Design, Sustainable Synthesis, and Programmed Reactions of Templated N-Heteroaryl-Fused Vinyl Sultams

Article abstract of DOI:10.1021/acs.joc.7b01340

A de novo design and synthesis of N-heteroaryl-fused vinyl sultams as templates for programming chemical reactions on vinyl sultam periphery or (hetero)aryl ring is described. The key features include rational designing and sustainable synthesis of the template, customized reactions of vinyl sultams at C=C bond or involving N-S bond cleavage, and reactions on the periphery of the heteroaryl ring for late-stage diversification. The simple, easy access to the template coupled with opportunities for the synthesis of diversely functionalized heterocyles from a single template constitutes a rare study in contemporary organic synthesis.

Full text of DOI:10.1021/acs.joc.7b01340

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Article
Design, Sustainable Synthesis, and Programmed
Reactions of Templated N-Heteroaryl Fused Vinyl Sultams
Joydev K. Laha, Shubhra Sharma, Seema Kirar, and Uttam Chand Banerjee
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01340 • Publication Date (Web): 21 Aug 2017
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Design, Sustainable Synthesis, and Programmed Reactions of Templated N-
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Heteroaryl Fused Vinyl Sultams
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Joydev K. Laha,*# Shubhra Sharma,# Seema Kirar, and Uttam C. Banerjee
#Department of Pharmaceutical Technology (Process Chemistry)
National Institute of Pharmaceutical Education and Research
S. A. S. Nagar, Punjab 160062, India
E-mail: jlaha@niper.ac.in
Department of Pharmaceutical Technology (Biotechnology)
National Institute of Pharmaceutical Education and Research
S. A. S. Nagar, Punjab 160062, India
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ABSTRACT
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A de novo design and synthesis of N-heteroaryl fused vinyl sultams as templates for
programming chemical reactions on vinyl sultam periphery or (hetero)aryl ring is described. The
key features include rational designing and sustainable synthesis of the template, customized
reactions of vinyl sultams at C=C bond or involving N-S bond cleavage, and reactions on the
periphery of the heteroaryl ring for late-stage diversification. The simple, easy access to the
template coupled with opportunities for the synthesis of diversely functionalized heterocyles
from a single template constitutes a rare study in contemporary organic synthesis.
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INTRODUCTION
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Template designing for programming chemical synthesis has received increasing attention over
the last two decades.1 Rational design of templates, their convenient access in fewest possible
steps, and employing them in sustainable chemical synthesis have brought the evolution of
sophisticated architectures of synthetic molecules closer to realization. Templates of various
origin including small organic molecules2 or bio-macromolecules3 have been developed to
perform a defined chemical task with remarkable fidelity. However, use of a template in diverse
chemical synthesis has been limited.3d
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Vinyl sulfonamides are privileged chemotypes employed in peptidomimetics,4 anti-infammatory
drugs and other medicinal agents,5 and biomaterials.6 Despite poor reactivity of C=C bond in
vinyl sulfonamides as compared to that in vinyl sulfones or sulfonates,7 vinyl sulfonamides have
a remarkable biomedical significance owing to their innate ability to act as irreversible inhibitors
of cysteine proteases through conjugate addition of the thiol group of the active site of cysteine
residue.8 While sulfonamide functionality has been demonstrated as carbonyl bioisostere making
key interactions with receptor proteins,9 it imparts, unlike carbonyl group, improved aqueous
solubility.10 Despite the presence of two key functional groups, chemical reactivity as Michael
acceptors although demonstrated less proficiently,8,11 and abilities to perform as agents for
probing biological systems,12 strategic design and development of vinyl sulfonamides has been
the study of limited investigations.13
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Scheme 1. Rational Design, Synthesis and Reactions of Templated N-Heteroaryl Fused
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Vinyl Sultams
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Therefore, a de novo design of vinyl sulfonamides, especially cylic vinyl sulfonamides (vinyl
sultams), their expedient access, and subsequent use in diversity organic synthesis could be an
aspiring object. The structural feature of a vinyl sultam I could include an endo-cyclic double
bond adopting a syn-geometry as platform for conjugate Michael addition, pharmacophoric
linchpin sulfonamide functionality, and chemoselective cleavage of N-S bond via hydrolytic or
nucleophilic cleavage (Scheme 1). These aspects could secure extensive functionalizations,
opportunities for the preparation of acyclic vinyl sulfonyl compounds, and preparation of
transposed acyclic vinyl sulfonamides by nucleophilic cleavage of N-S bond with amines.
Moreover, vinyl sultam I when fused to a heterocycle could display additional feature including
reactions on the periphery of the heterocycle and late-stage functionalization on the substituted
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arenes. Our previous experiences on palladium-catalyzed domino or convergent synthesis of
five-,14 six-,15 or seven-membered aryl-(hetero)aryl fused sultams16 and nucleophilic ring-
opening reactions of a highly reactive indole-aryl fused sultam14 provided a strong impetus to
strategic designing of templated sultams that are while elusive could execute programmed
chemical synthesis. Herein, we describe rational designing of an unprecedented template N-
heteroaryl fused vinyl sultam II, its sustainable synthesis, and multi-faceted reactivity affording
diverse functionalized N-heterocycles. The programmed reactions of vinyl sultams at C=C bond,
sultam ring-opening reactions via N-S bond cleavage, and reactions on the periphery of the
(hetero)aryl ring for further functionalization are the key demonstrations presented herein.
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RESULTS AND DISCUSSION
Based on our design, N-heterocycles bearing an aldehyde group at the 2-position and
arylmethanesulfonyl chloride deemed viable substrates for tandem N-sulfonylation followed by
intramolecular Knoevenagel condensation to form structurally distinct N-heterocycle fused vinyl
sultams. Our study began with the reaction of model substrates, pyrrole-2-carboxaldehyde (1a)
and phenylmethanesulfonyl chloride (2a), in the presence of a base forming pyrrole-fused vinyl
sultam 3a (Table 1). Reaction of 1a and 2a in the presence of 3 equiv of bases including NaNH2,
MHMDS (M = Li or K), and organic bases17 did not produce any product (entries 1-3). However,
the screening of other inorganic bases produced dissimilar results (entries 4-5). Interestingly,
NaOEt proved effective for N-S bond cleavages in sultams.
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Table 1. Optimization Studiesa
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Entr Base
y
Solvent
°C
%3ab
1
NaNH2
THF
THF
THF
THF
75
75
75
75
N.R
2c
3d
4e
MHMDS
org. base
MOBu-t
N.R
N.R
25-28
5e
NaOEt
EtOH
75
11
6f
7g
NaH
NaH
THF
THF
70
70
66
72
8h
NaH
THF
70
59
9g
NaH
NaH
NaH
NaH
DMF
110
110
rt
N.R
10g
11g
12g
1,4-
dioxane
Trace
Trace
27
THF
THF
50 °C
aReaction conditions: 1a (0.5 mmol), 2a (0.75 mmol),
b
base (1.5 equiv), solvent (2.5 mL), temp. 12 h. Isolated
c
yields. LiHMDS and KHMDS (3.0 equiv). DBU and
d
DBN (3 equiv). eLiOBu-t, KOBu-t, and NaOEt (3.0
f
g
h
equiv). NaH (3.0 equiv). NaH (2.5 equiv). NaH (2.0
equiv).
Among various inorganic bases, NaH in THF proved effective forming 3a in 66% yield (entry
6). While reducing the amount of NaH to 2.5 equiv had a positive impact in improving the yield,
further reduction to 2.0 equiv produced inferior result (entries 7-8). The other solvents such as
DMF or dioxane had detrimental effect on the yield of 3a (entries 9-10). In the attempts to isolate
the intermediate, on lowering the reaction temperature (entries 11-12), detrimental effects on the
yield of the product was observed. The best result was obtained when 1a (1 equiv) and 2a (1.5
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equiv) reacted in the presence of NaH (2.5 equiv) in THF (2.5 mL) at 70 °C for 12 h providing
3a in 72% isolated yield. The central challenge in this investigation was to find an optimum
condition that secured formation of vinyl sultam 3a.
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To expand the scope of the strategy, we utilized commercial or readily accessible pyrrole-2-
carboxaldehydes and arylmethanesulfonyl chlorides that could participate in the one-pot tandem
synthesis of pyrrole-fused vinyl sultams under the optimized conditions (Scheme 2).
