Gold(I)-promoted heterocyclization of internal alkynes: A comparative study of direct metallate 5-endo-dig cyclization versus a stepwise cyclization

Article abstract of DOI:10.1021/jo500748e

With cationic gold catalysts, internal alkynes bearing both propargylic acyloxy groups and tosylamide pronucleophiles were found to cyclize to give either five- or six-membered ring nitrogen heterocycles. A wide variety of gold catalysts, counterions, and solvents were examined to elucidate their effect on product distribution. In most cases, the direct 5-endo-dig cyclization was found to be the major pathway leading to good yields of dehydropyrrolidine products. Alkyne substrates bearing additional normal alkyl substituents at the propargylic position gave dehydropiperidines as the major product. This pathway is thought to proceed by way of a 1,2- Rautenstrauch rearrangement to produce a vinyl gold(I) carbene, which undergoes conjugate addition by the nitrogen pronucleophile. Structural and electronic factors were studied in the nitrogen pronucleophile and in the migrating acyloxy group. Each was found to have a minor effect on the product ratio.

Full text of DOI:10.1021/jo500748e

Article
pubs.acs.org/joc
Gold(I)-Promoted Heterocyclization of Internal Alkynes: A
Comparative Study of Direct Metallate 5‑endo-dig Cyclization versus
a Stepwise Cyclization
Jonathan M. French and Steven T. Diver*
Department of Chemistry, University at Buffalo, the State University of New York, Buffalo, New York 14260, United States
S
* Supporting Information
ABSTRACT: With cationic gold catalysts, internal alkynes
bearing both propargylic acyloxy groups and tosylamide
pronucleophiles were found to cyclize to give either five- or
six-membered ring nitrogen heterocycles. A wide variety of
gold catalysts, counterions, and solvents were examined to
elucidate their effect on product distribution. In most cases,
the direct 5-endo-dig cyclization was found to be the major
pathway leading to good yields of dehydropyrrolidine
products. Alkyne substrates bearing additional normal alkyl substituents at the propargylic position gave dehydropiperidines
as the major product. This pathway is thought to proceed by way of a 1,2- Rautenstrauch rearrangement to produce a vinyl
gold(I) carbene, which undergoes conjugate addition by the nitrogen pronucleophile. Structural and electronic factors were
studied in the nitrogen pronucleophile and in the migrating acyloxy group. Each was found to have a minor effect on the product
ratio.
In this manuscript, we describe our efforts to expand the scope
of this reaction via a gold(I) carbene intermediate B, which
provides an alternative entry into this ring system (Scheme 1b).
A systematic study of reaction conditions and structural effects
provides a better understanding of the interplay between these
two mechanistically distinct cyclization pathways, leading to
either dehydropyrrolidines or dehydropiperidines.
INTRODUCTION
■
Nitrogen-containing heterocycles are commonly found in
natural products and pharmaceutically relevant compounds;
as such, methods for their synthesis continue to be of significant
interest. Previously our group developed a method for the
generation of dehydropiperidines through a tandem enyne
metathesis/Brønsted acid-promoted 1,4-hydroamination reac-
tion sequence (Scheme 1a).1 This cyclization proved highly
effective, giving high yields of substituted dehydropiperidines.
However, a limitation of this methodology is the presence of a
methyl group at the 4-position on the resulting dehydropiper-
idine’s ring, arising from protonation of the methylene moiety.
In an effort to make six-membered heterocycles that were not
limited to those possessing a methyl group at the 4-position, we
sought late transition metals, which are known to activate
alkynes toward heterocyclization.2 Alkynophilic metal catalysts
such as Pt(II) and Au(I) are by now well-known promoters of
the Rautenstrauch rearrangement (1,2-acyloxy shift)3 of
propargylic acetates, which produces vinyl-substituted metal
carbene intermediates such as B (path a, Scheme 1b).4
However, most of the information on the 1,2-acyloxy
rearrangement of propargylic acetates is restricted to terminal
alkynes. In terminal alkynes, the success of the rearrangement is
determined by the steric and electronic nature of the terminal
alkyne substrate.4a Activation of internal alkynes by π-
electrophiles is more difficult because of the added steric effect
imposed by the other alkyne substituent, and is less studied. We
were interested in bifunctional substrates such as A where
either process could occur. How effectively would 5-endo-dig
cyclization occur to make the 5-membered dehydropyrrolidine
ring (path b, Scheme 1b)? Could the mechanistically distinct
Rautenstrauch rearrangement compete with the direct cycliza-
tion in an internal alkyne where binding is presumed to be
Scheme 1. Previous Approach and Two Mechanistically
Distinct Heterocyclizations
Received: April 1, 2014
© XXXX American Chemical Society
A
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Scheme 2. Synthesis of the Key Substrate for Initial Optimization Studies
Table 1. Catalyst Optimization
entry
catalyst
solvent
temp (°C)
time (h)
conversion (%)
product (3:4:5)
a
1
PtCI2
PhCH3
CH2CI2
MeCN
MeCN
CH2CI2
THF
reflux
12
12
16
16
12
16
16
4
75
75:00:00
00:00:54
00:00:05
00:44:49
00:82:18
00:19:81
00:26:74
00:12:88
00:20:80
00:22:78
00:03:97
00:05:95
00:05:95
−
2
AuCI3
reflux
54
3
(PPh3)AuOTf
(PPh3)AuOTf
(PPh3)AuOTf
(PPh3)AuOTf
(PPh3)AuSbF6
(PPh3)AuSbF6
(PPh3)AuSbF6
(IPr)AuOTf
(IPr)AuSbF6
(IPr)AuSbF6
(IPr)AuSbF6
(PPh3)AuCI
rt
5
4
reflux
rt
93
5
100
100
100
100
100
100
100
100
100
0
6
rt
7
THF
rt
8
PhCH3
CH2CI2
THF
rt
9
rt
12
12
12
4
10
11
12
13
14
15
16
rt
THF
reflux
rt
THF
CH2CI2
THF
rt
4
rt
16
16
4
a
AgSbF6
THF
rt
100
11
00:00:100
b
AgSbF6
THF
rt
00:00:11
a
b
10 mol % catalyst loading. 5 mol % catalyst loading.
weaker? Since there was no clear direction from the literature,
we designed internal alkyne A to contain two different pendant
nucleophiles, a propargylic acetate and a homopropargylic
sulfonamide. In terms of the Rautenstrauch pathway, alkyne A
would undergo a 1,2-acetate migration leading to vinyl carbene
B, which could then undergo cyclization. This pathway would
lead to the six-membered ring heterocycle, the dehydropiper-
idine. Alternatively, direct 5-endo-dig cyclization would lead to
the 5-membered dehydropyrrolidine. Each of these cyclo-
isomerizations would proceed with atom economy making
them efficient methods for heterocycle synthesis. Thus, we
expected that this bifunctional internal alkyne substrate would
potentially react through two different pathways, providing two
nitrogen heterocycles of different size. We were interested in
identifying reaction conditions so that either pathway would
predominate, delivering either the 5- or 6-membered
heterocyclic ring.
alcohol could then be taken directly into CH2Cl2 whereupon it
was acylated with acetyl chloride in the presence of triethyl-
amine. The bifunctional alkyne 2 was then purified by flash
column chromatography. Additional homopropargylic alkynes
were prepared similarly, and their preparation and character-
ization data can be found in the Experimental Section.
With the desired bifunctional substrate in hand, initial
cyclization attempts led us to consider using lower temper-
atures and cationic gold(I) catalysts. Initial results with PtCl2
resulted in formation of the pyrrole 3 (Table 1, entry 1). The
high temperature needed to dissolve the PtCl2 catalyst was also
thought to facilitate the loss of the acetate, ultimately leading to
formation of the pyrrole.6 Since most cationic gold reactions
are conducted at room temperature, a gold-based catalyst
system was sought because of the milder reaction conditions
possible. Lower temperatures were expected to result in less
pyrrole formation. Gold(III) chloride was initially screened and
found to deliver the dehydropyrrolidine. With this neutral
catalyst, the reaction did not go to completion within a 12 h
period (Table 1, entry 2). However, the major product of this
reaction was not the expected 6-membered dehydropiperidine,
but found to be the dehydropyrrolidine 5. This product is
derived from direct 5-endo-dig cyclization of the gold activated
alkyne, and there are few reports of dehydropyrrolidine
synthesis in the literature.7
RESULTS AND DISCUSSION
■
The required bifunctional internal alkyne was made through a
four-step synthesis (Scheme 2). The Barbier reaction was used
to introduce propargyl bromide into the imine5 resulting in
formation of the homopropargylic amine.1 The alkyne was
subsequently functionalized in a three step sequence. Treat-
ment of the alkyne with 2 equiv of n-butyl lithium resulted in
formation of the dianion. This deprotonation step was followed
by the introduction of the aldehyde, which resulted in the
formation of the propargyl alcohol upon work-up. The crude
The need for lower reaction temperatures led us to evaluate
gold(I) catalyst systems. The cationic gold(I) catalysts were
generated in standard fashion: prior to the reaction the gold
B
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c
Table 2. Gold(I)-Catalyzed Synthesis of Dehydropyrrolidines from Propargylic Acetates
a
b
This reaction was conducted at 1 mol % catalyst loading for 8 h. Percent of the product by 1H NMR relative to mesitylene, isolated in 67 and 29%
c
yield. Isolated yields after column chromatography.
chloride was mixed with the silver salt of choice, which resulted
in the precipitation of silver chloride. On the basis of the careful
study of Shi et al.,8 the resulting suspension was then filtered
through a plug of Celite and added directly into the reaction
vessel, eliminating potential side reactions that could be
promoted by the cationic silver(I) cocatalyst. Gold(I) triflate
in acetonitrile resulted in very poor conversions at room
temperature, perhaps because of the ability of acetonitrile to act
as a ligand for cationic gold (Table 1, entry 3). Increasing the
temperature of the reaction improved the conversion, yet
produced the allene as the major product (entry 4). Moving to
dichloromethane solvent resulted in full conversion (entry 5),
but allene 4 became the major product. The allene can be
formed either by two successive 1,2-acetate migrations4a or a
direct 3,3-acetate migration.4f,9 Switching the solvent to THF
still allowed full conversion, however there was a dramatic shift
in the selectivity of the reaction (entry 6). Under these
conditions, using THF as the reaction solvent resulted in the
favored formation of the dehydropyrrolidine (entry 6). The
counterion was also found to have a significant effect on the
reaction. The SbF6 counteranion resulted in a similar product
distribution that favored the formation of the dehydropyrro-
lidine (entry 7). Two other solvents were screened (entry 8 and
9); however, no significant solvent effect was found in these
cases.
Gold catalysts bearing a N-heterocyclic carbene (NHC)
supported ligand also showed significant counterion and
solvent effects. A combination of the 1,3-bis(2,6-
diisopropylphenyl)imidazol-2-ylidene N-heterocyclic carbene
(IPr) ligand with the triflate counterion delivered a similar
product distribution as was observed with the [Au(PPh3)]+
catalyst (Table 1, entry 10). Replacing the triflate anion with
the SbF6 anion resulted in complete conversion and high
selectivity for 5 within a 12 h reaction time (entry 11). As seen
in entry 12, this selectivity could be maintained even after
decreasing the temperature and the time of the reaction, and
demonstrated little solvent effect upon moving to dichloro-
methane (entry 13).
Several control experiments were done to assign the relative
contribution of Au(I) and Ag(I) in the heterocyclizations. First,
were neutral gold(I) catalysts effective? As a control experi-
ment, the gold source was screened without addition of the
silver salt, and as expected for an internal alkyne, no reactivity
was observed (Table 1, entry 14). Even though precautions
were taken to eliminate the presence of silver in the reaction,8
another control experiment was performed to evaluate the
innate reactivity of the silver salt. Silver(I) is a powerful π-acid
C
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Table 3. Effect of Reaction Conditions on 5- vs 6-Membered Ring Formation
entry
catalyst
solvent
product (20:21:22)
1
2
3
4
5
6
7
8
(PPh3)AuOTf
(PPh3)AuOTf
(PPh3)AuSbF6
(PPh3)AuSbF6
(IPr)AuOTf
(IPr)AuOTf
(IPr)AuSbF6
(IPr)AuSbF6
CH2CI2
THF
58:42:00
57:35:08
48:52:00
32:68:00
33:30:37
62:32:06
47:43:10
40:46:14
CH2CI2
THF
CH2CI2
THF
CH2CI2
THF
in its own right, and known to promote heterocyclizations and
cycloisomerizations.10 There are several examples of gold-
catalyzed reactions that suffer from a lower conversion or fail all
together without the presence of silver.11 Surprisingly, full
conversion was observed within 16 h with 10 mol % of Ag(I)
catalyst (entry 15). Under the gold-catalyzed conditions, the
reaction was complete in less than 4 h, yet the same conditions
under silver catalysis only resulted in 11% conversion (entry
16). The Ag(I) catalyst gave exclusive cyclization to the
dihydropyrrole 5 without any allene detected. This contrast
clearly demonstrates that cationic gold catalyst is the more
effective catalyst for heterocyclization leading to the dehy-
dropyrrolidine.
On the basis of the optimization studies, IPrAuSbF6 was
chosen as the ideal catalyst system as it provided high selectivity
and high turnover during the course of the reaction. Similar
product distributions were observed in both CH2Cl2 and THF.
THF was selected for the additional substrates as it is a more
environmentally friendly choice than dichloromethane, despite
the fact that under experimental conditions some solvent
polymerization was occasionally observed.12
shift of the proton next to the acetate. With dehydropyrrolidine
17, the chemical shift of this methine proton is affected by the
electron-withdrawing nature of the acetate, appearing downfield
at δ 6.09 ppm. In the dehydropiperidine 18, this proton is now
alpha to the nitrogen of the sulfonamide, and more shielded
than in the starting material. As a result of these changes, this
proton appears upfield at δ 4.52 ppm. The same dramatic
electron-withdrawing effect is observed in the carbon spectrum
as well. In the dehydropyrrolidine 17, the carbon bonded to the
acetate oxygen is downfield at δ 71.2 ppm, whereas the same
carbon of dehydropiperidine 18 is upfield at δ 52.8 ppm. The
new six-membered ring product most likely resulted from a 1,2-
acetate migration preceding cyclization onto the vinyl carbene
intermediate (above, Scheme 1b). On the basis of previous
results during optimization studies with unsubstituted prop-
argylic acetates under Ag(I) conditions (Table 1, entry 15), we
attempted a selective silver-catalyzed 5-endo dig cyclization with
substituted propargylic acetate 16. However, these same
conditions with catalytic AgSbF6 (5 mol %) were found
ineffective with 16 presumably because of the bulk imposed by
the additional propargylic substituent.
Several propargylic acetates were evaluated under the
optimized reaction conditions (Table 2). Simple propargylic
acetate (entry 1) resulted in clean formation of the
corresponding dehydropyrrolidine, which was isolated in 75%
yield. Substituents adjacent to the pendant nucleophile were
also well tolerated in the reaction without any observed drop in
yield (entry 2 and 3). The reaction also proceeded in high yield
for propargylic benzoates, and the catalyst loading could be
dropped to 1 mol % without diminishing the yield (entries 4
and 5). The product in entry 4 provided suitable crystals for an
X-ray diffraction study, and the solid state structure
determination confirmed our structural assignment based on
NMR data (Figure S1, Supporting Information). Additional
benzoates performed well in the cyclization giving excellent
chemical yields of dehydropyrrolidines (entries 6 and 7).
Additional substitution on the acyloxy bearing propargylic
carbon resulted in formation of a six-membered ring hetero-
cycle. After analyzing the propensity of 5-endo-dig cyclization
with substrates containing a variety of acetate and benzoate
protecting groups, substrates with propargylic substitution were
explored. The initial substrate 16 resulted in a mixture of
products (Table 2, entry 8), which proved separable by column
chromatography. The major product could be assigned as the
dehydropyrrolidine by analogy to the previous entries in Table
2. The second product was new. The distinguishing feature of
the new product, as observed by proton NMR, was a dramatic
To better study the interplay of the two cyclization pathways,
a simpler substrate was studied in greater detail. Internal alkyne
19 also afforded a mixture and 5- and 6-membered heterocycles
as the major products (entry 1, Table 3). For this
reoptimization study, we continued to take precautions to
ensure that silver was not present in the reaction.8 Introduction
of the triflate anion into the system resulted in the generation
of a significant amount of pyrrole side product (entries 2 and
5). Regardless of solvent choice or gold source (entries 1, 2, 5
and 6), the triflate counterion did not favor the formation of
the 6-membered heterocycle 21 (entry 2). Formation of the
pyrrole side product was also significant when using the IPr-
gold catalyst (entries 5−8). In each of these cases, the solvent
was found to have a minor effect on product distribution. The
(Ph3P)AuSbF6 catalyst provided the highest selectivity for 21
(entries 3 and 4), with THF providing the highest ratio in favor
of the 6-membered ring (entry 4). Further changes in the
solvent, gold catalyst or the counterion did not exceed the
maximum 2:1 product selectivity observed in entry 4. As a
result, other factors that might influence product selectivity
were subsequently explored.
In an effort to further change the observed product
distribution, a variety of acetate and benzoates were
investigated (Table 4). A more sterically hindered pivalate
group was found to give an almost 1:1 mixture of heterocycles
(entry 2). To the best of our knowledge, the effect of electronic
D
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group is already rather electron-deficient; however, further
electronic deactivation of this nucleophile might retard 5-endo-
dig cyclization. The (p-trifluoromethylbenzene)sulfonamide
gave a slight increase in formation of the dehydropiperidine
(entry 2). The (p-nitrobenzene)sulfonamide further favored the
formation of the dehydropiperidine (entry 3), but was not able
to completely shut down the 5-endo-dig cyclization pathway.
Electronic effects in the nitrogen protecting group have a minor
influence on product distribution.
