A simple approach to separate a mixture of homopropargylic and allenic alcohols

Article abstract of DOI:10.1021/ol801087s

(Chemical Equation Presented) A simple and practical approach to separate homopropargylic alcohol from allenic alcohol has been developed. It involves the formation of an insoluble silver acetylide species between silver nitrate and homopropargylic alcohol in aqueous acetone which can be separated from the allenic alcohol through a simple filtration. The homopropargylic alcohol can subsequently be recovered by hydrolysis with 1 N HCl. This protocol has been applied to the separation of a mixture of chiral homopropargylic and allenic alcohols in excellent yields with retention of absolute stereochemistry.

Full text of DOI:10.1021/ol801087s

ORGANIC
LETTERS
2008
Vol. 10, No. 16
3437-3439
A Simple Approach To Separate a
Mixture of Homopropargylic and Allenic
Alcohols
Fan Fu, Kim Le Mai Hoang, and Teck-Peng Loh*
DiVision of Chemistry and Biological Chemistry, School of Physical and Mathematical
Sciences, Nanyang Technological UniVersity, Singapore 637371, Singapore
teckpeng@ntu.edu.sg
Received May 15, 2008
ABSTRACT
A simple and practical approach to separate homopropargylic alcohol from allenic alcohol has been developed. It involves the formation of
an insoluble silver acetylide species between silver nitrate and homopropargylic alcohol in aqueous acetone which can be separated from the
allenic alcohol through a simple filtration. The homopropargylic alcohol can subsequently be recovered by hydrolysis with 1 N HCl. This
protocol has been applied to the separation of a mixture of chiral homopropargylic and allenic alcohols in excellent yields with retention of
absolute stereochemistry.
The availability of efficient synthetic methods for achieving
absolute stereoselectivity by catalytic processes in the
production of optically active compounds is of considerable
current interest because such products could be used as chiral
building blocks for the synthesis of valuable chiral sub-
stances. Recent progress in organic synthesis suggests that
the optically active homopropargylic and allenic alcohols1
are versatile building blocks for the enantioselective synthesis
of many biologically active compounds.2 Hence, many
methods have been developed for the enantioselective
synthesis of this class of compounds.3 The asymmetric
addition of propargyl or allenyl metals to carbonyl com-
pounds provides a practical method for the synthesis of these
(2) (a) O’Malley, S. J.; Leighton, J. L. Angew. Chem., Int. Ed. 2001,
40, 2915. (b) Yamamoto, H. In ComprehensiVe Organic Synthesis, Vol. 2,
Heathcock, C. H., Ed.; Pergamon Press: Oxford, 1991; Vol. 2, Chapter 1.3,
pp 81-98. (c) Epsztein, R. In ComprehensiVe Carbanion Chemistry;
BuncelE., Durst, T., Eds.; Elsevier: Amsterdam, 1984; part B, p 107. (d)
Helal, C. J.; Magriotis, P. A.; Corey, E. J. J. Am. Chem. Soc. 1996, 118,
10938. (e) Matsummura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. J. Am.
Chem. Soc. 1997, 119, 8738.
(3) (a) Keck, G. E.; Krishnamurthy, D.; Chen, X. Tetrahedron Lett. 1994,
35, 8323. (b) Bandini, M.; Cozzi, P. G.; Melchiorre, P.; Tino, R.; Umani-
Ronchi, A. Tetrahedron: Asymmetry 2001, 12, 1063. (c) Inoue, M.; Nakada,
M. Angew. Chem., Int. Ed. 2006, 45, 252. (d) Xia, G.; Yamamoto, H. J. Am.
Chem. Soc. 2007, 129, 496. (e) Denmark, S. E.; Wynn, T. J. Am. Chem.
Soc. 2001, 123, 6199. (f) Marshall, J. A.; Maxson, K. J. Org. Chem. 2000,
65, 630. (g) Han, J.-W.; Tokunaga, N.; Haayashi, T. J. Am. Chem. Soc.
2001, 123, 12915. (h) Nakajima, M.; Saito, M.; Hashimoto, S. Tetrahedron:
Asymmetry 2002, 13, 2449.
(1) (a) Carreira, E. M.; Frantz, D. E.; Fassler, R. J. Am. Chem. Soc.
2000, 122, 1806. (b) Yamamoto, Y.; Asao, N. Chem. ReV. 1993, 93, 2207.
(c) Schuster, H. F.; Coppola, G. M. In Allenes in Organic Synthesis; Wiley:
New York, 1984. (d) Landor, S. R., Ed. In The Chemistry of the Allenes;
Academic Press: New York, 1982. (e) Kobayashi, S.; Nishio, K. J. Am.
Chem. Soc. 1995, 117, 6392.
10.1021/ol801087s CCC: $40.75
Published on Web 07/17/2008
2008 American Chemical Society