Scheme 2. Synthesis of the Designed N-Heteroaryl Fused Vinyl Sultams
X
X
NaH- 2.5 equiv
CHO
ArCH2SO2Cl
1.5 equiv
THF- 2.5 mL
N
H
N
70 C, 12-14 h
S
1.0 equiv
Ar
(X = C,N)
O2
R
R3
R2
N
R
N
S
Ph
N
S
O2
R1
Ph
O2
S
Ph
O2
R1 = -H, R2 = R3 = -CO2Et,
R1 = -H, R2 = -CO2Et, R3 = -Me, 3i (79%)
R = -CO2Me, 3b (82%) R = -NO2, 3d (85%)
R = -CO2Et, 3c (73%)
R = -CN, 3e (89%)
R = -CO2Me, 3f (76%)
R = -Br, 3g (67%)
3h
(81%)
3j
R1 = -H, R2 = -CO2Me, R3 = -Me, (86%)
R1 = -Br, R2 = -Br, R3 = -H, 3k (65%)
OHC
N
N
N
N
EtO2C
N
N
S
S
S
SO2
O2
Ph
Ph
O2
O2
R = Br, 3l (38%)
R = Cl, 3m (61%)
R = Me, 3n (67%)
3q (67%)
Br
3o (78%)
Ph
3p
(71%)
CHO
CHO
N
N
S
N
N
N
S
O2
S
CF3
C
S
Ph
O
O2
O2
3u (96%)
O
O
O2
3v (<10%)
3r
3t
(35%)
(86%)
3s (00%)
Pyrrole-2-carboxaldehydes containing a functional group at 5- or 4-position were viable
substrates affording pyrrole-fused vinyl sultams 3b-3g in varying yields. Similarly, di-substituted
pyrrole-2-carboxaldehydes happened to be evenly competent producing sultams 3h-3k in good
yields. Notably, a di-bromo substituted vinyl sultam 3k could augur interesting post-synthetic
application. 4-substituted-phenylmethanesulfonyl chlorides (2b-d) also afforded the
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corresponding sultam 3l-n in moderate yields. Importantly, a bromo/chloro group could serve as
a synthetic handle for subsequent functionalization on arene ring. Other heterocycles, imidazole-
2-carboxaldehyde and indole-2-carboxaldehyde were subjected to the optimized condition
gratifyingly furnishing respective imidazole (3o) and indole-fused (3q) vinyl sultams in excellent
yields. However, imidazole-4-carboxaldehyde did not give a tandem fused vinyl sultam. Only N-
sulfonylated derivative of imidazole-4-carboxaldehyde 3p was isolated in this reaction. We next
set out to extend the methodology to synthesize kindred lactam. Reaction of phenylacetyl
chloride and pyrrole-2-carboxaldehyde gave the corresponding lactam 3r in 86% yield. Our
study indicates that use of an aliphatic methanesulfonyl chloride including (1S)-(+)-10-
camphorsulfonyl chloride or ethanesulfonyl chloride could exert a crucial challenge yielding N-
sulfonyl derivative 3t or 3u as the only isolable product. Only a limited success in the reaction of
1a and 2,2,2-trifluroethanesulfonyl chloride under the optimized condition was realized in the
synthesis of 3v. This experiment suggests that poor acidity of the methylene group in –
NCH2SO2- could explain the difficulty in intramolecular cyclization in 3t or 3u. The central
challenge in the preparation of N-heteroaryl fused vinyl sultams was to identify an optimized
condition, which yielded a sustainable synthesis of the vinyl sultams. Both the electron-
withdrawing and -donating groups screened in our study were well-tolerated to give sultams in
good to excellent yields.
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Next, we investigated the reactions of vinyl sultams at C=C bond (Scheme 3). Michael addition
of thiol 4 to the vinyl sultam 3b gave a diasteromeric mixture 4a and 4b which are easily
separable by column chromatography, furnishing cis- (J = 9.4 Hz) and trans- (J = 6.8 Hz)
isomers respectively in a ratio (7:3) as determined by the isolated yields (eq. 1). However,
reaction of aliphatic amines, such as n-propylamine or morpholine and 3b yielded only trans-
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isomer (J = 7.3 Hz) of 1,4-conjugate addition product, 4c and 4d, respectively (eq. 2). It is
noteworthy here that our template shows complete control of chemical reactivity at the vinyl
bond in the presence of sulfonamide bond. Hydrogenation or LAH reduction of vinylic C=C
bond in 3b gave reduced pyrrole-fused sultam 4e (eq. 3). 1,3-Dipolar cycloaddition reaction of
azomethine ylide, generated in situ from 5, was explored with vinyl sultams 3b-c, which yielded
novel pyrrolidine fused sultams bearing a quaternary center (4f-g) in good to excellent yields (eq.
4). The key discovery in this study was to uncover previously unexplored reactions of C=C
double bond of vinyl sultam template. The reduced pyrrole fused sultam 4e would have distinct
reactivity to that of 3b.
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Scheme 3. Reactions Explored at the C=C Bond of Pyrrole Fused Vinyl Sultam
During the course of our current study, one of our defined objectives was to uncover
previously unexplored chemoselective N-S bond cleavage (N-desulfonylation) 18 in vinyl sultams
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with a suitable nucleophile. Unlike our previous study on ring-cleavage of biaryl sultam,14 the
chemoselective N-S bond cleavage in vinyl sultams posed an intrinsic challenge due to the
presence of vinyl sulfonamide, a Michael acceptor. Predictably, the amine nucleophiles were
unsuccessful in N-S bond cleavage in pyrrole-fused sultams (cf. eq. 2, Scheme 3). However,
treatment of sultam 3a with excess NaOEt resulted N-S bond cleavage affording diarylvinyl
sulfonate (5a) and (E)-diarylalkene (5b) (eq. 5, Scheme 4).
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Scheme 4. Reactions explored at the N-S bond of vinyl sultam
Under a similar condition reaction of 3e and 6 gave diarylvinyl sulfonates 5c-d (eq. 6).
Importantly, the preparation of a vinyl sulfonate from vinyl sultam could complement the
literature protocol. However, reaction of 3b-c containing an ester group at C-5 position and
NaOEt furnished (E)-diarylalkenes 5e-f (eq. 7). Interestingly, phenylmagnesium bromide also
produced the similar results (eq 7). The formation of desulfonylated product 5e-f in the presence
of two different nucleophiles is especially noteworthy. Notably, the chemoselective N-S bond
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cleavage in pyrrole-fused sultams appears to be primarily dependent upon the substituents
present on the pyrrole ring.
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For studying the mechanism of the substituent dependent N-S bond cleavage, based on the
formation of products 5a and 5b, we carried out a control experiment for the synthesis of diaryl
alkene from diarylvinyl sulfonate in the presence of NaOEt. However, only a trace amount of 5b
was observed in 2 h suggesting slow desulfonylation. Based on our previous experiences on
nucleophilic ring opening of sultams via N-S bond cleavage, it may be stated that alkoxide reacts
with the pyrrole sultam to give vinyl sulfonate via ring opening of the sultam. The vinyl
sulfonate could undergo desulfonylation to yield the corresponding alkene.18a A plausible
mechanism could be the NaOEt mediated N-S bond cleavage followed by subsequent
desulfonylation from the anionic intermediate prior to proton abstraction. In the presence of an
electron-withdrawing group, the negative charge on pyrrole nitrogen is stabilized facilitating fast
desulfonylation resulting in diaryl alkenes, whereas in case of other substituents diarylvinyl
sulfonates are obtained.
In contrast to these results, reaction of pyrrole-fused vinyl sultams 3a-b,e and NaH at an elevated
temperature (70 °C) produced synthetically useful diarylalkynes 5g-i, demonstrating the simple,
yet rapid efficient synthesis of C2-alkynyl(NH)pyrroles (eq. 8). The formation of alkynes from
pyrrole sultam could follow a different pathway. In this case, a β-elimination could occur on
pyrrole sultam, which upon subsequent SO2 extrusion could form alkynes.18b However,
mechanism for the formation of alkenes or alkynes from pyrrole sultams is a subject of further
investigation. The key distinctive features of the pyrrole-fused vinyl sultam template include
ability to be diversified affording vinyl sulfonates, diarylalkenes, and diarylalkynes under N-S
bond cleavage conditions.
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We also explored the chemical reactivity of the pyrrole-fused sultam 3a towards aromatic
electrophilic substitution. Mono-bromination of pyrrole-fused sultam 6 using NBS occurred
exclusively at the C-5 position providing a synthetic handle for late-stage diversification (eq. 9).
