TfOH-catalyzed intramolecular alkyne-ketone metathesis leading to highly substituted five-membered cyclic enones

Article abstract of DOI:10.1039/b905954g

The intramolecular carbocyclization of tethered alkynyl ketones to five-membered cyclic enones is shown to be catalyzed by trifluoromethanesulfonic acid in MeOH, proceeding in good to excellent yields and with high selectivities.

Full text of DOI:10.1039/b905954g

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TfOH-catalyzed intramolecular alkyne–ketone metathesis leading
to highly substituted five-membered cyclic enoneswz
Tienan Jin,* Fan Yang, Chunli Liu and Yoshinori Yamamoto*
Received (in Cambridge, UK) 25th March 2009, Accepted 7th May 2009
First published as an Advance Article on the web 21st May 2009
DOI: 10.1039/b905954g
The intramolecular carbocyclization of tethered alkynyl ketones
to five-membered cyclic enones is shown to be catalyzed by
trifluoromethanesulfonic acid in MeOH, proceeding in good to
excellent yields and with high selectivities.
proceeds in good to excellent yields (eqn (2)). Further-
more, the reaction of 1,3-enynyl ketones produces the fused
polycyclic enones 3 containing a cyclopentenone ring efficiently
(eqn (2)).
The catalytic addition of C–O double bonds to C–C triple
bonds, so-called alkyne–carbonyl metathesis, is an attractive
method for the construction of highly substituted enones,
because it can be used to construct new C–C and C–O bonds
simultaneously in an efficient and atom-economic manner as
an alternative to the Wittig reaction. Although Lewis acid- or
Brønsted acid-catalyzed inter- and intramolecular alkyne–
aldehydes metathesis giving the corresponding enones has
been investigated extensively,1 the alkyne–ketone metathesis
was considered to be problematic due to the severe limitations
on the structure of the alkynes and ketones.2 For example,
Harding et al. reported that BF3 or HCl promotes intra-
molecular cyclization of 6-octyn-2-one to give a mixture of
five-membered cyclic enone and cyclohexenone.2f Recently,
Hsung et al. reported the BF3-catalyzed intramolecular
cyclization of special ynamide–ketones leading to the five-
membered cyclic enones selectively.2m
ð1Þ
ð2Þ
Initially, according to the previous results,3 we focused on
screening the reaction conditions, catalysts and solvents, for
the selective formation of the tetrasubstituted five-membered
cyclic enone 2a from 1a (Table 1). The use of AuCl3–AgSbF6,
AgSbF6, and TfOH in dichloroethane solvent afforded a
complex mixture of products containing a very poor yield of
2a (entries 1–3). Similarly, the use of other aprotic solvents,
such as toluene, THF, CH3CN, and 1,4-dioxane, gave 2a in
very low yields. Hence, we gave our attention to protic
solvents. Fortunately, when MeOH was used as a solvent in
We recently reported an efficient cationic Au(III)-catalyzed
alkyne–carbonyl metathesis of carbon tethered alkynyl
ketones to form highly substituted six-membered cyclic enones
(eqn (1)).3 Furthermore, we found that when 1,3-enynyl
ketones were employed, fused polycyclic enones could be
obtained under the same reaction conditions through tandem
alkyne–carbonyl metathesis and Nazarov cyclization
(eqn (1)).4 However, unfortunately, when the reaction was
applied to the formation of five-membered cyclic enones, we
failed to obtain the corresponding products in good yields,
instead a complex mixture of products was formed. It occurred
to us that the use of a p-electrophilic catalyst other than
coinage metals may produce the corresponding five-membered
cyclic enones in the alkyne–ketone metathesis. Herein we
report that, by the use of TfOH catalyst in MeOH, the
intramolecular transformation of the tethered alkynyl ketones
1 into the tetrasubstituted five-membered cyclic enones 2
Table 1 Optimization of reaction conditions for the formation of 2aa
Entry
Catalyst (mol%)
Solvent
Time/h
Yield (%)b
1
2
3
4
5
6
7
8
AuCl3–AgSbF6 (2/6)
AgSbF6 (5)
TfOH (5)
AgSbF6 (5)
TfOH (5)
Tf2NH (5)
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
9
7
9
19
4
4
18
22
22
22
22
22
22
30
20
28
87
90 (87)
90
80
HClO4 (5)
HSbF6ꢀH2O (5)
75
59
3
68
4
56
Department of Chemistry, Graduate School of Science,
Tohoku University, Sendai 980-8548, Japan.