Table 4. Effect of the Migrating Group on Product
Distribution
Propargylic substitution affects heterocycle product distribu-
tion. Prior to cyclization, the cationic gold coordinates to the
internal alkyne. Substitution at the propargylic position could
sterically and electronically influence binding by the gold
catalyst, altering selectivity. Alkyne 38 (Table 6, entry 1) was a
1:1 mixture of diastereomers prior to the reaction, after
cyclization both products 39 and 40 could be isolated as 1:1
mixture of diastereomers. Substitution adjacent to the nitrogen
nucleophile had modest effect on the product ratio (Table 6,
entries 1 and 2). However, substitution at the propargylic
position affected product distribution. The isopropyl sub-
stituent gave an erosion in the selectivity of the formation of
the 6-membered heterocycle (entry 3), and t-butyl substitution
(entry 4) resulted in only the dehydropyrrolidine 45. Placing a
phenyl substituent at the propargylic position resulted in
product decomposition, and nothing could be isolated from this
reaction (entry 5). Groups such as phenyl are highly stabilizing
to an incipient carbocation; decomposition is assumed to
proceed through this solvolytic pathway. It was discovered that
steric factors could be used to eliminate one reaction pathway;
however, none of the changes further increased the selective
formation of 6-membered heterocycle.
Fortunately in all but two cases, the product mixtures were
separable by chromatography. The benzoate and the p-
bromobenzoate-containing heterocycles 26 and 27 (Table 4,
entries 3 and 4) were inseparable mixtures. However,
saponification of the mixture with aqueous sodium hydroxide
in methanol gave products that were separable, permitting
isolation and characterization.14 The dehydropyrrolidine
benzoate gave rise to secondary alcohol 47, and the
dehydropiperidine gave rise to ketone 48. Because of the
significant polarity difference of the saponification products,
they were readily separable.
a
1
Ratio established by H NMR relative to mesitylene
variation of the migrating group in a 1,2-acetate migration has
not been systematically studied under these conditions.13 We
thought that the propensity of 1,2-acyloxy group migration
might be increased with more electron-rich acyloxy groups.
Conversely, rearrangement of less electron-rich acyloxy groups
would be less favorable and increase the likelihood of the direct
5-endo-dig cyclization. The electronically neutral benzoate, as
well as the electron-deficient p-nitrobenzoate, were both found
to favor the dehydropyrrolidine (entries 3 and 5). The product
mixture obtained in entry 3 proved inseparable. In entry 5, the
only product that could be isolated was the dehydropyrrolidine
29. The p-bromobenzoate 27 demonstrated a slight preference
for the dehydropyrrolidine as well, and the product mixture in
this case also proved inseparable (entry 4). Finally the p-
methoxybenzoate 30, which was expected to be the most
electron-rich benzoate, provided selectivity similar to that
observed with acetate (entry 6 vs entry 1). Similar to entry 5,
only the major product, in this case the dehydropiperidine, was
only isolated from entry 6. Overall, the electronic nature of the
acyloxy group could not be sufficiently enhanced in internal
alkyne substrates to override the direct metalate 5-endo-dig
cyclization pathway.
The saponification both helped corroborate the previously
established structural assignments for both products and
verified the ratios for the mixtures, which were determined by
1H NMR spectroscopy. Upon hydrolysis, there is a dramatic
effect on the chemical shift of the adjacent methine proton in
the dehydropyrrolidine (Scheme 3). In the benzoate, this
methine proton was found just over δ 6.0 ppm. Removal of the
The nucleophilicity of the pendant nitrogen nucleophile was
found to have little effect on the ratio of heterocycles. For this
study, we returned to dichloromethane as the solvent since an
almost 1:1 distribution of products is obtained (Table 5, entry
1) and perturbations would be easily detected. The sulfonamide
Table 5. Evaluation of a Variety of Sulfonamides on Product Distribution
a
entry
alkyne
R
conversion (%)
product
ratio (E:F)
1
2
3
19
32
35
CH3
CF3
100
100
100
20/21
33/34
36/37
48:52
44:56
38:62
NO2
a
1
Ratio established by H NMR relative to mesitylene
E
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Table 6. Influence of Propargylic Substitution on the Reaction
a
entry
alkyne
R
product
ratio (G:H)
1
2
3
4
5
38
19
41
44
46
R1 = CH3, R2 = Ph
R1 = CH3, R2 = H
R1 = i-Pr, R2 = H
R1 = t-Bu, R2 = H
R1 = Ph, R2 = Ph
39/40
20/21
42/43
45
34:66
32:68
43:57
100:0
decomp
a
1
Ratio established by H NMR relative to mesitylene
Scheme 3. Benzoate Hydrolysis
methane, THF) and stored under nitrogen. Commercially available
reagents were used without further purification, unless otherwise
noted. Gold catalysts and silver cocatalysts were stored in a nitrogen-
filled glovebox and transferred out of the box in one dram vials. Flash
column chromatography was carried out on untreated silica gel 60
(230−400 mesh) under air pressure. Thin layer chromatography was
performed on glass-backed silica plates (F254, 250 μm thickness),
visualized with UV light or stained with KMnO4 stain. 1H NMR
spectra were recorded at 500 MHz, and 13C NMR spectra were
recorded at 75 MHz. FT-IR spectra were recorded as thin films and
reported in wavenumbers.
Preparation of Alkyne Starting Materials. General Procedure
for the Synthesis of Homopropargylic Amines. This procedure was
adapted from a literature report.15 To a dry 500 mL round-bottom
flask was added imine (120.0 mmol, 1 equiv) and 120 mL of THF (1.0
M). To this solution was added activated zinc16 (9.42 g, 144.0 mmol),
and the solution was allowed to stir at room temperature. To this
solution was introduced, slowly via syringe, propargyl bromide (17.5
mL, 180.0 mmol) so as to not allow temperature to go over 25 °C.
After stirring for 30 min the reaction was judged complete by TLC and
quenched with NH4Cl (sat.) and extracted with 3 × 100 mL portions
of dichloromethane. The organic layers were collected, combined and
washed with brine, dried over MgSO4, and concentrated in vacuo. The
crude yellow solid was recrystallized from absolute ethanol, resulting in
pure alkynyl amine as a white solid.
General Procedure for the Synthesis of Propargyl Alcohols. In an
oven-dried 100 mL round-bottom flask kept under nitrogen, the
alkynyl sulfonamide (3 mmol, 1 equiv) was dissolved in 12 mL of THF
and cooled down to −78 °C. To this solution was added dropwise n-
butyl lithium (3.6 mmol, 1.2 equiv for Boc protected homopropargyl
amines and 6.6 mmol, 2.2 equiv for non-Boc protected homoprop-
amines), and stirring was continued at the same temperature for 1 h.
At this time, the requisite aldehyde was added as a solution in 5 mL of
THF (6.0 mmol, 2 equiv), and stirring was continued at −78 °C for 1
h, and then the mixture was warmed to 0 °C in an ice water bath for 1
h. The reaction was quenched with saturated aqueous NH4Cl (5 mL).
The mixture was diluted with ether (30 mL) and separated. The
combined extract containing the crude amino alcohol was dried over
sodium sulfate and concentrated in vacuo (rotary evaporator). The
propargyl alcohol was then column purified via column chromatog-
raphy using a gradient of 5−40% ethyl acetate in hexanes.
electron-withdrawing benzoate ester moves the proton upfield
by over 1 ppm, to a value of δ 4.78 ppm. The broad singlet
between δ 3.70 to 3.55 ppm was also indicative of the newly
formed hydroxyl group.
Hydrolysis of the vinyl benzoate in the dehydropiperidine
gave the expected ketone 48. The vinyl proton at δ 5.35 ppm of
the starting material was replaced by two protons, a doublet of
doublets at δ 2.67 ppm and a multiplet between δ 2.53 and 2.46
ppm. This is consistent with endocyclic axial and equatorial
protons adjacent to a ketone. That the hydrolysis of the
benzoate gave 48 was also confirmed on the basis of 13C
analysis; both the vinyl carbon at δ 116.2 ppm and the benzoate
carbonyl near δ 160 ppm were no longer present. Instead, a
new signal at δ 206.5 ppm appeared in product 48, indicative of
a carbonyl carbon of a cyclic ketone.
CONCLUSIONS
■
The factors influencing two mechanistically distinct hetero-
cyclization pathways were studied under gold(I) catalysis. With
unsubstituted propargylic acetates, direct 5-endo-dig cyclization
was found to occur in preference to the Rautenstrauch
rearrangement/cyclization providing an effective synthetic
route to dehydropyrrolidines. Propargylic acetates with
substitution at the propargylic center, however, do allow for a
competition between the 1,2-acetate migration and direct
cyclization. The 1,2-acyloxy shift leads to a dehydropiperidine
product by cyclization onto a putative Au(I) vinyl carbene
intermediate. Greater bulk at the promigratory acyloxy group
tended to favor direct cyclization to give the five-membered
ring. Further studies toward the selective synthesis of
dehydropiperidines using these methods are currently under-
way and will be reported in due course.
EXPERIMENTAL SECTION
General Information. Unless otherwise stated, reactions were
performed using oven-dried glassware under an atmosphere of
nitrogen. Solvents were dried by passage through alumina (dichloro-
■
F
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General Procedure for the Synthesis of Propargyl Acetates.
Procedure A. To a 50 mL round-bottom flask containing CH2Cl2 was
added the propargyl alcohol (1.0 equiv), and triethylamine (2.0 equiv).
The solution was cooled to 0 °C with an ice bath for 30 min, at which
point the corresponding acyl chloride (1.2 equiv) was added dropwise.
The reaction was left to warm to room temperature over 4 h and then
quenched with the addition of water. The organic layer was diluted
with CH2Cl2 and then washed with 1 N HCl and then washed with
brine. The organic layer was dried over sodium sulfate, and
concentrated in vacuo (rotary evaporator). The crude propargylic
ester was purified via flash column chromatography using a gradient
elution of 0−30% ethyl acetate in hexanes.
Procedure B. In an oven-dried 100 mL round-bottom flask kept
under nitrogen, the alkynyl sulfonamide (3 mmol, 1.0 equiv) was
dissolved in 12 mL of THF and cooled down to −78 °C. To this
solution was added dropwise n-butyl lithium (3.6 mmol, 1.2 equiv for
Boc protected homopropargyl amines and 6.6 mmol, 2.2 equiv for
non-Boc protected homopropamines), and stirring was continued at
the same temperature for 1 h. At this time, the requisite aldehyde was
added as a solution in 5 mL of THF (6.0 mmol, 2.0 equiv), and stirring
was continued at −78 °C for 1 h, and then the mixture was warmed to
0 °C in an ice water bath for 1 h. The reaction was quenched with
saturated aqueous NH4Cl (5 mL). The mixture was diluted with ether
(30 mL), and the organic layer was separated and washed with water
and brine. The combined extract containing the crude propargyl
alcohol was dried over sodium sulfate and concentrated in vacuo
(rotary evaporator). The propargyl alcohol was then dissolved in 10
mL of CH2Cl2, along with triethylamine (6 mmol, 2.0 equiv). The
solution was placed in an ice bath for 30 min, at which time to the
reaction was added the requisite acid chloride (3.6 mmol, 1.2 equiv),
and resulting solution was allowed to warm to room temperature for 4
h before being quenched with the addition of water. The reaction was
diluted with another 20 mL of CH2Cl2, the organic layer was
separated, washed with 10 mL of 1 M HCl, dried over sodium sulfate,
concentrated under a vacuum, and then column purified via flash
column chromatography using a gradient of 5−30% ethyl acetate in
hexanes to afford the propargyl acetates.
characterized compound and spectral data matched those previously
reported:17 1H NMR (500 MHz, CDCl3, ppm) δ 7.63 (d, J = 8.5 Hz, 2
H), 7.20−7.14 (m, 7 H), 5.37 (br s, 1 H), 4.52 (dt, J = 6.5, 6.0 Hz, 1
H), 2.64−2.62 (m, 2 H), 2.37 (s, 3 H), 2.41−2.37 (m, 2 H), 1.96 (s, 1
H).
5-(4-Methylphenylsulfonamido)-5-phenylpent-2-ynyl ace-
tate (2). According to the general procedure B of the synthesis of
propargylic acetates, 2 was obtained as a white solid in 80% yield (980
mg): mp 78−80 °C; Analytical TLC Rf = 0.22 (1:5 ethyl
1
acetate:petroleum ether); H NMR (500 MHz, CDCl3, ppm) δ 7.62
(d, J = 8.3 Hz, 2 H), 7.16−6.94 (m, 7 H), 5.29 (d, J = 7.3 Hz, 1 H),
4.54 (s, 2 H), 4.55−4.49 (m, 1 H), 2.70−2.65 (m, 2 H), 2.38 (s, 3 H),
2.08 (s, 3 H); 13C NMR (75 MHz, CDCl3, ppm) δ 170.3, 143.3, 139.2,
137.3, 129.4, 128.4, 127.1, 126.5, 82.1, 77.9, 55.8, 52.3, 27.7, 21.4, 20.7;
FT-IR (thin film, cm−1) 3273, 3232, 3036, 2921, 2251, 1740, 1596,
1426, 1332, 1234, 1164, 1091, 1062, 1021, 956, 915, 809; High-
resolution MS (ESI+, m/z) molecular ion [M + Na]+ calculated for
C20H21O4N1S1 394.1084, found 394.1074, error 2.4 ppm.
N-(But-3-ynyl)-4-methylbenzenesulfonamide (S1). See
Scheme 4. TsNHBoc (5.37 g, 19.8 mmol) was dissolved in THF
(25 mL) in a dry 250 mL round-bottom flask. Homopropargyl alcohol
(1.98 mL, 26.0 mmol) was added to the solution, followed by PPh3
(10.0 g, 40 mmol) and diethyl azodicarboxylate (5.22 g, 4.66 mL, 30
mmol) and let stir for 16 h. The reaction was concentrated to a yellow
oil, which was triturated with copious amounts of hexanes and filtered
to remove the triphenylphosphine oxide. The combined hexanes
washings could be concentrated to afford a light yellow solid. The
crude solid was then purified via flash column chromatography over
SiO2 using 10% ethyl acetate in hexanes as the mobile phase to afford
the alkyne in 62% yield (3.60 g) of S1 as a white solid. Compound S1
is a known, fully characterized compound and spectral data matched
those reported:18 1H NMR (500 MHz, CDCl3, ppm) δ 7.81 (d, J = 7.0
Hz, 2 H), 7.31 (d, J = 8.5 Hz, 2 H), 4.00 (t, J = 7.0 Hz, 2 H), 2.68−
2.64 (m, 2 H), 2.44 (s, 3 H), 2.02 (s, 1 H), 1.35 (s, 9 H).
5-(N-(tert-Butoxycarbonyl)-4-methylphenylsulfonamido)-
pent-2-ynyl acetate (S2). According to the general procedure B of
the synthesis of propargylic acetates, compound S2 was obtained as a
white solid in 88% yield (550 mg): mp 72−74 °C; Analytical TLC Rf =
0.27 (1:4 ethyl acetate:hexanes); 1H NMR (500 MHz, CDCl3, ppm) δ
7.80 (d, J = 8.0 Hz, 2 H), 7.32 (d, J = 8.0 Hz, 2 H), 4.65 (s, 2 H), 3.98
(t, J = 7.5 Hz, 2 H), 2.72−2.68 (m, 2 H), 2.44 (s, 3 H), 2.09 (s, 3 H),
1.35 (s, 9 H); 13C NMR (75 MHz, CDCl3, ppm) δ 170.2, 150.6, 144.2,
137.2, 129.2, 127.8, 84.5, 83.4, 76.1, 52.5, 45.1, 27.8, 21.6, 20.7, 20.2;
FT-IR (thin film, cm−1) 2980, 2936, 1731, 1597, 1439, 1358, 1292,
1225, 1157, 1091, 1026, 969, 914, 846, 815, 771, 741, 719, 675; High-
resolution MS (ESI+, m/z) molecular ion [M + Na]+ calculated for
C19H25O6N1S1 418.1295, found 418.1294, error 0.1 ppm.
General Procedure for Boc Deprotection. The Boc protected
sulfonamide was dissolved in 10 mL of CH2Cl2, and to the solution
was added 3 mL of TFA. The solution was left to stir for 4 h at room
temperature or until judged complete by TLC. The reaction was then
diluted with 30 mL of CH2Cl2 and then neutralized with the addition
of a saturated solution of sodium bicarbonate. The organic layer was
removed and dried over magnesium sulfate. The organic fraction was
then concentrated (rotary evaporator) and then purified via flash
column chromatography using a gradient elution of 0−30% ethyl
acetate in hexanes to afford the pure sulfonamide.
5-(4-Methylphenylsulfonamido)pent-2-ynyl acetate (6). Ac-
cording to the general procedure for TFA deprotection, propargylic
acetate 6 was obtained as a white solid in 94% yield (385 mg): mp 62−
64 °C; Analytical TLC Rf = 0.14 (1:4 ethyl acetate:hexanes); 1H NMR
(500 MHz, CDCl3, ppm) δ 7.77 (d, J = 8.5 Hz, 2 H), 7.32 (d, J = 8.0
Hz, 2 H), 5.24 (t, J = 6.0 Hz, 1 H), 4.60 (s, 2 H), 3.10 (dt, J = 6.5, 6.5
Hz, 2 H), 2.43 (s, 3 H), 2.41−2.37 (m, 2 H), 2.08 (s, 3 H); 13C NMR
(75 MHz, CDCl3, ppm) δ170.3, 143.5, 136.9, 129.7, 126.9, 83.2, 52.4,
41.5, 21.4, 20.7, 20.1; FT-IR (thin film, cm−1) 3273, 2950, 1732, 1597,
1434, 1323, 1230, 1156, 1095, 1021, 817, 662; High-resolution MS
(EI+, m/z) molecular ion [M]+ calculated for C14H17O4N1S1 295.0873,
found 295.0875, error 0.9 ppm.
4-Methyl-N-(1-phenylbut-3-ynyl)benzenesulfonamide (1).
According to the general procedure, alkynyl amine 1 was obtained
as a white solid in 90% yield (10.4 g). Compound 1 is a known, fully
Scheme 4. Synthesis of Alkyne 6
G
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The Journal of Organic Chemistry
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Scheme 5. Synthesis of Alkyne 8
Scheme 6. Synthesis of Alkyne 38
N-(1-Cyclohexylbut-3-ynyl)-4-methylbenzenesulfonamide
(S3). See Scheme 5. According to the general procedure,
homopropargyl amine S3 was obtained white solid in 59% yield
(1.45 g): mp 92−95 °C; Analytical TLC Rf = 0.55 (1:3 ethyl
ion [M]+ calculated for C25H22O6N2S1 478.1199, found 478.1193,
error 2.3 ppm.
