Highly efficient synthesis of tri- and tetrasubstituted conjugated enynes from Bronsted acid catalyzed alkoxylation of 1-cyclopropylprop-2-yn-1-ols with alcohols

Article abstract of DOI:10.1021/jo9008244

(Chemical Equation Presented) A highly efficient triflic acid catalyzed ring opening of a wide variety of 1-cyclopropyl-2-propyn-1-ols with alcohols as an efficient synthetic route to conjugated enynes is reported herein. The reaction was operationally st

Full text of DOI:10.1021/jo9008244

pubs.acs.org/joc
Highly Efficient Synthesis of Tri- and Tetrasubstituted Conjugated
Enynes from Brønsted Acid Catalyzed Alkoxylation of
1-Cyclopropylprop-2-yn-1-ols with Alcohols
Srinivasa Reddy Mothe and Philip Wai Hong Chan*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences,
Nanyang Technological University, Singapore 637371, Singapore
waihong@ntu.edu.sg
Received April 21, 2009
A highly efficient triflic acid catalyzed ring opening of a wide variety of 1-cyclopropyl-2-propyn-1-ols
with alcohols as an efficient synthetic route to conjugated enynes is reported herein. The reaction was
operationally straightforward and accomplished in good to excellent yields (44-100%), high product
turnovers (up to 10,000), and with complete regioselectivity under mild conditions with a low catalyst
loading of 0.01 mol %. The mechanism is suggested to involve protonation of the alcohol substrate by
the TfOH catalyst, followed by ionization of the starting material. This causes ring opening of the
cyclopropane moiety and trapping by the alcohol nucleophile to give the conjugated enyne product.
The synthetic utility of the present method was also exemplified by the efficient large-scale conversion
in gram quantities of one example studied in this work to the corresponding conjugated enyne
product in excellent yield and turnover number.
Introduction
sparse.1-4 We3 and others4 recently reported one such
approach that gave conjugated enynes as single regioisomers
from Au-, Ru2-, or Yb-catalyzed ring opening of 1-cyclo-
propyl-2-propyn-1-ols with N- and O-centered nucleophiles.
Although shown to be efficient, producing H2O as poten-
tially the only byproduct, the potential of this method for
scale-up applications has been lessened by the need for high
catalyst loadings. Added to this is the cost of the catalyst in
reactions mediated by gold and ruthenium and a substrate
scope limited to ones containing functional groups that
cannot take part in strong metal coordination. In this regard,
we envisioned that developing a Brønsted acid catalyzed
version of this regioselective enyne forming reaction could
hold promise as the basis to re-addressing these shortcom-
ings. An inexpensive and commercially available reagent
class that has a high tolerance to air and moisture, Brønsted
acids have been reported to be versatile in mediating a wide
Conjugated enynes are important targets in organic synth-
esis because of their demonstrated versatility as intermedi-
ates in numerous strategies to compounds of current
biological and materials interest. For this reason, simple
methods that can install this unsaturated hydrocarbon moi-
ety are highly desirable.1 This is all the more so if it can be
achieved without the competitive formation of undesired
regio- and stereoisomers, examples of which have remain
(1) For recent reviews, see: (a) Shirtcliff, L. D.; McClintock, S. P.; Haley,
M. M. Chem. Soc. Rev. 2008, 37, 343. (b) Doucet, H.; Hierso, J.-C. Angew.
Chem., Int. Ed. 2007, 46, 834. (c) Negishi, E.; Anastasia, L. Chem. Rev. 2003,
103, 1979. (d) Zeni, G.; Braga, A. L.; Stefani, H. A. Acc. Chem. Res. 2003,
36, 731.
(2) For recent examples, see: (a) Liu, Y.; Nishiura, M.; Wang, Y.; Hou,
Z. J. Am. Chem. Soc. 2006, 128, 5592. (b) Zhang, L.-M.; Wang, S.-Z. J. Am.
Chem. Soc. 2006, 128, 1442. (c) Pahadi, N. K.; Camacho, D. H.; Nakamura,
I.; Yamamoto, Y. J. Org. Chem. 2006, 71, 1152. (d) Miller, K. M.;
Luanphaisarnnont, T.; Molinaro, C.; Jamison, T. F. J. Am. Chem. Soc.