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In conclusion, we have demonstrated, for the first time, that N-heterocycle fused vinyl sultams
could be a useful template for programming chemical synthesis. The sustainable synthesis of the
templates from N-heterocycles bearing an aldehyde group and arylmethanesulfonyl chlorides
employing only sodium hydride as the reagent is especially noteworthy. The template presents a
formidable framework that enables a variety of previously unexplored paradigm of reactions.
The operational simplicity to prepare the templates and explicit use of classical reactions on the
designed templates are the central features of this study. Future strides in this area could unveil
many formidable templates that could reveal boundless importance of these templates in
diversity organic synthesis.
EXPERIMENTAL SECTION
General Methods: Unless noted otherwise, all reagents and solvents were purchased from
commercial sources and used as received. All palladium-catalyzed reactions were performed in a
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screw-cap sealed tube. The H and C NMR spectra were obtained in CDCl3 as solvent using a
400 MHz spectrometer with Me4Si as an internal standard. Coupling constants (J values) are
reported in Hz. Column chromatography was performed using silica gel (100-200 mesh). High
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resolution mass spectra (HRMS) were obtained using electron spray ionisation (ESI) technique
and as TOF mass analyser. All melting points were taken using a melting point apparatus
equipped with a calibrated thermometer and are uncorrected. New compounds were
characterized by melting point, IR, 1H NMR, 13C NMR, and HRMS data.
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1. Typical Procedure for Substituted Pyrrole synthesis (1aa-1ae)19
Following a literature procedure, to a solution of sodium hydride (2 equiv) in THF (10 mL),
solution of p-toluenesulfonylmethylisocyanide (10 mmol) and michael acceptor (10 mmol) in
THF (10 mL) was added dropwise. As reaction mixture turned brownish upon addition,reaction
was allowed to continue overnight. Following which water (10 mL) was added and it was
extracted with EtOAc (3 x 10 mL). The combined organic layer was concentrated under reduced
pressure and washed with hexane to give substituted pyrrole.
2. General Procedure for Formylation of Pyrroles (1b-c, 1e-f, 1h-j)20
The Vilsmeier reagent was prepared by adding POCl3 (5.0 mmol) dropwise to ice cold dry DMF
(5 mL) under stirring. The mixture was then stirred for 10-15 min at 0 °C. To the above
Vilsmeier reagent was added substituted pyrrole (1.0 mmol) as a solution in DCE (5.0 mL). Then
the mixture was allowed to warm to 100 °C and was stirred for 1.0 h. After the staring material
was consumed (monitored by TLC), the reaction mixture was poured into saturated sodium
chloride aqueous (50 mL). The mixture was extracted with dichloromethane (3 × 20 mL), the
combined organic phase was washed with water (3 × 20 mL), dried over MgSO4, filtered and
concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, Ethyl
acetate: Hexanes = 2:8 to 1:1) to give desired product.
3. Standard Procedure for Nitration of Pyrrole (1d)21
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In an oven-dried screw cap vial equipped with a magnetic stir bar, the solution of Pyrrole-2-
carboxaldehyde (0.5 mmol) in carbon tetrachloride (2.5 mL) was treated with copper nitrate
trihydrate (1.5 equiv) and acetic anhydride (5 equiv) and heated at 50 °C. After completion of the
reaction (monitored by TLC), the reaction mixture was quenched with H2O (10 mL) and
extracted with EtOAc (20 mL X 2). The organic layer was dried (Na2SO4) and concentrated,
which upon chromatography [silica, EtOAc: Hexanes = 1:9] gave the desired product.
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4. Standard Procedure for Bromination of Pyrroles (1g, 1k, 6)22
To the solution of substrate (0.5 mmol) in DMF (4.0 mL) at 0 °C was added recrystallized N-
Bromosuccinimide (1.1 equiv) which gave rusty solution. After completion of the reaction
(monitored by TLC), the mixture turned light yellow and was quenched with saturated solution
of sodium sulfite (10 mL) and extracted with EtOAc (10 mL X 2). The organic layer was dried
(Na2SO4) and concentrated, which upon chromatography [silica, EtOAc: Hexanes = 0.5:9.5]
gave the corresponding brominated product.
5. General procedure for the synthesis of arylmethanesulfonyl chloride (2b-d)23
4-substituted benzyl bromide (5.0 mmol) were added dropwise to a solution of sodium sulfite
(5.0 mmol) in aqueous NaOH (10%, 5 mL) and the reaction mixture was heated at reflux for 4 h.
After cooling the solution in an ice bath, the corresponding sodium arylmethanesulfonates were
purified by recrystallization from CH3OH (95%). The intermediate (2.5mmol) was then treated
with thionyl chloride (10.0mmol) in DMF (2.5 mL) for 3 h at room temperature. The residue was
subsequently poured into the ice-water mixture and the solid was then extracted with diethyl
ether (3-20 mL). After removing the solvent under reduced pressure, desired product was
obtained.
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6. Synthesis of N-Heteroaryl-fused Vinyl Sultams (3a-v)
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In an oven-dried screw cap vial equipped with a magnetic stir bar, sodium hydride (2.5 equiv)
was added portion wise to an ice cold solution of formylated pyrrole substrate (0.5mmol) in
freshly distilled anhydrous THF (2.5 mL). To this reaction mixture was added phenyl methane
sulfonyl chloride (1.5 equiv) portion wise and was heated at 70 °C for 12 h. The reaction mixture
was allowed to cool to room temperature and neutralized by the addition of saturated solution of
NaCl (10 mL). Then, it was extracted with ethyl acetate (2 x 10 mL). The combined organic
layer was dried (Na2SO4), concentrated under reduced pressure, and purified by column
chromatography on silica using (EtOAc: Hexanes = 1:9 to 3:7) as an eluent to give the desired
product.
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7. General Procedure for Michael Addition at Vinyl Sulfonamide using Thiols and Amines
(4a-d)
In an oven-dried screw cap vial equipped with a magnetic stir bar, substrate (0.2 mmol) was
treated with methyl 3-mercaptopropanoate (0.26 mmol) in the presence of triethylamine (1.2
equiv) in methanol (1 mL) at room temperature for 15min. The solvent was removed under
reduced pressure and the reaction mixture was then diluted with H2O (5 mL) and extracted with
EtOAc (10 mL X 2). The organic layer was dried (Na2SO4) and concentrated, which upon
chromatography [silica, EtOAc: Hexanes = 3:7] gave the corresponding michael addition
product.
In an oven-dried screw cap vial equipped with a magnetic stir bar, substrate (0.2 mmol) was
treated with amine (1 mL) at 40 °C for 1 h. After completion of the reaction (monitored by
TLC),Thesolvent was removed under reduced pressure and the reaction mixture was diluted with
H2O (5 mL) and extracted with EtOAc (10 mL X 2). The organic layer was dried (Na2SO4) and
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concentrated, which upon chromatography [silica, EtOAc: Hexanes = 2:8] gave the
corresponding michael addition product.
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8. General Procedure for Hydrogenation of Vinyl Sultams (4e)
The vinyl sultam substrate (0.2 mmol), Pd/C (10 mol%) and methanol were added in the reaction
tube and then sealed. The reaction tube was thrice evacuated and flushed with hydrogen and
heated at 40 °C under hydrogen atmosphere. After the staring material was consumed (monitored
by TLC), the reaction mixture was diluted with methanol and passed through celite.The
combined organic layer was concentrated under reduced pressure and washed with hexane to get
reduced product.
In a perfectly dried two-necked flask, an ice-cold solution of substrate (0.2 mmol) and freshly
distilled THF (3.0 mL) under nitrogen was treated with LAH (4 equiv) portion wise. The
reaction was allowed to warm at room temperature and after the starting material was consumed
(monitored by TLC),the reaction was quenched with sodium hydroxide and extracted withEtOAc
(20 mL X 2). The organic layer was dried (Na2SO4) and concentrated, which upon flash
chromatography [silica, EtOAc: Hexanes = 2:8] gave the corresponding reduced product.
