Gold-catalyzed tandem cycloisomerization and dimerization of chiral homopropargyl sulfonamides

Article abstract of DOI:10.1002/asia.201301058

A reaction built for two: A novel gold-catalyzed tandem cycloisomerization/dimerization of chiral homopropargyl sulfonamides has been developed. The reaction provides ready access to functionalized pyrrolidines in mostly good to excellent yields. Notably, excellent diastereoselectivities (>50:1) were also achieved in all cases. Copyright

Full text of DOI:10.1002/asia.201301058

COMMUNICATION
DOI: 10.1002/asia.201301058
Gold-Catalyzed Tandem Cycloisomerization and Dimerization of Chiral
Homopropargyl Sulfonamides
Yong-Fei Yu, Chao Shu, Cang-Hai Shen, Tian-Yi Li, and Long-Wu Ye*[a]
In the past decade, gold-catalyzed addition of a heteroa-
À
tom nucleophile to a C C multiple bond, in most cases an
alkyne, has proven to be a powerful tool in organic synthe-
sis,[1] providing easy access to an incredible variety of differ-
ent cyclic compounds, especially the heterocyclic motifs.[2] It
is surprising, however, that few examples have been report-
ed of gold-catalyzed 5-endo-dig cyclization of terminal
Scheme 2. Initial reaction design. Ts=toluene-4-sulfonyl.
alkyne.[3] A likely reason for this paucity is that this gold-
catalyzed cycloisomerization reaction[4] involves an anti-
Markovnikov addition, while Markovnikov regioselectivity
was normally observed for gold-catalyzed nucleophilic addi-
tion to terminal alkynes (Scheme 1).[5]
been long neglected in the area of Au-catalyzed cycloisome-
rization, affording enantioenriched pyrrolidines in generally
good to excellent yields. Mechanistic studies revealed that
the reaction presumably proceeds through a gold-catalyzed
5-endo-dig cyclization and subsequent dimerization cata-
lyzed both by gold and methanesulfonic acid (MsOH).
We set out to screen different conditions for this reaction
by using chiral homopropargyl sulfonamide 1a as the model
substrate. To our delight, in the presence of 5 mol%
[PPh3AuNTf2] and 1.0 equiv of MsOH, the tandem reaction
proceeded well to give the corresponding dimerization prod-
Scheme 1. Gold-catalyzed nucleophilic addition to a terminal alkyne.
1
uct 3a in 64% yield, as determined by H NMR spectrosco-
In our recent study toward such a gold-catalyzed 5-endo-
dig cyclization of terminal alkynes, we reported a gold-cata-
lyzed tandem cycloisomerization/oxidation of homoproparg-
yl alcohol for the synthesis of synthetically useful g-lac-
tones.[6] On the basis of this reaction, we developed a similar
gold-catalyzed oxidative cyclization of chiral homopropargyl
sulfonamides, leading to the enantioenriched g-lactam prod-
ucts.[7] Inspired by these results, we envisioned taking ad-
vantage of intermediate A, which could be further trans-
formed into the enamide intermediate 2 and iminium inter-
mediate B in the presence of acid. Finally, the enamide 2[8]
would attack the iminium intermediate B to lead to the for-
mation of dimer 3 (Scheme 2).[9] Herein, we describe the re-
alization of such a Au-catalyzed dimerization, which has
py (Table 1, entry 1). Then, the effect of acid was investigat-
ed, and it was found that the use of other acid failed to im-
prove the yield (Table 1, entries 1–3). Gratifyingly, the yield
could be further improved to 70% in the presence of
0.5 equiv MsOH (Table 1, entry 4). The reaction also
worked in the absence of acid, albeit in diminished yield
and with longer reaction time (Table 1, entry 5). Among the
different gold catalysts screened (Table 1, entries 7–14),
[IPrAuNTf2] was found to be the best one, and 92% yield
could be achieved (Table 1, entry 10). In the absence of
acid, only 65% yield was obtained even by employing
[IPrAuNTf2] as the gold catalyst (Table 1, entry 15). Without
using any gold catalyst, no 3a formation was observed
under the acidic reaction conditions, and AgNTf2 was not ef-
fective in promoting this reaction (Table 1, entry 17). Nota-
bly, PtCl2 could also catalyze this reaction, but with low effi-
ciency even at 808C (Table 1, entry 16).
[a] Y.-F. Yu,+ C. Shu,+ C.-H. Shen, T.-Y. Li, Prof. Dr. L.-W. Ye
Department of Chemistry and
Under the optimal reaction conditions, various chiral ho-
mopropargyl sulfonamides 1, easily prepared by using Ell-
manꢀs tert-butylsulfinimine chemistry,[7,10] were tested to ex-
amine the generality of the current reaction. As shown in
Table 2, except for the substrate 1p, which only gave 53%
yield (Table 2, entry 16), good to excellent yields could be
achieved in all cases, and no dihydropyrrole products 2 were
observed. In addition, the reaction was generally tolerant of
Fujian Provincial Key Laboratory of Chemical Biology
College of Chemistry and Chemical Engineering
Xiamen University
Xiamen, Fujian 361005 (P.R. China)
Fax : (+86)592-218-5833
E-mail: longwuye@xmu.edu.cn
[+] These authors contributed equally to this work.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201301058.
