Sulfinyl-Mediated Stereoselective Overman Rearrangements and Diels-Alder Cycloadditions

Article abstract of DOI:10.1021/acs.joc.6b00365

Sulfinyl trichloroacetamides are readily obtained in excellent yields through a highly stereoselective Overman rearrangement. Related bis-allylic substrates lead to amido 2-sulfinyl butadiene derivatives in excellent yields, with total chemo- and diastereoselectivity. These amido dienyl sulfoxides undergo highly selective Diels-Alder cycloadditions with N-phenylmaleimide with remarkable stereocontrol by the sulfoxide moiety.

Full text of DOI:10.1021/acs.joc.6b00365

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Article
Sulfinyl-Mediated Stereoselective Overman
Rearrangements and Diels-Alder Cycloadditions
Ignacio Colomer, Chirag Gheewala, Carmen Simal, Marina
Velado, Roberto Fernández de la Pradilla, and Alma Viso
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00365 • Publication Date (Web): 19 Apr 2016
Downloaded from http://pubs.acs.org on April 20, 2016
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Page 1 of 58
The Journal of Organic Chemistry
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SulfinylꢀMediated Stereoselective Overman
Rearrangements and DielsꢀAlder Cycloadditions
Ignacio Colomer, Chirag Gheewala, Carmen Simal, Marina Velado, Roberto Fernández de la Pradilla,*
and Alma Viso*
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Instituto de Química Orgánica General, IQOGꢀCSIC, Juan de la Cierva 3, 28006 Madrid, Spain
Fax: (+34) 915644853
Eꢀmail: iqofp19@iqog.csic.es (RFP); iqov379@iqog.csic.es (AV)
Table of Contents Graphic
R2
R2
O
S
Overman
54/46 - 100/0
18 examples
S* =
S*
S*
p-Tol
HO
rearrangement
P = COCCl3
R1
R1
NHP
O
R3
NHP
R3
R3
O
H
H
Ph N
PHN
Overman
Ph N
S*
S*
O
HO
rearrangement
S*
>
99/1
H
O
>
99/1
12 examples
R1
R1
R1
2
0 examples
Abstract: Sulfinyl trichloroacetamides are readily obtained in excellent yields through a highly
stereoselective Overman rearrangement. Related bisꢀallylic substrates lead to amido 2ꢀsulfinyl butadiene
derivatives in excellent yields, with total chemoꢀ and diastereoselectivity. These amido dienyl sulfoxides
undergo highly selective DielsꢀAlder cycloadditions with Nꢀphenylmaleimide with remarkable
stereocontrol by the sulfoxide moiety.
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INTRODUCTION
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1
Allylic amines are valuable building blocks in different fields such as synthetic methodology,
2
3
4
applications, medicinal chemistry, and synthesis of natural products. This importance has attracted the
attention of synthetic chemists to devise routes to produce these compounds efficiently. The addition to
imine derivatives of suitable nucleophiles is a popular approach for instance by means of MoritaꢀBaylisꢀ
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Hillman protocols, generally limited to electronꢀdeficient alkenes unsubstituted at the terminal position.
The condensation between sulfinimines and αꢀlithiated vinyl or dienyl sulfoxides gives rise to
6
enantiopure Nꢀsulfinyl allylic amines. The reductive coupling of alkynes with imines is also a valuable
7
variant of the imine electrophile theme.
8
Another general strategy to allylic amines relies on metalꢀcatalyzed allylic aminations promoted by Ir,
9
10
11
Pd, Pt and Fe. The metalꢀcatalyzed hydroamination of dienes is a valuable related methodology.
A
different strategy to these useful targets is the azaꢀClaisen [3,3]ꢀsigmatropic rearrangement of allylic
1
2
imidates, often referred to as the Overman rearrangement. The reaction is very powerful and proceeds
in functionalized molecules by means of a wellꢀdefined chair transition state that allows for an oxygenꢀ
nitrogen transposition with efficient chirality transfer by using enantiopure allylic alcohols as starting
1
3
materials. In this paper we provide the full details of our research on the Overman rearrangement of
sulfinyl allylic trichloroacetimidates that take place with good diastereoselectivities and yields, complete
chemoselectivity and preserve the valuable alkenyl sulfoxide moiety for subsequent chirality transfer
operations. This is illustrated by highly selective DielsꢀAlder cycloadditions of a variety of amido 2ꢀ
14
sulfinyl butadiene derivatives with Nꢀphenylmaleimide.
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The Journal of Organic Chemistry
RESULTS AND DISCUSSION
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Enantiomerically pure sulfoxides are useful and versatile chiral auxiliaries. Our group has pursued new
1
6,17
methodologies involving readily available αꢀhydroxy vinyl sulfoxides A (Scheme 1).
A relevant
example of these methodologies was the highly diastereoselective Claisen rearrangement of enol ethers B
to carbonyl derivatives C that brought about the generation of up to two stereogenic centers with
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preservation of a useful vinyl sulfoxide and with good control of the geometry of the alkene. Within
this context we decided to test the viability of the preparation of trichloroacetimidates D and their
Overman rearrangement to allylic trichloroacetamides E with a stereodefined alkenyl sulfoxide moiety.
The main aspects to be examined in this study were the geometry of the starting alkene, the relative
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2
stereochemistry of the chiral centers and the nature of representative R and R groups in substrates A. If
successful, this methodology could complement our previous synthesis of allylic amines by condensation
of αꢀlithio derivatives of sulfoxides H and enantiopure sulfinimines G to produce Nꢀsulfinyl amines F
6
with high selectivity and exclusive E geometry.
Scheme 1. Proposed Sulfinyl-Mediated Overman Rearrangement
this work
R2
R1
O
S
CCl R2
3
R2
O
S
O
S
HO
p-Tol
p-Tol
HN
O
p-Tol
R1
R
1
NHP
A
D
E, P = COCCl3
F, P = S*
O
1) LDA
N
S*
R2
O
S
R2
R3
S* =
O
S
S
p-Tol
2)
O
O
R1
p-Tol
O
p-Tol
G
S
p-Tol
X
3R1
R1
X
ꢀ
R
R2
B
C
H
previous work
(ref . 18)
previous work
(ref. 6)
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Preparation of Starting Materials. The preparation of enantiopure E substrates is summarized in
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scheme 2. Lithiation of alkenyl sulfoxides 1, and trapping with a variety of aldehydes gave good yields
(81ꢀ95%) of hydroxy vinyl sulfoxides 2 and 3, separable by chromatography on silica gel but with low
selectivities (24:76 to 48:52). Treatment of sulfinyl alcohols 2 with catalytic DBU and Cl CCN led
3
uneventfully to the desired trichloroacetimidates 4 in excellent yields (85ꢀ95%) after column
chromatography. Similar treatment of diastereomers 3 afforded imidates 5 in excellent yields after
0
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chromatography (93ꢀ96%). However, for those examples that had R = alkyl group, the H NMR spectra
clearly indicated that two inseparable species were present in solution (73:27 to 93:7 mixtures). The
major products were assigned the expected trichloroacetimidate structure 5 by comparison of their
spectral data with that of diastereomers 4. The minor products were tentatively assigned sulfurane
structures 5’, presumably in equilibrium with imidates 5. It should be pointed out that the yields and
selectivities of the Overman rearrangements of these cases are not compromised (see below).
Scheme 2. Synthesis of E-trichloroacetimidates
O
S
R2
R2
O
S
O
S
1) 2.5 equiv LDA
THF, −78 ºC
p
-Tol
HO
p-Tol
HO
p-Tol
+
2
R1
2) 3.0 equiv R CHO
R1
R1
THF, −78 ºC, 40 min
1
81-95%
2
3
2
/3 = 24/76 - 48/52
0
.20 equiv DBU
93-96%
5/5' = 73/27 - 100/0
1
R = n-Bu, Ph,
5.0 equiv Cl CCN
3
85-95%
CH CN
3
CH OTBDPS
2
2
R = Et, Ph, CH=CH ,
2
CCl R2
O
S
CCl R2
p-Tol
O
Cl C
N
(
(
E)-CH=CHMe,
E)-CH=CHPh
3
3
3
S
S
OH
HN
O
p-Tol
HN
O
p
-Tol
O
R1
R1
R2 R1
4
5
5'
The synthesis of racemic Z substrates is summarized in scheme 3. Lithiation of alkenyl sulfide 6 or tinꢀ
lithium exchange of stannane 7, and condensation with a variety of aldehydes led to Zꢀsulfenyl alcohols
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The Journal of Organic Chemistry
1
9,20
(±)ꢀ8.
Diastereoselective oxidation with mꢀCPBA gave separable mixtures of diastereomeric Zꢀ
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9
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5
5
6
hydroxy alkenyl sulfoxides (±)ꢀ9 and (±)ꢀ10 (19:81 to 46:54) in good yields (66ꢀ97%). Treatment with
DBU and Cl CCN produced the expected trichloroacetimidates (±)ꢀ11 (50ꢀ95%) as single species and
3
1
(
±)ꢀ12 (78ꢀ97%) as inseparable mixtures in variable ratios ( H NMR, 50:50 to 85:15 mixtures of imidates
±)ꢀ12 and sulfuranes (±)ꢀ12’) that again led to good yields of rearrangement products (see below).
