The versatility of α-chloropropargyl phenyl sulfide affords high stereo- and regioselectivities in indium-promoted coupling reactions under mild conditions

Article abstract of DOI:10.1021/jo015992l

Coupling reactions between α-chloropropargyl phenyl sulfide (11) and a series of aldehydes under aqueous conditions are reported. Not only is good stereoselectivity observed between syn and anti isomeric products, but excellent regioselectivity is also witnessed. In reactions using indium metal as a promoter, the propargyl functionality (12) is retained, unlike the use of more traditional metals that result in formation of products containing a mixture of both propargyl (12) and allene (13) moieties. The reaction is postulated to proceed via either a chelated or nonchelated route, controlled by the presence or absence of indium (111) chloride, and may be used to create synthetically useful building blocks. The formation of epoxyalkyne (14) molecules, which are found in many natural products and have wide use as synthetic templates, is presented as one example.

Full text of DOI:10.1021/jo015992l

136
J . Org. Chem. 2002, 67, 136-145
Th e Ver sa tility of r-Ch lor op r op a r gyl P h en yl Su lfid e Affor d s High
Ster eo- a n d Regioselectivities in In d iu m -P r om oted Cou p lin g
Rea ction s u n d er Mild Con d ition s
Thomas M. Mitzel,* Carolyn Palomo, and Keith J endza
Department of Chemistry, Trinity College, 300 Summit Street, Hartford, Connecticut 06106
tmitzel@mail.trincoll.edu
Received J uly 31, 2001
Coupling reactions between R-chloropropargyl phenyl sulfide (11) and a series of aldehydes under
aqueous conditions are reported. Not only is good stereoselectivity observed between syn and anti
isomeric products, but excellent regioselectivity is also witnessed. In reactions using indium metal
as a promoter, the propargyl functionality (12) is retained, unlike the use of more traditional metals
that result in formation of products containing a mixture of both propargyl (12) and allene (13)
moieties. The reaction is postulated to proceed via either a chelated or nonchelated route, controlled
by the presence or absence of indium (III) chloride, and may be used to create synthetically useful
building blocks. The formation of epoxyalkyne (14) molecules, which are found in many natural
products and have wide use as synthetic templates, is presented as one example.
In tr od u ction
One alternative to having the electrophilic component
command the stereochemical outcome of reactions would
be to have spatial relationships of newly forming stereo-
centers controlled by the nucleophile. One such set of
nucleophiles that could be utilized in this sense would
be R-chloroheteroatomic species, as shown in Scheme 1.4
The past decade has been witness to a large movement
toward environmentally benign chemistry and chemical
transformations. Chemists have sought to introduce more
mild catalysts, reagents, and solvent systems into their
work.1 Indium metal has found much success in this area
as it has been shown to promote the formation of C-C
bonds under aqueous conditions with high yields and
good control.1,2 Indium metal has also been shown to
possess good chelating properties under aqueous condi-
tions, allowing for good stereo- and regioselectivities to
be realized.2,3 Many of the past studies utilizing this
metal have focused on controlling ratios of syn/anti
product formation in Barbier-type reactions by placing
heteroatomic functional groups R or â to a carbonyl
functionality.3a,c,e These systems have allowed control of
product formation with diastereomeric ratios as high as
13:1.3e Placement of a heteroatomic group R or â to a
carbonyl moiety is often not trivial, however, and may
require multiple steps, making isolation and purification
an arduous process.
R-Chloroheteroatomic species were implemented for
use as early as the 1960s when Normant published a
study of R-chlorosulfide reactivity.5 He noted their ef-
fectiveness under Barbier- and Grignard-type conditions
in C-C bond-forming reactions in these investigations.5
Since then, other authors have used similar systems with
varying degrees of success.6 The chloride species in
Scheme 1 are interesting for a variety of reasons: (1)
Although not cited often in recent literature, their
successful use in Barbier-type chemistry is quite intrigu-
ing. (2) The nucleophile contains a stereocenter that may
be used to help control spatial alignments in product
formation, eliminating the need to synthesize such a
center R to the carbonyl in an electrophilic species. (3)
Many compounds of the type shown in Scheme 1 are
available in one step from easily obtainable starting
materials, removing synthetic hurdles and simplifying
the overall synthetic process.
In an effort to further studies in environmentally
benign chemistry and chemical transformations, as well
as to simplify and offer an alternative to known indium-
promoted chemistry,1 we decided to study R-chloro het-
eroatomic compounds for use as the nucleophilic compo-
nents in indium-promoted reactions under aqueous
conditions. This study focuses on stereo- and regiocontrol
of product formation within these parameters with an
(1) (a) Li, C.-J .; Chan, T.-H. Tetrahedron 1999, 55, 11149. (b) Li,
C.-J .; Chan, T.-H. Organic Reactions in Aqueous Media; J ohn Wiley
and Sons: New York, 1997; Chapter 4. (c) Li, C.-J . Chem. Rev. 1993,
93, 2023. (d) Chan, T.-H.; Li, C.-J .; Lee, M. C.; Wei, Z. Y. Can. J . Chem.
1994, 1181. (e) Kim, E.; Gordon, D. M.; Schmid, W.; Whitesides, G. M.
J . Org. Chem. 1993, 58, 5500. (f) Marshall, J . A.; Hinkle, K. W. J . Org.
Chem. 1995, 60, 1920. (g) Grieco, P. A.; Bahsas, A. J . Org. Chem. 1987,
52, 1378.
(2) For some recent examples of In-mediated reactions, refer to: (a)
Lu, W.; Chan, T. H. J . Org. Chem. 2001, 66, 3467-3473. (b) Li, C.-J .;
Li, J . Tetrahedron Lett. 2001, 42, 793. (c) Lee, P. H.; Ahn, H.; Lee, K.;
Sung, S.-Y.; Kim, S. Tetrahedron Lett. 2001, 42, 37. (d) Paquette, L.
A.; Rothhaar, R. R.; Isaac, M.; Rogers, L. M.; Rogers, R. D. J . Org.
Chem. 1998, 63, 5463. (e) Loh, T.-P.; Zhou, J . R. Tetrahedron Lett. 1999,
40, 9115.
(3) (a) Paquette, L. A.; Lobben, P. C. J . Org. Chem. 1998, 63, 6990.
(b) Paquette, L. A.; Bennett, G. D.; Chatriwalla, A.; Isaac, M. B. J .
Org. Chem. 1997, 62, 3370 (c) Paquette, L. A.; Lobben, P. C. J . Am.
Chem. Soc. 1996, 118, 1917, (d) Paquette, L. A.; Mitzel, J . Org. Chem.
1996, 61, 8799. (e) Paquette, L. A.; Mitzel, T. M. J . Am. Chem. Soc.
1996, 118, 1931.
(4) For nice reviews in this area: (a) Dilworth, B. M.; McKervey,
M. A. Tetrahedron 1986, 42, 3731. (b) Peterson, D. J . Organomet.
Chem. Rev. A 1972, 295 and references cited therein.
(5) (a) Normant, H.; Castro, C. R. Acad. Sci. Paris 1964, 259, 830
(6) (a) Nakatsuka, S.; Takai, K.; Utimata, K. J . Org. Chem. 1986,
51, 5045. (b) Gross, H.; Hoft, E. Angew. Chem., Int. Ed. Engl. 1967, 6,
335. (c) Cohen, T.; Matz, J . R. J . Am. Chem. Soc. 1985, 106, 6902.
10.1021/jo015992l CCC: $22.00 © 2002 American Chemical Society
Published on Web 12/11/2001

Versatility of R-Chloropropargyl Phenyl Sulfide
J . Org. Chem., Vol. 67, No. 1, 2002 137
Sch em e 1
F igu r e 1. Representative J values for hydroxy sulfides and
epoxides.
from H2O to DMF allows the reaction to proceed; how-
ever, yields are moderate at best. Use of R-chlorooxy
species proceeded more smoothly; however, loss of the
nucleophile was still problematic within these param-
eters. Following the reaction by thin-layer chromatogra-
phy (TLC 10:1 hexanes/ethyl acetate) shows a smooth
beginning to the reaction sequence. As the reaction
progresses, however, the nucleophile disappears, while
the aldehyde concentration remains unchanged. Addition
of DMF promotes a consistent rate of disappearance for
both the aldehyde and nucleophile while increasing
overall yields (entries 5-7, Table 1). Previous studies
have indicated that indium-promoted couplings become
more acidic as the reaction proceeds.3 This trend was also
seen in the present case and is believed to be the cause
of nucleophilic destruction of the R-chlorooxy species
during reaction under solely aqueous conditions. Admix-
ing DMF into the aqueous solvent or replacement of
water with DMF stabilizes the pH during reaction,
slowing destruction of the nucleophilic species. Entries
8-10 (Table 1) show that greatest consistency is realized
when R-chlorosulfide species are used to form the nu-
cleophilic species in these C-C bond-forming reactions.
The sulfide species studied during this phase of work
gave high yields under a plethora of conditions and ran
more cleanly than when other chlorides were used,
simplifying isolation of products. Although all systems
tested had shown success under the conditions imple-
mented, due to superior yields and easier isolation of
products, it was decided to focus on the sulfur species.10
Ster eoselective Stu d ies w ith R-Ch lor osu lfid es.