5-(4-Methylphenylsulfonamido)-5-phenylpent-2-ynyl 4-bro-
mobenzoate (12). According to the general procedure B of the
synthesis of propargylic acetates, 12 was obtained as a white solid in
82% yield (1204 mg): mp 108−110 °C; Analytical TLC Rf = 0.43 (1:4
ethyl acetate:hexanes); 1H NMR (500 MHz, CDCl3, ppm) δ 7.91 (d, J
= 8.5 Hz, 2 H), 7.62−7.60 (m, 4 H), 7.17−7.12 (m, 7 H), 5.24 (d, J =
7.5 Hz, 1 H), 4.78 (t, J = 2.0 Hz, 2 H), 4.55 (dt, J = 6.0, 6.0 Hz, 1 H),
2.71−2.66 (m, 2 H), 2.36 (s, 3 H); 13C NMR (75 MHz, CDCl3, ppm)
δ 165.3, 143.3, 139.2, 137.4, 131.8, 131.3, 129.4, 128.4, 127.8, 127.1,
126.5, 82.6, 77.9, 55.7, 53.1, 27.8, 21.5; IR (thin film, cm−1) 1725,
1590, 1268, 1160, 1097; High-resolution MS (ESI+, m/z) molecular
ion [M + Na]+ calculated for C25H22O4N1Br1S1 534.0345, found
534.0346, error 0.1 ppm.
1
acetate:petroleum ether); H NMR (400 MHz, CDCl3, ppm) δ 7.75
(d, J = 9.5 Hz, 2 H), 7.29 (d, J = 10.5 Hz, 2 H), 4.67 (d, J = 11.5 Hz, 1
H), 3.10 (m, 1 H), 2.42 (s, 3 H), 2.34−2.28 (m, 1 H) 2.19−2.13 (m, 1
H), 1.94−1.92 (m, 1 H), 1.84−1.49 (m, 6 H), 1.21−1.05 (m, 4 H);
13C NMR (75 MHz, CDCl3, ppm) δ 143.3, 138.1, 129.6, 127.3, 79.6,
71.3, 56.4, 40.2, 29.5, 28.7, 26.1, 26.0, 25.9, 25.8, 22.2, 21.5; IR (thin
film, cm−1) 3282, 2928, 2853, 1598, 1448, 1329, 1160, 1093, 961, 909,
814; High-resolution MS (ESI+, m/z) molecular ion [M + Na]+
calculated for C17H23O2N1S1 328.1346, found 328.1344, error 0.9
ppm.
N-(1-Cyclohexyl-5-hydroxypent-3-ynyl)-4-methylbenzene-
sulfonamide (S4). Following the general procedure for propargylic
alcohols, alkyne S4 was isolated as clear oil in 58% yield (928 mg):
Analytical TLC Rf = 0.09 (1:4 ethyl acetate:petroleum ether); 1H
NMR (500 MHz, CDCl3, ppm) δ 7.81 (d, J = 8.5 Hz, 2 H), 7.32 (d, J
= 8.0 Hz, 2 H), 5.54 (d, J = 9.5 Hz, 1 H), 4.18 (s, 2 H), 3.16−3.08 (m,
1 H), 2.74 (br s, 1 H), 2.43 (s, 3 H), 2.36−2. Thirty (m, 1 H), 2.24−
2.18 (m, 1 H), 1.82 (d, J = 13.0 Hz, 1 H), 1.70−1.47 (m, 5 H), 1.22−
1.02 (m, 3 H), 093−0.76 (m, 2 H); 13C NMR (75 MHz, CDCl3, ppm)
δ 143.3, 138.2, 129.6, 126.9, 81.5, 81.1, 56.9, 51.0, 40.3, 29.3, 28.9,
25.8, 22.3, 21.5; FT-IR (thin film, cm−1) 3520, 3284, 2930, 2853, 1598,
1447, 1330, 1160, 1093, 1065, 965, 915, 815; High-resolution MS
(ESI+, m/z) molecular ion [M + Na]+ calculated for C18H25O3N1S1
358.1447, found 358.1452, error 1.4 ppm.
5-(4-Methylphenylsulfonamido)-5-phenylpent-2-ynyl ben-
zoate (14). According to the general procedure B of the synthesis
of propargylic acetates, compound 14 was isolated as a clear oil in 87%
yield (1010 mg): Analytical TLC Rf = 0.29 (1:4 ethyl acetate:petro-
leum ether); 1H NMR (500 MHz, CDCl3, ppm) δ 8.02 (d, J = 7.5 Hz,
2 H), 7.63 (d, J = 8.0 Hz, 2 H), 7.56 (t, J = 7.0 Hz, 1 H), 7.43 (t, J =
7.5 Hz, 2 H), 7.15−7.07 (m, 7 H), 5.84 (d, J = 8.0 Hz, 1 H), 4.74 (s, 2
H), 4.55 (dt, J = 7.0, 6.5, Hz, 1 H), 2.67 (m, 2 H), 2.30 (s, 3 H);13C
NMR (75 MHz, CDCl3, ppm) δ 165.8, 143.0, 139.2, 137.3, 133.1,
129.6, 129.2, 128.3, 128.2, 127.5, 126.9, 126.4, 82.4, 77.7, 55.8, 52.8,
27.6, 21.2; FT-IR (thin film, cm−1) 3264, 3064, 2929, 2251, 1712,
1597, 1495, 1446, 1434, 1323, 1266, 1156, 1099, 1066, 960, 907, 817.
High-resolution MS (EI+, m/z) molecular ion [M]+ calculated for
C25H23O4N1S1 433.1342, found 433.1340, error 0.5 ppm.
N-(5-Hydroxy-1-phenylhex-3-ynyl)-4-methylbenzenesulfo-
namide (S5). See Scheme 6. Following the general procedure for
propargylic alcohols, isolated as a clear oil in 54% yield (625 mg):
Analytical TLC Rf = 0.05 (1:4 ethyl acetate:petroleum ether); 1H
NMR (500 MHz, CDCl3, ppm) δ 7.65 (d, J = 8.0 Hz, 2 H), 7.17−7.13
(m, 7 H), 6.16 (d, J = 7.5, 1 H), 4.50 (q, J = 7.5 Hz, 1 H), 4.42−4.37
(m, 1 H), 2.88 (t, J = 6.0 Hz, 1 H), 2.64−2.55 (m, 2 H), 2.34 (s, 3 H),
1.33 (d, J = 6.0 Hz, 3 H); 13C NMR (75 MHz, CDCl3, ppm) δ 143.2,
139.5, 137.2, 129.4, 129.3, 128.2, 127.5, 127.0, 126.5, 86.1, 78.9, 58.1,
56.1, 27.7, 24.1, 21.4; FT-IR (thin film, cm−1) 3277, 3064, 3032, 2981,
2929, 2250, 1592, 1434, 1346, 1228, 1168, 1089, 1062, 1032, 952, 814;
High-resolution MS (ESI+, m/z) molecular ion [M + Na]+ calculated
for C19H21O3N1S1 366.1134, found 366.1135, error 0.5 ppm.
6-(4-Methylphenylsulfonamido)-6-phenylhex-3-yn-2-yl ace-
tate (38). According to the general procedure A of the synthesis of
propargylic acetates, compound 38 was isolated as a 1:1 mixture of
diastereomers as a clear oil in 48% yield (338 mg): Analytical TLC Rf
= 0.21 (1:4 ethyl acetate:petroleum ether); 1H NMR (500 MHz,
CDCl3, ppm) δ 7.63−7.60 (m, 4 H), 7.18−7.12 (m, 14 H), 5.62 (d, J
= 7.5 Hz, 1 H), 5.58 (d, J = 7.5 Hz, 1 H), 5.28−5.24 (m, 2 H), 4.50−
4.47 (m, 2 H), 2.65−2.61 (m, 4 H), 2.36 (s, 6 H), 2.04 (s, 3 H), 2.02
(s, 3 H), 1.35 (d, J = 7.0 Hz, 6 H); 13C NMR (75 MHz, CDCl3, ppm)
δ170.1, 169.9, 143.1, 139.2, 137.3, 129.3, 128.2, 127.6, 127.5, 127.0,
126.9, 126.5, 82.3, 80.2, 60.5, 60.4, 55.9, 55.8, 27.7, 27.6, 21.3, 21.1,
21.0, 20.94, 20.9; FT-IR (thin film, cm−1) 3314, 3260, 3023, 2995,
2933, 1736, 1593, 1495, 1446, 1364, 1332, 1242, 1160, 1058, 1025,
5-Cyclohexyl-5-(4-methylphenylsulfonamido)pent-2-ynyl
acetate (8). According to the general procedure B of the synthesis of
propargylic acetates, 8 was obtained as a clear oil in 73% yield (758
1
mg): Analytical TLC Rf = 0.60 (1:3 ethyl acetate:hexanes); H NMR
(500 MHz, CDCl3, ppm) δ 7.78 (d, J = 8.5 Hz, 2 H), 7.30 (d, J = 8.0
Hz, 2 H), 5.14 (d, J = 9.5 Hz, 1 H), 4.56 (s, 2 H), 3.16−3.11 (m, 1 H),
2.42 (s, 3 H), 2.37−2.23 (m, 2 H), 2.08 (s, 3 H), 1.78 (d, J = 13.0 Hz,
1 H), 1.67−1.48 (m, 5 H), 1.21−0.76 (m, 5 H); 13C NMR (75 MHz,
CDCl3, ppm) δ 170.1, 143.0, 138.0, 129.4, 126.8, 82.7, 56.5, 52.4, 40.2,
29.2, 28.2, 25.9, 25.8, 25.7, 22.4, 21.3, 20.6; FT-IR (thin film, cm−1)
3283, 2927, 2853, 1745, 1598, 1494, 1447, 1378, 1329, 1226, 1160,
1093, 1065, 1026, 965, 915, 815, 732, 667; High-resolution MS (EI+,
m/z) molecular ion [M]+ calculated for C20H27O4N1S1 377.1655,
found 377.1657, error 0.6 ppm.
5-(4-Methylphenylsulfonamido)-5-phenylpent-2-ynyl 4-ni-
trobenzoate (10). According to the general procedure B of the
synthesis of propargylic acetates, 10 was obtained as an off-white solid
in 85% yield (1100 mg): mp 118−120 °C; Analytical TLC Rf = 0.35
(1:3 ethyl acetate:hexanes); 1H NMR (500 MHz, CDCl3, ppm) δ 8.31
(d, J = 8.5 Hz, 2 H), 8.22 (d, J = 8.5 Hz, 2 H), 7.61 (d, J = 8.5 Hz, 2
H), 7.16−7.10 (m, 7 H), 5.28 (br s, 1 H), 4.86 (s, 2 H), 4.56 (dt, J =
7.5, 6.0 Hz, 1 H), 2.79−2.68 (m, 2 H), 2.39 (s, 3 H); 13C NMR (75
MHz, CDCl3, ppm) δ 163.9, 143.2, 139.0, 137.2, 134.7, 130.8, 129.3,
128.3, 127.7, 127.0, 126.4, 123.5, 83.2, 77.3, 55.8, 53.8, 27.8, 21.5; FT-
IR (thin film, cm−1) 3289, 2921, 1728, 1597, 1524, 1434, 1348, 1270,
1160, 1099, 948, 813, 723; High-resolution MS (EI+, m/z) molecular
H
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The Journal of Organic Chemistry
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Scheme 7. Synthesis of Alkyne 19
Scheme 8. Synthesis of Alkyne 23
948, 915, 821, 731, 694; High-resolution MS (ESI+, m/z) molecular
ion [M + Na]+ calculated for C21H23O4N1S1 408.1240, found
408.1249, error 2.4 ppm.
tert-Butyl 5-hydroxyhex-3-ynyl(tosyl)carbamate (S6). See
Scheme 7. Following the general procedure for propargylic alcohols,
isolated as a white solid in 78% yield (4.4 g): mp 102−104 °C;
Analytical TLC Rf = 0.11 (1:4 ethyl acetate:petroleum ether); 1H
NMR (500 MHz, CDCl3, ppm) δ 7.80 (d, J = 8.0 Hz, 2 H), 7.32 (d, J
= 9.0, 2 H), 4.51−4.48 (m, 1 H), 4.00 (t, J = 7.0 Hz, 2 H), 2.68 (t, J =
7.5 Hz, 2 H), 2.59−2.53 (br s, 1 H), 2.44 (s, 3 H), 1.42 (d, J = 6.5 Hz,
3 H), 1.34 (s, 9 H); 13C NMR (75 MHz, CDCl3, ppm) δ 150.6, 144.2,
137.1, 129.2, 127.6, 84.6, 84.4, 80.3, 58.1, 45.2, 27.7, 24.3, 21.4, 19.9;
FT-IR (thin film, cm−1) 3517, 2972, 2930, 2238, 1731, 1595, 1448,
1364, 1275, 1155, 1086, 971, 913, 845, 809, 767, 730, 672; High-
resolution MS (ESI+, m/z) molecular ion [M + Na]+ calculated for
C18H25O5N1S1 390.1346, found 390.1340, error 1.4 ppm.
6-(N-(tert-Butoxycarbonyl)-4-methylphenylsulfonamido)-
hex-3-yn-2-yl acetate (S7). Following the general procedure A of
the synthesis of propargylic acetates, isolated as a clear oil in 90% yield
(530 mg): Analytical TLC Rf = 0.21 (1:4 ethyl acetate:petroleum
ether); 1H NMR (500 MHz, CDCl3, ppm) δ 7.80 (d, J = 8.0 Hz, 2 H),
7.32 (d, J = 8.0, 2 H), 5.45 (q, J = 7.0 Hz, 1 H), 3.97 (t, J = 7.5 Hz, 2
H), 2.68 (t, J = 6.5 Hz, 2 H), 2.44 (s, 3 H), 2.06 (s, 3 H), 1.45 (d, J =
6.5 Hz, 3 H), 1.34 (s, 9 H); 13C NMR (75 MHz, CDCl3, ppm) δ
169.9, 150.7, 144.2, 137.3, 129.2, 127.8, 84.5, 81.3, 80.6, 60.5, 45.2,
27.8, 21.6, 21.6, 21.1, 20.2; FT-IR (thin film, cm−1) 2976, 2931, 1734,
1597, 1443, 1369, 1292, 1237, 1157, 1090, 1059, 1018, 970, 913, 846,
814, 769, 742, 674; High-resolution MS (ESI+, m/z) molecular ion [M
+ Na]+ calculated for C20H27O6N1S1 432.1451, found 432.1461, error
2.4 ppm.
5-(4-Methylphenylsulfonamido)-1,5-diphenylpent-2-ynyl
acetate (46). According to the general procedure B of the synthesis
of propargylic acetates, compound 46 was isolated as a clear oil in 63%
yield (558 mg): Analytical TLC Rf = 0.38 (1:4 ethyl acetate:petroleum
ether); 1H NMR (500 MHz, CDCl3, ppm) δ 7.60−7.57 (m, 2 H), 7.32
(s, 5 H), 7.19−7.07 (m, 7 H), 6.30−6.27 (m, 1 H), 5.44 (t, J = 8.5 Hz,
1 H), 4.53 (dt, J = 7.0, 6.5 Hz, 1 H), 2.73−2.70 (m, 2 H), 2.35−2.34
(m, 3 H), 2.07−2.05 (m, 3 H); 13C NMR (75 MHz, CDCl3, ppm) δ
170.0, 169.8, 143.2, 139.1, 137.2, 136.6, 129.4, 128.8, 128.7, 128.5,
128.3, 127.7, 127.6, 127.5, 127.0, 126.6, 83.0, 82.9, 80.4, 65.8, 65.7,
55.9, 55.8, 27.7, 27.6, 21.4, 21.0; FT-IR (thin film, cm−1) 3292, 3272,
3024, 2923, 1733, 1598, 1495, 1454, 1331, 1232, 1157, 1092, 1022,
965, 912, 816, 701, 664; High-resolution MS (ESI+, m/z) molecular
ion [M + Na]+ calculated for C26H25O4N1S1 470.1397, found
470.1409, error 2.9 ppm.
7-(4-Methylphenylsulfonamido)-1-phenylhept-4-yn-3-yl ac-
etate (16). To an oven-dried three neck-round-bottom flask 4.3 g
(13.4 mmol, 1 equiv) of alkyne S1 was dissolved in 35 mL of THF.
The solution was cooled to −78 °C, and 15 mL (29.4 mmol, 2.2
equiv) of 2 M n-butyl lithium was added to the reaction in a dropwise
fashion. After 1 h, the requisite aldehyde (16.1 mmol, 1.2 equiv) was
added to the reaction, and it was allowed to warm to 0 °C over the
period of 1 h. The reaction was quenched by the addition of 0.95 mL
(13.4 mmol, 1.0 equiv) of acetyl chloride and allowed to warm to
room temperature for another hour. The reaction was then quenched
with the addition of ammonium chloride and extracted with diethyl
ether. The organic extracts were combined, washed with brine and
dried over magnesium sulfate. The crude oil was directly concentrated
and then dissolved in a minimum volume of dichloromethane and 3
mL of TFA. The reaction was allowed to stir for 3 h at room
temperature. The reaction was then quenched with the addition of
sodium carbonate until neutral pH was obtained (pH paper). The
reaction was diluted with more dichloromethane and washed with
brine. The organic layer was dried over magnesium sulfate and
concentrate to afford a yellow oil. The crude oil was then purified by
flash column chromatography on silica gel using a gradient elution of
10−40% ethyl acetate in hexanes to afford compound 16 as a yellow
oil in 56% yield (2.59 g): Analytical TLC Rf = 0.14 (1:4 ethyl
6-(4-Methylphenylsulfonamido)hex-3-yn-2-yl acetate (19).
