Enantioselective synthesis of 5,7-bicyclic ring systems from axially chiral allenes using a Rh(I)-catalyzed cyclocarbonylation reaction

Article abstract of DOI:10.1021/jo4002432

A transfer of chirality in an intramolecular Rh(I)-catalyzed allenic Pauson-Khand reaction (APKR) to access tetrahydroazulenones, tetrahydrocyclopenta[c]azepinones and dihydrocyclopenta[c]oxepinones enantioselectively (22-99% ee) is described. The substit

Full text of DOI:10.1021/jo4002432

Article
pubs.acs.org/joc
Enantioselective Synthesis of 5,7-Bicyclic Ring Systems from Axially
Chiral Allenes Using a Rh(I)-Catalyzed Cyclocarbonylation Reaction
Francois Grillet and Kay M. Brummond*
Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States
S
* Supporting Information
ABSTRACT: A transfer of chirality in an intramolecular Rh(I)-catalyzed allenic
Pauson−Khand reaction (APKR) to access tetrahydroazulenones,
tetrahydrocyclopenta[c]azepinones and dihydrocyclopenta[c]oxepinones enantiose-
lectively (22−99% ee) is described. The substitution pattern of the allene affected
the transfer of chiral information. Complete transfer of chirality was obtained for all
trisubstituted allenes, but loss of chiral information was observed for disubstituted
allenes. This work constitutes the first demonstration of a transfer of chiral information from an allene to the 5-position of a
cyclopentenone using a cyclocarbonylation reaction. The absolute configuration of the corresponding cyclocarbonylation product
was also established, something that is rarely done.
group.2 There are a number of synthetic methods available to
INTRODUCTION
■
prepare these highly oxidized rings, but the options narrow
Cyclopentanes serve as valuable building blocks in organic
rapidly when constructing five-membered carbocycles with
synthesis and are present in many naturally occurring
stereogenic centers enantioselectively.3
compounds. Among the various polycyclic skeletons possessing
There is a diverse array of methods to create stereogenic
five-membered carbocycles, the fused 5,5-, 5,6- and 5,7-bicyclic
centers of cyclopentanes in a stereoselective manner. A
ring systems are common structural features found in many
common synthetic strategy is to take advantage of the chiral
biologically relevant compounds.1 For many natural products,
pool as a source of enantiopure materials. One example is the
the five-membered rings are characterized by a relatively high
oxidation state (Figure 1). Swartzianin D (1) is an excellent
asymmetric synthesis of (+)-chinensiolide B (2), where the
cyclopentane moiety of this compound is generated via a
Favorskii rearrangement of (R)-carvone.4 Moreover, the
example of this, where every carbon of the five-membered ring
is occupied with a double bond, a carbonyl or a hydroxyl
cyclopentane ring of tecomanine (3), possessing a tetrahy-
drocyclopentapyridinone ring system, was also prepared from
(−)-carvone.5 Other approaches to install stereogenic centers
utilize existing stereocenters on rings adjacent to the five-
membered carbocycle. For instance, the methyl group located
at the C4 position of grosshemin (4) was installed by classic
alkylation of an enol acetate of a 5,7-bicyclic ring system to
yield a single product diastereoselectively.6 However, this
diastereoselective approach is not always reliable for cyclo-
pentenone-containing 5,7-ring systems. For example, in the
synthesis of (+)-achalensolide (5), reduction of the C1−C11
double bond of a dienone group via a hydrogenation reaction
afforded a 1:1 mixture of diastereomers.7 In some cases,
asymmetric reactions are used to introduce stereogenic atoms
but in less direct ways. For example, the five-membered
carbocycle of arglabin (6) was obtained via an enantioselective
cyclopropanation of a furan followed by a rearrangement to
produce a protected hydroxy-2-cyclopentenone.8 The key
stereodetermining step for C4 and C5 stereocenters of
connatusin B (7) were established using a Diels−Alder reaction
starting with cyclopentenone and enantiomerically pure cis-1,2-
dihydrocatechol.9
Figure 1. Bioactive and natural compounds containing cyclopentanes
with stereogenic centers.
Received: February 2, 2013
© XXXX American Chemical Society
A
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Other synthetic methods implemented for the preparation of
chiral nonracemic 2-cyclopentenones are the Nazarov cycliza-
tion and the Pauson−Khand reaction (PKR). The asymmetric
Nazarov cyclization has been made possible by the use of chiral
auxiliaries, chiral Lewis acids and transfer of axial to tetrahedral
chirality when using allenes.10 However, the electrocyclization
process requires an enantioselective formation of the stereo-
genic carbon beta to the carbonyl controlled by torquoselec-
tivity, followed by a diastereoselective addition of an electro-
phile to the intermediate enol to form a second stereogenic
center adjacent to the newly formed carbonyl.11 The
asymmetric PKR has been performed using chiral metal
complexes of rhodium,12 titanium,13 iridium14 and cobalt15 to
provide cyclopentenone-containing bicyclic ring systems in
good enantioselectivities. Nevertheless, like the Nazarov
cyclization, all reactions establish a stereogenic carbon beta to
the carbonyl. There are exceptions for both intra- and
intermolecular PKRs where a stereocenter adjacent to the
carbonyl is set. These reactions typically involve functionaliza-
tion of the alkene component with a chiral auxiliary and for
nearly all cases this chiral auxiliary is removed and the
stereogenic center is lost.16 While there are methods to
synthesize 2-cyclopentenones possessing a stereogenic center at
the C5 position stereoselectively, the scope of these protocols is
limited.17
enriched allene-ynes. The substitution pattern of the allene was
varied to include trisubstituted allenylsilane 13, trisubstituted
nonsilylated allenes 14−16 and disubstituted allenes 17−19
(Figure 2). The terminus of the alkyne was substituted with
Figure 2. Allene-yne precursors.
either hydrogen, alkyl, aryl, heterocyclic or silyl groups (R3 = H,
Me, cyclopropyl, Ph, 2- and 3-thiophene and TMS), and three
different tethers were prepared, two heteroatom-containing (X
= NTs, O) and one all carbon-containing (X = C(CO2Et)2).
Synthesis of Enantiomerically Enriched Allenes. Syn-
thesis of trisubstituted chiral allenyl alcohol (Ra)-22 was
performed in four steps starting from commercially available
( )-3-butyn-2-ol (20) in a manner analogous to that reported
by Brawn and Panek (Scheme 2, eq 1).20 Addition of n-
butyllithium to alkyne 20 in the presence of lithium chloride
followed by addition of phenyldimethylchlorosilane afforded
silylated alkyne 21 in 90% yield. Kinetic resolution of racemic
propargyl alcohol 21 using lipase AK “Amano” provided
enantioenriched propargyl alcohol (S)-21 (47% yield, >98% ee)
and the corresponding propargyl acetate (43% yield, >99% ee,
not shown). Enantioenriched propargyl alcohol (S)-21 was
reacted with trimethylorthoacetate and propionic acid to
produce the corresponding allenyl ester via a Johnson−Claisen
rearrangement. The methyl ester was reduced with lithium
borohydride to afford enantioenriched allenylsilane (Ra)-22 in
>93% ee. The enantiomeric excess was determined by chiral
HPLC analysis. Synthesis of racemic allenyl alcohol 25 involved
silylation of hept-2-yn-1-ol (23) followed by a retro-Brook
rearrangement to afford propargyl alcohol 24 in 55% yield for
the two steps (Scheme 2, eq 2). A Johnson−Claisen
rearrangement performed on alcohol 24 followed by reduction
of the methyl ester with lithium aluminum hydride provided
allene 25. Disubstituted allene (Ra)-26 was prepared by a
Johnson−Claisen rearrangement of commercially available (R)-
3-butyn-2-ol (20) followed by lithium aluminum hydride
reduction of the corresponding methyl ester (Scheme 2, eq
3). The enantiomeric excess of (Ra)-26 was based upon chiral
HPLC analysis of p-nitrobenzoyl ester 27, for which a >99% ee
was obtained. Allenyl alcohol (Ra)-29 was prepared from 1-
hexyne by a palladium-catalyzed carbonylation reaction
followed by reduction of the corresponding ynone carbonyl
with (R)-alpine borane (Scheme 2, eq 4).21 The resulting
propargyl alcohol (R)-28 was converted into a propargyl vinyl
ether with ethyl vinyl ether and mercury acetate. A gold(I)-
catalyzed [3,3]-sigmatropic rearrangement of the vinyl ether
followed by in situ reduction of the intermediate aldehyde
afforded allenyl alcohol (Ra)-29 in >79% ee.22 The enantio-
meric excess was determined by chiral HPLC analysis.
Previously, we demonstrated that a complete transfer of
chirality is obtained for chiral, nonracemic allenes 10 in the
molybdenum- or zirconium-mediated PKR to afford 2-cyclo-
pentenones 11 enantioselectively (Scheme 1).18 For both of
Scheme 1. APKR: Transfer of Axial Chirality
these transformations, the reaction occurs with the proximal
double bond of the allene to provide E-α-alkylidene or E-α-
silylidene 2-cyclopentenones with the stereogenic center beta
to the carbonyl group.19 Since a general protocol for the
asymmetric synthesis of C5-substituted bicyclic cyclopente-
nones is valuable, we considered employing chiral allenes in a
PKR to gain access to this motif. On the basis of these prior
results, we envisioned that transfer of chiral information from
allene 10 to a stereogenic center adjacent to the carbonyl group
of 2-cyclopentenone 12 should also be possible for the Rh(I)-
catalyzed cyclocarbonylation reaction, a transformation per-
formed by the selective reaction with the distal π-bond of allene
10 (Scheme 1). Herein are reported studies directed toward a
Rh(I)-catalyzed allenic Pauson−Khand reaction (APKR) to
afford 5,7-bicyclic ring systems enantioselectively.
RESULTS AND DISCUSSION
■
Investigations into the scope and limitations of the transfer of
allene axial chirality in the Rh(I)-catalyzed cyclocarbonylation
reaction began with the synthesis of a series of enantiomerically
Preparation of the Allenic Pauson−Khand Precursors.
Allene-ynes 13a−13e, 13g, 14c−14e, 14g, 17c, 17d and 17f
B
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a
Scheme 2. Synthesis of Racemic and Nonracemic Allenes
Scheme 3. Synthesis of Allene-ynes 13, 14 and 17 Containing
a Tosylamide Tether
a
a
(a) n-BuLi, LiCl, THF, −78 °C. (b) PhMe2SiCl (DPSCl), −78 °C to
rt, 90% (2 steps). (c) Lipase AK “Amano”, vinyl acetate, pentane, rt
47%. (d) MeC(OMe)3, propionic acid, xylenes, Δ, 78%. (e) LiBH4,
Et2O/MeOH, 0 °C, 86%. (f) n-BuLi, PhMe2SiCl, THF, −78 °C. (g) t-
BuLi, 55% (2 steps). (h) MeC(OMe)3, propionic acid, Δ, 76%. (i)
LiAlH4, THF, 0 °C, 74%. (j) MeC(OMe)3, propionic acid, Δ, 53%.
(k) LiAlH4, THF, 0 °C, 79%. (l) 4-Nitrobenzoyl chloride, 2,6-lutidine,
DMAP, DMA−MeCN, 0 °C, 63%. (m) CO (1 atm), PhI, PPh3, PdCl2,
Et3N, H2O, rt, 80%. (n) (R)-Alpine borane, rt, 78%. (o) Hg(OAc)2,
ethyl vinyl ether, rt, 56%. (p) [(PPh3Au)3O]BF4, CH2,Cl2, rt; NaBH4,
MeOH, rt, 91%.
a
(a) DIAD, PPh3, THF, 0 °C to rt. (b) LiHMDS, TMSCl, THF, −78
°C to rt.
Scheme 4. Synthesis of Allene-ynes 15 and 18 Containing an
Oxygen Tether
a
were all prepared using a Mitsunobu reaction of the
corresponding allenols and the appropriately substituted
propargyl tosylamides 30a−30g (Scheme 3). Reacting (Ra)-
22 with 3- and 2-thiophene-substituted propargyl tosylamides
30a and 30b gave allene-ynes 13a and 13b in 90 and 70% yield,
respectively. Similarly, high yields were obtained for the
Mitsunobu reaction between (Ra)-22 and 30c, 30d, 30e and
30g giving 13c, 13d, 13e and 13g in 92, 92, 90, and 73% yield,
respectively. Allene-ynes 14c, 14d, 14e and 14g were obtained
in a similar manner in high yields (77−93%) from the reaction
of trisubstituted allene (Ra)-29 and propargyl tosylamides 30c,
30d, 30e and 30g, respectively. Reacting (Ra)-26 with
propargyl tosylamides 30c, 30d and 30e afforded 17c, 17d
and 17e in 74, 85, and 84% yield, respectively. The
trimethylsilyl-substituted alkynes 13f, 14f and 17f were
prepared by deprotonation of allene-ynes 13e, 14e and 17e
with lithium hexamethyldisilylazide followed by addition of
trimethylsilyl chloride to provide the corresponding silylated
alkynes in 87, 80, and 84% yield, respectively.
a
(a) NaH, THF, 0 °C to rt. (b) LiHMDS, TMSCl, THF, −78 °C to rt.
Low yields for this series of compounds were attributed to the
sterically congested environment at the proximal double bond
of the allene. This hypothesis is supported by the complete
recovery of starting material for the reaction of trisubstituted
allenyl alcohol (Ra)-22 with 31d. The trimethylsilyl-substituted
alkynes 15f and 18f were prepared by deprotonation of allene-
ynes 15e and 18e using the same conditions as for allene-ynes
13f, 14f and 17f to provide the corresponding silylated alkynes
in 65 and 69% yield, respectively.
Allene-ynes 15c, 15d, 15f and 18c, 18d, 18f containing an
oxygen atom in the tether were synthesized by a Williamson
etherification reaction (Scheme 4). Reacting (Ra)-26 with
propargyl bromides 31c, 31d and 31e afforded allene-ynes 18c,
18d and 18e in 83, 63, and 41% yield, respectively. Reacting
(Ra)-29 with propargyl bromides 31c, 31d and 31e produced
ethers 15c, 15d and 15e in 27, 35, and 20% yield, respectively.
Preparation of allene-ynes 16c−16e was accomplished by
reaction of alcohol (Ra)-26 with methanesulfonyl chloride to
produce mesylate 32. Addition of the mesylate to the sodium
C
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salt of malonates 34c−34e provided the desired allene-ynes in
42−75% yields (Scheme 5). Allene-ynes 19c−19e were
Table 1. Optimization of the Cyclocarbonylation Reaction
Conditions
Scheme 5. Synthesis of Allene-ynes 16 and 19 Containing a
a
Malonate Tether
[Rh(CO)2Cl]2
(mol %)
time
(h)
T
(°C)
product and yield
(%)
entry
solvent
1
2
3
10
5
3
9
7
90
90
35c (95); 36c (0) PhMe
35c (75); 36c (9) PhMe
10
120 35c (61); 36c
PhMe
PhMe
PhMe
DCE
(35)
4
5
5
7
120 35c (42); 36c
(48)
1
24
24
120 35c (29); 36c
(26)
a
b
6
10
40
35c (72); 36c
(0)
a
b
PPh3 (30 mol %), AgBF4 (22 mol %). Yield based on recovered
starting material (conversion: 54%).
a
(a) MsCl, Et3N, THF, 0 °C to rt. (b) (EtO2C)2CHCH2CCR3
results from a competing β-hydride elimination of rhodium
metallocycle 37 to produce the alkene of intermediate 39. The
rhodium hydride of 39 then undergoes a reductive elimination
to generate the exocyclic alkene of 36 as a single diastereomer.
This side product has previously been observed for the
formation of seven-membered rings from allenes bearing a
phenylsulfonyl group.23 Increasing the reaction temperature to
120 °C afforded dienone 35 in 61% yield and triene 36 in 35%
yield (Table 1, entry 3). Decreasing the catalyst loading and
increasing the reaction temperature afforded dienone 35 and
triene 36 in a 1:1 ratio (Table 1, entries 4 and 5). Interestingly,
the addition of silver tetrafluoroborate and triphenylphosphine
afforded cyclocarbonylation product 35 in only 72% yield based
on recovered starting material. While the generality of this
reaction could benefit from the lower reaction temperatures
possible for the cationic Rh(I), our inability to take this reaction
to completion is deemed problematic.
34c R3 = Me, 34d R3 = Ph, 34e R3 = H, NaH, KI, DMF−THF, 70 °C.
(c) LiHMDS, TMSCl, THF −78 °C to rt.
obtained in an analogous manner from alcohol (Ra)-29 with
yields ranging from 57 to 69%. Reaction of 16e and 19e with
lithium hexamethyldisilylazide and trimethylsilylchloride af-
forded allene-ynes 16f and 19f in 84 and 80% yield,
respectively. Attempts to convert alcohol (Ra)-22 to the
corresponding allene-ynes using these conditions resulted in
an inseparable mixture of silylated and desilylated products. For
this reason, the silylated allene series of compounds bearing the
oxygen tether was not further pursued.
Optimization of the Cyclocarbonylation Reaction. A
brief examination of the cyclocarbonylation reaction conditions
was performed using 13c, and it was shown that the standard
conditions developed in our group for the Rh(I)-catalyzed
APKR provided compound 35 in 95% yield (Scheme 6 and
Table 1, entry 1). Attempts to lower the catalyst loading to 5
mol % decreased the yield of the cyclocarbonylation product 35
to 75% and resulted in a 9% yield of cross-conjugated triene 36
(Scheme 6 and Table 1, entry 2). Cross-conjugated triene 36
Transfer of Chirality in the Rh(I)-Catalyzed APKR. Each
of the silyl-substituted allene-ynes 13a−13g was subjected to
the optimized cyclocarbonylation reaction conditions. High
yields of the cyclocarbonylation products were obtained for the
allene-ynes bearing an internal alkyne (Table 2, entries 1−4, 6
Scheme 6. Cyclocarbonylation Reaction and Triene Formation
D
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A series of trisubstituted allenes 14, 15 and 16 were
examined in the cyclocarbonylation reaction, each possessing a
phenyl group on the terminus of the allene but differing in their
tether (X = NTs, O, C(CO2Et)2) and the substitution on the
terminus of the alkyne (R = Me, Ph, TMS, cyclopropyl). The
enantiomeric purity of each allene-yne was based upon the
enantiomeric excess of the starting homoallenyl alcohol (Ra)-
29, which was determined to be greater than 79%. For all cases
examined, a complete transfer of chirality was obtained (Table
3, entries 1−10). For allene-ynes 14c, 14d, 14f and 14g
Table 2. Transfer of Chirality using Trisubstituted Silylated
Allene-ynes
Table 3. Transfer of Chirality of Trisubstituted Allene-ynes
a
Enantiomeric ratios were determined by HPLC analysis using a
b
ChiralCel OD column. Cross-conjugated triene was obtained in 13%
yield.
and 7). The presence of heterocyclic-containing systems on the
alkyne did not affect the reaction (Table 2, entries 1 and 2).
Terminal alkyne 13e was converted to cyclocarbonylation
product 35e in 66% yield, along with a 13% yield of triene 36
(Table 2, entry 5). The enantiomeric purity of each of the
allene-ynes 13a−13g was based upon the enantiomeric excess
obtained for allenylsilane (Ra)-22, which was determined to be
greater than 93%. Each of the cycloadducts 35a−35g was
examined for their enantiomeric purity by HPLC analysis using
a ChiralCel OD column. For each of these compounds, the
enantiomeric excesses were found to be greater than 96%,
constituting a complete transfer of chirality from the allene-
ynes to the cyclocarbonylation products. While the transfer of
chiral information may not be surprising, the high configura-
tional stability of the dienone to the Rh(I) conditions was not
anticipated.
a
Enantiomeric excess of the disubstituted allenic alcohol >79% ee.
Determined by HPLC analysis using a ChiralCel OD column.
b
possessing a tosylamide tether, the reactions were complete in
30 min, affording dienones 42c, 42d, 42f and 42g in 75−88%
yield (Table 3, entries 1−4). The highest yielding substrate was
found to be allene-yne 14g possessing a cyclopropyl group on
the terminus of the alkyne, and the lowest yield was obtained
with aryl-substituted substrate 14d. For the oxygen containing
tethers, the yields varied considerably (Table 3, entries 5−7).
Methyl-substituted alkyne 15c produced 43c in 46% yield,
phenyl-substituted alkyne 15d afforded 43d in 69% yield, and
trimethylsilyl-substituted alkyne 15f provided 43f in 91% yield.
