether carbon atoms, were
transformed under the standard conditions into the corre-
sponding spirocycles 2m (and 2m’) and 2n (and 2n’) in good
yield as a 1.2:1 or 1:1 separable diastereomeric mixture
(Table 2, entries 12 and 13). Remarkably, the presence of both
a double bond and an oxygen atom in substrate 1o was also
tolerated: The desired spirocyles 2o and 2o’ were obtained in
61% yield as a 1:1 mixture of diastereomers (Table 2,
entry 14). Unfortunately, the reaction of substrates with a
carbonyl or tert-butyldimethylsilyl ether functional group
resulted in decomposition. Additional studies revealed that,
in contrast to substrates with an aryl or conjugated alkenyl
group at the alkyne terminus, alkynes substituted with an
alkyl group at this position did not undergo the present
catalytic cyclization to give the desired products.[7]
80[d]
(1.2:1)
8
1
9
4
45
64
71
10[c]
4
11[c]
1
Interestingly, the reaction of the diastereomeric alkynyl
tertiary alcohols 1p and 1p’ under the standard conditions
gave the same [3.2.1] bicyclic ketone 4p as a single diaste-
reomer [Eqs. (3) and (4)]. The reaction of 1q, with two
methylene carbon atoms in the tether (rather than one, as in
1p), gave the corresponding [3.3.1] bicyclic ketone 4q in 66%
yield as a single diastereomer [Eq. (5)]. On the other hand, a
mixture of diastereomers 1r was converted into a mixture of
diastereomers 4r in a 1.1:1 ratio [Eq. (6)]. These results
demonstrate that the newly developed method can be applied
to the synthesis of bicyclocarbocycles containing a one-
carbon-atom bridge.
12
13
14
1m: R1 =Bn
1n: R1 =Me
1o: R1 =allyl
5
5
5
2m/2m’
2n/2n’
2o/2o’
60[d]
(1.2:1)
60[d]
(1:1)
61[d]
(1:1)
[a] Reaction conditions: 1 (0.4 mmol), catalyst (10 mol%), dichloro-
ethane (2 mL, 0.2m), 508C. [b] Yield of the isolated product. [c] The
reaction was carried out at 808C. [d] The total yield is given for a mixture
of two diastereomers. Bn=benzyl.
A proposed reaction mechanism is shown in Scheme 1:
Protonation of the tertiary hydroxy group of 1a with a
Brønsted acid leads to the tertiary carbocation intermediate
A, which is converted rapidly into the corresponding enyne
3a through b elimination. There may be an equilibrium
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This method was applied to the formation of bridged bicyclic
ketones with high stereoselectivity. Investigations into the
extension of the present methodology to the construction of a
variety of useful carbocycles containing quaternary carbon
atoms and into a Brønsted acid catalyzed enyne cycloisome-
rization are in progress.
Experimental Section
Representative procedure: TfOH (0.04 mmol, 3.5 mL) was added to a
solution of 1-(5-phenylpent-4-ynyl)cyclopentanol (1a; 0.4 mmol,
91 mg) in dichloroethane (2 mL) at room temperature in a pressure
vial, and the resulting mixture was stirred at 508C for 1 h. The
reaction mixture was then cooled to room temperature, filtered
through a short Florisil pad, and eluted with diethyl ether. The filtrate
was concentrated, and the residue was purified by chromatography
on silica gel to afford phenyl spiro[4.4]non-1-ylmethanone (2a;
82 mg, 90%) as a yellow oil.
Received: April 2, 2009
Revised: May 1, 2009
Published online: July 6, 2009
Keywords: alkynes · cyclization · spirocycles · tertiary alcohols ·
.
triflic acid
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alkynyl-substituted cyclic tertiary alcohols via acetylene cations.
between A and 3a. Attack of the alkynyl moiety onto the
cation in A affords the benzylidene cation B. This high-energy
intermediate B may be stabilized by charge delocalization
involving the phenyl group.[3h,i,7,8] The subsequent reaction of
cation B with H2O produces the spirocyclic ketone 2a and
regenerates the Brønsted acid.
In summary, we have developed an efficient and general
method for the synthesis of spirocycles through the cyclization
of acetylene cations. Spirocyclic compounds with rings of
various sizes can be obtained under mild reaction conditions.
À
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Communications
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