Ytterbium(III) triflate-catalyzed amination of 1-cyclopropylprop-2-yn-1-ols as an expedient route to conjugated enynes

Full text of DOI:10.1021/jo8024626

SCHEME 1. Regioselective Yb(OTf)3-Catalyzed Formation
of Conjugated Enynes from Cyclopropylprop-2-yn-1-ols
Ytterbium(III) Triflate-Catalyzed Amination of
1-Cyclopropylprop-2-yn-1-ols as an Expedient
Route to Conjugated Enynes
Weidong Rao, Xiaoxiang Zhang, Ella Min Ling Sze, and
Philip Wai Hong Chan*
DiVision of Chemistry and Biological Chemistry, School of
Physical and Mathematical Sciences, Nanyang Technological
UniVersity, Singapore 637371, Singapore
potentially the only byproduct, to be applicable to a variety of
substituted 1-cyclopropyl-2-propyn-1-ols and sulfonamide and
alcohol nucleophiles using gold catalysis. However, this method
would also greatly benefit from the use of cheaper and
commercially available catalysts, such as lanthanide complexes.
To our knowledge, synthetic approaches that explore combining
rare earth metals as strong Lewis acid catalysts6 with alcohol
pro-electrophiles7 have thus far been limited to benzylation and
allylation of aromatic and 1,3-dicarbonyl compounds with
benzylic and allylic alcohols.8 As part of an ongoing program
examining the utility of alcohols as building blocks in organic
synthesis,4,9 we report in this Note the use of Yb(OTf)3 for ring
opening of substituted 1-cyclopropyl-2-propyn-1-ols with sul-
fonamides (Scheme 1). The conjugated enyne products were
afforded in yields and regioselective manner comparable to those
reported for the closely related Ru2- or Au-promoted approaches
to this synthetically useful building block.
Initially, we chose to focus our attentions on the nucleophilic
ring opening of 1-cyclopropyl-1,3-diphenylprop-2-yn-1-ol 1a
with p-toluenesulfonamide (TsNH2) 2a by a variety of Lewis
and Brønsted acid catalysts to establish the reaction conditions
(Table 1). This revealed that treating a toluene solution
containing 1 equiv of 1a and 2 equiv of 2a with 5 mol % of
Yb(OTf)3 at 100 °C for 5 h gave the best result (entry 1). Under
these conditions, (Z)-N-(4,6-diphenylhex-3-en-5-ynyl)-4-meth-
ylbenzenesulfonamide 3a was afforded in 75% yield, compa-
waihong@ntu.edu.sg
ReceiVed NoVember 4, 2008
Ytterbium(III) triflate-catalyzed ring opening of substituted
1-cyclopropyl-2-propyn-1-ols with sulfonamides as an ef-
ficient synthetic route to conjugated enynes is described
herein. The reaction was operationally straightforward and
accomplished in moderate to good yields and regioselective
manner in all except one case under mild conditions.
Establishing methods to conjugated enynes is currently an
active area in organic synthesis due to their frequent use as
building blocks in numerous strategies to compounds of
biological and material interest.1 While this has led to a myriad
of works devoted to this reaction, the number of methods that
can install this unsaturated hydrocarbon moiety without com-
petitive formation of undesired regio- and stereoisomers has
remained sparse.1,2 For this reason, the development of new
synthetic routes to conjugated enynes in an efficient and
stereoselective manner continues to be actively pursued. In a
recent notable advance, Nishibayashi and co-workers demon-
strated that trans-substituted conjugated enynes could be
obtained from regioselective diruthenium-catalyzed ring opening
of terminal 1-cyclopropyl-2-propyn-1-ols with aniline.3 Fol-
lowing this seminal work, we4 and Liang5 showed this atom-
economical ring opening process, which produces H2O as
(5) Xiao, H.-Q.; Shu, X.-Z.; Ji, K.-G.; Qi, C.-Z.; Liang, Y.-M. New J. Chem.
2007, 31, 2041.
(6) For recent reviews, see: (a) Itsuno, S. Polymer-Supported Metal Lewis
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Verlag GmbH: Weinheim, Germany, 2000; Vol. 2, p 945. (b) Shihasaki, M.;
Yarnada, K.-I.; Yoshikawa, N. Lanthanide Lewis Acids Catalysis. In Lewis Acids
in Organic Synthesis; Yamamoto, H., Ed.; Wiley-VCH Verlag GmbH: Weinheim,
Germany, 2000; Vol. 2, p 911. (c) Kobayashi, S. Sc(III) Lewis Acids. In Lewis
Acids in Organic Synthesis; Yamamoto, H., Ed.; Wiley-VCH Verlag GmbH:
Weinheim, Germany, 2000; Vol. 2, p 883. (d) Carbocation Chemistry; Olah,
G. A., Prakash, G. K. S., Eds.; John Wiley & Sons: New York, 2004. (e)
Nakamura, I.; Yamamoto, Y. Chem. ReV. 2004, 104, 2127. (f) Kagan, H. B.