Furthermore, all the reactions in the oxygen-containing series
were complete in less than 45 min. Finally, for the malonate-
containing series, the yields were high for all allene-ynes and
ranged from 88 to 92%. For this series (allene-ynes 16c, 16d
and 16f) the reactions required 120−150 min for completion,
but the longer reaction time did not affect the enantioselectivity
of the products. Thus, for each of the cases examined, the
enantioselectivity of the products was not dependent upon the
nature of the tether, the substituent on the alkyne terminus, or
the reaction time.
Performing the APKR on trisubstituted allene 40 resulted in
the formation the desilylated cyclocarbonylation product 41 in
quantitative yield (Scheme 7).24 Desilylation of α-silyl ketones
Scheme 7. Desilylation During the Cyclocarbonylation
Reaction
have been reported to occur upon purification by silica gel
chromatography.25 However, it appears that desilylation of the
resulting cyclocarbonylation product took place during the
reaction as evidenced by crude H NMR spectroscopy. Thus,
the loss of the stereogenic center precluded further examination
of this series of compounds.
A series of allene-ynes containing disubstituted allenes were
also examined for transfer of chiral information in the
cyclocarbonylation reaction. The reaction was performed
using three different tethers (X = NTs, O, C(CO2Et)2) and
varying the substitution on the terminus of the alkyne (R = Me,
Ph, H, TMS). For each of the allene-ynes reported in Table 4,
1
E
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excess is occurring prior to product formation and at the allene-
yne stage of the reaction.
Table 4. Transfer of Chirality Using Disubstituted Allene-
ynes
A mechanism is proposed to account for the erosion of
enantiomeric excesses of the disubstituted allenes. Inspired by
the work of Backvall, addition of an internal nucleophile to a
̈
rhodium-allene complex is postulated (Scheme 8).26 For the
Scheme 8. Postulated Mechanism for the Erosion of
Enantiomeric Excesses of Disubsubstituted Allenes in the
Cyclocarbonylation Reaction
time
(h)
product, %
yield
a
entry allene-yne
X
R
% ee
b
1
2
3
4
5
6
7
8
9
10
17c
17d
17f
18c
18d
18e
18f
19c
19d
19f
NTs
NTs
NTs
O
Me
Ph
4.6
3
45c, 73
45d, 84
45f, 83
46c, 40
46d, 90
46e, 24
46f, 76
47c, 71
47d, 96
47f, 94
81
c
88
d
TMS
Me
Ph
3
84
c
6.5
0.5
1.5
7
45
c
O
52
e
O
H
30
d
O
TMS
Me
Ph
22
f
C(CO2Et)2
C(CO2Et)2
C(CO2Et)2
22
1.5
10
58
c
72
d
TMS
50
a
The enantiomeric excess of the disubstituted allenic alcohol was
b
>99% ee. Determined using HPLC analysis (ChiralPak IA-3).
c
d
Determined using HPLC analysis (ChiralCel OD). Determined
e
using SFC analysis (ChiralPak IC). Determined using SFC analysis
(ChiralPak IA). Determined using HPLC analysis (Whelk O-1).
f
the enantiomeric purity was based upon the enantiomeric
excess obtained for allenyl ester (Ra)-27, which was determined
to be greater than 99%. Contrary to the trisubstituted allenes,
the degree of chiral information transferred from the
disubstituted allenes to the cyclopentenones was dependent
upon the tether and alkyne substitution. For example, allene-
ynes 17−19d containing a phenyl group on the alkyne afforded
the corresponding cyclocarbonylation products 45−47d in 88%
ee for the tosylamide tether (Table 4, entry 2), 52% ee for the
oxygen tether (Table 4, entry 5), and 72% ee for the malonate
tether (Table 4, entry 9). Furthermore, the decrease in
enantiomeric excess was also dependent on the substituent
on the alkyne. This was especially prevalent in the ether series
of allene-ynes where the enantiomeric excesses of the
cycloadducts ranged from 22−52% for trimethylsilyl, hydrogen,
methyl or phenyl substituents (Table 4, entries 4−7).
Determination of the enantiomeric excesses of the cyclo-
carbonylation products 45−47 proved to be more difficult than
in the trisubstituted series, in that a different chiral column was
needed for nearly every product.
Insight regarding the partial racemization in the disubstituted
series was obtained by reacting allene-yne 18c to the standard
conditions and allowing it to reach 60% conversion. The
enantiomeric excess of the cyclocarbonylation product 46c was
measured to be 43% after purification by silica gel
chromatography. The enantiomeric excess of 46c was 45%
when the reaction was allowed to go to completion, indicating
that racemization of the product was not occurring after the
product is formed (Table 4, entry 4). Next, the enantiomeric
excess of allene-ynes 17d and 18d were measured during the
reaction. Stopping the cyclocarbonylation reaction of 18d at
50% conversion afforded the unreacted allene-yne in 11% ee.
Similarly, stopping the reaction of allene-yne 17c at 29%
conversion afforded the allene in 15% ee. The enantiomeric
excesses (ee) of the allenes were determined by HPLC analysis
(ChiralPak AS-H). These three experiments provide strong
evidence to support the hypothesis that loss of enantiomeric
disubstituted allene A, coordination of the rhodium catalyst to
the proximal double bond of the allene affords the rhodium
complex B. Nucleophilic attack of the tethered heteroatom
(oxygen in the example depicted) to the central carbon initially
affords the corresponding η1-rhodium species that isomerizes to
the η3 complex C that in turn isomerizes to the η1-rhodium
species D. Free rotation around the designated carbon−carbon
bond of D leads to the η3-rhodium complex E. Reductive
elimination from intermediate E leads to the formation of
allene-yne F, the enantiomer of allene-yne A. Erosion in the
enantiomeric excesses correlates well with the relative
nucleophilicities of the heteroatoms in the tether. For example,
the highest enantiomeric excesses were obtained for the
cyclocarbonylation products with a tosylamide tether, whereas
the lowest enantiomeric excesses were obtained for the oxygen
tether. In the case of the malonate tether, formation of an
intermediate seven-membered ring would explain the race-
mization process.
For the trisubstituted allene series, the absence of
racemization is explained by selective complexation of the
rhodium catalyst with the less substituted distal double bond of
the allene and complexation from the face opposite of the DPS
group (intermediate G, Scheme 8). Moreover, the rhodium
metallocycle of intermediate G is not set up for an internal
nucleophilic addition but instead is well positioned to undergo
complexation with the alkyne, ultimately affording the desired
cyclocarbonylation product with no loss in enantiomeric
excesses.
Determination of the Absolute Configuration of the
Cyclocarbonylation Product. The fortuitous crystallization
of 35c at −20 °C allowed for the determination of the absolute
configuration by X-ray diffraction using the anomalous
F
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activated alumina columns. Toluene, acetonitrile, 2,6-lutidine and
triethylamine (Et3N) were freshly distilled from CaH2 prior to use.
N,N-Dimethylacetamide was dried over 4 Å molecular sieves for 12 h
prior to use. Flash chromatography was carried out on silica. Thin
layer chromatography (TLC) analysis was performed on precoated
scattering effect of the silicon and is in agreement with the
absolute configuration of that established for allenyl alcohol
(Ra)-22 (Scheme 9).27
1
silica gel F254 aluminum plates. H NMR and 13C NMR spectra were
Scheme 9. Absolute Configuration of Cyclocarbonylation
Product 35c
recorded in deuterated solvents and referenced to residual chloroform
1
(7.26 ppm, H, 77.0 ppm, 13C). Chemical shifts are reported in ppm,
and multiplicities are indicated by s (singlet), d (doublet), t (triplet), q
(quartet) and m (multiplet). Coupling constants, J, are reported in
hertz. All NMR spectra were obtained at rt. Infrared spectra were
recorded neat and are reported in cm−1. HRMS data were collected
using a TOF mass spectrometer.
General Procedure for Preparation of Allene-yne via
Mitsunobu Reaction. To a solution of the alcohol in THF cooled
to 0 °C (ice bath) was added triphenylphosphine (1.2 equiv), the
tosylamide (1.2 equiv) and diisopropylazodicarboxylate (1.2 equiv).
The reaction mixture was stirred until completion as judged by TLC
analysis. Concentration of the reaction mixture under reduced pressure
afforded the crude residue. The crude material was purified by flash
chromatography.
Furthermore, during attempts to establish the absolute
configuration of cyclocarbonylation product 35e by derivatiza-
tion with (S)-(−)-1-amino-2-(methoxymethyl)pyrrolidine
(SAMP), compound 48 was isolated instead of the expected
hydrazone (Scheme 10). Structurally similar compounds are
General Procedure for Preparation of Allene-yne via
Williamson Etherification. A solution of the alcohol in THF was
cooled to 0 °C (ice bath), and sodium hydride (2 equiv, 60%
dispersion in mineral oil) was added portionwise. The mixture was
stirred for 30 min at rt. The propargyl bromide (1.5 equiv) was added,
and the reaction was stirred at rt until completion as judged by TLC
analysis. The reaction was quenched by careful dropwise addition of
water over 5 min. The two layers were separated, and the aqueous
layer was extracted with Et2O. The organic layers were combined,
dried (Na2SO4), filtered and concentrated under reduced pressure.
The crude material was purified by flash chromatography.
Scheme 10. Synthesis of Compound 48
General Procedure for Preparation of Allene-yne via
Alkylation of the Malonate Moiety. The diethyl malonate23 (2
equiv) was added dropwise to a stirred suspension of sodium hydride
(2 equiv, 60% dispersion in mineral oil) in a DMF/THF (1:1) mixture
cooled to 0 °C (ice bath). After 1 h at 0 °C, hydrogen evolution had
ceased and the mesylate (1 equiv) in THF was added, followed by
potassium iodide (1.5 equiv). The reaction mixture was stirred at 70
°C for 12 h. The solution was cooled to rt, diluted with Et2O and
quenched by careful dropwise addition of a saturated solution of
NH4Cl. The layers were separated, and the aqueous layer was
extracted with Et2O. The combined organic phases were washed with
brine, dried (Na2SO4), filtered and concentrated under reduced
pressure. The crude material was purified by flash chromatography.
General Procedure for Preparation of Allene-yne via
Silylation of the Terminal Alkyne. To a solution of the allene-
yne (1 equiv) in THF cooled to −78 °C was added lithium
hexamethyldisilylamide (1 M in THF, 1.3 equiv), and the resulting
mixture was stirred at −78 °C for 1 h. Trimethylsilyl chloride (2
equiv) was then added, and the reaction was stirred for 1 h at −78 °C.
The mixture was quenched with a saturated solution of NH4Cl and
diluted with Et2O. The layers were separated, and the aqueous layer
was extracted with Et2O. The combined organic phases were washed
with brine, dried (Na2SO4), filtered and concentrated under reduced
pressure. The crude material was purified by flash chromatography.
General Procedure for the [Rh(CO)2Cl]2-Catalyzed Cyclo-
carbonylation Reaction. A flame-dried vial (15 × 45 mm) equipped
with a Teflon-coated stir-bar and a septa cap was charged with allene-
yne and toluene (0.1 M). The tube was evacuated for 3−5 s and
refilled with CO (g) (3×) using a balloon. To the allene-yne solution
was added [Rh(CO)2Cl]2 (0.1 equiv) in one portion, and the vial was
evacuated and refilled with CO (g) (3×). The vial was placed in a
preheated 90 °C oil bath and stirred under CO (g). After the reaction
was complete as judged by TLC analysis, the mixture was cooled to rt,
passed through a short plug of Celite using Et2O, and concentrated
under reduced pressure. The crude material was purified by flash
chromatography.
usually synthesized by performing the APKR on allenamides.28
This type of isomerization has previously been observed during
an APKR.29 The silicon group is shown to have no effect on
this unusual isomerization since compound 48 was also
obtained when the reaction was performed on the dienone
lacking the silicon group.
CONCLUSION
■
In summary, we have successfully performed a transfer of
chirality from a chiral nonracemic allene to a 4-alkylidene
cyclopentenone in a Rh(I)-catalyzed APKR. Complete transfer
of chirality was obtained for every trisubstituted allene.
Investigations regarding the loss of enantiomeric excess
observed when the APKR was performed with disubstituted
allene-ynes demonstrated that partial racemization of the
allenes was occurring during the reaction. Moreover, the
mildness of the reaction conditions are highlighted by the
absence of epimerization of the stereogenic center during the
reaction. The absolute configuration of cyclocarbonylation
product 35c was unambiguously established by X-ray crystallo-
graphic analysis. The absolute configuration of this dienone
corresponds to the predicted assignment, on the basis of the
absolute configuration of the propargylic alcohol precursor.
Finally, an unusual isomerization of the dienone was observed
during attempts to functionalize the carbonyl group, affording a
presumably more stable vinylogous amide.
EXPERIMENTAL SECTION
■
Unless otherwise noted, all reactions were performed under N2 in
flame-dried glassware using standard syringe, cannula, and septum
techniques. All commercially available compounds were used as
received unless otherwise noted. The reaction solvents tetrahydrofuran
(THF) and dichloromethane (CH2Cl2) were obtained by passing
commercially available predried, oxygen-free formulations through
(Ra)-Hexa-3,4-dien-1-yl 4-nitrobenzoate (27). (Ra)-Hexa-3,4-
dien-1-ol30 26 (48 mg, 0.49 mmol) was dissolved in N,N-
G
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dimethylacetamide (0.9 mL) and 2,6-lutidine (150 μL, 1.32 mmol).
This solution was added dropwise to a solution of p-nitrobenzoyl
chloride (118 mg, 0.64 mmol), 4-N,N-dimethylaminopyridine (12 mg,
0.098 mmol) in acetonitrile (0.7 mL) at 0 °C (ice bath). After
completion of the addition, the reaction mixture was stirred for 1 h at
0 °C. After quenching with a saturated solution of sodium bicarbonate
(3 mL), the mixture was extracted with Et2O (20 mL), washed with
water (5 mL), brine (5 mL), dried (Na2SO4), filtered and
concentrated under reduced pressure. Purification of the crude residue
using a Biotage normal phase automated purification system (4 g
SNAP column, gradient of 1−10% Et2O/hexanes) afforded compound
129.5 (2C), 127.6 (2C), 86.5, 86.3, 76.7, 73.4, 46.1, 36.4, 27.5, 21.3,
14.2; IR (thin film) 3289, 2974, 2925, 2856, 1960, 1593, 1454, 1344,
1160, 1102; HRMS (ES+) C16H20NO2S [M + H+] calculated
290.1215, found 290.1237; [α]2D0 = −37.6° (c 1.25, CH2Cl2).
(Ra)-N-(Hexa-3,4-dien-1-yl)-4-methyl-N-(3-(trimethylsilyl)-
prop-2-yn-1-yl)benzene sulfonamide (17f). Following the general
procedure for preparation of allene-yne via silylation of the terminal
alkyne, allene-yne 17e (70 mg, 0.24 mmol) in THF (1.8 mL) was
reacted with lithium hexamethyldisilylamide (314 μL, 1 M in THF,
0.31 mmol) and trimethylsilylchloride (61 μL, 0.48 mmol).
Purification of the crude residue using a Biotage normal phase
automated purification system (10 g SNAP column, gradient of 2−7%
Et2O/hexanes) afforded compound 17f (73.2 mg, 84%) as a colorless
oil: 1H NMR (300 MHz, CDCl3) δ 7.72 (d, J = 8.3 Hz, 2H), 7.28 (d, J
= 7.9 Hz, 2H), 5.09−5.02 (m, 2H), 4.15 (s, 2H), 3.25 (t, J = 7.4 Hz,
2H), 2.42 (s, 3H), 2.28−2.25 (m, 2H), 1.66−1.63 (m, 3H), −0.01 (s,
9H); 13C NMR (150 MHz, CDCl3) δ 205.3, 143.2, 135.9, 129.4 (2C),
127.7 (2C), 97.9, 90.8, 86.5, 86.3, 45.8, 37.3, 27.4, 21.5, 14.4, −0.5
(3C); IR (thin film) 2965, 2916, 2857, 2178, 1594, 1455, 1249, 1346,
115536, 1095; HRMS (ES+) C19H28NO2SSi [M + H+] calculated
362.1610, found 362.1628; [α]2D0 = −27.6° (c 1.05, CH2Cl2).
(S)-6-Methyl-2-tosyl-8-(trimethylsilyl)-1,2,3,4-
tetrahydrocyclopenta[c]azepin-7(6H)-one (45f). Following the
general procedure for the [Rh(CO)2Cl]2 catalyzed cyclocarbonylation
reaction, allene-yne 17f (42 mg, 0.12 mmol) and [Rh(CO)2Cl]2 (4.5
mg, 0.012 mmol) were reacted in toluene (3.6 mL) for 180 min.
Purification of the crude residue using a Biotage normal phase
automated purification system (4 g SNAP column, 65% Et2O/
hexanes) afforded compound 45f (37.5 mg, 83%) as a colorless oil: 1H
NMR (300 MHz, CDCl3) δ 7.64 (d, J = 8.3 Hz, 2H), 7.27 (d, J = 8.3
Hz, 2H), 5.70−5.67 (m, 1H), 4.53 (s, 2H), 3.56−3.52 (m, 2H), 2.64−
2.59 (m, 3H), 2.41 (s, 3H), 1.07 (d, J = 7.5 Hz, 3H), 0.30 (s, 9H); 13C
NMR (150 MHz, CDCl3) δ 211.3, 172.6, 143.6, 143.5, 141.9, 136.2,
129.7 (2C), 127.1 (2C), 124.8, 50.6, 48.8, 46.1, 31.0, 21.5, 14.9, −0.5
(3C); IR (thin film) 2958, 2921, 2864, 1691, 1536, 1340, 1164, 1091;
HRMS (ES+) C20H28NO3SSi [M + H+] calculated 390.1559, found
390.1549; [α]2D0 = +8.3° (c 0.8, CH2Cl2).
1
27 (73.4 mg, 61%) as a colorless oil: H NMR (700 MHz, CDCl3) δ
8.29 (d, J = 8.7 Hz, 2H), 8.22 (d, J = 8.7 Hz, 2H), 5.12−5.10 (m, 2H),
4.45−4.43 (m, 2H), 2.48−2.43 (m, 2H), 1.62−1.61 (m, 3H); 13C
NMR (175 MHz, CDCl3) δ 205.5, 164.6, 150.5, 135.7, 130.6 (2C),
123.5 (2C), 86.6, 85.8, 64.9, 28.2, 14.3; IR (thin film) 3113, 2954,
2901, 2852, 1965, 1720, 1532, 1352, 1274, 1103, 1111, 1013, 874;
HRMS (ES+) C13H13NO4 [M+] calculated 247.0845, found 247.0867;
[α]2D0 = −43.6° (c 0.55, CH2Cl2).
(Ra)-N-(Hexa-3,4-dien-1-yl)-4-methyl-N-(3-phenylprop-2-yn-
1-yl)benzene sulfonamide (17d). Following the general procedure
for preparation of allene-yne via Mitsunobu reaction, (Ra)-hexa-3,4-
dien-1-ol 26 (26.4 mg, 0.27 mmol) in THF (1.9 mL) was reacted with
triphenylphosphine (85 mg, 0.32 mmol), 4-methyl-N-(3-phenylprop-
2-yn-1-yl)benzenesulfonamide31 (92.1 mg, 0.32 mmol) and diisopro-
pylazodicarboxylate (64 μL, 0.32 mmol) for 12 h. Purification of the
crude residue using a Biotage normal phase automated purification
system (25 g SNAP column, gradient of 0−20% Et2O/hexanes)
1
afforded compound 17d (83.9 mg, 85%) as a colorless oil: H NMR
(600 MHz, CDCl3) δ 7.77 (d, J = 8.0 Hz, 2H), 7.28−7.22 (m, 5H),
7.08 (d, J = 7.3 Hz, 2H), 5.11−5.08 (m, 1H), 5.08−5.03 (m, 1H), 4.36
(s, 2H), 3.33 (t, J = 7.3 Hz, 2H), 2.34 (s, 3H), 2.32−2.31 (m, 2H),
1.66−1.64 (m, 3H); 13C NMR (150 MHz, CDCl3) δ 205.4, 143.3,
136.0, 131.5 (2C), 129.5 (2C), 128.4, 128.1 (2C), 127.7 (2C), 122.2,
86.6, 86.4, 85.6, 81.9, 46.1, 37.3, 27.6, 21.4, 14.4; IR (thin film) 3060,
3031, 2987, 2921, 2856, 2235, 1973, 1597, 1487, 1438, 1344, 1168,
1095, 1025, 907; HRMS (ES+) C22H23NO2NaS [M + Na] calculated
388.1347, found 388.1364; [α]2D0 = −25.5° (c 1.45, CH2Cl2).
