Zirconium-promoted epoxide rearrangement-alkynylation sequence

Article abstract of DOI:10.1021/jo702306k

(Chemical Equation Presented) Additions of terminal alkynes to electrophiles are important transformations in organic chemistry. Generally, activated terminal alkynes react with epoxides in an S_N2 fashion to form homopropargylic alcohols. We have developed a new synthetic method to form propargylic alcohols from epoxides and terminal alkynes via 1,2-shifts. This method involves cationic zirconium acetylides as both the activator of epoxides and nucleophiles. Due to the mild conditions to pre-activate alkynes with silver nitrate, this synthetic method is useful for both electron-rich and electron-deficient alkynes with other acid- and base-sensitive functional groups.

Full text of DOI:10.1021/jo702306k

Zirconium-Promoted Epoxide Rearrangement-Alkynylation
Sequence
Brian J. Albert and Kazunori Koide*
Department of Chemistry, UniVersity of Pittsburgh, Pittsburgh, PennsylVania 15260
koide@pitt.edu
ReceiVed October 24, 2007
Additions of terminal alkynes to electrophiles are important transformations in organic chemistry. Generally,
activated terminal alkynes react with epoxides in an SN2 fashion to form homopropargylic alcohols. We
have developed a new synthetic method to form propargylic alcohols from epoxides and terminal alkynes
via 1,2-shifts. This method involves cationic zirconium acetylides as both the activator of epoxides and
nucleophiles. Due to the mild conditions to pre-activate alkynes with silver nitrate, this synthetic method
is useful for both electron-rich and electron-deficient alkynes with other acid- and base-sensitive functional
groups.
SCHEME 1. Formations of Propargylic and
Homopropargylic Alcohols
Introduction
Alkynylation is an important transformation to add multiple
functionalizable carbons to electrophiles. For example, the
addition of a metal acetylide toward an aldehyde affords
propargylic alcohol A (Scheme 1). To generate the nucleophilic
metal acetylide, a terminal acetylene is treated with a strong
base such as n-BuLi.1 The lithium acetylide either can be used
directly or transformed into other metal acetylides2 before the
addition to aldehydes. More recently, Zn3 and Au4 acetylides
were generated directly from terminal acetylenes and used as
nucleophiles toward aldehydes and iminium ions.
Couplings of epoxides with terminal alkynes are widely used
to prepare homopropargylic alcohols B.2a,5 Such couplings are
achieved by using highly basic lithium acetylides and highly
acidic BF3‚OEt2.5b There are scarce examples for the transfor-
mation of an epoxide to propargyl alcohol C.6 This scarcity is
surprising because the acid-promoted rearrangements of ep-
oxides to aldehydes are often used in combination with various
nucleophiles.7 Here, we report that zirconium acetylides8 can
be applied to the transformation of epoxide to C.
(1) Midland, M. M.; Tramontano, A.; Cable, J. R. J. Org. Chem. 1980,
45, 28-29.
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Yamamoto, Y.; Nishii, S.; Maruyama, K. J. Chem. Soc., Chem. Commun.
1986, 102-103. (c) Evans, D. A.; Halstead, D. P.; Allison, B. D.
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J. Am. Chem. Soc. 1994, 116, 3151-3152. (e) Suzuki, M.; Kimura, Y.;
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1857. (d) Gao, G.; Moore, D.; Xie, R. G.; Pu, L. Org. Lett. 2002, 4, 4143-
4146. (e) Lu, G.; Li, X. S.; Chan, W. L.; Chan, A. S. C. Chem. Commun.
2002, 172-173. (f) Trost, B. M.; Weiss, A. H.; von Wangelin, A. J. J. Am.
Chem. Soc. 2006, 128, 8-9.
(5) (a) Takano, S.; Shimazaki, Y.; Ogasawara, K. Tetrahedron Lett. 1990,
31, 3325-3326. (b) Smith, A. B.; Zheng, J. Y. Synlett 2001, 1019-1023.
(c) Yamaguchi, M.; Hirao, I. Tetrahedron Lett. 1983, 24, 391-394. (d)
Pineschi, M. Eur. J. Org. Chem. 2006, 4979-4988.
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1975, 287-288. (b) Schauder, J. R.; Krief, A. Tetrahedron Lett. 1982, 23,
4389-4392. (c) Koreeda, M.; Koizumi, N. Tetrahedron Lett. 1978, 19,
1641-1644.
(4) Wei, C. M.; Li, C.-J. J. Am. Chem. Soc. 2003, 125, 9584-9585.
10.1021/jo702306k CCC: $40.75 © 2008 American Chemical Society
Published on Web 01/08/2008
J. Org. Chem. 2008, 73, 1093-1098
1093

Albert and Koide
TABLE 1. Epoxide Opening
effective at 23 °C using substoichiometric AgOTf and stoichio-
metric Cp2ZrCl2.