The next phase of our study focused on determining
whether the chlorosulfide compounds could form products
exhibiting stereocontrol. Diastereomeric products were
distinguished either by direct determination of vicinal
coupling constants in the hydroxy sulfides where possible
or by conversion to epoxide compounds (Figure 1).11
Table 2 summarizes work completed on stereoselec-
tivity investigations, revealing the overall diastereose-
lective control realized using a variety of R-chlorosulfides
and aldehydes. Entries 1-4 (Table 2), which used hex-
enal as the electrophile, seemed to fare more poorly with
respect to both yield and stereoselectivity. Product ratios
using this aldehyde were approximately 1:1 with isolated
yields in the range of 65-70%. Other systems were more
successful with ratios as high as 88:12 (entry 23, Table
2) seen for syn selectivity and 80:20 (entries 7, 18, and
21, Table 2) for anti selectivity. As noted in Table 2,
reactions run in the absence of InCl3 resulted in pre-
dominant formation of the anti diastereomer, while
Ta ble 1. In itia l Cou p lin g Rea ction s Usin g
r-Ch lor oh eter oa tom ic Rea gen ts10
a
Reactions were run at room temperature for a period of 1-20
h. Ratio of reagents was as follows: 1.0:1.5:1.1 (aldehyde/halide/
Indium). The reaction was run at 0.1 M with respect to the amount
of In. Reactions run in DMF alone as a solvent required premix-
ing of the chloride and indium metal with heating to 50 °C for 1
h for successful completion to occur.
b
emphasis toward the synthesis of epoxyalkyne7-9 func-
tional groups.
Resu lts a n d Discu ssion
Ea r ly Stu d ies. Early studies focused on determining
the feasibility of indium-promoted C-C bond-forming
reactions with R-chloroheteroatomic reagents and in-
volved silyl, thio, and oxy species as summarized in Table
1.10 As shown with entries 1-4 in Table 1, use of silyl
chlorides did not auger well in these studies. This is most
likely due to the lability of silicon under aqueous condi-
tions, destroying the nucleophilic reagent before reaction
occurs. As entries 2 and 4 of Table 1 reveal, switching
(7) (a) Kanger, T.; Piret, J .; Mu¨u¨risepp, A.-M.; Pehk, T.; Lopp, M.
Tetrahedron: Asymmetry 1998, 9, 2499. (b) Bohlmann, F.; Burkhardt,
T.; Zdero, C. Naturally Occurring Acetylenes: Academic Press: New
York, 1973.
(8) (a) For a nice review of this material: Nicolaou, K. C.; Dai, W.-
M. Angew. Chem., Int. Ed. Engl. 1991, 30, 1387. (b) Myers, A. G.;
Dragovich, P. S.; Kuo, E. Y. J . Am. Chem. Soc. 1992, 114, 9369. (c)
Lee, M. D.; Dunne, T. S.; Chang, C. C.; Ellestad, G. A.; Siegel, M. M.;
Morton, G. O.; McGahren, W. J .; Borders, D. B. J . Am. Chem. Soc.
1987, 109, 3466 and references therein.
(9) (a) Ko¨nig, B.; Pitsch, W.; Klein, M.; Vasold, R.; Prall, M.;
Schreiner, P. R. J . Org. Chem. 2001, 66, 1742. (b) Wang, G. X.; Iguchi,
S.; Hirama, M. J . Org. Chem. 2001, 66, 2146. (c) Gebauer, O.; Bru¨ckner,
R. Synthesis 2000, 588. (d) Myers, A. G.; Goldberg, S. D. Angew. Chem.,
Int. Ed. 2000, 39, 2732.
(10) Engstrom, G.; Morelli, M.; Palomo, C.; Mitzel, T. Tetrahedron
Lett. 1999, 40, 5967.
(11) (a) Paquette, L. A.; Mitzel, T. M.; Isaac, M. B.; Crasto, C. F.;
Schomer, W. M. J . Org. Chem. 1997, 62, 4293. (b) Sato, T.; Otera, J .;
Nozaki, H. J . Org. Chem. 1990, 55, 6116. (c) Shimagaki, M.; Maeda,
T.; Matsuzaki, Y.; Hori, I.; Nakata, T.; Oishi, T. Tetrahedron Lett. 1984,
25, 4775.

138 J . Org. Chem., Vol. 67, No. 1, 2002
Mitzel et al.
Ta ble 2. In itia l Ster eoselectivity Stu d ies
Sch em e 3
fashion. Following this scheme along the left-hand route,
we can see that the two R groups will be situated gauche
to each other. Steric hindrance encountered along this
route will raise the energy sufficiently to favor the right-
hand track of a nonchelated pathway. In the absence of
InCl3, it is presumed that this pathway is favored, giving
rise to predominantly anti product formation in our
systems.
When InCl3 is added to the reaction mixture, syn
product formation predominates. It is postulated that,
with the presence of InCl3, a chelated pathway is followed
as shown in Scheme 3. Indium trichloride (InCl3) chelates
to the sulfur and oxygen heteroatoms, giving a five-
membered ring intermediate. The R groups on each of
our two species may approach from either the same side
as shown on the right-hand track of Scheme 3 or from
the opposite sides as shown from the left-hand track of
Scheme 3. Steric hindrance encountered along the right-
hand pathway of this chelated route will raise the overall
energy sufficiently to favor the left-hand track. Following
the left-hand track leads to syn product formation, which
is what is witnessed when InCl3 is added to our reaction
mixtures. In previous work, Whitesides and others have
shown that it is possible to carry out reactions under
aqueous conditions with preformed allymetal reagents,1e-g
lending credence to Schemes 2 and 3. Chan and Li have
proposed a SET reaction on the metal surface,1a-d which
also has good merit and would still not discount a general
scheme such as shown above. While the precise mecha-
nism remains allusive, it has been suggested that it may
be a combination of SET and organometallic species1b and
that alteration of reaction conditions or reagents could
modify the pathway to some extent.
Sch em e 2
Entries 20-23 (Table 2) are interesting for a couple of
reasons. Not only are syn/anti ratios highest for this set
of entries of our study, but the chloride species used in
this system has a propargyl group integrated into its
skeletal structure. It was noted that the propargyl group
of the nucleophile was retained in this reaction (Scheme
4),12 which is interesting as there are few examples of
retention of the alkyne group when propargylic nucleo-
philes with terminal alkynes are used in coupling
reactions.12b,e Often, the final product is an allene or a
mixture of allene and alkyne moieties.12 We detected no
allene and surmise that the σ electron-withdrawing
reactions run in the presence of InCl3 resulted in pre-
dominant formation of the syn isomer. The reaction is
postulated to proceed via two possible pathways, a
nonchelated route (Scheme 2) and a chelated route
(Scheme 3).10
A nonchelated pathway has two possible tracks, as
shown in Scheme 2. In each of the two possible routes,
the heteroatoms will approach each other in an anti

Versatility of R-Chloropropargyl Phenyl Sulfide
J . Org. Chem., Vol. 67, No. 1, 2002 139
Ta ble 3. Cou p lin g Rea ction s Usin g “Tr a d ition a l”
Meth od s
Sch em e 4
capacity of sulfur stablizes the R-position, allowing for
attack to originate from this position in preference over
the γ- site.
Exposure of 12 to trimethyloxonium tetrafluoroborate13
leads to formation of an epoxy alkyne (14) in reasonable
to good yields (eq 1).10
Table 3 presents the results obtained when magnesium,
copper, and lithium intermediates are utilized. With
respect to those reactions in which a Grignard reagent
was formed, R-chloropropargylphenyl sulfide (11) was
added to a THF or DMF solution containing magnesium
metal. This mixture was stirred for a period of 1-3 h
with heating, at which time the aldehyde was added.
Entries 1-3 (Table 3) reveal the necessity of having to
activate the magnesium under Rieke conditions19 for this
reaction to proceed in a satisfactory manner. It was also
necessary to add the aldehyde slowly, over 6-8 h, with
a syringe pump. If the aldehyde was added too quickly,
decomposition of starting materials was noted, with no
discernible amount of product isolation attained. In each
of the procedures where magnesium metal was used to
promote coupling, a mixture of alkyne (12) and allene
(13) was isolated with very little preference observed for
either species. During several trials, CuCl was added to
the Grignard reagent, facilitating formation of a copper
intermediate. Products isolated under these conditions
were similar to those displayed when magnesium metal
was the sole component, although allene (13) to alkyne
(12) ratios were slightly increased. Deprotonation of
propargyl phenyl sulfide en route to epoxy alkyne forma-
tion was also undertaken. Propargyl phenyl sulfide was
dissolved in THF and the solution cooled to 0 °C, at which
time base was added via syringe pump over 3 h. Adding
the base more quickly led to decomposition of the sulfide.
After addition was complete, the solution was warmed
to room temperature and the aldehyde admixed over 6-8
h. Yields obtained following this technique were in the
70-80% range; however, as was evidenced with earlier
Grignard and copper reagent studies, little selectivity
between 12 and 13 was noted.
This interesting result deserved further scrutiny and
induced investigation toward the next phase of this
study.