E-mail: tjin@mail.tains.tohoku.ac.jp, yoshi@mail.tains.tohoku.ac.jp;
Fax: +81-022-795-6784; Tel: +81-022-795-6581
w This article is part of a ChemComm ‘Catalysis in Organic Synthesis’
web-theme issue showcasing high quality research in organic chemistry.
Please see our website (http://www.rsc.org/chemcomm/organic
webtheme2009) to access the other papers in this issue.
9
HCl (10)
10
11
12
13
CF3CO2H (5)
TfOH (5)
TfOH (5)
iPrOH
(CH2OH)2
TfOH (5)
a
Reaction conditions: 1a (0.4 mmol), catalyst (2–10 mol%), solvent
(0.2 M) at 80 1C. b 1H NMR yield was determined by using CH2Br2 as
an internal standard. Isolated yield is shown in parentheses.
z Electronic supplementary information (ESI) available: Experimental
procedures and characterization data. See DOI: 10.1039/b905954g
ꢁc
This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 3533–3535 | 3533

the presence of AgSbF6 catalyst, 2a was obtained in 87% yield
(entry 4). Further investigation of various Lewis acids and
Brønsted acids led to the finding that TfOH and Tf2NH
catalysts produce the expected cyclic enone 2a in a high yield
in a shorter reaction time (entries 5 and 6). Other Brønsted
acids such as HClO4, HSbF6, and HCl were also effective,
while CF3CO2H gave a trace amount of 2a (entries 7–10). It is
aromatic group at the alkynyl terminus produced the desired
enones 2d and 2e in high yields, though the reaction of 1e
required a longer reaction time (entries 3 and 4). Not only the
naphthyl substituted alkynyl ketone 1f, but also hetero-
aromatic ring, such as thiophenyl (1g) and furanyl (1h),
substituted alkynyl ketones afforded the corresponding enones
in high yields (entries 5–7). The reaction of 1i and 1j, having a
phenyl substituent and a geminal group in the tethered moiety,
proceeded smoothly to give 2i and 2j in 89% and 93%
yields, respectively (entries 8 and 9). The cyclopentane and
benzene tethered alkynyl ketones 1k and 1l were suitable
substrates for the formation of the bicyclic enones 2k and 2l
(entries 10 and 11).
i
noteworthy that other protic solvents, such as EtOH, PrOH,
and ethylene glycol, were less effective (entries 11–13). These
results indicate that the use of methanol is crucial for the
selective formation of the five-membered cyclic enones.
The substrate scope of TfOH-catalyzed cyclization of the
alkynyl ketones 1 is summarized in Table 2. The reaction of 1b
and 1c bearing a methyl and bulky isopropyl group at R2 in
the presence of 5 mol% of TfOH in MeOH at 80 1C gave the
corresponding tetrasubstituted five-membered cyclic enones 2b
and 2c in 90% and 75% yields, respectively (entries 1 and 2).