1-Oxaspiro[2.5]octane reacted with 1 in the presence of 1.2
equiv of Cp2ZrCl2 and 0.2 equiv of AgOTf to form 4 in 54%
yield (Table 2, entry 1). Acetylide 1 reacted with 1,2-epoxy-
5-hexene less efficiently, providing 5 in 33% yield, but this
epoxide reacted smoothly with electron-rich alkyne 6 to give 7
in 59% yield (entries 2 and 3). Styrene oxide reacted with 1 to
afford 8 in 64% yield using only 0.05 equiv of AgOTf (entry
4). Unstable allylic epoxide 9 reacted with 6 to give 10 in 53%
yield (entry 5). Interestingly, when 1,2-epoxy-3-phenoxypropane
was subjected to the same reaction conditions, we obtained
chlorohydrin 11 in 88% yield (entry 6). This unexpected result
may be due to the inductive effect of the aryloxy group that
destabilizes the necessary carbocation-like intermediate to
facilitate the 1,2-hydride shift. Epoxide 12 reacts with 1 and 6
to generate 13 and 14 in 46% and 52% yields, respectively,
demonstrating that additional oxygen substituents are tolerated
on the epoxide molecule (entries 7 and 8). We also found that
more hindered epoxides such as cyclohexene oxide and cyclo-
pentene oxide generated intractable mixtures under the reaction
conditions.
AgOTf
(equiv)
temp
(°C)
yield
(%)a
entry
1
2
3
4
0.2
0.2
0.5
1.0
23
40
23
23
44
57
58
43
a Isolated yields. BORSM ) based on recovered starting material.
Results and Discussion
At the outset of this study, we chose methyl propiolate as a
model alkyne because it contains three functionalizable carbons
and the reaction would produce highly versatile γ-hydroxy-R,â-
acetylenic esters.9 Silver acetylide 1 (Table 1), after extensive
washing with water and drying under high vacuum, can be
stored at an ambient temperature for many months in the dark
without any precaution to avoid moisture.10 If 1 is not washed
thoroughly, the resulting material decomposes within a week.
Despite a safety concern in the recent literature11a a falling
hammer test on 1 was negative, indicating that 1 can be handled
without extraordinary precautions (Figure S1, Supporting
Information).11b
Under the alkynylation reaction conditions, 2 was transformed
to alcohol 3 in 44% yield (79% based on recovered 2; Table 1,
entry 1). We were surprised by this result not only because this
reaction afforded the unexpected bond connectivity, but also
because the product may be more electrophilic than the substrate.
To improve the conversion efficiency further, this reaction was
heated to 40 °C in CH2Cl2, which afforded the same product in
57% yield (entry 2). We could also use more AgOTf (0.5 equiv)
at 23 °C for essentially the same efficiency (58%; entry 3).
Further addition of AgOTf (1.0 equiv) generated 3 albeit in 43%
yield (entry 4). From this study, this reaction was found to be
The next step was to determine the scope of this method with
respect to alkynes. Epoxide 2 was treated with 6 under the
reaction conditions, providing 15 in 69% isolated yield (entry
9). The phenylacetylene derivative 16 reacted with 2 to give
17 in 82% yield (entry 10). We coupled 2 and THP ether 18
(entry 11), and 19 was isolated in 82% yield. The similarly acid-
sensitive diethyl acetal 20 also reacted with 2 to afford alcohol
21 in 81% yield (entry 12). These results indicate that acid-
sensitive functional groups such as acetals are compatible.
One of the benefits of our alkynylation method is the specific
C-H activation of terminal alkynes in the presence of similarly
acidic hydrogens. To demonstrate this concept in a synthetically
useful context, we treated propargyl acetate HCtCCH2OAc
with AgNO3 in NH4OH to give 22 in 97% yield despite the
very similar pKa values of terminal alkynes and esters in general
(both ∼25). When this acetylide was coupled with 2, compound
23 was generated in 57% yield (entry 13). This compound is
of high synthetic value as demonstrated by the Carreira group.12
Selenide 24 reacted with 2 to form alcohol 25 in 52% yield
(entry 14). These alkynes used in the epoxide openings should
be readily applicable for additions to aldehydes.
(7) Wipf, P.; Xu, W. J. Org. Chem. 1993, 58, 825-826. (b) Rose, C.
B.; Taylor, S. K. J. Org. Chem. 1974, 39, 578-581.
(8) Shahi, S. P.; Koide, K. Angew. Chem., Int. Ed. 2004, 43, 2525-
2527.
(9) (a) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 2002, 124, 5025-
5036. (b) Sa¨ıah, M. K. E.; Pellicciari, R. Tetrahedron Lett. 1995, 36, 4497-
4500. (c) Mikami, K.; Yoshida, A. Tetrahedron 2001, 57, 889-898. (d)
Trost, B. M.; Crawley, M. L. J. Am. Chem. Soc. 2002, 124, 9328-9329.
(e) Molander, G. A.; St. Jean, J.; D. J. J. Org. Chem. 2002, 67, 3861-
3865. (f) Naka, T.; Koide, K. Tetrahedron Lett. 2003, 44, 443-445. (g)
Meta, C. T.; Koide, K. Org. Lett. 2004, 6, 1785-1787. (h) Sonye, J. P.;
Koide, K. J. Org. Chem. 2007, 72, 1846-1848. (i) Sonye, J. P.; Koide, K.
J. Org. Chem. 2006, 71, 6254-6257. (j) Sonye, J. P.; Koide, K. Org. Lett.
2006, 8, 199-202. (k) Sonye, J. P.; Koide, K. Synth. Commun. 2006, 36,
599-602.
To determine the stereochemical relationship between ep-
oxides and products, we subjected cis- and trans-stilbene oxides
to the reaction conditions (entries 15 and 16); in both cases,
the phenyl group migrated and produced alcohol 26 in 86-
88% yields. Thus, it appears that the migratory aptitude is a
predominant factor in determining a migrating group. Finally,
the enantioriched epoxide 27 (e.r., >40:1)13 was reacted with
16, forming alcohol 28 as a 1:1 diastereomeric mixture in 63-
79% yields (entry 17). The HPLC and NMR analyses of the
corresponding Mosher esters revealed that the enantiomeric
ratios of syn-28 and anti-28 were both 9:1, indicating that the
1,2-hydride shift proceeded with good stereospecificity. The
tentative stereochemistry assignment at the tertiary stereocenter
(10) (a) De Las Heras, F. G.; Tam, S. Y.-K.; Klein, R. S.; Fox, J. J. J.