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Long-Wu Ye et al.
Table 1. Optimization of reaction conditions.[a]
Entry
Gold catalyst
Acid [equiv]
Yield [%][b]
1
2
3
4
[Ph3PAuNTf2]
[Ph3PAuNTf2]
[Ph3PAuNTf2]
[Ph3PAuNTf2]
[Ph3PAuNTf2]
[Ph3PAuNTf2]
[Cy-JohnPhosAuNTf2]
[XPhosAuNTf2]
[BrettPhosAuNTf2]
[IPrAuNTf2]
MsOH (1.0)
CF3CO2H (1.0)
HNTf2 (1.0)
MsOH (0.5)
–
MsOH (1.5)
MsOH (0.5)
MsOH (0.5)
MsOH (0.5)
MsOH (0.5)
MsOH (0.5)
MsOH (0.5)
MsOH (0.5)
MsOH (0.5)
–
64
59
<5
70
57
53
62
75
78
5[c]
6
7
8
9
10
11
12
13
14
15[c]
16[f]
17
92
65
68
43
[Et3PAuNTf2]
[(4-CF3C6H4)3PAuNTf2]
A
AuIII[d]
<5[e]
65
[IPrAuNTf2]
PtCl2
AgNTf2
MsOH (0.5)
MsOH (0.5)
36
<5
[a] Reaction conditions: [1a]=0.10m; DCE=1, 2-dichloroethane, Tf=
SO2CF3, IPr=1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene. [b] Esti-
mated by H NMR spectroscopy using diethyl phthalate as internal refer-
Figure 1. Crystal structure of compound 3i. Thermal ellipsoids are set at
the 30% probability level.
1
ence. [c] Time=8 h. [d] Dichloro(2-picolinato)gold
remained unreacted. [f] Toluene, 808C.
ACHTUNGTREN(NUGN III). [e] 90% of 1a
various functional groups, including a remote benzyl ether
(OBn) group (Table 2, entry 6), N-phthaloyl (Table 2,
entry 5), and an azido group (Table 2, entry 4). Importantly,
the compounds 3a–n were formed with excellent diastereo-
selectivities (>50:1, determined by 1H NMR spectroscopy
of the crude reaction mixtures) and, according to the X-ray
analysis of 3i (Figure 1), the same stereochemical outcome
was assumed for all the pyrrolidines synthesized. It should
be mentioned that in these transformations, the ee values
could be well maintained, as we determined the ee values of
the compound 3c as a representative example (Table 2,
entry 3).
Although N-homopropargyl carboxamides are not suita-
ble substrates due to the competing gold-catalyzed amide 6-
exo-dig cyclization,[11] we were pleased to find that the reac-
tion could also proceed well for Ns and Bus protected sub-
strates 1q and 1r, resulting in high yields of the desired
products 3q and 3r (88% and 82% yields of isolated prod-
uct) with excellent diastereomeric ratios (>50:1). Notably,
both reactions were initially met with poor yields in the pre-
viously optimized reaction conditions; however, simply
switching the gold catalyst from [IPrAuNTf2] to [BrettPho-
sAuNTf2] resulted in a significant improvement of the yields
(Scheme 3).
Scheme 3. Gold-catalyzed tandem cycloisomerization/dimerization of
chiral homopropargyl amides 1q and 1r. Bus=tert-butylsulfonyl, Ns=2-
nitrobenzenesulfonyl.
employing 0.5 equivalents MsOH as the catalyst, 2a could
also be readily converted into 3a in 64% yield (Table 3,
entry 2). Moreover, treatment of 2a with a combination of
5 mol% gold and 0.5 equivalents MsOH produced the cor-
responding 3a in 78% yield (Table 3, entry 3). These results
clearly suggested that the dimerization process could be cat-
alyzed both by gold and protic acid, which allowed the rapid
isomerization of enamide into reactive iminium species and
eventually led to the formation of dimer. This finding is
quite consistent with the known acid-catalyzed dimerization
of enamide.[9]
In addition, we also monitored the tandem reaction by
1H NMR spectroscopy, as detailed in Figure 2. In this case,
the reaction was performed in the absence of MsOH in
order to better track the reaction intermediates. At the
early stage of the reaction, we could clearly observe the for-
mation of the dihydropyrrole 2a and the 2-hydroxypyrroli-
dine intermediate 4a,[13] which were gradually transformed
into the final dimer 3a. These observations strongly support
our initial hypothesis that the reaction involves the forma-
tion of enamide 2.