St er eo- a n d R egioselect ivit y St u d ies w it h P r o-
p a r gyl Su lfid es. Stereoselective formation of epoxy
alkynes (14) has emerged as an area of increasing
interest in recent years due to their unique skeletal
design and use in formation of more complicated struc-
tural systems.14,15 Procedures applied in formation of
epoxy alkynes such as use of m-CPBA16 and oxone17 and
ring closure of halohydrin precursors have been success-
ful, but only a limited number of examples are found in
the literature.18 An indium-based methodology using
propargyl sulfides such as shown in entries 20-23 (Table
2) would offer a nice addition in this area of chemistry.14-18
Our interest was piqued as to whether the alkyne (12)
was retained solely due to effects of sulfur or whether
the metal contributed to this regioselectivity as well. With
this in mind, our first area of focus centered on the ratio
of 12 to 13 formed using traditional methods, which have
historically relied upon lithium, magnesium, or copper
intermediates to ensure successful transformation.1,15
(12) (a) Kwon, J . S.; Pae, A. N.; Choi, K. I.; Koh, H. Y.; Kim, Y. Cho,
Y. S. Tetrahedron Lett. 2001, 42, 1957. (b) Kirihara, M.; Takuwa, T.;
Takizawa, S. Takefumi, M.; Nemoto, H. Tetrahedron 2000, 56, 8275.
(c) Cho, Y. S.; Lee, J . E.; Pae, A. N.; Choi, K. I.; Koh, H. Y. Tetrahedron
Lett. 1999, 40, 1725. (d) Isaac, M. B.; Chan, T.-H. Tetrahedron Lett.
1995, 36, 8957. (e) Wu, S. H.; Huang, B. Z.; Gao, X. Synth. Commun.
1990, 20, 1279. (f) Hanzaza, Y.; Inazawa, K.; Kon, A.; Aoki, H.;
Kobayashi, Y. Tetrahedron Lett. 1987, 28, 659.
(13) (a) Pirkle, W. H.; Rinaldi, P. L. J . Org. Chem. 1978, 43, 3803.
(b) Sato, T.; Otera, J .; Nozaki, H. J . Org. Chem, 1990, 55, 6116.
(14) (a) Kanger, T.; Piret, J .; Mu¨u¨risep, A. M.; Pek, T.; Lopp. M.
Tetrahedron: Asymmetry 1998, 9, 2499. (b) Wu, S. H.; Huang, B. Z.;
Gao, X. Synth. Commun. 1990, 20, 1279. (c) Bohlmann, F.; Burkhardt,
T.; Zdero, C. Naturally Occurring Acetylenes; Academic Press: New
York, 1973.
(15) (a) Bernard, N.; Chemla, F.; Normant, J . F. Tetrahedron Lett.
1998, 39, 6715. (b) Aurrecoechea, J . M.; Alonso, E.; Solay, M.
Tetrahedron 1998, 54, 3833. (c) Piotti, M. E.; Alper, H. J . Org. Chem.
1997, 62, 8484.
(16) Examples: Normant, J . F. Tetrahedron 1991, 47, 1677.
(17) Cao, G.-A.; Wang, Z. X.; Tu, Y.; Shi, Y. Tetrahedron Lett. 1998,
39, 4425 and ref. therein.
The next step in this study was to couple R-chloropro-
pargyl sulfide with various aldehydes using indium metal
as a promoter, allowing a direct comparison of this new
methodology with the more traditional coupling tech-
niques. Results garnered under these conditions are
shown in Table 4.
Not only was excellent regioselectivity observed but
good stereocontrol was also exhibited when coupling
(19) Rieke, R. D.; Bales, S. E.; Hudnall, P. M.; Burns, T. P.;
Poindexter, G. S. Organic Syntheses; Wiley: New York, 1988; Collect.
Vol. VI, p 845.
(18) Chemla, F.; Bernard, N.; Normant, J . F. Tetrahedron Lett. 1999,
40, 75.

140 J . Org. Chem., Vol. 67, No. 1, 2002
Mitzel et al.
Ta ble 5. Con ver sion of Hyd r oxy Su lfid es to Ep oxy
Ta ble 4. In d iu m -P r om oted Cou p lin g Rea ction s Usin g
r-Ch lor op r op a r gyl P h en yl Su lfid ea
Alk yn es
As seen in Table 5, successful formation of the epoxy
alkyne was evidenced with each system. Yields of conver-
sion ranged from 65 to 75% with no loss of syn/anti ratios
with respect to the beginning hydroxy sulfide compound
noted. With entries 3/4, 5/6, and 13/14 of Table 5, some
alkene product was detected. We were unable to isolate
and confirm the structure of this contaminant species;
however, overall conversions were quite successful, of-
fering easy entry into synthetically useful epoxy alkyne
molecules.
In conclusion, indium-promoted coupling of R-chloro-
propargyl phenyl sulfide with aldehyde functional groups
proceeds with superior regioselectivity to historically
traditional metal insertion or base conditions. Indium-
promoted couplings of these systems also proceed with
very good stereoselectivity, allowing easy entry into the
formation of epoxy alkyne compounds, which have both
natural14 and synthetic14,15 importance. Use of indium
metal to promote these reactions offers mild, more
environmentally benign conditions than traditional pro-
moters and has also proven to be more efficient. This
chemistry should open new pathways of study into this
area and in indium-promoted coupling reactions as a
whole. Further studies including the use of these species
to form enediyne and epoxydiyne molecules are currently
in progress.
a
Reactions were run at room temperature for a period of 1-30
h. The ratio of reagents was as follows: 1.0:1.5:1.1 (aldehyde/
halide/indium). The reaction was run at 0.1 M with respect to the
amount of In.
aldehydes with R-chloropropargyl sulfide using indium
metal as the promoter. Again, the two diastereomeric
products were distinguished either by direct determina-
tion of vicinal coupling constants in the hydroxy sulfides
where possible or by conversion to the corresponding
epoxides (Figure 1).11 As noted by entries 2, 6, 18, and
26 (Table 4), superior anti ratios were obtained in solvent
mixtures containing equal amounts of water and DMF.
Once again, addition of InCl3 to our aldehyde and
R-chloroalkyl phenyl sulfide mixtures favored formation
of syn isomers. As was seen with reactions run in the
absence of InCl3, solvent mixtures containing an equal
amount of water and DMF afforded the highest ratios of
syn to anti products when InCl3 was present. Attempts
to run reactions in DMF alone required premixing of the
indium and R-chloro sulfide species with heating to 50
°C for 1 h. After this time, the mixture was cooled and
aldehyde added. Product selectivities under these condi-
tions were not improved, and yields tended to average
under 50%. As a result, this pathway was not scrutinized
further.
Exp er im en ta l Section
Gen er a l Exp er im en ta l P r oced u r es. Tetrahydrofuran
was purified by distillation under an argon atmosphere over
sodium and benzophenone prior to use. Dimethylformamide
and CCl4 were purified by distillation over CaH2 prior to use.
All other solvents were used as purchased. All other reagents
were used as purchased from Aldrich Chemical Co. Selecto
Scientific 63-200 particle size silica gel was used for column
chromatography. Radial chromatography was performed using
a Chromatatron purchased from Harrison Research.
A. Gen er a l Exp er im en ta l P r oced u r e for Cou p lin g
Rea ction s P er for m ed in Wa ter a s a Solven t w ith In d iu m
Meta l a s a P r om oter . A magnetically stirred solution of
aldehyde (1.0 mmol) in 11 mL of deionized water was treated
with R-chloroalkyl phenyl sulfide (1.5 mmol) and indium
Systems listed in Table 4 were converted to epoxy
alkyne moieties by treatment of the hydroxy sulfide with
a solution of trimethyloxonium tetrafluoroborate13a or
TlOEt,13b resulting in formation of the desired epoxy-
alkyne (Table 5).

Versatility of R-Chloropropargyl Phenyl Sulfide
J . Org. Chem., Vol. 67, No. 1, 2002 141
powder (127 mg, 1.10 mmol). The solution was allowed to
proceed at room temperature until no aldehyde was detected
by TLC analysis. Dichloromethane (20 mL) was added, and
stirring was maintained for 30 min. The layers were separated,
and the aqueous phase was extracted with CH2Cl2 (2 × 10 mL).
The combined organic layers were dried and evaporated to
leave a light yellow oil. Purification was accomplished by flash
chromatography on silica gel (elution hexanes-ethyl acetate)
or by radial chromatography where possible. In some cases,
the hydroxy sulfide mixtures were analyzed without further
separation.
Hz), 6.99-7.24 (m, 15H), OH proton was not detected. 13C
NMR (75 MHz, CDCl3) δ: 51.5, 80.1, 125.4, 125.9, 126.1, 126.4
(3), 126.9, 127.3, 127.7 (3), 128.2 (2), 128.4 (2), 128.7 (2), 129.8,
135.2, 142.3. MS m/z: (M+) calcd 332.1235, obsd 332.1229.
Anal. Calcd for C22H20OS: C, 79.48; H, 6.06. Found: C, 79.71;
H, 6.14.
IV. Cou p lin g Rea ction betw een Ben za ld eh yd e (10)
a n d R-Ch lor oeth yl P h en yl Su lfid e (6). The general proce-
dure was followed as described in A. Purification was ac-
complished by radial chromatography on silica gel (elution
100:1 hexanes-ethyl acetate) to give a mixture of hydroxy
sulfides as a colorless oil. Yield ) 205 mg (0.84 mmol) ) 84%.