Following the general procedure for TFA deprotection, compound 19
was isolated as a clear oil in 77% yield (410 mg): Analytical TLC Rf =
0.14 (1:4 ethyl acetate:petroleum ether); 1H NMR (500 MHz, CDCl3,
ppm) δ 7.78 (d, J = 8.0 Hz, 2 H), 7.32 (d, J = 8.0, 2 H), 5.38−5.32 (m,
1 H), 5.18−5.15 (m, 1 H), 3.09 (dt, J = 7.0, 6.5 Hz, 2 H), 2.43 (s, 3
H), 2.38 (t, J = 6.5 Hz, 2 H), 2.06 (s, 3 H), 1.43 (d, J = 7.0 Hz, 3 H);
13C NMR (75 MHz, CDCl3, ppm) δ 170.0, 143.4, 136.9, 129.6, 126.9,
81.2, 81.0, 60.4, 41.6, 21.4, 21.3, 21.0, 20.0; FT-IR (thin film, cm−1)
3293, 2938, 1740, 1593, 1434, 1373, 1328, 1242, 1156, 1095, 1062,
1021, 952, 817, 662; High-resolution MS (ESI+, m/z) molecular ion
[M + Na]+ calculated for C15H19O4N1S1 332.0927, found 332.0921,
error 1.5 ppm.
6-(N-(tert-Butoxycarbonyl)-4-methylphenylsulfonamido)-
hex-3-yn-2-yl pivalate (S8). See Scheme 8. According to the general
procedure A of the synthesis of propargylic acetates, compound S8 was
isolated as a clear oil in 94% yield (345 mg): Analytical TLC Rf = 0.53
(1:4 ethyl acetate:petroleum ether); 1H NMR (500 MHz, CDCl3,
ppm) δ 7.80 (d, J = 8.0 Hz, 2 H), 7.32 (d, J = 8.5 Hz, 2 H), 5.42 (q, J =
6.5 Hz, 1 H), 3.97 (t, J = 8.0 Hz, 2 H), 2.67 (t, J = 6.5 Hz, 2 H), 2.44
(s, 3 H), 1.44 (d, J = 7.0 Hz, 2 H), 1.34 (s, 9 H), 1.20 (s, 9 H); 13C
NMR (75 MHz, CDCl3, ppm) δ 177.4, 150.7, 144.2, 137.2, 129.3,
127.8, 84.5, 80.9, 80.8, 60.5, 45.2, 38.6, 27.8, 27.0, 21.6, 21.4, 20.2; FT-
IR (thin film, cm−1) 2979, 2935, 1728, 1598, 1480, 1442, 1367, 1279,
1155, 1091, 1058, 971, 848, 813, 770, 717, 675; High-resolution MS
1
acetate:petroleum ether); H NMR (500 MHz, CDCl3, ppm) δ 7.76
(d, J = 8.0 Hz, 2 H), 7.29−7.26 (m, 4 H), 7.20−7.16 (m, 3 H), 5.25 (t,
J = 6.5 Hz, 1 H), 5.10 (t, J = 6.0 Hz, 1 H), 3.09 (dt, J = 7.0, 7.0 Hz, 2
H), 2.73 (t, J = 8.0 Hz, 2 H), 2.41−2.36 (m, 5 H), 2.06−2.01 (m, 5
H); 13C NMR (75 MHz, CDCl3, ppm) δ 170.0, 145.0, 143.4, 140.7,
140.5, 136.9, 136.4, 129.9, 126.6, 128.4, 128.3, 127.4, 126.9, 126.0,
82.3, 79.9, 63.7, 41.6, 36.1, 31.2, 21.4, 20.9, 20.0; FT-IR (thin film,
cm−1) 3292, 3024, 2923, 1733, 1598, 1495, 1454, 1331, 1232, 1157,
1092, 1022, 912, 815, 701; High-resolution MS (ESI+, m/z) molecular
ion [M + Na]+ calculated for C22H25O4N1S1 422.1397, found
422.1395, error 0.3 ppm.
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Scheme 9. Synthesis of Alkyne 26
Scheme 10. Synthesis of Alkyne 27
Scheme 11. Synthesis of Alkyne 28
(ESI+, m/z) molecular ion [M + Na]+ calculated for C23H33O6N1S1
474.1921, found 474.1929, error 1.8 ppm.
(q, J = 6.5 Hz, 2 H), 2.39 (s, 3 H), 2.36−2.35 (m, 2 H), 1.57 (d, J = 7.0
Hz, 3 H); 13C NMR (75 MHz, CDCl3, ppm) δ 165.6, 143.4, 136.9,
133.1, 129.8, 129.6, 128.3, 127.0, 81.5, 81.2, 61.1, 41.6, 21.4, 21.3, 19.9;
FT-IR (thin film, cm−1) 3284, 2988, 2938, 2251, 1721, 1599, 1451,
1318, 1267, 1161, 1095, 1059, 1026, 912, 862, 815, 713, 665; High-
resolution MS (ESI+, m/z) molecular ion [M]+ calculated for
C20H21O4N1S1 371.1186, found 371.1197, error 3.1 ppm.
6-(N-(tert-Butoxylcarbonyl)-4-methylphenylsulfonamido)-
hex-3-yn-2-yl 4-bromobenzoate (S10). See Scheme 10. According
to the general procedure A of the synthesis of propargylic acetates,
compound S10 was isolated as a white tacky oil in 91% yield (1370
mg): Analytical TLC Rf = 0.48 (1:4 ethyl acetate:petroleum ether); 1H
NMR (500 MHz, CDCl3, ppm) δ 7.94−7.91 (m, 2 H), 7.82−7.78 (m,
2 H), 7.60−7.56 (m, 2 H), 7.31−7.28 (m, 2 H), 5.69−5.66 (m, 1 H),
4.01 (t, J = 8.0 Hz, 2 H), 2.71 (t, J = 7.0 Hz, 2 H), 2.41 (s, 3 H), 1.59
(d, J = 6.5 Hz, 3 H), 1.35 (s, 9 H); 13C NMR (75 MHz, CDCl3, ppm)
δ 164.6, 150.6, 144.1, 137.2, 131.5, 131.2, 129.2, 128.9, 128.1, 127.7,
84.4, 81.7, 80.4, 61.4, 45.0, 27.7, 21.6, 21.5, 20.1; FT-IR (thin film,
cm−1) 2982, 2930, 2248, 1731, 1589, 1485, 1448, 1359, 1270, 1160,
1092, 1055, 1008, 971, 908, 845, 814, 756, 735, 672; High-resolution
MS (ESI+, m/z) molecular ion [M + Na]+ calculated for
C25H28O6N1Br1S1 572.0719, found 572.0721, error 0.3 ppm.
6-(4-Methylphenylsulfonamido)hex-3-yn-2-yl 4-bromoben-
zoate (27). Following the general procedure for TFA deprotection,
compound 27 was isolated as a clear oil in 88% yield (980 mg):
Analytical TLC Rf = 0.26 (1:4 ethyl acetate:petroleum ether); 1H
NMR (500 MHz, CDCl3, ppm) δ 7.91 (d, J = 8.5 Hz, 2 H), 7.76 (d, J
= 8.0 Hz, 2 H), 7.57 (d, J = 8.5 Hz, 2 H), 7.27 (d, J = 8.5, 2 H), 5.58
(q, J = 6.5 Hz, 1 H), 5.40 (t, J = 6.5 Hz, 1 H), 3.11 (q, J = 6.5 Hz, 2
H), 2.39−2.37 (m, 5 H), 1.56 (d, J = 6.5 Hz, 2 H); 13C NMR (75
MHz, CDCl3, ppm) δ 164.7, 143.3, 136.8, 131.5, 131.1,129.5, 128.6,
128.1, 126.8, 81.7, 80.7, 61.4, 41.5, 21.3, 21.2, 19.8; FT-IR (thin film,
cm−1) 3287, 2989, 2938, 2254, 1722, 1590, 1484, 1398, 1328, 1265,
1159, 1096, 1058, 1011, 911, 849, 814, 758, 734, 665; High-resolution
MS (EI+, m/z) molecular ion [M]+ calculated for C20H20O4N1Br1S1
449.0291, found 449.0262, error 6.5 ppm.
6-(4-Methylphenylsulfonamido)hex-3-yn-2-yl pivalate (23).
Following the general procedure for TFA deprotection, compound 23
was isolated as an oil in 79% yield (110 mg): Analytical TLC Rf = 0.25
(1:4 ethyl acetate:petroleum ether); 1H NMR (500 MHz, CDCl3,
ppm) δ 7.77 (d, J = 8.5 Hz, 2 H), 7.32(d, J = 7.5 Hz, 2 H), 5.32−5.28
(m, 1 H), 5.02 (t, J = 6.0 Hz, 1 H), 3.08 (q, J = 7.0 Hz, 2 H), 2.42 (s,
3H), 2.36 (dt, J = 6.5, 1.5 Hz, 2 H), 1.42 (d, J = 7.0 Hz, 3 H), 1.20 (s,
9 H); 13C NMR (75 MHz, CDCl3, ppm) δ 177.5, 143.4, 137.0, 129.7,
127.0, 81.4, 80.9, 60.3, 41.7, 38.6, 26.9, 21.5, 21.1, 19.9; FT-IR (thin
film, cm−1) 3285, 2975, 2936, 2873, 1727, 1598, 1480, 1331, 1280,
1159, 1094, 1059, 861, 815, 663; High-resolution MS (EI+, m/z)
molecular ion [M]+ calculated for C18H25O4N1S1 351.1499, found
351.1503, error 1.4 ppm.
6-(N-(tert-Butoxycarbonyl)-4-methylphenylsulfonamido)-
hex-3-yn-2-yl benzoate (S9). See Scheme 9. According to the
general procedure A of the synthesis of propargylic acetates,
compound S9 was isolated as a clear oil in 72% yield (930 mg):
Analytical TLC Rf = 0.43 (1:4 ethyl acetate:petroleum ether); 1H
NMR (500 MHz, CDCl3, ppm) δ 8.07 (d, J = 8.5 Hz, 2 H), 7.80 (d, J
= 7.0 Hz, 2 H), 7.58 (t, J = 6.5 Hz, 1 H), 7.45 (t, J = 7.0 Hz, 2 H), 7.29
(d, J = 8.0, 2 H), 5.71 (q, J = 6.5 Hz, 1 H), 4.01 (t, J = 7.0 Hz, 2 H),
2.72 (t, J = 7.5 Hz, 2 H), 2.40 (s, 3 H), 1.59 (d, J = 7.0 Hz, 3 H), 1.33
(s, 9 H); 13C NMR (75 MHz, CDCl3, ppm) δ 165.3, 150.6, 144.1,
137.1, 132.9, 129.9, 129.6, 129.2, 128.2, 127.7, 84.4, 81.5, 80.6, 61.1,
45.0, 27.7, 21.6, 21.4, 20.1; FT-IR (thin film, cm−1) 2982, 2940, 2259,
1726, 1600, 1453, 1348, 1259, 1160, 1086, 1055, 1024, 971, 913, 845,
814, 709, 672; High-resolution MS (ESI+, m/z) molecular ion [M +
Na]+ calculated for C25H29O6N1S1 494.1608, found 494.1611, error
0.8 ppm.
6-(4-Methylphenylsulfonamido)hex-3-yn-2-yl benzoate
(26). Following the general procedure for TFA deprotection,
compound 26 was isolated as a clear oil in 97% yield (710 mg):
Analytical TLC Rf = 0.21 (1:4 ethyl acetate:petroleum ether); 1H
NMR (500 MHz, CDCl3, ppm) δ 8.06 (d, J = 7.5 Hz, 2 H), 7.76 (d, J
= 8.0 Hz, 2 H), 7.56 (t, J = 7.0 Hz, 1 H), 7.46 (t, J = 8.0 Hz, 2 H), 7.25
(d, J = 8.5, 2 H), 5.59−5.55 (m, 1 H), 5.15 (t, J = 6.5 Hz, 1 H), 3.10
6-(N-(tert-Butoxylcarbonyl)-4-methylphenylsulfonamido)-
hex-3-yn-2-yl 4-nitrobenzoate (S11). See Scheme 11. According
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to the general procedure A of the synthesis of propargylic acetates,
compound S11 was isolated as an oil in 94% yield (1320 mg):
Analytical TLC Rf = 0.32 (1:4 ethyl acetate:petroleum ether); 1H
NMR (500 MHz, CDCl3, ppm) δ 8.30 (d, J = 9.0 Hz, 2 H), 8.25 (d, J
= 9.5 Hz, 2 H), 7.79 (d, J = 8.5 Hz, 2 H), 7.31(d, J = 8.5 Hz, 2 H), 5.72
(q, J = 7.0 Hz, 1 H), 4.02 (t, J = 7.0 Hz, 2 H), 2.73 (t, J = 7.5 Hz, 2 H),
2.43 (s, 3 H), 1.64 (d, J = 7.0 Hz, 3 H), 1.33 (s, 9 H); 13C NMR (75
MHz, CDCl3, ppm) δ 163.6, 150.7, 150.5, 144.2, 137.2, 135.5, 130.9,
129.2, 127.7, 123.4, 84.5, 82.3, 80.1, 62.3, 45.1, 27.8, 21.6, 20.2; FT-IR
(thin film, cm−1) 2983, 2253, 1728, 1607, 1529, 1354, 1269, 1157,
1118, 1092, 1056, 971, 913, 874, 842, 720, 673; High-resolution MS
(ESI+, m/z) molecular ion [M + Na]+ calculated for C25H28O8N2S1
539.1459, found 539.1475, error 3.1 ppm.
6-(4-Methylphenylsulfonamido)hex-3-yn-2-yl 4-nitroben-
zoate (28). Following the general procedure for TFA deprotection,
compound 28 was isolated as a white solid in 91% yield (950 mg): mp
117−119 °C; Analytical TLC Rf = 0.12 (1:4 ethyl acetate:petroleum
ether); 1H NMR (500 MHz, CDCl3, ppm) δ 8.31 (d, J = 8.5 Hz, 2 H),
8.25 (d, J = 9.0 Hz, 2 H), 7.77 (d, J = 7.5 Hz, 2 H), 7.30 (d, J = 7.5 Hz,
2 H), 5.62 (q, J = 6.5 Hz, 1 H), 4.88 (br s, 1 H), 3.12 (q, J = 7.0 Hz, 2
H), 2.42−2.39 (m, 5 H), 1.62 (d, J = 7.0 Hz, 3 H); 13C NMR (75
MHz, CDCl3, ppm) δ 163.8, 150.7, 143.6, 137.0, 135.2, 130.9, 129.7,
127.0, 123.5, 82.3, 80.7, 62.3, 41.5, 21.5, 21.4, 20.1; FT-IR (thin film,
cm−1) 3291, 2989, 2938, 2872, 2250, 1725, 1607, 1528, 1411, 1340,
1269, 1160, 1098, 1057, 873, 841, 815, 720, 550; High-resolution MS
(ESI+, m/z) molecular ion [M + Na]+ calculated for C20H20O6N2S1
439.0934, found 439.0913, error 4.8 ppm.
81.9, 67.9, 45.3, 34.4, 27.7, 21.5, 20.0, 18.0, 17.5; FT-IR (thin film,
cm−1) 3533, 2968, 2931, 2873, 1726, 1598, 1435, 1352, 1292, 1258,
1156, 1091, 1020, 971, 914, 843, 813, 734, 674; High-resolution MS
(ESI+, m/z) molecular ion [M + Na]+ calculated for C20H29O5N1S1
418.1659, found 418.1659, error 0.0 ppm.
7-(N-(tert-Butoxycarbonyl)-4-methylphenylsulfonamido)-2-
methylhept-4-yn-3-yl acetate (S13). According to the general
procedure A of the synthesis of propargylic acetates, compound S13
was isolated as a clear oil in 69% yield (380 mg): Analytical TLC Rf =
0.34 (1:4 ethyl acetate:petroleum ether); 1H NMR (500 MHz, CDCl3,
ppm) δ 7.80 (d, J = 8.5 Hz, 2 H), 7.32 (d, J = 8.0 Hz, 2 H), 5.21−5.20
(m, 1 H), 3.98 (t, J = 7.5 Hz, 2 H), 2.70 (t, J = 7.5 Hz, 2 H), 2.44 (s, 3
H), 2.08 (s, 3 H), 1.96 (sextet, J = 6.5 Hz, 1 H), 1.34 (s, 9 H), 1.00 (d,
J = 6.0 Hz, 3 H), 0.97 (d, J = 7.0 Hz, 3 H); 13C NMR (75 MHz,
CDCl3, ppm) δ 170.0, 150.6, 144.2, 137.2, 129.2, 127.7, 84.5, 82.3,
78.2, 69.1, 45.2, 32.3, 27.8, 21.5, 21.0, 20.2, 18.1, 17.5; FT-IR (thin
film, cm−1) 2973, 2933, 2876, 1726, 1598, 1433, 1357, 1291, 1234,
1156, 1091, 1019, 971, 908, 845, 814, 770, 721, 675; High-resolution
MS (ESI+, m/z) molecular ion [M + Na]+ calculated for
C22H31O6N1S1 460.1764, found 460.1763, error 0.2 ppm.