(
0
1
2
3
4
5
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8
9
0
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9
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9
0
1
2
3
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9
0
1
2
3
4
5
6
7
8
9
0
Scheme 3. Synthesis of Z-trichloroacetimidates
R2
O
S
R2
O
S
R2
m-CPBA
S
HO
(
p
-Tol
HO
p-Tol
HO
p-Tol
acetone
78 ºC, 40 min
+
−
R1
R1
R1
66-97%
±)-8
(±)-9
(±)-10
9
/10 = 19/81 - 46/54
0.20 equiv DBU
78-97%
1
1
) n-BuLi
R = n-Bu, Ph
5
0-95%
5.0 equiv Cl CCN
12/12' = 50/50 - 85/15
3
2
2) R CHO
2
R = Et, Ph, CH=CH ,
CH CN
3
2
THF, −78 ºC
(
(
E)-CH=CHMe,
E)-CH=CHPh
41-96%
2
2
p-Tol
CCl R
O
S
CCl R
O
S
Cl C
N
3
3
3
S
OH 1
R
S
Bu Sn
S
3
HN
O
p-Tol
HN
O
p
-Tol
O
p-Tol
p-Tol
or
R1
R1
R2
Ph
n-Bu
6
7
(±)-11
(±)-12
(±)-12'
Overman Rearrangement of Sulfinyl Trichloroacetimidates. The thermal rearrangement of imidate
a (Table 1) was then examined in toluene at different temperatures (60ꢀ110 ºC) with disappointing
4
results. In contrast, switching to DMF, in the presence of a few crystals of BHT to inhibit undesired
radicalꢀmediated processes, at 100 ºC gave an excellent yield of amides 13a:14a with good selectivity
(Table 1, entry 1). Under these optimized conditions we examined the rearrangements of a variety of
substrates with different substituents, geometries and relative configurations and the results are
summarized in Table 1.
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a
Table 1. Scope of the Sulfinyl-Mediated Overman Rearrangement
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
CCl R2
R2
R1
R2
R2
3
S*
S*
S*
S*
S*
R2
HN
O
R
O
S
+
R1
NHP
R1
4
NH R1
(±)-12
NHP
13
Cl C
3
O
S
14
S* =
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
p-Tol
P = COCCl3
CCl R2
3
R2
S*
S*
S*
R2
HN
O S
O R
+
1
R
NHP
15
R1
NHP
NH R1
R1
Cl3C
5
16
(±)-11
1
2
a
b,c
entry
SM
4a
R
R
major product
13a
dr (yield %)
1
2
3
4
5
6
7
8
9
nꢀBu
nꢀBu
nꢀBu
nꢀBu
Ph
Et
92/8 (90%)
96/4 (90%)
70/30 (75%)
100/0 (92%)
100/0 (83%)
100/0 (91%)
100/0 (51%)
100/0 (91%)
90/10 (70%)
95/5 (42%)
50/50 (86%)
80/20 (90%)
100/0 (85%)
5a
Et
Ph
Ph
Et
15a
4b
13b
5b
15b
4c
13c
5c
Ph
Et
15c
4d
Ph
Ph
Ph
13d
5d
Ph
15d
4e
CH OTBDPS Et
2
13e
10
5e
CH OTBDPS Et
15e
2
11
(±)ꢀ11a
(±)ꢀ12a
(±)ꢀ11b
nꢀBu
nꢀBu
nꢀBu
Et
Et
Ph
(±)ꢀ15a/(±)ꢀ16a
(±)ꢀ14a
1
2
3
1
(±)ꢀ16b
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1
1
1
1
4
(±)ꢀ12b
(±)ꢀ11c
(±)ꢀ12c
(±)ꢀ11d
(±)ꢀ12d
nꢀBu
Ph
Ph
Et
(±)ꢀ14b
(±)ꢀ15c/(±)ꢀ16c
(±)ꢀ14c
100/0 (95%)
54/46 (81%)
100/0 (55%)
ꢀ
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
5
6
7
Ph
Et
Ph
Ph
Ph
ꢀ
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
18
Ph
(±)ꢀ14d
95/5 (81%)
a
b
1
Reactions were performed in DMF with a catalytic amount of BHT at 100 ºC. Ratio determined by H
c
NMR analysis of crude reaction mixtures. Combined yield after chromatography.
1
In the case of E substrates with R = nꢀBu, the rearrangements are highꢀyielding and the selectivities are
high for both diastereomeric imidates (4a,b and 5a,b) in favor of the Z isomers 13 and 15 (Table 1,
1
entries 1ꢀ4), with the exception of entry 3 that had modest selectivity. Interestingly, substrates with R =
Ph were highly selective substrates leading to single isomers of the transposed amides with complete
stereocontrol and good yields in most cases (Table 1, entries 5ꢀ8). Thus, it appears that the loss of
conjugation in the rearrangement does not hamper the process. The protocol was then extended to
1
substrates with a functionalized R chain with good selectivities and moderate unoptimized yields (Table
1
, entries 9 and 10). It should be pointed out that in all cases Z amides are obtained from E imidates with
high selectivity, particularly from isomers 5, in contrast with a recent report on related unsaturated esters
21
that led mainly to E isomers. In this manner this methodology nicely complements our previous efforts
on the synthesis of related sulfinyl allylic amines (Scheme 1, H to F) that afforded exclusively E isomers.
1
The rearrangements of Z substrates with an alkyl R substituent were highꢀyielding but the selectivities
2
were remarkably different for the R groups studied (Et and Ph, Table 1, entries 11ꢀ14) but favoring the
1
obtention of products with E geometry ((±)ꢀ14, (±)ꢀ16). The related substrates with R = Ph were also
viable in this rearrangement except for (±)ꢀ11d that decomposed upon heating under the reaction
2
conditions (Table 1, entry 17). Again, substrate (±)ꢀ11c (R configuration at the allylic carbon and R =
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Et) gave a nonꢀselective mixture of products (±)ꢀ15c/(±)ꢀ16c (Table 1, entry 15; compare with entry 11).
In contrast the S isomers, (±)ꢀ12c,d gave highly selective rearrangements.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
The relative configurations of products 13 and 15 was assigned from their Z geometry (NOE’s measured
between the vinylic and allylic nitrogenꢀsubstituted protons were in the range 2ꢀ6% for several cases), the
known relative configuration of the starting materials 2 and 3, secured by an Xꢀray structure of a
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
9
derivative of 2a, and the accepted concerted mechanism of the rearrangement that occurs with
1
2a
suprafacial oxygen to nitrogen transposition,
fully consistent with our observation of at most 2
rearrangement products for each of these substrates, instead of a more complex mixture of isomers
derived from an ionizationꢀrecombination alternative pathway. Furthermore, some products (15a, 14b)
are obtained in sizable amounts from either E or Z precursors. This mechanism also supports the
proposed structures for E sulfinyl amides 14 and 16, the main products obtained from imidates (±)ꢀ11 and
1
9
(±)ꢀ12, derived from Zꢀsulfinyl alcohols (±)ꢀ9 and (±)ꢀ10.
At this point we examined the influence of the oxidation state at sulfur on this process and the sulfone
1
9
analog of 5a, 18, was prepared under standard conditions from 17.
The rearrangement of sulfonyl
imidate 18 afforded an 80:20 mixture of Z and E isomeric amides 19 (NOE between H3ꢀH5 = 5%) and 20
(Scheme 4) that were spectroscopically identical to those obtained by oxidation of an 80:20 mixture of
1
5a and 16a.
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The Journal of Organic Chemistry
Scheme 4. Rearrangement of E Sulfonyl Imidate 18
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Et
CCl Et
3
SO p-Tol
0.20 equiv DBU
SO p-Tol
2
2
HO
HN
O
5
.0 equiv Cl CCN
3
n-Bu
17
CH CN
n-Bu
3
90%
18
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
BHT, DMF
00 ºC, 89%
1
Et
O
S
O
S
Et
SO p-Tol
SO p-Tol
MMPP
2
2
p-Tol
Et
p-Tol
Et
+
5%
+
MeOH
80%
n-Bu
NHCOCCl3 n-Bu
NHCOCCl3
16a (20)
n-Bu
NHCOCCl3 n-Bu
NHCOCCl3
1
5a (80)
1
9 (80)
20 (20)
Overman Rearrangement of bis-Allylic Sulfinyl Trichloroacetimidates. Encouraged by the good
1
2f
behavior of our sulfinyl imidates 4,5,11,12, with trisubstituted alkenes in the Overman rearrangement,
we decided to explore another challenging aspect of this useful methodology, namely the
chemoselectivity of the process for bisꢀallylic substrates that generally takes place with poor
1
2a,12e,22
selectivity.
Indeed, we considered that the presence of a sulfinyl substituent on one of the allylic
moieties could effectively “deactivate” that alkene in the Overman rearrangement, relative to another
allylic moiety and thus provide a synthetically useful level of selectivity. To test this hypothesis,
diastereomeric bisꢀallylic substrates 2f and 3f were smoothly transformed to the trichloroacetimidates
that, after purification by chromatography on silica gel, were submitted to the standard reaction
conditions, to produce excellent yields of amido diene 21f with complete chemoselectivity (Table 2,
entries 1 and 2). Similarly, phenylꢀsubstituted diene 21g was obtained as a single isomer and in excellent
yields from the imidates derived from alcohols 2g and 3g (Table 2, entries 3 and 4).