1H NMR (300 MHz, CDCl3) δ 1.29 (d, 0.75 H, J ) 6.1 Hz),
1.33 (d, 2.25H, J ) 6.1 Hz), 3.10 (m, 1H), 4.69 (d, 0.25H, J )
7.9 Hz), 4.81 (d, 0.75H, J ) 4.1 Hz, 7.00-7.18 (m, 10H), OH
proton was not detected. 13C NMR (75 MHz, CDCl3) δ: (15.0,
16.1), (47.9, 48.5), (81.6, 82.0), 124.3, 125.8, 126.7 (2), 128.1,
128.3, 128.7 (2), 129.0 (2), (135.4, 135.9), (138.9, 140.4); MS
m/z: (M+) calcd 244.0922, obsd 244.0917. Anal. Calcd for
B. Gen er a l Exp er im en ta l P r oced u r e for Cou p lin g
Rea ction s P er for m ed in Wa ter /Dim eth ylfor m a m id e Mix-
tu r es w ith In d iu m Meta l a s a P r om oter . A magnetically
stirred solution of aldehyde (1.0 mmol) in a 50:50 mixture of
deionized water and dimethylformamide (11 mL) was treated
with R-chloroalkyl phenyl sulfide (1.5 mmol) and indium
powder (127 1.1 mmol). The solution was allowed to proceed
at room temperature until no aldehyde was seen (TLC
analysis). Dichloromethane (20 mL) was added, and stirring
was maintained for 30 min. The layers were separated and
the aqueous phase extracted with dichloromethane (2 × 10
mL). The combined organic layers were dried and evaporated
to leave a brown oil that was separated by silica gel (elution
hexanes-ethyl acetate) or by radial chromatography where
possible. In some cases, the hydroxy sulfide mixtures were
analyzed without further separation.
C
15H16OS: C, 73.73; H, 6.60. Found: C, 73.65; H, 6.67.
V. Cou p lin g Rea ction betw een Ben za ld eh yd e (10) a n d
R-Ch lor oben zyl P h en yl Su lfid e (9). The general procedure
was followed as described in A. Separation of diastereomers
was obtained by radial chromatography (elution with 50:1
hexanes-ethyl acetate) to give the hydroxy sulfides as light
yellow oils. Yield ) 425 mg (1.39 mmol) ) 70%.
1
Syn Isom er . H NMR (300 MHz, CDCl3) δ: 4.21 (d, 1H, J
C. Cou p lin g P r oced u r es Used d u r in g In itia l Ster eo-
selectivity Stu d ies. I. Cou p lin g Rea ction betw een 2-Hex-
en a l (1) a n d R-Ch lor oeth yl P h en yl Su lfid e (6). The general
procedure was followed as described in A. Purification was
accomplished by flash chromatography on silica gel (elution
150:1 hexanes-ethyl acetate) to give a mixture of hydroxy
sulfides as a light yellow oil. Yield ) 154 mg (0.65 mmol) )
) 7.7 Hz), 5.09 (d, 1H, J ) 7.7 Hz), 7.01-7.16 (m 15H), OH
proton was not detected. 13C NMR (75 MHz, CDCl3) δ: 54.8,
81.5, 124.4, 125.9, 126.0, 126.2, 126.9, 127.2, 127.4, 127.6 (2),
128.3 (2), 128.6 (3), 128.7, 135.2, 140.8, 141.3. MS m/z: (M+)
calcd 306.1078, obsd 306.1069. Anal. Calcd for C20H18OS: C,
78.39; H, 5.92. Found: C, 78.51; H, 6.01.
1
An ti Isom er . H NMR (300 MHz, CDCl3) δ: 4.37 (d, 1H, J
1
65%. H NMR (300 MHz, CDCl3) δ: 0.94-2.02 (m, 7H), 1.28
) 4.1 Hz), 5.27 (d, 1H, J ) 4.1 Hz), 7.00-7.16 (m, 15H), OH
proton was not detected. 13C NMR (75 MHz, CDCl3) δ: 52.5,
80.6, 125.6, 125.6, 125.9, 126.4 (3), 126.9, 127.3, 127.7 (3), 128.2
(2), 128.4 (2), 128.7 (2), 130.1, 135.2, 143.9. MS m/z: (M+) calcd
332.1235, obsd 332.1248. Anal. Calcd for C20H18OS: C, 78.39;
H, 5.92. Found: C, 78.99; H, 6.10.
(d, 1.8H, J ) 6.0 Hz), 1.32 (d, 1.2H, J ) 6.0 Hz), 2.82 (m, 1H),
4.05 (dd, 0.4H, J ) 7.1, 2.7 Hz), 4.17 (dd, 0.6H, J ) 4.5, 2.7
Hz), 5.41 (m, 1H), 5.69 (m, 1H), 7.03-7.16 (m, 5H), OH proton
was not detected. 13C NMR (75 MHz, CDCl3) δ: (14.1, 14.6),
16.2, 24.0, 33.1, (47.7, 48.1), (81.1, 82.0), 125.0, 126.3 (2), 128.3,
128.4, 128.5, 128.7, 137.1. MS m/z: (M+) calcd 236.1235, obsd
236.1291. Anal. Calcd for C14H20OS: C, 71.14; H, 8.53.
Found: C, 71.17; H, 8.48.
D. Cou p lin g Rea ction s Usin g th e P r op a r gyl P h en yl
Su lfid e Rea gen t. I. Cou p lin g P r oced u r es betw een Ald e-
h yd es a n d R-Ch lor op r op a r gyl P h en yl Su lfid e (11) Usin g
Ma gn esiu m a n d Cop p er In ter m ed ia tes To F or m Hy-
d r oxy Su lfid e Molecu les. A. Cou p lin g of Ben za ld eh yd e
(10) w ith R-Ch lor op r op a r gyl P h en yl Su lfid e (11) Usin g
Ma gn esiu m Meta l u n d er Riek e Con d ition s. The activated
magnesium was prepared by in situ reduction of magnesium
chloride with lithium naphthalenide using a procedure by
Rieke,12a Watanabe,12b and Arnold.12c To a solution of 50 mL
of tetrahydrofuran in a flanged 100 mL three-necked flask
equipped with an argon inlet and a Teflon-coated stirring bar
were added naphthalene (1.232 g, 9.6 mmol) and approxi-
mately 2.0 g of sand. The solution was stirred at a vigorous
rate, and lithium metal (66 mg, 9.6 mmol), which had been
pounded flat under mineral oil and cut into strips, was added
over 2 min. The mixture was stirred until a green color
predominated and lithium metal was no longer detected. After
formation of the lithium naphthalenide was complete, mag-
nesium chloride (450 mg, 4.8 mmol) was added to the solution
all at once. The suspension was stirred for 90 min, at which
time R-chloropropargyl phenyl sulfide (11) (870 mg, 4.8 mmol)
was added. The suspension was stirred for 2.5 h, and benzal-
dehyde (535 mg, 5.0 mmol), dissolved in 10 mL of tetrahydro-
furan, was added to the flask via syringe over 2.5 h. The
solution was stirred for 5 h at which time no 10 was seen (TLC
analysis). The solution was transferred to a 500 mL flask, and
100 mL of dichloromethane along with 100 mL of hydrochloric
acid (3 M solution) were added. Stirring was continued for an
additional 45 min. The layers were separated, and the aqueous
phase was extracted with dichloromethane (2 × 20 mL). The
combined organic layers were washed with a sodium bicarbon-
ate solution (saturated, 2 × 20 mL) and water (2 × 20 mL),
II. Cou p lin g Rea ction betw een p-Ch lor oben za ld eh yd e
(7) a n d R-Ch lor oeth yl P h en yl Su lfid e (6). The general
procedure was followed as described in A. Purification was
accomplished by flash chromatography on silica gel (elution
50:1 hexanes-ethyl acetate) to give a mixture of hydroxy
sulfides as a light yellow oil. Yield ) 440 mg (1.58 mmol) )
79%. 1H NMR (300 MHz, CDCl3) δ: 1.32 (d, 2.4H, J ) 5.8 Hz),
1.36 (d, 0.6H, J ) 5.8 Hz), 3.11 (m, 1H), 4.59 (d, 0.2H, J ) 7.3
Hz), 4.64 (d, 0.8H, J ) 4.7 Hz), 7.02-7.20 (m, 9H), OH proton
was not detected. 13C NMR (75 MHz, CDCl3) δ: (14.4, 14.9),
(48.5, 49.1), 81.7, 124.3, (126.4, 126.6), 126.8, 128.4 (2), 129.0
(2), 129.7, 129.9, (132.4, 132.7). MS m/z: (M+) calcd 278.0532,
obsd 278.0551. Anal. Calcd for C15H15ClOS: C, 64.62; H, 5.42.
Found: C, 64.83; H, 5.65.
III. Cou p lin g Rea ction betw een Cin n a m a ld eh yd e (8)
a n d R-Ch lor oben zyl P h en yl Su lfid e (9). The general
procedure was followed as described in A. Separation of
diastereomers was obtained by radial chromatography (elution
with 100:1 hexanes-ethyl acetate) to give the hydroxy sulfides
as light yellow oils. Yield ) 485 mg (1.46 mmol) ) 73%.
1
Syn Isom er . H NMR (300 MHz, CDCl3) δ: 3.93 (d, 1H, J
) 7.9 Hz), 4.51 (m, 1H), 6.19 (m, 1H), 6.57 (d, 1H, J ) 2.8 Hz),
6.99-7.21 (m, 15H), OH proton was not detected. 13C NMR
(75 MHz, CDCl3) δ: 51.9, 80.1, 125.0, 126.1, 126.2 (2), 126.4
(2), 126.9, 127.3, 127.5, 127.7 (2), 128.2, 128.3, 128.4 (2), 128.7
(2), 133.1, 135.1, 142.3. MS m/z: (M+) calcd 332.1235, obsd
332.1241. Anal. Calcd For C22H20OS: C, 79.48; H, 6.06.
Found: C, 79.21; H, 6.11.