9. General Procedure for Cycloaddition with AzomethineYlide Precursor (4f-g)24
In an oven-dried aluminium foil coated screw-cap vial with a magnetic bar, vinyl sultam (0.2
mmol, 1 equiv) and Ag(I)F (2.2 equiv) were taken. [Note: Ag(I)F was completely dried under
vacuum at 55-60 °C at least for 30 min with aluminium foil coating before use]. The vial was
purged three times with nitrogen and kept under ice bath. A solution of the azomethineylide
precursor (1.1 equiv) in anhydrous DCM (1 mL) was added dropwise . The ice-bath was
removed, and the reaction mixture was stirred at room temperature for 10-15 min under nitrogen
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atmosphere. The reaction mixture was then diluted with 5 mL DCM and passed through a celite
bed. The filtrate was concentrated in vacuo and purified by column chromatography (100-200#
silica, ethyl acetate: hexane) to give the desired spirocyclic compound.
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10. General Procedure for Cleavage of N-S bond to form Sulfonate Ester and/orDiaryl
Alkene using NaOEt(5a-f)
In an oven-dried screw cap vial equipped with a magnetic stir bar, a solution of substrate (0.2
mmol) in THF (2 mL) was treated with freshly prepared sodium ethoxide solution in ethanol
(0.25mmol) at room temperature. After the staring material was consumed (monitored by TLC),
the reaction mixture was quenched with H2O (10 mL) and extracted with EtOAc (20 mL X 2).
The organic layer was dried (Na2SO4) and concentrated, which upon chromatography [silica,
EtOAc: Hexanes = 1:9] gave the corresponding sulfonate ester and/ordiaryl alkene.
11. General Procedure for Cleavage of N-S bond using Phenylmagnesiumbromide (5e-f)
In an oven-dried screw cap vial equipped with a magnetic stir bar, a solution of substrate (0.2
mmol) in THF (1 mL) was treated with phenylmagnesiumbromide (0.5 mL, 1M solution in THF)
at 60 °C for 2 h. After the staring material was consumed (monitored by TLC), saturated solution
of ammonium chloride (2 mL) was added and the mixture was diluted with H2O (10 mL) and
extracted with EtOAc (20 mL X 2). The organic layer was dried (Na2SO4) and concentrated,
which upon chromatography [silica, EtOAc: Hexanes = 1:9] gave the desulfonylated product.
12. General Procedure for Synthesis of Diaryl Alkynes using NaH (5g-i)
In an oven-dried screw cap vial equipped with a magnetic stir bar, a solution of substrate
(0.2mmol) in THF (2 mL) was treated with sodium hydride (1.2 equiv) and allowed to heat at 70
°C. After the staring material was consumed (monitored by TLC), the reaction mixture was
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quenched with H2O (10 mL) and extracted with EtOAc (20 mL X 2). The organic layer was
dried (Na2SO4) and concentrated, which upon chromatography [silica, EtOAc: Hexanes =
0.5:9.5] gave the correspondingdiaryl alkynes.
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COMPOUNDS CHARACTERIZATION DATA
1H-Pyrrole-3-carbonitrile (1aa): Colorless liquid (71 mg, 77%); IR (DCM, cm-1): 3307, 2961,
2249, 1423, 1058, 729; 1H NMR (CDCl3): δ 9.35 (bs, 1H), 7.33-7.32 (m, 1H), 6.83 (dd, J = 2.3,
2.5 Hz, 1H), 6.49 (s, 1H); 13C NMR (CDCl3): δ 126.0, 119.4, 117.3, 111.6; HRMS (ESI) m/z
calcd for C5H5N2 [M+H]+ 93.0453, found 93.0451.
Methyl 1H-pyrrole-3-carboxylate (1ab): Colorless solid (114 mg, 89%); mp.87-89 °C; IR
(KBr, cm-1): 3382, 2952, 1687, 1335, 1161, 765; 1H NMR (CDCl3): δ 8.52 (bs, 1H), 7.44 (s, 1H),
13
6.77 (d, J = 2.2 Hz, 1H), 6.66 (s, 1H), 3.82 (s, 3H); C NMR (CDCl3): δ 165.4, 123.4, 118.7,
116.3, 109.8, 51.1; HRMS (ESI) m/z calcd for C6H8NO2 [M+H]+ 126.0555, found 126.0550.
1
Diethyl 1H-pyrrole-3,4-dicarboxylate (1ac): Colorless solid (194 mg, 92%); H NMR
(CDCl3): δ 9.59 (bs, 1H), 7.37 (s, 2H), 4.33 (d, J = 7.1 Hz, 4H), 1.36 (m, 6H); 13C NMR
(CDCl3): δ 164.0, 164.2, 125.6, 115.9, 60.2, 28.2, 14.3; HRMS (ESI) m/z calcd for C10H14NO4
[M+H]+ 212.0923, found 212.0927.
Ethyl 4-methyl-1H-pyrrole-3-carboxylate (1ad): Colorless solid (126 mg, 83%); mp.61-62 °C;
IR (KBr, cm-1): 3325, 2925, 1685, 1323, 1154, 778, 600; 1H NMR (CDCl3): δ 8.64 (bs, 1H), 7.39
(dd, J = 2.3, 3.0 Hz, 1H), 6.55 (dd, J = 0.9, 2.0 Hz, 1H), 4.31 (d, J = 7.2 Hz, 2H), 2.30 (d, J = 0.9
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Hz, 3H), 1.37 (t, J = 7.1 Hz, 3H); C NMR (CDCl3): δ 165.8, 124.4, 121.0, 117.3, 114.8, 59.4,
14.5, 11.7; HRMS (ESI) m/z calcd for C8H12NO2 [M+H]+ 154.0868, found 154.0872.
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Methyl 4-methyl-1H-pyrrole-3-carboxylate (1ae): Colorless solid (128 mg, 92%); mp.125-126
°C; IR (KBr, cm-1): 3326, 2920, 1688, 1325, 1154, 702; 1H NMR (CDCl3): δ 8.87 (bs, 1H), 7.38
(dd, J = 2.2, 3.1 Hz, 1H), 6.54 (dd, J = 1.0, 2.0 Hz, 1H), 3.81 (s, 3H), 2.30 (d, J = 0.9 Hz, 3H);
13C NMR (CDCl3): δ 165.6, 124.3, 121.0, 117.2, 115.0, 59.3, 11.6; HRMS (ESI) m/z calcd for
C7H10NO2 [M+H]+ 140.0712, found 140.0711.
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Methyl 5-formyl-1H-pyrrole-2-carboxylate (1b): Colorless solid (116 mg, 76%); mp.100-101
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°C; IR (KBr, cm-1): 3300, 2959, 1730, 1675, 1264, 761; H NMR (CDCl3): δ 10.04 (bs, 1H),
9.68 (s, 1H), 6.96 (dd, J = 1.6, 2.2 Hz, 2H), 3.93 (s, 3H); 13C NMR (CDCl3): δ 180.4, 160.8,
134.4, 128.1, 119.7, 115.2, 52.2; HRMS (ESI) m/z calcd for C7H8NO3 [M+H]+ 154.0504, found
154.0509.
Ethyl 5-formyl-1H-pyrrole-2-carboxylate (1c): Colorless solid (146 mg, 87%); mp.78-79 °C;
1
IR (KBr, cm-1): 3134, 2958, 1730, 1269, 994, 765; H NMR (CDCl3): δ 10.28 (bs, 1H), 9.68 (s,
1H), 6.96-6.93 (m, 2H), 4.42 (q, J = 7.1 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H); 13C NMR (CDCl3): δ
180.5, 160.4, 134.4, 128.6, 119.7, 115.6, 61.4, 14.2; HRMS (ESI) m/z calcd for C8H10NO3
[M+H]+ 168.0661, found 168.0665.
4-Nitro-1H-pyrrole-2-carbaldehyde (1d): Colorless solid (74 mg, 53%); mp.131-132 °C; IR
1
(KBr, cm-1): 3444, 2079, 1666, 1392, 1073, 752; H NMR (CDCl3): δ 10.29 (bs, 1H), 9.61 (s,
1H), 7.90 (s, 1H), 7.48 (s, 1H); 13C NMR (CDCl3): δ 186.4 (d, J = 7 Hz),142.3, 137.1, 131.5,
119.5;HRMS (ESI) m/z calcd for C5H5N2O3 [M+H]+ 141.0300, found 141.0302.
5-Formyl-1H-pyrrole-3-carbonitrile (1e): Colorless solid (78 mg, 65%); mp.143-145 °C; IR
1
(KBr, cm-1): 3304, 2917, 2224, 1667, 1422, 1057, 728; H NMR (DMSO-D6): δ 13.05 (bs, 1H),
9.55 (d, J = 0.7 Hz, 1H), 7.99 (s, 1H), 7.48 (d, J = 1.3 Hz, 1H); 13C NMR (DMSO-D6): δ 180.7,
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133.7, 133.5, 123.0, 116.2, 94.2; HRMS (ESI) m/z calcd for C6H5N2O [M+H]+ 121.0402, found
121.0407.