important intermediates.4 However, this process often leads
to both the homopropargylic and allenic alcohols at the same
time due to the metallotropic rearrangement5 between
propargyl and allenylic metal species (Scheme 1).
2,5-dihydrofurans, only the allenic alcohol was isolated
in the filtrate. However, when we proceeded to treat the
brown precipitated isolated earlier with 1 M HCl, the
homopropargylic alcohol was isolated cleanly after extrac-
tion with ether. It is noteworthy that the homopropargylic
alcohol was trapped in the precipitate and can only be
isolated by extraction with ether after treatment with 1 M
HCl. The formation of a precipitate in the presence of
alcoholic or ammoniacal silver nitrate has long been used
as a diagnostic test and a method of analysis for
compounds containing a terminal acetylenic group.8 The
mechanism probably involves the formation of a complex
between silver nitrate and calcium carbonate which reacts
with alkynes 5 to afford the corresponding silver acetylide
6 that precipitated (Scheme 2). This silver acetylide
Scheme 1
.
Metallotropic Rearrangement between Propargyl and
Allenyl Species
Recent work from our laboratory has demonstrated the
successful application of the novel chiral (S,S)-iPr-
pybox-In(III) complex and the chiral (S)-Binol-In(III)
complex as efficent Lewis acid catalysts for the enantiose-
lective propargylation and allenylation of aldehydes.6 Al-
though poor regioselectivity was observed due to metallot-
ropic rearrangement, the addition of allenyltributyl stannane
to a variety of aldehydes including aromatic, R,ꢀ-aromatic
and aliphatic aldehyes catalyzed by the chiral complexes
afforded the respective allenic and homopropargylic alcohols
mixture in good yields and high enantioselectivities (up to
92% ee).
Scheme 2
.
Mechanistic Hypothesis for Ag-Catalyzed Reaction
with Alkynes
The enantiomeric enriched homopropargylic and allenic
alcohols mixture are of little synthetic value if they are
inseparable via the usual chromatographic separation. Previ-
ous work by Claesson et al.7 reported the synthesis of 2,5-
dihydrofurans via cyclization of allenic alcohols catalyzed
by silver(I) nitrate. With an interest in this report, we attempt
to convert the allenic alcohols in the mixture into 2,5-
dihydrofurans with the homopropargylic alcohols remaining
intact. The 2,5-dihydrofurans can be separated from ho-
mopropargylic alcohols via column chromatography as they
have different Rf value.
In our initial study, we added a 1:1 ratio of 1-phenylbut-
3-yn-1-ol 1a and 1-phenylbuta-2,3-dien-1-ol 2a (0.5
mmol) to a mixture of silver(I) nitrate (0.6 mmol) and
calcium carbonate (0.6 mmol) in acetone/water (0.4 mL:
0.6 mL). The reaction mixture was stirred in the dark for
6 h, and a brown suspension was formed. The brown
precipitate was removed via suction filtration, and the
filtrate was dried with MgSO4 before removal of excess
solvent. Surprisingly, the heterocyclic-forming reaction did
not proceed essentially as intended. The 1H NMR spectrum
showed no traces of the homopropargylic alcohol and the
precipitate can be isolated by filtration. In the presence
of a proton source such as HCl, the silver acetylide species
would be hydrolyzed, generating back the alkynes species
5.
Having optimized the separation protocol, we extended
this procedure to a series of racemic aromatic, R,ꢀ unsatur-
ated and aliphatic homopropargylic and allenic alcohols
mixture. The results are shown in Table 1. The various
aromatic, R,ꢀ unsaturated and aliphatic allenic alcohols were
separated from the homopropargylic alcohols cleanly with
excellent yields. Moreover, when the chiral mixture of (R)-
1-phenylbut-3-yn-1-ol 7 and (R)-1-phenyl-buta-2,3-dien-1-
ol 8 was subjected to the separation protocol, (R)-1-
phenylbut-3-yn-1-ol 7 was separated from (R)-1-phenyl-buta-
2,3-dien-1-ol 8 cleanly with excellent yields and retention
of absolute stereochemistry.
In conclusion, a simple and practical approach to separate
homopropargylic alcohol from allenic alcohol has been
developed. It involves the formation of an insoluble silver
acetylide species in aqueous acetone which can be separated
from the allenic alcohol through a simple filtration. The
homopropargylic alcohol can subsequently be recovered by
hydrolysis with 1 N HCl. This approach is operationally
simple and can separate a wide variety of homopropargylic
(4) (a) Evans, D. A.; Sweeney, Z. K.; Rovis, T.; Tedrow, J. S. J. Am.
Chem. Soc. 2001, 123, 12095. (b) Haruta, R.; Ishiguro, M.; Ikeda, N.;
Yamamoto, H. J. Am. Chem. Soc. 1982, 104, 7667. (c) Yu, C.-M.; Yoon,
S.-K.; Baek, K.; Lee, J.-Y. Angew. Chem., Int. Ed. 1998, 37, 2392. (d) Yu,
C.-M.; Yoon, S.-K.; Choi, H.-S.; Beak, K. Chem. Commun. 1997, 763. (e)
Iseki, K.; Kuroki, Y.; Kobayashi, Y. Tetrahedron: Asymmetry 1998, 9, 2889.
(5) Normally, propargyl and allenyl metal compounds furnish allenyl
and propargylic adducts, respectively, in SE2′-type additions to carbonyl.
(6) Manuscript in preparation.
(8) (a) Davos, R. B.; Scheiber, D. H. J. Am. Chem. Soc. 1956, 78, 1675.
(b) Vogel, A. I. Practical Organic Chemistry, 3rd ed.; Longmans: London,
1967. (c) Viterisi, A.; Orsini, A.; Weibel, J.-M.; Pale, P. Tettrahedron Lett.
2006, 47, 2779. (d) Orsini, A.; Viterisi, A.; Bodlenner, A.; Weibel, J.-M.;
Pale, P. Tettrahedron Lett. 2005, 46, 2259.
(7) Olsson, L.-I.; Claesson, A. Synthesis 1979, 79, 743.
3438
Org. Lett., Vol. 10, No. 16, 2008

