Regulation of diastereoselectivity in the carbocyclization of allenyl (S)-N-tert-butylsulfinimines through a three-component assembly

Article abstract of DOI:10.1021/jo4025072

Allenyl sulfinimines can be stereoselectively cyclized with hexamethylditin under palladium catalysis conditions followed by a selection of additives for an activated transmetalation. Reactivity and diastereoselectivity for the cyclization strongly depend on the characteristics of additives. A highly diastereoselective synthesis of five-membered rings is achieved from the reaction of the corresponding allenyl (S)-N-tert-butylsulfinimies through the following sequence. After the distannylation of the allenyl group with hexamethylditin catalyzed by the Pd complex, stereochemical routes are additive dependent: addition of SnCl₄ affords a cis ring exclusively, whereas a trans ring is formed predominantly by the introduction of B- bromocatecholborane. Extension of the methodology to the synthesis of six-membered cis rings is achieved by using B-bromocatecholborane. Stereochemical relationships of products were unambiguously deduced by X-ray crystallography.

Full text of DOI:10.1021/jo4025072

Article
pubs.acs.org/joc
Regulation of Diastereoselectivity in the Carbocyclization of Allenyl
(S)‑N-tert-Butylsulfinimines through a Three-Component Assembly
Jihyun Kim, Hyuna Kim, Nana Kim, and Chan-Mo Yu*
Department of Chemistry, Sungkyunkwan University, Suwon 440-746, Korea
S
* Supporting Information
ABSTRACT: Allenyl sulfinimines can be stereoselectively
cyclized with hexamethylditin under palladium catalysis
conditions followed by a selection of additives for an activated
transmetalation. Reactivity and diastereoselectivity for the
cyclization strongly depend on the characteristics of additives.
A highly diastereoselective synthesis of five-membered rings is
achieved from the reaction of the corresponding allenyl (S)-N-
tert-butylsulfinimies through the following sequence. After the
distannylation of the allenyl group with hexamethylditin catalyzed by the Pd complex, stereochemical routes are additive
dependent: addition of SnCl4 affords a cis ring exclusively, whereas a trans ring is formed predominantly by the introduction of B-
bromocatecholborane. Extension of the methodology to the synthesis of six-membered cis rings is achieved by using B-
bromocatecholborane. Stereochemical relationships of products were unambiguously deduced by X-ray crystallography.
chemical transformations.3 For example, many advances in
INTRODUCTION
■
cyclization using allenyl moieties mediated by transition metals
During the past few decades, substantial progress has been
have been made through a variety of synthetic strategies.4 As
made for a variety of cyclization methods mediated by
part of our continuing efforts to utilize the allenyl functionality,5
we disclosed our discoveries of synthetic methods for the
synthesis of cyclic compounds from allenyl carbonyls and
hydrazones by using transition-metal catalysis.6 The major
advantage of methods involving the use of an allenyl
functionality for transition-metal catalysis is efficient conversion
to an activated nucleophile in the presence of a reactive
carbonyl equivalent. The characteristic features of our
approaches in terms of structural aspects of products have
encouraged us to carry out more investigations for designing an
asymmetric version from 1 to 2, which would expand the utility
of the method. Furthermore, synthetic applications can be
foreseen for the products to give a variety of bioactive
substances, including structures appearing in Figure 1.7
transition-metal catalysis.1 Nonetheless, only a limited number
of methods exist to establish both cis and trans rings selectively
through transition-metal catalysis, despite their plentiful
synthetic potential.2 We describe herein our inverstigation
into the carbocyclization of allenyl sulfinimines through a three-
component assembly of allenyl, sulfiniminyl, and stannyl
functionalities with regulation of stereochemical routes to
construct cis or trans rings selectively, as depicted in Figure 1.
Structurally unique allene functionalities have been utilized as
useful substrates and have played important roles in a variety of
Asymmetric nucleophilic addition to imine functionalities to
form chiral amines is one of the most fundamental reaction
types in synthetic chemistry.8 However, the lack of data
concerning intramolecular versions in the construction of cyclic
amine systems involving the use of transition-metal catalysts
surprised us,9 in view of the expected similarity of such a system
to the well-defined cycloisomerization reactions with carbon-
yls.10 We wish to report our discovery of a remarkable additive
effect by a simple selection of transmetalating reagents for 5 to
regulate cis or trans stereochemical routes for the conversion of
3 to 4, which allows the reaction to proceed in good yield with
high levels of diastereoselectivity (Scheme 1).
Figure 1. General cyclization strategy and examples of potential
applications.
Received: November 12, 2013
Published: January 15, 2014
© 2014 American Chemical Society
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Scheme 1. Cyclization Pathway
follows (Table 1, entries 2−7): (1) the use of 1.5 equiv of
SnCl4 proved to be most effective for the cyclization in terms of
RESULTS AND DISCUSSION
■
With this issue in mind, several allenyl (S)-N-tert-butylsulfini-
mines 3 were prepared according to the literature procedure,11
and our investigations began with 3a (X = N-SO2Tol) as a
model substrate under conditions similar to those previously
employed for the carbocyclization.6 The choice of the chiral N-
tert-butylsulfinimines 3 was based on the reliability in terms of
availability, the capability of π-facial stereoselectivity, and the
efficacy of the addition with a variety of nucleophiles.12 Initial
attempts to cyclize 3a with Me3SnSnMe3 in the presence of (π-
allyl)2Pd2Cl2 (2 mol %) at −40 °C for 3 h in CH2Cl2 indicated
that the conversion to the cyclized 4a could not be realized,
presumably due to the lack of reactivity of the sulfinimine
moiety. Afterward, this weak point paved the way for an
opportunity to find additives for the regulation of stereo-
chemical routes.