(Ra)-N-(But-2-yn-1-yl)-N-(hexa-3,4-dien-1-yl)-4-methylbenze-
nesulfonamide (17c). Following the general procedure for
preparation of allene-yne via Mitsunobu reaction, (Ra)-hexa-3,4-dien-
1-ol 26 (25 mg, 0.26 mmol) in THF (1.8 mL) was reacted with
triphenylphosphine (80.2 mg, 0.31 mmol), N-(but-2-yn-1-yl)-4-
methylbenzenesulfonamide31 (68.3 mg, 0.31 mmol) and diisopropy-
lazodicarboxylate (61 μL, 0.31 mmol) for 12 h. Purification of the
crude residue using a Biotage normal phase automated purification
system (10 g SNAP column, gradient of 10% Et2O/hexanes) afforded
(S)-6-Methyl-8-phenyl-2-tosyl-1,2,3,4-tetrahydrocyclopenta-
[c]azepin-7(6H)-one (45d). Following the general procedure for the
[Rh(CO)2Cl]2 catalyzed cyclocarbonylation reaction, allene-yne 17d
(40.4 mg, 0.11 mmol) and [Rh(CO)2Cl]2 (4.3 mg, 0.011 mmol) were
reacted in toluene (3.4 mL) for 180 min. Purification of the crude
residue using a Biotage normal phase automated purification system
(10 g SNAP column, 70% Et2O/hexanes) afforded compound 45d
1
(36.5 mg, 84%) as a colorless oil: H NMR (600 MHz, CDCl3) δ
7.54−7.53 (m, 2H), 7.46−7.45 (m, 2H), 7.41−7.39 (m, 1H), 7.29 (d, J
= 6.9 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 5.79−5.77 (m, 1H), 4.60−
4.53 (m, 2H), 3.67−3.63 (m, 1H), 3.63−3.61 (m, 1H), 2.78−2.77 (m,
1H), 2.70−2.68 (m, 2H), 2.40 (s, 3H), 1.17 (d, J = 7.5 Hz, 3H); 13C
NMR (150 MHz, CDCl3) δ 205.3, 160.2, 143.5, 141.2, 140.7, 136.5,
130.4, 129.6 (2C), 129.3 (2C), 128.7, 128.5 (2C), 127.0 (2C), 125.5,
49.1, 49.0, 45.2, 30.8, 21.5, 15.0; IR (thin film) 3060, 2974, 2925, 2876,
1699, 1601, 1499, 1450, 1336, 1160, 1095, 952; HRMS (ES+)
1
compound 17c (57 mg, 74%) as a colorless oil: H NMR (300 MHz,
CDCl3) δ 7.73 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 5.08−5.04
(m, 1H), 5.04−4.99 (m, 1H), 4.07−4.06 (m, 2H), 3.26−3.21 (t, J =
7.3 Hz, 2H), 2.42 (s, 3H), 2.26−2.23 (m, 2H), 1.66−1.63 (m, 3H),
1.57−1.55 (t, J = 2.4 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 205.3,
143.1, 136.1, 129.2 (2C), 127.8 (2C), 86.6, 86.3, 81.4, 71.8, 45.9, 36.9,
27.6, 21.5, 14.4, 3.2; IR (thin film) 2925, 2852, 1961, 1597, 1442,
1348, 1160, 1099; HRMS (ES+) C17H22NO2S [M + H+] calculated
304.1371, found 304.1363; [α]2D0 = −17.7° (c 2.6, CH2Cl2).
C23H24NO3S [M + H+] calculated 394.1477, found 394.1473; [α]2D0
+1.64° (c 1.4, CH2Cl2).
=
(S)-6,8-Dimethyl-2-tosyl-1,2,3,4-tetrahydrocyclopenta[c]-
azepin-7(6H)-one (45c). Following the general procedure for the
[Rh(CO)2Cl]2 catalyzed cyclocarbonylation reaction, allene-yne 17c
(16.9 mg, 0.056 mmol) and [Rh(CO)2Cl]2 (2.2 mg, 0.0056 mmol)
were reacted in toluene (1.7 mL) for 280 min. Purification of the crude
residue using a Biotage normal phase automated purification system (4
g SNAP column, 70% Et2O/hexanes) afforded compound 45c (13.5
mg, 73%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 7.66 (d, J
= 8.3 Hz, 2H), 7.29−7.26 (d, J = 8.3 Hz, 2H), 5.63 (t, J = 5.0 Hz, 1H),
4.43−4.41 (m, 2H), 3.55−3.51 (m, 2H), 2.70−2.59 (m, 3H), 2.42 (s,
3H), 1.81 (s, 3H), 1.10 (d, J = 7.4 Hz, 3H); 13C NMR (175 MHz,
CDCl3) 207.0, 159.8, 143.6, 140.8, 138.0, 136.2, 129.7 (2C), 127.0
(2C), 123.7, 49.0, 48.9, 44.6, 31.3, 21.5, 14.9, 8.4; IR (thin film) 2062,
2921, 2856, 2002, 1691, 1597, 1446, 1340, 1164, 1095; HRMS (ES+)
(Ra)-N-(Hexa-3,4-dien-1-yl)-4-methyl-N-(prop-2-yn-1-yl)-
benzenesulfonamide (17e). Following the general procedure for
preparation of allene-yne via Mitsunobu reaction, (Ra)-hexa-3,4-dien-
1-ol 26 (42.1 mg, 0.43 mmol) in THF (3 mL) was reacted with
triphenylphosphine (135 mg, 0.51 mmol), 4-methyl-N-(prop-2-yn-1-
yl)benzenesulfonamide31 (108 mg, 0.51 mmol) and diisopropylazodi-
carboxylate (101 μL, 0.51 mmol) for 6 h. Purification of the crude
residue using a Biotage normal phase automated purification system
(12 g SNAP column, gradient of 5−10% Et2O/hexanes) afforded
compound 17e (105 mg, 84%) as a colorless oil: 1H NMR (400 MHz,
CDCl3) δ 7.72 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 8.2 Hz, 2H), 5.10−5.07
(m, 1H), 5.02−4.99 (m, 1H), 4.14 (d, J = 2.5 Hz, 2H), 3.26 (t, J = 7.4
Hz, 2H), 2.42 (s, 3H), 2.26 (m, 2H), 2.03 (t, J = 2.5 Hz, 1H), 1.65−
1.63 (m, 3H); 13C NMR (175 MHz, CD2Cl2) δ 205.2, 143.7, 136.0,
H
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C18H22NO3S [M + H+] calculated 332.1320, found 332.1347; [α]2D0
+2.4° (c 0.85, CH2Cl2).
=
(S)-Diethyl 1,3-dimethyl-2-oxo-1,2,6,7-tetrahydroazulene-
5,5(4H)-dicarboxylate (47c). Following the general procedure for
the [Rh(CO)2Cl]2 catalyzed cyclocarbonylation reaction, allene-yne
19c (33.8 mg, 0.11 mmol) and [Rh(CO)2Cl]2 (4.4 mg, 0.011 mmol)
were reacted in toluene (3.6 mL) for 22 h. Purification of the residue
by flash chromatography (40% Et2O/hexanes) afforded compound
47c (25.7 mg, 71%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ
5.81−5.79 (m, 1H), 4.23−4.15 (m, 4H), 3.21 (s, 2H), 2.76−2.68 (m,
1H), 2.51−2.47 (m, 2H), 2.39−2.33 (m, 2H), 1.84 (s, 3H), 1.27−1.22
(m, 6H), 1.16 (d, J = 7.5 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ
208.1, 171.3, 171.2, 161.0, 143.6, 139.2, 125.9, 61.7 (2C), 56.2, 44.2,
33.9 (2C), 25.0, 15.0, 14.0 (2C), 8.3; IR (thin film) 2978, 2921, 1732,
1703, 1446, 1364, 1287, 1234, 1062, 1095; HRMS (ES+) C18H25O5
[M + H+] calculated 321.1702, found 321.1723; [α]2D0 = −12° (c 0.5,
CH2Cl2).
(Ra)-Hexa-3,4-dien-1-yl methanesulfonate (32). To a stirred
solution of (Ra)-hexa-3,4-dien-1-ol 26 (60.8 mg, 0.62 mmol) in THF
(8.7 mL), cooled to 0 °C (ice bath), was added triethylamine (95 μL,
0.68 mmol) followed by methanesulfonyl chloride (53 μL, 0.681
mmol). The resulting solution was stirred at rt for 12 h. The mixture
was diluted with Et2O (60 mL), washed with water (2 × 10 mL), dried
(Na2SO4), filtered and concentrated under reduced pressure.
Purification of the crude residue using a Biotage normal phase
automated purification system (12 g SNAP column, 35% Et2O/
hexanes) afforded compound 32 (84.1 mg, 77%) as a colorless oil: 1H
NMR (400 MHz, CDCl3) δ 5.22−5.12 (m, 1H), 5.05−5.03 (m, 1H),
4.25 (t, J = 6.8 Hz, 2H), 3.00 (s, 3H), 2.44−2.39 (m, 2H), 1.65 (dd, J
= 7.0, 3.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 205.4, 86.9, 84.8,
69.0, 37.2, 28.5, 14.1; IR (thin film) 3032, 2987, 2942, 1965, 1462,
1344, 1172, 964, 911; HRMS (ES+) C7H13O3S [M + H+] calculated
177.0585, found 177.0588; [α]2D0 = −32.4° (c 1.45, CH2Cl2).
(Ra)-Diethyl 2-(hexa-3,4-dien-1-yl)-2-(prop-2-yn-1-yl)-
malonate (19e). Following the general procedure for preparation
of allene-yne via alkylation of the malonate moiety, diethyl malonate
34e (189 mg, 0.95 mmol) was reacted with sodium hydride (28.6 mg,
60 wt % in oil, 0.71 mmol), mesylate 32 (84 mg, 0.48 mmol) and
potassium iodide (119 mg, 0.72 mmol) in DMF−THF (1:1, 13 mL).
Purification of the crude residue using a Biotage normal phase
automated purification system (50 g SNAP column, gradient of 2−7%
Et2O/hexanes) afforded compound 19e (75.5 mg, 57%) as a colorless
(Ra)-Diethyl 2-(hexa-3,4-dien-1-yl)-2-(3-phenylprop-2-yn-1-
yl)malonate (19d). Following the general procedure for preparation
of allene-yne via alkylation of the malonate moiety, diethyl malonate
34d (79.3 mg, 0.29 mmol) was reacted with sodium hydride (8.7 mg,
60 wt % in oil, 0.22 mmol), mesylate 32 (25.5 mg, 0.15 mmol) and
potassium iodide (36 mg, 0.22 mmol) in DMF−THF (1:1, 4 mL).
Purification of the crude residue using a Biotage normal phase
automated purification system (25 g SNAP column, gradient of 3−7%
Et2O/hexanes) afforded compound 19d (35.4 mg, 69%) as a colorless
1
oil: H NMR (300 MHz, CDCl3) δ 5.09−5.03 (m, 2H), 4.24−4.17
(m, 4H), 2.83 (s, 2H), 2.20−2.14 (m, 2H), 2.00 (t, J = 2.7 Hz, 1H),
1.96−1.87 (m, 2H), 1.66−1.63 (m, 3H), 1.25 (t, J = 7.1 Hz, 6H); 13C
NMR (100 MHz, CD2Cl2) δ 204.5, 170.0 (2C), 89.3, 86.3, 78.9, 71.0,
61.6 (2C), 56.4, 31.3, 23.7, 22.7, 14.2, 13.8 (2C); IR (thin film) 3293,
2892, 2938, 1736, 1454, 1270, 1193, 1095, 1030. HRMS (ES+)
1
oil: H NMR (300 MHz, CDCl3) δ 7.38−7.35 (m, 2H), 7.29−7.27
(m, 3H), 5.09−5.05 (m, 2H), 4.22 (q, J = 7.2 Hz, 4H), 3.05 (s, 2H),
2.25−2.20 (m, 2H), 1.98−1.95 (m, 2H), 1.65−1.62 (m, 3H), 1.26 (t, J
= 7.1 Hz, 6H); 13C NMR (175 MHz, CDCl3) δ 204.6, 170.3 (2C),
131.6 (2C), 128.1 (2C), 127.9, 123.3, 89.4, 86.4, 84.4, 83.4, 61.5 (2C),
56.9, 31.6, 23.8, 23.7, 14.4, 14.1 (2C); IR (thin film) 3465, 2987, 2921,
2856, 1965, 1732, 1597, 1487, 1446, 1368, 1270, 1197, 1091, 1030;
HRMS (ES+) C22H27O4 [M + H+] calculated 355.1909, found
355.1885; [α]2D0 = −19.6° (c 2.5, CH2Cl2).
C16H23O4 [M + H+] calculated 279.1596, found 279.1623; [α]2D0
−40° (c 2.2, CH2Cl2).
=
(Ra)-Diethyl 2-(hexa-3,4-dien-1-yl)-2-(3-(trimethylsilyl)prop-
2-yn-1-yl)malonate (19f). Following the general procedure for
preparation of allene-yne via silylation of the terminal alkyne, allene-
yne 19e (67.6 mg, 0.24 mmol) in THF (1.8 mL) was reacted with
lithium hexamethyldisilylamide (365 μL, 1 M in THF, 0.36 mmol) and
trimethylsilylchloride (62 μL, 0.49 mmol). Purification of the crude
residue using a Biotage normal phase automated purification system (4
g SNAP column, 5% Et2O/hexanes) afforded compound 19f (74.4 mg,
88%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 5.08−5.03 (m,
2H), 4.20−4.17 (m, 4H), 2.84 (s, 2H), 2.14−2.12 (m, 2H), 1.93−1.90
(m, 2H), 1.65−1.62 (m, 3H), 1.24 (t, J = 7.1 Hz, 6H), 0.12 (s, 9H);
13C NMR (175 MHz, CDCl3) δ 204.6, 170.1 (2C), 101.4, 89.4, 88.0,
(S)-Diethyl 1-methyl-2-oxo-3-phenyl-1,2,6,7-tetrahydroazu-
lene-5,5(4H)-dicarboxylate (47d). Following the general procedure
for the [Rh(CO)2Cl]2 catalyzed cyclocarbonylation reaction, allene-
yne 19d (22.6 mg, 0.064 mmol) and [Rh(CO)2Cl]2 (2.5 mg, 0.0064
mmol) were reacted in toluene (2 mL) for 100 min. Purification of the
residue by flash chromatography (45% Et2O/hexanes) afforded the
1
title compound 47d (23.3 mg, 96%) as a colorless oil: H NMR (300
MHz, CDCl3) δ 7.44−7.26 (m, 5H), 6.04−5.92 (m, 1H), 4.15−4.02
(m, 4H), 3.39 (s, 2H), 2.94−2.87 (q, J = 7.4 Hz, 1H), 2.56−2.52 (m,
2H), 2.45−2.41 (m, 2H), 1.27 (d, J = 7.5 Hz, 3H), 1.13 (q, J = 7.1 Hz,
6H); 13C NMR (175 MHz, CDCl3) δ 206.0, 171.1, 170.9, 161.3,
143.2, 141.9, 131.3, 129.4 (2C), 128.3 (2C), 128.2, 127.9, 61.7, 61.6,
56.3, 44.9, 34.5, 33.8, 25.1, 15.3, 13.9, 13.8; IR (thin film) 2966, 2929,
2852, 2365, 1732, 1699, 1450, 1364, 1242, 1176, 1078; HRMS (ES+)
86.3, 61.5 (2C), 56.7, 31.4, 24.2, 23.7, 14.4, 14.0 (2C), −0.1 (3C); IR
(thin film) 2958, 2925, 2860, 2186, 1740, 1471, 1442, 1254, 1197,
1103, 1034, 854; HRMS (ES+) C19H31O4Si [M + H+] calculated
351.1992, found 351.1990; [α]2D0 = −30.3° (c 1.85, CH2Cl2).
(S)-Diethyl 1-methyl-2-oxo-3-(trimethylsilyl)-1,2,6,7-tetrahy-
droazulene-5,5(4H)-dicarboxylate (47f). Following the general
procedure for the [Rh(CO)2Cl]2 catalyzed cyclocarbonylation
reaction, allene-yne 19f (33.9 mg, 0.097 mmol) and [Rh(CO)2Cl]2
(2.5 mg, 0.0097 mmol) were reacted in toluene (3.2 mL) for 10 h.
Purification of the crude residue using a Biotage normal phase
automated purification system (4 g SNAP column, 25% Et2O/
hexanes) afforded compound 47f (34.5 mg, 94%) as a colorless oil: 1H
NMR (300 MHz, CDCl3) δ 5.88−5.83 (m, 1H), 4.23−4.16 (m, 4H),
3.37−3.36 (m, 2H), 2.75−2.68 (m, 1H), 2.50−2.46 (m, 2H), 2.40−
2.34 (m, 2H), 1.24 (td, J = 7.1, 0.9 Hz, 6H), 1.14 (t, J = 7.4 Hz, 3H),
0.27 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 212.3, 173.4, 171.1,
171.0, 145.6, 142.8, 127.3, 61.7, 61.6, 56.3, 46.1, 36.5, 33.7, 25.2, 15.0,
14.0 (2C), −0.3 (3C); IR (Thin film) 2970, 2929, 2905, 1736, 1691,
1540, 1446, 1368, 1291, 1230, 1078, 1037, 841; HRMS (ES+)
C23H27O5 [M + H+] calculated 383.1858, found 383.1860; [α]2D0
−12.6° (c 0.95, CH2Cl2).
=
(Ra)-Diethyl 2-(but-2-yn-1-yl)-2-(hexa-3,4-dien-1-yl)-
malonate (19c). Following the general procedure for preparation
of allene-yne via alkylation of the malonate moiety, diethyl malonate
34c (94.4 mg, 0.45 mmol) was reacted with sodium hydride (15.3 mg,
60 wt % in oil, 0.38 mmol), mesylate 32 (56 mg, 0.32 mmol) and
potassium iodide (79.1 mg, 0.48 mmol) in DMF−THF (1:1, 6 mL).
Purification of the crude residue using a Biotage normal phase
automated purification system (25 g SNAP column, gradient of 4−6%
Et2O/hexanes) afforded compound 19c (59.6 mg, 63%) as a colorless
1
oil: H NMR (400 MHz, CDCl3) δ 5.07−5.02 (m, 2H), 4.18 (q, J =
C20H31O5Si [M + H+] calculated 379.1941, found 379.1967; [α]2D0
−5.5° (c 2.2, CH2Cl2).
=
7.1 Hz, 4H), 2.75 (s, 2H), 2.12−2.10 (m, 2H), 1.90−1.88 (m, 2H),
1.73 (s, 3H), 1.64−1.62 (m, 3H), 1.23 (t, J = 7.2 Hz, 6H); 13C NMR
(175 MHz, CDCl3) δ 204.6, 170.4 (2C), 89.4, 86.3, 78.5, 73.4, 61.3
(2C), 56.8, 31.4, 23.7, 23.1, 14.4, 14.0 (2C), 3.4; IR (thin film) 2983,
2934, 2859, 1736, 1438, 1360, 1275, 1225, 1193; HRMS (ES+)
(Ra)-6-(But-2-yn-1-yloxy)hexa-2,3-diene (18c). Following the
general procedure for preparation of allene-yne via Williamson
etherification, (Ra)-hexa-3,4-dien-1-ol 26 (32.3 mg, 0.33 mmol) in
THF (0.8 mL) was reacted with sodium hydride (26.5 mg, 60%
dispersion in mineral oil 0.66 mmol) and 1-bromobut-2-yne (61.3 mg,
C17H25O4 [M + H+] calculated 293.1753, found 293.1778; [α]2D0
−32.9° (c 0.85, CH2Cl2).