Table 1. Separation of Homopropargylic Alcohols and Allenic
Alcohol Using AgNO3 and CaCO3
Scheme 3
.
Separation of Chiral Allenic and Homopropargylic
Mixture
Council (A*STAR Grant No. 05/1/22/19/408) for funding
of this research.
entry
R
product
yielda(%)
1
2
3
4
5
6
7
Ph
1a:2a
1b:2b
1c:2c
1d:2d
1e:2e
1f:2f
81:93
81:95
94:93
98:97
80:96
81:98
92:95
Supporting Information Available: Experimental details,
characterization data, and stereochemical proofs. This mate-
rialisavailablefreeofchargeviatheInternetathttp://pubs.acs.org.
4-ClC6H5
4-OMeC6H5
2-Napthyl
PhCHCH
PhCH2CH2
n-C9H18
OL801087S
1g:2g
a Yield is determined based on the amount of material recovered after
the separation using AgNO3 and CaCO3.
(9) Representative Procedure for Separation of Allenic and Prop-
argylic Alcohol Mixture. To a 8 mL sample vial equipped with a stirring
bar were added AgNO3 (1.2 equiv) and CaCO3 (1.2 equiv) in acetone/
water (0.6-0.4 mL). The homopropargylic and allenylic alcohol mixture
(1 equiv) was added, and the mixture was stirred in the dark for 6 h to
afford a brown precipitate in solution. The precipitate was separated via
suction filtration, and the filtrate was dried over anhydrous magnesium
sulfate, filtered, and concentrated in vacuo to afford the pure allenic alcohol.
The precipitate was treated with 1 M HCl (3 mL) and stirred vigorously
for 5 min prior to extraction of the aqueous layer with diethyl ether (3 ×
10 mL). The combined organic extracts was washed with brine, dried over
anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford
the pure homopropargylic alcohol.
and allenic alcohol mixtures in excellent yields with the
retention of absolute stereochemistry. Hence, this catalytic
procedure could be broadly applicable to many synthetic
procedures.9
Acknowledgment. We gratefully acknowledge the Nan-
yang Technological University and Biomedical Research
Org. Lett., Vol. 10, No. 16, 2008
3439