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Table 2. Overman Rearrangement of Bis-allylic Substrates
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
R3
R3
R3
R3
PHN
PHN
1) Cl CCN
1) Cl CCN
DBU
3
3
S*
DBU
S*
S*
S*
HO
R
CH CN
CH CN HO
S
3
3
R1
2) BHT
100 ºC
DMF
R1
21
R1
R1
2) BHT
00 ºC
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
22
3
DMF
O
S
S* =
P = COCCl3
p
-Tol
R3
R3
R3
R3
PHN
PHN
1) Cl CCN
1) Cl CCN
3
3
S*
S*
DBU
S*
S*
DBU
HO
S
HO
R
CH CN
CH CN
3
3
R1
R1 2) BHT
R1
R1 2) BHT
100 ºC
DMF
100 ºC
DMF
(
±)-24
(±)-10
(
±)-9
(±)-23
1
3
a
entry
SM
R
R
product
21f
yield %
1
2
3
4
5
6
7
8
9
2f
3f
nꢀBu
nꢀBu
Ph
H
91%
99%
92%
98%
80%
97%
92%
95%
H
H
21f
2g
3g
2h
3h
2i
21g
21g
21h
22h
21i
Ph
H
nꢀBu
nꢀBu
nꢀBu
nꢀBu
Ph
Me
Me
Ph
Ph
Me
Me
Ph
Ph
3i
22i
b
2j
21j
83%
77%
b
10
3j
Ph
22j
11
2k
3k
Ph
21k
22k
80%
90%
12
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The Journal of Organic Chemistry
1
1
1
1
3
4
5
6
(±)ꢀ9h
(±)ꢀ10h
(±)ꢀ9i
nꢀBu
nꢀBu
nꢀBu
nꢀBu
Ph
Me
Me
Ph
(±)ꢀ23h
(±)ꢀ24h
(±)ꢀ23i
(±)ꢀ24i
(±)ꢀ23j
(±)ꢀ24j
(±)ꢀ23k
(±)ꢀ24k
88%
95%
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
b
85%
63%
60%
58%
b
b
b
c
(±)ꢀ10i
(±)ꢀ9j
Ph
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
17
Me
Me
Ph
18
19
20
(±)ꢀ10j
(±)ꢀ9k
(±)ꢀ10k
Ph
Ph
40%
75%
c
Ph
Ph
a
b
Reactions were performed in DMF with a catalytic amount of BHT at 100 ºC. Reactions performed at
c
6
0 ºC. Reaction performed at 80 ºC.
3
The creation of an additional stereocenter by using a substrate with a more substituted reactive alkene (R
≠
H) was next examined and, to our dismay, attempted purification by quick chromatography of the
1
trichloroacetimidates derived from 2h and 3h, quite clean by H NMR of the crude reaction mixtures,
resulted in good yields of hydroxy dienyl sulfoxides 25 and 26 but as inseparable practically
23
equimolecular mixtures (Scheme 5).
Scheme 5. Unselective Preparation of Hydroxy Dienyl Sulfoxides
Me
Me
Me
Me
HO
HO
1
) Cl CCN
1) Cl CCN
3
3
S* DBU
S*
S*
S*
DBU
HO
n-Bu
CH CN
CH CN HO
3
3
+
2) SiO2
n-Bu
n
-Bu
2) SiO2
0%
n
-Bu
7
6%
8
2h
25
26
3h
O
S
S* =
p-Tol
At this stage we decided to test the rearrangement on the trichloroacetimidates as crude products and this
gave the desired amido dienes 21h and 22h as single isomers, with complete chemoꢀ and stereoselectivity
1
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and in excellent overall yields from the starting alcohols (Table 2, entries 5 and 6). The process was
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
3
readily extended to other derivatives with different R and R groups to produce the expected dienyl
trichloroacetamides 21i-k and 22i-k in excellent yields (Table 2, entries 7ꢀ12). This protocol was also
effective for substrates with a Z alkenyl sulfoxide moiety (±)ꢀ9h-k and (±)ꢀ10h-k that gave the expected
dienes (±)ꢀ23h-k and (±)ꢀ24h-k as single isomers and in good yields in most cases. It should be
mentioned that the geometry of the transposed alkene is always E, as expected in most Overman
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
12
rearrangements.
Rationalization of Stereochemistry. Bisꢀallylic substrates (Table 2) follow the commonly accepted
reaction course for the Overman rearrangement, with the sulfinyl moiety acting just as a powerful
controlling element for chemoselectivity. The results found for the allylic sulfinyl imidates (Table 1) can
be accommodated by considering diastereomeric transition states of chairlike reactive conformations I-L
for diastereomers 5 and 11 that lead to the same products 15 and 16 (Figure 1). In the case of E vinyl
2
4
sulfoxides 5a-e, considering an sꢀcis arrangement between the alkene and the S=O bonds, approach of
1
,3
the NH fragment to the re face would entail reactive conformer J, disfavored by an A interaction
1
2
between R and R and the bulky pꢀTol group pointing toward the incoming unsaturated fragment. In
contrast, reactive conformer I has no significant interactions of the kind described above and thus would
lead almost exclusively to Z isomers 15 due to the favorable arrangement of stereocontrolling elements.
Figure 1. Stereochemical Outcome
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p-Tol
1
2
3
4
5
6
7
8
9
O
O
p-Tol
R2
R1
O
S
S
S
O
S
p-Tol
HN
R1
R1
O
A1,2
p-Tol
R2
R2
R2
HN
O
HN
O
NHCOCCl3
CCl3
2
R1
R = Et
CCl3
CCl3
1
5
K'
I
K
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Si-face attack
Si-face attack
CCl R2
O
S
2
CCl R
O
S
3
3
HN
O
S
p-Tol
HN
O
R
p-Tol
R1
R1
(±)-11a-c
5a-e
Re-face attack
Re-face attack
p-Tol
O
O
S
S
S
O
O
p-Tol
O
S
HN
p-Tol
HN
O
R2
p-Tol
HN
O
R1
R1
R1
CCl3
R1
NHCOCCl3
CCl3
CCl3
R2
A1,3
R2
R2
2
16
R = Ph, Et
L
L'
J
p-Tol
O
S
p
-Tol
R2
O
O
S
S
S
O
O
A1,2
p
-
Tol
HN
R1
HN
R1
A1,2
R2
O
O
p-Tol
HN
R2
R2
R1
CCl3
R1
NHCOCCl3
CCl3
CCl3
O'
1
3
M
O
Re-face attack
Re-face attack
CCl R2
O
S
2
CCl R
O
S
3
3
HN
O
R
p-Tol
HN
O
S
p-Tol
R1
R1
2a-d
4a-e
(±)-
1
Si-face attack
Si-face attack
p-Tol
O
O
p-Tol
S
O
S
S
S
O
HN
p-Tol
O
R1
R1
R2
p-Tol
HN
O
HN
O
R1
NHCOCCl3
CCl3
R2
A1,3
R1
R2
R2
1
4
CCl3
CCl3
N
P
P'
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The stereochemical outcome for Z sulfinyl imidates (±)ꢀ11 involves a delicate conformational balance
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
1,2
between conformers L/L’ and K/K’, with L being preferred when R = Ph to minimize A interactions
thus leading exclusively to E isomer 16 (Table 1, entry 13), and L and K’, providing mixtures of 15 and
2
1
6 for the sterically less demanding scenario when R = Et (Table 1, entries 11 and 15). It should be
pointed out that for the simple Z propenyl sulfoxide the energy difference between C=C/S=O and, C=C/Sꢀ
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
:
sꢀcis arrangements is very small and therefore both types of conformers could participate in the
24b
process.
The rationalization for the stereochemical outcome of diastereomeric E sulfinyl imidates 4 is not
1
,2
1,3
straightforward since conformer M, presents severe A interactions, and conformer N displays A
diaxial interactions, that appear to be determinant of the reaction course to produce Z sulfinyl amides 13
predominantly, albeit with lower yields and selectivities than diastereomeric substrates 5. Similarly, in
the case of Z sulfinyl imidates (±)ꢀ12, conformer P places the tolyl moiety above the chair and for
conformer O, the tolyl is away from the reactive center but the sulfinyl moiety is in close proximity to the
2
R substituent. Nonetheless, as discussed before for Z substrates (±)ꢀ11, alternative conformers O’, with
1
,2
severe A interactions, and P’, substantially more stable, should be examined and may account for the
predominant obtention of E sulfinyl amides 14 in these cases.
Survey of Reactivity of Amido Alkenyl Sulfoxides. At this point we set out to examine the viability of
intramolecular cyclizations with selected amido alkenyl sulfoxides, as well as the behavior of our sulfinyl
amido dienes in DielsꢀAlder processes. Regarding the possible cyclizations we tested the deprotection of
silyl ether 15e that led to oxazolidinone 27 in excellent yield (Scheme 6). We then explored the
dihydroxylation of amido diene 21g under standard Upjohn conditions that led cleanly to sulfonyl amido
2
5
diol (±)ꢀ28. Subsequent treatment under basic conditions afforded hydroxy oxazolidinone (±)ꢀ29 in
26
good yields. While it is possible that other conditions and/or protectionꢀdeprotection strategies could
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The Journal of Organic Chemistry
produce the desired cyclizations, the concurrent results obtained on the DielsꢀAlder chemistry of our
amido dienes (see below) prompted us to shift our efforts to this field.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Scheme 6. Synthesis of Oxazolidinones (±)-27 and (±)-29
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Et
O
S
Et
O
O
S
p-Tol
TBAF
THF
p-Tol
NHCOCCl3
NH
O
91%
OTBDPS
15e
27
O
O
NHCOCCl3
NHCOCCl3
OH
HN
HO
O
S
OsO
4
3
Me NO
base
SO p-Tol
SO p-Tol
2
2
p-Tol
HO
acetone:H O
solvent
2
rt
5%
Ph
Ph
(±)-28
Ph
8
DBU / toluene 83%
Cs CO / DMF 73%
2
1g
(±)-29
2
3
The diastereoselectivity of DielsꢀAlder cycloadditions of acyclic chiral dienes with a nitrogen substituent
at the allylic position has been studied and while the results are dependent on the diene structure and the
27
nature of the dienophile, it was established that for maleic anhydride, an endo approach syn to the
protected nitrogen functionality on a conformer that eclipses the allylic hydrogen and the diene was
2
7c
operative.