The electronic characteristics of an aromatic ring at R1 did not
exert a significant influence on the yield of 2. Substrates 1d and
1e having an electron-donating and an electron-withdrawing
In order to rationalize the role of methanol in this acid-
catalyzed alkyne–carbonyl metathesis, we performed the reac-
5
tion with the tethered alkynyl dimethoxy ketal 1a0 under the
standard reaction conditions (eqn (3)). The reaction was
accomplished in 1 h, affording a 2 : 1 mixture of the desired
enone 2a and the ketalized product 2a0 in 85% yield. Treat-
ment of the enone 2a with 5 mol% of TfOH in MeOH at 80 1C
did not give the ketalized product 2a0 at all. These experi-
mental results suggest that the present reaction proceeds
through in situ formation of ketal 1a0. However 2a0 was not
formed in the reaction of 1a. Perhaps 2a0 might be converted
to 2a under the conditions of Table 2. Accordingly, we
thought that not only 1a0 but also the hemi-ketal intermediate
A might be involved as reactive intermediates (Scheme 1). The
occurrence of a ketal species was further supported by the
following experiment (eqn (4)). In general, the reaction of
alkynyl ketones substituted with an alkyl group at R1 did not
proceed well.6 However, the reaction of the tethered alkynyl
dimethoxy ketals 1m0 and 1n0 having a n-butyl and c-hexyl
group at the alkynyl teminus gave the corresponding products
2m and 2n in 53% and 43% yields, respectively. This result
suggests that a ketal species gives the desired product more
easily and efficiently than the corresponding ketone.
Table 2 TfOH-catalyzed alkynyl ketone cyclization for the formation
of 2a
Yield
(%)b
Entry Substrates
1
1
Time/h Products
2
1b R2 = Me 4
2b 90
2c 75
i
2
3
1c R2 = Pr 15
1d R1 =
4-MeC6H4
4
2d 95
ð3Þ
ð4Þ
4
5
6
7
1e R1 =
4-ClC6H4
1f R1 =
2-naphthyl
1g R1 =
2-thiophenyl
1h R1 =
2-furanyl
36
7
2e 88
2f 85
2g 94
2h 89
4
7
8
9
1i Z =
CHPh
4
2i 89
2j 93
1j Z =
C(CO2Me)2
36
A proposed reaction mechanism is shown in Scheme 1. The
reaction of ketone 1a with TfOH in MeOH generates the
dimethoxy ketal and/or hemi-ketal A. Subsequent demethanola-
tion or dehydration affords the oxonium species B. The
intramolecular [2 + 2] cycloaddition would form the oxete
C,1b,2f which leads to 2a through a ring opening of oxete.7
Next, we extended this methodology to the tandem alkyne–
carbonyl metathesis and Nazarov reaction8 of 1,3-enynyl
ketones for the synthesis of various fused tri- and tetracyclic
enones containing a cyclopentenone ring. The reaction with
the enynyl ketones having cyclopentene (1o) and cyclohexene
10
1k
6
2k 83
11
1l
7
2l 91
a
Reaction conditions: 1 (0.4 mmol), TfOH (5 mol%) in MeOH
(0.2 M) at 80 1C in a pressure vial for the time shown in the Table.
Isolated yield.
b
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This journal is The Royal Society of Chemistry 2009
3534 | Chem. Commun., 2009, 3533–3535

with 25% of a single diastereomer 3r0, in which the double
bond was away from the ring-fused position (entry 4). Perhaps
the double bond migration took place to avoid ring strain. The
cyclopentane tethered enynyl ketone 1s underwent the tandem
cyclization smoothly to give a 1.7 : 1 mixture of two diastereo-
mers of the corresponding linear tetracycle 3s in 63% yield
(entry 5).
In conclusion, we have developed an efficient TfOH-
catalyzed alkyne–carbonyl metathesis for the selective syn-
thesis of five-membered cyclic enones from tethered alkynyl
ketones. The reaction proceeds through hemi-ketals or ketals
generated in situ in MeOH. Further extension of this method
led to the tandem alkyne–carbonyl metathesis and Nazarov
cyclization of 1,3-enynyl ketones, forming the fused tri- and
tetracyclic enones. Further investigation of mechanistic details
and application of the present methodology to the synthesis of
biologically active compounds are in progress.
Scheme 1 A proposed mechanism.