2-Methyl-7-(4-methylphenylsulfonamido)hept-4-yn-3-yl ac-
etate (41). Following the general procedure for TFA deprotection,
compound 41 was isolated as an oil in 76% yield (220 mg): Analytical
1
TLC Rf = 0.18 (1:4 ethyl acetate:petroleum ether); H NMR (500
MHz, CDCl3, ppm) δ 7.73 (d, J = 8.5 Hz, 2 H), 7.27 (d, J = 8.0 Hz, 2
H), 5.24 (t, J = 6.5 Hz, 1 H), 5.07−5.05 (m, 1 H), 3.04 (q, J = 7.0 Hz,
2 H), 2.38 (s, 3 H), 2.34 (dt, J = 7.0, 2.5 2 H), 2.03 (s, 3 H), 1.90
(sextet, J = 7.0 Hz, 1 H), 0.93 (d, J = 7.0 Hz, 3 H), 0.91 (d, J = 6.5, 3
H); 13C NMR (75 MHz, CDCl3, ppm) δ 170.1, 143.3, 136.8, 129.5,
126.8, 82.4, 78.5, 69.0, 41.6, 32.0, 21.3, 20.8, 19.8, 17.9, 17.4; FT-IR
(thin film, cm−1) 3285, 2967, 2932, 2875, 1738, 1727, 1598, 1427,
1371, 1331, 1236, 1160, 1094, 1020, 982, 911, 815, 733; High-
resolution MS (EI+, m/z) molecular ion [M]+ calculated for
C17H23O4N1S1 337.1342, found 337.1342, error 0.1 ppm.
tert-Butyl 5-hydroxy-6,6-dimethylhept-3-ynyl(tosyl)-
carbamate (S14). See Scheme 13. Following the general procedure
for the synthesis of propargylic alcohols, compound S14 was isolated
in 77% yield (1.93 g) as a clear oil which crystallized upon standing:
mp 91−93 °C; Analytical TLC Rf = 0.37 (1:4 ethyl acetate:petroleum
ether); 1H NMR (500 MHz, CDCl3, ppm) δ 7.79 (d, J = 8.5 Hz, 2 H),
7.31 (d, J = 8.5 Hz, 2 H), 4.02−3.97 (m, 3 H), 2.69 (t, J = 7.0 Hz, 2
H), 2.44 (s, 3 H), 1.96 (t, J = 5.0 Hz, 1 H), 1.33 (s, 9 H), 0.97 (s, 9
H); 13C NMR (75 MHz, CDCl3, ppm) δ 150.7, 144.2, 137.3, 129.3,
127.8, 84.6, 82.2, 77.2, 71.5, 45.4, 35.7, 27.8, 25.3, 21.6, 20.1; FT-IR
(thin film, cm−1) 3545, 2971, 2869, 1732, 1361, 1291, 1156, 1090,
1042, 1007, 971, 813, 675; High-resolution MS (ESI+, m/z) molecular
ion [M + Na]+ calculated for C21H31O5N1S1 432.1815, found
432.1823, error 0.8 ppm.
7-(N-(tert-Butoxycarbonyl)-4-methylphenylsulfonamide)-
2,2-dimethylhept-4-yn-3-yl acetate (S15). According to the
general procedure A of the synthesis of propargylic acetates,
compound S15 was isolated as an oil in 63% yield (520 mg):
Analytical TLC Rf = 0.43 (1:4 ethyl acetate:petroleum ether); 1H
NMR (500 MHz, CDCl3, ppm) δ 7.79 (d, J = 8.5 Hz, 2 H), 7.32 (d, J
= 9.0 Hz, 2 H), 5.11 (t, J = 1.5 Hz, 1 H), 3.97 (t, J = 7.5 Hz, 2 H), 2.70
(dt, J = 7.5, 1.5 Hz, 2 H), 2.44 (s, 3 H), 2.08 (s, 3 H), 1.34 (s, 9 H),
0.98 (s, 9 H); 13C NMR (75 MHz, CDCl3, ppm) δ 170.0, 150.6, 144.1,
137.1, 129.2, 127.7, 84.4, 82.0, 78.3, 71.9, 45.2, 34.9, 27.7, 25.4, 21.5,
20.8, 20.1; FT-IR (thin film, cm−1) 2973, 2871, 1732, 1598, 1479,
6-(4-Methylphenylsulfonamido)hex-3-yn-2-yl 4-methoxy-
benzoate (30). Following the general procedure for the synthesis
of propargyl acetates except the Boc deprotection was carried out
directly after the acylation without purifying or isolating the
intermediate structure. The resulting alkyne was isolated as a clear
oil in 54% yield (1.4 g) over two steps: Analytical TLC Rf = 0.05 (1:4
1
ethyl acetate:petroleum ether); H NMR (500 MHz, CDCl3, ppm) δ
8.03−7.99 (m, 2 H), 7.76 (d, J = 12.5 Hz, 2 H), 7.24 (d, J = 10 Hz, 2
H), 6.94−6.90 (m, 2 H), 5.56 (q, J = 10.5 Hz, 1 H), 5.07 (br s, 1 H),
3.86 (s, 3 H), 3.10 (q, J = 11.0 Hz, 2 H), 2.40−2.34 (m, 5 H), 1.62 (d,
J = 7.0 Hz, 3 H); 13C NMR (75 MHz, CDCl3, ppm) δ 165.4, 163.5,
143.4, 137.0, 131.8, 129.7, 127.0, 122.2, 113.6, 81.6, 81.3, 60.8, 55.4,
41.6, 21.5, 21.4, 19.9 ; FT-IR (thin film, cm−1) 3583, 3281, 2987, 2937,
2841, 2253, 1918, 1714, 1606, 1581, 1512, 1455, 1422, 1318, 1258,
1163, 1095, 1059, 1028, 912, 848, 815, 772, 732, 665; High-resolution
MS (ESI+, m/z) molecular ion [M + H]+ calculated for C21H23O5N1S1
402.1370, found 402.1371, error 0.4 ppm.
tert-Butyl 5-hydroxy-6-methylhept-3-ynyl(tosyl)carbamate
(S12). See Scheme 12. Following the general procedure for
propargylic alcohols, isolated as an oil in 97% yield (1.2 g): Analytical
1
TLC Rf = 0.27 (1:4 ethyl acetate:petroleum ether); H NMR (500
MHz, CDCl3, ppm) δ 7.80 (d, J = 8.0 Hz, 2 H), 7.32 (d, J = 8.5, 2 H),
4.14−4.11 (m, 1 H), 4.00 (t, J = 7.0 Hz, 2 H), 2.69 (t, J = 6.5 Hz, 2 H),
2.44 (s, 3 H), 2.20 (s, 1 H), 1.85 (d, J = 6.5 Hz, 1 H), 1.33 (s, 9 H),
0.99 (d, J = 6.5 Hz, 3 H), 0.98 (d, J = 7.0 Hz, 3 H); 13C NMR (75
MHz, CDCl3, ppm) δ 150.7, 144.2, 137.2, 129.2, 127.7, 84.5, 82.3,
Scheme 12. Synthesis of Alkyne 41
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Scheme 13. Synthesis of Alkyne 44
Scheme 14. Synthesis of Alkyne 32
1456, 1395, 1371, 1291, 1238, 1156, 1090, 1018, 972, 913, 844, 813,
771, 734, 675; High-resolution MS (ESI+, m/z) molecular ion [M +
Na]+ calculated for C23H33O6N1S1 474.1921, found 474.1912, error
1.7 ppm.
6-(tert-Butyldimethylsilyloxy)hex-3-yn-2-yl acetate (S17). To
a 100 mL oven-dried round-bottom flask was added 50 mL of freshly
distilled CH2Cl2 and 5.7 g (25.1 mmol, 1.0 equiv) of propargyl alcohol
S16 and 7.0 mL (50 mmol, 2.0 equiv) of triethyl amine. The reaction
was cooled to 0 °C in an ice/water bath for 30 min, at which point
2.15 mL (30 mmol, 1.2 equiv) of acetyl chloride was added to the
reaction. The reaction was then left to warm to room temperature over
the course of 4 h, at which point it was quenched with the addition of
water. The reaction was washed with 1 M HCl, water, and brine. The
organic fraction was then dried over sodium sulfate, concentrated in
vacuo (rotary evaporator) and purified over SiO2 using a gradient
elution of 0−20% diethyl ether in hexanes to afford the desired
product as a clear oil in 70% yield (4.7 g): Analytical TLC Rf = 0.62
(1:4 ethyl acetate:petroleum ether); 1H NMR (500 MHz, CDCl3,
ppm) δ 5.45−5.37 (m, 1 H), 3.67 (t, J = 7.5 Hz, 2 H), 2.38 (dt, J = 7.0,
2.0 Hz, 2 H), 2.02 (s, 3 H), 1.42 (d, J = 6.5 Hz, 3 H), 0.86 (s, 9 H),
0.03 (s, 6 H); 13C NMR (75 MHz, CDCl3, ppm) δ 169.8, 82.4, 79.6,
61.6, 60.6, 25.8, 23.0, 21.6, 21.0, 18.2, −5.4; FT-IR (thin film, cm−1)
2955, 2930, 2857, 1746, 1472, 1371, 1340, 1236, 1168, 1110, 1058,
1018, 950, 914, 838, 777; High-resolution MS (ESI+, m/z) molecular
ion [M + Na]+ calculated for C14H26O3Si1 293.1543, found 293.1543,
error 0.2 ppm.
2,2-Dimethyl-7-(4-methylphenylsulfonamido)hept-4-yn-3-yl
acetate (44). Following the general procedure for TFA deprotection,
compound 44 was isolated as an oil in 56% yield (254 mg): Analytical
1
TLC Rf = 0.17 (1:4 ethyl acetate:petroleum ether); H NMR (500
MHz, CDCl3, ppm) δ 7.77 (d, J = 8.0 Hz, 2 H), 7.32 (d, J = 8.5 Hz, 2
H), 5.15 (t, J = 6.5 Hz, 1 H), 4.98 (t, J = 2.0 Hz, 1 H), 3.08 (q, J = 7.0
Hz, 2 H), 2.43 (s, 3 H), 2.40 (dt, J = 7.0, 2.0 Hz, 2 H), 2.09 (s, 3 H),
0.96 (d, J = 7.0 Hz, 9 H); 13C NMR (75 MHz, CDCl3, ppm) δ 170.3,
143.3, 136.9, 129.6, 126.9, 82.3, 78.8, 72.1, 41.6, 34.7, 25.4, 21.4, 20.8,
19.9; FT-IR (thin film, cm−1) 3287, 2968, 1734, 1558, 1540, 1456,
1436, 1370, 1333, 1239, 1161, 1093, 1018, 977, 815, 662; High-
resolution MS (ESI+, m/z) molecular ion [M + Na]+ calculated for
C18H25O4N1S1 374.1397, found 374.1389, error 2.0 ppm.
6-(tert-Butyldimethylsilyloxy)hex-3-yn-2-ol (S16). See Scheme
14. To an oven-dried 3-neck flask under nitrogen was added 60 mL of
freshly distilled THF and 6 g (32.5 mmol, 1 equiv) of the TBS
protected homopropargylic alcohol. The solution was cooled to −78
°C in an acetone/dry ice bath for 30 min, at which point 19.5 mL (39
mmol, 1.2 equiv) of 2 M n-butyl lithium was added to the reaction.
After 1 h, 3.6 mL (65 mmol, 2.0 equiv) of acetaldehyde was added,
and the reaction was left to warm to 0 °C in an ice bath over 2 h. The
reaction was then quenched with the addition of aqueous ammonium
chloride, diluted with diethyl ether and washed with water and brine.
The organic extract was then dried over magnesium sulfate and then
concentrated in vacuo (rotary evaporator). The crude oil was column
purified over SiO2 using a gradient of 0−30% diethyl ether in hexanes
to afford the desired product as a clear oil in 97% yield (5.7 g):
Analytical TLC Rf = 0.38 (1:4 ethyl acetate:petroleum ether); 1H
NMR (500 MHz, CDCl3, ppm) δ 4.78−4.45 (m, 1 H), 3.67 (t, J = 7.5
Hz, 2 H), 2.39 (dt, J = 7.0, 2.0 Hz, 2 H), 1.92 (d, J = 5.0 Hz, 1 H), 1.40
(d, J = 7.0 Hz, 3 H), 0.87 (s, 9 H), 0.04 (s, 6 H); 13C NMR (75 MHz,
CDCl3, ppm) δ 83.3, 81.5, 61.8, 58.5, 25.9, 24.6, 23.0, 18.3, −5.3 ; FT-
IR (thin film, cm−1) 3361, 2955, 2930, 2858, 1472, 1387, 1362, 1333,
1255, 1155, 1108, 1005, 938, 913, 837, 777, 723, 663; High-resolution
MS (ESI+, m/z) molecular ion [M + Na]+ calculated for C12H24O2Si1
251.1438, found 251.1435, error 1.1 ppm.
6-Hydroxylhex-3-yn-2-yl acetate (S18). To an oven-dried 100
mL round-bottom flask was added 40 mL of freshly distilled THF, 6 g
(22.3 mmol, 1 equiv) of the propargylic acetate S17, and 26 mL (26.6
mmol, 1.2 equiv) of 1 M solution of TBAF in THF. The reaction was
left to stir at room temperature until judged compete by TLC (5 h), at
which point the reaction was quenched with the addition of aqueous
ammonium chloride, extracted with diethyl ether, dried over sodium
sulfate, concentrated in vacuo (rotary evaporator) and column purified
over SiO2 using a gradient of 20−100% diethyl ether in hexanes to
afford the desired alcohol as a clear oil in 79% yield (2.77 g): Analytical
1
TLC Rf = 0.08 (1:4 ethyl acetate:petroleum ether); H NMR (500
MHz, CDCl3, ppm) δ 5.42−4.40 (m, 1 H), 3.71 (t, J = 7.5 Hz, 2 H),
2.56 (br s, 1 H), 2.48 (dt, J = 7.0, 2.0 Hz, 2 H), 2.07 (s, 3 H), 1.48 (d, J
= 7.0 Hz, 3 H); 13C NMR (75 MHz, CDCl3, ppm) δ 170.1, 82.0, 80.3,
60.7, 22.9, 21.5, 21.0; FT-IR (thin film, cm−1) 3420, 2989, 2939, 2884,
1733, 1435, 1373, 1340, 1239, 1168, 1058, 1021, 949, 847; High-
resolution MS (ESI+, m/z) molecular ion [M + Na]+ calculated for
C8H12O3 179.0679, found 179.0679, error 0.7 ppm.
L
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6-(N-(tert-Butoxycarbonyl)-4-(trifluoromethyl)phenylsulfon-
amido)hex-3-yn-2-yl acetate (S19). To an oven-dried 100 mL 3-
neck round-bottom flask was added 25 mL of freshly distilled THF,
0.83 g (5.3 mml, 1.1 equiv) of homopropargyl alcohol S18, 1.6 g (4.8
mmol, 1.0 equiv) of t-butyl 4-trifluoromethylphenysulfonylcarbamate,
and 1.5 g (5.8 mmol, 1.2 equiv) of triphenyl phosphine. The solution
was then cooled to 0 °C in an ice water bath. To the cooled solution
was then added 1.0 g (5.8 mmol, 1.2 equiv) of DEAD as a solution in 5
mL of THF. The solution was then left to warm to room temperature
and left to react for 36 h. The reaction was then concentrated and
purified via flash column chromatography using a gradient elution of
0−30% diethyl ether in hexanes to afford the desired propargylic
acetate as a clear oil in 27% yield (520 mg): Analytical TLC Rf = 0.42
(1:4 ethyl acetate:petroleum ether); 1H NMR (500 MHz, CDCl3,
ppm) δ 8.02 (d, J = 8.0 Hz, 2 H), 7.74 (d, J = 8.0 Hz, 2 H), 5.35 (q, J =
7.0 Hz, 1 H) 3.92 (t, J = 7.0 Hz, 2 H), 2.62 (t, J = 7.0 Hz, 2 H), 1.97
(s, 3 H), 1.36 (d, J = 7.0, 2 H), 1.27 (s, 9 H); 13C NMR (75 MHz,
CDCl3, ppm) δ 169.6, 150.2, 143.6, 134.9 (q, JC,F = 33 Hz), 128.3,
125.7, 124.8 (q, JC,F= 271 Hz), 85.0, 80.9, 80.8, 60.3, 45.0, 27.6, 21.3,
20.8, 19.9; FT-IR (thin film, cm−1) 2985, 2939, 1748, 1608, 1564,
1443, 1405, 1368, 1323, 1295, 1247, 1134, 1092, 1063, 1017, 970, 946,
916, 845, 769, 715; High-resolution MS (ESI+, m/z) molecular ion [M
+ Na]+ calculated for C20H24O6N1F3S1 486.1169, found 486.1186,
error 3.6 ppm.
45.2, 27.8, 21.5, 21.0, 20.1; FT-IR (thin film, cm−1) 3108, 2984, 2938,
1733, 1534, 1370, 1351, 1292, 1238, 1172, 1154, 1090, 1059, 1014,
970, 855, 742, 683; High-resolution MS (ESI+, m/z) molecular ion [M
+ Na]+ calculated for C19H24O8N2S1 463.1146, found 463.1142, error
0.6 ppm.
6-(4-Nitrophenylsulfonamido)hex-3-yn-2-yl acetate (35).
Following the standard procedure for TFA deprotection, the desired
compound was isolated as clear oil in 88% yield (1.57 g): Analytical
1
TLC Rf = 0.11 (1:4 ethyl acetate:petroleum ether); H NMR (500
MHz, CDCl3, ppm) δ 8.39 (d, J = 9.0 Hz, 2 H), 8.11 (d, J = 9.0 Hz, 2
H), 5.30−5.20 (m, 2 H), 3.17 (dt, J = 6.5, 6.0 Hz, 2 H), 2.42 (t, J = 6.5
Hz, 2 H), 2.09 (s, 3 H), 1.45 (d, J = 7.5 Hz, 3 H); 13C NMR (75 MHz,
CDCl3, ppm) δ 170.4, 150.1, 146.0, 128.3, 124.4, 81.9, 80.9, 60.6, 41.7,
21.1, 20.1; FT-IR (thin film, cm−1) 3287, 306, 2987, 2938, 1732, 1531,
1429, 1372, 1350, 1310, 1239, 1164, 1094, 1060, 1019, 949, 855, 736,
685, 665; High-resolution MS (ESI+, m/z) molecular ion [M + Na]+
calculated for C14H16O6N2S1 363.0621, found 363.0614, error 2.0
ppm.
Optimization Procedure (Table 1). Unless otherwise noted, the
catalyst was introduced from an oven-dried one dram vial that
contained 5 mol % of the gold source and 5 mol % silver source; the
metal salts were dissolved in 1 mL of the reaction solvent. The
solution was allowed to stir at room temperature for 5 min and then
filtered through a 1 cm plug of oven-dried Celite and eluted directly
into a 50 mL Schlenk tube with another 1 mL of the reaction solvent.
To the Schlenk tube was then added the propargylic acetate (0.11
mmol, 1.0 equiv) in 1.5 mL of the reaction solvent, bringing the
reaction volume to 3.5 mL. The reaction was then left at room
temperature until judged complete as determined by TLC analysis.