On the other hand, our group has a long standing interest on the development of the Dielsꢀ
Alder chemistry of 2ꢀsulfinyl butadienes to produce adducts that preserve the useful vinyl sulfoxide
moiety and often with high diastereoselectivities that even override the powerful directing effect of an
28,29
allylic oxygen substituent.
Typically, for S sulfinyl dienes as drawn in this paper, simple Z or
S
unsubstituted 2ꢀsulfinyl dienes undergo highly selective DielsꢀAlder processes with maleimides and
maleic anhydride with an endo approach to the bottom face of the diene moiety (αꢀendo), as shown by Xꢀ
29g,h
29i
ray crystallography,
or chemical correlations. In this context, we were intrigued about the viability
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and, particularly, the selectivity of the cycloadditions of our amido sulfinyl dienes, especially for
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
diastereomers (±)ꢀ23, with opposing elements of stereocontrol.
At the early stage of the study we selected E,Z dienes (±)ꢀ23h and (±)ꢀ24h and Nꢀphenylmaleimide
(NPM) as dienophile. To our delight, the cycloadditions took place smoothly in toluene at rt to produce
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
the expected isoindoles (±)ꢀ30h and (±)ꢀ31h respectively as single isomers and in excellent yields (Table
3, entries 1 and 2). Cycloadducts (±)ꢀ30h and (±)ꢀ31h had spectral features, including NOE’s (H3aꢀH4 =
8
% and 6%; H4ꢀH7 = 5% and 7%; H7ꢀH7a = 4% and 5% respectively), compatible with the proposed
structures derived from the known reaction pathway of these dienes discussed above. Encouraged by
1
these results, the generality of the methodology was explored for substrates with different R (nꢀBu, Ph)
3
and R (Ph, Me) groups and the results found were parallel to the first examples with the cycloadditions
taking place under mild conditions in good yields and with complete diastereoselectivities (Table 3,
entries 3ꢀ8).
a
Table 3. Sulfinyl-Directed Diels-Alder Cycloadditions (E,Z-dienes)
β
-endo
α
-endo
Cl COCHN
O
S
3
H
H
O
S
R3
4
3a
p-Tol
O
O
H
Cl COCHN
N
7
H
R1
3
p-Tol
R3
O
7a
Ph
H
R1
N
O
toluene, rt
Ph
(
±)-23h-k
(±)-30h-k
Cl COCHN
O
3
H
H
O
S
S
R3
H
O
p-Tol
O
O
R3
Cl COCHN
N
Ph
H
R1
p-Tol
3
H
R1
N
O
toluene, rt
Ph
(±)-24h-k
(±)-31h-k
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1
3
a
entry
SM
R
R
product
yield %
84%
82%
75%
71%
80%
76%
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
2
3
4
5
6
7
8
(±)ꢀ23h
(±)ꢀ24h
(±)ꢀ23i
(±)ꢀ24i
(±)ꢀ23j
(±)ꢀ24j
(±)ꢀ23k
(±)ꢀ24k
nꢀBu
nꢀBu
nꢀBu
nꢀBu
Ph
Me
Me
Ph
(±)ꢀ30h
(±)ꢀ31h
(±)ꢀ30i
(±)ꢀ31i
(±)ꢀ30j
(±)ꢀ31j
(±)ꢀ30k
(±)ꢀ31k
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Ph
Me
Me
Ph
Ph
b
Ph
73%
b
Ph
Ph
80%
a
b
Reactions were performed in toluene at rt. Reactions performed in toluene at 70 ºC.
To evaluate the stereodirecting importance of each chiral element in these molecules we examined the
cycloaddition of amido sulfonyl diene (±)ꢀ34, prepared by oxidation with MMPP of (±)ꢀ24h, with NPM
30
1
13
that afforded a 66/34 mixture of (±)ꢀ33 and (±)ꢀentꢀ32. The H and C NMR features of these adducts
were compared to those of (±)ꢀ32 and (±)ꢀ33 obtained upon straightforward oxidation of the sulfinyl
adducts with MMPP (Scheme 7). These results indicate that the stereochemical outcome of the Dielsꢀ
Alder cycloaddition of these acyclic E,Z amido sulfinyl dienes is primarily controlled by the chiral
sulfoxide moiety. Indeed, should the amido group have been the main source of stereocontrol of the
cycloaddition, the oxidation of (±)ꢀ30h and (±)ꢀ31h would have afforded products with identical NMR
spectral features.
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Scheme 7. Oxidation and Diels-Alder with E,Z Sulfonyl Diene
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Cl COCHN
3
H
SO p-Tol
2
Me
H
H
MMPP
MeOH
(±)-30h
O
n-Bu
H
N
84%
O
Ph
(
±)-32
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Cl COCHN
3
H
SO p-Tol
2
Me
H
O
H
MMPP
MeOH
(±)-31h
(±)-24h
n-Bu
H
N
82%
O
Ph
(±)-33
Cl COCHN
3
H
SO p-Tol
2
Cl COCHN
3
Me
H
+ O
SO p-Tol
NPM
2
n-Bu
H
MMPP
Me
(±)-33 (66)
toluene
7%
H
MeOH
N
7
8
5%
n-Bu
O
Ph
±)-ent-32 (34)
(±)-34
(
Encouraged by these results that allow for the generation of four stereogenic centers in a single step while
preserving the versatile alkenyl sulfoxide fragment and with an “external” protected amino group,
amenable to serve as a handle for carbonyl differentiation, we decided to examine the behavior of the
related E,E amido sulfinyl dienes 21 and 22 and the results obtained are gathered in table 4. Not
unexpectedly, the cycloaddition of these dienes required harsher conditions (120 ºC, 4ꢀ11 days) and were
not as highꢀyielding as those of the E,Z isomers discussed above. Nevertheless, moderate yields of the
31
desired sulfinyl isoindoles were isolated as single isomers without significant optimization.
The
structures of these adducts were based on the proposed reaction course discussed above and confirmed
with a detailed study of their NMR features including the observed couplings between H7ꢀH7a for
35j/36j, in comparison with diastereomers 30j/31j, as well as, an observed 5% NOE between H4 and an
nꢀBu methylene for 36h.
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The Journal of Organic Chemistry
1
2
3
a
Table 4. Sulfinyl-Directed Diels-Alder Cycloadditions (E,E-dienes)
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
β
-endo
α
-endo
Cl COCHN
O
3
H
S
H
O
S
Me
p-Tol
R1
4
3a
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
O
O
H
Cl COCHN
N
7
3
p-Tol
O
7a
Me
Ph
H
R1
N
O
toluene, 120 ºC
Ph
21h-j
35h-j
Cl COCHN
O
S
3
H
H
O
S
Me
p-Tol
O
O
N
Ph
H
R1
Me
p-Tol
O
Cl COCHN
H
3
N
R1
2h-j
O
toluene, 120 ºC
Ph
2
36h-j
1
a
entry
SM
21h
22h
21j
22j
R
product
yield %
52%
1
2
3
4
nꢀBu
nꢀBu
Ph
35h
36h
35j
36j
55%
49%
Ph
62%
a
Reactions were performed in toluene at 120 ºC.
Parallel to the E,Z isomers, we examined the oxidation of dienyl sulfoxide 22h that gave dienyl sulfone
37 in moderate yield (Scheme 8). The cycloaddition between 37 and NPM produced a 75/25 mixture of
diastereomeric sulfonyl isoindoles 38 and ent-39. The NMR features of these adducts were compared to
those of 38 and 39 obtained by oxidation of the sulfinyl adducts 35h and 36h with MMPP (Scheme 8).
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These results suggest that for these E,E sulfinyl dienes, the chiral sulfur is the main element of
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
stereocontrol in the DielsꢀAlder processes examined.