We subsequently speculated that the activation of the
intermediate 5 might require an additional transmetalating
reagent to enhance nucleophilic addition to the sulfinimine
part.13 After surveying numerous conditions with potent Lewis
acids, we found that TiCl4 could be a useful additive in the
cyclization. Initial experiments on the distannylation of 3a
followed by addition of TiCl4 (1.1 equiv) at −78 °C for 5 h in
CH2Cl2 afforded encouraging but marginal results. Although
the cyclized product 4a was produced during the reaction as the
major component along with another unidentified diasteromer
in a ratio of 9:1, the problem of low chemical yield (41%)
remained to be solved.
a
Table 1. Additive Effect for the Cyclization of 3a
b
c
entry
additive
none
solvent
major product
dr
yield, %
d
1
CH2Cl2
CH2Cl2
toluene
CH2Cl2
CH2Cl2
toluene
EtCN2
NA
e
2
TiCl4
TiCl4
cis-4a
91:9
93:7
91:9
41
23
21
78
54
26
57
74
33
e
e
3
cis-4a
4
Ti(OiPr)2Cl2
SnCl4
cis-4a
5
cis-4a
4a only
4a only
4a only
6
SnCl4
cis-4a
7
SnCl4
cis-4a
f
g
8
CB-Br
CH2Cl2
toluene
toluene
trans-6a
trans-6a
trans-6a
86:14
g
9
CB-Br
97:3
g
10
Me2BBr
95:5
a
After the distannylation of 3a as described in Scheme 1, additive was
b
added at −78 °C and the reaction was performed for 1−5 h. Use of
c
d
1.1−1.5 equiv. Isolated and purified yield. No cyclized products.
e
f
Stereochemically unidentified minor product. CB = catecholboryl.
6a:4a.
g
chemical yields, (2) the reaction performed at −78 °C in
CH2Cl2 resulted in the best chemical yields in comparison with
other solvents such as toluene and CH3CH2CN, and (3) the
stereochemical relationship for cis-4a was deduced by X-ray
crystallographic analysis. With the notion that this approach
might lead to a general and efficient method for the synthesis of
4, we set out to explore other substrates to produce structurally
varying products. Indeed, the method turned out to be
successful with 3b,c in forming exclusively the cyclic products
4b,c, respectively, in moderate to good yields, as shown in
Scheme 2.
We were delighted to find that SnCl4 could be a more
effective reagent in terms of diastereoselectivity and chemical
yield (single diastereomer, 78% yield), as shown in Scheme 2.
During the orienting experiments, key findings emerged as
Stereochemical model A in Scheme 2 could illustrate a
possible stereochemical route for the cis product. From a
mechanistic perspective, two major functions for the stereo-
selectivity in the course of cyclization are immediately
discernible: transmetalation and the chelation effect. After the
distannylation of an allenyl group, the resulting allylic stannane
must be transmetalated by SnCl4 to give the more reactive
allylic trichlorostannane and subsequently an intramolecular
allylic addition to the sulfinimine as depicted in A. The
enhanced reactivity can be explained by assuming that the tight
chelation of allylic tin with a sulfinyl moiety in a hexacoordinate
array could result in the extent of LUMO decrease for the
sulfinimine part14 as well as HOMO increase for the
trichlorostannyl part similar to the Lewis base catalyzed
carbonyl addition.15 Obtainment of the products can be
accounted for by the intervention of the pseudopericyclic
transannular model A with minimum steric interactions and
optimal orbital interactions, which lead to the only reaction
pathway to the product, as illustrated in Scheme 2.
Scheme 2. cis-Selective Carbocyclization of 3
In an effort to expand the scope of chemical transformation
in the synthesis of cis-4, we focused on the design of a reaction
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pathway to afford trans-6 as a result of a reversal of
diastereoselectivity on the basis of transannular stereochemical
model B, as depicted in Scheme 3.
the application of this approach to achieve the synthesis of six-
membered rings. However, all attempts to cyclize 8a under
various conditions with SnCl4 turned out to be unpromising.
Fortunately, the reaction of 8a under similar conditions with B-
bromocatecholborane resulted in the formation of 9a as a single
diastereomer in 75% yield, as shown in Scheme 4.
Scheme 3. trans-Selective Carbocyclization of 3
Scheme 4. Extension of the Method to Six-Membered Rings
Carbocyclization must take place through the stereochemical
model D, which could be the only reaction pathway to the
product. In addition, the method was successful with 8b and
afforded product 9b in high purity. The stereochemical
relationship of 9a was also confirmed by X-ray analysis.
The products cis-4 and trans-6 are readily amenable to
further chemical conversion to useful synthetic intermediates by
the functional group transformations of vinylstannane. For
example, the bromovinylic amine 10 was obtained in 63% yield
by the treatment of 4a with Br2 (2 equiv) at −78 °C.
Acetylation of 10 with acyl chloride in the presence of pyridine
afforded 11. Vinyl bromides can be converted to various useful
substances. For example, the Sonogashira reaction of 11 with
phenylacetylene provided 12 in 67% yield.17 The copper-
catalyzed coupling reaction of 7 with 2-methylallyl chloride was
also effective in affording 13 in 78% yield, as shown in Scheme
5.18
We reasoned that if model A, assembled from the allyltin
species with a sulfinyl moiety, was possible only with 6-
coordination, then it might be possible to reverse π-facial
selectivity with 4-coordinating species such as borane
substances via the model B in a predictable fashion. The key
to this prediction is difficulty of assembling model C for a cis
product under 4-coordination due to a severe steric interaction
between the existing stannyl group and the tetrahedral borane
system in the intramolecular allylic transfer reaction, as
illustrated in Scheme 3.
Indeed, after surveying the reaction conditions (Table 1,
entries 8−10), a reversal of diastereoselectivity was realized by
replacement of SnCl4 to B-bromocatecholborane. We observed
several crucial factors as follows: (1) B-bromocatecholborane
proved to be the most effective promoter for the cyclization in
comparison with Me2BBr and 9-BBN-Br, (2) the reaction
performed at −78 °C in toluene resulted in the best chemical
yield (74% yield) and diastereoselectivity (6a:4a, 97:3 dr) in
comparison to that in CH2Cl2 (57%, 86:14 dr), (3) the scope of
the reaction was extended to the allenyl sulfinimines 3b,c in
forming the corresponding 6b,c, with high levels of
diastereoselectivity, and (4) the relative stereochemistry was
confirmed by X-ray crystallography after the conversion of 6a
with Br2 (1 equiv) to 7. It is worthy of note that the
coordination of the sulfinyl unit with borane species in the
stereochemical model C must be crucial in promoting the
reaction to afford the unexpected minor product cis-4, as
illustrated in Scheme 3.12,16
Scheme 5. Synthetic Manipulations of Products
In light of the above results for the diastereoselective
synthesis of cis-4 and trans-6, we next turned our attention to
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(+)-(S)-N-(Hepta-5,6-dienylidene)-2-methylpropane-2-sulfi-
namide (3b). Compound 3b (0.52 g, 2.44 mmol, 81% yield) was
prepared from the corresponding allenyl aldehyde (0.33 g, 3.0 mmol)
as a pale yellow oil according to the above general procedure for 3a:
CONCLUSION
■
In summary, readily available allenyl (S)-N-tert-butylsulfini-
mines 3 with hexamethylditin have been shown to undergo a
diastereoselective carbocylization through a three-component
assembly, providing a five-membered cis- or trans-ring system.
