A ring closing metathesis-manganese dioxide oxidation sequence for the synthesis of substituted pyrroles

Article abstract of DOI:10.1016/j.tet.2016.03.088

The combination of ring closing, or enyne metathesis with oxidation in order to prepare N-sulfonyl pyrroles is described. Reasonable to good yields were obtained for a variety of substituents and the procedure may also be conducted in one-pot. 2-Bromo N-sulfonyl adducts prepared in this manner were subjected to an intramolecular Heck-type cyclisation, forming cyclic sulfonamides.

Full text of DOI:10.1016/j.tet.2016.03.088

Tetrahedron 72 (2016) 2552e2559
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A ring closing metathesis-manganese dioxide oxidation sequence
for the synthesis of substituted pyrroles
*
Aaron Keeley, Shane McCauley, Paul Evans
Centre for Synthesis and Chemical Biology, School of Chemistry, University College Dublin, Dublin 4, Ireland
a r t i c l e i n f o
a b s t r a c t
Article history:
The combination of ring closing, or enyne metathesis with oxidation in order to prepare N-sulfonyl
pyrroles is described. Reasonable to good yields were obtained for a variety of substituents and the
procedure may also be conducted in one-pot. 2-Bromo N-sulfonyl adducts prepared in this manner were
subjected to an intramolecular Heck-type cyclisation, forming cyclic sulfonamides.
Ó 2016 Elsevier Ltd. All rights reserved.
Received 4 February 2016
Received in revised form 8 March 2016
Accepted 21 March 2016
Available online 26 March 2016
Keywords:
Sulfonamide
Sultam
Heterocycle
Biaryl
Dehydrogenation
Heck reaction
1. Introduction
reactions4 have been used to convert the intermediate non-
aromatic compounds into the aromatic products.
The synthesis of aromatic heterocycles is of interest, in part due
to their many applications. Several well-developed, classical
methods e such as the Paal-Knorr reaction and its variants for
example e are available to chemists for the construction of this
compound class.1 More recently, the advent of structurally well-
defined ruthenium metathesis catalysts (see Fig. 1, 1e3) for inter
and intramolecular carbon-carbon bond formation has opened up
alternative strategies for the assembly of aromatic heterocycles.2 As
shown in Scheme 1, post metathesis, elimination3 and oxidation
Ph
(ii) H+
Ph
MeO
Ph
(i) 2
MeO
N
N
N
Ts
Ts
Ts
5: 74%
4
1, FeCl3·6H2O,
N
Ph
N
Ph
N
Ph
DCM, O2, 40 °C
NMes
MesN
Cl
6
7: 82%
NMes
Ph
MesN
Cl
Scheme 1. Selected examples of metathesis followed by elimination,3c or oxidation4g
for the synthesis of pyrroles.
PCy3
Ru
PCy3
Ph
Ru
O
Cl
Cl
Cl
Ru
For several years we have investigated the synthesis and
chemistry of a range of benzo-fused cyclic sulfonamides (e.g., 10)5
and as an extension of this work also considered methods for the
synthesis of N-sulfonyl pyrroles (Scheme 2). N-Sulfonyl pyrroles
represent useful compounds,6 methods exist for their regiose-
lective functionalisation, for example and they participate in Diel-
seAlder cycloaddition reactions.7 This paper describes a robust
Cl
PCy3
1
2
3
Fig. 1. Ruthenium-based catalysts for ring closing metathesis (RCM).
metathesis-oxidation strategy to prepare
a
range of N-
* Corresponding author. E-mail address: paul.evans@ucd.ie (P. Evans).
http://dx.doi.org/10.1016/j.tet.2016.03.088
0040-4020/Ó 2016 Elsevier Ltd. All rights reserved.

A. Keeley et al. / Tetrahedron 72 (2016) 2552e2559
2553
MeO
MeO
Br
MeO
MeO
Br
MeO
MeO
(i)
(ii)
(v)
N
N
N
N
S
O2
S
O2
S
10
8
9
O2
(iii)
(iv)
MeO
MeO
Br
MeO
MeO
Br
MeO
MeO
N
N
S
O2
S
O2
S
O
12
11
O2
13
(i) 1 (5 mol%), DCM, rt, 95%; (ii) Pd(OAc) , PPh , K CO , DMF, 110 °C, 15 h; then H , rt,
2
3
2
3
2
12 h, 52%; (iii) 1 (5 mol%), PhH, rt, 0.75 h; then TBHP (2 equiv.) rt, 18 h, 38% 11 and 22% 12;
(iv) MnO (20 equiv.), PhH, 80 °C, 1 h, quant.; (v) Intramolecular Heck-type reaction.
2
Scheme 2. An RCM-oxidation-based route to N-sulfonyl pyrrole 11.
functionalised pyrroles and includes some preliminary Pd-
mediated cyclisation reactions as a means to prepare more elabo-
rate fused scaffolds (e.g., 13).
amounts of the heterogeneous oxidant the reactions were found to
afford the product in lower yields than those reported in Scheme 3
and did not reach completion in the same reaction period.
R1
R1
R1
R1
2. Results and discussion
As outlined in Scheme 2, we have previously reported how an
intramolecular Heck reaction (IHR) of N-sulfonyl dihydropyrrole 9,
followed by alkene reduction, generates cyclic sulfonamide 10
whose behaviour in the presence of reductants has been studie-
d.5a,d In relation to this study we became interested in the analo-
gous chemistry of the N-sulfonyl pyrrole family of compounds;
exemplified by the sulfonyl tethered 2-aryl pyrrole 13. Thus,
a means to access functionalised N-sulfonyl pyrroles (of the type
11) was considered. As depicted in Scheme 2, one attractive method
utilises RCM whereupon, in the same reaction vessel, the initially
formed dihydropyrrole (e.g., 9) is oxidised into the corresponding
pyrrole (e.g., 11).4f This method relies on the addition of tert-butyl
hydroperoxide (TBHP) to the initially formed dihydropyrrole which
may act as an oxidant directly, or may convert the low-oxidation
state ruthenium into a more aggressive oxidant. Our initial explo-
ration of this method provided interesting results. Treatment of 8
with Grubbs catalyst 1, under the recommended conditions4f
resulted in a rapid RCM to generate 9. At this stage TBHP was
added and the mixture was stirred overnight (for approximately
18 h). Purification by flash column chromatography provided the
expected N-sulfonyl pyrrole 11 as the main product (38%). However,
the oxidation did not proceed to completion and dihydropyrrole 9
(22%) was isolated. Additionally, unsaturated lactam 12 (22%) was
also detected. Based on this finding we sought an alternative
method that might avoid side product formation. Since it is well-
appreciated that manganese(IV) dioxide can oxidise non-aromatic
precursors8 the use of this reagent was considered. As shown in
Scheme 2, treatment of dihydropyrrole 9 with an excess of MnO2, in
benzene at reflux, efficiently led to the formation of pyrrole 11.
Based on the success and efficiency of this heterogeneous re-
action its similar use was studied for a range of N-sulfonyl dihy-
dropyrroles. As shown in Scheme 3 efficient conversion was
observed for several different aryl substitution patterns. Benzene
(Entries 1 and 2) could be replaced with toluene also at reflux
(Entry 3). In these examples, presumably due to the temperature,
reaction periods of 1e3 h were typically required to achieve com-
plete oxidation. The use of less than 20 equiv of MnO2 was studied.
In these cases the reactions do proceed, however, with smaller
N
N
MnO2 (20 eq.),
PhH, 80 °C
R
R
R
SO2
SO2
or PhMe, 110 °C;
or DCM, 40 °C
R
X
X
14-17
18-21
R1
Yielda
90%b
89%b
Entry Substrate Product
R
H
X
1
2
3
4
14
15
16
17
18
Br
H
H
19 OCH2O Br
OMe Br (CH2)4 58%c 69%d
20
21
NO2
98%d
H
H
a
c
b
Isolated yields following chromatographic purification; PhH;
d
PhMe; DCM
Scheme 3. Manganese(IV) dioxide mediated oxidation of N-sulfonyl dihydropyrroles.
In terms of purification; simple filtration, in order to remove the
manganese-based material was performed through CeliteÒ. In the
case of benzene, NMR spectroscopy typically indicated no further
purification was necessary and it may be the case that the spent
Grubbs catalyst is converted into an insoluble species at this stage.
However, when toluene was used small amounts of benzaldehyde
were produced and therefore, chromatographic purification be-
came necessary.