Scheme 8. Oxidation and Diels-Alder with E,E Sulfonyl Diene
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Cl COCHN
3
H
SO p-Tol
2
Me
O
MMPP
MeOH
H
35h
n-Bu
H
83%
N
O
Ph
39
Cl COCHN
3
H
SO p-Tol
2
Me
H
O
MMPP
MeOH
n-Bu
36h
H
N
93%
O
Ph
38
Cl COCHN
3
MMPP
SO p-Tol
2
Me
NPM
2
2h
MeOH
38 (75) + ent-39 (25)
toluene, 7 d
20 ºC
7%
62%
n-Bu
1
3
37
CONCLUSIONS
In summary, the thermal Overman rearrangement of simple allylic sulfinyl trichloroacetimidates takes
place with high yields and selectivities in most cases. For bisꢀallylic substrates, the rearrangement is
completely chemoselective involving just the alkene that does not bear the sulfinyl moiety and producing
amido 2ꢀsulfinyl butadienes as single isomers and in good to excellent yields. Subsequent highly
diastereoselective DielsꢀAlder cycloadditions, with facial control by the sulfinyl chiral center, lead to
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The Journal of Organic Chemistry
densely functionalized sulfinyl isoindoles. Further applications of these methodologies are being
explored in our laboratories.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
EXPERIMENTAL SECTION
Materials and methods. Reagents and solvents were handled using standard syringe techniques. All
reactions were carried out under an argon atmosphere. Diisopropylamine (iꢀPr NH) was purified by
2
distillation from CaH . Aldehydes were purified by distillation and stored over Na SO . Anhydrous
2
2
4
solvents were purified by filtration on a solvent purification system (SPS). Crude products were purified
by flash chromatography on 230ꢀ400 mesh silica gel with distilled solvents. Analytical TLC was carried
out on silica gel plates with detection by UV light or 10% phosphomolybdic acid solution in ethanol. All
reagents were commercial products. Through this section, the volume of solvents is reported in mL/mmol
1
13
1
of starting material. H and C NMR spectra were recorded at 300, 400 or 500 MHz ( H) and with the
residual solvent signal as internal reference (CDCl , 7.26 and 77.0 ppm) unless otherwise noted. Optical
3
rotations were measured at 20 ºC using a sodium lamp. High resolution mass spectra (HRMS) were
recorded using Accurate Mass QꢀTOF spectrometer. Vinyl sulfoxides 1 were prepared as E/Z mixtures
that completely isomerized to the E isomer upon lithiation. Compounds 1a,b, 2f-i, 3f-i, 4a-d, 4f,g, 5a-d,
5
f,g, 8h, (±)-9h, (±)-10h, (±)-11b, (±)-12b, 13a-d, 14a,b, 15a-d, 16a, 18, 19, 20, 21f-i, 22h,i, (±)-23h,
(±)-24h, 25, 26, 28, 29, (±)-30h, (±)-31h, (±)-32, (±)-33, (±)-34 were described in the Supporting
14
Information of our preliminary communication.
General procedure for the synthesis of (E)-hydroxy vinyl sulfoxides. To a cold (–78 ºC) solution of
freshly distilled iꢀPr NH (2.6 equiv) in anhydrous THF (3.5 mL/mmol) was added 1.6 M nꢀBuLi (2.5
2
equiv) and the resulting LDA solution was stirred at the same temperature. After 10 min, a solution of a
Z/E mixture of vinyl sulfoxides (1 equiv) in anhydrous THF (2 mL/mmol) was added dropwise slowly to
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produce a pale yellow solution. After stirring for an additional 10 min at –78 ºC, freshly distilled aldehyde
3.0 equiv) was added dropwise and the resulting colorless solution was stirred at this temperature for 10
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
min. The reaction mixture was quenched with a saturated solution of NH Cl and the aqueous layer was
4
extracted with EtOAc. The combined organic layers were washed with brine, dried (Na SO ) and
2
4
concentrated in vacuo. The crude product was purified by column chromatography on silica gel with the
appropriate mixture of solvents to afford (E)ꢀhydroxy vinyl sulfoxides 2 and 3.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Synthesis of (+)-(3R,4E,S )-6-(tert-Butyldiphenylsilyloxy)-4-(p-tolylsulfinyl)hex-4-en-3-ol, 2e, and
S
3
2
(
+)-(3S,4E,S )-6-(tert-Butyldiphenylsilyloxy)-4-(p-tolylsulfinyl)hex-4-en-3-ol, 3e. From E/Z-1c (640
S
mg, 1.47 mmol) in THF (3.0 mL), LDA, and propionaldehyde (256 mg, 4.42 mmol) following the general
procedure, a 39:61 mixture of 2e and 3e was obtained. Chromatographic purification (10ꢀ30% EtOAcꢀ
hexane) gave 2e (229 mg, 32%) and 3e (358 mg, 49%) as yellow oils. Data for 2e: R 0.30 (30% EtOAcꢀ
f
2
0
1
hexane). [α] +2.70 (c 1.16, CHCl ). H NMR (400 MHz, CDCl ) δ 0.73 (t, 3 H, J = 7.4 Hz), 1.06 (s, 9
D
3
3
H), 1.28ꢀ1.38 (m, 1 H), 1.48ꢀ1.59 (m, 1 H), 2.16 (d, 1 H, J = 5.3 Hz), 2.41 (s, 3 H), 4.09 (dt, 1 H, J = 8.7,
5.3 Hz), 4.47 (d, 2 H, J = 5.6 Hz), 6.60 (t, 1 H, J = 5.6 Hz), 7.26ꢀ7.28 (m, 2 H), 7.35ꢀ7.47 (m, 6 H), 7.50
13
(
d, 2 H, J = 8.2 Hz), 7.64ꢀ7.67 (m, 4 H). C NMR (100 MHz, CDCl ) δ 10.5, 19.3, 21.7, 26.9 (3 C),
3
3
1
1
0.2, 60.9, 70.7, 125.5 (2 C), 128.1 (4 C), 130.1 (2 C), 130.2 (2 C), 132.9, 133.0, 134.5, 135.80 (2 C),
35.83 (2 C), 140.8, 141.8, 147.3. IR (film): 3400, 3071, 3050, 2962, 2931, 2857, 1636, 1590, 1492,
–1
472, 1463, 1428, 1391, 1374, 1304, 1260, 1179, 1112, 1081, 1029, 1013, 823, 809, 740, 703, 614 cm .
+
HRMS (ES) m/z Calcd for C H O SSi [M+H] 493.2227, found 493.2210. Data for 3e: R 0.20 (30%
2
9
37
3
f
20
1
EtOAcꢀhexane). [α] +31.4 (c 3.67, CHCl ). H NMR (400 MHz, CDCl ) δ 0.70 (t, 3 H, J = 7.4 Hz),
D
3
3
1
4
7
.06 (s, 9 H), 1.09ꢀ1.14 (m, 1 H), 1.32ꢀ1.43 (m, 1 H), 2.40 (s, 3 H), 2.88 (s, 1 H), 4.02 (dd, 1 H, J = 8.8,
.6 Hz), 4.45 (dd, 1 H, J = 14.9, 6.0 Hz), 4.57 (dd, 1 H, J = 14.9, 5.0 Hz), 6.51 (dd, 1 H, J = 5.9, 5.0 Hz),
13
.28 (d, 2 H, J = 8.0 Hz), 7.37ꢀ7.47 (m, 6 H), 7.49 (d, 2 H, J = 8.2 Hz), 7.66ꢀ7.68 (m, 4 H). C NMR
(100 MHz, CDCl ) δ 10.3, 19.1, 21.4, 26.7 (3 C), 30.0, 60.9, 69.8, 125.6 (2 C), 127.81 (2 C), 127.82 (2
3
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The Journal of Organic Chemistry
C), 129.86 (2 C), 129.9 (2 C), 132.7, 132.8, 133.4, 135.5 (2 C), 135.6 (2 C), 139.6, 141.8, 147.3. IR
film): 3368, 3072, 3051, 2962, 2931, 2857, 1590, 1492, 1472, 1463, 1428, 1373, 1265, 1112, 1082,
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
–1
+
1014, 823, 810, 739, 703, 614 cm . HRMS (ES) m/z Calcd for C H O SSi [M+H] 493.2227, found
29
37
3
4
93.2229.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Synthesis of (+)-(3R,1E,4E,S )-1-Phenyl-2-(p-tolylsulfinyl)hexa-1,4-dien-3-ol, 2j, and (–)-
S
33
(3S,1E,4E,S )-1-Phenyl-2-(p-tolylsulfinyl)hexa-1,4-dien-3-ol, 3j. From E/Z-1b (540 mg, 2.23 mmol)
S
in THF (7.8 mL), LDA, and crotonaldehyde (0.55 mL, 6.69 mmol), following the general procedure, a
2
4:76 mixture of 2j and 3j was obtained. Chromatographic purification (10ꢀ50% Et OꢀCH Cl ) gave 2j
2 2 2
2
0
(
140 mg, 20%) and 3j (432 mg, 62%) as yellow oils. Data for 2j: R 0.20 (30% EtOAcꢀhexane). [α]
f
D
1
+
133.1 (c 2.00, CHCl ). H NMR (400 MHz, CDCl ) δ 1.60 (dt, 3 H, J = 6.1, 1.0 Hz), 2.40 (s, 3 H), 3.11
3
3
(d, 1 H, J = 5.5 Hz), 5.28 (t, 1 H, J = 5.1 Hz), 5.52ꢀ5.67 (m, 2 H), 7.28 (d, 2 H, J = 8.5 Hz), 7.34ꢀ7.51 (m,
13
6
H), 7.62 (d, 2 H, J = 8.2 Hz). C NMR (100 MHz, CDCl ) δ 17.4, 21.3, 69.4, 125.8 (2 C), 128.2, 128.4
3
(2 C), 128.6, 129.5 (2 C), 129.61 (2 C), 129.63, 132.7, 133.7, 140.8, 141.5, 145.8. IR (film): 3337, 3051,
–
1
3027, 2917, 2855, 1668, 1627, 1596, 1492, 1447, 1399, 1378, 1265, 1081, 1028, 809, 736, 700, 625 cm .