2004, 126, 4130.
(4) (a) Yamauchi, Y.; Onodera, G.; Sakata, K.; Yuki, M.; Miyake, Y.;
Uemura, S.; Nishibayashi, Y. J. Am. Chem. Soc. 2007, 129, 5175.
(b) Xiao, H.-Q.; Shu, X.-Z.; Ji, K.-G.; Qi, C.-Z.; Liang, Y.-M. New J. Chem.
2007, 31, 2041.
(3) (a) Rao, W.; Zhang, X.; Sze, E. M. L.; Chan, P. W. H. J. Org. Chem.
2009, 74, 1740. (b) Rao, W.; Chan, P. W. H. Chem.;Eur. J. 2008, 14, 10486.
DOI: 10.1021/jo9008244
r
Published on Web 07/24/2009
J. Org. Chem. 2009, 74, 5887–5893 5887
2009 American Chemical Society

Mothe and Chan
SCHEME 1. Regioselective TfOH-Catalyzed Synthesis of
Conjugated Enyne from 1-Cyclopropyl-2-propyn-1-ols
JOCArticle
variety of organic transformations in excellent yields and
with high selectivity.5 In recent years, this has hitherto
included stereoselective Brønsted acid mediated C-X
(X=C, N, O, S) bond formation strategies that make use
of alcohol pro-electrophiles such as allylic, benzylic, and
propargylic alcohols.6 To our knowledge, however, an
efficient Brønsted acid catalyzed protocol for the regioselec-
tive synthesis of conjugated enynes from 1-cyclopropyl-2-
propyn-1-ols has not been extensively explored.7 As part of a
program examining the utility of alcohols as pro-electro-
philes in organic synthesis,3,8 we report herein TfOH-cata-
lyzed ring opening of 1-cyclopropyl-2-propyn-1-ols with
alcohols (Scheme 1).9 The conjugated enyne products were
afforded in excellent yields, high product turnovers, and
regioselectivities comparable to those reported for the clo-
sely related metal-promoted approaches to this synthetically
useful building block.
TABLE 1. Optimization of Reaction Conditionsa
Results and Discussion
All 1-cyclopropyl-2-propyn-1-ols studied in this work
were prepared from reaction of the corresponding cyclopro-
pyl ketone and substituted alkyne pretreated with LDA or
catalyst loading
(mol %)
product
yield (%) turnover
entry catalyst
solvent
1
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
Tf2NH
p-TsOH
TFA
5
5
1
100
81
20
16
100
(5) For recent reviews, see: (a) Akiyama, T. Chem. Rev. 2007, 107, 5744.
(b) Busca, G. Chem. Rev. 2007, 107, 5366. (c) Shao, L.-X.; Shi, M. Curr. Org.
Chem. 2007, 11, 1135. (d) Yamamoto, H. Tetrahedron 2007, 63, 8377.
(e) Yamamoto, H.; Boxer, M. B. Chimia 2007, 61, 279. (f) Ishihara, K.;
Yamamoto, H. In New Frontiers in Asymmetric Catalysis; Mikami, K.,
Lautens, M., Eds; John Wiley & Sons: New York, 2007; p 359. (g) Enders, D.;
Grondal, C.; Huettl, M. R. M. Angew. Chem., Int. Ed. 2007, 46, 1570.
(h) Yamamoto, H. In Asymmetric Synthesis; Christmann, M., Braese, S., Eds;
Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, Germany, 2007; p 153.
(i) Akiyama, T.; Itoh, J.; Fuchibe, K. Adv. Synth. Catal. 2006, 348, 999.
(6) For reviews on the use of alcohols as pro-electrophiles, see:
(a) Bandini, M.; Tragni, M. Org. Biomol. Chem. 2009, 7, 1501. (b) Muzart,
J. Tetrahedron 2008, 64, 5815. (c) Muzart, J. Eur. J. Org. Chem. 2007, 3077.
(d) Muzart, J. Tetrahedron 2005, 61, 4179. (e) Tamaru, Y. Eur. J. Org. Chem.