In an attempt to move away from benzene and to obviate the
formation of PhCHO as a side product when toluene was used,
dichloromethane was considered. As Entries 3 and 4 indicate sim-
ilar yields may be achieved using this solvent. However, longer
reaction periods were required in order to achieve these compa-
rable yields. The preparation of pyrrole 21 demonstrated compat-
ibility with the nitro-containing nosyl protecting group (Entry 4).9
Based on the optimisation study described above the possibility
of telescoping the RCM and the Mn-mediated oxidation was con-
sidered. As shown in Scheme 4 this proved to be feasible and the
different phases could be performed sequentially in the same

2554
A. Keeley et al. / Tetrahedron 72 (2016) 2552e2559
reaction vessel. Entries 1 to 4 show that a range of different N-
substituted diallyl compounds were subjected to RCM in DCM at
room temperature with Grubbs catalyst 1. On completion of me-
tathesis, MnO2 was added and the mixture was heated to reflux
overnight. Good to excellent yields of the N-sulfonyl (11, 26), amido
(27) and phenyl (7) pyrrole products (Entries 1e4) were observed
demonstrating the compatibility of this sequence with alternative
N-substutents.
N
SO2
N
SO2
R
R
R
R
(i)
X
X
30: R = X = H;
32: R = X = H; 53%
33: R = OMe, X = Br; 81%
31: R = OMe, X = Br
R1
R1
R1
X
X
(iii)
(i)
N
R
N
R
N
R
O2S
N
or (ii)
O2S
H
N
N
6,8,22-25
7,11,26-29
(ii)
(iii)
(i) 1 (3 mol%), DCM, rt, 1 h to 18 h; (ii) 3 (3 mol%),
DCM, 40 °C, 3 - 15 h (or PhMe 80 °C); (iii) MnO
(20 equiv.), 40 °C, 18 h (or PhMe 110 °C).
2
N
SO2
N
H
N
SO2
38
Entry
Product
R
R1 Yielda
Substrate
b
H
H
H
H
1
2
3
4
8
22
23
6
11
26
27
7
95%
74%
91%
84%
ArSO2
PhSO2
Bz
Ph
X
X
36: X = NO2; 50%
37: X = Br; 85%;
34: X = NO2;
35: X = Br
5c
24
25
28
29
(i) 1 (3 mol%), DCM, rt, 3 h; then MnO (20 equiv.), 40 °C, 18-24 h;
2
Ph
PhSO2
Me 68%
Ph
6d
(ii) 1 (3-5 mol%), DCM, rt, 1 h; then MnO (30-42 equiv.), 40 °C, 24 h;
2
71%
(iii) 36, PhSH, K CO , DMF, rt, 24 h, 75%.
2
3
a
b
c
Isolated yields; For structure see Scheme 2; 3, DCM,
Scheme 5. One-pot enyne metathesis-oxidation for the synthesis of substituted
c
40 °C, 15 h; 3, PhMe, 80 °C, 3 h.
pyrroles.
Scheme 4. One-pot RCM-oxidation for the synthesis of substituted pyrroles.
temperatures, average to good yields of the corresponding cyclic
sulfonamides were obtained. In the case of the tetrasubstituted
pyrrole 41, a single crystal X-ray structure provided unequivocal
structural confirmation.16
It is interesting to note that compound 18 has been reported to
undergo a Suzuki-type reaction, demonstrating that, under the
specified reaction conditions at least, this type of cross coupling
proceeds at a faster rate than the intramolecular processes reported
here.17
Following these positive results, bis-pyrrole 37 was subjected to
identical conditions in the hope that a double, regioselective,
intramolecular Heck-type process might occur. Unfortunately, this
proved too ambitious and a complex reaction mixture was pro-
duced, which could not be simplified chromatographically.
In order to prepare more densely substituted pyrroles the sec-
ond generation Hoveyda Grubbs catalyst 3 was used at elevated
temperature for the RCM reaction phase. Thus, in either DCM (Entry
5) or toluene (Entry 6) the 3-methyl and 3-phenyl substituted
pyrroles 28 and 29 were ultimately accessed in acceptable yield.
Following the success of the alkene metathesis approach a con-
ceptually similar enyne metathesis-oxidation sequence was in-
vestigated. As described in Scheme 5, alkynes 30 and 31 were
initially treated with 1 in order to affect enyne metathesis,
whereupon the in situ formed 3-substituted pyrrolines were then
treated with MnO2. In this manner, pyrroles 32 and 33 were syn-
thesised in reasonable to good yield.10 In an extension of this idea,
alkynes 34 and 35, synthesised by double propargylation using 1,4-
dichlorobut-2-yne with the corresponding N-allyl sulfonamides,11
were converted into bis-pyrroles 36 and 37. To demonstrate the
potential utility of this method, under standard conditions9 the
nosyl groups in compound 36 were cleaved in order to prepare bis-
pyrrole 38.12
3. Conclusion
In summary, a protocol has been reported for the conversion of
a range of dihydropyrroles into the corresponding pyrroles which
relies on MnO2 as the heterogeneous oxidant. In turn the dihy-
dropyrroles were accessed by ring closing or enyne metathesis and
the two processes can be performed in one reaction vessel if de-
sired. In optimised cases yields obtained were good and the re-
actions cleanly proceeded to completion. Indeed in certain
instances microanalytically pure material can be obtained by sim-
ple filtration suggesting that the remaining ruthenium catalyst may
be absorbed by the heterogeneous manganese. Appropriately
substituted N-sulfonyl pyrroles were converted into their parent
pyrrole (e.g., 38) and subjected to intramolecular Heck-type cycli-
sations demonstrating their potential further use.7
There are reports concerning the use of pyrroles in intra-
molecular Heck-type processes,13 however, as a substrate class
these systems have not been as widely studied as typical al-
kenes.14,15 Mechanistically, it is likely that this type of substrate
undergoes reaction via a pathway involving a CeH activation in the
ring forming step as opposed to
p-bond insertion (termed con-
certed metallation deprotonation pathway).14 The IHR of several of
the previously discussed 2-bromo-functionalised N-sulfonyl pyr-
roles was considered. In all cases, as shown in Scheme 6, under
standard Heck-type conditions using Pd(OAc)2 as a pre-catalyst,
triphenylphosphine and potassium carbonate in DMF at elevated

A. Keeley et al. / Tetrahedron 72 (2016) 2552e2559
2555
4.2. General method for pyrrole formation
All one-pot reactions were carried out in the same solvent and
consisted of two phases. Part one: The substrate was treated with
either Grubbs first generation 1 (3e5 mol %), or Hoveyda-Grubbs
second generation catalyst 3 (3e5 mol %) and monitored using
TLC (and/or 1H NMR spectroscopy) to ensure reactions were com-
plete. Part two: MnO2 (20 equiv) was added and the mixture heated
to reflux. Commercial MnO2 was stored at temperatures over
100 ꢀC prior to use and was weighed and briefly cooled in air before
addition. Following oxidation the mixture was cooled and filtered
under vacuum through CeliteÒ, washing with an appropriate sol-
vent. Solvent removal under reduced pressure afforded the crude
material which was purified by flash column chromatography
where necessary.
4.2.1. 1-((2-Bromo-4,5-dimethoxyphenyl)sulfonyl)-1H-pyrrole
11
(MnO2 method). 1-((2-Bromo-4,5-dimethoxyphenyl)sulfonyl)dihy-
dropyrrole 95a (74 mg, 0.21 mmol, 1 equiv) was dissolved in PhH
(5 mL). To this reaction mixture MnO2 (370 mg, 4.25 mmol,
20 equiv) was added. Stirring was continued at reflux for 1 h. The
reaction mixture was allowed to cool to room temperature and the
insoluble MnO2 was filtered under vacuum through CeliteÒ and
washed with DCM (2ꢁ10 mL). Following solvent removal under
reduced pressure and purification by flash column chromatography
(c-Hex-EtOAc; 4:1), 11 (73 mg, quant.) was isolated as a colourless
crystalline solid. Mp 129e131 ꢀC; Rf¼0.30 (c-Hex-EtOAc; 3:1);
vmax¼2366, 2341, 1506, 1429, 1220, 1167, 1054, 755, 673, 615,
571 cmꢂ1; HRMS (ESI): calcd for [(C12H12NO4S79BrþH)]þ 345.9749,
found 345.9760; 1H NMR (400 MHz, CDCl3) 7.37 (1H, s, CH),
7.24e7.21 (2H, m, CH), 7.08 (1H, s, CH), 6.31e6.29 (2H, m, CH), 3.89
(3H, s, CH3), 3.80 (3H, s, CH3) ppm; 13C NMR (100 MHz, CDCl3)
d
¼153.2, 148.2, 129.9, 121.5, 117.7, 112.9, 112.7, 112.5, 56.6, 56.4 ppm;
Anal. found (Calcd) for C12H12BrNO4S: C, 41.71% (41.63%); H, 3.31%
(3.49%); N, 3.88% (4.05%).
Scheme 6. Intramolecular Heck reaction of pyrrole-based sulfonamides 11, 18e20 and
single crystal X-ray crystallographic structure of 41 (Ortep plots to 50% probability).