+
HRMS (ES) m/z Calcd for C H OS [M+H–(H O)] 295.1151, found 295.1169. Data for 3j: R 0.15
1
9
19
2
f
2
0
1
(30% EtOAcꢀhexane). [α] –20.4 (c 1.94, CHCl ). H NMR (400 MHz, CDCl ) δ 1.38 (dt, 3 H, J =
D
3
3
6
.6, 1.5 Hz), 2.40 (s, 3 H), 4.37 (d, 1 H, J = 3.9 Hz), 5.08ꢀ5.14 (m, 1 H), 5.33ꢀ5.41 (m, 2 H), 7.26 (d, 2 H,
1
3
J = 8.4 Hz), 7.33ꢀ7.48 (m, 6 H), 7.62 (d, 2 H, J = 8.2 Hz). C NMR (100 MHz, CDCl ) δ 17.3, 21.2,
3
68.8, 126.3 (2 C), 127.8, 128.2 (2 C), 128.4, 129.2, 129.4 (2 C), 129.7 (2 C), 131.1, 133.8, 140.0, 141.5,
1
46.8. IR (film): 3338, 3052, 2981, 2938, 2855, 1623, 1596, 1576, 1492, 1448, 1265, 1124, 1082, 1028,
–
1
+
1
013, 966, 810, 737, 702, 626 cm . HRMS (ES) m/z Calcd for C H OS [M+H–(H O)] 295.1151,
19 19 2
found 295.1171.
Synthesis of (+)-(3R,1E,4E,S )-1,5-Diphenyl-2-(p-tolylsulfinyl)penta-1,4-dien-3-ol, 2k, and (–)-
S
33
(3S,1E,4E,S )-1,5-Diphenyl-2-(p-tolylsulfinyl)penta-1,4-dien-3-ol, 3k. From E/Z-1b (412 mg, 1.70
S
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mmol) in THF (13.0 mL), LDA, and cinnamaldehyde (0.60 mL, 5.10 mmol), following the general
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
procedure, a 43:57 mixture of 2k and 3k was obtained. Chromatographic purification (10ꢀ50% Et Oꢀ
2
CH Cl ) gave 2k (254 mg, 40%) as a colorless oil and 3k (318 mg, 50%) as a white solid. Data for 2k: R
f
2
2
20
1
0
.35 (20% Et OꢀCH Cl ). [α] +89.4 (c 2.10, CHCl ). H NMR, COSY (400 MHz, CDCl ) δ 2.31 (s, 3
2
2
2
D
3
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
H, CH pꢀTol), 3.34 (d, 1 H, J = 6.8 Hz, OH), 5.52 (ddd, 1 H, J = 8.8, 5.1, 1.8 Hz, Hꢀ3), 6.06 (dd, 1 H, J =
3
1
5.9, 5.0 Hz, Hꢀ4), 6.44 (dd, 1 H, J = 15.9, 1.7 Hz, Hꢀ5), 7.10ꢀ7.12 (m, 2 H, Ar), 7.20ꢀ7.26 (m, 5 H, Ar),
1
3
7
.35ꢀ7.41 (m, 3 H, Ar), 7.47ꢀ7.49 (m, 2 H, Ar), 7.55ꢀ7.58 (m, 3 H, Hꢀ1 and Ar). C NMR, HSQC (100
MHz, CDCl ) δ 21.3 (CH pꢀTol), 70.3 (Cꢀ3), 125.7 (2 C), 126.5 (2 C), 127.7, 128.2, 128.3 (2 C), 128.7
3
3
(2 C), 129.1, 129.6 (2 C), 129.9 (2 C), 131.0, 133.6, 134.6, 136.1, 140.1, 141.8, 144.9. IR (film): 3339,
3081, 3057, 3026, 2979, 2922, 2867, 1626, 1597, 1577, 1493, 1448, 1399, 1304, 1266, 1207, 1180, 1157,
–
1
+
1
081, 1028, 967, 809, 751, 737, 695 cm . HRMS (ES) m/z Calcd for C H O S [M+H] 375.1419,
24 23 2
2
0
found 375.1393. Data for 3k: R 0.20 (20% Et OꢀCH Cl ). [α] –50.4 (c 1.50, CHCl ). mp 117ꢀ120
f
2
2
2
D
3
1
ºC. H NMR, COSY (400 MHz, CDCl ) δ 2.25 (s, 3 H, CH pꢀTol), 3.90 (d, 1 H, J = 4.4 Hz, OH), 5.56
3
3
(td, 1 H, J = 5.4, 1.1 Hz, Hꢀ3), 5.70 (dd, 1 H, J = 15.9, 5.3 Hz, Hꢀ4), 6.25 (dd, 1 H, J = 15.9, 1.6 Hz, Hꢀ5),
6.97ꢀ6.99 (m, 2 H, Ar), 7.17ꢀ7.21 (m, 5 H, Ar), 7.33ꢀ7.38 (m, 3 H, Ar), 7.41 (s, 1 H, Hꢀ1), 7.44ꢀ7.47 (m, 2
13
H, Ar), 7.60 (m, 2 H, J = 8.2 Hz, pꢀTol). C NMR, HSQC (100 MHz, CDCl ) δ 21.3 (CH pꢀTol), 69.0
3
3
(Cꢀ3), 126.40 (2 C), 126.43 (2 C), 127.6, 127.9, 128.2 (2 C), 128.5 (2 C), 128.7, 129.7 (2 C), 129.8 (2 C),
1
1
31.0, 132.0, 133.8, 136.2, 139.9, 142.2, 146.8. IR (KBr): 3338, 3081, 3056, 3025, 2921, 1634, 1597,
–
1
577, 1493, 1447, 1400, 1304, 1082, 1027, 1012, 968, 808, 753, 694 cm . HRMS (ES) m/z Calcd for
+
C H O S [M+H] 375.1419, found 375.1396.
24
23
2
General procedure for the synthesis of (Z)-hydroxy vinyl sulfides. To a cold solution (–78 ºC) of the
vinyl stannane or sulfide in anhydrous THF (5.0 mL/mmol) was added a solution 1.6 M of nꢀBuLi (1.2ꢀ
2
.0 equiv) and was stirred at this temperature. After 10 min freshly distilled aldehyde (2.0ꢀ3.0 equiv) was
added dropwise and the resulting solution was stirred at this temperature for 10 min. The reaction mixture
was quenched with a saturated solution of NH Cl and the aqueous layer was extracted with EtOAc. The
4
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combined organic extracts were washed with a saturated solution of NaCl, dried (MgSO ) and
4
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
concentrated under reduced pressure to give a crude product that was purified by column chromatography
using the appropriate mixture of solvents.
34
Synthesis of (±)-(2Z)-1,3-Diphenyl-2-(p-tolylsulfenyl)prop-2-en-1-ol, (±)-8d. From 6 (337 mg, 1.49
mmol), nꢀBuLi (1.86 mL, 2.98 mmol) and benzaldehyde (0.46 mL, 4.47 mmol) in THF, following the
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
general procedure and after chromatographic purification (10ꢀ30% EtOAcꢀhexane), (±)ꢀ8d (379 mg,
1
7
7%) was obtained as a yellow oil. Data for (±)ꢀ8d: R 0.30 (30% EtOAcꢀhexane). H NMR (400 MHz,
f
CDCl ) δ 2.17 (d, 1 H, J = 0.2 Hz), 2.31 (s, 3 H), 5.26 (s, 1 H), 7.06 (dd, 2 H, J = 8.6, 0.8 Hz), 7.19 (d, 2
3
13
H, J = 8.2 Hz), 7.18ꢀ7.38 (m, 9 H, Hꢀ3), 7.63ꢀ7.65 (m, 2 H). C NMR (100 MHz, CDCl ) δ 21.0, 76.4,
3
125.9, 126.9 (2 C), 127.9, 127.98, 128.0 (2 C), 128.4 (2 C), 129.6 (2 C), 129.9 (2 C), 130.1 (2 C), 130.4,
–
1
1
33.8, 135.6, 136.5, 136.8. IR (film): 3406, 3055, 2987, 1492, 1422, 1266, 896, 749, 705 cm . HRMS
+
(
ES) m/z Calcd for C H NaOS [M+Na] 355.1127, found 355.1122.
2
2
20
1
9
Synthesis of (±)-(3R,1E,4Z)-1-Phenyl-4-(p-tolylsulfenyl)nona-1,4-dien-3-ol, (±)-8i. From 7 (347 mg,
.70 mmol), nꢀBuLi (0.53 mL, 0.84 mmol) and cinnamaldehyde (0.26 mL, 2.10 mmol) in THF, following
0
the general procedure and after chromatographic purification (10ꢀ30% EtOAcꢀhexane), (±)ꢀ8i (206 mg,
1
87%) was obtained as a yellow oil. Data for (±)ꢀ8i: R 0.40 (30% EtOAcꢀhexane). H NMR (400 MHz,
f
CDCl ) δ 0.89 (t, 3 H, J = 7.2 Hz), 1.29ꢀ1.44 (m, 4 H), 2.30 (s, 3 H), 2.35ꢀ2.41 (m, 2 H), 4.76 (d, 1 H, J =
3
6
7
7
.0 Hz), 6.19 (dd, 1 H, J = 15.9, 6.0 Hz), δ 6.35 (td, 1 H, J = 7.2, 0.8 Hz), 6.55 (dd, 1 H, J = 15.9, 1.3 Hz),
1
3
.07 (d, 2 H, J = 8.0 Hz), 7.20ꢀ7.30 (m, 7 H). C NMR (100 MHz, CDCl ) δ 13.9, 21.0, 22.4, 29.5, 31.1,
3
5.6, 126.6 (2 C), 127.6, 128.5 (2 C), 129.0 (2 C), 129.8 (2 C), 129.9, 130.0, 131.7, 134.9, 136.1, 136.6,
139.4. IR (film): 3435, 3054, 2959, 2928, 2859, 1723, 1635, 1600, 1449, 1492, 1422, 1379, 1399, 1265,
–1
–
1
085, 1018, 968, 896, 808, 739, 704 cm . HRMS (ES) m/z Calcd for C H OS [M–H] 337.1632, found
22 25
3
37.1621.
