Hydration and Intramolecular Cyclization of Homopropargyl Sulfonamide Derivatives Catalyzed by Silver Hexafluoroantimonate(V): Synthesis of Structurally Diverse 2,3-Dihydro-1H-Pyrroles

Article abstract of DOI:10.1002/adsc.201701121

We have developed an efficient, simple protocol for synthesis of structurally diverse functionalized 2,3-dihydro-1H-pyrroles by hydration and intramolecular cyclization of homopropargyl sulfonamide derivatives. Mechanistic experiments revealed that the sulfonamide nitrogen participated in the hydration reaction by chelating the Ag atom of the catalyst to assist in the formation of the hydration intermediate. The protocol accommodated a wide range of substrates and was used for a formal synthesis of (S)-nicotine. (Figure presented.).

Full text of DOI:10.1002/adsc.201701121

Title: Hydration and Intramolecular Cyclization of Homopropargyl
Sulfonamide Derivatives Catalyzed by AgSbF6: Synthesis of
Structurally Diverse 2,3-Dihydro-1H-Pyrroles
Authors: Xiuling Yu, Zhonglin Guo, Hongjian Song, Yuxiu Liu, and
qingmin wang
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201701121
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10.1002/adsc.201701121
Advanced Synthesis & Catalysis
COMMUNICATION
Hydration and Intramolecular Cyclization of Homopropargyl
Sulfonamide Derivatives Catalyzed by Silver
Hexafluoroantimonate(V): Synthesis of Structurally Diverse
2,3-Dihydro-1H-Pyrroles
Xiuling Yu a, Zhonglin Guo a, Hongjian Songa,*, Yuxiu Liu a and Qingmin Wang a, b*
a
State Key Laboratory of Elemento-Organic Chemistry, Research Institute of Elemento-Organic Chemistry, College of
Chemistry, Nankai University, Tianjin 300071 (China)
Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071 (China)
b
E-mail: songhongjian@nankai.edu.cn, wangqm@nankai.edu.cn.
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
(Scheme 1a)[8] and 5-endo-dig cyclization of
Abstract. We have developed an efficient, simple protocol
for synthesis of structurally diverse functionalized 2,3- homopropargyl sulfonamides promoted by tetra-n-
butylammonium fluoride (Scheme 1b).[9] However,
dihydro-1H-pyrroles by hydration and intramolecular
cyclization of homopropargyl sulfonamide derivatives.
Mechanistic experiments revealed that the sulfonamide
nitrogen participated in the hydration reaction by chelating
the Ag atom of the catalyst to assist in the formation of the
hydration intermediate. The protocol accommodated a wide
range of substrates and was used for a formal synthesis of
(S)-nicotine.
the existing methods generally require complex
substrates, use expensive catalysts, or have a limited
substrate scope. Accordingly, the development of
new, efficient methods that address these drawbacks
is highly desirable.
Keywords: Cyclization; Heterocycle; Hydration; Silver;
Sulfonamides
Heterocyclic compounds are widely distributed in
nature and have shown great potential as inspirations
for the design of new molecules with interesting
properties and biological activities.[1] Five-membered
N-heterocycles such as pyrroles and pyrrolidines are
found in many bioactive natural products, as well as
pharmaceuticals and pesticides.[2] Examples include
nicotine, which has insecticidal activity;[3] crispine A,
which was isolated from Carduus crispus Linn. and
has significant cytotoxic activity;[4] and the polycyclic
insecticide chlorfenapyr (Figure 1).
Figure 1. Natural Products and Agrochemicals with
Pyrrole or Pyrrolidine Ring Systems.
Scheme 1. Catalytic Cyclization and Hydration Reactions
of Alkynes.
The pyrrole moiety has attracted considerable
interest because of its many applications,[5] and much
research effort has been devoted to the development
of new approaches to the synthesis of this moiety.[6,7]
Representative methods include Au/Ag-catalyzed
dehydrative cyclization of propargyl alcohols
In addition to these cyclization reactions, alkynes
undergo numerous other potentially useful
1
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10.1002/adsc.201701121
Advanced Synthesis & Catalysis
transformations. For example, recent rapid progress
in the area of transition-metal-catalyzed reactions of
alkynes has resulted in methods for easy access to an
incredible variety of functionalized carbonyl
derivatives (Scheme 1c).[10] Alkyne hydration to form
carbonyl derivatives is of particular interest, owing to
the wide availability of alkynyl substrates and the
fundamental importance of the carbonyl motif in
modern organic synthesis.[11] As part of our ongoing
work on the construction of alkaloid skeletons, we
herein report the synthesis of 2,3-dihydro-1H-
pyrroles via hydration and subsequent intramolecular
no better results than AgSbF6 (entries 11–13), and the
reaction did not proceed in the absence of a silver salt
(entry 14). Extensive screening of various other
reaction parameters revealed that the optimal reaction
conditions were 10 mol % AgSbF6 in 1,2-
dichloroethane at 80 °C for 24 h (entry 4).