=
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The Journal of Organic Chemistry
Article
0.46 mmol) for 12 h. Purification of the crude residue using a Biotage
normal phase automated purification system (12 g SNAP column,
gradient of 0−3% Et2O/hexanes) afforded compound 18c (37.4 mg,
83%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 5.09−5.04 (m,
2H), 4.10−4.08 (m, 2H), 3.56−3.51 (m, 2H), 2.29−2.25 (m, 2H),
1.86−1.84 (m, 3H), 1.66−1.62 (m, 3H); 13C NMR (150 MHz,
CDCl3) δ 205.2, 86.6, 85.8, 82.1, 75.2, 69.3, 58.5, 29.1, 14.3, 3.5; IR
(thin film) 2925, 2860, 1446, 1356, 1140, 1095; HRMS (ES+)
[Rh(CO)2Cl]2 catalyzed cyclocarbonylation reaction, allene-yne 18f
(29.8 mg, 0.14 mmol) and [Rh(CO)2Cl]2 (5.6 mg, 0.014 mmol) were
reacted in toluene (4.7 mL) for 7 h. Purification of the crude residue
using a Biotage normal phase automated purification system (4 g
SNAP column, 40% Et2O/hexanes) afforded compound 46f (25.6 mg,
76%) as a colorless oil: 1H NMR (600 MHz, CDCl3) δ 5.85−5.84 (m,
1H), 4.84 (s, 2H), 3.94 (t, J = 5.4 Hz, 2H), 2.80−2.78 (m, 1H), 2.63−
2.60 (m, 2H), 1.21 (d, J = 7.5 Hz, 3H), 0.23 (s, 9H); 13C NMR (150
MHz, CDCl3) δ 211.5, 177.1, 142.9, 139.8, 126.1, 73.0, 71.5, 46.2,
33.8, 15.3, −0.4 (3C); IR (thin film) 2958, 2925, 2869, 1687, 1528,
1250, 1193, 1136; HRMS (ES+) C13H21O2Si [M + H+] calculated
237.1311, found 237.1283; [α]2D0 = −1.6° (c 1.6, CH2Cl2).
C10H15O [M + H+] calculated 151.1123, found 151.1150; [α]2D0
−20.5°(c 1.85, CH2Cl2).
=
(S)-6,8-Dimethyl-3,4-dihydro-1H-cyclopenta[c]oxepin-7(6H)-
one (46c). Following the general procedure for the [Rh(CO)2Cl]2
catalyzed cyclocarbonylation reaction, allene-yne 18c (27.1 mg, 0.20
mmol) and [Rh(CO)2Cl]2 (7.6 mg, 0.020 mmol) were reacted in
toluene (6.4 mL) for 390 min. Purification of the crude residue using a
Biotage normal phase automated purification system (4 g SNAP
column, 60% Et2O/hexanes) afforded compound 46c (14.1 mg, 40%)
as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 5.79−5.76 (m, 1H),
4.74 (s, 2H), 3.94 (t, J = 5.3 Hz, 2H), 2.87−2.74 (m, 1H), 2.63−2.58
(m, 2H), 1.74 (s, 3H), 1.23 (d, J = 7.5 Hz, 3H); 13C NMR (150 MHz,
CDCl3) δ 207.2, 164.0, 140.6, 136.2, 124.6, 71.6, 71.0, 44.6, 33.8, 15.2,
8.1; IR (thin film) 2966, 2925, 2872, 1695, 1597, 1458, 1372, 1328,
1225, 1205, 1140; HRMS (ES+) C11H15O2 [M + H+] calculated
179.1072, found 179.1051; [α]2D0 = +2.9° (c 1.05, CH2Cl2).
(Ra)-6-(Prop-2-yn-1-yloxy)hexa-2,3-diene (18e). Following the
general procedure for preparation of allene-yne via Williamson
etherification (Ra)-hexa-3,4-dien-1-ol 26 (70.7 mg, 0.72 mmol) in
THF (1.7 mL) was reacted with sodium hydride (58 mg, 60%
dispersion in mineral oil 1.44 mmol) and propargyl bromide (161 mg,
80 wt % in toluene, 1.08 mmol) for 11 h. Purification of the crude
residue using a Biotage normal phase automated purification system
(12 g SNAP column, gradient of 0−2% Et2O/hexanes) afforded
compound 18e (43.4 mg, 44%) as a colorless oil: 1H NMR (600 MHz,
CDCl3) δ 5.09−5.06 (m, 2H), 4.16 (d, J = 2.4 Hz, 2H), 3.58 (t, J = 6.8
Hz, 2H), 2.42 (t, J = 2.4 Hz, 1H), 2.30−2.26 (m, 2H), 1.66−1.64 (m,
3H); 13C NMR (150 MHz, CD2Cl2) δ 205.1, 86.6, 85.8, 80.0, 73.8,
69.4, 57.9, 29.2, 14.2; IR (thin film) 2933, 2852, 1454, 1356, 1099;
HRMS (ES+) C9H11O [M − H+] calculated 135.0810, found
135.0835; [α]2D0 = −41.5° (c 1.35, CH2Cl2).
(Ra)-(3-(Hexa-3,4-dien-1-yloxy)prop-1-yn-1-yl)benzene
(18d). Following the general procedure for preparation of allene-yne
via Williamson etherification, (Ra)-hexa-3,4-dien-1-ol 26 (62.8 mg,
0.64 mmol) in THF (1.5 mL) was reacted with sodium hydride (51.2
mg, 60% dispersion in mineral oil, 1.27 mmol) and (3-bromoprop-1-
yn-1-yl)benzene (187.2 mg, 0.96 mmol) for 3 h. Purification of the
crude residue using a Biotage normal phase automated purification
system (10 g SNAP column, gradient of 0−3% Et2O/hexanes)
1
afforded compound 18d (85.2 mg, 63%) as a colorless oil: H NMR
(400 MHz, CDCl3) δ 7.46−7.45 (m, 2H), 7.32−7.30 (m, 3H), 5.12−
5.08 (m, 2H), 4.38 (s, 2H), 3.65 (t, J = 6.8 Hz, 2H), 2.34−2.31 (m,
2H), 1.67−1.64 (m, 3H); 13C NMR (150 MHz, CDCl3) δ 205.3,
131.7 (2C), 128.3, 128.2 (2C), 122.7, 86.7, 86.0, 85.9, 85.3, 69.5, 58.8,
29.2, 14.4; IR (thin film) 3060, 2917, 2845, 1969, 1491, 1442, 1360,
1099; HRMS (ES+) C15H17O [M + H+] calculated 213.1279, found
213.1280; [α]2D0 = −41.5° (c 0.65, CH2Cl2).
(S)-6-Methyl-8-phenyl-3,4-dihydro-1H-cyclopenta[c]oxepin-
7(6H)-one (46d). Following the general procedure for the [Rh-
(CO)2Cl]2 catalyzed cyclocarbonylation reaction, allene-yne 18d (29.6
mg, 0.14 mmol) and [Rh(CO)2Cl]2 (5.4 mg, 0.014 mmol) were
reacted in toluene (4.4 mL) for 30 min. Purification of the crude
residue using a Biotage normal phase automated purification system (4
g SNAP column, 45% Et2O/hexanes) afforded compound 46d (30 mg,
90%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 7.41−7.34 (m,
3H), 7.25−7.24 (m, 2H), 5.96−5.94 (m, 1H), 4.85 (s, 2H), 4.03−3.98
(m, 2H), 3.01−2.98 (m, 1H), 2.69−2.67 (m, 2H), 1.34 (d, J = 7.5 Hz,
3H); 13C NMR (175 MHz, CDCl3) δ 205.6, 164.4, 140.7, 139.1,
130.9, 129.3 (2C), 128.4, 128.3 (2C), 126.8, 71.9, 71.5, 45.3, 33.6,
15.5; IR (thin film) 2962, 2925, 2868, 1669, 1446, 1131; HRMS (ES+)
(S)-6-Methyl-3,4-dihydro-1H-cyclopenta[c]oxepin-7(6H)-one
(46e). Following the general procedure for the [Rh(CO)2Cl]2
catalyzed cyclocarbonylation reaction, allene-yne 18e (45.5 mg, 0.33
mmol) and [Rh(CO)2Cl]2 (13 mg, 0.033 mmol) were reacted in
toluene (10.9 mL) for 105 min. Purification of the crude residue using
a Biotage normal phase automated purification system (10 g SNAP
column, 20−65% Et2O/hexanes) afforded compound 46e (13.3 mg,
C16H17O2 [M + H+] calculated 241.1229, found 241.1204; [α]2D0
−24° (c 0.25, CH2Cl2).
=
(Ra)-N-(But-2-yn-1-yl)-N-(3-(dimethyl(phenyl)silyl)hexa-3,4-
dien-1-yl)-4-methyl benzenesulfonamide (13c). Following the
general procedure for preparation of allene-yne via Mitsunobu
reaction, alcohol (Ra)-22 (157 mg, 0.675 mmol) in THF (4.4 mL)
was reacted with triphenylphosphine (213 mg, 0.81 mmol), N-(but-2-
yn-1-yl)-4-methylbenzenesulfonamide31 30c (181 mg, 0.81 mmol) and
diisopropylazodicarboxylate (160 μL, 0.81 mmol) for 3 h. Purification
of the crude residue using a Biotage normal phase automated
purification system (25 g SNAP column, gradient of 0−30% Et2O/
hexanes) afforded compound 13c (272 mg, 92%) as a colorless oil: 1H
NMR (600 MHz, CDCl3) δ 7.65 (d, J = 7.8 Hz, 2H), 7.51 (d, J = 7.6
Hz, 2H), 7.38−7.32 (m, 3H), 7.24 (d, J = 7.8 Hz, 2H), 4.92−4.80 (m,
1H), 3.96 (d, J = 2.5 Hz, 2H), 3.22−3.10 (m, 2H), 2.41 (s, 3H), 2.16
(m, 2H), 1.63 (d, J = 6.9 Hz, 3H), 1.52 (t, J = 2.5 Hz, 3H), 0.36 (s,
6H); 13C NMR (150 MHz, CDCl3) δ 2078.0, 142.9, 137.9, 136.2,
133.7 (2C), 129.1 (2C), 129.0, 127.7 (2C), 127.7 (2C), 91.2, 81.2,
81.2, 72.0, 46.4, 37.1, 27.9, 21.4, 13.7, 3.2, −3.1, −3.2; IR (thin film)
3064, 2962, 2921, 2855, 2300, 2218, 1936, 1593, 1491; HRMS (ES+)
C25H32NO2SSi [M + H+] calculated 438.1923, found 438.1926; [α]2D0
= +3.8° (c 1.7, CH2Cl2).
1
24%) as a colorless oil: H NMR (600 MHz, CDCl3) δ 6.00 (s, 1H),
5.91−5.89 (m, 2H), 4.78−4.77 (m, 2H), 3.96−3.92 (m, 2H), 2.88−
2.84 (m, 1H), 2.63−2.61 (m, 1H), 1.25 (d, J = 7.6 Hz, 3H); 13C NMR
(150 MHz, CDCl3) δ 207.6, 171.4, 141.6, 127.9, 127.6, 71.9, 71.8,
45.8, 33.8, 15.0; IR (thin film) 2925, 2864, 1699, 1565, 1458, 1368,
1201, 1120, 1070; HRMS (ES+) C10H13O2 [M + H+] calculated
165.0916, found 165.0897; [α]2D0 = +14.1° (c 0.85, CH2Cl2).
(Ra )-(3-(Hexa-3,4-dien-1-yloxy)prop-1-yn-1-yl)-
trimethylsilane (18f). Following the general procedure for
preparation of allene-yne via silylation of the terminal alkyne, allene-
yne 18e (72.4 mg, 0.53 mmol) in THF (4.2 mL) was reacted with
lithium hexamethyldisilylamide (798 μL, 1 M in THF, 0.80 mmol) and
trimethylsilyl chloride (135 μL, 1.06 mmol). Purification of the crude
residue using a Biotage normal phase automated purification system
(10 g SNAP column, gradient of 0−1% Et2O/hexanes) afforded
1
compound 18f (76 mg, 69%) as a colorless oil: H NMR (600 MHz,
CDCl3) δ 5.10−5.05 (m, 2H), 4.15 (s, 2H), 3.56 (t, J = 6.8 Hz, 2H),
2.30−2.26 (m, 2H), 1.64−1.63 (m, 3H), 0.18 (s, 9H); 13C NMR (150
MHz, CDCl3) δ 205.3, 101.7, 91.1, 86.7, 85.9, 69.5, 58.8, 29.1, 14.4,
−0.2 (3C); IR (thin film) 2954, 2897, 2178, 1258, 1107, 919, 850;
HRMS (ES+) C12H20OSi [M − H]+ calculated 207.1205, found
207.1189; [α]2D0 = −33.3° (c 1.35, CH2Cl2).
(S)-5-(Dimethyl(phenyl)silyl)-6,8-dimethyl-2-tosyl-1,2,3,4-
tetrahydrocyclo penta[c]azepin-7(6H)-one (35c). Following the
general procedure for the [Rh(CO)2Cl]2 catalyzed cyclocarbonylation
reaction, allene-yne 13c (22.5 mg, 0.051 mmol) and [Rh(CO)2Cl]2 (2
mg, 0.005 mmol) were reacted in toluene (1.6 mL) for 3 h.
Purification of the crude residue by flash chromatography (55% Et2O/
hexanes) afforded the title compound 35c (22.8 mg, 95%) as a yellow
(S)-6-Methyl-8-(trimethylsilyl)-3,4-dihydro-1H-cyclopenta-
[c]oxepin-7(6H)-one (46f). Following the general procedure for the
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1
oil: H NMR (300 MHz, CDCl3) δ 7.55 (d, J = 8.1 Hz, 2H), 7.40−
1H), 3.88 (s, 2H), 3.13 (t, J = 6.1 Hz, 2H), 2.4−2.36 (m, 5H), 0.40 (s,
6H); 13C NMR (175 MHz, CDCl3) δ 151.9, 143.4, 143.0, 138.6,
136.9, 136.0, 135.3, 133.8 (2C), 129.5 (2C), 129.0, 127.9 (2C), 127.3
(2C), 117.1, 117.1, 51.1, 45.2, 31.8, 21.4, −0.7 (2C); IR (thin film)
3060, 2962, 2921, 2847, 1343, 1164, 1106; HRMS (ES+)
C24H30NO2SSi [M + H+] calculated 424.1767, found 424.1787.
(Ra)-N-(3-(Dimethyl(phenyl)silyl)hexa-3,4-dien-1-yl)-4-meth-
yl-N-(3-(trimethylsilyl)prop-2-yn-1-yl)benzenesulfonamide
(13f). Following the general procedure for preparation of allene-yne
via silylation of the terminal alkyne, allene-yne 13e (92 mg, 0.22
mmol) in THF (2 mL) was reacted with lithium hexamethyldisily-
lamide (0.28 mL, 1 M in THF, 0.28 mmol) and trimethylsilyl chloride
(55 μL, 0.434 mmol). Purification of the crude residue by silica gel
chromatography using 10% Et2O/hexanes to afford compound 13f
7.34 (m, 5H), 7.22 (d, J = 8.1 Hz, 2H), 4.60 (d, J = 17.0 Hz, 1H), 4.46
(d, J = 17.0 Hz, 1H), 3.45 (t, J = 6.1 Hz, 2H), 2.56−2.51 (m, 3H), 2.40
(s, 3H), 1.89 (s, 3H), 0.91 (d, J = 7.4 Hz, 3H), 0.38 (s, 6H); 13C NMR
(150 MHz, CDCl3) δ 208.4, 160.9, 153.9, 143.5, 138.3, 137.1, 136.4,
133.8 (2C), 133.3, 129.5, 129.4 (2C), 128.0 (2C), 127.1 (2C), 48.0,
43.8, 43.0, 29.7, 21.4, 18.4, 8.2, −1.3, −1.6; IR (thin film) 2978, 2925,
2872, 1703, 1605, 1466, 1344, 1258, 1160, 1102; HRMS (ES+)
C26H31NO3SSiNa [M + Na+] calculated 488.1692, found 488.1708;
[α]2D0 = +157° (c 1.0, CH2Cl2).
(Z)-5-(Dimethyl(phenyl)silyl)-3-ethylidene-1-tosyl-4-vinyl-
2,3,6,7-tetrahydro-1H-azepine (36). Following the general proce-
dure for the [Rh(CO)2Cl]2 catalyzed cyclocarbonylation reaction,
allene-yne 13c (32.5 mg, 0.074 mmol) and [Rh(CO)2Cl]2 (1.4 mg,
0.004 mmol) were reacted in toluene (2.3 mL) for 7 h. Purification of
the crude residue by flash chromatography (55% Et2O/hexanes)
afforded the cyclocarbonylation product 35 (14.4 mg, 42%) and triene
36 (15.6 mg, 48%) as yellow oils: 1H NMR (300 MHz, CDCl3) δ 7.63
(d, J = 8.3 Hz, 2H), 7.47−7.44 (m, 2H), 7.34−7.32 (m, 4H), 7.29 (s,
1H), 6.55 (dd, J = 16.9, 10.5 Hz, 1H), 5.52−5.45 (m, 1H), 5.15 (dd, J
= 16.9, 1.9 Hz, 1H), 5.00 (dd, J = 10.5, 1.9 Hz, 1H), 3.82 (s, 2H),
3.07−3.03 (t, J = 5.9 Hz, 2H), 2.42 (s, 3H), 2.34 (t, J = 5.9 Hz, 2H),
1.78 (d, J = 7.0 Hz, 3H), 0.39 (s, 6H); 13C NMR (150 MHz, CDCl3) δ
153.7, 143.0, 138.9, 137.6, 135.7, 134.9, 133.9 (2C), 133.8, 129.6 (2C),
128.9, 127.9 (2C), 127.4 (2C), 127.3, 117.1, 46.6, 46.0, 31.7, 21.5,
13.3, −0.6 (2C); IR (thin film) 2966, 2921, 2847, 2010, 1515, 1462,
1429, 1336, 1254, 1160, 1103; HRMS (ES+) C25H32NO2SSi [M +
H+] calculated 438.1923, found 438.1917.
(Ra)-N-(3-(Dimethyl(phenyl)silyl)hexa-3,4-dien-1-yl)-4-meth-
yl-N-(prop-2-yn-1-yl)benzene sulfonamide (13e). Following the
general procedure for preparation of allene-yne via Mitsunobu
reaction, alcohol (Ra)-22 (309 mg, 1.32 mmol) in THF (8.2 mL)
was reacted with triphenylphosphine (415.4 mg, 1.58 mmol), 4-
methyl-N-(prop-2-yn-1-yl)benzenesulfonamide31 30e (331 mg, 1.58
mmol) and diisopropylazodicarboxylate (274 μL, 1.58 mmol) for 2 h.
Purification of the crude residue using a Biotage normal phase
automated purification system (25 g SNAP column, gradient of 0−
30% Et2O/hexanes) afforded compound 13e (500 mg, 90%) as a
colorless oil: 1H NMR (600 MHz, CDCl3) δ 7.65 (d, J = 8.0 Hz, 2H),
7.51 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 7.0 Hz, 3H), 7.25−7.24 (m, 2H),
4.92−4.82 (m, 1H), 4.03 (d, J = 2.6 Hz, 2H), 3.22−3.18 (m, 2H), 2.42
(s, 3H), 2.18−2.15 (m, 2H), 1.96 (t, J = 2.5 Hz, 1H), 1.63 (d, J = 7.0
Hz, 3H), 0.36 (s, 6H); 13C NMR (175 MHz, CD2Cl2) 208.0, 143.6,
138.0, 136.1, 133.8 (2C), 129.4 (2C), 129.1, 127.8 (2C), 127.5 (2C),
91.2, 81.4, 76.9, 73.3, 46.5, 36.6, 27.9, 21.3, 13.5, −3.3, −3.4; IR (thin
film) 3289, 2962, 2917, 2860, 1936, 1597, 1495, 1450, 1348; HRMS
(ES+) C24H30NO2SSi [M + H+] calculated 424.1767, found 424.1797;
[α]2D0 = +3.8° (c 1.65, CH2Cl2).
1
(93.3 mg, 87%) as a clear yellow oil: H NMR (600 MHz, CDCl3) δ
7.64 (d, J = 8.3 Hz, 2H), 7.52 (dd, J = 7.4, 2.0 Hz, 2H), 7.38−7.35 (m,
3H), 7.25−7.23 (d, J = 8.3 Hz, 2H), 4.87 (m, 1H), 4.05 (s, 2H), 3.22−
3.18 (m, 2H), 2.40 (s, 3H), 2.19−2.16 (m, 2H), 1.63 (d, J = 7.0 Hz,
3H), 0.36 (d, J = 1.3 Hz, 6H), −0.02 (s, 9H); 13C NMR (150 MHz,
CDCl3) δ 208.0, 143.1, 137.9, 136.1, 133.8 (2C), 129.4 (2C), 129.1,
127.8 (2C), 127.6 (2C), 98.2, 91.2, 90.6, 81.3, 46.3, 37.4, 27.8, 21.45,
13.7, −0.5 (3C), −3.0, −3.1; IR (thin film) 3064, 2958, 2913, 2173,
1940, 1601, 1348; HRMS (ES+) C27H38NO2SSi2 [M + H+] calculated
496.2162, found 496.2152; [α]2D0 = +1.2° (c 1.65, CH2Cl2).
(S)-5-(Dimethyl(phenyl)silyl)-6-methyl-2-tosyl-8-(trimethyl-
silyl)-1,2,3,4-tetrahydrocyclopenta[c]azepin-7(6H)-one (35f).