3
4
Synthesis of (±)-(1Z,4E)-1-Phenyl-2-(p-tolylsulfenyl)hexa-1,4-dien-3-ol, (±)-8j. From 6 (585 mg,
2
.59 mmol), nꢀBuLi (1.94 mL, 3.10 mmol) and crotonaldehyde (0.64 mL, 7.75 mmol) in THF, following
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the general procedure and after chromatographic purification (10ꢀ30% Et Oꢀhexane), (±)ꢀ8j (314 mg,
2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
4
1%) was obtained as a yellow oil. Data for (±)ꢀ8j: R 0.30 (20% Et Oꢀhexane). H NMR (500 MHz,
f
2
CDCl ) δ 1.71 (d, 3 H, J = 6.5 Hz), 2.08 (br s, 1 H), 2.30 (s, 3 H), 4.62 (br d, 1 H, J = 6.3 Hz), 5.58 (ddd,
3
1
6
1
3
H, J = 15.3, 6.5, 1.5 Hz), 5.70 (dqd, 1 H, J = 15.2, 6.5, 1.0 Hz), 7.06 (d, 2 H, J = 7.9 Hz), 7.22ꢀ7.33 (m,
1
3
H), 7.64 (d, 2 H, J = 7.9 Hz). C NMR (125 MHz, CDCl ) δ 17.8, 21.0, 75.4, 127.8, 128.0 (2 C),
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
28.6, 129.5 (2 C), 129.8 (2 C), 129.9 (2 C), 130.7, 131.6, 133.5, 135.8, 136.3, 136.6. IR (film): 3430,
–1
055, 2987, 2686, 2306, 1645, 1606, 1552, 1422, 1266, 896, 748, 705 cm . HRMS (ES) m/z Calcd for
+
C H NaOS [M+Na] 319.1127, found 319.1123.
19
20
3
4
Synthesis of (±)-(1Z,4E)-1,5-Diphenyl-2-(p-tolylsulfenyl)penta-1,4-dien-3-ol, (±)-8k. From 6 (349
mg, 1.54 mmol), nꢀBuLi (1.16 mL, 1.85 mmol), and cinnamaldehyde (0.39 mL, 3.08 mmol) in THF,
following the general procedure and after chromatographic purification (5ꢀ10% EtOAcꢀhexane), (±)ꢀ8k
1
(
397 mg, 72%) was obtained as a yellow oil. Data for (±)ꢀ8k: R 0.15 (10% EtOAcꢀhexane). H NMR
f
(
500 MHz, CDCl ) δ 2.31 (s, 3 H), 4.88 (d, 1 H, J = 6.3 Hz), 6.27 (dd, 1 H, J = 15.9, 6.4 Hz), 6.59 (d, 1
3
13
H, J = 15.9 Hz), 7.08 (d, 2 H, J = 8.0 Hz), 7.25ꢀ7.36 (m, 11 H), 7.69 (d, 2 H, J = 7.6 Hz). C NMR (125
MHz, CDCl ) δ 21.0, 75.6, 126.6 (2 C), 127.7, 128.0, 128.1 (2 C), 128.5 (2 C), 129.6 (2 C), 129.8, 129.9
3
(2 C), 130.1 (2 C), 130.6, 131.4, 134.1, 135.6, 135.9, 136.5, 136.8. IR (film): 3393, 3057, 3024, 2922,
–
1
2
856, 1598, 1492, 1446, 1399, 1084, 1068, 1030, 1017, 965, 807, 753, 692 cm . HRMS (ES) m/z Calcd
+
for C H S [M+H–(H O)] 341.1359, found 341.1362.
2
4
21
2
General procedure for the synthesis of (Z)-hydroxy vinyl sulfoxides by oxidation. To a cold solution
–78 ºC) of the starting material (1.0 equiv) in acetone (8.0 mL/mmol) was added mꢀCPBA (2.0 equiv,
7% w/w) and K CO (3.0 equiv). The solution was stirred at this temperature for 10 min and then
(
7
2
3
allowed to warm up slowly while monitored by TLC. The reaction mixture was quenched with a 1.0 M
aqueous solution of Na S O , a saturated solution of NaHCO and H O. The aqueous layer was extracted
2
2
4
3
2
with EtOAc and the combined organic extracts were washed with a saturated aqueous solution of NaCl,
dried (Na SO ) and concentrated under reduced pressure. The crude product was purified by column
2
4
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chromatography using the appropriate mixture of solvents.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Synthesis of (±)-(1R,2Z,S )-1,3-Diphenyl-2-(p-tolylsulfinyl)prop-2-en-1-ol, (±)-9d, and (1S,2Z,S )-
S
S
1,3-Diphenyl-2-(p-tolylsulfinyl)prop-2-en-1-ol, (±)-10d. From (±)ꢀ8d (195 mg, 0.59 mmol), mꢀCPBA
(
263 mg, 1.17 mmol) and K CO (243 mg, 1.76 mmol) in acetone, according to the general procedure, a
2 3
1
9:81 mixture of (±)ꢀ9d and (±)ꢀ10d was obtained. Chromatographic purification (1ꢀ10% Et OꢀCH Cl )
2 2 2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
gave (±)ꢀ9d (30 mg, 15%) as a yellow oil and (±)ꢀ10d (130 mg, 64%) as a white solid. Data for (±)ꢀ9d: Rf
1
0
.30 (5% Et OꢀCH Cl ). H NMR (400 MHz, CDCl ) δ 2.38 (s, 3 H), 3.05 (d, 1 H, J = 4.5 Hz), 5.91 (d, 1
2
2
2
3
1
3
H, J = 4.5 Hz), 6.93 (s, 1 H), 7.22ꢀ7.45 (m, 14 H). C NMR (100 MHz, CDCl ) δ 21.3, 71.1, 124.9 (2
3
C), 126.5 (2 C), 127.5, 128.3 (2 C), 128.5 (2 C), 129.0, 129.3 (2 C), 129.6 (2 C), 133.6, 138.8, 139.8,
141.1, 147.5. IR (film): 3369, 3059, 3030, 2923, 1623, 1597, 1493, 1448, 1401, 1312, 1302, 1266, 1184,
–1
1
144, 1084, 1029, 1012, 926, 895, 811, 752, 736, 557 cm . HRMS (ES) m/z Calcd for C H O S
22 21 2
+
1
[
M+H] 349.1257, found 349.1264. Data for (±)ꢀ10d: R 0.30 (10% Et OꢀCH Cl ). mp 153ꢀ155 ºC. H
f 2 2 2
NMR (400 MHz, CDCl ) δ 2.46 (s, 3 H), 4.41 (s, 1 H), 5.69 (s, 1 H), 6.73 (s, 1 H), 7.15 (d, 2 H, J = 6.5
3
13
Hz), 7.44ꢀ7.50 (m, 10 H), 7.51 (d, 2 H, J = 8.3 Hz). C NMR (100 MHz, CDCl ) δ 21.4, 71.3, 124.5 (2
3
C), 126.5 (2 C), 127.6, 128.2 (2 C), 128.5 (2 C), 129.1, 129.6 (2 C), 130.1 (2 C), 133.4, 138.6, 138.8,
1
1
3
39.6, 141.3, 147.2. IR (KBr): 3414, 3059, 2965, 2926, 1642, 1492, 1448, 1397, 1324, 1269, 1180, 1079,
–
1
+
039, 1013, 927, 808, 752, 715, 697 cm . HRMS (ES) m/z Calcd for C H OS [M+H–(H O)]
22 19
2
31.1151, found 331.1171.