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Methyl 5-formyl-1H-pyrrole-3-carboxylate (1f): Colorless solid (120 mg, 79%); mp.135-136
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°C; IR (KBr, cm-1): 3255, 1664, 1398, 1185, 1001, 764; H NMR (CDCl3): δ 10.53 (bs, 1H),
9.57 (d, J = 0.9 Hz, 1H), 7.74-7.73 (m, 1H), 7.42 (dd, J = 1.4, 2.4 Hz, 1H), 3.87 (s, 3H); 13C
NMR (CDCl3): δ 180.1, 164.0, 133.0, 130.0, 121.6, 118.7, 51.5; HRMS (ESI) m/z calcd for
C7H8NO3 [M+H]+ 154.0504, found 154.0506.
4-Bromo-1H-pyrrole-2-carbaldehyde (1g): Colorless solid (79 mg, 46%); mp.122-124 °C; IR
(KBr, cm-1): 3252, 3108, 2923, 1667, 1357, 770; 1H NMR (CDCl3): δ9.96 (bs, 1H), 9.47 (s, 1H),
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7.13 (s, 1H), 6.98 (s, 1H); C NMR (CDCl3): δ 178.9, 132.6, 126.1, 122.2, 98.8; HRMS (ESI)
m/z calcd for C5H5BrNO [M+H]+ 173.9555, found 173.9558.
Diethyl 2-formyl-1H-pyrrole-3,4-dicarboxylate (1h): Colorless solid (164 mg, 69%); mp.149-
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151 °C; IR (KBr, cm-1): 34433, 2825, 2067, 1667, 1285, 1190, 766; H NMR (CDCl3): δ 10.48
(bs, 1H), 9.90 (d, J = 0.5 Hz, 1H), 7.61-7.60 (m, 1H), 4.46 (q, J = 7.1 Hz, 2H), 4.35 (q, J = 7.1
Hz, 1H), 1.42-1.33 (m, 6H); 13C NMR (CDCl3): δ 180.9, 163.2, 162.7, 132.4, 128.7, 124.3,
118.3, 61.8, 60.8, 14.2, 14.1; HRMS (ESI) m/z calcd for C11H14NO5 [M+H]+ 240.0872, found
240.0871.
Ethyl 5-formyl-4-methyl-1H-pyrrole-3-carboxylate (1i): Colorless solid (135 mg, 75%);
1
mp.118-120 °C; IR (KBr, cm-1): 3325, 2855, 1685, 1451, 1154, 778; H NMR (CDCl3): δ 10.37
(bs, 1H), 9.71 (s, 1H), 7.69 (d, J = 3.3 Hz, 1H), 4.34 (d, J = 7.1 Hz, 2H), 2.62 (s, 3H), 1.38 (d, J
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= 7.1 Hz, 3H); C NMR (CDCl3): δ 178.5, 164.2, 134.5, 130.7, 130.5, 117.2, 59.9, 14.4, 10.0;
HRMS (ESI) m/z calcd for C9H12NO3 [M+H]+ 182.0817, found 182.0814.
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Methyl 5-formyl-4-methyl-1H-pyrrole-3-carboxylate (1j): Colorless solid (131 mg, 79%);
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mp.137-138 °C; IR (KBr, cm-1): 3246, 2927, 1638, 1264, 1171, 805; H NMR (CDCl3): δ 10.18
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(bs, 1H), 9.72 (s, 1H), 7.67 (d, J = 3.4 Hz, 1H), 3.85 (s, 3H), 2.62 (s, 3H); C NMR (CDCl3): δ
178.5, 164.5, 134.3, 130.5, 130.5, 116.9, 51.2, 9.9; HRMS (ESI) m/z calcd for C8H10NO3
[M+H]+ 168.0661, found 168.0659.
4,5-Dibromo-1H-pyrrole-2-carbaldehyde (1k): Colorless solid (164 mg, 69%); mp.144-146
1
°C; IR (KBr, cm-1): 3434, 3108, 2860, 1661, 1357, 770; H NMR (CDCl3): δ 10.56 (bs, 1H),
9.35 (s, 1H), 6.98 (s, 1H);13C NMR (CDCl3): δ 181.0, 132.4, 129.1, 124.3, 118.1; HRMS (ESI)
m/z calcd for C5H4Br2NO [M+H]+ 251.8660, found 251.8663.
(4-Bromophenyl)methanesulfonyl chloride (2b): Colorless solid (126 mg, 83%); mp.110-112
1
°C; IR (KBr, cm-1): 3397, 2921, 1770, 1371, 1246, 749; H NMR (DMSO-D6): δ 7.44 (dd, J =
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1.8, 6.5 Hz, 2H), 7.25 (d, J = 8.6 Hz, 2H), 3.69 (s, 2H); C NMR (DMSO-D6): δ 139.6, 137.6,
135.6, 124.8, 61.7; HRMS (ESI) m/z calcd for C7H7BrClO2S [M+H]+ 268.9039, found 268.9033.
1
(4-Chlorophenyl)methanesulfonyl chloride (2c): Colorless solid (85 mg, 77%); H NMR
(CDCl3): δ 7.48-7.43 (m, 4H), 4.85 (s, 2H).
p-Tolylmethanesulfonyl chloride (2d): Colorless solid (82 mg, 81%); 1H NMR (CDCl3): δ 7.39
(d, J = 8.0 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 4.85 (s, 2H).
2-Phenylpyrrolo[1,2-b]isothiazole 1,1-dioxide (3a): Colorless solid (16 6 mg, 72%); mp.118-
1
120 °C; IR (KBr, cm-1): 2924, 1588, 1323, 1170, 756, 651; H NMR (CDCl3): δ 7.72-7.69 (m,
2H), 7.51-7.44 (m, 3H), 7.26 (s, 1H), 7.22 (d, J = 3.0 Hz, 1H), 6.43 (t, J = 3.2 Hz, 1H), 6.37 (dd,
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J = 0.7 Hz, 3.3 Hz, 1H); C NMR (CDCl3): δ 140.2, 129.9, 129.3, 128.6, 127.1, 125.7, 118.5,
118.4, 116.9, 109.4; HRMS (ESI) m/z calcd for C12H10NO2S [M+H]+232.0432, found 232.0428.
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Methyl 2-phenylpyrrolo[1,2-b]isothiazole-6-carboxylate 1,1-dioxide (3b): Yellowish solid
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(118 mg, 82%); mp.154-155 °C; IR (KBr, cm-1): 3418, 2924, 2853, 1645, 1154, 749; H NMR
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(CDCl3): δ 7.74-7.71 (m, 2H), 7.48-7.47 (m, 3H), 7.19 (s, 1H), 7.01 (d, J = 3.6 Hz, 1H), 6.32 (d,
J = 3.6 Hz, 1H), 3.96 (s, 3H); 13C NMR (CDCl3): δ 159.1, 142.7, 133.0, 130.6, 129.4, 126.7,
126.4, 126.1, 122.6, 116.4, 108.6, 52.4; HRMS (ESI) m/z calcd for C14H12NO4S [M+H]+
290.0487, found 290.0492.
Ethyl 2-phenylpyrrolo[1,2-b]isothiazole-6-carboxylate 1,1-dioxide (3c): Yellowish solid (110
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mg, 73%); mp.125-127 °C; IR (KBr, cm-1): 3421, 2924, 1289, 1182, 751; H NMR (CDCl3): δ
7.75-7.73 (m, 2H), 7.50-7.47 (m, 3H), 7.20 (s, 1H), 7.03 (d, J = 3.6 Hz, 1H), 6.33 (d, J = 3.6 Hz,
1H) 4.47 (q, J = 7.1 Hz, 2H), 1.46 (t, J = 7.1 Hz, 3H); 13C NMR (CDCl3): δ 158.6, 142.5, 132.9,
130.5, 129.4, 126.9, 126.7, 126.1, 122.6, 116.4, 108.6, 61.7, 14.1; HRMS (ESI) m/z calcd for
C15H14NO4S [M+H]+ 304.0644, found 304.0648.