Following the general procedure for the [Rh(CO)2Cl]2 catalyzed
cyclocarbonylation reaction, allene-yne 13f (25 mg, 0.050 mmol) and
[Rh(CO)2Cl]2 (2 mg, 0.005 mmol) were reacted in toluene (1.6 mL)
for 3 h. Purification of the crude residue by flash chromatography
(55% Et2O/hexanes) afforded the title compound 35f (23.4 mg, 89%)
1
as a yellow oil: H NMR (300 MHz, CDCl3) δ 7.58 (d, J = 8.1 Hz,
2H), 7.39−7.33 (m, 6H), 7.23 (s, 1H), 4.65 (d, J = 17.2 Hz, 1H), 4.56
(d, J = 17.2 Hz, 1H), 3.48−3.31 (m, 2H), 2.61−2.48 (m, 3H), 2.40 (s,
3H), 0.89 (d, J = 7.4 Hz, 3H), 0.36 (d, J = 9.0 Hz, 15H); 13C NMR
(175 MHz, CDCl3) δ 212.5, 174.1, 156.1, 143.4, 142.1, 137.1, 136.5,
134.3, 133.9 (2C), 129.5 (3C), 128.0 (2C), 127.2 (2C), 47.3, 45.5,
45.1, 29.7, 21.5, 18.8, −0.5 (3C), −1.23, −1.6; IR (thin film) 3060,
2962, 2921, 2855, 2247, 1932, 1691, 1601, 1544, 1462, 1352, 1254,
1164; HRMS (ES+) C28H38NO2SSi [M + H+] calculated 524.2111,
found 524.2101; [α]2D0 = +70.4° (c 0.75, CH2Cl2).
(Ra)-N-(3-(Dimethyl(phenyl)silyl)hexa-3,4-dien-1-yl)-4-meth-
yl-N-(3-phenylprop-2-yn-1-yl) benzenesulfonamide (13d). Fol-
lowing the general procedure for preparation of allene-yne via
Mitsunobu reaction, alcohol (Ra)-22 (93.6 mg, 0.402 mmol) in
THF (2.8 mL) was reacted with triphenylphosphine (127 mg, 0.48
mmol), 4-methyl-N-(3-phenylprop-2-yn-1-yl)benzenesulfonamide31
30d (134 mg, 0.48 mmol) and diisopropylazodicarboxylate (95 μL,
0.48 mmol) for 3 h. Purification of the crude residue using a Biotage
normal phase automated purification system (25 g SNAP column,
gradient of 0−30% Et2O/hexanes) afforded compound 13d (185 mg,
92%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 7.67 (d, J = 8.4
Hz, 2H), 7.52−7.49 (m, 2H), 7.35−7.32 (m, 4H), 7.23−7.19 (m, 3H),
7.04 (dd, J = 8.0, 1.7 Hz, 2H), 4.90−4.86 (m, 1H), 4.24 (s, 2H), 3.29−
3.23 (m, 2H), 2.33 (s, 3H), 2.23 (td, J = 8.1, 2.7 Hz, 2H), 1.63 (d, J =
7.0 Hz, 3H), 0.36 (d, J = 0.8 Hz, 6H); 13C NMR (175 MHz, CDCl3) δ
208.0, 143.2, 137.9, 136.0, 133.7 (2C), 131.4 (2C), 129.4 (2C), 129.1,
128.3, 128.0 (2C), 127.8 (2C), 127.6 (2C), 122.2, 91.2, 85.4, 82.0,
81.3, 46.5, 37.4, 27.9, 21.4, 13.7, −3.1, −3.1; IR (thin film) 3068, 2953,
2921, 2855, 2238, 1940, 1589, 1486; HRMS (ES+) C30H34NO2SSi [M
+ H+] calculated 500.2080, found 500.2086; [α]2D0 = +8.7° (c 1.15,
CH2Cl2).
(S)-5-(Dimethyl(phenyl)silyl)-6-methyl-2-tosyl-1,2,3,4-
tetrahydrocyclopenta[c]azepin-7(6H)-one (35e). Following the
general procedure for the [Rh(CO)2Cl]2 catalyzed cyclocarbonylation
reaction, allene-yne 13e (41 mg, 0.097 mmol) and [Rh(CO)2Cl]2 (4.2
mg, 0.009 mmol) were reacted in toluene (3 mL) for 2.5 h.
Purification of the crude residue by flash chromatography (65% Et2O/
hexanes) afforded the cyclocarbonylation product 35e (28.9 mg, 66%)
1
and triene 49 (6.1 mg, 13%) as yellow oils: H NMR (400 MHz,
CDCl3) δ 7.60 (d, J = 8.3 Hz, 2H), 7.39−7.35 (m, 5H), 7.34−7.24 (m,
2H), 6.04 (s, 1H), 4.54 (q, J = 16.9 Hz, 2H), 3.43−3.41 (m, 2H),
2.59−2.54 (m, 3H), 2.40 (s, 3H), 0.93 (d, J = 7.5 Hz, 3H), 0.39 (s,
6H); 13C NMR (175 MHz, CDCl3) 208.3, 167.4, 154.1, 143.6, 137.6,
136.7, 136.1, 133.8 (2C), 130.6, 129.7, 129.5 (2C), 128.1 (2C), 127.3
(2C), 47.8, 45.3, 45.3, 29.8, 21.5, 18.4, −1.5, −1.8; IR (thin film) 3056,
2974, 2925, 2868, 2014, 1699, 1573, 1462, 1340, 1164; HRMS (ES+)
C25H30NO3SSi [M + H+] calculated 452.1716, found 452.1693; [α]2D0
= +100.4° (c 2.5, CH2Cl2).
5-(Dimethyl(phenyl)silyl)-3-methylene-1-tosyl-4-vinyl-
2,3,6,7-tetrahydro-1H-azepine (49). 1H NMR (300 MHz, CDCl3)
δ 7.63 (d, J = 8.2 Hz, 2H), 7.50−7.44 (m, 2H), 7.35−7.33 (m, 3H),
7.29−7.26 (m, 2H), 6.55 (dd, J = 16.9, 10.5 Hz, 1H), 5.37 (d, J = 1.5
Hz, 1H), 5.26−5.16 (m, 1H), 5.03 (dd, J = 10.5, 1.7 Hz, 1H), 4.99 (s,
(S)-5-(Dimethyl(phenyl)silyl)-6-methyl-8-phenyl-2-tosyl-
1,2,3,4-tetrahydrocyclopenta[c]azepin-7(6H)-one (35d). Follow-
ing the general procedure for the [Rh(CO)2Cl]2 catalyzed cyclo-
carbonylation reaction, allene-yne 13d (41.5 mg, 0.083 mmol) and
[Rh(CO)2Cl]2 (3.2 mg, 0.003 mmol) were reacted in toluene (2.5
mL) for 3 h. Purification of the crude residue by flash chromatography
(55% Et2O/hexanes) afforded the title compound 35d (40.1 mg, 92%)
1
as a yellow oil: H NMR (300 MHz, CDCl3) δ 7.49−7.32 (m, 12H),
K
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The Journal of Organic Chemistry
Article
7.21 (d, J = 8.0 Hz, 2H), 4.63 (s, 2H), 3.51 (t, J = 6.1 Hz, 2H), 2.71 (q,
J = 7.3 Hz, 1H), 2.65−2.58 (t, J = 5.4 Hz, 2H), 2.40 (s, 3H), 0.97 (t, J
= 8.4 Hz, 3H), 0.45 (s, 6H); 13C NMR (175 MHz, CDCl3) δ 206.4,
161.4, 153.7, 143.4, 140.7, 137.0, 136.6, 135.7, 133.9 (2C), 129.9,
129.6 (3C), 129.4 (2C), 128.9, 128.6 (2C), 128.1 (2C), 127.1 (2C),
48.2, 44.6, 43.7, 29.8, 21.5, 18.7, −1.2, −1.5; IR (thin film) 2970, 2917,
2859, 2018, 1736, 1707, 1454, 1340, 1164; HRMS (ES+)
C31H34NO3SSi [M + H+] calculated 528.2029, found 528.2034;
[α]2D0 = +192° (c 0.75, CH2Cl2).
4-Methyl-N-(3-(thiophen-3-yl)prop-2-yn-1-yl)-
benzenesulfonamide (30a). A mixture of propargyltosylamide (444
mg, 1.97 mmol), 3-bromothiophene (963 mg, 5.91 mmol), palladium
dichloride bistriphenylphosphine (27.7 mg, 0.039 mmol), copper
iodide (15 mg, 0.079 mmol) in piperidine (3.9 mL) were heated at 80
°C for 17 h. The solution was concentrated under reduced pressure.
Purification of the crude residue using a Biotage normal phase
automated purification system (25 g SNAP column, gradient of 5−
25% EtOAc/hexanes) afforded compound 30a (155.6 mg, 27%) as a
white foam: 1H NMR (600 MHz, CDCl3) δ 7.81 (d, J = 8.2 Hz, 2H),
7.28 (d, J = 8.2 Hz, 2H), 7.24−7.15 (m, 2H), 6.84 (d, J = 4.4 Hz, 1H),
4.69−4.65 (m, 1H), 4.05 (d, J = 6.1 Hz, 2H), 2.38 (s, 3H); 13C NMR
(150 MHz, CDCl3) δ 143.7, 136.8, 129.6 (2C), 129.5, 129.1, 127.5
(2C), 125.2, 121.1, 82.8, 79.9, 33.8, 21.5; IR (thin film) 3265, 1593,
1430, 1324, 1156, 1091, 1042, 813, 788; HRMS (ES+) C14H12NO2S2
[M + H+] calculated 290.0276, found 290.0299.
(Ra)-N-(3-(Dimethyl(phenyl)silyl)hexa-3,4-dien-1-yl)-4-meth-
yl-N-(3-(thiophen-3-yl)prop-2-yn-1-yl)benzenesulfonamide
(13a). Following the general procedure for preparation of allene-yne
via Mitsunobu reaction, alcohol (Ra)-22 (39.8 mg, 0.171 mmol) in
THF (1.2 mL) was reacted with triphenylphosphine (54 mg, 0.21
mmol), 4-methyl-N-(3-(thiophen-3-yl)prop-2-yn-1-yl)-
benzenesulfonamide 30a (60 mg, 0.21 mmol) and diisopropylazodi-
carboxylate (41 μL, 0.21 mmol) for 10 h. Purification of the crude
residue using a Biotage normal phase automated purification system
(10 g SNAP column, gradient of 2−4% EtOAc/hexanes) afforded
compound 13a (77.6 mg, 90%) as a colorless oil: 1H NMR (300 MHz,
CDCl3) δ 7.67 (d, J = 8.3 Hz, 2H), 7.51 (dd, J = 7.8, 1.7 Hz, 2H),
7.37−7.34 (m, 3H), 7.22−7.19 (m, 3H), 7.09 (dd, J = 3.0, 1.1 Hz,
1H), 6.76 (dd, J = 5.0, 1.2 Hz, 1H), 4.90−4.86 (m, 1H), 4.22 (d, J =
1.6 Hz, 2H), 3.24 (dd, J = 8.9, 6.9 Hz, 2H), 2.35 (s, 3H), 2.23−2.20
(m, 2H), 1.63 (d, J = 7.0 Hz, 3H), 0.36 (d, J = 2.0 Hz, 6H); 13C NMR
(150 MHz, CDCl3) δ 208.0, 143.2, 137.9, 136.1, 133.8 (2C), 129.6,
129.4 (2C), 129.1, 128.7, 127.8 (2C), 127.7 (2C), 125.1, 121.3, 91.2,
81.7, 81.4, 80.5, 46.6, 37.4, 28.0, 21.5, 13.7, −3.0 (2C); IR (thin film)
3109, 2958, 2921, 2864, 1936, 1732, 1593, 1458, 1434, 1352, 1164,
1111; HRMS (ES+) C28H31NO2NaS2Si [M + Na+] calculated
528.1463, found 528.1414; [α]2D0 = +4° (c 1.75, CH2Cl2).
0.092 mmol) in acetonitrile (3 mL) was stirred at rt for 19 h. The
residue obtained after removal of acetonitrile was taken up in CH2Cl2
(30 mL) and washed with water (10 mL). The organic phase was
separated, dried (Na2SO4), filtered and concentrated under reduced
pressure. Purification of the crude residue by silica gel column
chromatography (Hex/Et2O 50%), afforded compound 30b (316 mg,
59%) as a white foam: 1H NMR (300 MHz, CDCl3) δ 7.80 (d, J = 8.2
Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 7.21 (dd, J = 5.1, 1.2 Hz, 1H), 6.97
(d, J = 3.6 Hz, 1H), 6.92−6.89 (m, 1H), 4.63−4.62 (m, 1H), 4.09 (d, J
= 6.2 Hz, 2H), 2.38 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 143.9,
136.6, 132.4, 129.7 (2C), 127.4 (2C), 126.8, 121.9, 87.1, 78.1, 33.9,
21.6; IR (thin film) 3265, 2361, 1589, 1491, 1422, 1344, 1315, 1160,
1091, 1038, 845; HRMS (ES+) C14H12NO2S2 [M − H+] calculated
290.0309, found 290.0316.
(Ra)-N-(3-(Dimethyl(phenyl)silyl)hexa-3,4-dien-1-yl)-4-meth-
yl-N-(3-(thiophen-2-yl)prop-2-yn-1-yl)benzenesulfonamide
(13b). Following the general procedure for preparation of allene-yne
via Mitsunobu reaction, alcohol (Ra)-22 (35.2 mg, 0.151 mmol) in
THF (1.0 mL) was reacted with triphenylphosphine (48 mg, 0.18
mmol), 4-methyl-N-(3-(thiophen-2-yl)prop-2-yn-1-yl)-
benzenesulfonamide 30b (53 mg, 0.18 mmol) and diisopropylazodi-
carboxylate (36 μL, 0.18 mmol) for 11 h. Purification of the crude
residue using a Biotage normal phase automated purification system
(10 g SNAP column, gradient of 2−4% EtOAc/hexanes) afforded
compound 13b (69.3 mg, 90%) as a colorless oil: 1H NMR (600 MHz,
CDCl3) δ 7.67 (d, J = 8.0 Hz, 2H), 7.52−7.50 (m, 2H), 7.36−7.33 (m,
3H), 7.24−7.20 (m, 3H), 6.90 (d, J = 3.3 Hz, 2H), 4.90−4.86 (m,
1H), 4.25 (s, 2H), 3.25−3.20 (m, 2H), 2.36 (s, 3H), 2.24−2.18 (m,
2H), 1.63 (d, J = 7.0 Hz, 3H), 0.36 (s, 6H); 13C NMR (150 MHz,
CDCl3) δ 208.0, 143.3, 137.9, 135.8, 133.8 (2C), 132.1, 129.5 (2C),
129.1, 127.8 (2C), 127.6 (2C), 127.2, 126.7, 122.2, 91.2, 86.1, 81.4,
78.6, 46.5, 37.5, 27.9, 21.5, 13.7, −3.1 (2C); IR (thin film) 2954, 2925,
2852, 2353, 2329, 1936, 1593, 1430, 1352, 1250, 1185, 1168, 1107;
HRMS (ES+) C28H31NO2NaS2Si [M + H+] calculated 528.1463,
found 528.1494; [α]2D0 = +2° (c 1.8, CH2Cl2).
(S)-5-(Dimethyl(phenyl)silyl)-6-methyl-8-(thiophen-2-yl)-2-
tosyl-1,2,3,4-tetrahydrocyclopenta[c]azepin-7(6H)-one (35b).
Following the general procedure for the [Rh(CO)2Cl]2 catalyzed
cyclocarbonylation reaction, allene-yne 13b (28.3 mg, 0.056 mmol)
and [Rh(CO)2Cl]2 (2.2 mg, 0.006 mmol) were reacted in toluene (1.8
mL) for 3 h. Purification of the crude residue using a Biotage normal
phase automated purification system (4 g SNAP column, gradient of
5−25% EtOAc/hexanes) afforded compound 35b (24.9 mg, 84%) as a
colorless oil: 1H NMR (600 MHz, CDCl3) δ 7.56 (d, J = 5.2 Hz, 2H),
7.45−7.35 (m, 8H), 7.21−7.19 (m, 3H), 4.89−4.82 (m, 2H), 3.55−
3.53 (m, 2H), 2.63−2.60 (m, 2H), 2.39 (s, 3H), 0.95 (d, J = 7.4 Hz,
3H), 0.43 (d, J = 5.6 Hz, 6H); 13C NMR (150 MHz, CDCl3) δ 205.3,
158.9, 153.5, 143.5, 136.9, 136.5, 135.8, 133.9 (2C), 133.7, 130.9,
129.6, 129.4 (2C), 129.2, 129.0, 128.1 (2C), 127.4, 127.0 (2C), 48.6,
44.3, 43.9, 30.0, 21.5, 18.8, −1.2, −1.5; IR (thin film) 3060, 2954,
2929, 2872, 1704, 1589, 1434, 1344, 1246, 1152, 1103, 1017; HRMS
(ES+) C29H30NO3S2Si [M − H+] calculated 532.1436, found
532.1453; [α]2D0 = +188° (c 1.80, CH2Cl2).
(S)-5-(Dimethyl(phenyl)silyl)-6-methyl-8-(thiophen-3-yl)-2-
tosyl-1,2,3,4-tetrahydrocyclopenta[c]azepin-7(6H)-one (35a).
Following the general procedure for the [Rh(CO)2Cl]2 catalyzed
cyclocarbonylation reaction, allene-yne 13a (17.8 mg, 0.036 mmol)
and [Rh(CO)2Cl]2 (1.4 mg, 0.003 mmol) were reacted in toluene (1.2
mL) for 2.5 h. Purification of the crude residue using a Biotage normal
phase automated purification system (4 g SNAP column, gradient of
5−25% EtOAc/hexanes) afforded compound 35a (13.5 mg, 72%) as a
tert-Butyl (3-cyclopropylprop-2-yn-1-yl)(tosyl)carbamate
(50). Following the general procedure for preparation of allene-yne
via Mitsunobu reaction, 3-cyclopropylprop-2-yn-1-ol (283 mg, 2.94
mmol) in THF (21 mL) was reacted with triphenylphosphine (927
mg, 3.53 mmol), tert-butyl tosylcarbamate (959 mg, 3.53 mmol) and
diisopropylazodicarboxylate (0.7 mL, 3.53 mmol) for 11 h. Purification
of the crude residue by silica gel chromatography using 20% Et2O/
1
colorless oil: H NMR (300 MHz, CDCl3) δ 7.68−7.66 (m, 1H),
7.47−7.42 (m, 5H), 7.39−7.33 (m, 4H), 7.22 (d, J = 8.0 Hz, 2H), 4.73
(s, 2H), 3.52 (t, J = 6.1 Hz, 2H), 2.68−2.58 (m, 3H), 2.40 (s, 3H),
0.98 (d, J = 7.4 Hz, 3H), 0.43 (d, J = 1.3 Hz, 6H); 13C NMR (150
MHz, CDCl3) δ 206.4, 159.9, 153.8, 143.5, 137.1, 136.5, 135.6, 135.5,
133.9 (2C), 130.4, 129.6, 129.4 (2C), 128.1 (2C), 127.9, 127.1 (2C),
126.8, 125.9, 48.3, 44.5, 43.8, 29.9, 21.5, 18.8, −1.2, −1.5; IR (thin
film) 2958, 2925, 1695, 1605, 1467, 1430, 1344, 1246, 1160, 1107,
964; HRMS (ES+) C29H31NO3NaS2Si [M + Na+] calculated 556.1412,
found 556.1465; [α]2D0 = +174° (c 1.15, CH2Cl2).
1
hexanes afforded compound 50 (535 mg, 52%) as a colorless oil: H
NMR (400 MHz, CDCl3) δ 1H NMR 7.93 (d, J = 8.3 Hz, 2H), 7.35−
7.28 (m, 2H), 4.57 (d, J = 2.0 Hz, 2H), 2.45 (s, 3H), 1.34 (s, 9H),
1.27−1.23 (m, 1H), 0.78−0.74 (m, 2H), 0.67−0.64 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ 150.3, 144.2, 136.9, 129.0 (2C), 128.2
(2C), 87.5, 84.5, 70.5, 36.4, 27.8 (3C), 21.6, 7.9 (2C), −0.6; IR (thin
film) 2974, 2925, 2251, 2235, 1724, 1597, 1356, 1311, 1279, 1091,
1070; HRMS (ES+) C14H16NO4S [M − C5H10O2 + H+] calculated
294.0800, found 294.0810.