2005, 2647. For selected examples on Brønsted acid catalyzed reactions with
alcohol pro-electrophiles, see: (e) Bras, J. L.; Muzart, J. Tetrahedron 2007, 63,
2b
3
100
100
100
49
4
5
6
7
0.1
0.01
0.005
0.001
0.01
0.01
0.01
0.01
5
1 000
10 000
9 800
-
7 500
7 000
6 500
2 000
11
c
-
8d
9d
10d
11
12e
13f
14f
PhMe
(CH2Cl)2
THF
75
70
65
20
55
40
10
5
5
8
2
HCl
aAll reactions were performed at reflux for 15 min with 0.2 mmol of 1a
in 2 mL of 2a. bReaction conducted at room temperature for 24 h.
cNo reaction based on TLC and 1H NMR analysis of the crude mixture.
ꢀ
ꢀ
7942. (f) Sanz, R.; Martınez, A.; Guilarte, V.; Alvarez-Gutierrez, J. M.;
Rodrıguez, F. Eur. J. Org. Chem. 2007, 4642. (g) Sanz, R.; Miguel, D.;
ꢀ
ꢀ
Martınez, A.; Alvarez-Gutierrez, J. M.; Rodrıguez, F. Org. Lett. 2007, 9,
2027. (h) Sanz, R.; Martınez, A.; Miguel, D.; Alvarez-Gutierrez, J. M.;
ꢀ
ꢀ
dReaction conducted with 5 equiv of 2a. Reaction conducted for 24 h.
e
Rodrıguez, F. Org. Lett. 2007, 9, 727. (i) Shirakawa, S.; Kobayashi, S. Org.
fReaction conducted for 2 h.
ꢀ
ꢀ
Lett. 2007, 9, 311. (j) Sanz, R.; Martınez, A.; Miguel, D.; Alvarez-Gutierrez,
J. M.; Rodrıguez, F. Adv. Synth. Catal. 2006, 348, 1841. (k) Motokura, K.;
Fujita, N.; Mori, K.; Mizugaki, T.; Ebitani, K.; Kaneda, K. Angew. Chem.,
ethynylmagnesium bromide in place of the alkyne and LDA,
or alkynone with cyclopropylmagnesium bromide following
literature procedures.10 With 1-cyclopropyl-1,3-diphenyl-
prop-2-yn-1-ol 1a and EtOH 2a as the probe substrates,
a survey of different reaction conditions initially revealed
alkoxylation of 1a with a 2 mL stock solution of 2a containing
5 mol % of TfOH at reflux for 15 min gave the best result
(Table 1, entry 1). Under these conditions, (Z)-(6-ethoxyhex-
3-en-1-yne-1,3-diyl)dibenzene 3a was obtained as the sole
product in quantitative yield. The cis-stereochemistry of the
conjugated enyne product was confirmed by comparison with
X-ray crystallographic analysis and NOE spectroscopic data
of closely related adducts (vide infra) and reported literature
values.3,4 Our studies subsequently showed that a gradual
decrease in the catalyst loading of TfOH from 5 to 1 to 0.1 to
0.01 mol % was found to result in no apparent loss in catalytic
activity, and in each of these reactions the same product
yield was attained (entries 3-5). On the other hand, further
ꢀ
ꢀ
Int. Ed. 2006, 45, 2605. (l) Sanz, R.; Martınez, A.; Alvarez-Gutierrez, J. M.;
Rodrıguez, F. Eur. J. Org. Chem. 2006, 1383. (m) Young, J.-J.; Jung, L.-J.;
Cheng, K.-M. Tetrahedron Lett. 2000, 41, 3415.
(7) Liang and co-workers reported one example of p-TsOH-catalyzed
alkoxylation of a 1-cyclopropyl-2-propyn-1-ol with MeOH that gave the
corresponding conjugated enyne product in 58% yield; see ref 4b.
(8) (a) Zhang, X.; Rao, W.; Sally; Chan, P. W. H. Org. Biomol. Chem.