This highly stereoselective transformation involves the
distannylation of an allene unit with hexamethylditin by
palladium catalyst, the transmetalation of the allylic trimethys-
tannyl moiety to more reactive trichlorostannyl or catechol-
boryl species, and subsequently an intramolecular allylic
transfer reaction with a chiral sulfinimine. Diastereoselectivity
for five-membered cis or trans rings was determined by the
characteristic feature of transmetalating reagents: 6-coordinat-
ing tin for the cis ring and 4-coordinating boron for the trans
ring. The cyclizations are very effective for a series of allenyl
sulfinimines, providing enantiomerically enriched carbocycles
and heterocycles, which promise to be synthetically useful.
TLC, Rf = 0.37 (3/1 hexanes/EtOAc); [α]20 = +295.6° (c 0.2,
D
CHCl3); IR (film) 2955, 2360, 1955, 1621, 1362, 1082 cm−1; 1H
NMR (300 MHz, CDCl3) δ 1.16 (s, 9H), 1.73 (m, 2H), 2.05 (m, 2H),
2.54 (ddd, J = 7.4, 7.4, 4.5 Hz, 2H), 4.66 (m, 2H), 5.06 (tt, J = 6.6, 6.6
Hz, 2H), 8.04 (t, J = 4.5 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 22.3,
24.7, 27.5, 35.3, 56.4, 75.2, 89.0, 169.1, 208.6. Anal. Calcd for
C11H19NOS: C, 61.93; H, 8.98; N, 6.57. Found: C, 61.88; H, 9.11; N,
6.63.
(+)-(S)-N-{2-(Buta-2,3-dienyloxy)ethylidene}-2-methylpro-
pane-2-sulfinamide (3c). Compound 3c (0.46 g, 2.13 mmol, 77%
yield) was prepared from the corresponding allenyl aldehyde (0.31 g,
2.76 mmol) as a pale yellow oil according to the above general
procedure for 3a: TLC, Rf = 0.51 (1/1 hexanes/EtOAc); [α]20
=
D
+263.3° (c 0.2, CHCl3); IR (film) 2926, 1955, 1632, 1456, 1363, 1242,
1
1082 cm−1; H NMR (300 MHz, CDCl3) δ 1.17 (s, 9H), 4.12 (m,
2H), 4.39 (dd, J = 3.3, 1.5 Hz, 2H), 4.80 (m, 2H), 5.23 (tt, J = 6.9, 6.9
Hz, 1H), 8.07 (t, J = 3.3 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 22.6,
57.3, 69.4, 71.1, 76.3, 87.3, 166.9, 209.9. Anal. Calcd for C10H17NO2S:
C, 55.78; H, 7.96; N, 6.51. Found: C, 55.64; H, 8,02; N, 6.43.
General Procedure for the Cyclization of cis Five-Membered
Rings: (+)-(S)-2-Methyl-N-[(3R, 4R)-1-tosyl-4-{1-
(trimethylstannyl)vinyl}pyrrolidin-3-yl]propane-2-sulfinamide
(4a). A flame-dried flask containing allenyl sulfinimine 3a (154 mg,
0.42 mmol) was charged with freshly dried CH2Cl2 (2 mL) followed
by (π-allyl)2PdCl2 (3.06 mg, 2 mol %) diluted in CH2Cl2 (0.5 mL).
The resulting mixture was cooled to −40 °C. To this mixture was
added dropwise hexamethyldistannane (180 mg, 0.55 mmol) in
CH2Cl2 (1.5 mL) over 10 min along the wall of the flask while the
temperature was kept below −40 °C. After addition, the solution was
stirred for an additional 1 h at −40 °C. Conversion was checked by
TLC, and the mixture was then cooled to −78 °C immediately upon
completion of the reaction. To this reaction mixture was added
precooled SnCl4 (165 mg, 0.63 mmol) in CH2Cl2 (1 mL) over 10 min
along the wall of the flask while the temperature was kept below −78
°C. After the reaction mixture was stirred for 2 h at −78 °C, aqueous
NaHCO3 (2 mL) was added, and then the mixture was diluted with
EtOAc (10 mL). The aqueous layer was extracted with EtOAc (5 mL).
After the combined organic solution was dried over anhydrous
Na2SO4, the solvents were removed under reduced pressure. Column
chromatography (3/1 hexanes/EtOAc) afforded 4a (175 mg, 0.33
mmol, 78%) as a white solid: TLC, Rf = 0.37 (1/1 hexanes/EtOAc);
EXPERIMENTAL SECTION
■
General Methods. Unless otherwise stated, all reactions were run
in flame-dried glassware under an atmosphere of nitrogen or argon
using dry, deoxygenated solvents. Tetrahydrofuran (THF) was dried
by refluxing over sodium/benzophenone ketyl until a permanent
purple coloration appeared and distilled prior to use. Dichloromethane
(CH2Cl2) was distilled from CaH2 prior to use. Solvents were also
purified by passage through an alumina column under argon. All liquid
reagents were distilled properly prior to use, unless otherwise
indicated. Purification was conducted by flash column chromatography
on silica gel (230−400 mesh), with a mixture of hexane and ethyl
acetate as eluent, unless otherwise stated. All reactions were monitored
by thin-layer chromatography carried out on Merck silica gel plate (60
F254) using UV light as the visualizing agent and ethanolic
anisaldehyde solution and heat as the developing agent. Silica gel
(230−400 mesh) was used for column chromatography. The reported
1
yields are for chromatographically pure isolated products. H NMR
spectra were recorded in CDCl3 as a solvent with TMS or residual
chloroform as the internal standard (δ 7.26 ppm). 13C NMR spectra
were measured in CDCl3 as a solvent and are reported related to
CHCl3 (δ 77.16 ppm). Optical rotations were measured at ambient
temperature. All X-ray data were collected at our departmental X-ray
facility.