Org. Chem. 1976, 41, 84-90. (b) Davis, R. B.; Scheiber, D. H. J. Am.
Chem. Soc. 1956, 78, 1675-1678.
(11) (a) Persson, T.; Nielsen, J. Org. Lett. 2006, 8, 3219-3222. (b) When
compound 1 on aluminum foil was hit with a hammer, there was no sign
of a spark or explosive nature of 1. This material was also heated to 150
°C, and we did not observe any alarming phenomena except for slow
decomposition. Although more extensive studies may be needed, the silver
acetylides shown in this paper were prepared multiple times without an
accident. Also, we safely performed the Cp2ZrCl2/AgOTf-promoted alky-
nylation in the following papers on 140 mmol scale as part of the FR901464/
meayamycin synthesis: Albert B. J.; Sivaramakrishnan, A.; Naka, T.;
Czaicki, N. L.; Koide, K., J. Am. Chem. Soc. 2007, 129, 2648-2659; Albert,
B. J.; Sivaramakrishnan, A.; Naka, T.; Koide, K. J. Am. Chem. Soc. 2006,
128, 2792-2793.
(12) El-Sayed, E.; Anand, N. K.; Carreira, E. M. Org. Lett. 2001, 3,
3017-3020.
(13) Lebel, H.; Jacobsen, E. N. Tetrahedron Lett. 1999, 40, 7303-7306.
1094 J. Org. Chem., Vol. 73, No. 3, 2008

Epoxy Rearrangement-Alkynylation Sequence
TABLE 2. Epoxide Openinge
SCHEME 2. Proposed Mechanism
TABLE 3. Control Experiments
reagents
chlorohydrins,
entry
(equiv)
isolated yield (%)
decanal
1
2
3
4
Cp2ZrCl2 (1.6)
AgOTf (0.5)
Cp2ZrCl2 (1.2), AgOTf (0.5)
1 (1.6), Cp2ZrCl2 (1.2)
83
none
87
none
none
trace
none
22
is based on the literature.14 The observed specificity is remark-
able because related 1,1-disubstituted epoxides exhibited poor
to no stereospecificity under different reaction conditions.15
Our proposed mechanism is shown in Scheme 2. Transmeta-
lation of silver acetylide D and Cp2ZrCl2 gives zirconium
acetylide E, which then reacts with AgOTf to give the more
Lewis acidic zirconium acetylide F.16 This acetylide coordinates
with an epoxide to form complex G. Subsequent 1,2-hydride
shift gives the aldehyde-zirconium complex H, allowing for
the carbonyl alkynylation to afford zirconium alkoxide I. This
complex can then undergo triflate-chloride exchange with
zirconium acetylide E, explaining the need for a substoichio-
metric amount of AgOTf. Alternatively, E and H could undergo
triflate-chloride exchange to form F and ate complex K, which
undergoes carbonyl alkynylation to form alkoxide J. This
alternative mechanism may explain why the use of stoichio-
metric AgOTf resulted in lower yield (Table 1, entry 4) due to
the poor availability of chloride ions.
On the basis of this proposed mechanism, we examined the
role of the additives (Table 3). Treatment of 2 with Cp2ZrCl2
generated chlorohydrins 29 and 30 in 83% combined yield in a
5:1 ratio with no formation of decanal (entry 1). We also
(14) (a) Jung, M. E.; Anderson, K. L. Tetrahedron Lett. 1997, 38, 2605-
2608. (b) Maruoka, K.; Ooi, T.; Yamamoto, H. Tetrahedron 1992, 48,
3303-3312. (c) Blackett, B. N.; Coxon, J. M.; Hartshorn, M. P.; Richards,
K. E. J. Am. Chem. Soc. 1970, 92, 2574-2575.
a 0.2 equiv of AgOTf was used. b 0.05 equiv of AgOTf was used.
c dr ) 2:1 (unassigned). d dr ) 1:1. e Reagents and conditions: silver
acetylide (1.6 equiv), Cp2ZrCl2 (1.2 equiv), AgOTf (0.5 equiv), CH2Cl2,
23 °C.
(15) (a) Karame, I.; Tommasino, M. L.; Lemaire, M. Tetrahedron Lett.
2003, 44, 7687-7689. (b) Hara, N.; Mochizuki, A.; Tatara, A.; Fujimoto,
Y. Tetrahedron: Asymmetry 2000, 11, 1859-1868.
(16) Maeta, H.; Hashimoto, T.; Hasegawa, T.; Suzuki, K. Tetrahedron
Lett. 1992, 33, 5965-5968.
J. Org. Chem, Vol. 73, No. 3, 2008 1095

Albert and Koide
SCHEME 3. Characterized Species
Conclusions
We have developed the first general method to couple
epoxides with terminal alkynes to form propargylic alcohols.
Various functional groups are compatible with these newly
developed alkynylation conditions. Synthetic use of silver
acetylides has been limited to only a few types of reactions.10a,18
This study shows that the formation of silver acetylides followed
by zirconium acetylides of electron-deficient electron-and rich
alkynes is a powerful method to couple functionalized alkynes
to epoxides.