4.2.2. 1-((2-Bromo-4,5-dimethoxyphenyl)sulfonyl)-1H-pyrrole
11
(TBHP method). Under N2 a solution of 8 (58 mg, 0.15 mmol,
1 equiv) in degassed benzene (1 mL) was treated at room tem-
perature with 1 (6 mg, 0.07 mmol, 5 mol %). Stirring was continued
4. Experimental
for 45 min at which point TBHP, a 5.5 M solution in decane (60 mL,
4.1. General directions
0.33 mmol, 2 equiv) was added. Stirring was continued at room
temperature for 18 h whereupon the mixture was purified by flash
column chromatography (c-Hex-EtOAc; 3:1) which gave 11 (20 mg,
38%) as a colourless solid with data as above. Further elution gave
the dihydropyrrole 95a (12 mg, 22%) and unsaturated lactam 12
(12 mg, 22%) as a viscous oil. Data for 12: Rf¼0.10 (c-Hex-EtOAc;
3:1) vmax¼3061, 2930, 2846, 1722, 1585, 1502, 1438, 1363, 1335,
Reagents from commercial suppliers were used without further
purification and anhydrous DMF, toluene (PhMe), cyclohexane (c-
Hex) and DCM were purchased and used as such. Thin layer chro-
matography (TLC) was carried out on Merck silica gel aluminium
sheets (60 F254). Merck silica gel (60, 0.040e0.063 mm) was used
for the flash column chromatography. NMR spectra were recorded
on Varian 300 MHz, 400 MHz, or 500 MHz spectrometers and
calibrated using trimethylsilane (TMS). All values are reported in
ppm. IR spectra were recorded on a Bruker Alpha FTIR spectrom-
eter. High Resolution Mass Spectra (HRMS) were recorded using
a Waters Crop, Micromass LCT, Electrospray Ionisation (ESI) spec-
trometer. Elemental analysis was performed at UCD. Melting Points
were determined in an open capillary on a Gallenkamp melting
1262, 1154, 1019, 732 cmꢂ1
;
HRMS (ESI): calcd for
[(C12H12NO5S79BrþNa)]þ 383.9517, found 383.9533; 1H NMR
(400 MHz, CDCl3) 7.82 (1H, s, CH), 7.34 (1H, dt, J¼6.0, 2.0 Hz, CH),
7.06 (1H, s, CH), 6.05 (1H, dt, J¼6.0, 2.0 Hz, CH), 4.79 (2H, t, J¼2.0 Hz,
CH2), 3.97 (3H, s, CH3), 3.86 (3H, s, CH3) ppm; 13C NMR (100 MHz,
CDCl3) 169.9, 153.4, 147.9, 147.1, 129.0, 126.6, 116.9, 115.9, 111.8, 56.6,
56.55, 53.1 ppm.
4.2.3. 1-((2-Bromophenyl)sulfonyl)-1H-pyrrole 18. 13bDihydropyrrole
145a (25 mg, 0.087 mmol, 1 equiv) was dissolved in PhH (5 mL). To
this reaction mixture MnO2 (153 mg, 1.76 mmol, 20 equiv) was
added. Stirring was continued at reflux for 18 h and as described
above the reaction mixture was allowed to cool to room tempera-
ture, filtered and washed with DCM (2ꢁ20 mL). Solvent removal
under reduced pressure gave 18 (22 mg, 90%) as colourless crystal-
line solid. Mp 90e93 ꢀC (lit.13b mp 83e85 ꢀC); Rf¼0.45 (c-Hex-EtOAc,
12:1); 1H NMR (400 MHz, CDCl3) 7.76e7.71 (2H, m, CH), 7.47e7.40
point
apparatus
and
are
uncorrected.
2-Bromo-4,5-
dimethoxybenzene-1-sulfonyl
bromobenzenesulfonamide,5e
dimethoxybenzenesulfonamide,5e
chloride,5a
N-allyl-2-
N-allyl-2-bromo-4,5-
N-allylaniline,4f,18
N,N-dia-
llylbenzene sulfonamide 22,19 N,N-diallylbenzamide 23,20 N,N-
diallylaniline 6,4f N-allyl-N-(2-methylallyl)aniline 24,4g N-allyl-
benzenesulfonamide,21 6-bromobenzo[d]-[1,3]-dioxole-5-sulfonyl
chloride,22 1-((2-nitrophenyl)sulfonyl)dihydropyrrole 17,23 3-
bromo-2-phenylprop-1-ene5e and N-allyl-2-nitrobenzene sulfona-
mide5e were all prepared according to literature.
(2H, m, CH), 7.24e7.23 (2H, m, CH), 6.34e6.33 (2H, m, CH) ppm; 13
C

2556
A. Keeley et al. / Tetrahedron 72 (2016) 2552e2559
NMR (100 MHz, CDCl3) 138.9, 136.9, 134.6, 130.3, 127.9, 121.7, 120.3,
113.0 ppm.
(100 MHz, CDCl3) 152.9, 147.9, 130.7, 129.3, 123.2, 122.5, 117.6, 112.7,
112.3, 110.9, 56.6, 56.4, 23.1, 22.9, 22.85, 22.6 ppm.
24
4.2.4. 1-[(6-Bromobenzo[d]-[1,3]-dioxol-5-yl)sulfonyl]-2,5-dihydro-
1H-pyrrole 15. At 0 ꢀC a solution of 6-bromobenzo[d]-[1,3]-dioxole-
5-sulfonyl chloride22 (1.232 g, 4.114 mmol, 1 equiv) in DCM (40 mL)
was treated sequentially with Et3N (0.86 mL, 6.17 mmol, 1.5 equiv)
and then diallylamine (0.61 mL, 4.94 mmol, 1.25 equiv). The mix-
ture was stirred for 18 h during which time room temperature was
reached. H2O (25 mL) was added followed by 1 M HCl (25 mL). The
resultant aqueous layer was further extracted with DCM (2ꢁ20 mL)
and the combined organic layers were dried over MgSO4. Filtration,
solvent removal under reduced pressure and purification by flash
column chromatography (c-Hex-EtOAc; 5:1) gave N,N-diallyl-6-
bromobenzo[d]-[1,3]-dioxole-5-sulfonamide (1.09 g, 74%) as a vis-
cous oil [Rf¼0.40 (c-Hex-EtOAc; 4:1); 1H NMR (400 MHz, CDCl3)
7.61 (1H, s, CH), 7.12 (1H, s, CH), 6.10 (2H, s, CH2), 5.72e5.63 (2H, m,
CH), 5.20e5.14 (4H, m, CH2), 4.21 (4H, s, CH2) ppm; 13C NMR
(100 MHz, CDCl3) 151.9, 147.2, 132.6, 119.1, 114.9, 113.2, 112.1, 106.1,
102.9, 49.0 ppm]. N,N-Diallyl-6-bromobenzo[d]-[1,3]-dioxole-5-
sulfonamide (510 mg, 1.42 mmol, 1 equiv) in degassed DCM
(15 mL) was treated with 1 (58 mg, 0.070 mmol, 5 mol %). Stirring
was continued at rt for 15 h. Silica gel (ca. 1 g) was added and the
solvent was removed under reduced pressure. Purification by flash
column chromatography (c-Hex-EtOAc; 6:1 to 4:1) gave 15
(470 mg, quant.) as a colourless solid. Mp¼111 ꢀC; Rf¼0.35 (c-Hex-
EtOAc; 2:1); vmax¼3101, 3054, 2915, 2868, 1611, 1504, 1489, 1327,
1243, 1165, 1149, 1094, 1034, 922 cmꢂ1; HRMS (ESI): calcd for
[(C11H10NO4S79BrþH)]þ 331.9592, found 331.9580; 1H NMR
(400 MHz, CDCl3) 7.59 (1H, s, CH), 7.12 (1H, s, CH), 6.06 (2H, s, CH2),
5.77 (2H, s(br), CH), 4.21 (4H, s, CH2) ppm; 13C NMR (100 MHz,
CDCl3) 151.3, 147.0, 131.8, 125.1, 115.0, 113.1, 111.6, 102.9, 54.8 ppm;
Anal. found (Calcd) for C11H10BrNO4S: C, 39.73% (39.76%); H, 2.94%
(3.01%); N, 4.09% (4.22%).
4.2.7. 1-((2-Nitrophenyl)sulfonyl)-1H-pyrrole 21.