General Procedure for the Synthesis of Allenyl Sulfinimines:
(+)-(S)-N-(Buta-2,3-dienyl)-N-{2-(tert-butylsulfinylimino)ethyl}-
4-methylbenzenesulfonamide (3a). A solution of Ti(OEt)4 (0.6
mL. 0.654 g, 2.86 mmol), diglyme (0.14 mL, 0.98 mmol), and allenyl
aldehyde (0.37 g, 1.39 mmol) in THF (4 mL) was prepared under a
nitrogen atmosphere. Then, (S)-tert-butanesulfinamide (0.17 g, 1.4
mmol) in THF (1 mL) was added and the reaction mixture was heated
to reflux. Conversion was checked by TLC and the mixture cooled
immediately upon completion. Once at room temperature, the mixture
was poured into an equal volume of water while rapidly stirring. The
resulting suspension was filtered through a plug of Celite and the filter
cake was washed with EtOAc. The filtrate was transferred to a
separatory funnel where the organic layer was washed with brine. The
brine layer was extracted once with a small volume of EtOAc, and the
combined organic portions dried over Na2SO4, filtered, and
concentrated. The crude product was purified by SiO2 column
chromatography to give 3a (0.425 g, 1.15 mmol, 83%) as a pale yellow
mp 96 °C, [α]20 = +65.6° (c 0.4, CHCl3); IR (film) 3292, 2895,
D
1
2357, 1331, 1158, 1065, 1015 cm−1; H NMR (300 MHz, CDCl3) δ
119
117
0.20 (s, 9H, J
= 54.7 Hz, J
= 52.4 Hz), 1.00 (s, 9H), 2.41
Sn−H
Sn−H
(s, 3H), 3.08−3.14 (m, 1H), 3.22 (bs, 1H), 3.42−3.5 (m, 4H), 3.87
(m, 1H), 5.53 (dd, J = 1.5, 1.5 Hz, 1H, JSn−H = 68.3 Hz), 5.73 (dd, J =
1.5, 1.5 Hz, 1H, JSn−H = 137.1 Hz), 7.31 (d, J = 8.1 Hz, 2H), 7.72 (d, J
= 8.1 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ −8.7, 21.8, 22.6, 48.3,
51.5, 53.1, 53.2, 56.1, 127.6, 129.5, 130.0, 134.6, 143.7, 150.0. Anal.
Calcd for C20H34N2O3S2Sn: C, 45.04; H, 6.43; N, 5.25. Found: C,
45.13; H, 6.44; N, 5.08. For X-ray crystallography, see the Supporting
Information.
(+)-(S)-2-Methyl-N-[(1S,2R)-2-{1-(trimethylstannyl)vinyl}-
cyclopentyl]propane-2-sulfinamide (4b). Compound 4b (167
mg, 0.44 mmol, 83% yield) was prepared from 3b (112 mg, 0.53
mmol) as a pale yellow amorphous solid according to the above
general procedure for 4a: TLC, Rf = 0.35 (3/1 hexanes/EtOAc);
solid: TLC, Rf = 0.3 (2/1 hexanes/EtOAc); [α]20 = +127.2° (c 0.2,
D
[α]20 = +184.9° (c 0.2, CHCl3); IR (film) 3280, 2954, 1454, 1363,
CHCl3); IR (film) 3053, 2983, 2926, 1954, 1624, 1345, 1265, 1160,
D
−1
1
1
119
1091 cm−1; 1H NMR (300 MHz, CDCl3) δ 1.15 (s, 9H), 2.40 (s,
1075 cm ; H NMR (300 MHz, CDCl3) δ 0.17 (s, 9H, J Sn−H = 54.0
Hz, J = 51.8 Hz), 1.14 (s, 9H), 1.62−2.04 (m, 6H), 2.86 (m,
117Sn−H
3H), 3.87−3.94 (m, 2H), 4.23 (dd, 2H, J = 3.3, 8.4 Hz), 4.68−4.72
(m, 2H), 4.89−4.98 (m, 1H), 7.29 (d, J = 8.4 Hz, 2H), 7.69 (d, J = 8.4
Hz, 2H), 7.90 (t, J = 3.3 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 21.8,
22.6, 47.7, 50.7, 57.4, 77.0, 85.7, 127.5, 130.1, 136.9, 144.0, 165.1,
210.0. Anal. Calcd for C17H24N2O3S2: C, 55.41; H, 6.56; N, 7.60.
Found: C, 55.24; H, 6.63; N, 7.44.
1H), 3.20 (s, 1H), 3.75 (m, 1H), 5.46 (dd, J = 1.8, 1.8 Hz, 1H, JSn−H
=
72.7 Hz), 5.80 (dd, J = 1.8, 1.8 Hz, 1H, JSn−H = 148.9 Hz); 13C NMR
(75 MHz, CDCl3) δ −8.8, 21.5, 22.9, 25.7, 31.4, 54.2, 55.0, 55.6, 127.2,
154.1. Anal. Calcd for C14H29NOSSn: C, 44.47; H, 7.73; N, 3.70.
Found: C, 44.44; H, 7.89; N, 3.51.
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(−)-(S)-2-Methyl-N-[(3R,4S)-4-{1-(trimethylstannyl)vinyl}-
tetrahydrofuran-3-yl]propane-2-sulfinamide (4c). Compound
4c (118 mg, 0.31 mmol, 61% yield) was prepared from 3c (110 mg,
0.51 mmol) as a pale yellow amorphous solid according to the above
general procedure for 4a: TLC, Rf = 0.24 (1/1 hexanes/EtOAc);
4.08 (m, 2H), 5.47 (dd, J = 1.8, 1.8 Hz, 1H, JSn−H = 73.0 Hz), 5.76 (dd,
J = 1.8, 1.8 Hz, 1H, JSn−H = 146.8 Hz); 13C NMR (75 MHz, CDCl3) δ
−8.2, 23.2, 53.7, 56.8, 58.5, 70.8, 74.2, 129.2, 151.5. Anal. Calcd for
C13H27NO2SSn: C, 41.07; H, 7.16; N, 3.68. Found: C, 40.95; H, 7.21;
N, 3.45.