Experimental Section
General Procedure for the Preparation of the Silver Acetyl-
ides. To a stirred solution of AgNO3 (2.1-283 mmol, 2.1 equiv)
in deionized H2O (1.0-84 mL) and MeOH19 (0.4-50 mL) was
added NH4OH (28-30%, 0.4-54 mL) until the solution became
clear again at 23 °C under ambient light. After 30 min at the same
temperature, terminal alkynes (1.0-138 mmol, 1 equiv) in MeOH
(0.3-6 mL) were added dropwise. After an additional 10-30 min
of vigorous stirring at the same temperature, the reaction mixture
was filtered through a frit, then thoroughly rinsed with deionized
H2O (8 × 5-250 mL) and MeOH (5-250 mL). The resulting solids
were dried under high vacuum overnight over P2O5 to give the
appropriate silver acetylides (79%-quantitative yield) as powders.
Although the silver acetylides shown in this paper were powders,
we noted that more hydrophobic silver acetylides were oils. In these
instances, we diluted the reaction mixture with H2O and extracted
twice with CH2Cl2. The combined organic layers were dried over
Na2SO4, filtered, and concentrated under reduced pressure to give
the silver acetylides as oils.
subjected the same epoxide to AgOTf and found no reaction
(entry 2). Therefore, neither Cp2ZrCl2 nor AgOTf were able to
induce the 1,2-hydride shift. Exposure of 2 to Cp2ZrCl2 and
AgOTf gave 29 and 30 in 87% combined yield in a 1:1 ratio
with a trace amount of decanal (entry 3). Although the
combination of Cp2ZrCl2 and AgOTf presumably generates Cp2-
ZrCl(OTf) in situ and allows for the 1,2-hyride shift to occur,
chlorohydrin formation promoted by Cp2ZrCl2 and/or Cp2ZrCl-
(OTf) is strongly preferred. Treatment of 2 to the mixture of 1
and Cp2ZrCl2, precursors to [Cp2ClZr-CtC-CO2Me], pro-
vided 29 and 30 in 22% combined yield in a 3:1 ratio (entry
4). This result shows that zirconium acetylide [Cp2ClZr-Ct
C-CO2Me] is not responsible for the transformation of 2 to 3
but suppresses chlorohydrin formation to some extent. To test
whether chlorohydrin formation is reversible under the reaction
conditions, 29 and 30 were subjected to the alkynylation reaction
conditions. However, neither 3 nor decanal were observed,
indicating that chlorohydrin formation is irreversible under the
reaction conditions. Therefore, silver acetylide, Cp2ZrCl2, and
AgOTf are all needed for the 1,2-hyride shift-alkynylation
sequence in accordance with our proposed mechanism.
General Procedure for the Addition of Silver Acetylides to
Epoxides. To a stirred solution (or suspension for poorly soluble
silver acetylides) of silver acetylide (0.8-16 mmol, 1.6 equiv) in
CH2Cl2 (1.8-30 mL) was added epoxide (0.5-9.9 mmol, 1 equiv)
followed by the addition of Cp2ZrCl2 (0.6-12 mmol, 1.2 equiv)
and AgOTf (0.025-5.0 mmol, 0.05-0.5 equiv) in one portion at
23 °C under ambient light. After vigorous stirring at the same
temperature for 1-10 h the solution was quenched with saturated
aqueous NH4Cl or saturated aqueous NaHCO3 (0.5-6 mL). After
stirring for 15-30 min at the same temperature, the reaction mixture
was filtered through a pad of Celite 545 and Na2SO4, rinsed with
Et2O (2 × 5-30 mL), and concentrated under reduced pressure.
The resulting residues were purified by flash chromatography
(EtOAc/hexanes) on silica gel to afford the corresponding alcohols.
Data for 3: colorless oil; Rf 0.29 (20% EtOAc in hexanes); IR
(neat) 3419 (br, O-H), 2924, 2855, 2237, 1717, 1436, 1251, 1065,
We proceeded to study the mechanism by NMR (Scheme
3). First, we were able to characterize 2017 by 1H and 13C NMR
(Supporting Information). Addition of Cp2ZrCl2 to 20 generated
zirconium acetylide 31 via transmetalation, which was cor-
1
roborated by H and 13C NMR. Treatment of this zirconium
acetylide with AgOTf (1 equiv) generated a new species
showing downfield chemical shifts compared to 31 (Supporting
Information), which we believe is 32. Both 31 and 32 were
sensitive toward moisture and could not be isolated after aqueous
workups, only giving 3,3-diethoxypropyne. To probe the Lewis
acidities of 31 and 32, we used Ph2CdO as a Lewis base due
to its attenuated reactivity. Treatment of 31 with Ph2CdO
resulted in the slight upfield chemical shifts observed in 13C
NMR spectrum of Ph2CdO, implying an equilibrium between
the starting material and the plausible complex 33. When 32
and Ph2CdO were mixed, the observed 13C chemical shifts for
Ph2CdO were now shifted downfield, which we interpret as
34. These results show that the Zr atoms in both 31 and 32 are
Lewis acidic, and 34 contains a Zr-bound electrophile in a higher
population. This is also consistent with our previous observations
that AgOTf was required to induce 1,2-hydride shift.