The requisite
dihydropyrrole 1723 (0.55 g, 1.9 mmol, 1 equiv) in DCM (20 mL) was
treated with MnO2 (5.60 g, 64.9 mmol, 30 equiv) and stirring was
continued at reflux for 24 h. The reaction mixture was allowed to
cool to room temperature and the insoluble MnO2 was filtered
through CeliteÒ, washed with DCM (2ꢁ20 mL) and the product 21
(0.48 g, 98%) was isolated as a colourless solid following solvent
removal under reduced pressure. Mp 85 ꢀC; Rf¼0.30 (c-Hex-EtOAc,
3:1); vmax¼3142, 3088, 2917, 2849, 1541, 1376, 1173, 1061, 751,
585 cmꢂ1; HRMS (EI): calcd for [(C10H8N2O4S)]þ 252.0205, found
252.0211; 1H NMR (400 MHz, CDCl3) 7.61e7.26 (4H, m, CH), 7.23
(2H, dd, J¼5.0, 2.5 Hz, CH), 6.38e6.37 (2H, m, CH) ppm; 13C NMR
(100 MHz, CDCl3) 147.6, 134.9, 134.8, 132.5, 129.5, 124.8, 121.7,
113.8 ppm.
4.2.8. 1-Benzenesulfonyl-1H-pyrrole 26. 25Under a nitrogen atmo-
sphere, N,N-diallylbenzene sulfonamide 2221 (660 mg, 2.78 mmol,
1 equiv) was dissolved in DCM (30 mL). Grubbs catalyst 1
(69.5 mg, 0.084 mmol, 3.0 mol %) was added and the reaction was
stirred at room temperature for 3 h. MnO2 (6.09 g, 70.0 mmol,
25 equiv) was then added to the reaction flask and heated to
reflux with stirring for 18 h. On cooling the contents of the re-
action were filtered through CeliteÒ and washed with DCM
(2ꢁ20 mL). The filtrate was concentrated under reduced pressure
and purified by flash column chromatography (c-Hex-EtOAc; 6:1)
which gave 26 (426 mg, 74%) as a pale yellow solid. Mp¼86e88 ꢀC
(lit.25 mp¼87e88 ꢀC); Rf¼0.50 (c-Hex-EtOAc; 6:1); 1H NMR
(400 MHz, CDCl3) 7.87e7.84 (2H, m, CH) 7.61e7.57 (1H, m, CH),
7.52e7.48 (2H, m, CH), 7.17e7.16 (2H, m, CH), 6.31e629 (2H, m,
CH), ppm; 13C NMR (100 MHz, CDCl3) 139.1, 133.7, 129.3, 126.7,
120.8, 113.6 ppm; Anal. found (Calcd) for C10H9NO2S: C, 57.76%
(57.95%); H, 4.07% (4.38%); N, 6.91% (6.76%).
4.2.5. 1-((3,4-Dioxolophenyl)sulfonyl)-1H-pyrrole 19. A solution of
15 (77 mg, 0.23 mmol, 1 equiv) in benzene (5 mL) was treated with
MnO2 (405 mg, 4.66 mmol, 20 equiv). The mixture was heated to
reflux with stirring for 3 h. On cooling the mixture was filtered
through CeliteÒ and the residue washed with DCM (2ꢁ10 mL). The
solvent was removed under reduced pressure to give 19 (68 mg,
89%) as a colourless crystalline solid. Mp¼154e156 ꢀC; Rf¼0.30 (c-
Hex-EtOAc; 3:1); vmax¼3152, 3112, 3009, 2959, 2918, 2853, 1608,
4.2.9. Phenylpyrrol-1-yl-methanone 27. 4gAs described above, un-
der a nitrogen atmosphere, N,N-diallylbenzamide 2220 (315 mg,
1.57 mmol, 1 equiv) was dissolved in DCM (15 mL). Grubbs catalyst
1 (38.5 mg, 0.047 mmol, 3.0 mol %) was added to the reaction
vessel. The reaction flask was stirred at room temperature for 2.5 h
before MnO2 (3.80 g, 43.7 mmol, 28 equiv) was added and the re-
action mixture was heated to reflux for 18 h. The contents of the
reaction vessel were filtered through CeliteÒ, concentrated under
reduced pressure and purified using column chromatography (c-
Hex-EtOAc; 6:1) to yield 27 (244 mg, 91%) as a yellow oil. Rf¼0.45
(c-Hex-EtOAc; 6:1); HRMS (EI): calcd for C11H9NO 171.0684, found
171.0683; 1H NMR (400 MHz, CDCl3) 7.76e7.74 (2H, m, CH)
7.62e7.58 (1H, m, CH), 7.53e7.49 (2H, m, CH), 7.28 (2H, s, CH), 6.35
(2H, s, CH) ppm; 13C NMR (100 MHz, CDCl3) 167.7, 133.2, 132.2,
129.5, 128.4, 121.3, 113.1 ppm.
1503, 1479, 1371, 1353, 1249, 1189, 1145, 1057, 1026, 734 cmꢂ1
;
HRMS (EI): calcd for [(C11H8NO4S79Br)]þ 328.9357, found 328.9371;
1H NMR (400 MHz, CDCl3) 7.34 (1H, s, CH), 7.19 (2H, t, J¼2.5 Hz, CH),
7.09 (1H, s, CH), 6.27 (2H, t, J¼2.5 Hz, CH), 6.07 (2H, s, CH2) ppm; 13
C
NMR (100 MHz, CDCl3) 152.4, 147.5, 131.6, 121.4, 115.4, 113.9, 112.8,
110.4, 103.2 ppm.
4.2.6. 1-((2-Bromo-4,5-dimethoxyphenyl)sulfonyl)-4,5,6,7-
tetrahydro-1H-indole 20. According to the procedure described
above, a solution of 165c (195 mg, 0.485 mmol, 1 equiv) in DCM
(15 mL) was treated with MnO2 (854 mg, 9.82 mmol, 20 equiv) at
reflux for 18 h. On cooling the mixture was filtered through CeliteÒ,
washing with DCM (2ꢁ10 mL). Following solvent removal the crude
product was purified by gradient elution flash column chroma-
tography (c-Hex-EtOAc; 9:1 to 3:1) to afford 20 (134 mg, 69%) as
a colourless viscous oil. Rf¼0.25 (c-Hex-EtOAc; 3:1); vmax¼3090,
3061, 3011, 2934, 2845, 1585, 1503, 1437, 1364, 1261, 1215, 1164,
1117, 1020 cmꢂ1; HRMS (ESI): calcd for [(C16H18NO4S79BrþH)]þ
400.0218, found 400.0226; 1H NMR (400 MHz, CDCl3) 7.31 (1H, d,
J¼Hz, CH), 7.17 (1H, s, CH), 7.10 (1H, s, CH), 6.04 (1H, d, J¼Hz, CH),
3.95 (3H, s, CH3), 3.82 (3H, s, CH3), 2.49e2.46 (2H, m, CH2),
2.44e2.41 (2H, m, CH2), 1.75e1.57 (4H, m, CH2) ppm; 13C NMR
4.2.10. 1-Phenyl-1H-pyrrole 7. 4gUnder a nitrogen atmosphere N,N-
diallylaniline 64f (120 mg, 0.694 mmol, 1 equiv) was dissolved in
DCM (15 mL). Grubbs catalyst 1 (17.3 mg, 0.021 mmol, 3.0 mol %)
was added to the reaction flask. The mixture was stirred at room
temperature for 3 h before MnO2 (1.22 g, 14.0 mol, 20 equiv) was
added. The reaction was heated to reflux and stirred for 18 h. On
cooling the resultant mixture was filtered through CeliteÒ and
washed with DCM (2ꢁ10 mL). The crude product, obtained after
solvent removal under reduced pressure, was purified by flash
column chromatography (c-Hex-EtOAc; 6:1) which gave 7 (83 mg,
84%) as a yellow solid. Mp¼59e60 ꢀC (lit.4g mp¼59e60 ꢀC); Rf¼0.65
(c-Hex-EtOAc; 6:1); HRMS (EI): calcd for C10H9N 143.0735, found
143.0728; 1H NMR (400 MHz, CDCl3) 7.45e7.39 (4H, m, CH)

A. Keeley et al. / Tetrahedron 72 (2016) 2552e2559
2557
7.27e7.23 (1H, m, CH), 7.10 (2H, s, CH), 6.35 (2H, s, CH) ppm; 13C
NMR (100 MHz, CDCl3) 140.8, 129.5, 125.6, 120.5, 119.3, 110.3 ppm.