1
An ti Isom er . H NMR (300 MHz, CDCl3) δ: 4.01 (d, 1H, J
) 4.9 Hz), 4.55 (m, 1H0, 6.05 (m, 1H), 6.52 (d, 1H, J ) 2.7

142 J . Org. Chem., Vol. 67, No. 1, 2002
Mitzel et al.
dried, and evaporated to leave a light yellow oil. The products
were analyzed by H NMR with no further purification.
stirring for 40 min. The layers were separated, and the
aqueous layer was extracted with dichloromethane (2 × 20
mL). The combined organic layers were washed with a sodium
bicarbonate solution (saturated, 2 × 20 mL) and water (2 ×
20 mL), dried, and evaporated to leave a light yellow oil. The
1
1
products were analyzed by H NMR with no further purifica-
tion in the manner previously described for 10 in section I. A.
D. Cou p lin g of Ald eh yd es 15 a n d 16 w ith P h en ylp r o-
p a r gyl Su lfid e u n d er Ba sic Con d ition s Usin g Eth ylm a g-
n esiu m Br om id e. Processing and analysis of these reactions
proceeded in the manner described above for 8 under basic
conditions using ethylmagnesium bromide in section II. C.
III. Cou p lin g P r oced u r es Usin g In d iu m In ter m ed ia tes
in Wa ter a s Solven t. A. Cou p lin g of Ben za ld eh yd e (10)
w ith R-Ch lor op r op a r gyl P h en yl Su lfid e (11) Usin g In -
d iu m Meta l in Wa ter . The general procedure was followed
as described in A. Purification was accomplished by flash
chromatography on silica gel (elution with 40:1 hexanes-ethyl
acetate) to give a mixture of hydroxy sulfides as a light yellow
oil.
Mixture ratios, in general, between allene and alkyne
products were determined by comparing the allene proton
shift, which is approximately δ 6.0-6.5 ppm, and the terminal
proton of the alkyne moiety, which occurs between δ 1.7 and
2.6 ppm depending on the nature of R.
B. Cou p lin g of Ben za ld eh yd e (10) w ith R-Ch lor op r o-
p a r gyl P h en yl Su lfid e (11) Usin g a Cop p er In ter m ed ia te.
The same procedure as described for coupling procedures using
magnesium metal were used with the following change:
After formation of the Grignard reagent was complete,
copper(I) chloride (475 mg, 4.8 mmol) was added with stirring
for 60 min. The aldehyde was added in the usual manner, with
workup as described above to leave a light yellow oil. The
1H NMR (300 MHz, CDCl3) δ: 1.77 (d, 1.6 Hz, 0.3H), 1.82
(d, J ) 1.6 Hz, 0.7H), 4.05 (dd, J ) 1.6, 8.1 Hz, 0.3H), 4.12
(dd, J ) 1.6, 5.1, 0.7H), 4.71 (d, J ) 8.1 Hz, 0.3H), 4.82 (d, J
) 5.1 Hz, 0.7H), 7.19-7.02 (m, 10H) OH proton not detected.
13C NMR (75 MHz, CDCl3) δ: (44.9, 50.1), (67.1, 67.5), (77.5,
77.9), (85.5, 86.1), 125.5, 126.6 (2), 127.3, 127.4, 127.5, 128.7
(3), 128.8, 135.6 140.9. MS m/z: (M+) calcd 254.0766, obsd
237.3447 (loss of H2O, parent not observed). Anal. Calcd for
1
products were analyzed by H NMR with no further purifica-
tion in the manner described in section I. A. above.
C. Cou p lin g of Ald eh yd es 8, 15, a n d 16 w ith R-Ch lo-
r opr opar gyl P h en yl Su lfide (11) Usin g Magn esiu m Metal
u n d er Riek e Con d ition s. Processing and analysis of these
reactions proceeded in the manner described above in section
I. A.
C
16H14OS: C, 75.55; H, 5.55. Found: C, 75.89; H, 5.61.
Cou p lin g of Ald eh yd es 8, 15, a n d 16 w ith R-Ch lor o-
p r op a r gyl P h en yl Su lfid e (11) Usin g a Cop p er In ter m e-
d ia te. Processing and analysis of these reactions proceeded
in the manner described above in section I. B.
II. Cou p lin g P r oced u r es for P h en ylp r op a r gyl Su lfid e
u n d er Ba sic Con d ition s. A. Cou p lin g of Cin n a m a ld e-
h yd e (8) w ith P h en ylp r op a r gyl Su lfid e u n d er Ba sic
Con d ition s Usin g n -Bu tyllith iu m . Propargyl phenyl sulfide
(604 mg, 4.0 mmol) was dissolved in 20 mL of tetrahydrofuran
in a flame-dried 100 mL flask under a nitrogen atmosphere.
The solution was cooled to 0 °C, and n-butyllithium (2 mL, 2
M solution) was added via syringe pump over 3 h. The solution
was allowed to warm to room temperature. Cinnamaldehyde
(527 mg, 4.0 mmol), dissolved in 10 mL of tetrahydrofuran,
was added to the flask over 7 h via syring pump. The solution
was stirred for an additional 1.5 h at which time no aldehyde
was detected (TLC analysis). Dichloromethane (20 mL) and
hydrochloric acid (3.0 M solution, 20 mL) were added with
stirring for 40 min. The layers were separated and the aqueous
layer extracted with dichloromethane (2 × 20 mL). The
combined organic layers were washed with a sodium bicarbon-
ate solution (saturated, 2 × 20 mL) and water (2 × 20 mL),
dried, and evaporated to leave a light yellow oil. The products
B. Cou p lin g of Ald eh yd es 1, 8, a n d 15-18 w ith R-Ch lo-
r op r op a r gyl P h en yl Su lfid e (11) Usin g In d iu m Meta l in
Wa ter . Processing and analysis of these reactions proceeded,
for the most part, in the manner described above for 10 in
section III. Any deviations are listed below in the appropriate
areas.
1. An a lysis of P r od u ct Mixtu r e Obta in ed fr om Cou -
p lin g of 1 w ith R-Ch lor op r op a r gyl P h en yl Su lfid e (11).
1H NMR (300 MHz, CDCl3) δ: 1.98-0.99 (m, 7H), 1.87 (d, J
) 1.9 Hz, 0.34H), 1.90 (d, J ) 1.9 Hz, 0.66H), 3.67 (dd, J )
1.9, 7.2 Hz, 0.34H), 3.73 (dd, J ) 1.9, 4.2 Hz, 0.66H), 4.2 (m,
1H), 5.67 (m, 1H), 5.75 (m, 1H), 7.15-7.10 (m, 5H), OH proton
was not detected. 13C NMR (75 MHz, CDCl3) δ: (14.5, 15.1),
23.4, (35.8, 36.1), 42.2, (67.8, 68.1), (85.3, 87.6), (71.7, 72.1),
123.2, 123.3, 125.0, 128.4 (2), 128.8, 129.3, 136.8. MS m/z: (M+)
calcd 246.1078, obsd 246.1061. Anal. Calcd for C15H19OS: C,
73.13; H, 7.36. Found: C, 74.00; H, 7.53.
1
were analyzed by H NMR with no further purification in the
manner previously described for 10 in section I. A.
B. Cou p lin g of Ald eh yd es 15 a n d 16 w ith P h en ylp r o-
p a r gyl Su lfid e u n d er Ba sic Con d ition s Usin g n -Bu tyl-
lith iu m . Processing and analysis of these reactions proceeded
in the manner described above for 8 under basic conditions
using n-butyllithium in section II. A.
2. An a lysis of P r od u ct Mixtu r e Obta in ed fr om Cou -
p lin g of 8 w ith R-Ch lor op r op a r gyl P h en yl Su lfid e (11).
1H NMR (300 MHz, CDCl3) δ: 1.87 (d, J ) 2.1 Hz, 0.4H), 1.95
(d, J ) 2.1 Hz, 0.6H), 3.58 (dd, J ) 2.1, 7.6 Hz, 0.4H), 3.69
(dd, J ) 2.1, 4.7 Hz, 0.6H), 4.2 (m, 1H), 6.25 (m, 1H), 6.62 (d,
J ) Hz, 1H), 7.30-7.08 (m, 10H) OH proton not detected. 13C
NMR (75 MHz, CDCl3) δ: (42.8, 43.1), 65.5, 76.9, (87.1, 87.5),
125.1, 126.2, 126.3, 126.5, 126.7 (2), 127.3, 127.7, 128.6 (3),
128.9, 134.2, 136.0. MS m/z: (M+) calcd 280.0922, obsd
C. Cou p lin g of Cin n a m a ld eh yd e (8) w ith P h en ylp r o-
p a r gyl Su lfid e u n d er Ba sic Con d ition s Usin g Eth ylm a g-
n esiu m Br om id e. Propargyl phenyl sulfide (604 mg, 4.0
mmol) was dissolved in 20 mL of tetrahydrofuran in a flame-
dried 100 mL flask under a nitrogen atmosphere. The solution
was cooled to 0 °C, and ethylmagnesium bromide (2 mL, 2 M
solution) was added via syringe pump over 3 h. The solution
was allowed to warm to room temperature. Cinnamaldehyde
(8) (527 mg, 4.0 mmol), dissolved in 10 mL of tetrahydrofuran,
was added to the flask over 7 h via syring pump. The solution
was stirred for an additional 2.5 h at which time no aldehyde
was detected (TLC analysis). Dichloromethane (20 mL) and
hydrochloric acid (3.0 M solution, 20 mL) were added with
280.0887. Anal. Calcd for
Found: C, 76.99; H, 5.61.