1
752 cm-1; H NMR (300 MHz, 293 K, CDCl3) δ 4.50 (br app q,
1H, J ) 6.4 Hz), 3.80 (s, 3H), 1.91 (d, 1H, J ) 5.8 Hz), 1.82-
1.73 (m, 2H), 1.53-1.22 (m, 14H), 0.89 (t, 3H, J ) 6.7 Hz); 13C
NMR (75 MHz, 293 K, CDCl3) δ 153.8, 88.4, 76.1, 62.1, 52.8,
36.8, 31.8, 29.44, 29.39, 29.2, 29.1, 24.9, 22.6, 14.0; HRMS (EI+)
calcd for C14H24O3 [M]+ 240.1725, found 240.1735.
Procedure and Data for the Preparation of 1-Oxaspiro[2.5]-
octane. See ref 20.
Data for 4: see ref 8.
Data for 5: colorless oil; Rf 0.40 (30% EtOAc in hexanes); IR
(neat) 3412 (br, O-H), 2952, 2237, 1718, 1436, 1254, 1068, 914,
1
752 cm-1; H NMR (300 MHz, 293 K, 1% CD3OD in CDCl3) δ
5.79 (dddd, 1H, J ) 16.8, 10.2, 6.6, 6.6 Hz), 5.06-4.94 (m, 2H),
4.46 (app t, 1H, J ) 6.6 Hz), 3.78 (s, 3H), 2.13-2.04 (m, 2H),
1.80-1.51 (m, 4H); 13C NMR (75 MHz, 293 K, CDCl3) δ 153.9,
138.0, 115.0, 88.6, 75.9, 61.6, 52.7, 36.1, 33.1, 24.0; LRMS (EI+)
(18) Dillinger, S.; Bertus, P.; Pale, P. Org. Lett. 2001, 3, 1661-1664.
(19) EtOH was used instead of MeOH for the preparation of the silver
acetylide 20 from 3,3-diethoxypropyne.
(17) Many silver acetylides including 1 could not be used due to its poor
solubility in organic solvents, but acetylide 20 was soluble in organic
solvents and thus used.
(20) Michnik, T. J.; Matteson, D. S. Synlett 1991, 631-632.
1096 J. Org. Chem., Vol. 73, No. 3, 2008

Epoxy Rearrangement-Alkynylation Sequence
C10H11O2 [M - H3O]+ 163 (58%), C9H9O2 [M - CH5O]+ 149
(14%), C7H11O [M - C2H4O2]+ 122 (26%).
29.52, 29.48, 29.27, 29.26, 25.2, 22.7, 21.9, 18.4, 14.1, 13.5; HRMS
(EI+) calcd for C16H30O [M]+ 238.2297, found 238.2288.
Data for 17: pale yellow oil; Rf 0.31 (15% EtOAc in hexanes);
IR (neat) 3329 (br, O-H), 2924, 2855, 2229, 1599, 1490, 1070,
1027, 755 cm-1; 1H NMR (300 MHz, 293 K, 1% CD3OD in CDCl3)
δ 7.45-7.39 (m, 2H), 7.34-7.28 (m, 3H), 4.57 (app t, 1H, J )
6.6 Hz), 1.83-1.74 (m, 2H), 1.57-1.23 (m, 14H), 0.87 (t, 3H, J
) 6.6 Hz); 13C NMR (75 MHz, 293 K, CDCl3) δ 131.7, 128.3,
128.2, 122.7, 90.3, 84.8, 63.0, 37.9, 31.9, 29.5, 29.3, 25.2, 22.7,
14.1; HRMS (EI+) calcd for C18H26O [M]+ 258.1984, found
258.1975.
Data for 7: colorless oil; Rf 0.27 (15% EtOAc in hexanes); IR
(neat) 3345 (br O-H), 2933, 2863, 2232, 1641, 1459, 996, 911
1
cm-1; H NMR (300 MHz, 293 K, 1% CD3OD in CDCl3) δ 5.79
(dddd, 1H, J ) 17.2, 10.0, 6.5, 6.5 Hz), 4.99 (dddd, 1H, J ) 17.2,
1.5, 1.5, 1.5 Hz), 4.93 (br d, 1H, J ) 10.0 Hz), 4.31 (br app t, 1H,
J ) 3.9 Hz), 2.18 (app td, 2H, J ) 7.0, 2.0 Hz), 2.06 (br app q,
2H, J ) 7.5 Hz), 1.71-1.58 (m, 2H), 1.56-1.33 (m, 6H), 0.88 (t,
3H, J ) 7.3 Hz); 13C NMR (125 MHz, 293 K, CDCl3) δ 138.5,
114.6, 85.3, 81.1, 62.2, 37.4, 33.2, 30.7, 24.4, 21.8, 18.2, 13.5;
LRMS (EI+) C12H19O [M - H]+ 179 (5%), C9H13O [M - C3H7]+
137 (75%), C7H11O [M - C5H9]+ 111 (100%).
Data for 19: colorless oil; Rf 0.14 (15% EtOAc in hexanes); IR
(neat) 3423 (br, O-H), 2924, 2854, 1466, 1343, 1201, 1120, 1024,
1
902 cm-1; H NMR (300 MHz, 293 K, 1% CD3OD in CDCl3) δ
Data for 8: see ref 8.
4.81 (br s, 1H), 4.40-4.33 (m, 1H), 4.33 (dd, 1H, J ) 15.6, 1.5
Hz), 4.25 (dd, 1H, J ) 15.6, 1.2 Hz), 3.88-3.79 (m, 1H), 3.56-
3.49 (m, 1H), 1.88-1.20 (m, 22H), 0.87 (t, 3H, J ) 5.9 Hz); 13C
NMR (75 MHz, 293 K, CDCl3) δ 96.9, 87.4, 80.2, 62.1, 62.0, 54.3,
37.6, 31.8, 30.1, 29.47, 29.45, 29.22, 29.21, 25.2, 25.1, 22.6, 18.9,
14.0; HRMS (ESI+) calcd for C18H32O3 [M + Na]+ 319.2249,
found 319.2250.