(3ꢁ15 mL). The combined ethereal extracts were dried over MgSO4,
filtered and the solvent removed under reduced pressure. Further
purification by flash column chromatography (c-Hex-EtOAc; 3:1)
gave 30 (0.835 g, 96%) as a waxy solid. Rf¼0.55 (c-Hex-EtOAc; 3:1);
vmax¼3067, 2920, 2296, 2227, 1703, 1479, 1329, 1157, 1090, 996, 720,
552 cmꢂ1; HRMS (EI): calcd for [(C13H15NO2S)]þ 248.0745, found
248.0742; 1H NMR (300 MHz, CDCl3) 7.87e7.84 (2H, m, CH),
7.60e7.47 (3H, m, CH), 5.78e5.69 (1H, m, CH), 5.30e5.23 (2H, m,
CH2), 4.04 (2H, q, J¼2.5 Hz, CH2), 3.80 (2H, d, J¼6.5 Hz, CH2),1.52 (3H,
4.2.11. 3-Methyl-1-phenyl-1H-pyrrole 28. 4gAs above, under N2
a degassed solution of compound 24 (75 mg, 0.41 mmol, 1 equiv) in
anhydrous DCM (8 mL) was treated with Hoveyda-Grubbs catalyst
3 (12.5 mg, 0.02 mmol, 5.0 mol %). Stirring was continued at reflux
for 15 h. On cooling MnO2 (695 mg, 7.99 mmol, 20 equiv) was added
and stirring was continued at reflux for 18 h. The reaction mixture
was allowed to cool to room temperature, filtered through CeliteÒ
and washed with DCM (2ꢁ20 mL). Following solvent removal un-
der reduced pressure purification was performed by flash column
chromatography (c-Hex-EtOAc; 19:1) which gave 28 (44 mg, 68%)
as a colourless solid. Mp 50e52 ꢀC (lit.4g mp 46e49 ꢀC); Rf¼0.60 (c-
Hex-EtOAc; 12:1); 1H NMR (400 MHz, CDCl3) 7.42e7.35 (4H, m,
CH), 7.21 (1H, t, J¼7.0 Hz, CH), 7.00 (1H, s, CH), 6.88 (1H, s, CH), 6.19
(1H, s, CH), 2.18 (3H, s, CH3) ppm; 13C NMR (100 MHz, CDCl3) 140.7,
129.4, 125.1, 121.1, 119.9, 118.9, 117.1, 111.9, 12.0 ppm.
t, J¼2.5 Hz, CH3) ppm; 13C NMR (100 MHz, CDCl3):
¼139.2, 132.4,
d
132.1, 128.6, 127.8, 119.6, 81.9, 77.3, 49.0, 36.3, 3.2 ppm.
4.2.15. 1-(Phenylsulfonyl)-3-(prop-1-en-2-yl)-1H-pyrrole 32. 27Un-
der N2 a degassed solution of compound 30 (700 mg, 2.81 mmol,
1 equiv) in anhydrous DCM (35 mL) was treated with 1 (76 mg,
0.092 mmol, 3.0 mol %). Stirring was continued at room tempera-
ture for 3 h. To this reaction mixture MnO2 (8.03 g, 92.3 mmol,
33 equiv) was added. Stirring was continued at reflux for 24 h. The
reaction mixture was allowed to cool to room temperature and
filtered through CeliteÒ and washed with DCM (2ꢁ30 mL). The
crude material was purified by flash column chromatography (c-
Hex-EtOAc; 3:1) which gave 32 (370 mg, 53%) as a waxy pale yellow
solid. Rf¼0.55 (c-Hex-EtOAc; 3:1); vmax¼3140, 3067, 2922, 1584,
1447, 1365, 1171, 1059, 754, 724, 624 cmꢂ1; HRMS (EI): calcd for
[(C13H13NO2S)]þ 247.0667, found 247.0663; 1H NMR (300 MHz,
CDCl3) 7.85 (2H, d, J¼8.0 Hz, CH), 7.59e7.47 (3H, m, CH), 7.13e7.11
(2H, m, CH), 6.47e6.45 (1H, m, CH), 5.22 (1H, s, CH2), 4.91 (1H, s,
CH2), 1.99 (3H, s, CH3) ppm; 13C NMR (100 MHz, CDCl3) 138.9, 135.8,
133.8, 129.7, 129.3, 126.7, 121.4, 116.9, 111.4, 110.9, 27.3 ppm.
4.2.12. N-Allyl-N-(2-phenylallyl)benzene sulfonamide 25. 26N-Allyl-
benzene sulfonamide21 (500 mg, 2.53 mmol, 1 equiv) was dissolved
in DMF (25 mL) and cooled to 0 ꢀC. Sodium hydride, 60% w/w in
mineral oil (130 mg, 3.25 mmol, 1.3 equiv), was added and the mix-
ture was stirred for 0.5 h. 3-Bromo-2-phenylprop-1-ene5e (820 mg,
4.16 mmol, 1.65 equiv) was added in a dropwise fashion and the re-
action mixture was stirred for 3 h during which period room tem-
perature was reached. Et2O (30 mL) and H2O (30 mL) were added and
the phases were separated. The resultant aqueous phase was further
extracted with Et2O (2ꢁ30 mL) and the combined ethereal extracts
were dried over MgSO4. The crude product, obtained after filtration
and solvent removal, was purified by column chromatography (c-
Hex-EtOAc; 6:1) which gave 25 (0.45 g, 57%) as a viscous yellow oil.
Rf¼0.40 (c-Hex-EtOAc; 6:1); 1H NMR (300 MHz; CDCl3) 7.75 (2H, dd,
2H, J¼8.5,1.25 Hz, CH), 7.25e7.47 (8H, m, CH), 5.52e5.38 (1H, m, CH),
5.43 (1H, s, CH2), 5.21 (1H, s, CH2), 5.06 (1H, d, J¼10.0 Hz, CH2), 5.04
(1H, d, J¼16.0 Hz, CH2), 4.24 (2H, s, CH2), 3.73 (2H, d, J¼6.5 Hz, CH2)
ppm; 13C NMR (100 MHz, CDCl3) 142.9, 140.4, 138.9, 133.1, 132.6,
129.6, 128.9, 128.5, 127.7, 126.9, 119.9, 116.9, 50.9, 49.9.
4.2.16. N-Allyl-2-bromo-N-(but-2-yn-1-yl)-4,5-dimethoxybenzene
sulfonamide 31. N-Allyl-2-bromo-4,5-dimethoxybenzene sulfona-
mide5e (300 mg, 0.89 mmol, 1 equiv) was dissolved in DMF (15 mL)
and cooled to 0 ꢀC. Sodium hydride, 60% w/w in mineral oil (46 mg,
1.2 mmol, 1.3 equiv) was added and the mixture was stirred for
0.5 h. 1-Bromobut-2-yne (0.13 mL, 1.5 mmol, 1.65 equiv) was added
in a dropwise fashion and stirring was continued for 2 h. Over this
period room temperature was reached and Et2O (25 mL) and H2O
(25 mL) were added. The resultant aqueous phase was further
extracted with Et2O (3ꢁ10 mL) and the combined ethereal extracts
were dried over MgSO4. The crude product, obtained after filtration
and solvent removal, was purified by column chromatography (c-
Hex-EtOAc; 5:1) which gave 31 (327 mg, 94%) as a colourless oil.
Rf¼0.20 (c-Hex/EtOAc; 2:1); vmax¼3087, 3008, 2921, 2845,1585,
1503, 1462, 1439, 1361, 1262, 1023, 597; HRMS (ESI): calcd for
[(C15H18NO4S79BrþNa)]þ 410.0042 found 410.0038; 1H NMR
(500 MHz, CDCl3): 7.61 (1H, s, CH), 7.13 (1H, s, CH), 5.68e5.73 (1H,
m, CH), 5.28 (1H, dd, J¼17.0, 1.5 Hz, CH2), 5.22 (1H, dd, J¼10.5,
1.5 Hz, CH2), 4.04 (2H, q, J¼2.5 Hz, CH2), 4.00 (2H, d, J¼6.5 Hz, CH2),
3.87 (3H, s, CH3), 3.85 (3H, s, CH3), 1.71 (3H, t, J¼2.5 Hz, CH3) ppm;
13C NMR (100 MHz, CDCl3) 152.2, 147.7, 132.3, 130.8, 119.5, 117.4,
114.6, 112.2, 81.0, 72.5, 56.5, 56.4, 49.2, 36.2, 3.5 ppm.
4.2.13. 3-Phenyl-1-(phenylsulfonyl)-1H-pyrrole 29. 6cUnder N2
a degassed solution of compound 25 (330 mg, 1.05 mmol, 1 equiv)
in anhydrous toluene (25 mL) was treated with Hoveyda-Grubbs
catalyst 3 (33 mg, 0.053 mmol, 5.0 mol %). Stirring was continued
at 80 ꢀC for 3 h after which time MnO2 (520 mg, 5.98 mmol, 5 equiv)
was added and stirring was continued at reflux for 15 h. The re-
action mixture was allowed to cool to room temperature and fil-
tered through CeliteÒ. The residue was washed with PhMe
(2ꢁ20 mL). Solvent removal under reduced pressure gave the crude
product which was purified by flash column chromatography (c-
Hex-EtOAc; 4:1) to afford 25 (210 mg, 71%) as a waxy solid. Rf¼0.30
(c-Hex-EtOAc; 4:1); vmax¼3063, 2923, 2853, 1729, 1447, 1364, 1364,
1170, 1129, 1061, 753, 724, 683, 586 cmꢂ1 1H NMR (300 MHz,
;
CDCl3) 7.92 (2H, dd, J¼8.5, 1.25 Hz, CH), 7.65e7.35 (8H, m, CH),
7.25e7.23 (2H, m, CH), 6.64 (1H, dd, J¼3.0, 1.75 Hz, CH) ppm; 13C
NMR (100 MHz, CDCl3) 139.1, 134.1, 134.0, 130.0, 129.6, 128.9, 127.5,
127.0, 125.7, 121.8, 116.5, 112.5 ppm.