4-Methyl-N-(3-(thiophen-2-yl)prop-2-yn-1-yl)-
benzenesulfonamide (30b). A mixture of propargyltosylamide
(415.9 mg, 1.84 mmol), 2-iodothiophene (215 μL, 2.03 mmol),
palladium dichloride bistriphenylphosphine (25.9 mg, 0.037 mmol),
copper iodide (14.1 mg, 0.074 mmol) and triethylamine (1.29 mL,
L
dx.doi.org/10.1021/jo4002432 | J. Org. Chem. XXXX, XXX, XXX−XXX

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N-(3-Cyclopropylprop-2-yn-1-yl)-4-methylbenzenesulfona-
mide (30g). To a solution of tert-butyl (3-cyclopropylprop-2-yn-1-
yl)(tosyl)carbamate 50 (102.7 mg, 0.293 mmol) in methanol (1.7 mL)
and THF (0.7 mL) was added lithium hydroxide (88 mg, 1.17 mmol).
After stirring for 12 h at rt, the mixture was diluted with CH2Cl2 (40
mL) and HCl 1 M (10 mL). The organic layer was separated, washed
with brine (10 mL) and dried (Na2SO4). The solvent was removed
under reduced pressure. Purification of the crude residue by silica gel
chromatography using 40% Et2O/hexanes afforded compound 30g
(52.3 mg, 71%) as a white foam: 1H NMR (300 MHz, CDCl3) δ 7.76
(d, J = 8.3 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 4.55 (br. s, 1H), 3.76−
3.76 (m, 2H), 2.43 (s, 3H), 1.03 (m, 1H), 0.65−0.62 (m, 2H), 0.42−
0.40 (m, 2H); 13C NMR (150 MHz, CDCl3) δ 143.5, 136.8, 129.5
(2C), 127.4 (2C), 88.4, 69.3, 33.4, 21.5, 7.8 (2C), −0.9; IR (thin film)
3265, 1438, 1315, 1160, 1095, 1058, 1030; HRMS (ES+) C13H16NO2S
[M + H+] calculated 250.0902, found 250.0888.
Hz, 3H); 13C NMR (175 MHz, CDCl3) δ 202.3, 143.4, 135.6, 135.4,
131.4 (2C), 129.4 (2C), 128.6 (2C), 128.3, 128.1 (2C), 127.7 (2C),
126.6, 126.5 (2C), 122.1, 105.4, 96.0, 85.7, 81.6, 44.8, 37.31, 32.1, 31.2,
29.7, 22.4, 21.4, 13.9; IR (thin film) 2958, 2925, 2855, 1597, 1495,
1458, 1352, 1160, 1095, 918; HRMS (ES+) C31H34NO2S [M + H+]
calculated 484.2310, found 484.2283; [α]2D0 = −54.3° (c 1.15, CH2Cl2).
(S)-6-Methyl-8-phenyl-2-tosyl-1,2,3,4-tetrahydrocyclopenta-
[c]azepin-7(6H)-one (42d). Following the general procedure for the
[Rh(CO)2Cl]2 catalyzed cyclocarbonylation reaction, allene-yne 14d
(22.7 mg, 0.054 mmol) and [Rh(CO)2Cl]2 (2.1 mg, 0.0054 mmol)
were reacted in toluene (1.7 mL) for 30 min. Purification of the crude
residue by silica gel chromatography using 60% Et2O/hexanes afforded
compound 42d (21.6 mg, 76%) as a colorless oil: 1H NMR (300 MHz,
CDCl3) δ 7.50−7.32 (m, 7H), 7.24−7.20 (m, 5H), 6.96−6.93 (m,
2H), 4.83 (d, J = 16.9 Hz, 1H), 4.61 (d, J = 16.8 Hz, 1H), 3.91 (s, 1H),
3.72−3.65 (m, 2H), 2.76−2.71 (m, 1H), 2.59−2.50 (m, 1H), 2.41 (s,
3H), 1.93−1.87 (m, 2H), 1.02−0.98 (m, 2H), 0.88−0.86 (m, 2H),
0.69 (t, J = 7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 201.8, 162.8,
143.5, 141.4, 139.4, 137.8, 136.8, 136.0, 130.3, 129.6 (2C), 129.5 (2C),
128.7 (2C), 128.6, 128.5 (2C), 127.6 (2C), 127.2 (2C), 126.9, 55.4,
47.9, 44.3, 37.1, 31.1, 29.2, 22.7, 21.6, 13.7; IR (thin film) 2954, 2929,
2864, 1699, 1499, 1339, 1164, 1095; HRMS (ES+) C32H34NO3S [M +
H+] calculated 512.2259, found 512.2232; [α]2D0 = +61.1° (c 0.90,
CH2Cl2).
(Ra)-N-(Hexa-3,4-dien-1-yl)-4-methyl-N-(3-phenylprop-2-yn-
1-yl)benzene sulfonamide (14c). Following the general procedure
for preparation of allene-yne via Mitsunobu reaction, alcohol (Ra)-29
(50.7 mg, 0.23 mmol) in THF (1.7 mL) was reacted with
triphenylphosphine (74 mg, 0.28 mmol), N-(but-2-yn-1-yl)-4-methyl-
benzenesulfonamide31 (63 mg, 0.28 mmol) and diisopropylazodicar-
boxylate (56 μL, 0.28 mmol) for 12 h. Purification of the crude residue
by silica gel chromatography using 10% Et2O/hexanes afforded
compound 14c (91.9 mg, 93%) as a colorless oil: 1H NMR (600 MHz,
CDCl3) δ 7.69−7.68 (d, J = 8.3 Hz, 2H), 7.30−7.26 (m, 4H), 7.23−
7.22 (m, 3H), 6.14 (t, J = 2.9 Hz, 1H), 4.08−3.99 (m, 2H), 3.36−3.32
(m, 1H), 3.28−3.23 (m, 1H), 2.39 (s, 3H), 2.37−2.36 (m, 2H), 2.13−
2.07 (m, 2H), 1.51 (t, J = 2.4 Hz, 3H), 1.46−1.43 (m, 2H), 1.37−1.33
(m, 2H), 0.88 (t, J = 7.3 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ
202.2, 143.1, 135.9, 135.5, 129.2 (2C), 128.5 (2C), 127.7 (2C), 126.6,
126.5 (2C), 105.4, 95.9, 81.5, 71.7, 44.7, 37.0, 32.1, 31.2, 29.7, 22.4,
21.5, 13.9, 3.2; IR (thin film) 2954, 2925, 2864, 1593, 1499, 1458,
1344, 1164, 1091, 915; HRMS (ES+) C26H32NO2S [M + H+]
calculated 422.2154, found 422.2120; [α]2D0 = −43.5° (c 1.15, CH2Cl2).
(S)-5-Butyl-8-methyl-6-phenyl-2-tosyl-1, 2, 3, 4-
tetrahydrocyclopenta[c]azepin-7(6H)-one (42c). Following the
general procedure for the [Rh(CO)2Cl]2 catalyzed cyclocarbonylation
reaction, allene-yne 14c (33.5 mg, 0.079 mmol) and [Rh(CO)2Cl]2
(3.1 mg, 0.0079 mmol) were reacted in toluene (2.5 mL) for 90 min.
Purification of the crude residue using a Biotage normal phase
automated purification system (12 g SNAP column, gradient of 5−
30% EtOAc/hexanes) afforded compound 42c (29.1 mg, 82%) as a
colorless oil: 1H NMR (600 MHz, CDCl3) δ 7.68 (d, J = 8.2 Hz, 2H),
7.29 (d, J = 8.1 Hz, 2H), 7.19−7.18 (m, 3H), 6.89−6.88 (m, 2H), 4.67
(d, J = 16.9 Hz, 1H), 4.50 (d, J = 16.9 Hz, 1H), 3.77 (s, 1H), 3.61−
3.60 (m, 2H), 2.61−2.53 (m, 2H), 2.42 (s, 3H), 1.86 (s, 3H), 1.83−
1.78 (m, 2H), 1.12−1.10 (m, 1H), 1.02−0.95 (m, 2H), 0.84−0.83 (m,
1H), 0.67 (t, J = 7.3 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 203.6,
162.3, 143.7, 139.2, 137.9, 136.4, 136.3, 135.9, 129.7 (2C), 128.6 (2C),
127.5 (2C), 127.1 (2C), 126.8, 54.9, 47.8, 44.6, 36.9, 31.8, 29.3, 22.6,
21.6, 13.7, 8.6; IR (thin film) 2954, 2925, 2860, 2361, 2333, 1699,
1597, 1487, 1454, 1344, 1266, 1152, 1095; HRMS (ES+) C27H32NO3S
[M + H+] calculated 450.2103, found 450.2058; [α]2D0 = +111.2° (c
0.90, CH2Cl2).
(Ra)-N-(3-Cyclopropylprop-2-yn-1-yl)-N-(3-(dimethyl-
(phenyl)silyl)hexa-3,4-dien-1-yl)-4-methylbenzenesulfona-
mide (13g). Following the general procedure for preparation of
allene-yne via Mitsunobu reaction, alcohol (Ra)-22 (45 mg, 0.19
mmol) in THF (1.4 mL) was reacted with triphenylphosphine (61.1
mg, 0.23 mmol), N-(3-cyclopropylprop-2-yn-1-yl)-4-methylbenzene-
sulfonamide 30g (58.3 mg, 0.23 mmol) and diisopropylazodicarbox-
ylate (46 μL, 0.23 mmol) for 11 h. Purification of the crude residue
using a Biotage normal phase automated purification system (12 g
SNAP column, gradient of 1−7% EtOAc/hexanes) afforded
1
compound 13g (63.7 mg, 73%) as a colorless oil: H NMR (400
MHz, CDCl3) δ 7.66 (d, J = 8.3 Hz, 2H), 7.56−7.54 (m, 2H), 7.40−
7.38 (m, 3H), 7.29−7.27 (dd, J = 8.8, 1.2 Hz, 2H), 4.92−4.89 (m,
1H), 4.00 (d, J = 2.0 Hz, 2H), 3.22−3.18 (m, 2H), 2.45 (s, 3H), 2.21−
2.16 (m, 2H), 1.67 (d, J = 7.0 Hz, 3H), 1.00−0.96 (m, 1H), 0.65−0.61
(m, 2H), 0.40 (d, J = 1.0 Hz, 6H), 0.33 (m, 2H); 13C NMR (100
MHz, CDCl3) δ 208.0, 142.9, 137.9, 136.3, 133.8 (2C), 129.2 (2C),
129.1, 127.8 (2C), 127.6 (2C), 91.3, 88.9, 81.2, 67.9, 46.3, 37.0, 27.9,
21.5, 13.7, 7.8 (2C), −0.9, −3.0, −3.1; IR (thin film) 2954, 2921, 2251,
1932, 1601, 1454, 1430, 1348, 1254, 1164, 1107, 1030; HRMS (ES+)
C27H34NO2SSi [M + H+] calculated 464.2080, found 464.2053; [α]2D0
= +5.7° (c 0.70, CH2Cl2).
(S)-8-Cyclopropyl-5-(dimethyl(phenyl)silyl)-6-methyl-2-
tosyl-1,2,3,4-tetrahydrocyclopenta[c]azepin-7(6H)-one (35g).
Following the general procedure for the [Rh(CO)2Cl]2 catalyzed
cyclocarbonylation reaction, allene-yne 13g (24.5 mg, 0.053 mmol)
and [Rh(CO)2Cl]2 (2.1 mg, 0.0053 mmol) were reacted in toluene
(1.8 mL) for 135 min. Purification of the crude residue by silica gel
chromatography using 40% Et2O/hexanes afforded compound 35g
(22.1 mg, 83%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 7.62
(d, J = 8.0 Hz, 2H), 7.36−7.32 (m, 5H), 7.25−7.21 (m, 2H), 4.65−
4.64 (m, 2H), 3.43−3.43 (m, 2H), 2.55−2.51 (m, J = 4.8 Hz, 2H),
2.41−2.38 (m, 4H), 1.62−1.57 (m, 1H), 1.30−1.25 (m, 2H), 0.93−
0.90 (m, 2H), 0.81 (d, J = 7.4 Hz, 3H), 0.36−0.35 (t, 3H); 13C NMR
(150 MHz, CDCl3) δ 207.5, 160.6, 153.2, 143.4, 141.4, 137.2, 136.3,
133.8 (2C), 132.2, 129.5, 129.3 (2C), 127.9 (2C), 127.3 (2C), 48.1,
44.3, 42.5, 29.5, 21.5, 18.4, 8.1, 6.1, 6.0, −1.2, −1.5; IR (thin film)
2962, 2925, 2868, 2018, 1695, 1589, 1467, 1348, 1250, 1160, 1103;
HRMS (ES+) C28H34NO3SSi [M + H+] calculated 492.2029, found
492.2042; [α]2D0 = +113.8° (c 1.45, CH2Cl2).
(Ra)-N-(Hexa-3,4-dien-1-yl)-4-methyl-N-(3-phenylprop-2-yn-
1-yl)benzenesulfonamide (14d). Following the general procedure
for preparation of allene-yne via Mitsunobu reaction, alcohol (Ra)-29
(45 mg, 0.21 mmol) in THF (1.5 mL) was reacted with
triphenylphosphine (65.5 mg, 0.25 mmol), 4-methyl-N-(3-phenyl-
prop-2-yn-1-yl)benzenesulfonamide30 30d (71.2 mg, 0.25 mmol) and
diisopropylazodicarboxylate (49 μL, 0.25 mmol) for 11 h. Purification
of the crude residue by silica gel chromatography using 1% Et2O/
hexanes afforded compound 14d (80.2 mg, 92%) as a colorless oil: 1H
NMR (700 MHz, CDCl3) δ 7.70 (d, J = 8.3 Hz, 2H), 7.27−7.25 (m,
5H), 7.20−7.16 (m, 5H), 7.00 (d, J = 7.0 Hz, 2H), 6.15−6.13 (m,
1H), 4.34 (d, J = 18.5 Hz, 2H), 4.27 (d, J = 18.5 Hz, 2H), 3.47−3.43
(m, 1H), 3.34−3.30 (m, 1H), 2.44−2.41 (m, 2H), 2.29 (s, 3H), 2.15−
2.09 (m, 2H), 1.45−1.44 (m, 1H), 1.35−1.32 (m, 2H), 0.86 (t, J = 7.3
(Ra)-4-Methyl-N-(3-(2-phenylvinylidene)heptyl)-N-(prop-2-
yn-1-yl)benzenesulfonamide (14e). Following the general proce-
dure for preparation of allene-yne via Mitsunobu reaction, alcohol
(Ra)-29 (114.4 mg, 0.53 mmol) in THF (3.8 mL) was reacted with
triphenylphosphine (166 mg, 0.63 mmol), 4-methyl-N-(prop-2-yn-1-
yl)benzenesulfonamide30 30e (133 mg, 0.63 mmol) and diisopropy-
lazodicarboxylate (125 μL, 0.63 mmol) for 12 h. Purification of the
M
dx.doi.org/10.1021/jo4002432 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
crude residue using a Biotage normal phase automated purification
system (25 g SNAP column, gradient of 0−7% EtOAc/hexanes)
(Ra )-Diethyl 2-(3-phenylprop-2-yn-1-yl)-2-(3-(2-
phenylvinylidene)heptyl) malonate (16d). Following the general
procedure for preparation of allene-yne via alkylation of the malonate
moiety, diethyl malonate 34d (87.2 mg, 0.32 mmol) was reacted with
sodium hydride (10.6 mg, 60 wt % in oil, 0.26 mmol), mesylate 33
(62.5 mg, 0.18 mmol) and potassium iodide (44 mg, 0.27 mmol) in
DMF−THF (1:1, 3.6 mL). Purification of the crude residue by silica
gel chromatography using 5% Et2O/hexanes afforded compound 16d
1
afforded compound 14e (182.1 mg, 85%) as a colorless oil: H NMR
(300 MHz, CDCl3) δ 7.66 (d, J = 8.1 Hz, 2H), 7.29−7.24 (m, 4H),
7.22−7.19 (m, 3H), 6.13−6.11 (m, 1H), 4.10−4.07 (m, 2H), 3.37−
3.26 (m, 2H), 2.42−2.33 (m, 5H), 2.09−2.07 (m, 2H), 1.98 (t, J = 2.5
Hz, 1H), 1.43−1.31 (m, 4H), 0.86 (t, J = 7.1 Hz, 3H); 13C NMR (100
MHz, CD2Cl2) δ 202.2, 143.7, 135.8, 135.5, 129.5 (2C), 128.5 (2C),
127.6 (2C), 126.7, 126.5 (2C), 105.4, 95.9, 76.7, 73.6, 44.8, 36.6, 32.1,
31.1, 29.7, 22.5, 21.3, 13.7; IR (thin film) 3289, 2958, 2929, 2872,
1949, 1712, 1593, 1491, 1462, 1352, 1160, 1091 1001; HRMS (ES+)
1
(58.7 mg, 70%) as a colorless oil: H NMR (300 MHz, CDCl3) δ
7.31−7.27 (m, 5H), 7.25−7.14 (m, 5H), 6.17 (t, J = 2.9 Hz, 1H), 4.23
(q, J = 7.2 Hz, 4H), 3.08 (s, 2H), 2.37−2.31 (m, 2H), 2.16−2.06 (m,
4H), 1.50−1.38 (m, 2H), 1.36−1.31 (m, 2H), 1.26 (t, J = 7.1 Hz, 6H),
0.87 (t, J = 7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 202.0, 170.2
(2C), 135.8, 131.6 (2C), 128.4 (2C), 128.1 (2C), 127.8, 126.4 (2C),
126.3, 123.2, 107.8, 96.0, 84.2, 83.5, 61.6 (2C), 56.9, 32.4, 30.5, 29.8,
27.5, 23.9, 22.5, 14.1 (2C), 13.9; IR (thin film) 2966, 2925, 2864,
1736, 1499, 1462, 1438, 1266, 1189, 1099, 1074, 1025; HRMS (ES+)
C25H29NO2S [M+] calculated 407.1919, found 407.1888; [α]2D0
−63.8° (c 0.80, CH2Cl2).
=
(Ra)-4-Methyl-N-(3-(2-phenylvinylidene)heptyl)-N-(3-
(trimethylsilyl)prop-2-yn-1-yl)benzenesulfonamide (14f). Fol-
lowing the general procedure for preparation of allene-yne via
silylation of the terminal alkyne, allene-yne 14e (81.7 mg, 0.20
mmol) in THF (1.6 mL) was reacted with lithium hexamethyldisi-
lylamide (301 μL, 1 M in THF, 0.30 mmol) and trimethylsilylchloride
(51 μL, 0.40 mmol). Purification of the crude product using a Biotage
normal phase automated purification system (12 g SNAP column,
gradient of 0−8% EtOAc/hexanes) afforded compound 14f (76.8 mg,
80%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 7.70 (d, J = 8.1
Hz, 2H), 7.33−7.26 (m, 4H), 7.23−7.21 (m, 3H), 6.17 (t, J = 3.0 Hz,
1H), 4.22−4.06 (m, 2H), 3.44−3.37 (m, 1H), 3.33−3.26 (m, 1H),
2.44−2.39 (m, 5H), 2.16−2.14 (m, 2H), 1.51−1.37 (m, 4H), 0.91 (t, J
= 7.1 Hz, 3H), −0.02 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 202.2,
143.2, 135.7, 135.4, 129.4 (2C), 128.5 (2C), 127.7 (2C), 126.6, 126.5
(2C), 105.3, 97.8, 95.9, 90.9, 44.6, 37.4, 32.1, 31.1, 29.7, 22.4, 21.5,
13.9, −0.5 (3C); IR (thin film) 3031, 2958, 2929, 2868, 2118, 1953,
1598, 1503, 1458, 1356, 1246, 1164, 1103, 1021, 919; HRMS (ES+)
C31H36O4 [M + H+] calculated 473.2692, found 473.2734; [α]2D0
−35.7° (c 1.85, CH2Cl2).