The resulting mixture was quenched with two to three drops of
triethylamine and concentrated in vacuo. Mesitylene was added as an
6-(4-(Trifluoromethyl)phenylsulfonamido)hex-3-yn-2-yl ace-
tate (32). Following the general procedure for TFA deprotection, the
following alkyne was isolated in quantitative yield (314 mg) as clear
1
oil: Analytical TLC Rf = 0.14 (1:4 ethyl acetate:petroleum ether); H
NMR (500 MHz, CDCl3, ppm) δ 7.96 (d, J = 8.5 Hz, 2 H), 7.71 (d, J
= 8.5 Hz, 2 H), 5.66 (br s, 1 H) 5.25−5.21 (m, 1 H), 3.06 (dd, J = 6.5,
6.0 Hz, 2 H), 2.33 (dt, J = 7.0, 2.0 Hz, 2 H), 1.96 (s, 3 H), 1.33 (d, J =
7.0, 2 H); 13C NMR (75 MHz, CDCl3, ppm) δ 170.1, 143.6, 134.7 (q,
JC,F = 33 Hz), 128.5 (q, JC,F= 271 Hz), 127.4, 126.1, 80.9, 60.4, 41.6,
21.0, 20.8, 19.9; FT-IR (thin film, cm−1) 3288, 2991, 2941, 2877, 1726,
1609, 1432, 1405, 1373, 1324, 1246, 1169, 1132, 1097, 1063, 1018,
950, 845, 711; High-resolution MS (ESI+, m/z) molecular ion [M +
Na]+ calculated for C15H16O4N1F3S1 386.0644, found 386.0638, error
1.6 ppm.
1
internal standard, and the ratio of products was determined by H
NMR relative to the internal standard. Conversion was determined by
integrating the doublet of triplets at 4.50 ppm (1 H) of the starting
material, to the doublet of triplets at 4.28 ppm (1 H) in the allene, and
to the doublet of doublet at 5.03 ppm (1 H), all relative to mesitylene.
When the reaction reached full conversion, the ratio of products was
determined by using the same two signals from the allene and the
dehydropyrrolidine.
6-(N-(tert-Butoxycarbonyl)-4-nitrophenylsulfonamide)hex-
3-yn-2-yl acetate (S20). See Scheme 15. To an oven-dried 250 mL
2-Methyl-5-phenyl-1-tosyl-1H-pyrrole (3). The pyrrole was
isolated from entry 1 (Table 1) by flash column chromatography using
silica gel (gradient elution 0−10% ethyl acetate in petroleum ether) as
an oil in 70% yield (27 mg): Analytical TLC Rf = 0.50 (1:4 ethyl
acetate:hexanes); 1H NMR (500 MHz, CDCl3, ppm) δ 7.33−7.29 (m,
7 H), 7.16 (d, J = 8.0 Hz, 2 H), 6.04 (d, J = 3.0 Hz, 1 H), 6.00−5.98
(m, 1 H), 2.51 (s, 3 H), 2.36 (s, 3 H); 13C NMR (75 MHz, CDCl3,
ppm) δ 144.3, 137.7, 136.4, 134.3, 133.2, 130.6, 129.4, 127.7, 127.2,
126.4, 115.2, 113.5, 21.5, 16.0; FT-IR (thin film, cm−1) 2928, 1596,
1530, 1483, 1443, 1369, 1306, 1247, 1188, 1173, 1118, 1015, 979, 913,
811, 761, 693, 657; High-resolution MS (EI+, m/z) molecular ion
[M]+ calculated for C18H17O2N1S1 311.0975, found 311.0983, error
2.6 ppm.
Scheme 15. Synthesis of Alkyne 35
5-(4-Methylphenylsulfonamido)-5-phenylpenta-1,2-dien-3-
yl acetate (4). The allene was isolated, for characterization purposes,
by combining several experiments from the initial optimization studies,
the compound was purified by flash column chromatography using
silica gel (gradient elution 0−40% ethyl acetate in petroleum ether)
affording 95 mg of 4 as clear oil: Analytical TLC Rf = 0.08 (1:4 ethyl
acetate:pentane); 1H NMR (500 MHz, CDCl3, ppm) δ 7.52 (d, J = 8.5
Hz, 2 H), 7.15−7.09 (m, 5 H), 6.96−6.94 (m, 2 H), 5.21 (d, J = 8.5
Hz, 1 H), 4.62 −(d, J = 6.5 Hz, 2 H), 4.28 (dt, J = 9.0, 9.0 Hz, 1 H),
2.57−2.46 (m, 2 H), 2.35 (s, 3 H), 2.16 (s, 3 H), 2.05−2.00 (m, 2 H),
13C (75 MHz, CDCl3, ppm) δ 203.5, 170.2, 143.0, 140.3, 137.4, 129.3,
128.5, 127.4, 126.9, 126.1, 68.9, 57.4, 35.0, 30.5, 21.3, 20.4; FT-IR
(thin film, cm−1) 3285, 3060, 3023, 2925, 2251, 1748, 1728, 1597,
1495, 1454, 1417, 1377, 1328, 1230, 1156, 1066, 911, 817, 735, 702;
High-resolution MS (EI+, m/z) molecular ion [M]+ calculated for
C20H21O4N1S1 371.1186, found 371.1196, error 2.7 ppm.
3-neck round-bottom flask was added 75 mL of freshly distilled THF,
2.8 g (17.9 mml, 1.2 equiv) of homopropargyl alcohol S18, 4.5 g (15.0
mmol, 1.0 equiv) of t-butyl 4-nitrophenysulfonylcarbamate, and 4.7 g
(17.9 mmol, 1.2 equiv) of triphenyl phosphine. The solution was then
cooled to 0 °C in an ice water bath. To the cooled solution was then
added 3.1 g (17.9 mmol, 1.2 equiv) of DEAD as a solution in 7 mL of
THF. The solution was then left to warm to room temperature and left
to react for 36 h. The reaction was then concentrated and purified via
flash column chromatography using a gradient elution of 0−30%
diethyl ether in hexanes to afford the desired propargylic acetate as a
clear oil in 85% yield (5.6 g): Analytical TLC Rf = 0.28 (1:4 ethyl
1
acetate:petroleum ether); H NMR (500 MHz, CDCl3, ppm) δ 8.39
(d, J = 8.5 Hz, 2 H), 8.16 (d, J = 8.5 Hz, 2 H), 5.43 (q, J = 6.5 Hz, 1
H), 4.00 (t, J = 7.0 Hz, 2 H), 2.70 (t, J = 6.5 Hz, 2 H), 2.06 (s, 3 H),
1.46 (d, J = 6.0 Hz, 3 H), 1.37 (s, 9 H); 13C NMR (75 MHz, CDCl3,
ppm) δ 169.8, 150.3, 150.2, 145.6, 129.2, 123.9, 85.6, 81.2, 80.8, 60.4,
General Procedure for the Synthesis of Dehydropyrroli-
dines (Table 2). To an oven-dried one dram vial was added 5 mol %
M
dx.doi.org/10.1021/jo500748e | J. Org. Chem. XXXX, XXX, XXX−XXX

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IPrAuCl and 5 mol % AgSbF6; the metal salts were dissolved in 1 mL
of THF. The solution was allowed to stir at room temperature for 5
min and then filtered through a 1 cm plug of oven-dried Celite and
eluted directly into a 50 mL Schlenk tube with another 1 mL of THF.
To the Schlenk tube was then added the propargylic acetate (0.3
mmol, 1.0 equiv) in 7 mL of THF, bringing the reaction volume to 9
mL. The reaction was then left at room temperature until judged
complete as determined by TLC analysis. The resulting mixture was
quenched with two to three drops of triethylamine and concentrated
in vacuo. Purification by chromatography on flash grade silica gel
(230−400 mesh) using gradient elution (0−40% ethyl acetate in
petroleum ether) afforded the analytically pure dehydropyrrolidines or
dehydropiperidines.
acetate:hexanes); 1H NMR (500 MHz, CDCl3, ppm) δ 7.88 (d, J = 9.0
Hz, 2 H), 7.71 (d, J = 8.5 Hz, 2 H), 7.58 (d, J = 9.0 Hz, 2 H), 7.35−
7.24 (m, 7 H), 5.36 (m, 2 H), 5.32 (s, 1 H), 5.17 (dd, J = 9.5, 2.0 Hz, 1
H), 2.66 (m, 1 H), 2.39 (s, 3 H), 2.28 (m, 1 H); 13C NMR (75 MHz,
CDCl3, ppm) δ 165.1, 143.9, 142.6, 138.6, 134.9, 131.7, 131.2, 129.7,
128.7, 128.6, 128.3, 127.6, 127.4, 125.7, 115.2, 64.8, 60.9, 37.2, 21.5;
FT-IR (thin film, cm−1) 1723, 1591, 1353, 1269, 1165, 1102, 1012;
High-resolution MS (ESI+, m/z) molecular ion [M + Na]+ calculated
for C25H22O4N1Br1S1 534.0345, found 534.0349, error 0.7 ppm.
(5-Phenyl-1-tosyl-4,5-dihydro-1H-pyrrol-2-yl)methyl ben-
zoate (15). According to the general procedure, dehydropyrrolidine
15 was obtained from alkyne 14 as a an oil in 86% yield (112 mg):
1
Analytical TLC Rf = 0.4 (1:4 ethyl acetate:hexanes); H NMR (500
(5-Phenyl-1-tosyl-4,5-dihydro-1H-pyrrol-2-yl)methyl acetate
(5). According to the general procedure, dehydropyrrolidine 5 was
obtained from alkyne 2 as a clear oil in 89% yield (89 mg): Analytical
TLC Rf = 0.33 (1:4 ethyl acetate:hexanes); 1H NMR (500 MHz,
CDCl3, ppm) δ 7.76 (d, J = 8.5 Hz, 2 H), 7.37−7.29 (m, 7 H), 5.28 (d,
J = 1.0 Hz, 1 H), 5.23 (dd, J = 14.5, 1.0 Hz, 1 H), 5.14 (dd, J = 7.0, 2.5
Hz, 1 H), 5.03 (dd, J = 14.0, 1.5 Hz, 1 H), 2.66 (m, 1 H), 2.47 (s, 3
H), 2.30 (m, 1 H), 2.14 (s, 3 H); 13C NMR (75 MHz, CDCl3, ppm) δ
170.3, 143.9, 142.7, 138.8, 134.8, 129.7, 128.8, 127.5, 127.5, 125.7,
114.4, 64.8, 60.4, 37.2, 21.6, 20.8; FT-IR (thin film, cm−1) 2938, 1744,
1597, 1495, 1450, 1348, 1225, 1164, 1119, 1086, 670; High-resolution
MS (ESI+, m/z) molecular ion [M + Na]+ calculated for
C20H21O4N1S1 394.1084, found 394.1081, error 0.7 ppm.
MHz, CDCl3, ppm) δ 8.08 (t, J = 8.0 Hz, 2 H), 7.77 (t, J = 8.5 Hz, 2
H), 7.60 (t, J = 7.0 Hz, 1 H), 7.47−7.43 (m, 2 H), 7.38−7.25 (m, 7
H), 5.47 (d, J = 14 Hz, 1 H), 5.35 (s, 1 H), 5.26 (d, J = 15 Hz, 1 H),
5.19−5.16 (m, 1 H), 2.72−2.65 (m, 1 H), 2.40 (s, 3 H), 2.29−2.26
(m, 1 H), 13C NMR (75 MHz, CDCl3, ppm) δ 165.8, 143.9, 142.7,
138.8, 134.9, 133.1, 129.7, 128.5, 128.4, 127.5, 127.4, 125.7, 114.8,
64.8, 60.7, 37.2, 21.5; FT-IR (thin film, cm−1) 3060, 2950, 1724, 1593,
1491, 1446, 1352, 1270, 1164, 1111, 1082, 1025, 911, 809, 711, 618;
High-resolution MS (EI+, m/z) molecular ion [M]+ calculated for
C25H23O4N1S1 433.1342, found 433.1334, error 1.8 ppm.
3-Phenyl-1-(1-tosyl-4,5-dihydro-1H-pyrrol-2-yl)propyl ace-
tate (17). According to the general procedure, dehydropyrrolidine
17 was obtained from alkyne 16 as a white solid in 67% yield (140
mg): mp 140−142 °C; Analytical TLC Rf = 0.22 (1:4 ethyl
(1-Tosyl-4,5-dihydro-1H-pyrrol-2-yl)methyl acetate (7). Ac-
cording to the general procedure, dehydropyrrolidine 7 was obtained
from alkyne 6 as a white solid in 75% yield (75 mg): mp 78−80 °C;
1
acetate:hexanes); H NMR (500 MHz, CDCl3, ppm) δ 7.87 (dd, J
= 8.5, 2.5 Hz, 2 H), 7.32−7.25 (m, 4 H), 7.23 (d, J = 8.0 Hz, 2 H),
7.18 (t, J = 8.0 Hz, 1 H), 6.10−6.08 (m, 1 H), 5.15 (s, 1 H), 3.78−3.71
(m, 2 H), 2.78−2.67 (m, 2 H), 2.46−2.41 (m, 4 H), 2.14−2.07 (m, 5
H), 1.94−1.87 (m, 1 H); 13C NMR (75 MHz, CDCl3, ppm) δ 170.1,
143.8, 143.1, 141.4, 133.4, 129.6, 128.4, 128.3, 128.0, 125.8, 112.9,
71.2, 51.2, 34.8, 31.6, 27.2, 21.5, 20.9; IR (thin film, cm−1) 3026, 2859,
1743, 1597, 1495, 1451, 1349, 1294, 1232, 1163, 1090, 1044, 979, 933,
815, 751, 694, 665; High-resolution MS (ESI+, m/z) molecular ion [M
+ Na]+ calculated for C22H25O4N1S1 422.1397, found 422.1413, error
4.0 ppm.
2-Phenethyl-1-tosyl-1,2,5,6-tetrahydropyridin-3-yl acetate
(18). According to the general procedure, dehydropiperidine 18 was
obtained from alkyne 16 as an oil in 29% yield (64 mg): Analytical
TLC Rf = 0.16 (1:4 ethyl acetate:hexanes); 1H NMR (500 MHz,
CDCl3, ppm) δ 7.71 (d, J = 7.5 Hz, 2 H), 7.29−7.25 (m, 4 H), 7.20−
7.17 (m, 3 H), 5.40−5.38 (m, 1 H), 4.52 (d, J = 4.0 Hz, 1 H), 3.98
(dd, J = 14.5, 6.0 Hz, 1 H), 3.34−3.27 (m, 1 H), 2.81−2.68 (m, 2 H),
2.41 (s, 3 H), 2.05 (s, 3 H), 2.01−1.90 (m, 3 H), 1.83 (dd, J = 16.5, 3.5
Hz, 1 H); 13C NMR (75 MHz, CDCl3, ppm) δ 168.5, 146.3, 143.4,
141.4, 137.9, 129.7, 128.3, 128.3, 126.9, 125.9, 114.6, 52.8, 38.4, 36.8,
32.3, 25.2, 21.5, 20.9; IR (thin film, cm−1) 3026, 2943, 2861, 1759,
1692, 1598, 1564, 1495, 1453, 1366, 1339, 1223, 1203, 1160, 1133,
1096, 1044, 1018, 953, 920, 814, 709, 690, 656; High-resolution MS
(ESI+, m/z) molecular ion [M + Na]+ calculated for C22H25N1O4S1
422.1397, found 422.1398, error 0.4 ppm.
Optimization of Heterocycle Synthesis (Table 3). To an oven-
dried one dram vial was added 5 mol % of the gold catalyst and 5 mol
% of the silver cocatalyst; the metal salts were dissolved in 1 mL of the
reaction solvent. The solution was allowed to stir at room temperature
for 5 min and then filtered through a 1 cm plug of oven-dried Celite
and eluted directly into a 50 mL Schlenk tube with another 1 mL of
the reaction solvent. To the Schlenk tube was then added the
propargylic acetate (0.3 mmol, 1.0 equiv) in 7 mL of the reaction
solvent, bringing the total reaction volume to 9 mL. After 4 h, the
reaction was quenched by the addition of two to three drops of
triethylamine and concentrated in vacuo. 0.1 mmol of mesitylene was
added to the crude reaction mixture, and the ratio of the three
products was determined by 1H NMR analysis. The product ratio was
established by integrating the singlet at 5.99 ppm (1 H) of the pyrrole,
the singlet at 5.19 ppm (1 H) of the dehydropyrrolidine, and the
singlet at 4.58 ppm (1 H) of the dehydropiperidine. All three products
1
Analytical TLC Rf = 0.19 (1:4 ethyl acetate:hexanes); H NMR (500
MHz, CDCl3, ppm) δ 7.75 (d, J = 8.5 Hz, 2 H), 7.34 (d, J = 8.0 Hz, 2
H), 5.25 (s, 1 H), 4.99 (s, 2 H), 3.82 (t, J = 8.5, 2 H), 2.43 (s, 3 H)
2.23−2.20 (m, 2 H), 2.10 (s, 3 H); 13C NMR (75 MHz, CDCl3, ppm)
δ 170.3, 143.9, 138.9, 134.2, 129.7, 127.6, 114.7, 60.0, 50.4, 27.4, 21.5,
20.8; IR (thin film, cm−1) 2938, 1744, 1659, 1601, 1450, 1348, 1238,
1160, 1091, 1054, 813; High-resolution MS (ESI+, m/z) molecular ion
[M + Na]+ calculated for C14H17O4N1S1 318.0771, found 318.0767,
error 0.9 ppm.