4.2.17. 1-((2-Bromo-4,5-dimethoxyphenyl)sulfonyl)-3-(prop-1-en-2-
yl)-1H-pyrrole 33. Under N2 a degassed solution of 31 (300 mg,
0.772 mmol, 1 equiv) in anhydrous DCM (15 mL) was treated with 1
(19 mg, 0.023 mmol, 3 mol %). Stirring was continued at room
temperature for 3 h. To this reaction mixture MnO2 (1.16 g,
13.1 mmol, 20 equiv) was added and stirring was continued at
reflux for 18 h. The reaction mixture was allowed to cool to room
temperature and filtered through CeliteÒ washing with DCM
(2ꢁ20 mL). The crude material obtained following solvent removal
under reduced pressure was purified by flash column chromatog-
raphy (c-Hex-EtOAc; 4:1) and recrystallization dissolving in DCM
followed by layering with c-Hex which gave 33 (240 mg, 81%) as
a colourless crystalline solid. Mp 93e95 ꢀC (DCM); Rf¼0.35 (c-Hex-
4.2.14. N-Allyl-N-(but-2-yn-1-yl)benzene sulfonamide 30. N-Allyl-
benzene sulfonamide21 (690 mg, 3.50 mmol, 1 equiv) was dissolved
in DMF (40 mL) and cooled to 0 ꢀC. Sodium hydride 60% w/w in
mineral oil (180 mg, 4.50 mmol, 1.3 equiv) was added and the
mixture was stirred for 0.5 h. 1-Bromobut-2-yne (0.5 mL, 5.6 mmol,
1.6 equiv) was added in a dropwise fashion. Stirring was continued
for 2 h during which period room temperature was reached. Et2O
(30 mL) and H2O (30 mL) were added and the phases were sepa-
rated. The resultant aqueous phase was further extracted with Et2O

2558
A. Keeley et al. / Tetrahedron 72 (2016) 2552e2559
EtOAc; 2:1); vmax¼2987, 2968, 2921, 1505, 1369, 1256, 1165, 1065,
795, 673, 603 cmꢂ1; HRMS (ESI): calcd for [(C15H16NO4S79BrþNa)]þ
407.9881, found 407.9900; 1H NMR (500 MHz, CDCl3) 7.45 (1H, s,
CH), 7.15e7.19 (2H, m, CH), 7.13 (1H, s, CH), 6.47 (1H, d, J¼3.5 Hz,
CH), 5.23 (1H, s(br), CH2), 4.94e4.91 (1H, m, CH2), 3.87 (3H, s, CH3),
3.85 (3H, s, CH3), 2.00 (3H, d, J¼1.0 Hz, CH3) ppm; 13C NMR
(100 MHz, CDCl3) 153.3, 148.2, 136.0, 129.8, 129.6, 122.2, 117.7, 117.5,
113.0, 112.5, 110.8, 110.4, 56.6, 56.4, 21.0 ppm.
(40 mL), and 1,4-dichlorobutyne (0.14 mL, 1.4 mmol, 1 equiv) was
added in a dropwise fashion along with K2CO3 (2.00 g, 14.5 mmol,
4 equiv). The reaction mixture was heated to reflux for 48 h, cooled
to room temperature and EtOAc (40 mL) and H2O (40 mL) were
added. The resultant aqueous phase was further extracted with
EtOAc (3ꢁ15 mL). The combined organic phases were dried over
MgSO4. The crude product, obtained after filtration and solvent
removal, was purified by flash column chromatography (c-Hex-
EtOAc; 4:1) which gave 35 (0.80 g, 93%) as a yellow oil. Rf¼0.40 (c-
Hex-EtOAc; 4:1); vmax¼3086, 2980, 2921, 1739, 1574, 1423, 1329,
1156, 1057, 930, 897, 755, 565 cmꢂ1; HRMS (ESI): calcd for
[(C22H22N2O4S729Br2þNa)]þ 622.9285, found 622.9282; 1H NMR
(300 MHz, CDCl3) 8.12 (2H, d, J¼8.5, Hz, CH), 7.73 (2H, d, J¼8.5 Hz,
CH), 7.47e7.37 (4H, m, CH), 5.69e5.61 (2H, m, CH), 5.28e5.20 (4H,
4 . 2 . 18 . N , N 0- ( b u t - 2 - y n - 1, 4 - d i y l ) - b i s - ( N - a l l y l - 2 -
nitrobenzenesulfonamide) 34. N-Allyl-2-nitrobenzene sulfonami-
de5e (700 mg, 2.89 mmol, 2.5 equiv) was dissolved in MeCN (30 mL)
before K2CO3 (600 mg, 4.34 mmol, 4 equiv) and 1,4-dichlorobutyne
(0.11 mL, 1.1 mmol, 1 equiv) were added. The reaction mixture was
heated to reflux for 48 h. On cooling to room temperature EtOAc
(40 mL) and H2O (40 mL) were added. The resultant aqueous phase
was further extracted with EtOAc (3ꢁ15 mL) and the combined
organic phases were dried over MgSO4. After filtration and solvent
removal the crude product was purified by flash column chroma-
tography (c-Hex-EtOAc; 3:1) which gave 34 (580 mg, 97%) as
a yellow oil. Rf¼0.40 (c-Hex-EtOAc; 1:1); vmax¼3142, 3086, 2979,
m, CH2), 4.06 (4H, s, CH2), 3.93 (4H, dd, J¼1.5, 6.5 Hz, CH2) ppm; 13
C
NMR (100 MHz, CDCl3) 138.9, 135.6, 133.7, 132.2, 131.8, 127.6, 120.5,
120.0, 78.7, 49.3, 35.9.
4.2.22. 1,10-Bis-((2-bromophenyl)sulfonyl)-1H,10H-3,30-bipyrrole
37. Under N2, a degassed solution of compound 35 (100 mg,
0.166 mmol, 1 equiv) in anhydrous DCM (5 mL) was treated with 1
(6.8 mg, 0.008 mmol, 5 mol %). Stirring was continued at room
temperature for 1 h before MnO2 (300 mg, 3.45 mmol, 21 equiv) was
added. The reaction mixture was stirred and heated to reflux for
12 h. At this stage a further portion of MnO2 (300 mg, 3.45 mmol,
21 equiv) was added and the mixturewas further heated to reflux for
12 h. The reaction mixture was allowed to cool to room temperature
filtered through CeliteÒ and washed with DCM (2ꢁ20 mL). Solvent
removal under reduced pressure and purification by flash column
chromatography (c-Hex-EtOAc; 3:1) gave 37 (81 mg, 85%) as a col-
ourless crystalline solid. Mp 227e230 ꢀC; Rf¼0.30 (c-Hex-EtOAc;
2921, 1739, 1575, 1423, 1329, 1156, 1057, 930, 897, 755, 565 cmꢂ1
;
HRMS (EI): calcd for [(C22H22N4O8S2)]þ 534.0879, found 534.0880;
1H NMR (400 MHz, CDCl3) 8.00e7.97 (2H, m, CH), 7.71e7.67 (4H, m,
CH), 7.64e7.61 (2H, m, CH), 5.61 (2H, ddt, J¼16.5, 10.0, 6.5 Hz, CH),
5.22e5.17 (4H, m, CH2), 4.01 (4H, s, CH2), 3.86 (4H, d, J¼6.5 Hz, CH2)
ppm; 13C NMR (100 MHz, CDCl3) 148.0, 133.9, 132.8, 131.9, 131.4,
130.8, 124.0, 119.7, 78.5, 49.4, 35.8 ppm.
4.2.19. 1,10-Bis-((2-nitrophenyl)sulfonyl)-1H,10H-3,30-bipyrrole
36. Under N2 a degassed solution of compound 34 (400 mg,
0.749 mmol, 1 equiv) in anhydrous DCM (8 mL) was treated with 1
(18 mg, 0.022 mmol, 3 mol %). Stirring was continued at room tem-
perature for 1 h before MnO2 (1.40 g,16.1 mmol, 20 equiv) was added
and the reaction mixture was heated to reflux for 12 h. An additional
portion of MnO2 (0.70 g, 8.1 mmol,10 equiv) was added and stirring at
reflux was continued for 12 h. The reaction mixture was allowed to
cool to room temperature and filtered through CeliteÒ. The residue
waswashedwithDCM(2ꢁ20mL)andsolventremovalunderreduced
pressure gave the crude product. Purification by flash column chro-
matography(c-Hex-EtOAc;1:1)gave36(188mg, 50%)asapalebrown
solid. Rf¼0.30 (c-Hex-EtOAc; 1:1); vmax¼3131, 2852,1733,1592,1439,
1370, 1352, 1230, 1155, 1040, 851, 656 cmꢂ1; HRMS (EI): calcd for
[(C20H14N4O8S2)]þ 502.0253, found 502.0301; 1H NMR (400 MHz,
CDCl3):7.77e7.66(8H,m,CH),7.34(2H,t,J¼1.5Hz,CH),7.25e7.23 (2H,
m,CH),6.51(2H,dd,J¼3.5,1.5Hz, CH)ppm;13CNMR(100MHz,CDCl3)
148.0, 135.2,132.8, 132.6,129.9, 124.9,122.7, 119.6,117.3, 112.3 ppm.