5-Nitro-2-phenylpyrrolo[1,2-b]isothiazole 1,1-dioxide (3d): Yellowish solid (117 mg, 85%);
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mp.187-188 °C; IR (KBr, cm-1): 3269, 2882, 1508, 1310, 1104, 749; H NMR (CDCl3): δ 8.05
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(s, 1H), 7.72-7.70 (m, 2H), 7.54-7.53 (m, 3H), 7.30 (s, 1H), 6.92 (d, J = 1.0 Hz, 1H); C NMR
(CDCl3): δ 141.8, 131.2, 129.7, 127.1, 126.2, 125.7, 117.9, 117.0, 103.3; HRMS (ESI) m/z calcd
for C12H9N2O4S [M+H]+ 277.0283, found 277.0285.
2-Phenylpyrrolo[1,2-b]isothiazole-5-carbonitrile 1,1-dioxide (3e): Off-white solid (113 mg,
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89%); mp.138-140 °C; IR (KBr, cm-1): 3433, 3124, 2232, 1634, 1342, 1158, 749; H NMR
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(CDCl3): δ 7.71-7.68 (m, 3H), 7.53 (t, J = 3.2 Hz, 3H), 7.28 (s, 1H), 6.58 (d, J = 0.9, 1H); C
NMR (CDCl3): δ 131.0, 129.6, 128.6, 126.1, 125.9, 124.6, 117.1, 113.7, 109.8, 101.6; HRMS
(ESI) m/z calcd for C13H9N2O2S [M+H]+ 257.0385, found 257.0379.
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Methyl 2-phenylpyrrolo[1,2-b]isothiazole-5-carboxylate 1,1-dioxide (3f): Yellowish solid
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(109 mg, 76%); mp.183-184 °C; IR (KBr, cm-1): 3439, 2924, 2091, 1644, 1206, 750; H NMR
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(DMSO-D6): δ 8.53 (s, 1H), 8.11 (s, 1H), 7.77 (d, J = 7.1 Hz, 2H), 7.59-7.52 (m, 3H), 6.87 (s,
1H), 3.79 (s, 3H); 13C NMR (CDCl3): δ 163.3, 140.8, 130.5, 129.5, 128.4, 126.4, 125.9, 123.9,
122.4, 118.1, 108.9, 51.8; HRMS (ESI) m/z calcd for C14H12NO4S [M+H]+ 290.0487, found
290.0482.
5-Bromo-2-phenylpyrrolo[1,2-b]isothiazole 1,1-dioxide (3g): Off-white solid (103mg, 67%);
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mp.138-139 °C; IR (KBr, cm-1): 3420, 1445, 1216, 1143, 921, 754, 569; H NMR (CDCl3): δ
7.70-7.68 (m, 2H), 7.52-7.47 (m, 3H), 7.23 (s, 2H), 6.39 (s, 1H); 13C NMR (CDCl3): δ 140.6,
130.4, 129.4, 128.3, 126.5, 125.9, 117.6, 117.4, 111.5, 104.6; HRMS (ESI) m/z calcd for
C12H9BrNO2S [M+H]+ 309.9537, found 309.9533.
Diethyl 2-phenylpyrrolo[1,2-b]isothiazole-4,5-dicarboxylate 1,1-dioxide (3h): Colorless solid
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(164 mg, 81%); mp.231-233 °C; IR (KBr, cm-1): 3272, 2975, 1710, 1667, 1255, 1066, 752; H
NMR (CDCl3): δ 7.75-7.73 (m, 2H), 7.70 (d, J = 0.3 Hz, 1H), 7.62 (s, 1H), 7.53-7.52 (m, 3H),
4.44 (q, J = 7.1 Hz, 2H), 4.44 (q, J = 7.1 Hz, 2H), 1.44 (t, J = 7.1 Hz, 3H), 1.40 (t, J = 7.1 Hz,
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3H); C NMR (CDCl3): δ 161.7, 161.4, 130.6, 130.0, 129.3, 127.7, 126.6, 124.8, 119.5, 114.4,
61.6, 61.2, 14.3, 14.1; HRMS (ESI) m/z calcd for C18H18NO6S [M+H]+ 376.0855, found
376.0857.
Ethyl 4-methyl-2-phenylpyrrolo[1,2-b]isothiazole-5-carboxylate 1,1-dioxide (3i): Colorless
solid (125 mg, 79%); mp.290-292 °C; IR (KBr, cm-1): 3421, 1711, 1637, 1355, 1150, 1070, 763,
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568; H NMR (CDCl3): δ 7.78 (s, 1H), 7.70-7.68 (dd, J = 1.7, 8.1 Hz, 2H), 7.50-7.45 (m, 3H),
7.30 (s, 1H), 4.35 (q, J = 7.1 Hz, 2H), 2.38 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H); 13C NMR (CDCl3): δ
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163.1, 130.2, 130.1, 129.4, 128.9, 127.7, 127.6, 125.7, 124.6, 123.3, 122.6, 120.5, 120.2, 60.3,
14.2, 11.4; HRMS (ESI) m/z calcd for C16H16NO4S [M+H]+ 318.0800, found 318.0797.
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Methyl 4-methyl-2-phenylpyrrolo[1,2-b]isothiazole-5-carboxylate 1,1-dioxide (3j): Colorless
solid (130 mg, 86%); mp.143-145 °C; IR (KBr, cm-1): 3444, 2924, 1634, 1332, 1161, 749, 562;
1H NMR (CDCl3): δ 7.77 (s, 1H), 7.70 (dd, J = 1.6, 7.8 Hz, 2H), 7.51-4.45 (m, 3H), 7.30 (s, 1H),
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3.86 (s, 3H), 2.38 (s, 3H); C NMR (CDCl3): δ 163.8, 138.9, 130.1, 129.4, 126.8, 126.6, 125.7,
123.3, 122.5, 121.5, 117.2, 51.5, 10.2; HRMS (ESI) m/z calcd for C15H14NO4S [M+H]+
304.0644, found 304.0648.
5,6-Dibromo-2-phenylpyrrolo[1,2-b]isothiazole 1,1-dioxide (3k): Colorless solid (125 mg,
65%); mp.193-196 °C; IR (KBr, cm-1): 3432, 2924, 2075, 1638, 1247, 749; 1H NMR (CDCl3): δ
7.68-7.66 (m, 2H), 7.50-7.48 (m, 3H), 7.11 (s, 1H), 6.38 (s, 1H); 13C NMR (CDCl3): δ 140.3,
130.5, 129.8, 129.5, 126.3, 126.0, 116.5, 112.1, 107.2, 103.3; HRMS (ESI) m/z calcd for
C12H8Br2NO2S [M+H]+ 387.8642, found 387.8649.
Ethyl 2-(4-bromophenyl)pyrrolo[1,2-b]isothiazole-6-carboxylate 1,1-dioxide (3l): Colorless
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solid (72 mg, 38%); mp.189-191 °C; IR (KBr, cm-1): 3434, 2923, 1638, 1459, 1329, 749; H
NMR (CDCl3): δ 7.65-7.60 (m, 4H), 7.21 (s, 1H), 7.04 (d, J = 3.7 Hz, 1H), 6.36 (d, J = 3.7 Hz,
1H), 4.48 (q, J = 7.1 Hz, 2H), 1.46 (t, J = 7.0 Hz, 3H); 13C NMR (CDCl3): δ 158.6, 141.5, 132.7,
127.5, 127.2, 125.7, 125.0, 122.6, 116.8, 109.0, 107.5, 61.8, 14.1; HRMS (ESI) m/z calcd for
C15H13BrNO4S [M+H]+ 381.9749, found 381.9744.
Ethyl 2-(4-chlorophenyl)pyrrolo[1,2-b]isothiazole-6-carboxylate 1,1-dioxide (3m): Yellow
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solid (103 mg, 61%); mp.174-176 °C; IR (KBr, cm-1): 3439, 2925, 1656, 1459, 743; H NMR
(CDCl3): δ 7.69 (d, J = 8.5 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H), 7.19 (s, 1H), 7.04 (d, J = 3.6 Hz,
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1H), 6.35 (d, J = 3.6 Hz, 1H), 4.48 (q, J = 7.0 Hz, 2H), 1.46 (d, J = 7.1 Hz, 3H); 13C NMR
(CDCl3): δ 158.5, 141.5, 136.7, 132.6, 129.7, 127.4, 127.1, 125.2, 122.6, 116.8, 108.9, 61.8,
14.1; HRMS (ESI) m/z calcd for C15H13ClNO4S [M+H]+ 338.0254, found 338.0250.