Data for 21: colorless oil; Rf 0.22 (15% EtOAc in hexanes); IR
(neat) 3425 (br, O-H), 2925, 2856, 2241, 1467, 1328, 1145, 1054,
1012 cm-1; 1H NMR (300 MHz, 293 K, 1% CD3OD in CDCl3) δ
5.29 (d, 1H, J ) 1.2 Hz), 4.39 (br app t, 1H, J ) 6.6 Hz), 3.81-
3.68 (m, 2H), 3.63-3.56 (m, 2H), 1.75-1.66 (m, 2H), 1.52-1.18
(m, 20H), 0.87 (t, 3H, J ) 6.8 Hz); 13C NMR (75 MHz, 293 K,
CDCl3) δ 91.2, 86.5, 80.0, 62.2, 60.9, 60.8, 37.4, 31.8, 29.5, 29.3,
29.2, 25.1, 22.6, 15.0, 14.1; HRMS (EI+) calcd for C15H27O2 [M
- OEt]+ 239.2011, found 239.2007.
Procedure for the Preparation of 9. See ref 20.
Data for 9: see ref 21.
Data for 10: colorless oil; Rf 0.28 (15% EtOAc in hexanes); IR
(neat) 3360 (br O-H), 2931, 2862, 2224, 1451, 1379, 1140, 1047,
1
725 cm-1; H NMR (300 MHz, 293 K, 1% CD3OD in CDCl3) δ
5.90-5.66 (m, 2H), 4.19 (br app s, 1H), 2.40-2.28 (m, 1H), 2.21
(app t, 2H, J ) 6.5 Hz), 2.06-1.94 (m, 2H), 1.92-1.73 (m, 2H),
1.64-1.35 (m, 6H), 0.90 (t, 3H, J ) 7.1 Hz); 13C NMR (75 MHz,
293 K, CDCl3) δ 130.1, 129.9, 127.2, 126.5, 86.2, 86.1, 80.2, 80.0,
66.2, 66.0, 42.4, 30.7, 25.18, 25.16, 24.5, 21.8, 21.4, 21.0, 18.3,
13.5; HRMS (EI+) calcd for C13H20O [M]+ 192.1514, found
192.1508.
Data for 11: see ref 22.
Procedure for the Preparation of 12. To a stirred solution of
1-tert-butyldimethylsiloxy-3-butene (935 mg, 5.02 mmol) in CH2-
Cl2 (17 mL) was added mCPBA (70%, 2.47 g, 10.0 mmol) at
0 °C. After 10 min at the same temperature, the reaction was
allowed to warm to 23 °C. After 14 h at the same temperature, the
reaction was quenched by the addition of saturated aqueous
NaHCO3 (10 mL) and saturated aqueous Na2SO3 (10 mL). The
reaction mixture was then vigorously stirred for an additional 15
min, then diluted with hexanes (25 mL), and the layers were
separated. The organic layer was then washed with saturated
aqueous NaHCO3 (20 mL), dried over anhydrous Na2SO4, filtered,
and concentrated under reduced pressure. The resulting residue was
purified by flash chromatography (1-5% EtOAc in hexanes) on
silica gel (50 mL) to afford 12 (964 mg, 95%) as a colorless oil.
Data for 12: see ref 23.
Data for 23: colorless oil; Rf 0.24 (20% EtOAc in hexanes); IR
(neat) 3424 (br, O-H), 2925, 2855, 1750, 1457, 1379, 1226, 1028
1
cm-1; H NMR (300 MHz, 293 K, 1% CD3OD in CDCl3) δ 4.73
(d, 1H, J ) 18.2 Hz), 4.67 (d, 1H, J ) 18.2 Hz), 4.37 (br app t,
1H, J ) 6.3 Hz), 2.10 (s, 3H), 1.73-1.64 (m, 2H), 1.48-1.21 (m,
14H), 0.87 (t, 3H, J ) 6.6 Hz); 13C NMR (75 MHz, 293 K, CDCl3)
δ 170.3, 88.0, 78.6, 62.3, 62.2, 53.3, 37.5, 31.8, 29.5, 29.3, 29.2,
25.1, 22.6, 20.7, 14.1; HRMS (ESI+) calcd for C15H26O3 [M +
Na]+ 277.1780, found 277.1829.
Procedure for the Preparation of p-Nitrophenyl Propargyl
Selenide. To a stirred solution of 2-nitrophenylselenocyanate (2.27
g, 10.0 mmol) and propargyl alcohol (650 µL, 11.2 mmol) in THF
n
(35 mL) was added Bu3P (3.0 mL, 12 mmol) dropwise at 0 °C.
Data for 13: pale yellow oil; Rf 0.30 (20% EtOAc in hexanes);
IR (neat) 3411 (br O-H), 2954, 2858, 2237, 1720 (CdO), 1436,
1255, 1100, 837 cm-1; 1H NMR (300 MHz, 293 K, 1% CD3OD in
CDCl3) δ 4.53 (br app t, 1H, J ) 5.3 Hz), 3.77 (s, 3H), 3.76-3.60
(m, 2H), 1.96-1.64 (m, 4H), 0.90 (s, 9H), 0.083 (s, 3H), 0.079 (s,
3H); 13C NMR (75 MHz, 293 K, CDCl3) δ 153.9, 88.6, 76.0, 63.0,
61.5, 52.6, 34.5, 28.3, 25.8, 18.3, -5.48, -5.53; HRMS (ESI+)
calcd for C14H27O4Si [M + H]+ 287.1679, found 287.1675.