C18H16OS: C, 77.11; H, 5.75.
3. An a lysis of P r od u ct Mixtu r e Obta in ed fr om Cou -
p lin g of 15 w ith R-Ch lor op r op a r gyl P h en yl Su lfid e (11).
Separation proceeded in the same manner as described above;
1
however, separation was not obtained, and the H NMR was
not conclusive. Ratios for this set of diastereomers were
obtained upon transformation of the hydroxy sulfide to the
epoxyalkyne as described in the following section. 1H NMR

Versatility of R-Chloropropargyl Phenyl Sulfide
J . Org. Chem., Vol. 67, No. 1, 2002 143
(300 MHz, CDCl3) δ: 1.44-0.95 (m, 11H), 1.75 (m, 1H), 3.5
(m, 1H), 3.63 (m, 1H), 7.21-7.05 (m, 5H), OH was not detected.
13C NMR (75 MHz, CDCl3) δ (14.1, 14.7), 22.4, 23.3, 32.5, 33.4,
(42.8, 43.4), (65.3, 66.0), (74.0, 74.4), 82.1, 125.3, 125.7 (2),
128.5 (2), (137.1, 137.7). MS m/z: (M+) calcd 248.1235, obsd
2. An a lysis of P r od u ct Mixtu r e Obta in ed fr om Cou -
p lin g of 8 w ith R-Ch lor op r op a r gyl P h en yl Su lfid e (11).
1
Relevant H NMR shifts (δ): 3.58 (dd, J ) 2.1, 7.6 Hz, 0.26H),
3.69 (dd, J ) 2.1, 4.7 Hz, 0.74H).
3. An a lysis of P r od u ct Mixtu r e Obta in ed fr om Cou -
p lin g of 15 w ith R-Ch lor op r op a r gyl P h en yl Su lfid e (11).
Separation proceeded in the same manner as described above;
248.1216. Anal. Calcd. for
Found: C, 72.81; H, 7.91.
C15H20OS: C, 72.53; H, 8.12.
1
4. An a lysis of Isola ted P r od u cts Obta in ed fr om Cou -
p lin g of 16 w ith R-Ch lor op r op a r gyl P h en yl Su lfid e (11).
Separation of diastereomers was obtained by radial chroma-
tography (elution with 50:1 hexanes-ethyl acetate) to give the
hydroxy sulfides as colorless oils.
however, separation was not obtained, and the H NMR was
not conclusive. Ratios for this set of diastereomers were
obtained upon transformation of the hydroxy sulfide to the
epoxyalkyne as described in the following section.
4. An a lysis of Isola ted P r od u cts Obta in ed fr om Cou -
p lin g of 16 w ith R-Ch lor op r op a r gyl P h en yl Su lfid e (11).
Separation of diastereomers was obtained by radial chroma-
tography (elution with 50:1 hexanes-ethyl acetate) to give the
hydroxy sulfides as colorless oils. Relevant 1H NMR shifts
(δ): syn isomer (3.60 (dd, J ) 1.9, 6.9 Hz, 1H)); anti isomer
(3.65 (dd, J ) 1.7, 3.7 Hz, 1H)).
1
Syn Isom er . H NMR (300 MHz, CDCl3) δ: 1.55-1.23 (m,
11H), 1.91 (d, J ) 1.9 Hz, 1H), 3.50 (m, 1H), 3.60 (dd, J ) 1.9,
6.9 Hz, 1H), 7.18-7.02 (m, 5 H), OH proton was not detected.
13C NMR (75 MHz, CDCl3) δ: 24.4, 24.6, 25.3, 25.9, 27.4, 34.0,
41.2, 66.1, 77.3, 84.0, 124.9, 126.6 (2), 128.7, 129.0, 135.8. MS
m/z: (M+) calcd 260.1235, obsd 260.1226. Anal. Calcd for
C16H20OS: C, 73.80; H, 7.74. Found: C, 73.99; H, 7.61.
An ti Isom er . 1H NMR (300 MHz, CDCl3) δ: 1.55-1.23 (m,
11H), 1.96 (d, J ) 1.7 Hz, 1H), 3.50 (m, 1H), 3.65 (dd, J ) 1.7,
3.7 Hz, 1H), 7.18-7.02 (m, 5 H), OH proton was not detected.
13C NMR (75 MHz, CDCl3) δ: 24.3, 24.4, 25.3, 25.5, 27.4, 33.1,
40.6, 66.1, 76.2, 83.0, 124.7, 126.6 (2), 128.8, 129.0, 135.8. MS
m/z: (M+) calcd 260.1235, obsd 260.1244. Anal. Calcd for
5. An a lysis of P r od u ct Mixtu r e Obta in ed fr om Cou -
p lin g of 17 w ith R-Ch lor op r op a r gyl P h en yl Su lfid e (11).
1
Relevant H NMR shifts (δ): 3.95 (dd, J ) 1.7, 8.3 Hz, 0.35H),
4.04 (dd, J ) 1.7, 5.2 Hz, 0.65H).
6. An a lysis of Isola ted P r od u cts Obta in ed fr om Cou -
p lin g of 18 w ith R-Ch lor op r op a r gyl P h en yl Su lfid e (11).
Separation of diastereomers was obtained by radial chroma-
tography (elution with 50:1 hexanes-ethyl acetate) to give the
hydroxy sulfides as colorless oils. Relevant 1H NMR shifts
(δ): syn isomer (3.95 (dd, J ) 1.8, 8.2 Hz, 1.0H)), anti isomer
(4.06 (dd, J ) 1.8, 4.1 Hz, 1.0H)).
V. Cou p lin g P r oced u r es Usin g In d iu m In ter m ed ia tes
a n d In Cl3 in Wa ter . A. Cou p lin g of Ben za ld eh yd e (10)
w ith R-Ch lor op r op a r gyl P h en yl Su lfid e (11) Usin g In -
d iu m Meta l a n d In Cl3 in Wa ter . The general procedure was
followed as described in A with the exception that 1 mmol of
InCl3 was added to the reaction mixture for every 1 mmol of
aldehyde used. Purification was accomplished by flash chro-
matography on silica gel (elution with 40:1 hexanes-ethyl
acetate) to give a mixture of hydroxy sulfides as a light yellow
oil.Relevant 1H NMR shifts (δ): 4.05 (dd, J ) 1.6, 8.1 Hz,
0.78H), 4.12 (dd, J ) 1.6, 5.1 Hz, 0.22H).
C
16H20OS: C, 73.80; H, 7.74. Found: C, 73.41; H, 7.59
4. An a lysis of P r od u ct Mixtu r e Obta in ed fr om Cou -
p lin g of 17 w ith R-Ch lor op r op a r gyl P h en yl Su lfid e (11).
1H NMR (300 MHz, CDCl3) δ: 1.80 (d, J ) 1.8 Hz, 1H), 3.95
(dd, J ) 1.7, 8.3 Hz, 0.33H), 4.04 (dd, J ) 1.7, 5.2 Hz, 0.67H),
4.83 (m, 1H), 7.19-7.04 (m, 7H), 7.21 (m, 2H), OH proton was
not detected. 13C NMR (75 MHz, CDCl3) δ: 44.8, (67.7, 68.1),
77.6, (86.7, 87.0), 124.8, 125.3 (2), 127.7 (3), (127.9, 128.1),
129.1 (2), 123.7, 136.0, 139.1. MS m/z: (M+) calcd 288.0376,
obsd 288.0397. Anal. Calcd for C16H13ClOS: C, 66.54; H, 4.54.
Found: C, 66.50; H, 4.57.
5. An a lysis of Isola ted P r od u cts Obta in ed fr om Cou -
p lin g of 18 w ith R-Ch lor op r op a r gyl P h en yl Su lfid e (11).
Separation of diastereomers was obtained by radial chroma-
tography (elution with 50:1 hexanes-ethyl acetate) to give the
hydroxy sulfides as colorless oils.
Syn Isom er . 1H NMR (300 MHz, CDCl3) δ 1.77 (d, J )
1.8H), 3.95 (dd, J ) 1.8, 8.2 Hz, 1.0H), 4.75 (m, 1H), 6.67 (m,
2H), 7.03 (m, 2H, 7.21-7.06 (m, 5H), OH proton was not
detected. 13C NMR (75 MHz, CDCl3) δ 44.7, 67.7, 77.6, 86.7,
115.7 (2), 124.8, 125.3 (2), 127.7 (3), 127.8, 134.1, 134.9, 156.2.
MS m/z: (M+) calcd 270.0175, obsd 270.1069. Anal. Calcd for
B. Cou p lin g of Ald eh yd es 1, 8, a n d 15-18 w ith R-Ch lo-
r op r op a r gyl P h en yl Su lfid e (11) Usin g In d iu m Meta l in
a
Wa ter /Dim eth ylfor m a m id e Mixtu r e. Processing and
analysis of these reactions proceeded in the manner described
above for 10 in section III.
1. An a lysis of P r od u ct Mixtu r e Obta in ed fr om Cou -
C
16H14O2S: C, 71.08; H, 5.22. Found: C, 71.13; H, 5.26.
p lin g of 1 w ith R-Ch lor op r op a r gyl P h en yl Su lfid e (11).