Table 2. Effect of Phenyl-Group Substituent on Reaction
Outcome.[a]
cyclization
of
homopropargyl
sulfonamide
derivatives (Scheme 1d).
Table 1. Optimization of Reaction Conditions.[a]
Entry Sulfonamide R1
Product
Yield
(%)
1
2
3
4
5
6
7
8
H
3-Me
4-Me
4-MeO
4-t-Bu
4-F
4-Cl
4-Br
4-CF3O
4-CH3CO
4-MeOCO
4-NO2
3,4-Me
3,4-F
92
72
65
68
67
81
92
50
40
72
45
40
52
62
50
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
Entr Catalyst
y
Solvent
DCE
T
t
2a Yield
(°C) (h) (%)[b]
1
2
3
4
5
6
7
8
9
Sc(OTf)3 DCE
In(OTf)3
Cu(OAc)2 DCE
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
80
80
80
80
60
80
60
24
24
24
24
24
10
24
24
24
0
0
0
92
65
71
57
trace
trace
9
10
11
12
13
14
15
DCE
DCE
DCE
CHCl3
acetonitrile 80
1,4-
3,5-Cl
[a]Reaction conditions: 1 (1 equiv) and AgSbF6 (10 mol %)
in DCE (5 mL) at 80 °C under argon for 24 h. Isolated
yields are provided.
80
dioxane
toluene
DCE
DCE
DCE
10
11
12
13
14
AgSbF6
AgOTf
AgOAc
AgBF4
—
80
80
80
80
80
24
24
24
24
24
trace
69
36
47
0
With the optimized conditions in hand, we
investigated the substrate scope of the reaction (Table
2). First, we carried out reactions of homopropargyl
sulfonamides with various substituents on the phenyl
group. Most of the tested substrates gave the
corresponding 2,3-dihydro-1H-pyrroles in good to
excellent yields (2a–2o), indicating that neither the
electronic properties nor the position of the phenyl
substituent influenced the reaction outcome.
Specifically, substrates with an electron-donating
substituent (1b–1e), a weakly electron-withdrawing
substituent (1f–1h), or no substituent at all (1a)
afforded the desired compounds in good yields.
Substrates with a strongly electron-withdrawing
group, such as trifluoromethyl, nitro, carbonyl, or
methoxycarbonyl, could also be converted to the
desired products (2i–2l), albeit in slightly lower
yields. Disubstituted products 2m–2o could be
obtained in moderate yields (>50%).
DCE
[a]Reactions were conducted with 1a (1 equiv) in the
presence of catalyst (10 mol %) under argon in 1,2-
dichloroethane (DCE) for 24 h at 80 °C, unless otherwise
stated. Ts = 4-methylphenylsulfonyl. [b]Isolated yields are
provided.
We began by investigating the reaction of 4-
methyl-N-(4-phenylbut-3-ynyl)benzenesulfonamide
(1a) with transition-metal catalysts (10 mol %) in 1,2-
dichloroethane (DCE) under argon for 24 h at 80 °C
(Table 1, entries 1–4). To our delight, the reaction
efficiently afforded desired 2,3-dihydro-1H-pyrrole
2a in 92% yield when AgSbF6 was used as the
catalyst (entry 4). Neither lowering the reaction
temperature to 60 °C (entry 5) nor shortening the
reaction time to 10 h (entry 6) provided any benefit.
The nature of the solvent greatly influenced the
reaction outcome (entries 7–10). Specifically, only a
trace of 2a was obtained when the solvent was
acetonitrile, 1,4-dioxane, or toluene, and the yield
was only 57% in CHCl3. Other Ag(I) catalysts gave
Next, we evaluated substrates bearing various
other aryl groups (Table 3). Products containing a
biphenyl ring (2p, 60%), thiophene ring (2q, 45%), or
pyridyl ring (2r, 65%) could be obtained under the
optimized conditions. In addition, we prepared
substrates 1s–1v to investigate the influence of the
2
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10.1002/adsc.201701121
Advanced Synthesis & Catalysis
nature of the protecting group on the cyclization
reaction. The electronic properties of the substituent
on the benzenesulfonyl group had some influence on
the reaction outcome: compounds with a chloro
substituent (1s), a t-Bu substituent (1u), or no
substituent (1v) gave the expected products in about
70% yield, whereas bromo-substituted compound 1t
gave a lower yield. The reaction also worked well
when we changed the benzenesulfonyl group to a
methyl sulfonyl group: compound 2w was obtained in
60% isolated yield. No hydrolysis or cyclization
product was obtained when n-propyl-substituted
homopropargyl sulfonamide 1x was employed as the
substrate (see Supporting Information).