=
(S)-Diethyl 8-butyl-2-oxo-1,3-diphenyl-1,2,6,7-tetrahydroa-
zulene-5,5(4H)-dicarboxylate (44d). Following the general proce-
dure for the [Rh(CO)2Cl]2 catalyzed cyclocarbonylation reaction,
allene-yne 16d (36.8 mg, 0.078 mmol) and [Rh(CO)2Cl]2 (3 mg,
0.0078 mmol) were reacted in toluene (2.6 mL) for 2 h. Purification of
the crude residue by flash chromatography (40% Et2O/hexanes)
afforded the title compound 44d (35.6 mg, 92%) as a colorless oil: 1H
NMR (600 MHz, CDCl3) δ 7.37−7.34 (m, 2H), 7.30−7.28 (m, 3H),
7.21−7.19 (m, 5H), 4.15−4.10 (m, 2H), 4.09 (s, 1H), 4.02−3.99 (m,
1H), 3.96−3.93 (m, 1H), 3.59 (d, J = 14.9 Hz, 1H), 3.50 (d, J = 14.9
Hz, 1H), 2.58−2.42 (m, 4H), 1.97−1.93 (m, 2H), 1.28−1.25 (m, 2H),
1.10−1.08 (td, J = 7.1, 2.1 Hz, 6H), 1.01−0.96 (m, 2H), 0.71 (t, J =
7.3 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 202.2, 171.3, 171.2,
164.4, 146.3, 140.9, 138.3, 137.1, 131.4, 129.4 (2C), 128.7 (2C), 128.1
(2C), 127.8, 127.6 (2C), 126.8, 61.8, 61.7, 56.1, 55.7, 37.5, 33.5, 32.7,
29.1, 28.6, 22.7, 13.8 (3C); IR (thin film) 2962, 2925, 2856, 1728,
1699, 1605, 1577, 1503, 1454, 1373, 1274, 1234, 1181; HRMS (ES+)
C28H37NO2SSi [M+] calculated 479.2314, found 479.2278; [α]2D0
−58.8° (c 1.70, CH2Cl2).
=
(S)-5-Butyl-6-phenyl-2-tosyl-8-(trimethylsilyl)-1,2,3,4-
tetrahydrocyclopenta[c]azepin-7(6H)-one (42f). Following the
general procedure for the [Rh(CO)2Cl]2 catalyzed cyclocarbonylation
reaction, allene-yne 14f (32.8 mg, 0.068 mmol) and [Rh(CO)2Cl]2
(2.7 mg, 0.068 mmol) were reacted in toluene (2.2 mL) for 30 min.
Purification of the crude product using a Biotage normal phase
automated purification system (4 g SNAP column, gradient of 5−25%
EtOAc/hexanes) afforded compound 42f (26.9 mg, 78%) as a white
C32H37O5 [M + H+] calculated 501.2641, found 501.2623; [α]2D0
+105° (c 1.60, CH2Cl2).
=
(Ra)-Diethyl 2-(3-(2-phenylvinylidene)heptyl)-2-(prop-2-yn-
1-yl)malonate (16e). Following the general procedure for prepara-
tion of allene-yne via alkylation of the malonate moiety, diethyl
malonate 34e (98 mg, 0.49 mmol) was reacted with sodium hydride
(16.5 mg, 60 wt % in oil, 0.41 mmol), mesylate 33 (97 mg, 0.27
mmol) and potassium iodide (68.3 mg, 0.41 mmol) in DMF−THF
(1:1, 5.6 mL). Purification of the crude residue using a Biotage normal
phase automated purification system (25 g SNAP column, gradient of
0−5% EtOAc/hexanes) afforded compound 16e (45.5 mg, 42%) as a
1
foam: H NMR (300 MHz, CDCl3) δ 7.68 (d, J = 8.1 Hz, 2H), 7.30
(d, J = 8.0 Hz, 2H), 7.20−7.18 (m, 3H), 6.92−6.89 (m, 2H), 4.80 (d, J
= 16.9 Hz, 1H), 4.53 (d, J = 16.9 Hz, 1H), 3.76 (s, 1H), 3.59−3.57 (m,
2H), 2.59−2.50 (m, 2H), 2.43 (s, 3H), 1.84−1.80 (m, 2H), 1.02−0.90
(m, 4H), 0.66 (t, J = 7.1 Hz, 3H), 0.31 (s, 9H); 13C NMR (175 MHz,
CDCl3) δ 207.8, 175.4, 143.5, 140.5 (2C), 139.4, 138.3, 136.0, 129.7
(2C), 128.7 (2C), 127.4 (2C), 127.2 (2C), 126.6, 56.6, 47.3, 46.1,
37.4, 31.5, 29.2, 22.6, 21.6, 13.7, −0.4 (3C); IR (thin film) 3024, 2954,
2921, 2864, 1683, 1593, 1540, 1491, 1454, 1348, 1242, 1164, 1099;
HRMS (ES+) C29H37NO3SSi [M+] calculated 507.2263, found
507.2297; [α]2D0 = +105° (c 1.15, CH2Cl2).
1
colorless oil: H NMR (600 MHz, CDCl3) δ 7.28−7.26 (m, 4H),
7.17−7.15 (m, 1H), 6.15 (t, J = 3.0 Hz, 1H), 4.21−4.18 (q, J = 7.1 Hz,
4H), 2.84 (d, J = 2.7 Hz, 2H), 2.27−2.24 (m, 2H), 2.10−2.08 (m,
2H), 2.04−1.99 (m, 1H), 1.97 (t, J = 2.7 Hz, 1H), 1.45−1.42 (m, 2H),
1.36−1.32 (m, 2H), 1.23 (td, J = 7.1, 2.8 Hz, 6H), 0.87 (t, J = 7.3 Hz,
3H); 13C NMR (150 MHz, CD2Cl2) δ 201.9, 169.9 (2C), 135.8, 128.4
(2C), 126.5 (2C), 126.4, 107.9, 95.9, 78.8, 71.1, 61.6 (2C), 56.4, 32.4,
30.2, 29.8, 27.2, 22.7, 22.5, 13.8 (2C), 13.7; IR (thin film) 3297, 2962,
2925, 2868, 1740, 1467, 1438, 1270, 1193, 1099, 1070; HRMS (ES+)
(Ra)-3-(2-Phenylvinylidene)heptyl methanesulfonate (33).
To a stirred solution of alcohol (Ra)-29 (197.2 mg, 0.911 mmol) in
THF (19 mL), cooled to 0 °C (ice bath), was added triethylamine
(152 μL, 1.09 mmol) followed by methanesulfonyl chloride (85 μL,
1.09 mmol). The resulting solution was stirred at rt for 18 h. The
mixture was diluted with Et2O (60 mL) and washed with water (2 ×
10 mL). The organic phase was dried (Na2SO4), filtered and
concentrated under reduced pressure. Purification of the crude residue
by silica gel chromatography using 40% Et2O/hexanes afforded
C25H32O4 [M + H+] calculated 397.2379, found 397.2376; [α]2D0
−52.7° (c 1.5, CH2Cl2).
=
(Ra)-Diethyl 2-(3-(2-phenylvinylidene)heptyl)-2-(3-
(trimethylsilyl)prop-2-yn-1-yl)malonate (16f). Following the
general procedure for preparation of allene-yne via silylation of the
terminal alkyne, allene-yne 16e (44.1 mg, 0.11 mmol) in THF (1 mL)
was reacted with lithium hexamethyldisilylamide (200 μL, 1 M in
THF, 0.20 mmol) and trimethylsilylchloride (35 μL, 0.28 mmol).
Purification of the crude product using a Biotage normal phase
automated purification system (4 g SNAP column, gradient of 1−3%
EtOAc/hexanes) to afford compound 16f (43 mg, 84%) as a colorless
1
compound 33 (247 mg, 92%) as a colorless oil: H NMR (600 MHz,
CDCl3) δ 7.37−7.32 (m, 4H), 7.26−7.25 (m, 1H), 6.29−6.28 (m,
1H), 4.43−4.36 (m, 2H), 2.90 (s, 3H), 2.61−2.59 (m, 2H), 2.19−2.18
(m, 2H), 1.55−1.53 (m, 2H), 1.45−1.41 (m, 2H), 0.96 (t, J = 7.3 Hz,
3H); 13C NMR (150 MHz, CDCl3) δ 201.7, 134.7, 128.4 (2C), 126.6,
126.3 (2C), 103.9, 96.6, 67.6, 36.7, 32.3, 31.8, 29.3, 22.1, 13.6; IR (thin
film) 3027, 2958, 2925, 2864, 1953, 1597, 1495, 1462, 1364, 1181,
960, 899; HRMS (ES+) C16H22O3S [M+] calculated 294.1290, found
294.1284; [α]2D0 = −16.3° (c 0.95, CH2Cl2).
1
oil: H NMR (300 MHz, CDCl3) δ 7.28−7.26 (m, 4H), 7.18−7.14
(m, 1H), 6.16−6.14 (m, 1H), 4.22−4.15 (m, 4H), 2.85 (s, 2H), 2.27−
2.21 (m, 2H), 2.12−1.99 (m, 4H), 1.46−1.33 (m, 4H), 1.23 (td, J =
N
dx.doi.org/10.1021/jo4002432 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
7.1, 1.8 Hz, 6H), 0.88 (t, J = 7.2 Hz, 3H), 0.08 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 202.1, 170.1 (2C), 135.8, 128.5 (2C), 126.5 (2C),
126.4, 107.8, 101.2, 95.9, 88.1, 61.5 (2C), 56.8, 32.3, 30.4, 29.8, 27.5,
24.2, 22.5, 14.0 (2C), 13.9, −0.1 (3C); IR (thin film) 2950, 2921,
2856, 2178, 1941, 1728, 1458, 1437, 1266, 1193, 1030; HRMS (ES+)
oil: H NMR (600 MHz, CDCl3) δ 7.39−7.38 (m, 2H), 7.29−7.26
(m, 7H), 7.17−7.15 (m, 1H), 6.17−6.16 (m, 1H), 4.35−4.29 (m, 2H),
3.76−3.70 (m, 2H), 2.44−2.42 (m, 2H), 2.13−2.12 (m, 2H), 1.50−
1.44 (m, 2H), 1.39−1.34 (m, 2H), 0.88 (t, J = 7.3 Hz, 3H); 13C NMR
(150 MHz, CDCl3) δ 202.3, 135.8, 131.7 (2C), 128.5 (2C), 128.3,
128.2 (2C), 126.5 (2C), 126.4, 122.7, 105.5, 95.9, 86.1, 85.2, 68.3,
58.8, 32.8, 32.7, 29.8, 22.5, 13.9; IR (thin film) 3060, 3019, 2962, 2929,
2864, 1949, 1675, 1605, 1495, 1462, 1442, 1352, 1099, 1030; HRMS
(ES+) C24H27O1 [M + H+] calculated 331.2062, found 331.2025;
[α]2D0 = −12.4° (c 1.05, CH2Cl2).
C28H41O4Si [M + H+] calculated 469.2774, found 469.2762; [α]2D0
−34.7° (c 2.65, CH2Cl2).
=
(S)-Diethyl 8-butyl-2-oxo-1-phenyl-3-(trimethylsilyl)-1,2,6,7-
tetrahydroazulene-5,5(4H)-dicarboxylate (44f). Following the
general procedure for the [Rh(CO)2Cl]2 catalyzed cyclocarbonylation
reaction, allene-yne 16f (26.1 mg, 0.056 mmol) and [Rh(CO)2Cl]2
(2.2 mg, 0.0056 mmol) were reacted in toluene (1.9 mL) for 2 h.
Purification of the crude residue by flash chromatography (15% Et2O/
hexanes) afforded compound 44f (24.8 mg, 90%) as a colorless oil: 1H
NMR (600 MHz, CDCl3) δ 7.29−7.21 (m, 2H), 7.20−7.18 (m, 1H),
7.12−7.10 (m, 2H), 4.31−4.18 (m, 4H), 3.93 (s, 1H), 3.56 (d, J = 14.8
Hz, 1H), 3.46 (d, J = 14.8 Hz, 1H), 2.56−2.54 (m, 1H), 2.50−2.46
(m, 1H), 2.42−2.39 (m, 2H), 1.94−1.87 (m, 2H), 1.29 (td, J = 7.1, 2.4
Hz, 6H), 1.26−1.22 (m, 1H), 1.11−0.94 (m, 3H), 0.71 (t, J = 7.3 Hz,
3H), 0.25 (s, 9H); 13C NMR (150 MHz, CDCl3) δ 208.5, 176.3,
171.4, 171.3, 145.6, 141.4, 139.9, 138.9, 128.6 (2C), 127.5 (2C), 126.5,
61.8, 61.7, 57.1, 56.3, 37.8, 34.7, 33.6, 29.1, 28.9, 22.7, 14.0, 14.0, 13.8,
−0.3 (3C); IR (thin film) 2954, 2921, 2856, 1732, 1683, 1540, 1454,
1266, 1242, 1185, 1050; HRMS (ES+) C29H41O5Si [M + H+]
calculated 497.2723, found 497.2733; [α]2D0 = +55.6° (c 2.1, CH2Cl2).
(Ra)-Diethyl 2-(but-2-yn-1-yl)-2-(3-(2-phenylvinylidene)-
heptyl)malonate (16c). Following the general procedure for
preparation of allene-yne via alkylation of the malonate moiety,
diethyl malonate 34c (96 mg, 0.35 mmol) was reacted with sodium
hydride (11.7 mg, 60 wt % in oil, 0.29 mmol), mesylate 33 (68.7 mg,
0.19 mmol) and potassium iodide (48.3 mg, 0.29 mmol) in DMF−
THF (1:1, 4 mL). Purification of the crude residue by flash
chromatography (5% Et2O/hexanes) afforded compound 16c (60.1
mg, 75%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.26−7.24
(m, 4H), 7.16−7.13 (m, 1H), 6.14 (t, J = 2.8 Hz, 1H), 4.17 (q, J = 7.1
Hz, 4H), 2.76−2.75 (m, 2H), 2.24−2.19 (m, 2H), 2.10−2.07 (m, 2H),
2.06−1.97 (m, 2H), 1.66 (t, J = 2.6 Hz, 3H), 1.44−1.42 (m, 2H),
1.36−1.32 (m, 2H), 1.21 (td, J = 7.1, 1.0 Hz, 6H), 0.86 (t, J = 7.2 Hz,
3H); 13C NMR (150 MHz, CDCl3) δ 202.1, 170.5 (2C), 135.9, 128.4
(2C), 126.5 (2C), 126.4, 107.9, 95.9, 78.8, 73.2, 61.4 (2C), 56.8, 32.4,
30.2, 29.8, 27.3, 23.1, 22.5, 14.0 (2C), 13.9, 3.4; IR (thin film) 2958,
2933, 2860, 1728, 1462, 1446, 1266, 1193, 1103, 1066; HRMS (ES+)
(S)-5-Butyl-6,8-diphenyl-3,4-dihydro-1H-cyclopenta[c]-
oxepin-7(6H)-one (43d). Following the general procedure for the
[Rh(CO)2Cl]2 catalyzed cyclocarbonylation reaction, allene-yne 15d
(41 mg, 0.124 mmol) and [Rh(CO)2Cl]2 (4.8 mg, 0.0124 mmol) were
reacted in toluene (4.1 mL) for 30 min. Purification of the crude
residue by flash chromatography (30% Et2O/hexanes) afforded
1
compound 43d (30.6 mg, 69%) as a colorless oil: H NMR (300
MHz, CDCl3) δ 7.38−7.28 (m, 7H), 7.25−7.22 (m, 3H), 4.88 (s, 2H),
4.20 (s, 1H), 4.08−4.04 (m, 2H), 2.84−2.75 (m, 1H), 2.63−2.56 (m,
1H), 2.06−1.99 (m, 2H), 1.30−1.26 (m, 2H), 1.13−1.06 (m, 3H),
0.73 (t, J = 7.1 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 201.8, 167.6,
141.8, 138.3, 138.2, 136.1, 130.9, 129.4 (2C), 128.7 (2C), 128.2 (2C),
128.1, 127.6 (2C), 126.9, 70.0, 67.3, 56.2, 36.9, 35.1, 29.7, 22.7, 13.8;
IR (thin film) 3064, 3031, 2958, 2925, 2860, 2030, 1695, 1605, 1499,
1458, 1373, 1275, 1140; HRMS (ES+) C25H27O2 [M + H+] calculated
359.2011, found 359.1980; [α]2D0 = +124.2° (c 1.2, CH2Cl2).
(Ra)-(3-(2-(But-2-yn-1-yloxy)ethyl)hepta-1,2-dien-1-yl)-
benzene (15c). Following the general procedure for preparation of
allene-yne via Williamson etherification, alcohol (Ra)-29 (105 mg,
0.442 mmol) in THF (1.1 mL) was reacted with sodium hydride (38.8
mg, 60% dispersion in mineral oil, 0.97 mmol) and 1-bromobut-2-yne
(97 mg, 0.73 mmol) for 11 h. Purification of the crude residue by flash
chromatography (1% Et2O/hexanes) afforded compound 15c (33 mg,
27%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 7.29−7.27 (m,
4H), 7.19−7.14 (m, 1H), 6.16−6.12 (m, 1H), 4.04−4.03 (m, 2H),
3.65−3.58 (m, 2H), 2.40−2.35 (m, 2H), 2.10−2.07 (m, 2H), 1.80 (t, J
= 2.3 Hz, 3H), 1.46−1.32 (m, 4H), 0.87 (t, J = 7.2 Hz, 3H); 13C NMR
(175 MHz, CDCl3) δ 202.2, 135.8, 128.5 (2C), 126.6 (2C), 126.5,
105.5, 95.8, 82.3, 75.2, 68.2, 58.7, 32.8, 32.6, 29.7, 22.5, 13.9, 3.6; IR
(thin film) 2954, 2929, 2852, 1495, 1462, 1356, 1140, 1095; HRMS
(ES+) C19H25O [M + H+] calculated 269.1905, found 269.1889; [α]2D0
= −16.1° (c 2.3, CH2Cl2).
(S)-5-Butyl-8-methyl-6-phenyl-3,4-dihydro-1H-cyclopenta-
[c]oxepin-7(6H)-one (43c). Following the general procedure for the
[Rh(CO)2Cl]2 catalyzed cyclocarbonylation reaction, allene-yne 15c
(19 mg, 0.0719 mmol) and [Rh(CO)2Cl]2 (2.8 mg, 0.00719 mmol)
were reacted in toluene (2.5 mL) for 45 min. Purification of the crude
residue by flash chromatography (20% Et2O/hexanes) afforded
compound 43c (10 mg, 46%) as a colorless oil: 1H NMR (300
MHz, CDCl3) δ 7.44−7.27 (m, 2H), 7.27−7.15 (m, 3H), 4.82−4.80
(m, 2H), 4.03−3.94 (m, 3H), 2.59 (t, J = 5.5 Hz, 2H), 1.98−1.89 (m,
2H), 1.74 (s, 3H), 1.18−0.97 (m, 4H), 0.70 (t, J = 7.1 Hz, 3H); 13C
NMR (175 MHz, CDCl3) δ 203.3, 166.8, 140.4, 138.5, 134.9, 134.8,
128.7 (2C), 127.5 (2C), 126.8, 70.4, 69.6, 55.7, 37.1, 36.8, 29.9, 22.7,
13.8, 8.3; IR (thin film) 2950, 2921, 2852, 1691, 1458, 1270, 1152;
HRMS (ES+) C20H25O2 [M + H+] calculated 297.1855, found
297.1834; [α]2D0 = +191° (c 1.0, CH2Cl2).
(Ra)-(3-(2-(Prop-2-yn-1-yloxy)ethyl)hepta-1,2-dien-1-yl)-
benzene (15e). Following the general procedure for preparation of
allene-yne via Williamson etherification, alcohol (Ra)-29 (221.6 mg,
2.05 mmol) in THF (2.4 mL) was reacted with sodium hydride (82
mg, 60% dispersion in mineral oil, 0.97 mmol) and propargyl bromide
(229 mg, 1.54 mmol) for 11 h. Purification of the crude residue by
flash chromatography (0.7% Et2O/hexanes) afforded compound 15e
C26H35O4 [M + H+] calculated 411.2535, found 411.2528; [α]2D0
−53° (c 1.35, CH2Cl2).
=
(S)-Diethyl 8-butyl-3-methyl-2-oxo-1-phenyl-1,2,6,7-tetra-
hydroazulene-5,5(4H)-dicarboxylate (44c). Following the general
procedure for the [Rh(CO)2Cl]2 catalyzed cyclocarbonylation
reaction, allene-yne 16c (33.2 mg, 0.081 mmol) and [Rh(CO)2Cl]2
(3.2 mg, 0.0081 mmol) were reacted in toluene (2.7 mL) for 2.5 h.