2009, DOI: 10.1039/B908447A. (b) Kothandaraman, P.; Rao, W.; Zhang, X.;
Chan, P. W. H. Tetrahedron 2009, 65, 1833. (c) Rao, W.; Chan, P. W. H. Org.
Biomol. Chem. 2008, 6, 2426. (d) Zhang, X.; Rao, W.; Chan, P. W. H. Synlett
2008, special issue, 2204. (e) Wu, W.; Rao, W.; Er, Y. Q.; Loh, K. J.; Poh, C. Y.;
Chan, P. W. H. Tetrahedron Lett. 2008, 49, 2620; Tetrahedron Lett. 2008, 49,
4981. (f) Rao, W.; Tay, A. H. L.; Goh, P. J.; Choy, J. M. L.; Ke, J. K.; Chan, P. W. H.
Tetrahedron Lett. 2008, 49, 122; Tetrahedron Lett. 2008, 49, 5112.
(9) For selected examples of other reactions mediated by TfOH, see:
(a) Juma, B.; Adeel, M.; Villinger, A.; Reinke, H.; Spannenberg, A.; Fischer,
C.; Langer, P. Adv. Synth. Catal. 2009, 351, 1073. (b) Singh, R.; Parai, M. K.;
Panda, G. Org. Biomol. Chem. 2009, 7, 1858. (c) Li, A.; DeSchepper, D. J.;
Klumpp, D. A. Tetrahedron Lett. 2009, 50, 1924. (d) Zhu, Z.-B.; Shi, M.
J. Org. Chem. 2009, 74, 2481. (e) Kalbarczyk, K. P.; Diver, S. T. J. Org.
Chem. 2009, 74, 2193. (f) Lu, J.-M.; Zhu, Z.-B.; Shi, M. Chem.;Eur. J. 2009,
15, 963. (g) Zhang, C.; Murarka, S.; Seidel, D. J. Org. Chem. 2009, 74, 419.
(h) Li, X.; Ye, S.; He, C.; Yu, Z.-X. Eur. J. Org. Chem. 2008, 4296. (i) Li, W.;
€ €
Shi, M. J. Org. Chem. 2008, 73, 4151. (j) Abid, M.; Teixeira, L.; Torok, B.
Org. Lett. 2008, 10, 933. (k) Rosenfeld, D. C.; Shekhar, S.; Takemiya, A.;
Utsunomiya, M.; Hartwig, J. F. Org. Lett. 2006, 8, 4179. (l) Li, Z.; Zhang, J.;
Brouwer, C.; Yang, C.-G.; Reich, N. W.; He, C. Org. Lett. 2006, 8, 4175.
~
(m) Coulombel, L.; Dunach, E. Green Chem. 2004, 6, 499. (n) Schlummer, B.;
Hartwig, J. F. Org. Lett. 2002, 4, 1471.
(10) Please refer to Supporting Information, refs 3 and 4, and see:
(a) Enholm, E. J.; Jia, Z. J. J. Org. Chem. 1997, 62, 9159. (b) Toda, F.; Imai,
N. J. Chem. Soc. Perkin Trans. 1 1994, 2673.
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Mothe and Chan
JOCArticle
investigations showed that reducing the catalyst loading 2-
fold to 0.005 mol % gave 3a in a lower yield of 49% (entry 6).
Moreover, no product formation could be detected by TLC or
1H NMR analysis of the crude mixture when 0.001 mol % of
TfOH was employed, even on extending the reaction time to
20 h (entry 7). Similarly, a lower product yield of 81% was
obtained on repeating the reaction with 5 mol % of TfOH at
room temperature for 24 h (entry 2). In addition, comparable
product yields of 65-75% were afforded when the reaction
was repeated with 5 equiv of 2a in solvents such as toluene,
1,2-dichloroethane, and THF (entries 8-10). Performing the
reaction with other inexpensive and commercially available
Brønsted acid catalysts was also found to be less effective
(entries 11-14). Inthese latterreactions, the use of0.01 mol%
of Tf2NH or 5 mol % of p-TsOH, TFA, and HCl gave 3a in
markedly lower yields of 10-55% along with a side product
found to give the corresponding enyne adducts 3w and 3x in
excellent yields and product turnovers (entries 22 and 23).