Synthesis
of
(±)-(1E,3R,4Z,S )-1-Phenyl-4-(p-tolylsulfinyl)nona-1,4-dien-3-ol,
(±)-9i,
and
S
(1E,3S,4Z,S )-1-Phenyl-4-(p-tolylsulfinyl)nona-1,4-dien-3-ol, (±)-10i. From (±)ꢀ8i (103 mg, 0.304
S
mmol), mꢀCPBA (136 mg, 0.609 mmol) and K CO (126 mg, 0.913 mmol) in acetone, according to the
2
3
general procedure, a 33:67 mixture of (±)ꢀ9i and (±)ꢀ10i was obtained. Chromatographic purification (5ꢀ
20% EtOAcꢀhexane) gave (±)ꢀ9i (35 mg, 32%) and (±)ꢀ10i (70 mg, 65%) as yellow oils. Data for (±)ꢀ9i:
1
R 0.30 (20% EtOAcꢀhexane). H NMR (400 MHz, CDCl ) δ 0.94 (t, 3 H, J = 7.1 Hz), 1.35ꢀ1.55 (m, 4
f
3
H), 2.32ꢀ2.41 (m, 1 H), 2.35 (s, 3 H), 2.60ꢀ2.69 (m, 1 H), 5.24 (d, 1 H, J = 5.4 Hz), 6.04 (dd, 1 H, J =
2
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1
5.9, 5.4 Hz), 6.30 (dd, 1 H, J = 8.8, 6.6 Hz), 6.59 (dd, 1 H, J = 15.9, 1.4 Hz), 7.18ꢀ7.27 (m, 7 H), 7.53 (d,
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
3
2
H, J = 8.3 Hz). C NMR (100 MHz, CDCl ) δ 14.1, 21.5, 22.6, 29.1, 31.3, 72.6, 125.0 (2 C), 126.8 (2
3
C), 127.8, 128.6 (2 C), 130.0, 130.2 (2 C), 130.3, 136.7, 139.8, 141.2, 141.3, 144.0. IR (film): 3378,
3
1
3
=
058, 3026, 2957, 2927, 2859, 1636, 1598, 1476, 1493, 1448, 1430, 1396, 1380, 1290, 1253, 1135, 1080,
–1
+
024, 1011, 971, 808, 755, 693 cm . HRMS (ES) m/z Calcd for C H NaO S [M+Na] 377.1546, found
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
22 26
2
1
77.1534. Data for (±)ꢀ10i: R 0.20 (20% EtOAcꢀhexane). H NMR (400 MHz, CDCl ) δ 0.95 (t, 3 H, J
f
3
7.2 Hz), 1.38ꢀ1.56 (m, 4 H), 2.40 (s, 3 H), 2.44ꢀ2.53 (m, 1 H), 2.69ꢀ2.79 (m, 1 H), 5.09 (d, 1 H, J = 5.6
Hz), 5.92 (dd, 1 H, J = 15.9, 5.6 Hz), 6.36 (dd, 1 H, J = 8.8, 6.8 Hz), 6.48 (dd, 1 H, J = 15.9, 1.5 Hz),
1
3
7
.20ꢀ7.34 (m, 7 H), 7.50 (d, 2 H, J = 8.3 Hz). C NMR (100 MHz, CDCl ) δ 13.8, 21.3, 22.3, 28.7, 31.2,
3
6
8.5, 124.2 (2 C), 126.4 (2 C), 127.6, 128.1, 128.4 (2 C), 130.0 (2 C), 130.9, 136.4, 138.4, 140.6, 141.3,
144.8. IR (film): 3417, 3055, 2987, 2962, 2931, 2874, 2861, 1637, 1599, 1493, 1422, 1266, 1099, 1081,
–1
+
1
012, 1013, 896, 809, 741, 705 cm . HRMS (ES) m/z Calcd for C H NaO S [M+Na] 377.1546, found
22 26 2
3
77.1547.
Synthesis of (±)-(1Z,3R,4E,S )-1-Phenyl-2-(p-tolylsulfinyl)hexa-1,4-dien-3-ol, (±)-9j, and (±)-
S
(1Z,3S,4E,S )-1-Phenyl-2-(p-tolylsulfinyl)hexa-1,4-dien-3-ol, (±)-10j. From (±)ꢀ8j (283 mg, 0.96
S
mmol), mꢀCPBA (428 mg, 1.91 mmol) and K CO (396 mg, 2.87 mmol) in acetone, according to the
2
3
general procedure, a 32:68 mixture of (±)ꢀ9j and (±)ꢀ10j was obtained. Chromatographic purification (30ꢀ
4
0% Et Oꢀhexane) gave (±)ꢀ9j (70 mg, 24%) and (±)ꢀ10j (146 mg, 49%) as yellow oils. Data for (±)ꢀ9j:
2
1
R 0.30 (40% Et Oꢀhexane). H NMR (400 MHz, CDCl ) δ 1.68 (ddd, 3 H, J = 6.5, 1.6, 1.2 Hz), 2.39 (s,
f
2
3
3
1
H), 2.99 (br s, 1 H), 5.16 (t, 1 H, J = 5.5 Hz), 5.58 (ddq, 1 H, J = 15.3, 5.5, 1.6 Hz), 5.80 (dqd, 1 H, J =
1
3
5.3, 6.5, 1.2 Hz), 7.25ꢀ7.27 (m, 3 H), 7.36ꢀ7.47 (m, 7 H). C NMR (100 MHz, CDCl ) δ 17.6, 21.3,
3
70.7, 124.9 (2 C), 127.7, 128.5 (2 C), 128.9, 129.6 (2 C), 129.8 (2 C), 131.3, 133.7, 137.4, 139.8, 140.9,
1
1
46.0. IR (film): 3368, 3053, 3026, 2963, 2917, 2856, 1622, 1596, 1576, 1492, 1446, 1266, 1210, 1119,
–1
080, 1027, 1012, 971, 926, 809, 753, 735, 697, 638 cm . HRMS (ES) m/z Calcd for C H NaO S
19
20
2
+
1
[M+Na] 335.1076, found 335.1075. Data for (±)ꢀ10j: R 0.20 (40% Et Oꢀhexane). H NMR (400 MHz,
f
2
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Page 29 of 58
The Journal of Organic Chemistry
CDCl ) δ 1.65 (d, 3 H, J = 6.5 Hz), 2.41 (s, 3 H), 4.09 (br s, 1 H), 5.04 (d, 1 H, J = 6.0 Hz), 5.42 (dd, 1 H,
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
3
J = 15.1, 6.0 Hz), 5.61 (dq, 1 H, J = 15.1, 6.5 Hz), 7.29ꢀ7.53 (m, 10 H). C NMR (100 MHz, CDCl ) δ
3
17.6, 21.3, 69.1, 124.6 (2 C), 128.2, 128.5 (2 C), 129.0, 129.6 (2 C), 129.7, 129.9 (2 C), 133.6, 137.5,
1
38.4, 141.1, 145.9. IR (film): 3293, 3024, 2917, 1618, 1595, 1491, 1449, 1299, 1175, 1121, 1072, 1022,
–1
9
74, 946, 928, 905, 876, 834, 801, 750, 693, 623 cm . HRMS (ES) m/z Calcd for C H NaO S
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
19 20
2
+
[
M+Na] 335.1076, found 335.1081.
Synthesis of (±)-(1Z,3R,4E,S )-1,5-Diphenyl-2-(p-tolylsulfinyl)penta-1,4-dien-3-ol, (±)-9k, and (±)-
S
(1Z,3S,4E,S )-1,5-Diphenyl-2-(p-tolylsulfinyl)penta-1,4-dien-3-ol, (±)-10k. From (±)ꢀ8k (397 mg, 1.11
S
mmol), mꢀCPBA (497 mg, 2.22 mmol) and K CO (459 mg, 3.33 mmol) in acetone, according to the
2
3
general procedure, a 36:64 mixture of (±)ꢀ9k and (±)ꢀ10k was obtained. Chromatographic purification
(40ꢀ60% Et Oꢀhexane) gave (±)ꢀ9k (100 mg, 24%) as a yellow oil and (±)ꢀ10k (175 mg, 42%) as a white
2
1
solid. Data for (±)ꢀ9k: R 0.40 (50% Et Oꢀhexane). H NMR (300 MHz, CDCl ) δ 2.34 (s, 3 H), 3.30 (d,
f
2
3
1
H, J = 5.3 Hz), 5.39 (app t, 1 H, J = 5.3 Hz), 6.20 (dd, 1 H, J = 15.9, 5.3 Hz), 6.68 (dd, 1 H, J = 15.9,
1
3
1.6 Hz), 7.22ꢀ7.51 (m, 15 H). C NMR (100 MHz, CDCl ) δ 21.3, 72.2, 124.8 (2 C), 126.6 (2 C), 127.6,
3
1
1
8
28.4 (2 C), 128.6 (2 C), 129.2, 129.8 (2 C), 130.0 (2 C), 130.3, 133.6, 136.4, 138.3, 139.5, 141.1,
45.20, 145.21. IR (film): 3370, 3054, 2985, 2926, 1599, 1492, 1447, 1421, 1265, 1030, 1013, 971, 896,
–1
+
10, 750, 702 cm . HRMS (ES) m/z Calcd for C H NaO S [M+Na] 397.1233, found 397.1230. Data
2
4
22
2
1
for (±)ꢀ10k: R 0.30 (50% Et Oꢀhexane). mp 120ꢀ122 ºC. H NMR (300 MHz, CDCl ) δ 2.39 (s, 3 H),
f
2
3
4.08 (app d, 1 H, J = 2.1 Hz), 5.27 (td, 1 H, J = 5.6, 2.1 Hz), 6.03 (dd, 1 H, J = 15.9, 5.6 Hz), 6.56 (dd, 1
1
3
H, J = 15.9, 1.6 Hz), 7.23ꢀ7.53 (m, 15 H). C NMR (100 MHz, CDCl ) δ 21.3, 68.7, 124.5 (2 C), 126.4
3
(2 C), 127.6, 128.2, 128.4 (2 C), 128.6 (2 C), 129.1, 129.7 (2 C), 130.0 (2 C), 131.1, 133.5, 136.3, 137.9,
138.4, 141.2, 145.9. IR (KBr): 3368, 3055, 3027, 2923, 1621, 1599, 1492, 1447, 1265, 1080, 1041, 966,
–1
+
8
08, 754, 694 cm . HRMS (ES) m/z Calcd for C H NaO S [M+Na] 397.1233, found 397.1257.
24 22 2
General procedure for the synthesis of vinyl sulfinyl trichloroacetimidates. To a cold solution (0 ºC)
of the starting material (1.0 equiv) in anhydrous CH CN (10.0 mL/mmol) was added DBU (0.20 equiv)
3
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