2:1); vmax¼1178,1155,1070,1043, 766, 738, 699, 651, 606, 585 cmꢂ1
;
1H NMR (500 MHz, CDCl3) 7.86 (2H, dd, J¼7.5, 2.0 Hz, CH), 7.74e7.71
(2H, m, CH), 7.48e7.42 (4H, m, CH), 7.29 (2H, s, CH), 7.25 (2H, d, J¼2.5,
Hz, CH), 6.43 (2H, dd, J¼3.0, 1.5 Hz, CH) ppm; 13C NMR (100 MHz,
CDCl3) 138.6, 136.0, 134.8, 130.6, 128.1, 122.8, 121.9, 120.4, 117.0,
115.0 ppm; Anal. found (Calcd) for C20H14Br2N2O4S2: C, 41.40
(42.12); H, 2.47 (2.47); N, 4.88 (4.91).
4.2.23. 7,8-Dimethoxybenzo-[d]-pyrrolo-[1,2-b]-isothiazole 5,5-
dioxide 13. Under N2 a mixture of 11 (200 mg, 0.578 mmol,
1 equiv), Pd(OAc)2 (13 mg, 0.058 mmol, 10 mol %), PPh3 (30.3 mg,
0.116 mmol, 20 mol %) and K2CO3 (160 mg, 1.16 mmol, 2 equiv) in
anhydrous DMF (8 mL) was heated to 110 ꢀC for 15 h. The reaction
mixture was cooled and EtOAc (10 mL) and H2O (10 mL) were
added. The resultant aqueous layer was further extracted with
EtOAc (5ꢁ10 mL) and the combined organic extracts were dried
over MgSO4. Filtration followed by solvent removal under reduced
pressure gave the crude product which was purified by flash col-
umn chromatography (c-Hex-EtOAc; 2:1) which afforded 13
(100 mg, 65%) as a colourless crystalline solid. Mp¼170e173 ꢀC;
Rf¼0.30 (c-Hex-EtOAc; 2:1); vmax¼3108, 2962, 2849, 1606, 1495,
1441, 1321, 1240, 1159, 1038, 844, 714, 621, 584 cmꢂ1; HRMS (ESI):
calcd for [(C12H11NO4SþH)]þ 266.0487, found 266.0495; 1H NMR
(400 MHz, CDCl3) 7.18 (1H, s, CH), 7.10 (1H, dd, J¼3.0, 1.0 Hz, CH),
6.96 (1H, s, CH), 6.38e6.35 (2H, m, CH), 3.99 (3H, s, CH3), 3.94 (3H, s,
CH3) ppm; 13C NMR (100 MHz, CDCl3) 154.1, 149.1, 129.3, 128.2,
122.4, 116.8, 116.1, 104.6, 104.0, 102.9, 56.5, 56.4 ppm.
4.2.20. 1H,10H-3,30-bis-pyrrole 38. 12aAt room temperature a mix-
ture of compound 36 (56 mg, 0.11 mmol, 1 equiv) and K2CO3
(50 mg, 0.36 mmol, 3.3 equiv) in DMF (5 mL) was treated with PhSH
(14
mL, 0.14 mmol, 1.3 equiv). Stirring was continued at room
temperature for 24 h whereupon EtOAc (8 mL) and water (10 mL)
were added. The resultant aqueous layer was further extracted with
EtOAc (5ꢁ8 mL) and the combined organic extracts were dried over
MgSO4. Filtration followed by solvent removal and column chro-
matography (c-Hex-EtOAc; 2:1) afforded 38 (11 mg, 75%) as an
amorphous yellow solid with data matching literature.12a Rf¼0.45
(c-Hex/EtOAc; 2:1); vmax¼3344, 3281, 2923, 1672, 1637, 1075,
720 cmꢂ1
;
1H NMR (300 MHz, CDCl3) 8.12 (2H, s, NH), 6.93e6.92
4.2.24. Benzo-[d]-pyrrolo-[1,2-b]-isothiazole 5,5-dioxide 39. 13bFol-
lowing the procedure described above: Under N2, 18 (144 mg,
0.503 mmol, 1 equiv), Pd(OAc)2 (11.6 mg, 0.052 mmol, 10 mol %),
PPh3 (27.2 mg, 0.104 mmol, 20 mol %) and K2CO3 (143 mg,
1.04 mmol, 2 equiv) in anhydrous DMF (8 mL) were heated at 110 ꢀC
for 15 h. On cooling EtOAc (10 mL) and H2O (10 mL) were added.
The resultant aqueous layer was further extracted with EtOAc
(2H, m, CH), 6.81e6.79 (2H, m, CH) 6.41e6.39 (2H, m, CH); 13C NMR
(100 MHz, CDCl3) 119.6, 118, 113.2, 106.7 ppm.
4 . 2 . 2 1. N , N 0- ( b u t - 2 - y n - 1, 4 - d i y l ) - b i s - ( N - a l l y l - 2 -
bromobenzenesulfonamide) 35. N-Allyl-2-bromobenzene sulfona-
mide5e (1.00 g, 3.62 mmol, 2.5 equiv) was dissolved in MeCN

A. Keeley et al. / Tetrahedron 72 (2016) 2552e2559
2559
2. For reviews concerning metathesis in the synthesis of N- and O-heterocycles,
including metathesis followed by oxidation, see: (a) Deiters, A.; Martin, S. F.
Chem. Rev. 2004, 104, 2199e2238; (b) Donohoe, T. J.; Orr, A. J.; Bingham, M.
Angew. Chem., Int. Ed. 2006, 45, 2664e2670; (c) Donohoe, T. J.; Fishlock, L. P.;
Procopiou, P. A. Chem.dEur. J. 2008, 14, 5716e5726; (d) van Otterlo, W. A. L.; de
Koning, C. B. Chem. Rev. 2009, 109, 3743e3782.
(5ꢁ10 mL) and the combined organic extracts were dried over
MgSO4. Filtration followed by solvent removal under reduced
pressure and purification by flash column chromatography (c-Hex-
EtOAc; 6:1) afforded 37 (82 mg, 79%) as a colourless solid. Mp
133e135 ꢀC (lit.13b mp¼98e100 ꢀC). Rf¼0.30 (c-Hex-EtOAc, 6:1);
vmax¼2961, 2922, 2141, 2118, 1457, 1322, 1160, 1063, 746, 706, 586,
ꢀ
3. (a) Declerck, V.; Ribiere, P.; Martinez; Lamaty, F. J. Org. Chem. 2004, 69,
8372e8381; (b) Donohoe, T. J.; Orr, A. J.; Gosby, K.; Bingham, M. Eur. J. Org.
Chem. 2005, 1969e1971; (c) Donohoe, T. J.; Kershaw, N. M.; Orr, A. J.; Wheel-
house, K. M. P.; Fishlock, L. P.; Lacy, A. R.; Bingham, M.; Procopiou, P. A. Tetra-
hedron 2008, 64, 809e820; (d) Donohoe, T. J.; Ironmonger, A.; Kershaw, N. M.
Angew. Chem., Int. Ed. 2008, 47, 7314e7316; (e) Donohoe, T. J.; Bower, J. F. Proc.
Nat. Acad. Sci. 2010, 107, 3373e3376; (f) Chachignon, H.; Scalacci, N.; Petricci, E.;
Castagnolo, D. J. Org. Chem. 2015, 80, 5287e5295.
4. (a) Robertson, J.; Kuhnert, N.; Zhao, Y. Heterocycles 2000, 53, 2415e2420; (b)
Yang, C.; Murray, W. V.; Wilson, L. J. Tetrahedron Lett. 2003, 44, 1783e1786; (c)
Dieltiens, N.; Stevens, C. V.; De Vos, D.; Allaert, B.; Drozdzark, R.; Verpoort, F.