Table 3. Effects of Other Aryl and Protecting Groups on
Reaction Outcome.[a]
Scheme 2. Control Experiments.
Two possible pathways for this intramolecular
cyclization reaction are depicted in Scheme 3.
Pathway 1 involves initial coordination of Ag(I) to
the triple bond of 1a with assistance from the tethered
nucleophile (HNTs), followed by regioselective
hydration to afford 3a via key intermediate A. Then
intramolecular cyclization of 3a affords cation 4a,
which loses a proton to generate 2a. Pathway 2,
which involves intramolecular hydroamination
catalyzed by AgSbF6, cannot be ruled out.
[a]Reaction conditions: 1 (1 equiv) and AgSbF6 (10 mol %)
in DCE (5 mL) at 80 °C under argon for 24 h. Isolated
yields are provided.
To study the reaction mechanism, we performed
some control experiments. When zeolites (4Å) were
present in the reaction mixture, the yield of 2a
dropped to 15% (Scheme 2a); this result suggests that
water played an important role in the reaction. When
1a was subjected to the standard conditions for a
shorter duration (10 h), we obtained hydrolysis
product 3a (40%) in addition to 2a (47%) (Scheme
2b). Subjecting 3a to the same conditions for 12 h
smoothly afforded 2a (Scheme 2c), but 3a could not
be transformed to 2a in the absence of a silver salt
(Scheme 2d), suggesting that AgSbF6 promoted the
intramolecular cyclization reaction. We also
evaluated the reactivity of alkyne 1a' under the
optimized conditions and found that hydrolysis
product 3a' did not form after 10 h (Scheme 2e).
Alkyne 1a did not provide the corresponding
hydration product (3a) either (Scheme 2f). These
results suggest that the presence of the tethered
nucleophile and its location relative to the triple bond
were crucial to the success of the reaction.[12]
Scheme 3. Proposed Reaction Pathways.
Because 2,3-dihydro-1H-pyrrole 2r is a key
intermediate in
a
reported synthesis of (S)-
nicotine,[11,12] the protocol described herein allowed
for a rapid formal synthesis of this natural product
starting from 3-iodopyridine and Ts-protected but-3-
yn-1-amine 1r, as shown in Scheme 4.
3
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10.1002/adsc.201701121
Advanced Synthesis & Catalysis
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M. Chong, J. Am. Chem. Soc. 2006, 128, 9646; b) J.
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Scheme 4. Formal Synthesis of (S)-Nicotine.
In summary, we have developed an efficient,
simple protocol for the synthesis of a range of
functionalized of 2,3-dihydro-1H-pyrroles, including
an intermediate in the reported synthesis of (S)-
nicotine.
[6] J.-J. Li in Name Reactions in Heterocyclic Chemistry
(Wiley-VCH: Weinheim, 2004).
Experimental Section
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A homopropargyl sulfonamide 1 (1 equiv), AgSbF6 (10
mol %), and DCE (5.0 mL) were added sequentially to a
Schlenk tube. The reaction mixture was stirred at 80 °C
under argon. When TLC indicated complete consumption
of the starting material, DCM and H2O were added to the
reaction mixture. After separation of the organic layer, the
water layer was extracted with DCM. The combined
organic layers were dried over anhydrous Na2SO4 and
filtered, the filtrate was evaporated, and the residue was
purified via column chromatography on silica gel with
petroleum ether/ethyl acetate as the eluent to afford the
desired product.
Acknowledgments
We are grateful to the National Natural Science Foundation of
China (21732002, 21672117, 21602117) and the Tianjin Natural
Science Foundation (16JCZDJC32400) for generous financial
support for our programs.
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Advanced Synthesis & Catalysis
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5
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10.1002/adsc.201701121
Advanced Synthesis & Catalysis
COMMUNICATION
Hydration and Intramolecular Cyclization of
Homopropargyl Sulfonamide Derivatives
Catalyzed by Silver Hexafluoroantimonate(V):
Synthesis of Structurally Diverse 2,3-Dihydro-1H-
Pyrroles
Adv. Synth. Catal. Year, Volume, Page – Page
Xiuling Yua, Zhonglin Guoa, Hongjian Songa*,
Yuxiu Liua and Qingmin Wanga,b*
6
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