Similarly, an inspection of entries 24 and 25 in Table 2
showed tetrasubstituted conjugated enynes 3y and 3z could
be obtained in yields of 95% and 92% and with turnover
numbers of 9,500 and 9,200, respectively, for the alkoxylat-
ion of 1-cyclopropyl-2-propyn-1-ols bearing a quaternary
carbon center. Additionally, the present procedure worked
well for starting alcohols with a pendant furan or thiophene
functionality, providing the corresponding enyne adducts
3r-χ in excellent yields and product turnovers (entries
26-28). This is noteworthy as such aromatic ring structures
are commonly found in a myriad of bioactive natural and
pharmaceutical compounds.12 As anticipated, reaction of
the secondary 1-cyclopropyl-2-propyn-1-ol 1δ under the
standard conditions was the only case that was found to give
the ethereal substitution product 5 as the sole adduct in 91%
yield (entry 29). A similar outcome in product chemoselec-
tivity leading to preferential formation of the substitution
adduct from reaction of a secondary 1-cyclopropyl-2-pro-
pyn-1-ol with aniline has also been reported for the analo-
gous Ru2-catalyzed approach.4a
In this work, the reaction of 1a with a variety of different
alcohol nucleophiles was also examined (Table 3). Under the
standard conditions, reaction of 1a with benzyl alcohol 2b gave
the corresponding conjugated enyne adduct 3δ in 80% yield
and with a turnover number of 8,000 (entry 1). Similarly,
reaction of 1a with alcohols bearing a terminal alkene moiety
gave 3ε and 3O in 75% and 82% yield and with turnovers of
7,500 and 8,200, respectively (entries 2 and 3). In our hands,
comparable product yields and turnovers were also obtained in
instances where it was initially envisaged that reactions with
nucleophiles containing a sterically demanding group on the
R-carbon such as an i-Pent, t-Bu, and cyclohexyl group as in
2e-g would detrimentally influence the reactivity of the present
procedure (entries 4-6).
1
that could not be identified by H NMR analysis or low
resolution mass spectrometry. On the basis of the above
results, reaction of 1a with 2a in the presence of 0.01 mol %
of TfOH at reflux for 15 min was deemed to provide the
optimal conditions (entry 5).11 Under these conditions, a
product turnover of 10,000 was also obtained, which to our
knowledge is the highest thus far achieved for this reaction.
Using these optimized conditions, we were pleased to find that
a quantitative product yield of 2.01 g and the same turnover
could be reproduced when the reaction was repeated on a
large scale with 1.8 g (7.3 mmol) of 1a.
To determine the generality of the present procedure, we
next turned our attentions to the reactions of a variety of 1-
cyclopropyl-2-propyn-1-ols with 2a (Table 2). This revealed
that the reactions of substituted 1-cyclopropyl-2-propyn-1-
ols containing pendant electron-withdrawing or electron-
donating groups with 2a gave the corresponding conjugated
enyne products 3b-e and 3j-k in yields of 88-98% and with
turnovers up to 9,800 (entries 1-4, 9 and 10). Similarly, the
analogous reactions involving starting alcohols containing a
combination of electron-withdrawing and electron-donating
groups with 2a afforded the corresponding enyne products in
comparable yields of 90-92% and with turnovers up to
9,200 (entries 5 and 6). More notably, 1-cyclopropyl-2-
propyn-1-ols bearing a pyridine or nitrile moiety were found
to proceed well under the present conditions and furnish the
corresponding conjugated enyne adducts 3h-k in excellent
yields and product turnovers (entries 7-10). This compares
well with our previous works, which reported that a closely
related pyridine-containing alcohol substrate was resistant
to the ring-opening process with p-TsNH2 using ytterbium
catalysis.3a Likewise, substituted 1-cyclopropyl-2-propyn-1-
ols 1l-n and 1z with a sterically bulky naphthalene group
were found to afford 3l-n and 3z in excellent yields and
product turnovers (entries 11-13 and 25). A similar outcome
was found for reactions of 1-cyclopropyl-2-propyn-1-ols
containing alkyl groups or both an alkyl and aryl substituent
or a terminal alkyne moiety. In these reactions, the
corresponding enyne adducts 3o-v were furnished in yields
of 75-96% and with up to 9,600 turnovers (entries 14-21).