Chem. ReV. 2002, 102, 1805.
(7) For recent reviews on the use of alcohols as pro-electrophiles, see: (a)
Muzart, J. Tetrahedron 2008, 64, 5815. (b) Muzart, J. Tetrahedron 2005, 61,
4179. (c) Muzart, J. Eur. J. Org. Chem. 2007, 3077. (d) Tamaru, Y. Eur. J.
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Huang, W.; Wang, J.; Shen, Q.; Zhou, X. Tetrahedron Lett. 2007, 48, 3969. (c)
Tsuchimoto, T.; Tobita, K.; Hiyama, T.; Fukuzawa, S. J. Org. Chem. 1997, 62,
6997. (d) Tsuchimoto, T.; Tobita, K.; Hiyama, T.; Fukuzawa, S. Synlett 1996,
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(9) (a) Zhang, X.; Rao, W.; Chan, P. W. H. Synlett 2008, Special Issue, 2204.
(b) Rao, W.; Chan, P. W. H. Org. Biomol. Chem. 2008, 6, 2426. (c) 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. (d) Chang, J. W. W.; Chee,
S.; Mak, S.; Buranaprasertsuk, P.; Chavasiri, W.; Chan, P. W. H. Tetrahedron
Lett. 2008, 49, 2018. (e) 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.
(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) Zeni, G.; Braga, A. L.; Stefani, H. A. Acc.
Chem. Res. 2003, 36, 731.
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J. Am. Chem. Soc. 2006, 128, 5592. (b) Zhang, L.-M.; Wang, S.-Z. J. Am. Chem.
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1740 J. Org. Chem. 2009, 74, 1740–1743
10.1021/jo8024626 CCC: $40.75 2009 American Chemical Society
Published on Web 01/07/2009

TABLE 1. Optimization of the Reaction Conditionsa
thylene group was found to proceed well and afford 3f in a
good yield (entry 5). The present procedure was also shown to
work well for 1-cyclopropyl-2-propyn-1-ols containing alkyl and
aryl substituent combinations, giving 3h and 3j-l in 55-73%
yield (entries 7 and 9-11). However, moderate yields were
obtained for reactions with alcohols containing a cyclopropane
group on the alkyne moiety or a terminal acetylene group as in
1g and 1i (entries 6 and 8). On the other hand, starting alcohols
with pendant thiophene functionalities provided the corre-
sponding conjugated enyne products in good yields (entries
12-14). This is noteworthy as such aromatic ring structures
are commonly found in a myriad of bioactive natural and
pharmaceutical compounds.10 Under the standard conditions,
reaction of 1p with 2a was the only case that was found to
be ineffective, giving no product formation based on TLC
yield (%)
entry
catalyst
solvent
3a
4a
5a
1
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Cu(OTf)2
AgOTf
PhMe
PhMe
1,2-dichloroethane
MeCN
THF
PhMe
PhMe
PhMe
75
53
55
b
b
b
2c
3
15
-
-
-
-
6
-
-
-
3
12
28
-
-
6
4
5
6
7
b
54
39
d
b
8
InCl3
-
-
-
-
1
9
10
11
FeCl3 ·6H2O
TsOH·H2O
TfOH
PhMe
PhMe
PhMe
d
d
23
and H NMR analysis and recovery of the starting alcohol
in near quantitative yield (entry 15).
Depending on the nature of the substituent on the carbinol
carbon of the alcohol substrate, the products shown in Table 2
were exclusively obtained as either the Z-isomer for alkyl or
aryl groups on the carbinol carbon in all except one case.
Similarly, the E-product was furnished for heteroarene groups
on the carbinol carbon.11 The trans-stereochemistry in 3e and
3g and cis-stereochemistry in 3m were also confirmed by NOE
analysis (see Supporting Information for details). Reaction of
1l was the only instance in which the corresponding enyne
adduct was obtained as a mixture of Z and E isomers in a ratio
of Z/E ) 83:17 (entry 11). A similar effect of a bulky substituent
at the carbinol carbon of the substrate on product regioselectivity
has also been reported in the analogous Ru2- and Au-mediated
approaches.3,5
a All reactions were performed at 100 °C for 5 h with catalyst/1a/2a
ratio of 1:20:40. b Trace amount of compound isolated after flash
column chromatography. c Reaction conducted with 1 equiv of 2a. d No
reaction.