[α]20 = −4.1° (c 0.5, CHCl3); IR (film) 3209, 2915, 1642, 1364,
Bromination of Vinyl Stannyl Group in 6a: (S)-N-{(3S,4R)-4-
(1-Bromovinyl)-1-tosylpyrrolidin-3-yl}-2-methylpropane-2-sul-
finamide (7). To a solution of 6a (128 mg, 0.24 mmol) in CH2Cl2 (3
mL) at −78 °C was slowly added bromine solution (12.5 mg, 0.24
mmol, used freshly prepared 0.5 M in CH2Cl2). After it was stirred for
1 h, the mixture was quenched with 10% Na2CO3 and then extracted
with CH2Cl2 (2×). The organic layer was dried over anhydrous
MgSO4, filtered, and concentrated under reduced pressure. The crude
product was purified by flash column chromatography (3/1 hexanes/
EtOAc and then EtOAc only) to give 7 (50.6 mg, 0.11 mmol, 44%)
along with recovered 6a (18 mg, 14%), and desulfinylated product (13
mg, 0.04 mmol, 16%). Compound 7 was recrystallized with a mixture
of ether and hexane to give needlelike crystals: TLC, Rf = 0.25 (1/1
hexanes/EtOAc); [α]20D = +6.4° (c 0.3, CHCl3); IR (film) 3404, 2924,
1629, 1207, 1109, 1041 cm−1; 1H NMR (300 MHz, CDCl3) δ 0.15 (s,
9H), 2.45 (s, 3H), 2.89 (dd, J = 8.1, 8.1 Hz, 1H), 3.14−3.29 (m, 2H),
3.54 (dd, J = 10.2, 8.1 Hz, 1H), 3.70−3.84 (m, 2H), 5.55 (d, J = 2.1
Hz, 1H), 5.75 (d, J = 2.1 Hz, 1H), 7.35 (d, J = 8.1 Hz, 2H), 7.73 (d, J
= 8.1 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 21.8, 22.6, 50.1, 53.2,
55.1, 56.4, 59.2, 76.8, 120.9, 127.9, 130.1, 130.4, 144.2. We could not
obtain elemental analysis data at this time due to a shortage of sample.
For X-ray crystallography, see the Supporting Information.
(+)-(S)-N-(Buta-2,3-dienyl)-N-{3-(tert-butylsulfinylimino)-
propyl}-4-methylbenzenesulfonamide (8a). Compound 8a
(0.285 g, 0.75 mmol, 75% yield) was prepared from the corresponding
allenyl aldehyde (0.28 g, 1.0 mmol) as a yellow oil according to the
above general procedure for 3a: TLC, Rf = 0.43 (2/1 hexanes/
EtOAc); [α]20D = +75.4° (c 0.2, CHCl3); IR (film) 2980, 2925, 2359,
1954, 1623, 1160, 1085 cm−1; 1H NMR (300 MHz, CDCl3) δ 1.17 (s,
9H), 2.42 (s, 3H), 2.80−2.86 (m, 2H), 3.48 (t, J = 7.2 Hz, 2H), 3.83−
3.87 (m, 2H), 4.69−4.73 (m, 2H), 4.92 (tt, J = 6.9, 6.9 Hz, 1H), 7.30
(d, J = 8.1 Hz, 2H), 7.68 (d, J = 8.1 Hz, 2H), 8.03 (t, J = 3.9 Hz, 1H);
13C NMR (75 MHz, CDCl3) δ 21.8, 22.6, 35.7, 43.4, 47.7, 57.0, 76.8,
D
1271, 1053 cm−1; 1H NMR (300 MHz, CDCl3) δ 0.19 (s, 9H, J
119Sn−H
117
= 54.2 Hz, J Sn−H = 52.0 Hz), 1.20 (s, 9H), 2.93 (ddd, J = 6.9, 6.9, 6.9
Hz, 1H), 3.22 (d, J = 7.8 Hz, 1H), 3.58−3.74 (m, 3H), 3.97−4.17 (m,
2H), 5.29 (dd, J = 1.8, 1.8 Hz, 1H, JSn−H = 67.9 Hz), 5.79 (dd, J = 1.8,
1.8 Hz, 1H, JSn−H = 141.8 Hz); 13C NMR (75 MHz, CDCl3) δ −8.3,
22.9, 56.2, 58.1, 62.3, 72.2, 74.1, 127.7, 152.7. Anal. Calcd for
C13H27NO2SSn: C, 41.07; H, 7.16; N, 3.68. Found: C, 41.17; H, 6.98;
N, 3.27.
General Procedure for the Cyclization of trans Five-
Membered Rings: (+)-(S)-2-Methyl-N-[(3S,4R)-1-tosyl-4-{1-
(trimethylstannyl)vinyl}pyrrolidin-3-yl]propane-2-sulfinamide
(6a). A flame-dried flask containing allenyl sulfinimine 3a (168 mg,
0.46 mmol) was charged with dry toluene (2 mL) followed by (π-
allyl)2PdCl2 (3.4 mg, 2 mol %) diluted in toluene (0.5 mL). The
resulting mixture was cooled to −40 °C. To this mixture was added
dropwise hexamethyldistannane (196 mg, 0.60 mmol) in toluene (1.5
mL) over 10 min along the wall of the flask while the temperature was
kept below −40 °C. After addition, the solution was stirred for an
additional 2 h at −40 °C. Reaction progress was monitored by TLC,
and the mixture was then cooled to −78 °C immediately upon
completion of the reaction. To this reaction mixture was added
dropwise B-bromocatecholborane (147 mg, 0.74 mmol) in toluene
(1.5 mL) over 15 min along the wall of the flask while the temperature
was kept below −78 °C. After the reaction mixture was stirred for 2 h
at −78 °C, aqueous NaHCO3 (3 mL) was added, and then the mixture
was diluted with EtOAc (10 mL). The aqueous layer was extracted
with EtOAc (5 mL). After the combined organic solution was dried
over anhydrous Na2SO4, the solvents were removed under reduced
pressure. A 1H NMR spectrum of crude products indicated the
formation of 6a along with 4a in a ratio of 97:3. Final purification was
effected by flash column chromatography (3/1 hexanes/EtOAc) to
afford 6a (182 mg, 0.34 mmol, 74%) as a pale yellow amorphous solid:
TLC, Rf = 0.3 (1/1 hexanes/EtOAc); [α]20D = +45.9° (c 0.2, CHCl3);
86.1, 127.5, 130.1, 136.8, 143.9, 166.7, 209.8. Anal. Calcd for
C18H26N2O3S2: C, 56.51; H, 6.85; N, 7.32. Found: C, 56.67; H,
6.77; N, 7.47.