Reactions of starting alcohols with an alkene or alkyne
moiety on the carbinol carbon as in 1w and 1x were also
At this juncture, we would like to highlight the chemo- and
regioselective nature of the present reaction. Our studies
found that the (Z)-isomer was obtained as the sole product
for all of the reactions described in Table 2 where the tertiary
starting alcohol contained a pendant internal alkyne moiety.
Similarly, the (E)-product was furnished exclusively from
reactions with substrates containing a terminal alkyne.
For reactions affording the tetrasubstituted conjugated
enynes 3y and 3z, the E:Z product selectivities obtained were
found to be comparable to the cis:trans ratios of the respec-
1
tive racemic starting alcohols based on H NMR measure-
ments. Reaction of 1x was the only other example that was
found to give the corresponding conjugated enyne 3x as an
inseparable mixture of E/Z isomers in a ratio of 5: 1 (entry 23
in Table 2). The presence of a bulky substituent on the
acetylene moiety of the substrate such as a naphthalene
ring as in 1l-n and 1z was also found to have no influence
on the regioselective outcome of the reaction. In addition,
no side products were obtained under our experimental
conditions based on 1H NMR analysis of the crude mixtures
in all except one case, which is consistent with our earlier
(12) (a) Fraxedas, J. Molecular Organic Materials: From Molecules to
Crystalline Solids; Cambridge University Press: Cambridge, 2006. (b) Kleeman,
A.; Engel, J. Pharmaceutical Sustances: Synthesis, Patents, Applications, 4th
ed.; Thieme: Stuttgart, 2001. (c) Humphrey, M.; Chamberlin, A. R. Chem. Rev.
1997, 97, 2243.
(11) The reaction of 1a with 2a in the presence of 0.01 mol % of TfOH at
reflux for 15 min was repeated 3 times to ensure the accuracy and reprodu-
cibility of the reported yield of 3a.
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TABLE 2. TfOH-Catalyzed Alkoxylation of 1a-δ with 2aa
5890 J. Org. Chem. Vol. 74, No. 16, 2009

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JOCArticle
TABLE 2. Continued
aAll reactions were performed at reflux for 15 min with 0.2 mmol of 1 in 2 mL of a stock solution of 2a containing 0.01 mol % of TfOH. bReaction
conducted for 25 min. cReaction conducted for 30 min. dReaction conducted for 20 min. eYield in parentheses denotes that isolated for the cyclopropyl
enyne side product 4. fProduct obtained as an inseparable 5:1 mixture of E/Z isomers. gStarting alcohol used as a mixture of diastereomers in a ratio=3:2.
hProduct obtained as an inseparable 3:2 mixture of E/Z isomers. iStarting alcohol used as a mixture of diastereomers in a ratio=3:1. jProduct obtained as
an inseparable 3:2 mixture of E/Z isomers. kReaction conducted for 10 min.
findings for the reaction of 1a with 2a. Under our conditions,
reaction of 1t was the only instance that was found to afford
3t in 44% yield and along with 4 as a side product in 42%
yield (entry 19 in Table 2). The cis stereochemistry in 3j was
determined by X-ray crystallographic analysis13 (see Figure
S70 in Supporting Information) and NOE measurements,
and the trans regiochemistry in 3u was confirmed by NOE
analysis.
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JOCArticle
TABLE 3. TfOH-Catalyzed Alkoxylation of 1a with 2b-ga
substitutent is so that formation of the more sterically hin-
dered tri- or tetrasubstituted enyne adduct can be avoided.15
The origin of the elimination and ethereal substitution pro-
ducts 4 and 5 could be due to the respective deprotonation and
direct attack by 2a of this resultant carbocation species before
ring fragmentation could occur.