Data for 14: colorless oil; Rf 0.31 (15% EtOAc in hexanes); IR
(neat) 3385 (br O-H), 2931, 2859, 2235, 1468, 1387, 1254, 1103,
After 40 min at the same temperature, the reaction was poured onto
saturated aqueous NaHCO3 (300 mL). The layers were separated,
and the aqueous layer was extracted with Et2O (3 × 100 mL). The
combined organic layers were dried over anhydrous Na2SO4,
filtered, and concentrated under reduced pressure. The resulting
residue was purified by column chromatography (1f 5% Et2O in
hexanes) on silica gel (250 mL) to afford p-nitrophenyl propargyl
selenide (1.90 g, 79%) as a yellow solid.
Data for p-nitrophenyl propargyl selenide: yellow solid; mp
85-86 °C; Rf 0.29 (15% EtOAc in hexanes); IR (KBr pellet) 3272,
1
837 cm-1; H NMR (300 MHz, 293 K, 1% CD3OD in CDCl3) δ
3088, 2925, 1589, 1565, 1497, 1352, 1306, 1100, 1038, 731 cm-1
;
4.39 (br s, 1H), 3.71-3.63 (m, 2H), 2.24-2.16 (m, 2H), 1.82-
1.64 (m, 4H), 1.51-1.23 (m, 4H), 0.93-0.87 (m, 12H), 0.07 (s,
6H); 13C NMR (75 MHz, 293 K, CDCl3) δ 85.2, 81.1, 63.2, 62.2,
35.5, 30.7, 28.5, 25.9, 21.9, 18.34, 18.27, 13.5, -5.4; HRMS (ESI+)
calcd for C16H32O2NaSi [M + Na]+ 307.2069, found 307.2070.
Data for 15: colorless oil; Rf 0.40 (15% EtOAc in hexanes); IR
(neat) 3384 (br, O-H), 2926, 2855, 2233, 1466, 1379, 1026, 722
1H NMR (300 MHz, 293 K, CDCl3) δ 8.37 (dd, 1H, J ) 8.4, 1.2
Hz), 7.69 (dd, 1H, J ) 8.1, 1.2 Hz), 7.62 (ddd, 1H, J ) 8.1, 6.9,
1.5 Hz), 7.39 (ddd, 1H, J ) 8.4, 6.9, 1.5 Hz), 3.55 (d, 2H, J ) 2.7
Hz), 2.28 (t, 1H, J ) 2.7 Hz); 13C NMR (75 MHz, 293 K, CDCl3)
δ 146.0, 134.0, 132.9, 128.8, 126.4, 125.9, 79.5, 72.1, 11.4; HRMS
(EI+) calcd for C9H7NO280Se [M]+ 240.9642, found 240.9633.
Data for 25: pale yellow solid; mp 71-72 °C; Rf 0.34 (30%
EtOAc in hexanes); IR (KBr pellet) 3332 (br, O-H), 2923, 2850,
1
cm-1; H NMR (300 MHz, 293 K, 1% CD3OD in CDCl3) δ 4.35
(br app t, 1H, J ) 6.4 Hz), 2.22 (app td, 2H, J ) 6.9, 1.8 Hz),
1
1589, 1567, 1503, 1330, 1306, 1038, 729 cm-1; H NMR (300
1.72-1.60 (m, 2H), 1.55-1.24 (m, 18H), 0.96-0.85 (m, 6H); 13
C
MHz, 293 K, 1% CD3OD in CDCl3) δ 8.34 (dd, 1H, J ) 8.3, 1.3
Hz), 7.65 (dd, 1H, J ) 8.1, 1.3 Hz), 7.58 (ddd, 1H, J ) 8.1, 7.2,
1.5 Hz), 7.36 (ddd, 1H, J ) 8.3, 7.2, 1.5 Hz), 4.33 (br app t, 1H,
J ) 6.6 Hz), 3.62-3.55 (m, 2H), 1.71-1.15 (m, 16H), 0.87 (t,
3H, J ) 6.8 Hz); 13C NMR (75 MHz, 293 K, CDCl3) δ 146.2,
133.9, 133.2, 129.0, 126.4, 125.8, 85.2, 80.2, 62.6, 37.8, 31.8, 29.5
NMR (75 MHz, 293 K, CDCl3) δ 85.4, 81.4, 62.8, 38.2, 31.9 30.8,
(21) Tanis, S. P.; McMills, P. M. J. Org. Chem. 1985, 50, 5587-5589.
(22) Pchelka, B. K.; Loupy, A. Tetrahedron 2006, 62, 10968-10979.
(23) Lawson, E. N.; Jamie, J. F.; Kitching, W. J. J. Org. Chem. 1992,
57, 353-358.
J. Org. Chem, Vol. 73, No. 3, 2008 1097

Albert and Koide
(2 carbons overlapped), 29.25, 29.20, 25.1, 22.6, 14.1, 12.0; HRMS
(EI+) calcd for C19H27NO380Se [M]+ 397.1156, found 397.1141.