1
IR (film) 3270, 2957, 2233, 1346, 1164, 1069, 1014 cm−1; H NMR
119Sn−H
117Sn−H
= 54.3 Hz, J
(300 MHz, CDCl3) δ 0.09 (s, 9H, J
= 51.0
Hz), 1.08 (s, 9H), 2.41 (s, 3H), 2.77 (ddd, J = 7.8, 7.8, 7.8 Hz, 1H),
2.96−3.11 (m, 3H), 3.39−3.47 (m, 2H), 3.70 (dd, J = 10.5, 6.9 Hz,
1H), 5.24 (dd, J = 1.8, 1.8 Hz, 1H, JSn−H = 66.6 Hz), 5.69 (dd, J = 1.8,
1.8 Hz, 1H, JSn−H = 138.6 Hz), 7.32 (d, J = 8.1 Hz, 2H), 7.69 (d, J =
8.1 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ −8.3, 21.8, 22.7, 51.1,
53.7, 56.1, 56.3, 60.2, 127.9, 128.9, 130.1, 133.1, 144.0, 151.7. Anal.
Calcd for C20H34N2O3S2Sn: C, 45.04; H, 6.43; N, 5.25. Found: C,
44.88; H, 6.51; N, 5.11.
(+)-(S)-2-Methyl-N-(octa-6,7-dienylidene)propane-2-sulfina-
mide (8b). Compound 8b (0.38 g, 1.67 mmol, 71% yield) was
prepared from the corresponding allenyl aldehyde (0.29 g, 2.33 mmol)
as a pale yellow oil according to the above general procedure for 3a:
TLC, Rf = 0.4 (4:1 hexanes/EtOAc); [α]20D = +299.6° (c 0.2, CHCl3);
1
IR (film) 2928, 2861, 1955, 1621, 1455, 1362, 1083 cm−1; H NMR
(300 MHz, CDCl3) δ 1.17 (s, 9H), 1.44−1.52 (m, 2H), 1.60−1.70 (m,
2H), 1.97−2.05 (m, 2H), 2.51 (m, 2H), 4.64 (m, 2H), 5.07 (tt, J = 6.9,
6.9 Hz, 1H), 8.04 (t, J = 4.8 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ
22.6, 25.1, 28.1, 28.8, 36.2, 56.8, 75.2, 89.8, 169.8, 208.8. Anal. Calcd
for C11H21NOS: C, 63.39; H, 9.31; N, 6.16. Found: C, 63.44; H, 9.50;
N, 6.08.
(+)-(S)-2-Methyl-N-[(1R,2R)-2-{1-(trimethylstannyl)vinyl}-
cyclopentyl]propane-2-sulfinamide (6b). Compound 6b (127
mg, 0.33 mmol, 60% yield) was prepared from 3b (120 mg, 0.56
mmol) as a pale yellow oil according to the above general procedure
for 6a: TLC, Rf = 0.15 (1/1 hexanes/EtOAc); [α]20D = +14.5° (c 0.2,
CHCl3); IR (film) 3218, 2956, 2869, 1469, 1363, 1055 cm−1; 1H
General Procedure for cis Six-Membered Rings: (+)-(S)-2-
Methyl-N-[(3S,4R)-1-tosyl-3-{1-(trimethylstannyl)vinyl}-
piperidin-4-yl]propane-2-sulfinamide (9a). A flame-dried flask
containing allenyl sulfinimine 8a (156 mg, 0.41 mmol) was charged
with dry toluene (2 mL) followed by (π-allyl)2PdCl2 (3.0 mg, 2 mol
%) diluted in toluene (0.5 mL). The resulting mixture was cooled to
−40 °C. To this mixture was added dropwise hexamethyldistannane
(175 mg, 0.53 mmol) in toluene (1.5 mL) over 10 min along the wall
of the flask while the temperature was kept below −40 °C. After
addition, the solution was stirred for an additional 2 h at −40 °C. The
reaction progress was monitored by TLC, and the mixture was then
cooled to −78 °C immediately upon completion of the reaction. To
this reaction mixture was added dropwise B-bromocatecholborane
(124 mg, 0.62 mmol) in toluene (1.5 mL) over 15 min along the wall
of the flask while the temperature was kept below −78 °C. After the
reaction mixture was stirred for 2 h at −78 °C, aqueous NaHCO3 (3
mL) was added, and the mixture was then diluted with EtOAc (10
119
Sn−H
117
Sn−H
NMR (300 MHz, CDCl3) δ 0.16 (s, 9H, J
= 53.7 Hz, J
=
51.6 Hz), 1.17 (s, 9H), 1.34−1.91 (m, 5H), 2.20 (m, 1H), 2.49 (ddd, J
= 9.0, 9.0, 9.0 Hz, 1H), 3.02 (d, 7.5 Hz, 1H), 3.38 (m, 1H), 5.18 (dd, J
= 1.5, 1.5 Hz, 1H, JSn−H = 70.1 Hz), 5.69 (dd, J = 1.5, 1.5 Hz, 1H, JSn−H
= 152.2 Hz); 13C NMR (75 MHz, CDCl3) δ −8.0, 22.3, 23.0, 31.5,
34.5, 56.3, 59.6, 63.1, 126.3, 157.2. Anal. Calcd for C14H29NOSSn: C,
44.47; H, 7.73; N, 3.70. Found: C, 44.51; H, 7.69; N, 3.54.