Purification of the crude residue by flash chromatography (30% Et2O/
hexanes) afforded compound 44c (31.2 mg, 88%) as a colorless oil: 1H
NMR (600 MHz, CDCl3) δ 7.29−7.27 (m, 3H), 7.22−7.19 (m, 1H),
7.13−7.12 (m, 2H), 4.26−4.23 (m, 4H), 3.95 (s, 1H), 3.39 (m, 2H),
2.50−2.47 (m, 3H), 2.39−2.36 (m, 1H), 1.90−1.89 (m, 2H), 1.85 (s,
3H), 1.30 (td, J = 7.1, 2.5 Hz, 6H), 1.26−1.22 (m, 2H), 1.10−0.87 (m,
2H), 0.72 (t, J = 7.3 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 204.3,
171.5, 171.4, 164.1, 143.4, 138.5, 137.7, 137.3, 128.6 (2C), 127.5 (2C),
126.6, 61.8 (2C), 55.9, 55.1, 37.1, 33.8, 32.6, 29.1, 28.6, 22.6, 14.0
(2C), 13.8, 8.5; IR (thin film) 2950, 2921, 2856, 1732, 1691, 1597,
1450, 1381, 1361, 1270, 1230, 1185; HRMS (ES+) C27H35O5 [M +
H+] calculated 439.2484, found 439.2467; [α]2D0 = +128° (c 2.0,
CH2Cl2).
(Ra)-(3-(2-((3-Phenylprop-2-yn-1-yl)oxy)ethyl)hepta-1,2-
dien-1-yl)benzene (15d). Following the general procedure for
preparation of allene-yne via Williamson etherification, alcohol (Ra)-29
(95.8 mg, 0.44 mmol) in THF (1 mL) was reacted with sodium
hydride (35.4 mg, 60% dispersion in mineral oil, 0.89 mmol) and (3-
bromoprop-1-yn-1-yl)benzene (130 mg, 0.66 mmol) for 11 h.
Purification of the crude residue by flash chromatography (1%
Et2O/hexanes) afforded compound 15d (51.3 mg, 35%) as a colorless
1
(51.9 mg, 20%) as a colorless oil: H NMR (300 MHz, CDCl3) δ
7.26−7.22 (m, 4H), 7.16−7.11 (m, 1H), 6.11 (m, 1H), 4.05 (t, J = 2.0
Hz, 2H), 3.66−3.58 (m, 2H), 2.38−2.33 (m, 3H), 2.10−2.04 (m, 2H),
1.43−1.30 (m, 4H), 0.84 (t, J = 7.2 Hz, 3H); 13C NMR (175 MHz,
CD2Cl2) δ 202.2, 135.8, 128.4 (2C), 126.5 (2C), 126.4, 105.5, 95.5,
79.9, 73.8, 68.2, 57.9, 32.6, 32.6, 29.7, 22.5, 13.7; IR (thin film) 3309,
O
dx.doi.org/10.1021/jo4002432 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
2954, 2921, 2856, 1728, 1663, 1593, 1467, 1360, 1254, 1160, 1103;
HRMS (ES+) C18H23O [M + H+] calculated 255.1749, found
255.1756; [α]2D0 = −14.0° (c 1.0, CH2Cl2).
2.41 (s, 3H), 1.78−1.72 (m, 2H), 1.62−1.59 (m, 1H), 1.30−1.27 (m,
1H), 1.21−1.18 (m, 1H), 1.08−1.06 (m, 1H), 1.01−0.96 (m, 1H),
0.94−0.90 (m, 1H), 0.87−0.85 (m, 2H), 0.80−0.77 (m, 1H), 0.66 (t, J
= 7.3 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 202.7, 162.1, 143.6,
139.4, 138.4, 137.9, 136.0, 135.7, 129.6 (2C), 128.6 (2C), 127.4 (2C),
127.3 (2C), 126.7, 55.3, 47.9, 43.8, 36.9, 31.2, 29.2, 22.6, 21.6, 13.7,
8.3, 5.9, 5.7; IR (thin film) 2962, 2917, 2860, 1695, 1454, 1344, 1172,
1087, 1021; HRMS (ES+) C29H34NO3S [M + H+] calculated
476.2259, found 476.2271; [α]2D0 = +72° (c 0.75, CH2Cl2).
(Ra)-Trimethyl(3-((3-(2-phenylvinylidene)heptyl)oxy)prop-1-
yn-1-yl)silane (15f). Following the general procedure for preparation
of allene-yne via silylation of the terminal alkyne, allene-yne 15e (48
mg, 0.19 mmol) in THF (1.7 mL) was reacted with lithium
hexamethyldisilylamide (340 μL, 1 M in THF, 0.34 mmol) and
trimethylsilylchloride (60 μL, 0.47 mmol). Purification of the crude
residue using a Biotage normal phase automated purification system (4
g SNAP column, gradient of 0−2% EtOAc/hexanes) to afford
compound 15f (39.9 mg, 65%) as a colorless oil: 1H NMR (600 MHz,
CDCl3) δ 7.30−7.28 (m, 4H), 7.20−7.18 (m, 1H), 6.17−6.16 (m,
1H), 4.12−4.11 (m, 2H), 3.70−3.62 (m, 2H), 2.43−2.40 (m, 2H),
2.14−2.12 (m, 2H), 1.50−1.46 (m, 2H), 1.40−1.34 (m, 2H), 0.90 (t, J
= 7.3 Hz, 3H), 0.17 (s, 9H); 13C NMR (150 MHz, CDCl3) δ 202.2,
135.7, 128.5 (2C), 126.5 (2C), 126.4, 105.4, 101.6, 95.7, 91.2, 68.2,
58.9, 32.7, 32.6, 29.7, 22.5, 13.9, −0.2 (3C); IR (thin film) 2954, 2925,
2856, 2169, 1949, 1716, 1597, 1491, 1458, 1356, 1250, 1099; HRMS
(ES+) C21H31OSi [M + H+] calculated 327.2144, found 327.2128;
[α]2D0 = −18.8° (c 0.85, CH2Cl2).
1-(Dimethyl(phenyl)silyl)hept-2-yn-1-ol (24). To a solution of
hept-2-yn-1-ol 23 (5.48 g, 48.9 mmol) in THF (74 mL) cooled to −78
°C was added n-BuLi (33.6 mL, 1.0 M in hexanes, 53.7 mmol) and
chlorodimethylphenylsilane (9.17 g, 53.7 mmol). After the addition
was complete, the bath was removed and the reaction mixture was
stirred at rt for 20 h. The solution was cooled to −78 °C and tert-
butyllithium (34.5 mL, 1.7 M in hexanes, 58.6 mmol) was added
dropwise. The mixture was then stirred at −45 °C for 2 h. The
solution was cooled to −78 °C and quenched slowly with a 10%
solution of acetic acid in THF (20 mL). The mixture was diluted with
NaHCO3 (100 mL) and extracted with Et2O (400 mL). The organic
phase was separated and extracted with NaHCO3 (4 × 150 mL). The
organic phase was washed with brine, dried (Na2SO4), filtered and
concentrated under reduced pressure. Purification of the crude residue
using a Biotage normal phase automated purification system (120 g
SNAP column, gradient of 1−25% EtOAc/hexanes) afforded
(S)-5-Butyl-6-phenyl-8-(trimethylsilyl)-3,4-dihydro-1H-
cyclopenta[c]oxepin-7(6H)-one (43f). Following the general
procedure for the [Rh(CO)2Cl]2 catalyzed cyclocarbonylation
reaction, allene-yne 15f (25.1 mg, 0.077 mmol) and [Rh(CO)2Cl]2
(3 mg, 0.0077 mmol) were reacted in toluene (2.5 mL) for 45 min.
Purification of the crude residue by flash chromatography (15% Et2O/
hexanes) afforded compound 43f (24.9 mg, 91%) as a colorless oil: 1H
NMR (400 MHz, CDCl3) δ 7.29−7.25 (m, 2H), 7.21−7.14 (m, 3H),
4.94−4.82 (m, 2H), 4.02−3.97 (m, 3H), 2.72−2.65 (m, 1H), 2.60−
2.52 (m, 1H), 2.00−1.91 (m, 2H), 1.27−1.26 (m, 1H), 1.08−1.03 (m,
3H), 0.71 (t, J = 7.1 Hz, 3H), 0.21 (s, 9H); 13C NMR (175 MHz,
CDCl3) δ 207.5, 180.1, 141.8, 138.8, 138.4, 138.2, 128.7 (2C), 127.4
(2C), 126.6, 69.8, 69.7, 57.4, 37.3, 36.0, 29.7, 22.7, 13.8, −0.3 (3C); IR
(thin film) 2954, 2925, 2964, 1695, 1544, 1446, 1250, 1152, 841;
HRMS (ES+) C22H31O2Si [M + H+] calculated 355.2093, found
355.2114; [α]2D0 = +191.0° (c 2.3, CH2Cl2).
(Ra)-N-(3-Cyclopropylprop-2-yn-1-yl)-4-methyl-N-(3-(2-phe-
nylvinylidene) heptyl)benzenesulfonamide (14g). Following the
general procedure for preparation of allene-yne via Mitsunobu
reaction, alcohol (Ra)-29 (37.8 mg, 0.18 mmol) in THF (1.3 mL)
was reacted with triphenylphosphine (55 mg, 0.21 mmol), N-(3-
cyclopropylprop-2-yn-1-yl)-4-methylbenzenesulfonamide 30g (52.3
mg, 0.21 mmol) and diisopropylazodicarboxylate (42 μL, 0.21
mmol) for 11 h. Purification of the crude residue using a Biotage
normal phase automated purification system (12 g SNAP column,
gradient of 0−6% EtOAc/hexanes) afforded compound 14g (78.2 mg,
78%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 7.9
Hz, 6H), 7.29−7.24 (m, 4H), 7.21−7.16 (m, 3H), 6.12 (s, 1H), 4.07−
3.96 (m, 2H), 3.36−3.29 (m, 1H), 3.25−3.18 (m, 1H), 2.37 (s, 3H),
2.36−2.34 (m, 2H), 2.15−2.06 (m, 2H), 1.45−1.41 (m, 2H), 1.36−
1.30 (m, 2H), 0.91−0.90 (m, 1H), 0.86 (t, J = 7.2 Hz, 3H), 0.56−0.53
(m, 2H), 0.26−0.24 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 202.3,
143.1, 135.9, 135.5, 129.3 (2C), 128.5 (2C), 127.7 (2C), 126.6, 126.5
(2C), 105.4, 95.9, 89.3, 67.7, 44.6, 37.0, 32.1, 31.2, 29.7, 22.5, 21.5,
13.9, 7.8 (2C), −0.9; IR (thin film) 3027, 2962, 2940, 2860, 2251,
1945, 1593, 1491, 1458, 1348, 1164, 1099; HRMS (ES+) C28H34NO2S
[M + H+] calculated 448.2310, found 448.2329; [α]2D0 = −83.6° (c
0.55, CH2Cl2).
1
compound 24 (6.65 g, 55%) as a colorless oil: H NMR (600 MHz,
CDCl3) δ 7.63−7.62 (m, 2H), 7.40−7.37 (m, 3H), 4.25 (t, J = 2.4 Hz,
1H), 2.25−2.23 (m, 2H), 1.49−1.45 (m, 2H), 1.40−1.37 (m, 2H),
0.94−0.93 (m, 1H), 0.90 (t, J = 7.3 Hz, 3H), 0.43 (d, J = 7.0 Hz, 6H);
13C NMR (150 MHz, CDCl3) δ 135.5, 134.3 (2C), 129.6, 127.8 (2C),
89.0, 79.9, 56.2, 30.9, 21.9, 18.7, 13.6, −5.5, −5.9; IR (thin film) 3440,
2954, 2929, 2860, 1248, 1120, 968; HRMS (ES+) C15H23OSi [M +
H+] calculated 247.1518, found 247.1496.
Methyl 3-(2-(dimethyl(phenyl)silyl)vinylidene)heptanoate
(51). A 25 mL round-bottom flask was charged with propargyl
alcohol 24 (1.01 g, 4.1 mmol), trimethylorthoacetate (3.13 mL, 24.5
mmol) and propionic acid (52 μL, 0.69 mmol). The resulting solution
was stirred at 160 °C for 12 h using a Dean−Stark apparatus. After
cooling to rt, the mixture was concentrated under a 10 mmHg vacuum
for 2 h. Purification of the crude residue by silica gel chromatography
using 2% Et2O/hexanes afforded compound 51 (940 mg, 76%) as a
1
colorless oil: H NMR (700 MHz, CDCl3) δ 7.55−7.54 (m, 2H),
7.36−7.35 (m, 3H), 5.15 (t, J = 3.4 Hz, 1H), 3.66 (s, 3H), 2.96 (qd, J
= 15.1, 3.0 Hz, 2H), 1.99−1.98 (m, 2H), 1.37−1.31 (m, 4H), 0.88 (t, J
= 7.0 Hz, 3H), 0.36 (s, 6H); 13C NMR (150 MHz, CDCl3) 209.8,
172.0, 138.6, 133.7 (2C), 129.0, 127.7 (2C), 91.5, 82.9, 51.7, 38.2,
31.0, 29.8, 22.4, 13.9, −2.28, −2.32; IR (thin film) 2958, 2921, 2860,
1940, 1744, 1434, 1368, 1168; HRMS (ES+) C18H27O2Si [M + H+]
calculated 303.1780, found 303.1755.
3-(2-(Dimethyl(phenyl)silyl)vinylidene)heptan-1-ol (25). A 25
mL round-bottom flask was charged with lithium aluminum hydride
(4.1 mL of a 1 M solution in Et2O, 4.02 mmol) and THF (4 mL). The
resulting mixture was cooled to 0 °C and a solution of ester 51 (810.5
mg, 2.68 mmol) in THF (4.7 mL) was added dropwise. The solution
was stirred for 1 h at rt. The reaction mixture was cooled to 0 °C (ice
bath), diluted with Et2O (30 mL) and quenched very slowly with
water (2 mL). The phases were separated, the organic phase was
washed with brine (10 mL), dried (Na2SO4), filtered and concentrated
under reduced pressure. Purification of the crude residue by silica gel
chromatography using 30% Et2O/hexanes afforded compound 25
(S)-5-Butyl-8-cyclopropyl-6-phenyl-2-tosyl-1,2,3,4-
tetrahydrocyclopenta[c]azepin-7(6H)-one (42g). Following the
general procedure for the [Rh(CO)2Cl]2 catalyzed cyclocarbonylation
reaction, allene-yne 14g (31 mg, 0.069 mmol) and [Rh(CO)2Cl]2 (2.7
mg, 0.0069 mmol) were reacted in toluene (2.2 mL) for 35 min.
Purification of the crude residue by silica gel chromatography using
40% Et2O/hexanes afforded compound 42g (29.1 mg, 88%) as a
colorless oil: 1H NMR (600 MHz, CDCl3) δ 7.75 (d, J = 8.3 Hz, 2H),
7.28 (d, J = 8.2 Hz, 2H), 7.15 (m, 3H), 6.75−6.73 (m, 2H), 4.88 (d, J
= 16.9 Hz, 1H), 4.61 (d, J = 16.9 Hz, 1H), 3.67−3.65 (m, 1H), 3.64 (s,
1H), 3.57−3.53 (m, 1H), 2.68−2.63 (m, 1H), 2.53−2.48 (m, 1H),
1
(541 mg, 74%) as a colorless oil: H NMR (600 MHz, CDCl3) δ
7.56−7.54 (m, 2H), 7.38−7.36 (m, 3H), 5.15−5.14 (m, 1H), 3.67−
3.65 (m, 2H), 2.19−2.17 (m, 3H), 1.94−1.92 (m, 2H), 1.38−1.34 (m,
4H), 0.90 (m, 3H), 0.37−0.36 (m, 6H); 13C NMR (150 MHz, CDCl3)
δ 209.0, 138.4, 133.6 (2C), 129.0, 127.7 (2C), 93.8, 82.8, 60.8, 34.9,
31.4, 29.9, 22.4, 13.9, −2.2, −2.3; IR (thin film) 3342, 2962, 2933,
2844, 1945, 1458, 1453, 1381, 1242; HRMS (ES+) C17H25OSi [M −
H+] calculated 273.1675, found 273.1653.
N-(But-2-yn-1-yl)-N-(3-(2-(dimethyl(phenyl)silyl)vinylidene)-
heptyl)-4-methylbenzenesulfonamide (40). Following the gen-
P
dx.doi.org/10.1021/jo4002432 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
eral procedure for preparation of allene-yne via Mitsunobu reaction,
alcohol 25 (54.8 mg, 0.2 mmol) in THF (1.5 mL) was reacted with
triphenylphosphine (63 mg, 0.24 mmol), N-(but-2-yn-1-yl)-4-methyl-
benzenesulfonamide31 30c (54 mg, 0.24 mmol) and NaHCO3 (48 μL,
0.24 mmol) for 2.5 h. Purification of the crude residue by silica gel
chromatography using 5% Et2O/hexanes afforded compound 40 (46.7
mg, 49%) as a colorless oil: 1H NMR (600 MHz, CDCl3) δ 7.74 (d, J
= 8.1 Hz, 2H), 7.57 (d, J = 5.0 Hz, 2H), 7.39−7.37 (m, 3H), 7.29 (d, J
= 7.4 Hz, 2H), 5.15−5.14 (m, 1H), 4.09 (d, J = 2.6 Hz, 2H), 3.24 (t, J
= 8.0 Hz, 2H), 2.44 (s, 3H), 2.22−2.20 (m, 2H), 1.96−1.95 (m, 2H),
1.56 (t, J = 2.3 Hz, 3H), 1.38−1.35 (m, 5H), 0.92 (t, J = 7.0 Hz, 3H),
0.37 (s, 6H); 13C NMR (150 MHz, CDCl3) δ 208.9, 143.0, 138.5,
136.0, 133.6 (2C), 129.2 (2C), 129.0, 127.7 (2C), 127.6 (2C), 94.1,
82.9, 81.4, 71.7, 44.9, 37.0, 31.3, 29.8 (2C), 22.4, 21.4, 13.9, 3.2, −2.2,
−2.3; IR (thin film) 3395, 3064, 2954, 2860, 2165, 1669, 1593, 1438,
1361, 1254, 1160; HRMS (ES+) C28H36NO2SSi [M − H+] calculated
478.2236, found 478.2238.
5-Butyl-8-methyl-2-tosyl-1,2,3,4-tetrahydrocyclopenta[c]-
azepin-7(6H)-one (41). Following the general procedure for the
[Rh(CO)2Cl]2 catalyzed cyclocarbonylation reaction, allene-yne 40
(33.5 mg, 0.07 mmol) and [Rh(CO)2Cl]2 (2.7 mg, 0.007 mmol) were
reacted in toluene (2.3 mL) for 6 h. Purification of the crude residue
by silica gel chromatography using 65% Et2O/hexanes afforded
compound 41 (25.1 mg, 96%) as a colorless oil: 1H NMR (700 MHz,
CDCl3) δ 7.58 (d, J = 8.2 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 4.45 (s,
2H), 3.57 (t, J = 14.0 Hz, 2H), 2.70 (s, 2H), 2.54 (t, J = 6.0 Hz, 2H),
2.39 (s, 3H), 2.00 (t, J = 7.4 Hz, 2H), 1.82 (s, 3H), 1.27−1.24 (m,
4H), 0.88 (t, J = 6.9 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 203.9,
161.5, 143.5, 138.6, 137.0, 136.1, 131.1, 129.4 (2C), 127.0 (2C), 47.9,
45.4, 39.2, 37.0, 32.6, 30.0, 22.6, 21.5, 14.0, 8.2; IR (thin film) 2954,
2929, 2856, 1703, 1462, 1352, 1160; HRMS (ES+) C21H28NO3S [M +
H+] calculated 374.1790, found 374.1806.
ACKNOWLEDGMENTS
■
We greatly acknowledge the National Institute of Health
(P50GM067982 and GM54161) for funding this project. We
also thank Chiral Technologies, Inc., Prof. Peter Wipf, Dr. Erin
M. Skoda, and Lotus Separation for their help in the HPLC and
SFC analysis. Finally we also thank Dr. Steve Geib for
crystallographic studies.
REFERENCES
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1
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ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H and 13C NMR spectra for all new compounds;
HPLC chromatogram of the racemic and enantioenriched
compounds; coordinates for the crystallographic analysis (CIF)
for compounds 35c and 48. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
(14) (a) Kwong, F. Y.; Lee, H. W.; Lam, W. H.; Qiu, L.; Chan, A. S.
C. Tetrahedron: Asymmetry 2006, 17, 1238−1252. (b) Shibata, T.;
Toshida, N.; Yamasaki, M.; Maekawa, S.; Takagi, K. Tetrahedron 2005,
61, 9974−9979. (c) Shibata, T.; Takagi, K. J. Am. Chem. Soc. 2000,
122, 9852−9853.
Corresponding Author
*E-mail: kbrummon@pitt.edu.
Notes
The authors declare no competing financial interest.
Q
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