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Ethyl 2-(p-tolyl)pyrrolo[1,2-b]isothiazole-6-carboxylate 1,1-dioxide (3n): Off-white solid
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(106 mg, 67%); mp.143-144 °C; IR (KBr, cm-1): 3429, 2918, 1638, 1329, 566; H NMR
(CDCl3): δ 7.65 (d, J = 8.2 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 7.14 (s, 1H), 7.03 (d, J = 3.6 Hz,
1H), 6.30 (d, J = 3.6 Hz, 1H), 4.47 (q, J = 7.1 Hz, 2H), 2.42 (s, 3H), 1.46 (q, J = 7.2 Hz, 3H); 13C
NMR (CDCl3): δ 158.7, 142.8, 141.1, 133.1, 130.1, 126.7, 126.1, 123.9, 122.5, 115.3, 108.2,
61.7, 22.6, 14.1; HRMS (ESI) m/z calcd for C16H16NO4S [M+H]+ 318.0800, found 318.0804.
6-Phenylimidazo[1,2-b]isothiazole 5,5-dioxide (3o): Yellow solid (90 mg, 78%); mp.140-141
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°C; IR (KBr, cm-1): 3428, 3032, 1348, 1173, 757, 558; H NMR (CDCl3): δ 7.77-7.74 (m, 2H),
7.55-7.53 (m, 3H), 7.40 (d, J = 1.0 Hz, 1H), 7.36 (s, 1H), 7.30 (d, J = 1.5 Hz, 1H); 13C NMR
(CDCl3): δ 148.0, 144.3, 136.0, 131.4, 129.6, 126.5, 125.9, 116.6, 115.2; HRMS (ESI) m/z calcd
for C11H9N2O2S [M+H]+ 233.0385, found 233.0383.
1-(Benzylsulfonyl)-1H-imidazole-4-carbaldehyde (3p): Colorless solid (88 mg, 71%); mp.167-
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168 °C; IR (KBr, cm-1): 3284, 3131, 1680, 1423, 1204, 763, 526; H NMR (CDCl3): δ 9.87 (s,
1H), 7.63 (d, J = 1.1 Hz, 1H), 7.52 (s, J = 1.0 Hz, 1H), 7.45 (t, J = 7.4 Hz, 1H), 7.38 (t, J = 7.2
Hz, 2H), 7.10 (d, J = 7.3 Hz, 2H), 4.62 (s, 2H); 13C NMR (DMSO-D6): δ 181.8, 138.6, 135.6,
132.8, 130.7, 128.9, 127.9, 126.6, 57.9; HRMS (ESI) m/z calcd for C11H11N2O3S [M+H]+
251.0490, found 251.0494.
2-Phenylisothiazolo[2,3-a]indole 1,1-dioxide (3q): Yellow solid (164 mg, 67%); mp.152-154
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°C; IR (KBr, cm-1): 2925, 2854, 1731, 1458, 1273, 758; H NMR (CDCl3): δ 7.81 (dd, J = 1.6,
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7.8 Hz, 2H), 7.73 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 7.9 Hz, 1H), 7.53-7.48 (m. 3H), 7.44-7.37 (m,
1H), 7.37 (s, 1H), 7.28-7.24 (m, 1H), 6.69 (s, 1H); 13C NMR (CDCl3): δ 143.5, 134.0, 132.8,
132.7, 130.5, 129.4, 126.9, 126.7, 126.1, 123.4, 122.9, 118.0, 111.5, 105.4; HRMS (ESI) m/z
calcd for C16H12NO2S [M+H]+ 282.0589, found 282.0586.
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2-Phenyl-3H-pyrrolizin-3-one (3r): Reddish solid (83 mg, 86%); mp.110-111 °C; IR (KBr, cm-
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1): 3443, 1728, 1377, 1240, 779; H NMR (CDCl3): δ 7.80-7.77 (m, 2H), 7.43-7.39 (m, 2H),
7.36-7.32 (m, 1H), 7.23 (s, 1H), 6.98-6.97 (m 1H), 6.07-6.05 (m, 2H); 13C NMR (CDCl3): δ
165.0, 135.9, 133.1, 131.2, 129.8, 128.6, 128.4, 126.3, 118.8, 115.8, 111.5;HRMS (ESI) m/z
calcd for C13H10NO [M+H]+ 196.0762, found 196.0754.
1-((((1R)-7,7-Dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methyl)sulfonyl)-1H-pyrrole-2-
carbaldehyde (3t): Colorless solid (54 mg, 35%); mp.93-94 °C; IR (KBr, cm-1): 3148, 2924,
2857, 1713, 1568, 1386, 1089, 757, 675; 1H NMR (CDCl3): δ 9.73 (d, J = 0.7 Hz, 1H), 7.62-7.61
(m, 1H), 7.24 (dd, J = 1.7, 3.7 Hz, 1H), 6.43 (t, J = 3.5 Hz, 1H), 4.11 (d, J = 14.7 Hz, 1H), 3.98
(d, J = 14.6 Hz, 1H), 2.55-2.38 (m, 2H), 2.18-2.06 (m, 2H), 1.99 (d, J = 18.5 Hz, 1H), 1.83-1.76
(m, 1H), 1.52-1.48 (m, 1H), 1.21 (s, 3H), 0.96 (s, 3H); 13C NMR (CDCl3): δ 214.0, 178.2, 133.0,
130.8, 129.1, 111.3, 58.9, 52.5, 48.3, 42.6, 42.5, 27.0, 25.2, 19.8, 19.6; HRMS (ESI) m/z calcd
for C15H20NO4S [M+H]+ 310.1113, found 310.1110.
1-(Ethylsulfonyl)-1H-pyrrole-2-carbaldehyde (3u): Viscous oil (89 mg, 96%); IR (DCM, cm-
1): 3127, 2926, 1726,1364, 1167, 908, 611; 1H NMR (CDCl3): δ 9.74 (s, 1H), 7.59-7.58 (m, 1H),
7.26 (dd, J = 1.7, 3.4 Hz, 1H), 6.45 (t, J = 3.4 Hz, 1H), 3.86 (q, J = 7.4 Hz, 2H), 1.38 (t, J = 7.4
Hz, 3H); 13C NMR (CDCl3): δ 178.4, 133.2, 131.2, 128.5, 111.6, 49.6, 7.9; HRMS (ESI) m/z
calcd for C7H10NO3S [M+H]+ 188.0381, found 188.0388.
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2-(Trifluoromethyl)pyrrolo[1,2-b]isothiazole 1,1-dioxide (3v): Semi-solid (10 mg, 9%); IR
(DCM, cm-1):2928, 1645, 1030, 774, 630; 1H NMR (CDCl3): δ 7.56 (s, 1H), 7.27 (d, J = 2.9 Hz,
1H), 6.62 (d, J = 3.4 Hz, 1H), 6.50 (t, J = 3.2 Hz, 1H);13C NMR (CDCl3): δ 128.9, 128.9, 128.5,
125.5, 121.0, 117.9, 114.5; HRMS (ESI) m/z calcd for C7H5F3NO2S [M+H]+ 223.9993, found
223.9989.
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Methyl 3-((3-methoxy-3-oxopropyl)thio)-2-phenyl-2,3-dihydropyrrolo[1,2-b]isothiazole-6-
carboxylate 1,1-dioxide (4a): Yellow Semi-solid (52 mg, 64%); IR (DCM, cm-1): 2953, 2852,
1
1723, 1482, 1366, 1166, 753, 571, 529; H NMR (CDCl3): δ 7.58-7.50 (m, 5H), 7.14 (d, J = 3.6
Hz, 1H), 6.37 (d, J = 3.6 Hz, 1H), 5.10 (d, J = 9.4 Hz, 1H), 4.79 (d, J = 9.4 Hz, 1H), 3.92 (s, 3H),
3.67 (s, 3H), 2.69-2.66 (m, 2H), 2.48-2.44 (m, 2H); 13C NMR (CDCl3): δ 171.6, 159.1, 135.9,
130.6, 130.1, 129.4, 127.3, 123.2, 121.8, 106.9, 52.1, 52.0, 44.0, 34.2, 25.9; HRMS (ESI) m/z
calcd for C18H20NO6S2 [M+H]+ 410.0732, found 410.0734.