Data for 26: Rf 0.40 (20% EtOAc in hexanes); IR (neat) 3420
for 15-30 min at the same temperature, the reaction mixture was
filtered through a pad of Celite 545 and Na2SO4, rinsed with Et2O
(3 × 5 mL), and concentrated under reduced pressure. The resulting
residues were purified by flash chromatography (EtOAc/hexanes)
on silica gel to afford the corresponding products.
1
(br, O-H), 3028, 2931, 2228, 1495, 1452, 1032, 746 cm-1; H
NMR (300 MHz, 293 K, 1% CD3OD in CDCl3) δ 7.42-7.18 (m,
10H), 5.02 (ddd, 1H, J ) 7.2, 1.8, 1.8 Hz), 4.20 (br d, 1H, J ) 7.2
Hz), 2.16-1.95 (m, 3H), 1.40-1.16 (m, 4H), 0.82 (t, 3H, J ) 7.2
Hz); 13C NMR (75 MHz, 293 K, 1% CD3OD in CDCl3) δ 141.2,
140.6, 128.9, 128.8, 128.3, 128.1, 126.7, 126.6, 87.6, 79.9, 65.2,
58.2, 30.4, 21.6, 18.2, 13.4; HRMS (ESI+) calcd for C20H22ONa
[M + Na]+ 301.1568, found 301.1579.
Data for 29 and 27: see ref 24.
Procedure for the Preparation of 31 and 33 from 20. To an
NMR tube was added 20 (35-49 mg, 0.15-0.20 mmol) followed
by CD2Cl2 (0.8 mL) under Ar at 23 °C. To the homogeneous
solution was added Cp2ZrCl2 (1.1 equiv) and the resulting mixture
was vortexted for 5 min. NMR experiments were then performed
on the rapidly generated acetylide 31. To this solution was added
benzophenone (1.0 equiv) and the mixture was vortexed for 2 min.
NMR experiments were then performed on equilibrium between
31 and 33. See Tables S1 and S2 in the Supporting Information
for NMR data.
Procedure for the Preparation of 32 and 34 from 31. To an
NMR tube containing 31 (0.15-0.20 mmol) in CD2Cl2 (0.8 mL)
was added AgOTf (1.0 equiv) under Ar at 23 °C, and the mixture
was then vortexed for 5 min. NMR experiments were immediately
performed on the rapidly generated acetylide 32. To this solution
was added benzophenone (1.0 equiv) and the mixture was vortexed
for 2 min. NMR experiments were then performed on equilibrium
between 32 and 34 (see Tables S1 and S2 in the Supporting
Information for data).
Procedure for the Preparation of rac-27. To a stirred solution
of cyclohexylmethyl ketone (1.4 mL, 10 mmol) and CH2Br2 in THF
n
(30 mL) was added BuLi (1.6 M in hexanes, 7.0 mL) down the
flask sides over 15 min at -78 °C. After an additional 30 min at
the same temperature, the reaction was warmed to 23 °C. After
2.75 h at the same temperature, the reaction mixture was poured
onto saturated aqueous NH4Cl (40 mL) and concentrated under
reduced pressure to remove most of the THF. The resulting aqueous
residue was extracted with Et2O (2 × 25 mL). The combined
organic layers were dried over anhydrous Na2SO4, filtered, and
concentrated under reduced pressure. The resulting residue was
purified by column chromatography (2f 4% EtOAc in hexanes)
on silica gel (50 mL) to afford rac-27 (1.08 g, 77%) as a colorless
oil.
Procedure and Data for the Preparation of (R)-27. See ref
13.
Acknowledgment. We thank the University of Pittsburgh
and the U.S. National Institutes of Health (1R01CA120792-
01) for their financial support. We thank Dr. Shatrughan P. Shahi
for initial experimentations. We thank Dr. Damodaran Krishnan
(NMR) and Dr. John Williams (MS) for their technical
assistance. B.J.A. is thankful for a Graduate Excellence Fel-
lowship.
Data for 28: Rf 0.27 (10% EtOAc in hexanes); IR (neat) 3417
1
(br, O-H), 2924, 1637, 1490, 1447, 1000, 755 cm-1; H NMR
(300 MHz, 293 K, 1% CD3OD in CDCl3) δ 7.41-7.38 (m), 7.33-
7.28 (m), 4.61 (d, J ) 5.7 Hz), 1.82-1.52 (m), 1.36-1.10 (m),
1.06 (t, J ) 6.6 Hz), 1.03 (t, J ) 6.9 Hz); 13C NMR (75 MHz, 293
K, CDCl3) δ 131.7, 131.6, 128.3, 122.8, 90.2, 89.2, 85.9, 85.3,
65.40, 65.35, 45.0, 44.8, 39.5, 35.0, 31.6, 31.4, 29.2, 28.7, 26.71,
26.64, 26.59, 26.47, 11.43, 11.40; HRMS (EI+) calcd for C17H22O
[M]+ 242.1671, found 242.1676.
Supporting Information Available: Experimental procedures
and full spectroscopic data for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
General Procedure for the Preparation of 29, 30, and Decanal
from 2. To a stirred solution of 2 (45 µL, 0.24 mmol) in CH2Cl2
(1.0 mL) were added the other reaction components (equivalents
based on optimized alkynylation reaction conditions) at 23 °C. After
3.5-19 h at the same temperature, the reaction was quenched by
the addition of saturated aqueous NaHCO3 (0.3 mL). After stirring
JO702306K
(24) Barry, C. N.; Evans, S. A. J. Org. Chem. 1983, 48, 2825-2828.
1098 J. Org. Chem., Vol. 73, No. 3, 2008