An ti Isom er . 1H NMR (300 MHz, CDCl3) δ: 1.80 (d, J )
1
Relevant H NMR shifts (δ): 3.67 (dd, J ) 1.9, 7.2 Hz, 0.77H),
1.8, 1H), 4.06 (dd, J ) 1.8, 4.1 Hz, 1.0H), 4.75 (m, 1H), 6.65
(m, 2H), 7.03 (m, 2H, 7.25-7.09 (m, 5H), OH proton was not
detected. 13C NMR (75 MHz, CDCl3) δ: 43.9, 67.4, 77.2, 86.2,
115.1 (2), 125.0, 125.3 (2), 127.4 (3), 127.8, 133.9, 134.5, 155.7.
MS m/z: (M+) calcd 270.0175, obsd 270.1057. Anal. Calcd for
3.73 (dd, J ) 1.9, 4.2 Hz, 0.23H).
2. An a lysis of P r od u ct Mixtu r e Obta in ed fr om Cou -
p lin g of 8 w ith R-Ch lor op r op a r gyl P h en yl Su lfid e (11).
1
Relevant H NMR shifts (δ): 3.58 (dd, J ) 2.1, 7.6 Hz, 0.68H),
3.69 (dd, J ) 2.1, 4.7 Hz, 0.32H).
C
16H14O2S: C, 71.08; H, 5.22. Found: C, 71.01; H, 5.24.
3. An a lysis of P r od u ct Mixtu r e Obta in ed fr om Cou -
p lin g of 15 w ith R-Ch lor op r op a r gyl P h en yl Su lfid e (11).
Separation proceeded in the same manner as described above;
IV. Cou p lin g P r oced u r es Usin g In d iu m In ter m ed ia tes
in a Wa ter /Dim eth ylfor m a m id e Mixtu r e a s Solven t. A.
Cou p lin g of Ben za ld eh yd e (10) w ith R-Ch lor op r op a r gyl
P h en yl Su lfid e (11) Usin g In d iu m Meta l in a Wa ter /
Dim eth ylfor m a m id e Mixtu r e. The general procedure was
followed as described in B. Purification was accomplished by
flash chromatography on silica gel (elution with 40:1 hexanes-
ethyl acetate) to give a mixture of hydroxy sulfides as a light
yellow oil. Analysis was carried out in the manner specified
for section III. A. Relevant 1H NMR shifts (δ): 4.05 (dd, J )
1.6, 8.1 Hz, 0.2H), 4.12 (dd, J ) 1.6, 5.1, 0.8H).
1
however, separation was not obtained, and the H NMR was
not conclusive. Ratios for this set of diastereomers were
obtained upon transformation of the hydroxy sulfide to the
epoxyalkyne as described in the following section.
4. An a lysis of Isola ted P r od u cts Obta in ed fr om Cou -
p lin g of 16 w ith R-Ch lor op r op a r gyl P h en yl Su lfid e (11).
Separation of diastereomers was obtained by radial chroma-
tography (elution with 50:1 hexanes-ethyl acetate) to give the
hydroxy sulfides as colorless oils. Relevant 1H NMR shifts
(δ): syn isomer (3.60 (dd, J ) 1.9, 6.9 Hz, 1H)); anti isomer
(3.65 (dd, J ) 1.7, 3.7 Hz, 1H)).
B. Cou p lin g of Ald eh yd es 1, 8, a n d 15-18 w ith R-Ch lo-
r op r op a r gyl P h en yl Su lfid e (11) Usin g In d iu m Meta l in
a
Wa ter /Dim eth ylfor m a m id e Mixtu r e. Processing and
5. An a lysis of P r od u ct Mixtu r e Obta in ed fr om Cou -
analysis of these reactions proceeded in the manner described
above for 10 in section III.
p lin g of 17 w ith R-Ch lor op r op a r gyl P h en yl Su lfid e (11).
1
Relevant H NMR shifts (δ): 3.95 (dd, J ) 1.7, 8.3 Hz, 0.66H),
1. An a lysis of P r od u ct Mixtu r e Obta in ed fr om Cou -
p lin g of 1 w ith R-Ch lor op r op a r gyl P h en yl Su lfid e (11).
4.04 (dd, J ) 1.7, 5.2 Hz, 0.33H).
1
Relevant H NMR shifts (δ): 3.67 (dd, J ) 1.9, 7.2 Hz, 0.32H),
6. An a lysis of Isola ted P r od u cts Obta in ed fr om Cou -
p lin g of 18 w ith R-Ch lor op r op a r gyl P h en yl Su lfid e (11).
3.73 (dd, J ) 1.9, 4.2 Hz, 0.68H).

144 J . Org. Chem., Vol. 67, No. 1, 2002
Mitzel et al.
Separation of diastereomers was obtained by radial chroma-
tography (elution with 50:1 hexanes-ethyl acetate) to give the
hydroxy sulfides as colorless oils. Relevant 1H NMR shifts
(δ): syn isomer (3.95 (dd, J ) 1.8, 8.2 Hz, 1.0H)); anti isomer
(4.06 (dd, J ) 1.8, 4.1 Hz, 1.0H)).
144.0575, obsd 144.0462. Anal. Calcd for C10H8O: C, 83.31;
H. Found: C, 83.29; H, 5.55.
VI. Cou p lin g P r oced u r es Usin g In d iu m In ter m ed ia tes
a n d In Cl3 in a Wa ter /Dim eth ylfor m a m id e Mixtu r e. A.
Cou p lin g of Ben za ld eh yd e (10) w ith R-Ch lor op r op a r gyl
P h en yl Su lfid e Usin g In d iu m Meta l a n d In Cl3 in
a
Wa ter /Dim eth ylfor m a m id e Mixtu r e. The general proce-
dure was followed as described in B with the exception that 1
mmol of InCl3 was added to the reaction mixture for every 1
mmol of aldehyde used. Purification was accomplished by flash
chromatography on silica gel (elution with 40:1 hexanes-ethyl
acetate) to give a mixture of hydroxy sulfides as a light yellow
oil.
2. F or m a t ion of 20-25 fr om t h e Hyd r oxy Su lfid e
P r ecu r sor . Processing and analysis of these reactions pro-
ceeded in the manner described above for 19 in section VII.
a . An a lysis of P r od u ct Mixtu r e of 2-Eth yn yl-3-styr y-
loxir a n e (20). 1H NMR (300 MHz, CDCl3) δ: 2.35 (d, J ) 1.9
Hz, 0.10H), 2.50 (d, J ) 1.9 Hz, 0.90H), 3.20, (dd, J ) 1.9, 2.3
Hz, 0.10H), 3.61 (dd, J ) 1.9, 4.1 Hz, 0.90H), 6.25 (m, 1H),
6.62 (m, 1H), 7.31-7.10 (m, 5H). 13C NMR (75 MHz, CDCl3)
δ: (47.9, 48.2), (57.5, 58.0), (66.9, 67.3), (87.1, 88.0), (126.5 (2),
127.1 (2)), 127.3, 127.7, 127.8, 128.4 (2), (135.0, 136.1). MS
m/z: (M+) calcd 170.0732, obsd 170.0687. Anal. Calcd for
Processing and analysis of these reactions proceeded in the
1
manner described above for 10 in section III. Relevant H NMR
shifts (δ): 4.05 (dd, J ) 1.6, 8.1 Hz, 0.88H), 4.12 (dd, J ) 1.6,
5.1, 0.12H).
B. Cou p lin g of Ald eh yd es 1, 8, a n d 15-18 w ith R-Ch lo-
r op r op a r gyl P h en yl Su lfid e (12) Usin g In d iu m Meta l in
a
Wa ter /Dim eth ylfor m a m id e Mixtu r e. 1. An a lysis of
P r od u ct Mixtu r e Obta in ed fr om Cou p lin g of 1 w ith
1
C
12H10O: C, 84.68; H, 5.92. Found: C, 84.57; H, 5.96.
R-Ch lor op r op a r gyl P h en yl Su lfid e (11). Relevant H NMR
b. An a lysis of P r od u ct Mixtu r e of 2-Eth yn yl-3-p en t-
shifts (δ): 3.67 (dd, J ) 1.9, 7.2 Hz, 0.76H), 3.73 (dd, J ) 1.9,
1-en yloxir a n e (21). 1H NMR (300 MHz, CDCl3) δ: 1.97-1.00
(m, 7H), 2.43 (m, 1H), 3.2 (m, 1H), 3.45 (dd, J ) 2.0, 2.3 Hz,
0.23H), 3.60 (dd, J ) 2.0, 4.4 Hz, 0.77H), 5.65 (m, 1H, 5.70
(m, 1H). 13C NMR (75 MHz, CDCl3) δ: 14, 23.3, 25.7, 47.9,
(57.7, 5.1), (65.9, 66.8), (84.7, 85.2), (127.8, 128.3), (128.9,
129.6). MS m/z: (M+) calcd 136.0888, obsd 136.0905. Anal.
Calcd for C9H12O: C, 79.37; H, 8.88. Found: C, 79.46; H, 8.91.
c. An a lysis of P r od u ct Mixtu r e of 2-(4-Ch lor op h en yl)-
4.2 Hz, 0.24H).
2. An a lysis of P r od u ct Mixtu r e Obta in ed fr om Cou -
p lin g of 8 w ith R-Ch lor op r op a r gyl P h en yl Su lfid e (11).