(−)-(S)-2-Methyl-N-[(3S,4S)-4-{1-(trimethylstannyl)vinyl}-
tetrahydrofuran-3-yl]propane-2-sulfinamide (6c). Compound
6c (119 mg, 0.31 mmol, 67% yield) was prepared from 3c (100 mg,
0.47 mmol) as a pale yellow oil according to the above general
procedure for 6a: TLC, Rf = 0.3 (1/1 hexanes/EtOAc); [α]20
=
D
−9.5° (c 0.2, CHCl3); IR (film) 3079, 2590, 1474, 1291, 1058 cm−1;
1
119
117Sn−H
H NMR (300 MHz, CDCl3) δ 0.18 (s, 9H, J Sn−H = 53.9 Hz, J
= 51.7 Hz), 1.18 (s, 9H), 3.21 (m, 2H), 3.82−3.89 (m, 3H), 4.01−
1044
dx.doi.org/10.1021/jo4025072 | J. Org. Chem. 2014, 79, 1040−1046

The Journal of Organic Chemistry
Article
mL). The aqueous layer was extracted with EtOAc (5 mL). After
drying combined organic solution was dried over anhydrous Na2SO4,
the solvents were removed under reduced pressure. Final purification
was effected by flash column chromatography (3/1 hexanes/EtOAc)
to afford 9a (168 mg, 0.31 mmol, 75%) as a white solid: TLC, Rf =
(−)-N-{(3R,4R)-4-(4-Phenylbut-1-en-3-yn-2-yl)-1-tosylpyrroli-
din-3-yl}acetamide (12). A mixture of 11 (48 mg, 0.12 mmol),
phenylacetylene (26 mg, 0.25 mmol), Pd(PPh3)2Cl2 (1 mg, 1 mol %),
CuI (1 mg, 0.005 mmol), and Et3N (1 mL) in THF (4 mL) was stirred
at 50 °C for 16 h under nitrogen. After the reaction mixture was
cooled to room temperature, the crude product was concentrated
under reduced pressure. Final purification was effected by flash column
chromatography (1/1 hexanes/EtOAc) to afford 12 (34 mg, 0.08
mmol, 67%) as a yellow oil: TLC, Rf = 0.27 (1/2 hexanes/EtOAc);
0.22 (1/1 hexanes/EtOAc); mp 113−115 °C, [α]20 = +17.9° (c 0.2,
D
CHCl3); IR (film) 3053, 2983, 2924, 1420, 1343, 1271, 1165, 1062
−1
1
119
cm ; H NMR (300 MHz, CDCl3) δ 0.18 (s, 9H, J Sn−H = 54.1 Hz,
= 51.8 Hz), 1.10 (s, 9H), 1.94−2.21 (m, 2H), 2.44 (s, 3H),
117Sn−H
J
[α]20 = −4.1° (c 0.4, CHCl3); IR (film) 3275, 3055, 2960, 2925,
D
2.74−2.91 (m, 3H), 3.16 (d, J = 6.9 Hz, 1H), 3.35−3.46 (m, 3H), 5.40
(dd, J = 1.2, 1.2 Hz, 1H, JSn−H = 73.3 Hz), 5.58 (dd, J = 1.2, 1.2 Hz,
1H, JSn−H = 148.4 Hz), 7.33 (d, J = 8.1 Hz, 2H), 7.65 (d, J = 8.1 Hz,
2H); 13C NMR (75 MHz, CDCl3) δ −8.2, 21.8, 22.9, 31.6, 42.0, 45.8,
47.9, 52.5, 57.0, 127.5, 127.9, 130.1, 133.4, 144.0, 154.2. Anal. Calcd
for C21H36N2O3S2Sn: C, 46.08; H, 6.63; N, 5.12. Found: C, 46.18; H,
6.54; N, 5.11. For X-ray crystallography, see the Supporting
Information.
2854, 1734, 1670, 1263, 1161, 1091, 1027 cm−1; 1H NMR (300 MHz,
CDCl3) δ 1.80 (s, 3H), 2.40 (s, 3H), 3.11 (dd, J = 14.7, 7.5 Hz, 1H),
3.39−3.63 (m, 4H), 4.51 (m, 1H), 5.41 (s,1H), 5.57 (d, J = 7.5 Hz,
1H), 5.62 (s, 1H), 7.29 (d, J = 8.1 Hz, 2H), 7.37 (m, 5H), 7.74 (d, J =
8.1 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 21.7, 23.4, 46.9, 49.8,
51.9, 53.2, 76.7, 87.6, 92.2, 120.9, 122.1, 125.7, 127, 127.7, 128.7,
129.1, 131.7, 144.0, 170.0. Anal. Calcd for C23H24N2O3S: C, 67.62; H,
5.92; N, 6.86. Found: C, 67.68; H, 5.89; N, 7.01..
(−)-(S)-2-Methyl-N-[(1R,2S)-2-{1-(trimethylstannyl)vinyl}-
cyclohexyl]propane-2-sulfinamide (9b). Compound 9b (123 mg,
0.31 mmol, 67% yield) was prepared from 8b (95 mg, 0.47 mmol) as a
pale yellow oil according to the above general procedure for 9a: TLC,
(−)-(S)-2-Methyl-N-{(3S,4R)-4-(4-methylpenta-1,4-dien-2-yl)-
1-tosylpyrrolidin-3-yl}propane-2-sulfinamide (13). A flame-dried
flask was charged with CuI (5.5 mg, 0.029 mmol) and 7 (30 mg, 0.056
mmol) in THF (1 mL). To the mixture was added 3-chloro-2-
methylpropene (10 mg, 0.11 mmol) dissolved in DMSO (1.5 mL)
under a nitrogen atmosphere. After it was stirred for 2 h, the resulting
mixture was quenched with NH4OH aqueous solution and dried over
anhydrous Na2SO4. The crude product was concentrated under
reduced pressure and was purified by SiO2 column chromatography to
give 13 (18 mg, 0.042 mmol, 75%) as a pale yellow oil: TLC, Rf = 0.33
Rf = 0.67 (1/1 hexanes/EtOAc); [α]20 = −34.7° (c 0.2, CHCl3); IR
D
(film) 2927, 2856, 1450, 1363, 1063 cm−1; 1H NMR (300 MHz,
119
Sn−H
117
Sn−H
CDCl3) δ 0.13 (s, 9H, J
= 53.3 Hz, J
= 52.2 Hz), 1.16 (s,
9H), 1.43−1.68 (m, 6H), 1.80 (m, 1H), 2.15 (m, 1H), 2.38 (m, 1H),
3.31 (d, J = 8.1 Hz, 1H), 3.58 (m, 1H), 5.27 (t, J = 1.5, 1.5 Hz, 1H,
JSn−H = 77.4 Hz), 5.60 (t, J = 1.5, 1.5 Hz, 1H, JSn−H = 158.2 Hz); 13C
NMR (75 MHz, CDCl3) δ −8.6, 20.4, 23.3, 25.1, 25.8, 33.6, 49.5, 55.2,
56.9, 125.0, 157.9. Anal. Calcd for C15H31NOSSn: C, 45.94; H, 7.97;
N, 3.57. Found: C, 46.11; H, 7.89; N, 3.53.