Table 3 TfOH-catalyzed tandem cyclization of 1,3-enynyl ketones 1a
Notes and references
1 (a) For alkyne–aldehyde metathesis, see: M. Curini, F. Epifano,
F. Maltese and O. Rosati, Synlett, 2003, 552; (b) J. U. Rhee and
M. Krische, Org. Lett., 2005, 7, 2493; (c) A. Saito, M. Umakoshi,
N. Yagyu and Y. Hanazawa, Org. Lett., 2008, 10, 1783;
(d) G. S. Viswanathan and C.-J. Lee, Tetrahedron Lett., 2002, 43,
1613; (e) C. Gonzalez-Rodrıguez, L. Escalante, J. A. Varela,
L. Castedo and C. Saa, Org. Lett., 2009, 11, 1531.
2 (a) C. E. Harding and M. Hanack, Tetrahedron Lett., 1971, 12,
1253; (b) R. J. Balf, B. Rao and L. Weiler, Can. J. Chem., 1971, 49,
3135; (c) M. Hanack, C. E. Harding and J. Derocque, Chem. Ber.,
1972, 105, 421; (d) G. L. Lang and T.-W. Hall, J. Org. Chem., 1974,
39, 3819; (e) C. E. Harding and G. R. Stanford, J. Org. Chem., 1989,
54, 3054; (f) C. E. Harding and S. L. King, J. Org. Chem., 1992, 57,
883; (g) J. Siso, A. Balog and D. P. Curran, J. Org. Chem., 1992, 57,
4341; (h) J. R. Grunwell, M. F. Wempe and J. Mitchell, Tetrahedron
Lett., 1993, 34, 7163; (i) A. Balog and D. P. Curran, J. Org. Chem.,
1995, 60, 337; (j) A. Balog, S. J. Geib and D. P. Curran, J. Org.
Chem., 1995, 60, 345; (k) M. F. Wempe and J. R. Grunwell, J. Org.
Chem., 1995, 60, 2714; (l) M. F. Wempe and J. R. Grunwell,
Tetrahedron Lett., 2000, 41, 6709; (m) K. C. M. Kurtz,
R. P. Hsung and Y. Zhang, Org. Lett., 2006, 8, 231.
3 T. Jin and Y. Yamamoto, Org. Lett., 2007, 9, 5259.
4 T. Jin and Y. Yamamoto, Org. Lett., 2008, 10, 3137.
5 The ketals 1a0, 1m0, and 1n0 were prepared according to the
literature procedure, see: N. Hamada, K. Kazahaya, H. Shimizu
and T. Sato, Synlett, 2004, 1074.
6 Under the standard reaction conditions, an alkyl-substituted alkynyl
ketone, such as 1m (R1 = nBu, R2 = Et, in Table 2), produced the
corresponding enone 2m in 17% NMR yield even at a higher
temperature (100 1C) for a prolonged time (48 h).
Yield
(%)b
Entry Substrates
1
Time/h Products
3
1
1o 20
3o 68
3p 80
2
3
4
1p
1q
1r
7
4
4
3q 80
(7 : 1)
3r 63
3r0 25
3s 63c
5
1s 36
(1.7 : 1)
7 The following mechanism is also conceivable. Interaction of a
cationic carbon of B, attached to MeO+, with a triple bond
makes it electron-deficient, and then addition of MeOH to the triple
bond followed by C–C bond formation produces an intermediate
D. Bond reorganization–demethoxylation–ketalization–hydrolysis
affords 2a.
a
Reaction conditions: 1 (0.4 mmol), TfOH (5 mol%) in MeOH
b
c
(0.2 M) at 80 1C in a pressure vial. Isolated yield. A mixture of
two diastereomers.
(1p) moieties gave the corresponding linear tricycles 3o and 3p
in 68% and 80% yield, respectively (Table 3, entries 1 and 2).
The enynyl ketone 1q bearing a sterically bulky tert-butyl on
the 4-position of the cyclohexene ring was subjected to the
reaction conditions affording a 7 : 1 mixture of diastereomers
3q with the cis-anti isomer as a major diastereomer (entry 3).
The reaction of the enynyl ketone 1r having a cycloheptene
moiety afforded 63% of the corresponding tricycle 3r along
8 For recent reviews of Nazarov reaction, see: (a) M. A. Tius, Eur. J.
Org. Chem., 2005, 2193; (b) H. Pellissier, Tetrahedron, 2005, 61,
6479; (c) A. J. Frontier and C. Collison, Tetrahedron, 2005, 61, 7577.
ꢁc
This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 3533–3535 | 3535