1
Relevant H NMR shifts (δ): 3.58 (dd, J ) 2.1, 7.6 Hz, 0.90H),
3.69 (dd, J ) 2.1, 4.7 Hz, 0.10H).
3. An a lysis of P r od u ct Mixtu r e Obta in ed fr om Cou -
p lin g of 15 w ith R-Ch lor op r op a r gyl P h en yl Su lfid e (11).
Separation proceeded in the same manner as described above;
1
1
3-eth yn yloxir a n e (22). H NMR (300 MHz, CDCl3) δ: 2.49
however, separation was not obtained, and the H NMR was
(d, J ) 1.8 Hz, 0.33H), 2.55 (d, J ) 1.9 Hz, 0.66H), 3.73 (dd, J
) 1.8, 2.4 Hz, 0.33H), 3.77 (m, 1H), 4.11 (dd, J ) 1.9, 4.0 Hz,
0.66H), 7.14 (m, 2H), 7.19 (m, 2H). 13C NMR (75 MHz, CDCl3)
δ: (49.9, 50.5), (62.6, 63.4), (66.9, 67.3), (84.9, 85.4), (126.8 (2),
127.1 (2)), (127.5 (2), 128.9 (2)), 133.5, (135.8, 136.2). MS m/z:
(M+) calcd 178.0815, obsd 178.0884. Anal. Calcd for C10H7-
ClO: C, 67.24; H, 3.95. Found: C, 67.19; H, 3.97.
not conclusive. Ratios for this set of diastereomers were
obtained upon transformation of the hydroxy sulfide to the
epoxyalkyne as described in the following section.
4. An a lysis of Isola ted P r od u cts Obta in ed fr om Cou -
p lin g of 16 w ith R-Ch lor op r op a r gyl P h en yl Su lfid e (11).
Separation of diastereomers was obtained by radial chroma-
tography (elution with 50:1 hexanes-ethyl acetate) to give the
hydroxy sulfides as colorless oils. Relevant 1H NMR shifts
(δ): syn isomer (3.60 (dd, J ) 1.9, 6.9 Hz, 1H)); anti isomer
(3.65 (dd, J ) 1.7, 3.7 Hz, 1H)).
d . An a lysis of 2-(4-Hyd r oxyp h en yl)-3-eth yn yloxir a n e
(23). Isomers were separated during the coupling reaction (see
1
section III. B. 6). Syn Isom er . H NMR (300 MHz, CDCl3) δ:
2.51 (d, J ) 1.8 Hz, 1H), 3.75 (d, J ) 4.3 Hz, 1H), 4.15 (dd, J
) 1.8, 4.3 Hz, 1H), 6.64 (m, 2H), 7.0 (m, 2H), OH proton not
detected. 13C NMR (75 MHz, CDCl3) δ 51.0, 62.7, 67.7, 84.1
115.5 (2), 125.7 (2), 130.5, 156.8. MS m/z: (M+) calcd 160.0524,
obsd 160.0491. Anal. Calcd for C10H8O2: C, 74.99; H, 5.03.
Found: C, 75.05; H, 4.99.
5. An a lysis of P r od u ct Mixtu r e Obta in ed fr om Cou -
p lin g of 17 w ith R-Ch lor op r op a r gyl P h en yl Su lfid e (11).
1
Relevant H NMR shifts (δ): 3.95 (dd, J ) 1.7, 8.3 Hz, 0.63H),
4.04 (dd, J ) 1.7, 5.2 Hz, 0.37H).
6. An a lysis of Isola ted P r od u cts Obta in ed fr om Cou -
p lin g of 18 w ith R-Ch lor op r op a r gyl P h en yl Su lfid e (11).
Separation of diastereomers was obtained by radial chroma-
tography (elution with 50:1 hexanes-ethyl acetate) to give the
hydroxy sulfides as colorless oils. Relevant 1H NMR shifts
(δ): syn isomer (3.95 (dd, J ) 1.8, 8.2 Hz, 1.0H)); anti isomer
(4.06 (dd, J ) 1.8, 4.1 Hz, 1.0H)).
An ti Isom er . 1H NMR (300 MHz, CDCl3) δ: 2.50 (d J )
1.8 Hz, 1H), 3.71 (d, J ) 2.0 Hz, 1H), 3.81 (dd, J ) 1.8, 2.0 Hz,
1H), 6.62 (m, 2H), 7.3 (m, 2H), OH proton not detected. 13C
NMR (75 MHz, CDCl3) δ: 51.9, 63.4, 68.1, 84.9, 116.0 (2), 126.8
(2), 130.1, 157.0. MS m/z: (M+) calcd 160.0524, obsd 160.0613.
Anal. Calcd for C10H8O2: C, 74.99; H, 5.03. Found: C, 74.89;
H, 5.01.
VII. F or m a tion of Ep oxy Alk yn e Com p ou n d s fr om
Hyd r oxy Su lfid es. A. Use of Tr im eth yloxon iu m Tet-
r a flu or obor a te. 1. F or m a tion of 2-Eth yn yl-3-p h en ylox-
ir a n e (19) fr om th e Hyd r oxy Su lfid e P r ecu r sor . A solution
of the hydroxy sulfide mixture (100 mg 0.394 mmol) in
dichloromethane (8 mL) was treated with trimethyloxonium
tetrafluoroborate (66 mg (0.435 mmol). The solution was
stirred at room temperature for 8 h and diluted with 7%
sodium hydroxide solution (aqueous, 5 mL). After 20 min of
stirring, the separated organic layer was dried and concen-
trated. Purification was accomplished by radial chromatogra-
phy on silica gel (elution with 80:1 hexanes-ethyl acetate) to
give a mixture of diastereomers as a colorless oil in an 8.8:1.2
e. An a lysis of 2-Cycloh exyl-3-eth yn yloxir a n e (24). Iso-
mers were separated during the coupling reaction (see section
1
III, B. 2). Syn Isom er . H NMR (300 MHz, CDCl3) δ: 1.79-
1.24 (m, 11H), 2.39 (d, J ) 1.6 Hz, 1H), 2.5 (m, 1H), 3.59, (dd,
J ) 1.6, 4.4 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ: 24.5, 24.6,
26.8, 27.0, 27.4, 29.8, 45.5, 60.4, 66.0, 81.5. MS m/z: (M+) calcd
150.1045, obsd 150.1091. Anal. Calcd For C10H14O: C, 79.96;
H, 9.39. Found: C, 79.90; H, 9.31.
An ti Isom er . 1H NMR (300 MHz, CDCl3) δ: 1.70-1.24 (m,
11H), 2.43 (d, j ) 1.6 Hz, 1H), 2.5 (m, 1H), 3.35 (dd, J ) 1.6,
2.0 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ: 24.5, 24.6, 26.7,
27.0, 27.5, 29.8, 46.0, 61.3, 65.9, 82.8. MS m/z: (M+) calcd
150.1045, obsd 150.1103. Anal. Calcd for C10H14O: C, 79.96;
H, 9.39. Found: C, 79.89; H, 9.32.
1
ratio. H NMR (300 MHz, CDCl3) δ: 2.45 (d, J ) 1.8 Hz, 1H),
3.57 (dd, J ) 1.8, 2.5 Hz, 0.12H), 3.71 (d, J ) 2.5 Hz 0.12H),
3.99 (dd, J ) 1.8, 4.6 Hz, 0.88H), 4.15 (d, J ) 4.6 Hz, 0.88H),
7.21-7.19 (m, 5H). 13C NMR (75 MHz, CDCl3) δ: (50.1, 50.3),
(62.1, 62.5), (66.3, 66.7), (87.1, 87.5), (125.4 (2), 126.1 (2)),
128.2, 128.4, (128.9, 131.2), 137.5. MS m/z: (M+) calcd
f. An a lysis of P r od u ct Mixtu r e of 2-Eth yn yl-3-p en ty-
1
loxir a n e (25). H NMR (300 MHz, CDCl3) δ: 1.42-0.91 (m,
11H), 2.45 (m, 2H), 3.45 (dd,J ) 1.6, 2.1 Hz, 0.47H), 3.64 (dd,

Versatility of R-Chloropropargyl Phenyl Sulfide
J . Org. Chem., Vol. 67, No. 1, 2002 145
J ) 1.6, 4.4 Hz, 0.53H). 13C NMR (75 MHz, CDCl3) δ 14.1,
23.1, 25.1, 30.0, 32.5, (47.0, 47.5), (54.6, 54.9), (65.9, 66.7),
(85.7, 86.2). MS m/z: (M+) calcd 138.1045 obsd 138.0997. Anal.
Calcd for C9H14O: C, 78.21; H, 10.21. Found: C, 78.29; H,
10.27.
with a saturated NaHCO3 solution (aqueous) and a saturated
NaCl solution (aqueous). The organic layer was then dried and
concentrated. Purification and analysis of products proceeded
in the manner previously described (see section VII, A).
A. Use of TlOEt. 1. F or m a tion of 19 fr om th e Hyd r oxy
Su lfid e P r ecu r sor . A solution of the hydroxy sulfide mixture
(100 mg 0.394 mmol) in chloroform (8 mL) was treated with
TlOEt (130 mg, 0.516 mmol). The solution was stirred at room
temperature for 10 h and diluted with ether. After 20 min of
stirring, the insolubles were removed by filtration through a
short Celite pad. The resulting organic solution was washed
Ack n ow led gm en t. Financial support received from
a Pfizer Undergraduate Research Award Grant and by
the Trinity College Internal Grant Foundation is greatly
acknowledged.
J O015992L