To probe the reaction mechanism, we first prepared the
dihydropyrrole substrate 2a[12] to investigate the reaction.
As shown in the reaction in Table 3, dihydropyrrole 2a
could dimerize in the presence of 5 mol% gold catalyst to
afford the corresponding 3a in 53% yield as determined by
1H NMR spectroscopy (Table 3, entry 1). Interestingly, by
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Long-Wu Ye et al.
Table 2. Reaction scope study.[a]
Entry
1
Substrate
1
Product
3
Yield [%]
85
1a
3a
2
1b
3b
84
3
4
5
6
1c
1d
1e
1 f
3c[b]
3d
3e
85
80
75
88
3 f
7
1g
1h
1i
3g
3h
3i
86
86
87
84
90
8
9
10
11
1j
3j
1k
3k
12
13
14
1l
3l
87
92
85
1m
1n
3m
3n
15
16
1o
1p
3o
3p
84
53
[a] Reactions run in vials; [3]=0.10m; yields of isolated products are reported. [b] 99% ee, determined using HPLC on a chiral stationary phase.
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Long-Wu Ye et al.
Table 3. Reaction of dihydropyrrole.
Entry
Catalyst
Yield [%][a]
1
2
3
[IPrAuNTf2] (5 mol%)
MsOH (0.5 equiv)
[IPrAuNTf2] (5 mol%), MsOH (0.5 equiv)
53
64
78
1
[a] Determined by H NMR spectroscopy.
Scheme 4. Plausible catalytic cyclization mechanism.
react with the iminium ion formed by protonation of 2’, or
formed by protonation and elimination of 4’, to deliver the
final dimer.[16]
In conclusion, we have developed a novel gold-catalyzed
tandem reaction, which presumably involves gold-catalyzed
cycloisomerization/gold- and acid-catalyzed dimerization.
Various enantioenriched pyrrolidines can be prepared in
generally good to excellent yields with excellent diastereose-
lectivities from chiral homopropargyl sulfonamides. Other
notable features of this method include the use of readily
available substrates, the simple procedure, the mild reaction
conditions, and in particular, the tolerance of moisture and
air (’open flask’). Further related investigations on the gold-
catalyzed cycloisomerization-initiated tandem process are
under way.
Figure 2. Progression of the tandem reaction as monitored by 1H NMR
spectroscopy.
Experimental Section
Finally, we performed deuterium labeling studies. It was
found that when substrate 1a’ (88% D) was treated under
the previously optimized reaction conditions, no deuterium
loss was observed [Eq. (1)], which indicates the reaction is
presumably triggered by a gold-catalyzed 5-endo-dig cycliza-
tion of homopropargyl sulfonamide but does not goes
through the gold vinylidene intermediate pathway.[14]
Typical procedure for gold-catalyzed tandem cycloisomerization/
dimerization of chiral homopropargyl sulfonamides
MsOH (2.0 mL, 0.10m in DCE) and [IPrAuNTf2] (9.0 mg, 0.01 mmol)
were added to
a solution of the homopropargyl sulfonamides
1 (0.40 mmol) in DCE (2.0 mL) at room temperature. The reaction mix-
ture was stirred at room temperature, and the progress of the reaction
was monitored by TLC. The reaction typically took 5 h. Upon comple-
tion, the reaction was diluted with CH2Cl2 (30 mL) and washed with satu-
rated aqueous NaHCO3 (2ꢂ15 mL). The resulting solution was extracted
again with CH2Cl2 (30 mL), and the combined organic layers were dried
with MgSO4. The mixture was then concentrated, and the residue was pu-
rified by chromatography on silica gel (hexanes/ethyl acetate, 10:1) to
afford the desired products 3.
On the basis of these experimental observations, a plausi-
ble mechanism[15] is proposed for this tandem reaction
(Scheme 4). It may initially involve the formation of a p
complex through coordination of the gold catalyst to the
triple bond of chiral homopropargyl sulfonamide 1’. A sub-
sequent 5-endo-dig cyclization was expected to give the
vinyl gold intermediate A’, which was transformed into the
enamide intermediate 2’ and the 2-hydroxypyrrolidine inter-
mediate 4’. Finally, both intermediates 2’ and 4’ could be fur-
ther converted into 3’ catalyzed both by gold and acid. Al-
ternatively, the vinylgold intermediate A’ might directly
Acknowledgements
We are grateful for the financial support from the National Natural Sci-
ence Foundation of China (No. 21102119 and 21272191), the Natural Sci-
ence Foundation of Fujian Province of China (No. 2012J01051), NFFTBS
(No. J1210014), and PCSIRT. We also thank Professor Dr. Liming Zhang
(University of California Santa Barbara) for the helpful discussions.
Keywords: cycloisomerization
·
dimerization
· domino
reactions · gold · homogeneous catalysis
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Received: August 7, 2013
Published online: October 2, 2013
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