(1/1 hexanes/EtOAc); [α]20 = −7.90° (c 0.2, CHCl3); IR (film)
D
1
3277, 2928, 1465, 1345, 1160, 1059, 677 cm−1; H NMR (300 MHz,
CDCl3) δ 1.02 (s, 9H), 1.63 (s, 3H), 2.41 (s, 3H), 2.73 (s, 2H), 2.82
(ddd, J = 10.5, 6.3, 5.1 Hz, 1H), 3.14 (bs, 1H), 3.34−3.56 (m, 4H),
3.91 (dd, J = 4.2, 4.2 Hz, 1H), 4.73 (s, 1H), 4.82 (s, 1H), 4.90 (s, 1H),
5.16 (s, 1H), 7.31 (d, J = 8.1 Hz, 2H), 7.71 (d, J = 8.1 Hz, 2H); 13C
NMR (75 MHz, CDCl3) δ 21.6, 21.9, 22.5, 45.4, 46.9, 48.4, 52.1, 53.8,
56.0, 113.9, 116.1, 127.5, 129.9, 134.7, 141.4, 141.9, 143.6. Anal. Calcd
for C21H32N2O3S2: C, 59.40; H, 7.60; N, 6.60. Found: C, 59.61; H,
7.55; N, 6.44.
(+)-(3R,4R)-4-(1-Bromovinyl)-1-tosylpyrrolidin-3-amine (10).
To a solution of 4a (140 mg, 0.26 mmol) in CH2Cl2 (4 mL) at −78
°C was slowly added bromine solution (27.5 mg, 0.53 mmol, used
freshly prepared 0.5 M in CH2Cl2). After it was stirred for 2 h at −78
°C, the mixture was quenched with 10% Na2CO3 and then extracted
with CH2Cl2 (2×). The organic layer was dried over anhydrous
MgSO4, filtered, and concentrated under reduced pressure. The crude
product was purified by flash column chromatography (1/2 hexanes/
EtOAc and then EtOAc only) to give 10 (56.5 mg, 0.16 mmol, 63%)
as a yellow oil: TLC, Rf = 0.18 (1:2 hexanes/EtOAc); [α]20D = +17.5°
(c 0.2, CHCl3); IR (film) 3379, 2927, 2387, 2283, 1538, 1348, 1162
cm−1; 1H NMR (300 MHz, CDCl3) δ 2.43 (s, 3H), 2.97 (m, 1H), 3.25
(dd, J = 1.2, 9.9 Hz, 1H), 3.37 (dd, J = 9.9, 9.9 Hz, 1H), 3.47−3.58 (m,
2H), 3.69−3.71 (m, 1H), 5.57 (dd, J = 2.7, 1.2 Hz, 1H), 5.65 (dd, J =
2.7, 1.2 Hz, 1H), 7.33 (d, J = 8.1 Hz, 2H), 7.73 (d, J = 8.1 Hz, 2H);
13C NMR (75 MHz, CDCl3) δ 21.7, 47.7, 53.1, 53.4, 55.2, 119.7 127.6,
ASSOCIATED CONTENT
■
S
* Supporting Information
CIF files and tables giving crystallographic data for 4a, 7, and
9a and figures giving 1H and 13C NMR spectra for all products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
128.6, 130, 133.8, 143.9. Anal. Calcd for C13H17BrN2O2S: C, 45.22; H,
4.96; N, 8.11. Found: C, 45.13; H, 5.18; N, 8.33.
AUTHOR INFORMATION
■
(+)-N-{(3R,4R)-4-(1-Bromovinyl)-1-tosylpyrrolidin-3-yl}-
acetamide (11). A flame-dried flask containing 10 (45 mg, 0.13
mmol) was charged with dry CH2Cl2 (3 mL) followed by Et3N (21
mg, 0.2 mmol). After the mixture was cooled to 0 °C, acetyl chloride
(13 mg, 0.18 mmol) diluted in CH2Cl2 (2 mL) was added. After it was
stirred for an additional 1 h at 0 °C, the solution was warmed to room
temperature and stirred overnight. The mixture was quenched with 5
N HCl and then saturated NH4OH, and then it was extracted with
CH2Cl2 (2×). The organic layer was dried over anhydrous Na2SO4,
filtered, and concentrated under reduced pressure. The crude product
was purified by flash column chromatography (1/1 hexanes/EtOAc)
to give 11 (42 mg, 0.11 mmol, 83%) as a yellow oil: TLC, Rf = 0.51
Corresponding Author
*E-mail for C.-M.Y.: cmyu@skku.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are grateful to the National Research Foundation
of Korea (2012R1A1A2006930 and NRF-2009-0076852) for
generous financial support of this research.
(EtOAc only); [α]20 = +11.6° (c 0.2, CHCl3); IR (film) 3369, 3054,
D
2925, 1675, 1346, 1265, 1165, 1093 cm−1; 1H NMR (300 MHz,
CDCl3) δ 1.87 (s, 3H), 2.45 (s, 3H), 3.23 (ddd, J = 7.5, 7.2, 7.5 Hz,
1H), 3.40−3.57 (m, 4H), 4.57 (m, 1H), 5.38 (d, J = 7.5 Hz, 1H), 5.65
(dd, J = 1.2, 1.2 Hz, 1H), 5.69 (dd, J = 1.2, 1.2 Hz, 1H), 7.36 (d, J =
8.1 Hz, 2H), 7.72 (d, 2H, J = 8.1 Hz); 13C NMR (75 MHz, CDCl3) δ
21.9, 23.5, 49.7, 50.2, 51.2, 53.1, 121.0, 127.9, 128.5, 130.3, 133.4,
144.4, 170.3. Anal. Calcd for C15H19BrN2O3S: C, 46.52; H, 4.94; N,
7.23. Found: C, 46.68; H, 5.09; N, 7.35.
REFERENCES
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