Conclusion
In summary, we have presented a Brønsted acid catalyzed
method for the nucleophilic ring opening of 1-cyclopropyl-2-
propyn-1-ols with alcohols as an expedient route to conju-
gated enynes. The reaction was shown to be applicable to a
wide variety of starting alcohols containing electronic and
sterically demanding substrate combinations that compli-
mented the metal-mediated versions of this reaction.3,4 The
efficiency of the present operationally straightforward meth-
od was exemplified by the excellent product yields and
turnover numbers along with complete regioselectivities
achieved with a low catalyst loading of 0.01 mol %. More-
over, the approach offers a potential scale-up strategy for the
regioselective synthesis of conjugated enynes, which was
demonstrated by the large-scale synthesis of one example
in quantitative yield and with a high turnover number. This is
notable as the present catalytic method makes use of in-
expensive and easily accessible alcohol substrates in combi-
nation with the low cost and green credentials5-7,8d-f,9 often
associated with such metal-free catalytic systems.
aAll reactions were performed at reflux for 20 min with 0.2 mmol of 1a
in 2 mL of a stock solution of 2 containing 0.01 mol % of TfOH.
bReaction conducted for 15 min.
SCHEME 2. Tentative Mechanism for TfOH-Catalyzed Al-
koxylation of 1-Cyclopropyl-2-propyn-1-ols with Alcohols
Experimental Section
Experimental Procedure for TfOH-Catalyzed Preparation of
Conjugated Enyne (3). To round-bottom flask containing 1
(0.2 mmol) was added TfOH (0. 01 mol %) in the form of 2
mL of a stock solution containing 0.88 μL of TfOH in 1 L of 2
under a nitrogen atmosphere at room temperature. The reaction
mixture was stirred at reflux and monitored to completion by
TLC analysis. The crude mixture was quenched with water,
extracted with EtOAc (3 ꢀ 10 mL), and concentrated under
reduced pressure. Purification by flash column chromatography
on silica gel (eluent, n-hexane/EtOAc=19: 1) furnished the title
compound 3.
Although highly speculative, we propose the mechanism of
the present reaction to proceed in a manner similar to that
reported for the closely related Yb-catalyzed amination of 1-
cyclopropyl-2-propyn-1-ols with sulfonamides.3a As outlined in
Scheme 2, this could involve activation of the alcohol substrate
through protonation of the hydroxyl group by the Brønsted
acid. This results in the formation of a protonated intermediate
6, which can undergo elimination to give a putative carboca-
tion species 7. It is possible that subsequent cyclopropylcarbi-
nol-homoallylic rearrangement of this newly formed cationic
species and trapping with 2 would deliver the enyne 3.14 The E/
Z product selectivities obtained when R3=H could be due to 7
adopting the conformation shown in Scheme 2 with the least
amount of unfavorable steric interactions between the substit-
uents and cyclopropane ring.15 However, for reactions when
R3 =Me that lead to the tetrasubstituted conjugated enyne
adduct, such conformational changes may be less favored due
to steric interactions between the substituents resulting from
rotation of the Cx-C(cyclopropyl) bond in 7. For reactions
where R4 = Ph, we postulate that a possible reason for
preferential SN10 attack at the carbon center bearing the
(Z)-6-Ethoxy-1,3-diphenylhex-3-en-1-yne (3a). Light brown
1
oil; H NMR (CDCl3, 300 MHz) δ 7.71-7.68 (m, 2H), 7.57-
7.53 (m, 2H), 7.40-7.30 (m, 6H), 6.55 (t, 1H, J=7.3 Hz), 3.64
(t, 2H, J=6.7 Hz), 3.57 (q, 2H, J=7.0 Hz), 2.90 (q, 2H, J=
6.8 Hz), 1.25 (t, 3H, J=6.9 Hz); 13C NMR (CDCl3, 75 MHz)
δ 138.1, 134.7, 131.6, 128.39, 128.38, 128.3, 127.7, 126.1, 124.9,
123.4, 95.6, 86.6, 69.5, 66.2, 32.1, 15.3; IR (neat, cm-1) 3419,
3018, 2399, 1645, 1215, 756, 669; HRMS (ESI) calcd for
C20H21O 277.1592, found 277.1605.