(5-Cyclohexyl-1-tosyl-4,5-dihydro-1H-pyrrol-2-yl)methyl ac-
etate (9). According to the general procedure, dehydropyrrolidine 9
was obtained from alkyne 8 as a white solid in 88% yield (100 mg):
mp 135−137 °C; analytical TLC Rf = 0.36 (1:4 ethyl acetate:hexanes);
1H NMR (500 MHz, CDCl3, ppm) δ 7.71 (d, J = 8.5 Hz, 2 H), 7.30
(d, J = 8.0 Hz, 2 H), 5.22 (s, 1 H), 5.15 (d, J = 14.5 Hz, 1 H), 4.85 (d,
J = 14.5 Hz, 1 H), 3.86−3.83 (m, 1 H), 2.42 (s, 3 H), 2.10 (s, 3 H),
1.99−1.92 (m, 2 H), 1.77−1.56 (m, 7 H), 1.26−0.97 (m, 5 H); 13C
NMR (75 MHz, CDCl3, ppm) δ 170.3, 143.7, 138.7, 134.4, 129.5,
127.5, 125.6, 117.0, 67.5, 60.6, 42.9, 30.1, 28.3, 27.2, 26.5, 26.1, 26.0,
21.5, 20.8; FT-IR (thin film, cm−1) 3199, 2929, 1748, 1446, 1344,
1221, 1168, 1054; High-resolution MS (EI+, m/z) molecular ion [M]+
calculated for C20H27O4N1S1 377.1655, found 377.1662, error 1.8
ppm.
(5-Phenyl-1-tosyl-4,5-dihydro-1H-pyrrol-2-yl)methyl 4-ni-
trobenzoate (11). According to the general procedure, dehydro-
pyrrolidine 11 was obtained from alkyne 10 as a white solid in 89%
yield (125 mg): mp 147−149 °C; Analytical TLC Rf = 0.21 (1:4 ethyl
acetate:hexanes); 1H NMR (500 MHz, CDCl3, ppm) δ 8.29 (d, J = 9.5
Hz, 2 H), 8.20 (d, J = 9.0 Hz, 2 H), 7.74 (d, 8.5 Hz, 2 H), 7.38 (d, J =
8 Hz, 2 H) 7.30−7.27 (m, 5 H), 5.42−5.33 (m, 3 H), 5.17 (dd, J = 9.5,
2.5 Hz, 1 H), 2.71−2.65 (m, 1 H), 2.41 (s, 3 H), 2.33−2.29 (m, 1 H);
13C NMR (75 MHz, CDCl3, ppm) δ 163.8, 150.4, 143.9, 142.4, 138.0,
135.0, 134.7, 130.7, 129.7, 128.5, 127.6, 127.3, 125.6, 123.4, 115.9,
64.8, 61.5, 37.1 21.6; FT-IR (thin film, cm−1) 1724, 1654, 1597, 1528,
1491, 1446, 1348, 1279, 1168, 1103, 1013, 952, 845, 723 ; High-
resolution MS (ESI+, m/z) molecular ion [M + Na]+ calculated for
C25H22O6N2S1 501.1091, found 501.1089, error 0.3 ppm.
(5-Phenyl-1-tosyl-4,5-dihydro-1H-pyrrol-2-yl)methyl 4-bro-
mobenzoate (13). According to the general procedure, dehydro-
pyrrolidine 13 was obtained from alkyne 12 as a white solid in 89%
yield (134 mg): mp 122−125 °C; Analytical TLC Rf = 0.29 (1:5 ethyl
N
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could be separated by standard column chromatography and were
characterized as such.
6.05−6.01 (m, 1 H), 5.16 (s, 1 H), 3.84−3.71 (m, 2 H), 2.42 (s, 3 H),
2.13−2.07 (m, 1 H), 1.97−1.92 (m, 1 H), 1.54 (d, J = 6.0 Hz, 3 H),
1.25 (s, 9 H); 13C NMR (75 MHz, CDCl3, ppm) δ 177.1, 145.1, 143.7,
133.6, 129.6, 127.9, 112.1, 67.3, 51.2, 38.7, 27.3, 27.2, 21.5, 20.1; IR
(thin film, cm−1) 2976, 2913, 2858, 1727, 1650, 1596, 1480, 146, 1349,
1281, 1163, 1083, 982, 911, 815, 732, 714, 665; High-resolution MS
(ESI+, m/z) molecular ion [M + Na]+ calculated for C18H25O4N1S1
374.1397, found 374.1391, error 1.3 ppm.
2-Methyl-1-tosyl-1,2,5,6-tetrahydropyridin-3-yl pivalate
(25). According to the general procedure, dehydropiperidine 25 was
obtained from alkyne 23 as an oil in 32% yield (30 mg): Analytical
TLC Rf = 0.32 (1:4 ethyl acetate:hexanes); 1H NMR (500 MHz,
CDCl3, ppm) δ 7.72 (d, J = 7.5 Hz, 2 H), 7.29 (d, J = 8.0 Hz, 2 H),
5.32 (s, 1 H), 4.58 (s, 1 H), 3.90 (dd, J = 14.0, 5.0 Hz, 1 H), 3.30−3.24
(m, 1 H), 2.41 (s, 3 H), 1.88 (dd, J = 16.5, 3.5 Hz, 1 H), 1.29 (d, J =
6.5 Hz, 3 H), 1.20 (s, 9 H); 13C NMR (75 MHz, CDCl3, ppm) δ
176.5, 146.3, 143.2, 138.0, 129.7, 126.8, 115.9, 48.8, 38.8, 37.8, 26.9,
26.0, 21.5, 20.7; IR (thin film, cm−1) 2976, 2922, 2858, 1727, 1455,
1347, 1283, 1157, 1084, 984, 912, 812, 731, 667; High-resolution MS
(ESI+, m/z) molecular ion [M]+ calculated for C18H25O4N1S1
374.1397, found 374.1388, error 2.0 ppm.
1-(1-Tosyl-4,5-dihydro-1H-pyrrol-2-yl)ethyl 4-nitrobenzoate
(29). According to the general procedure, dehydropyrrolidine 29 was
obtained from alkyne 28 as a white solid in 70% yield (87 mg): mp
135 °C (decomposition); Analytical TLC Rf = 0.28 (1:4 ethyl
acetate:hexanes); 1H NMR (500 MHz, CDCl3, ppm) δ 8.31 (d, J = 8.0
Hz, 2 H), 8.28 (d, J = 8.0 Hz, 2 H), 7.86 (d, J = 8.5 Hz, 2 H), 7.34 (d, J
= 8.0 Hz, 2 H), 6.34−6.33 (m, 1 H), 5.29 (s, 1 H), 3.90−3.79 (m, 2
H), 2.42 (s, 3 H), 2.18−2.12 (m, 1 H), 2.05−2.00 (m, 1 H), 1.71 (d, J
= 6.0 Hz, 3 H); 13C NMR (75 MHz, CDCl3, ppm) δ 163.6, 150.5,
144.0, 143.9, 135.5, 133.7, 130.8, 129.6, 129.2, 127.7, 123.5, 113.4,
69.0, 51.2, 27.3, 21.5, 19.9; IR (thin film, cm−1) 3111, 2938, 2860,
1727, 1651, 1598, 1528, 1448, 1347, 1273, 1163, 1102, 1014, 982, 912,
874, 841, 815, 720, 586; High-resolution MS (ESI+, m/z) molecular
ion [M + Na]+ calculated for C20H20O6N2S1 439.0934, found
439.0926, error 1.7 ppm.
1-(1-Tosyl-4,5-dihydro-1H-pyrrol-2-yl)ethyl acetate (20). Ac-
cording to the general procedure, dehydropyrrolidine 20 was obtained
from alkyne 19 as an oil in 26% yield (25 mg): Analytical TLC Rf =
0.31 (1:4 ethyl acetate:hexanes); 1H NMR (500 MHz, CDCl3, ppm) δ
7.84 (d, J = 8.0 Hz, 2 H), 7.33 (d, J = 8.5 Hz, 2 H), 6.07−6.02 (m, 1
H), 5.19 (s, 1 H), 3.86−3.73 (m, 2 H), 2.42 (s, 3 H), 2.16−2.10 (m, 4
H), 2.00−1.94 (m, 1 H), 1.55 (d, J = 6.5 Hz, 3 H); 13C NMR (75
MHz, CDCl3, ppm) δ 170.0, 144.7, 143.8, 133.7, 129.6, 127.9, 112.5,
67.5, 51.2, 27.3, 21.5, 21.1, 20.0; IR (thin film, cm−1) 3292, 2986,
2933, 1740, 1593, 1373, 1348, 1238, 1164, 1078, 1013, 817, 662;
High-resolution MS (ESI+, m/z) molecular ion [M + Na]+ calculated
for C15H19O4N1S1 332.0927, found 332.0934, error 2.2 ppm.
2-Methyl-1-tosyl-1,2,5,6-tetrahydropyridin-3-yl acetate (21).
According to the general procedure, dehydropiperidine 21 was
obtained from alkyne 19 as an oil in 64% yield (60 mg): Analytical
TLC Rf = 0.25 (1:4 ethyl acetate:hexanes); 1H NMR (500 MHz,
CDCl3, ppm) δ 7.71 (d, J = 8.0 Hz, 2 H), 7.29 (d, J = 8.0 Hz, 2 H),
5.35−5.33 (m, 1 H), 4.58 (s, 1 H), 3.92 (dd, J = 14.5, 6.0 Hz, 1 H),
3.30−3.24 (m, 1 H), 2.42 (s, 3 H), 2.16−2.11 (m, 1 H), 2.07 (s, 3 H),
1.91 (dd, J = 17.5, 4.0 Hz, 1 H), 1.29 (d, J = 6.5 Hz, 3 H); 13C NMR
(75 MHz, CDCl3, ppm) δ 168.7, 146.0, 143.2, 138.0, 129.7, 126.8,
116.2, 48.8, 37.8, 26.0, 21.5, 20.9, 20.7 ; IR (thin film, cm−1) 2974,
2933, 1753, 1687, 1589, 1454, 1360, 1336, 1221, 1201, 1156, 1136,
1082, 997, 915, 817, 715; High-resolution MS (EI+, m/z) molecular
ion [M]+ calculated for C15H19O4N1S1 309.1029, found 309.1026,
error 1.2 ppm.
2-Ethyl-1-tosyl-1H-pyrrole (22). The pyrrole 22 was isolated, for
characterization purposes, by combining several experiments from the
optimization studies (Table 3), the compound was purified by flash
column chromatography using silica gel (gradient elution 0−10% ethyl
acetate in petroleum ether): Analytical TLC Rf = 0.55 (1:4 ethyl
acetate:hexanes); 1H NMR (500 MHz, CDCl3, ppm) δ 7.65 (d, J = 8.5
Hz, 2 H), 7.29−7.27 (m, 3 H), 6.20 (t, J = 3.0 Hz, 1 H), 5.99 (s, 1 H),
2.69 (q, J = 8.0 Hz, 2 H), 2.40 (s, 3 H), 1.16 (t, J = 7.5 Hz, 3 H); 13C
NMR (75 MHz, CDCl3, ppm) δ 144.7, 137.3, 136.4, 129.9, 126.7,
122.2, 111.1, 110.9, 21.6, 20.4, 12.6; FT-IR (thin film, cm−1) 2974,
2919, 1596, 1484, 1441, 1365, 1177, 155, 1126, 1092, 1051, 872, 813,
685; High-resolution MS (ESI+, m/z) molecular ion [M + H]+
calculated for C13H15O2N1S1 250.0896, found 250.0895, error 0.2
ppm.
2-Methyl-1-tosyl-1,2,5,6-tetrahydropyridin-3-yl 4-methoxy-
benzoate (31). According to the general procedure, dehydropiper-
idine 31 was obtained from alkyne 30 as an oil in 58% yield (72 mg):
1
Analytical TLC Rf = 0.29 (1:4 ethyl acetate:hexanes); H NMR (500
MHz, CDCl3, ppm) δ 7.96 (d, J = 9.0 Hz, 2 H), 7.75 (d, J = 8.5 Hz, 2
H), 7.31 (d, J = 8.0 Hz, 2 H), 6.92 (d, J = 9.0 Hz, 2 H), 5.47−5.46 (m,
1 H), 4.64 (br s, 1 H), 3.96 (dd, J = 14.5, 6.0 Hz, 1 H), 3.86 (s, 3 H),
3.37−3.31 (m, 1 H), 2.43 (s, 3 H), 2.31−2.24 (m, 1 H), 2.04 (dd, J =
16.5, 2.5, 1 H), 1.33 (d, J = 6.5 Hz, 3 H); 13C NMR (75 MHz, CDCl3,
ppm) δ 164.2, 163.8, 146.4, 143.2, 138.1, 131.9, 129.7, 126.8, 121.6,
116.4, 113.7, 55.5, 48.9, 37.9, 26.3, 21.5, 20.7; IR (thin film, cm−1)
3078, 2980, 2933, 2842, 1731, 1605, 1511, 1458, 1444, 1365, 1338,
1258, 1167, 1141, 1095, 1028, 995, 903, 848, 815, 765, 687, 613; High-
resolution MS (ESI+, m/z) molecular ion [M + Na]+ calculated for
C21H23O5N1S1 424.1189, found 424.1181, error 1.8 ppm.
Study of Role of Sulfonamide on Product Ratio (Table 5). To
an oven-dried one dram vial was added 5 mol % of the PPh3AuCl and
5 mol % of AgSbF6; the metal salts were dissolved in 1 mL of
dichloromethane. The solution was allowed to stir at room
temperature for 5 min and then filtered through a 1 cm plug of
oven-dried Celite and eluted directly into a 50 mL Schlenk tube with
another 1 mL of dichloromethane. To the Schlenk tube was then
added the propargylic acetate (0.3 mmol, 1.0 equiv) in 7 mL of
dichloromethane, bringing the total reaction volume to 9 mL. After 4
h, the reaction was quenched with the addition of two to three drops
of triethylamine and concentrated in vacuo. 0.1 mmol of mesitylene
was added to the crude reaction mixture, and the ratio of the two
products was determined by 1H NMR analysis. The product ratio
between the dehydropyrrolidine and the dehydropiperidine was
established by integrating the singlet at 5.24 ppm (1 H) of the
dehydropyrrolidine, and the singlet at 4.62 ppm (1 H) of the
dehydropiperidine.
Effect of the Acyl Group on Product Ratio (Table 4). To an
oven-dried one dram vial was added 5 mol % of the PPh3AuCl and 5
mol % of AgSbF6; the metal salts were dissolved in 1 mL of THF. The
solution was allowed to stir at room temperature for 5 min and then
filtered through a 1 cm plug of oven-dried Celite and eluted directly
into a 50 mL Schlenk tube with another 1 mL of THF. To the Schlenk
tube was then added the propargylic acetate (0.3 mmol, 1.0 equiv) in 7
mL of THF, bringing the reaction volume to 9 mL. After 4 h, the
reaction was quenched with the addition of two to three drops of
triethylamine and concentrated in vacuo. 0.1 mmol of mesitylene was
added to the crude reaction mixture, and the ratio of the three
1
products was determined by H NMR analysis. The product ratio
between the dehydropyrrolidine and the dehydropiperidine was
established by integrating the singlet at 5.19 ppm (1 H) of the
dehydropyrrolidine, and the singlet at 4.58 ppm (1 H) of the
dehydropiperidine. All products could be separated by standard
column chromatography except for the benzoate (alkyne 26) and the
p-bromo benzoate (alkyne 27). The ratio of these products was
established by 1H NMR by analogy to the previously isolated
compounds. These two compounds were separated by hydrolysis of
the benzoate and separation of the resulting alcohol and ketone
products. These two products were characterized after hydrolysis, and
yield reported is of the material isolated after hydrolysis.
1-(1-Tosyl-4,5-dihydro-1H-pyrrol-2-yl)ethyl pivalate (24).
According to the general procedure, dehydropyrrolidine 24 was
obtained from alkyne 23 as an oil in 26% yield (25 mg): Analytical
TLC Rf = 0.41 (1:4 ethyl acetate:hexanes); 1H NMR (500 MHz,
CDCl3, ppm) δ 7.84 (d, J = 8.0 Hz, 2 H), 7.33 (d, J = 8.0 Hz, 2 H),
1-(1-(4-(Trifluoromethyl)phenylsulfonyl)-4,5-dihydro-1H-
pyrrol-2-yl)ethyl acetate (33). According to the general procedure,
O
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dehydropyrrolidine 33 was obtained from alkyne 32 as an oil in 33%
yield (100 mg): Analytical TLC Rf = 0.34 (1:4 ethyl acetate:hexanes);
1H NMR (500 MHz, CDCl3, ppm) δ 8.14 (d, J = 8.0 Hz, 2 H), 7.82
dehydropyrrolidine, and the singlet at 4.62 ppm (1 H) of the
dehydropiperidine.
1-(5-Phenyl-1-tosyl-4,5-dihydro-1H-pyrrol-2-yl)ethyl acetate
(39). According to the general procedure, dehydropyrrolidine 39 was
obtained from alkyne 38 as a 1:1 mixture of diastereomers, and white
solid in 32% yield (37 mg): mp 132−135 °C (decomposition);
(d, J = 9.0 Hz, 2 H), 6.06−6.01 (m, 1 H), 5.24−5.22 (m, 1 H), 3.91−
3.84 (m, 1 H), 3.78−3.72 (m, 1 H), 2.22−2.14 (m, 1 H), 2.12 (s, 3 H),
2.02−1.94 (m, 1 H), 1.56 (d, J = 6.5 Hz, 3 H); 13C NMR (75 MHz,
CDCl3, ppm) δ 170.0, 144.4, 140.2, 134.8 (q, JC,F = 33.2 Hz), 128.5,
126.2, 125.0 (q, JC,F = 271.4 Hz), 112.9, 67.3, 51.3, 27.2, 21.0, 20.0; IR
(thin film, cm−1) 3103, 2992, 2940, 2862, 1742, 1653, 1607, 1449,
1404, 1355, 1324, 1241, 1169, 1134, 1110, 1084, 1063, 1016, 984, 930,
845, 786, 739, 719; High-resolution MS (ESI+, m/z) molecular ion [M
+ Na]+ calculated for C15H16O4N1F3S1 386.0644, found 386.0651,
error 1.8 ppm.