rable to those obtained for the closely related Ru2- and Au-
catalyzed reactions with terminal or activated starting alcohols.3,5
The cis-stereochemistry of the conjugated enyne product was
confirmed by comparison with NOE spectroscopic data of
closely related adducts (see below) and reported literature
values.3,5 In our hands, the dimeric byproducts 4a and 5a were
also isolated in trace amounts. In contrast, a lower product yield
along with significantly higher amounts of the dimeric byproduct
was obtained by repeating the reaction with 1 equiv of 2 (entry
2). Similarly, performing the reaction in other solvents was
found to be less effective (entries 3-5). When 1,2-dichloroet-
hane was employed as the solvent, a lower product yield of
55% along with 5a in a higher yield of 28% was obtained (entry
To further explore the scope of the Yb(OTf)3-catalzyed
reactions, the ring opening of 1a with a variety of different
nitrogen nucleophiles was examined (Table 3). Under the
standard conditions, reaction of 1a with benzenesulfonamide
2b afforded 3q in 60% yield (entry 1). Under similar conditions,
arylsulfonamides 2c and 2d, which contain either a para-
substituted electron-donating or electron-withdrawing group,
respectively, were found to be good nitrogen sources, giving
the corresponding conjugated enynes 3r and 3s in yields of
69-80% (entries 2 and 3). In contrast, other nitrogen sources
such as aniline 2e, tert-butyl carbamate 2f, and N-aminophthal-
imide 2g were found to be less effective (entries 4-6). When
aniline 2e was employed as the nucleophile, the reaction was
found to proceed to give 3t in 31% yield along with a mixture
of byproducts that could not be identified by 1H NMR analysis
(entry 4). Interestingly, the analogous reaction with 2f gave the
deprotected amino-enyne adduct 3u, albeit in a markedly lower
yield of 15% along with recovery of 1a in 55% yield (entry 5).
In addition, reaction of 1a with a more nucleophilic nitrogen
source such as 2g did not proceed as anticipated. Under our
experimental conditions, the reaction afforded amino-substituted
adduct 6a as the sole product in 62% yield (entry 6).
1
3). On the other hand, TLC and H NMR analysis of crude
mixtures of reactions conducted in either MeCN or THF detected
only the starting alcohol and sulfonamide, which were recovered
in near quantitative yields (entries 4 and 5). An inspection of
entries 6-11 in Table 1 also revealed the reaction proceeded
less well with other common and commercially available Lewis
and Brønsted acid catalysts. In these latter reactions, the use of
Cu(OTf)2 and AgOTf and TfOH resulted in the formation of
3a in markedly lower yields along with slightly higher yields
of either or both 4a and 5a (entries 6 and 7). However, switching
the catalyst to InCl3, FeCl3 ·6H2O, or TsOH ·H2O was found to
result in no reaction observed on the basis of TLC analysis
(entries 8-10). A low product yield of 23% obtained for the
analogous TfOH-mediated reaction also provided evidence that,
in the presence of potentially TfOH, the cationic Yb(III)
complex is the catalytically active species (entry 11).
To define the scope of the present procedure, we next turned
our attentions to the reactions of a variety of unactivated
1-cyclopropyl-2-propyn-1-ols with 2a (Table 2). Reactions of
substituted 1-cyclopropyl-2-propyn-1-ols containing a pendant
electron-withdrawing group on the carbinol carbon with 2a gave
the corresponding conjugated enyne products 3b-d in yields
of 67-70% (entries 1-3). Similarly, the analogous reaction of
1e, which contains electron-donating groups at both the alkyne
and carbinol carbon centers, with 2a affords the corresponding
product 3e in 56% yield (entry 4). Likewise, the substituted
1-cyclopropyl-2-propyn-1-ol 1f bearing a sterically bulky naph-
(10) Fraxedas, J. Molecular Organic Materials: From Molecules to Crystal-
line 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) Similar to that found in optimization studies with 1a and 2a, trace
amounts of the dimers 4 and 5 were also detected in the 1H NMR spectra of the
crude mixtures of the enyne products shown in Table 2. However, these side
products were not spectroscopically characterized due to the very small quantities
obtained after flash column chromatography.
J. Org. Chem. Vol. 74, No. 4, 2009 1741

TABLE 2. Yb(OTf)3-Catalyzed Amination of 1b-p with 2aa
a All reactions were performed at 100 °C with Yb(OTf)3/1/2a ratio of 1:20:40. b Isolated as a mixture of Z/E isomers in a ratio of 83:17. c No reaction
1
based on TLC and H NMR analysis of the crude mixture.