(6-Ethoxy-4-methyl-6-phenylhex-3-en-1-yne-1,3-diyl)diben-
zene (3y). Colorless oil; mixture of E/Z isomers=3: 2; 1H NMR
(CDCl3, 400 MHz) δ 7.32-7.03 (m, 24H), 4.61 (t, 1H, J=6.9 Hz,
E or Z regioisomer), 4.29 (q, 1H, J=5.8 Hz, E or Z regioisomer),
3.41-3.15 (m, 3H), 2.95-2.85 (m, 2H, E or Z regioisomer), 2.61-
2.34 (m, 2H, E or Z regioisomer), 2.16 (s, 3H, E or Z regioisomer),
1.66 (s, 3H, E or Z regioisomer), 1.11 (t, 3H, J=6.9 Hz, E or Z
regioisomer), 1.06 (t, 3H, J=7.0 Hz, E or Z regioisomer); 13C
NMR (CDCl3, 100 MHz) δ 144.6, 143.7, 142.6, 142.4, 139.3,
139.2, 131.3, 129.3, 129.1, 128.3, 128.27, 128.26, 128.22, 128.12,
128.10, 127.7, 127.5, 127.4, 126.9, 126.8, 126.6, 126.4, 124.0, 121.4,
120.9, 93.4, 93.0, 90.4, 90.2, 81.7, 80.6, 64.3, 64.2, 46.2, 43.2, 22.1,
21.5, 15.4, 15.3; IR (neat, cm-1) 3419, 3019, 1595, 1215, 1097, 759,
701, 667; HRMS (ESI) calcd for C27H27O 367.2062, found
367.2075.
(13) CCDC 720922 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
(14) The involvement of a cyclopropylmethyl carbocation formed in situ
has also been proposed for the catalytic hydroamination of methylenecyclo-
propanes; see: (a) Siriwardana, A. I.; Kathriarachchi, K. K. A. D. S.;
Nakamura, I.; Yamamoto, Y. Heterocycles 2005, 66, 333. (b) Chen, Y.; Shi,
M. J. Org. Chem. 2004, 69, 426. (c) Shi, M.; Chen, Y.; Xu, B.; Tang, J.
Tetrahedron Lett. 2002, 43, 8019.
(15) For similar regioselectivties reported in other cyclopropylmethyl
carbocation fragmentation processes, see: Honda, M.; Mita, T.; Nishizawa,
T.; Sano, T.; Segi, M.; Nakajima, T. Tetrahedron Lett. 2006, 47, 5751 and
references therein.
5892 J. Org. Chem. Vol. 74, No. 16, 2009

Mothe and Chan
JOCArticle
(Z)-6-(Benzyloxy)-1,3-diphenylhex-3-en-1-yne (3δ). Yellow
oil; H NMR (CDCl3, 300 MHz) δ 7.77-7.74 (m, 2H), 7.62-
Acknowledgment. This work is supported by a College of
Science Start-Up Grant from Nanyang Technological Uni-
versity.
1
7.58 (m, 2H), 7.46-7.32 (m, 12H), 6.61 (t, 1H, J=7.3 Hz), 4.64
(s, 2H), 3.76 (t, 2H, J=6.6 Hz), 3.01 (q, 2H, J=6.7 Hz); 13C
NMR (CDCl3, 75 MHz) δ 138.5, 138.1, 134.6, 131.6, 128.49,
128.46, 128.4, 127.9, 127.8, 127.7, 127.6, 126.1, 125.1, 123.4,
95.7, 86.7, 72.9, 69.2, 32.1; IR (neat, cm-1) 3427, 3018, 2399,
1637, 1423, 1215, 927, 756, 669; HRMS (ESI) calcd for C25H23O
339.1749, found 339.1751.
Supporting Information Available: 1H and 13C NMR spec-
tra for starting alcohols 1 and conjugated enynes 3, NOE spectra
of 3j and 3u, CIF file of 3j. This material is available free of
charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 74, No. 16, 2009 5893