Methyl 3-((3-methoxy-3-oxopropyl)thio)-2-phenyl-2,3-dihydropyrrolo[1,2-b]isothiazole-6-
carboxylate 1,1-dioxide (4b): Yellow Semi-solid (22 mg, 28%); IR (DCM, cm-1): 2926, 2844,
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1721, 1478, 1369, 1170, 775, 580; H NMR (CDCl3): δ 7.45-7.38 (m, 3H), 7.24 (d, J = 7.3 Hz,
2H), 7.13 (d, J = 3.7 Hz, 1H), 6.36 (d, J = 3.6 Hz, 1H), 5.30 (d, J = 6.8 Hz, 1H), 5.09 (d, J = 6.8
Hz, 1H), 3.91 (s, 3H), 3.69 (s, 3H), 2.79-2.64 (m, 2H), 2.56 (t, J = 6.9 Hz, 2H); 13C NMR
(CDCl3): δ 171.8, 159.1, 137.8, 130.2, 130.1, 128.9, 128.8, 123.2, 122.5, 106.7, 52.2, 52.0, 43.4,
34.5, 27.8;HRMS (ESI) m/z calcd for C18H20NO6S2 [M+H]+ 410.0732, found 410.0734.
Methyl 2-phenyl-3-(propylamino)-2,3-dihydropyrrolo[1,2-b]isothiazole-6-carboxylate 1,1-
dioxide (4c): Viscous oil (66 mg, 95%); IR (DCM, cm-1): 3332, 2927, 1706, 1497, 1497, 1353,
1167, 751, 598; 1H NMR (CDCl3): δ 7.48 (s, 5H), 7.14 (d, J = 3.7 Hz, 1H), 6.33 (q, J = 0.8, 3.6
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Hz, 1H), 4.99 (d, J = 7.3 Hz, 1H), 4.85 (dd, J = 0.8, 7.3 Hz, 1H), 3.91 (s, 3H), 2.64-2.53 (m, 2H),
1.49-1.40 (m, 2H), 0.89 (t, J = 7.3 Hz, 3H); 13C NMR (CDCl3): δ 159.2, 138.7, 130.1, 129.7,
129.3, 128.7, 123.2, 121.2, 105.7, 58.1, 52.0, 47.9, 23.3, 11.5; HRMS (ESI) m/z calcd for
C17H21N2O4S [M+H]+ 349.1222, found 349.1218.
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Methyl 3-morpholino-2-phenyl-2,3-dihydropyrrolo[1,2-b]isothiazole-6-carboxylate 1,1-
dioxide (4d): Colorless solid (69 mg, 93%); mp.178-180 °C; IR (KBr, cm-1):3390, 2928, 2852,
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1705, 1493, 1353, 1154, 1083, 856, 750, 574; H NMR (CDCl3): δ 7.50-7.47 (m, 5H), 7.15 (d, J
= 3.6 Hz, 1H), 6.29 (d, J = 3.6 Hz, 1H), 5.18 (d, J = 7.2 Hz, 1H), 4.90 (d, J = 7.2 Hz, 1H), 3.89
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(s, 3H), 3.67-3.61 (m, 4H), 2.59-2.53 (m, 4H); C NMR (CDCl3): δ 159.1, 136.0, 130.1, 129.7,
129.7, 129.4, 123.5, 121.4, 106.5, 70.3, 66.9, 65.5, 52.1, 49.2; HRMS (ESI) m/z calcd for
C18H21N2O5S [M+H]+ 377.1171, found 377.1165.
Methyl 2-phenyl-2,3-dihydropyrrolo[1,2-b]isothiazole-6-carboxylate 1,1-dioxide (4e):
Colorless solid (54 mg, 93%); mp.148-149 °C; IR (KBr, cm-1): 2953, 1712, 1483, 1360, 1170,
754, 585; 1H NMR (CDCl3): δ 7.52-7.48 (m, 5H), 7.11 (d, J = 3.6 Hz, 1H), 6.16 (d, J = 3.6 Hz,
1H), 5.21 (t, J = 8.8 Hz, 1H), 3.91 (s, 3H), 3.76-3.61 (m, 2H); 13C NMR (CDCl3): δ 159.2, 134.8,
130.2, 129.3, 129.3, 129.0, 123.2, 121.1, 105.5, 71.2, 52.0, 28.0; HRMS (ESI) m/z calcd for
C14H14NO4S [M+H]+ 292.0644, found 292.0645.
Methyl 2-benzyl-3a-phenyl-2,3,3a,8b-tetrahydro-1H-dipyrrolo[1,2-b:3',4'-d]isothiazole-6-
carboxylate 4,4-dioxide (4f): Yellow solid (68 mg, 81%); mp.126-127 °C; IR (KBr, cm-1):
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2924, 2853, 1713, 1441, 1157, 954, 753; H NMR (CDCl3): δ 7.42-7.41 (m, 2H), 7.34-7.29 (m,
8H), 7.20 (d, J = 3.6 Hz, 1H), 6.12 (d, J = 3.5 Hz, 1H), 4.43-4.38 (m, 2H), 3.89 (s, 3H), 3.81 (d, J
= 13.5 Hz, 1H), 3.70 (d, J = 13.5 Hz, 1H), 3.24 (d, J = 8.8 Hz, 1H), 2.99 (d, J = 10.8 Hz, 1H),
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2.82 (t, J = 7.0 Hz, 1H); C NMR (CDCl3): δ 159.2, 138.5, 137.2, 134.8, 129.4, 129.0, 128.4,
128.3, 127.9, 127.3, 124.8, 120.6, 104.1, 83.2, 62.1, 60.8, 58.3, 51.9, 45.8; HRMS (ESI) m/z
calcd for C23H23N2O4S [M+H]+ 423.1379, found 423.1373.
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Ethyl
2-benzyl-3a-phenyl-2,3,3a,8b-tetrahydro-1H-dipyrrolo[1,2-b:3',4'-d]isothiazole-6-
carboxylate 4,4-dioxide (4g): Colorless solid (77 mg, 89%); mp.111-112 °C; IR (KBr, cm-1):
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2924, 2853, 1713, 1485, 1175, 698, 585; H NMR (CDCl3): δ 7.43-7.27 (m, 10H), 7.21 (d, J =
3.6 Hz, 1H), 6.11 (d, J = 3.6 Hz, 1H), 4.42-4.31 (m, 4H), 3.79 (q, J = 13.5 Hz, 2H), 3.22 (d, J =
8.8 Hz, 1H), 3.01 (d, J = 10.7 Hz, 1H), 2.81 (dd, J = 6.8, 8.6 Hz, 1H), 1.39 (t, J = 7.1 Hz, 3H);
13C NMR (CDCl3): δ 158.7, 137.2, 134.7, 129.5, 129.0, 128.5, 127.8, 124.6, 121.1, 104.2, 83.2,
68.5, 61.1, 60.6, 58.4, 45.7, 14.1; HRMS (ESI) m/z calcd for C24H25N2O4S [M+H]+ 437.1535,
found 437.1538.
(Z)-Ethyl 1-phenyl-2-(1H-pyrrol-2-yl)ethenesulfonate (5a): Off-white solid (22 mg, 41%);
mp.85-87 °C; IR (KBr, cm-1): 3351, 3107, 2339, 1655, 1187, 825, 623; 1H NMR (CDCl3): δ 7.63
(s, 1H), 7.57-7.50 (m, 5H), 6.71 (d, J = 0.9 Hz, 1H), 6.45 (s, 1H), 6.20-6.18 (m, 1H), 4.20 (q, J =
13
7.1 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H); C NMR (CDCl3): δ 131.5, 130.7, 130.0, 130.0, 129.7,
126.6, 125.8, 123.7, 118.7, 110.4, 66.8, 14.8; HRMS (ESI) m/z calcd for C14H16NO3S [M+H]+
278.0851, found 278.0854.
(E)-2-styryl-1H-pyrrole (5b): Colorless solid (13 mg, 34%); mp.128-130 °C; IR (KBr, cm-1):
3297, 2971, 1639, 1385, 1102; 1H NMR (CDCl3): δ 8.38 (bs, 1H), 7.47 (d, J = 7.5 Hz, 2H), 7.38
(t, J = 7.4 Hz, 2H), 7.27 (t, J = 7.2 Hz, 1H), 7.03 (d, J = 16.4 Hz, 1H), 6.84 (d, J = 1.1 Hz, 1H),
6.71 (d, J = 16.4 Hz, 1H), 6.40 (s, 1H), 6.30-6.28 (m, 1H); 13C NMR (CDCl3): δ 137.5, 130.8,
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