We tentatively propose the present Yb(OTf)3-catalyzed
conjugated enyne forming reaction to proceed by the mechanism
outlined in Scheme 2, although it is highly speculative. This
could involve activation of the alcohol substrate through
coordination with the hydroxyl functionality. This delivers an
ytterbium(III)-chelated intermediate 7 which can undergo
elimination to give a putative carbocation species 8 and [Yb]-
OH, which releases the metal catalyst by protodemetalation. It
is possible that this newly formed cationic species subsequently
undergoes cyclopropylcarbinol homoallylic rearrangement and
trapping with 2 to deliver the enyne 3.12 The obtained E/Z
product stereoselectivities could be due to the carbocation
intermediate 8 adopting the conformer shown in Scheme 2 that
would limit unfavorable steric interactions between the substit-
uents and cyclopropane ring protons.13 The role of the catalyst
in facilitating dehydroxylation of the alcohol substrate would
account for our earlier findings showing no product formation
for the reaction of 1p with 2a (entry 15 in Table 2). It would
not be inconceivable that such interactions are presumably
weakened due the introduction of a strongly chelating
pyridine moiety on the alcohol substrate. The origin of the
N,N-aminophthalimide product 6a could be due to direct
attack of this resultant carbocation species by 2g before ring
fragmentation could occur. Indeed, this is further supported
by the fact that, when a toluene solution containing 1a was
treated with indole 9 under the conditions shown in Scheme
3, the indole-substituted adduct 6b was obtained in 99% yield.
In these reactions, the exclusive formation of 6a and 6b
suggested that, when a carbocation species such as 8 cannot
be regenerated, the cyclopropane moiety is resistant to the
ring opening process.
(12) A similar mechanism involving in situ formation of a cyclopropylmethyl
carbocation has also been proposed for catalytic hydroamination of methyl-
enecyclopropanes, 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.
(13) For similar E/Z stereoselectivties observed 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. .
1742 J. Org. Chem. Vol. 74, No. 4, 2009

TABLE 3. Yb(OTf)3-Catalyzed Amination of 1a with 2b-ga
SCHEME 3. Yb(OTf)3-Catalyzed Reaction of 1a with
Indole 9
unactivated 1-cyclopropyl-2-propyn-1-ols with arylsulfonamides
has been reported. These results show that the reaction tolerates
a structurally diverse set of alcohol substrates and complement
earlier works with terminal and activated starting alcohols
3
mediated by Ru2 and Au5 catalysts. The product yields and
regioselectivity obtained are also comparable. In addition, the
present method benefits from the use of not only alcohol
substrates that can be accessed in one step from commercially
available and low cost starting materials but also an ytterbium
catalyst that is also less expensive. Our studies suggest Yb(OTf)3-
mediated activation of the substituted 1-cyclopropyl-2-propyn-
1-ol substrate that leads to ionization of the alcohol. This
possibly triggers subsequent ring opening of the cyclopropane
moiety followed by trapping with the sulfonamide nucleophile
to give the conjugated enyne product. Efforts to apply the
method to natural product synthesis are currently underway and
will be reported in due course.
a All reactions were performed at 100 °C with Yb(OTf)3/1a/2 ratio of
1:20:40. b Starting alcohol 1a recovered in 55% yield.
Experimental Section
SCHEME 2. Tentative Mechanism for Yb(OTf)3-Catalyzed
Amination of 1-Cyclopropylprop-2-yn-1-ols with
Sulfonamides
Representative Experimental Procedure for Yb(OTf)3-Cat-
alyzed Preparation of Conjugated Enyne 3: To a solution of 1a
(74.5 mg, 0.3 mmol), 2a (102.7 mg 0.6 mmol), and 4 Å molecular
sieves (200 mg) in toluene (3 mL) was added Yb(OTf)3 (9.3 mg,
15 µmol) under an argon atmosphere. The reaction mixture was
stirred at 100 °C and monitored to completion by TLC analysis.
The crude mixture was filtered through Celite, washed with EtOAc
(20 mL), and concentrated under reduced pressure. Purification by
flash column chromatography on silica gel (eluent: n-hexane/EtOAc
) 7:1) furnished 3a (90 mg, 75%) as a pale yellow oil.
Acknowledgment. This work is supported by a University
Research Committee Grant (RG55/06) and Supplementary
Equipment Purchase Grant (RG134/06) from Nanyang Tech-
nological University. The authors would like to thank the
reviewers for their comments and suggestions.
Supporting Information Available: Characterization data
1
and H and 13C NMR spectra for the starting alcohols 1 and
conjugated enyne products 3, NOE spectra of compounds 3e,
3g, and 3m. This material is available free of charge via the
Internet at http://pubs.acs.org.
In summary, an efficient ytterbium-catalyzed synthetic route
to conjugated enynes based on nucleophilic ring opening of
JO8024626
J. Org. Chem. Vol. 74, No. 4, 2009 1743