2-Methyl-1-(4-(trifluoromethyl)phenylsulfonyl)-1,2,5,6-tet-
rahydropyridin-3-yl acetate (34). According to the general
procedure, dehydropiperidine 34 was obtained from alkyne 32 as an
oil in 53% yield (160 mg): Analytical TLC Rf = 0.26 (1:4 ethyl
acetate:hexanes); 1H NMR (500 MHz, CDCl3, ppm) δ 7.97 (d, J = 8.0
Hz, 2 H), 7.77 (d, J = 8.5 Hz, 2 H), 5.37−5.36 (m, 1 H), 4.63 (t, J =
7.0 Hz, 1 H), 3.98 (dd, J = 14.0, 6.0 Hz, 1 H), 3.35−3.29 (m, 1 H),
2.20−2.12 (m, 1 H), 2.07 (s, 3 H), 1.95 (dd, J = 17.0, 4.5 Hz, 1 H);
13C NMR (75 MHz, CDCl3, ppm) δ 168.6, 146.0, 144.6, 134.8 (q, JC,F
1
Analytical TLC Rf = 0.30 (1:4 ethyl acetate:hexanes); H NMR (500
MHz, CDCl3, ppm) δ 7.68 (d, J = 8.0 Hz, 2 H), 7.40 (d, J = 7.5 Hz, 2
H), 7.32 (t, J = 7.0 Hz, 2 H), 7.28−7.24 (m, 3 H), 6.00 (q, J = 6.5 Hz,
1 H), 5.35 (s, 1 H), 5.29 (dd, J = 9.5, 2.0 Hz, 1 H), 2.72−2.65 (m, 1
H), 2.42 (s, 3 H), 2.25−2.21 (m, 1 H), 2.07 (s, 3 H), 1.51 (d, J = 7.0
Hz, 3 H); 13C NMR (75 MHz, CDCl3, ppm) δ 170.1, 143.9, 143.7,
142.8, 135.6, 129.6, 128.5, 127.4, 127.3, 125.7, 114.7, 65.8, 64.7, 37.2,
21.5, 21.1, 18.2; IR (thin film, cm−1) 3029, 2938, 1739, 1598, 1450,
1350, 1240, 1165, 1090, 996, 814, 736, 670; High-resolution MS
(ESI+, m/z) molecular ion [M + Na]+ calculated for C21H23O4N1S1
408.1240, found 408.1238, error 0.4 ppm.
2-Methyl-6-phenyl-1-tosyl-1,2,5,6-tetrahydropyridin-3-yl
acetate (40). According to the general procedure, dehydropyrrolidine
40 was obtained from alkyne 38 as a 1:1mixture of diastereomers, as a
clear oil in 60% yield (69 mg): Analytical TLC Rf = 0.24 (1:4 ethyl
acetate:hexanes); 1H NMR (500 MHz, CDCl3, ppm) δ 7.92 (d, J = 8.5
Hz, 2 H), 7.76 (d, J = 8.0 Hz, 2 H), 7.62 (d, J = 7.5 Hz, 2 H), 7.37−
7.31 (m, 10 H), 7.29−7.25 (m, 2 H), 6.20−6.18 (m, 1 H), 5.41 (d, J =
7.0 Hz, 1 H), 5.31−5.30 (m, 1 H), 5.12−5.10 (m, 1 H), 5.04 (d, J =
9.5 Hz, 1 H), 4.62−4.60 (m, 1 H), 2.47−2.41 (m, 7 H), 2.36−2.31 (m,
1 H), 2.22−2.18 (m, 1 H), 2.13−2.11 (m, 6 H), 1.63 (d, J = 6.5 Hz, 3
H), 0.78 (d, J = 6.5 Hz, 3 H); 13C NMR (75 MHz, CDCl3, ppm) δ
169.9, 168.8, 144.3, 144.0, 143.9, 143.4, 142.8, 140.0, 137.8, 133.8,
129.9, 129.7, 128.6, 128.2, 128.1, 127.9, 127.6, 127.5, 126.7, 125.7,
115.7, 111.1, 68.2, 65.2, 52.1, 49.6, 36.5, 26.6, 22.0, 21.6, 21.1, 21.0,
20.; IR (thin film, cm−1) 2962, 1744, 1597, 1499, 1446, 1368, 1348,
1242, 1217, 1164, 1136, 1091, 993, 915, 817, 735, 715; High-
resolution MS (ESI+, m/z) molecular ion [M + Na]+ calculated for
C21H23O4N1S1, 408.1240 found 408.1241, error 0.4 ppm.
= 33.1 Hz), 127.2, 126.4, 125.0 (q, JC,F = 270.2 Hz), 116.1, 49.1, 37.9,
26.0, 20.8, 20.7; IR (thin film, cm−1) 2978, 2935, 1761, 1695, 1608,
1460, 1432, 1404, 1365, 1324, 1274, 1225, 1206, 1164, 1137, 1108,
1090, 1062, 1015, 995, 969, 909, 844, 786, 737, 717, 682, 625; High-
resolution MS (ESI+, m/z) molecular ion [M + Na]+ calculated for
C15H16O4 N1F3S1 386.0644, found 386.0645, error 0.4 ppm.
1-(1-(4-Nitrophenylsulfonyl)-4,5-dihydro-1H-pyrrol-2-yl)-
ethyl acetate (36). According to the general procedure, dehy-
dropyrrolidine 36 was obtained from alkyne 35 as an oil in 31% yield
1
(63 mg): Analytical TLC Rf = 0.20 (1:4 ethyl acetate:hexanes); H
NMR (500 MHz, CDCl3, ppm) δ 8.39 (d, J = 8.0 Hz, 2 H), 8.21 (d, J
= 9.0 Hz, 2 H), 6.02−6.00 (m, 1 H), 5.24 (s, 1 H), 3.93−3.87 (m, 1
H), 3.79 (dt, J = 10.0, 5.0 Hz, 1 H), 2.24−2.17 (m, 1 H), 2.11 (s, 3 H),
2.03−1.95 (m, 1 H), 1.56 (d, J = 7.0 Hz, 3 H); 13C NMR (75 MHz,
CDCl3, ppm) δ 170.1, 150.3, 144.3, 142.4, 129.2, 124.2, 113.0, 67.3,
51.4, 27.2, 21.0, 20.0; IR (thin film, cm−1) 3106, 2989, 2938, 2866,
1740, 1606, 1531, 1351, 1309, 1240, 1168, 1085, 1042, 1014, 985, 856,
740, 686; High-resolution MS (ESI+, m/z) molecular ion [M + Na]+
calculated for C14H16O6N2S1 363.0621, found 363.0627, error 1.6
ppm.
2-Methyl-1-(4-nitrophenylsulfonyl)-1,2,5,6-tetrahydropyri-
din-3-yl acetate (37). According to the general procedure,
dehydropiperidine 37 was obtained from alkyne 35 as an oil in 39%
yield (79 mg): Analytical TLC Rf = 0.12 (1:4 ethyl acetate:hexanes);
1H NMR (500 MHz, CDCl3, ppm) δ 8.35 (d, J = 8.5 Hz, 2 H), 8.03
(d, J = 9.0 Hz, 2 H), 5.37−5.36 (m, 1 H), 4.62 (t, J = 6.5 Hz, 1 H),
4.01 (dd, J = 14.5, 6.5 Hz, 1 H), 3.38−3.32 (m, 1 H), 2.18−2.10 (m, 1
H), 2.05 (s, 3 H), 1.94−1.86 (m, 1 H), 1.34 (d, J = 7.0 Hz, 3 H); 13C
NMR (75 MHz, CDCl3, ppm) δ 168.5, 149.9, 146.8, 146.0, 127.9,
124.5, 116.0, 49.3, 37.9, 25.9, 20.7; IR (thin film, cm−1) 3106, 2978,
2934, 1759, 1693, 1606, 1530, 1461, 1431, 1350, 1311, 1274, 1225,
1205, 1163, 1138, 1109, 1087, 1012, 996, 969, 910, 855, 740, 692, 624;
High-resolution MS (ESI+, m/z) molecular ion [M + Na]+ calculated
for C14H16O6N2S1 363.0621, found 363.0618, error 0.9 ppm.
2-Methyl-1-(1-tosyl-4,5-dihydro-1H-pyrrol-2-yl)propyl ace-
tate (42). According to the general procedure, dehydropyrrolidine
42 was obtained from alkyne 41 as an oil in 15% yield (15 mg):
1
Analytical TLC Rf = 0.43 (1:4 ethyl acetate:hexanes); H NMR (500
MHz, CDCl3, ppm) δ 7.89 (d, J = 7.5 Hz, 2 H), 7.33 (d, J = 8.5 Hz, 2
H), 5.99 (s, 1 H), 5.12 (s, 1 H), 3.82−3.74 (m, 2 H), 2.54−2.48 (m, 1
H), 2.42 (s, 3 H), 2.13 (s, 3 H), 2.11−2.05 (m, 1 H), 1.89−1.81 (m, 1
H), 1.03 (d, J = 7.0 Hz, 3 H), 0.87 (d, J = 6.5 Hz, 3 H); 13C NMR (75
MHz, CDCl3, ppm) δ 170.4, 143.8, 142.4, 133.4, 129.5, 128.1, 113.8,
75.1, 51.3, 29.5, 27.2, 21.5, 20.8, 19.2, 15.3; IR (thin film, cm−1) 2966,
2932, 2874, 1741, 1597, 1467, 1350, 1239, 1163, 1091, 1026, 986, 905,
816, 773, 708, 691, 670; High-resolution MS (ESI+, m/z) molecular
ion [M + Na]+ calculated for C17H23O4N1S1 360.1240, found
360.1245, error 1.4 ppm.
2-Isopropyl-1-tosyl-1,2,5,6-tetrahydropyridin-3-yl acetate
(43). According to the general procedure, dehydropiperidine 43 was
obtained from alkyne 41 as an oil in 34% yield (35 mg): Analytical
TLC Rf = 0.33 (1:4 ethyl acetate:hexanes); 1H NMR (500 MHz,
CDCl3, ppm) δ 7.71 (d, J = 8.0 Hz, 2 H), 7.27 (d, J = 8.5 Hz, 2 H),
5.48−5.47 (m, 1 H), 4.16 (t, J = 3.5 Hz, 1 H), 3.93−3.87 (dd, J = 15.0,
6.5 Hz, 1 H), 3.30−3.24 (m, 1 H), 2.41 (s, 3 H), 2.04 (s, 3 H), 1.95−
1.82 (m, 2 H), 1.77 (dd, J = 16.5, 4.5 Hz, 1 H), 1.03 (d, J = 6.5 Hz, 3
H), 0.99 (d, J = 6.0 Hz, 3 H); 13C NMR (75 MHz, CDCl3, ppm) δ
168.6, 146.2, 143.2, 138.1, 129.6, 126.9, 133.4, 58.6, 39.1, 33.8, 24.7,
21.5, 20.8, 20.1, 19.1; IR (thin film, cm−1) 2963, 2928, 2873, 1756,
1692, 1598, 1452, 1367, 1338, 1221, 1204, 1159, 1134, 1092, 1045,
1010, 952, 918, 815, 714, 660; High-resolution MS (ESI+, m/z)
molecular ion [M + Na]+ calculated for C17H23O4N1S1 360.1240,
found 360.1237, error 0.8 ppm.
Influence of Propargylic Substitution on the Product Ratio
(Table 6). To an oven-dried one dram vial was added 5 mol % of the
PPh3AuCl and 5 mol % of AgSbF6; the metal salts were dissolved in 1
mL of THF. The solution was allowed to stir at room temperature for
5 min and then filtered through a 1 cm plug of oven-dried Celite and
eluted directly into a 50 mL Schlenk tube with another 1 mL of THF.
To the Schlenk tube was then added the propargylic acetate (0.3
mmol, 1.0 equiv) in 7 mL of THF, bringing the total reaction volume
to 9 mL. After 4 h, the reaction was quenched by the addition of two
to three drops of triethylamine and concentrated in vacuo. 0.1 mmol of
mesitylene was added to the crude reaction mixture, and the ratio of
2,2,-Dimethyl-1-(1-tosyl-4,5-dihydro-1H-pyrrol-2-yl)propyl
acetate (45). According to the general procedure, dehydropyrrolidine
45 was obtained from alkyne 44 as an oil in 86% yield (172 mg):
1
1
the two products was determined by H NMR analysis. The product
Analytical TLC Rf = 0.42 (1:4 ethyl acetate:hexanes); H NMR (500
ratio between the dehydropyrrolidine and the dehydropiperidine was
established by integrating the singlet at 5.24 ppm (1 H) of the
MHz, CDCl3, ppm) δ 7.90 (d, J = 8.5 Hz, 2 H), 7.27 (d, J = 9.0 Hz, 2
H), 6.07 (s, 1 H), 5.24 (s, 1 H), 3.90−3.85 (m, 1 H), 3.74−3.67 (m, 1
P
dx.doi.org/10.1021/jo500748e | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
H), 2.39 (s, 3 H), 2.10 (s, 3 H), 2.00−1.93 (m, 1 H), 1.73−1.66 (m, 1
H), 1.02 (s, 9 H); 13C NMR (75 MHz, CDCl3, ppm) δ 169.6, 143.5,
142.6, 134.0, 129.4, 128.1, 116.7, 76.7, 51.4, 35.2, 27.0, 26.2, 21.5, 20.9;
IR (thin film, cm−1)2968, 2869, 1738, 1370, 1346, 1244, 1162, 1090,
1048, 1023, 991, 916, 817, 688; High-resolution MS (ESI+, m/z)
molecular ion [M + Na]+ calculated for C18H25O4N1S1 374.1397,
found 374.1388, error 2.0 ppm.
Procedure for the Hydrolysis of the Benzoate Esters. This
procedure was used if the mixture of five- and six-membered
heterocycles was inseparable. The benzoate ester was dissolved in 10
mL of a 1/1 v/v mixture of MeOH and water that contained 2.5 equiv
of powdered sodium hydroxide,14 and the mixture was allowed to stir
at room temperature for 16 h. The reaction was then concentrated
under a vacuum and dissolved in ether and washed with water. The
aqueous layer was separated and further extracted with ether. The
organic extracts were combined and washed with brine, dried over
magnesium sulfate, and concentrated under a vacuum. The crude oil
was then purified by flash chromatography to afford the respective
alcohol and ketone products.
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1-(1-Tosyl-4,5-dihydro-1H-pyrrol-2-yl)ethanol (47). According
to the general procedure, dehydropyrrolidine 47 was obtained as an oil
in 49% yield (30 mg): Analytical TLC Rf = 0.11 (1:4 ethyl
́
(f) Mauleon, P.; Krinsky, J. L.; Toste, F. D. J. Am. Chem. Soc. 2009,
1
acetate:hexanes); H NMR (500 MHz, CDCl3, ppm) δ 7.75 (d, J =
131, 4513−4520.
8.5 Hz, 2 H), 7.33 (d, J = 8.0 Hz, 2 H), 5.30−5.29 (m, 1 H), 4.79 (q, J
= 6.0 Hz, 1 H), 3.86−3.75 (m, 2 H), 3.62 (br s, 1 H), 2.44 (s, 3 H),
2.16−2.10 (m, 2 H), 1.46 (d, J = 6.0 Hz, 3 H); 13C NMR (75 MHz,
CDCl3, ppm) δ 147.5, 144.0, 134.1, 129.8, 127.4, 127.0, 113.4, 63.5,
50.9, 27.3, 21.5, 20.8; FT-IR (thin film, cm−1) 3523, 2978, 2927, 1716,
1597, 1448, 1340, 1161, 1091, 982, 815, 715, 665; High-resolution MS
(EI+, m/z) molecular ion [M]+ calculated for C13H17O3N1S1 267.0924,
found 267.0928, error 1.8 ppm.
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2-Methyl-1-tosylpiperidin-3-one (48). According to the general
(8) Wang, D.; Cai, R.; Sharma, S.; Jirak, J.; Thummanapelli, S. K.;
Akhmedov, N. G.; Zhang, H.; Liu, X.; Petersen, J. L.; Shi, X. J. Am.
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procedure, piperidinone 48 was obtained as an oil in 20% yield (12
1
mg): Analytical TLC Rf = 0.20 (1:4 ethyl acetate:hexanes); H NMR
(500 MHz, CDCl3, ppm) δ 7.76 (t, J = 8.0 Hz, 2 H), 7.33 (d, J = 8.5
Hz, 2 H), 4.60 (quintet, J = 6.5 Hz, 1 H), 4.14−4.10 (m, 1 H), 3.35−
3.30 (m, 1 H), 2.67 (dd, J = 15.0, 7.0 Hz, 1 H), 2.53−2.46 (m, 1 H),
2.44 (s, 3 H), 2.33−2.29 (m, 1 H), 2.21 (dt, J = 16.5, 2.0 Hz, 1 H),
1.06 (d, J = 7.5 Hz, 3 H); 13C NMR (75 MHz, CDCl3, ppm) δ 206.5,
143.8, 137.2, 129.9, 127.0, 50.3, 47.1, 40.6, 39.9, 21.5, 18.0; FT-IR
(thin film, cm−1) 2973, 2922, 1720, 1597, 1358, 1339, 1228, 1160,
1115, 1090, 1019, 977, 926, 816, 712; High-resolution MS (ESI+, m/z)
molecular ion [M + H]+ calculated for C13H17O3N1S1 268.1002, found
268.1009, error 3.0 ppm.
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ASSOCIATED CONTENT
* Supporting Information
■
S
Complete proton and carbon-13 NMR spectra and the X-ray
structure of compound 11 (CIF). This material is available free
of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: diver@buffalo.edu.
■
(16) Wang, J.-X.; Jia, X.; Meng, T.; Xin, L. Synthesis 2005, 17, 2838−
2844.
(17) Ding, C. H.; Dai, L. X.; Hou, X. L. Tetrahedron 2005, 61, 9586−
9593.
(18) Teichert, J. F.; Zhang, S.; van Zijl, A. W.; Slaa, J. W.; Minnaard,
A. J.; Feringa, B. L. Org. Lett. 2010, 12, 4658−4660.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the NSF (CHE-0848560 and CHE-
1012839) and the Kapoor Graduate Fellowship awarded to
J.M.F. for financial support of this work. We also thank Dr. Bill
Brennesel (U. of Rochester) for the crystal structure
determination of 11.
REFERENCES
■
(1) Kalbarczyk, K. P.; Diver, S. T. J. Org. Chem. 2009, 74, 2193−
2196.
Q
dx.doi.org/10.1021/jo500748e | J. Org. Chem. XXXX, XXX, XXX−XXX