Tetrahedron Lett. 2004, 45, 8995e8998; (d) Bennasar, M.-L.; Roca, T.; Monerris,
M.; García-Díaz, D. Tetrahedron Lett. 2005, 46, 4035e4038; (e) Moonen, K.;
Dieltiens, N.; Stevens, C. V. J. Org. Chem. 2006, 71, 4006e4009; (f) Schmidt, B.;
Krehl, S.; Jablowski, E. Org. Biomol. Chem. 2012, 10, 5119e5130; (g) Chen, W.;
Wang, J. Organometallics 2013, 32, 1958e1963.
5. (a) Evans, P.; McCabe, T.; Morgan, B. S.; Reau, S. Org. Lett. 2005, 7, 43e46; (b)
Evans, P. J. Org. Chem. 2007, 72, 1830e1833; (c) Klein, J. E. M. N.; Geoghegan, K.;
Meral, N.; Evans, P. Chem. Commun. 2010, 937e939; (d) Geoghegan, K.; Kelleher,
S.; Evans, P. J. Org. Chem. 2011, 76, 2187e2194; (e) Geoghegan, K.; Evans, P.;
Rozas, I.; Alkorta, I. Chem.dEur. J. 2012, 18, 13379e13387; (f) Geoghegan, K.;
Evans, P. J. Org. Chem. 2013, 78, 3410e3415.
6. For recent methods for the synthesis of N-sulfonyl substituted pyrroles see: (a)
Xin, X.; Wang, D.; Li, X.; Wan, B. Angew. Chem., Int. Ed. 2012, 51, 1693e1697; (b)
Shin, Y. H.; Maheswara, M.; Hwang, J. Y.; Kang, E. J. Eur. J. Org. Chem. 2014,
2305e2311; (c) Rajasekar, S.; Anbarasan, P. J. Org. Chem. 2014, 79, 8428e8434.
7. See for example: (a) Lautens, M.; Fillion, E. J. Org. Chem. 1997, 62, 4418e4427;
(b) Paulvannan, K. J. Org. Chem. 2004, 69, 1207e1214; (c) Dinsmore, A.; Billing,
D. G.; Mandy, K.; Michael, J. P.; Mogano, D.; Patil, S. Org. Lett. 2004, 6, 293e296;
(d) Zonta, C.; Fabris, F.; De Lucchi, O. Org. Lett. 2005, 7, 1003e1006; (e) Ohta, T.;
Fukuda, T.; Ishibashi, F.; Iwao, M. J. Org. Chem. 2009, 74, 8143e8153; (f) Ro-
driguez, R. A.; Pan, C.-M.; Yabe, Y.; Kawamata, Y.; Eastgate, M. D.; Baran, P. S. J.
Am. Chem. Soc. 2014, 136, 6908e6911; (g) Shibata, M.; Fuchigami, R.; Kotaka, R.;
Namba, K.; Tanino, K. Tetrahedron 2015, 71, 4495e4499.
466, 420 cmꢂ1
;
HRMS (ESI): calcd for [(C10H7NO2SþNa)]þ
228.0094, found 228.0099; 1H NMR (500 MHz, CDCl3) 7.73 (1H, d,
J¼8.0 Hz, CH), 7.61e7.53 (2H, m, CH), 7.37 (1H, dt, J¼8.0, 1.0 Hz, CH),
7.14 (1H, d, J¼3.5 Hz, CH), 6.48 (1H, d, J¼3.5 Hz, CH), 6.42 (1H, t,
J¼3.5 Hz, CH) ppm; 13C NMR (100 MHz, CDCl3) 136.8, 134.3, 129.3,
128.1, 127.7, 122.5, 120.9, 117.2, 116.3, 105.4 ppm.
4.2.25. [1,3]-dioxolo-[40,50:4,5]-benzo-[1,2-d]-pyrrolo-[1,2-b]-iso-
thiazole 5,5-dioxide 40. As described above: Under N2, 19 (55 mg,
0.16 mmol, 1 equiv), Pd(OAc)2 (3.7 mg, 0.017 mmol, 10 mol %), PPh3
(8.7 mg, 0.033 mmol, 20 mol %) and K2CO3 (46 mg, 0.33 mmol,
2 equiv) in anhydrous DMF (5 mL) was heated at 110 ꢀC for 18 h. After
cooling EtOAc (8 mL) and H2O (8 mL) were added. The resultant
aqueous layer was further extracted with EtOAc (5ꢁ10 mL) and the
combined organic extracts were dried over MgSO4. Filtration fol-
lowed by solvent removal under reduced pressure and purification by
flash column chromatography (c-Hex-EtOAc; 3:1) gave 40 (15 mg,
38%) as a pale yellow crystalline solid. Mp¼215e218 ꢀC; Rf¼0.40 (c-
Hex-EtOAc; 3:1); vmax¼3442, 3144, 3057, 2920, 2851, 1602, 1475,
1322, 1102, 996, 817, 699, 546 cmꢂ1
; HRMS (EI): calcd for
[(C11H7NO4S)]þ 249.0096, found 249.0101;1H NMR (400 MHz, CDCl3)
7.14 (1H, s, CH), 7.12e7.11 (1H, m, CH), 6.95 (1H, s, CH), 6.40e6.35 (2H,
m, CH), 6.13 (2H, s, CH2) ppm; 13C NMR (100 MHz, CDCl3) 154.1,149.1,
129.3, 128.2, 122.4, 116.8, 116.1, 104.6, 104.0, 102.9, 102.5 ppm.
8. For a review concerning the oxidation of heterocyclic compounds with MnO2
see: Soldatenkov, A. T.; Polyanskii, K. B.; Kolyadina, N. M.; Soldatova, S. A. Chem.
Het. Comp. 2009, 45, 633e657 For references concerning the oxidation of par-
tially oxidised N-heterocycles with MnO2 see: (a) Brandange, S.; Holmgren, E.;
Leijonmarck, H.; Rodriguez, B. Acta Chem. Scand. 1995, 49, 922e928; (b) Yagi, T.;
Aoyama, T.; Shioiri, T. Synlett 1997, 1063e1064.
4.2.26. 2,3-Dimethoxy-7,8,9,10-tetrahydrobenzo[4,5]isothiazolo[2,3-
a]indole 5,5-dioxide 41. As described above a mixture of 20 (93 mg,
0.23 mmol, 1 equiv), Pd(OAc)2 (6 mg, 0.03 mmol, 10 mol %), PPh3
(14 mg, 0.053 mmol, 20 mol %) and K2CO3 (76 mg, 0.55 mmol,
2 equiv) in anhydrous DMF (5 mL) was heated to 110 ꢀC under N2
for 15 h. The reaction mixture was cooled and EtOAc (10 mL) and
H2O (10 mL) were added. The resultant aqueous layer was further
extracted with EtOAc (3ꢁ5 mL) and the combined organic extracts
were dried over MgSO4. Filtration followed by solvent removal
under reduced pressure gave the crude product which was purified
by flash column chromatography (c-Hex-EtOAc; 3:1) which affor-
€
9. Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett. 1995, 36, 6373e6374.
10. For a review concerning the uses of C-vinyl pyrroles see Trofimov, B. A.; So-
benina, L. N.; Demenev, A. P.; Mikhaleva, A. I. Chem. Rev. 2004, 104, 2481e2506.
ꢁ
11. Clavier, H.; Correa, A.; Escudero-Adan, E. C.; Benet-Buchholz, J.; Cavallo, L.;
Nolan, S. P. Chem.dEur. J. 2009, 15, 10244e10254.
12. (a) Gleiter, R.; Ritter, J. Tetrahedron 1996, 52, 10383e10388 For alternative syn-
theses and the use of 3,30-bis-pyrroles see: (b) Carter, P.; Fitzjohn, S.; Halazy, S.;
Magnus, P. J. Am. Chem. Soc. 1987, 109, 2711e2717; (c) Kaschel, J.; Schneider, T. F.;
Kratzert, D.; Stalke, D.; Werz, D. B. Angew. Chem., Int. Ed. 2012, 51, 11153e11156.
13. (a) Grigg, R.; Sridharan, V.; Stevenson, P.; Sukirthalingam, S.; Worakun, T. Tet-
rahedron 1990, 46, 4003e4018; (b) Conde, N.; Churruca, F.; SanMartin, R.;
Herrero, M. T.; Domínguez, E. Adv. Synth. Catal. 2015, 357, 1525e1531.
14. The Mizoroki-Heck Reaction; Oestreich, M., Ed.; Wiley: UK, 2009.
15. For recent examples of this type of chemistry for the synthesis of cyclic sul-
fonamides see: (a) Mondal, S.; Debnath, S.; Pal, S.; Das, A. Synthesis 2015,
3423e3433; (b) Laha, J. K.; Sharma, S.; Dayal, N. Eur. J. Org. Chem. 2015,
7885e7891 For a review detailing the synthesis of cyclic sulfonamides/sultams
see:; (c) Majumdar, K. C.; Mondal, S.. Chem. Rev., 2011, 111, 7749e7773.
16. X-Ray crystallographic data for compound 41: CCDC code: 1451156.
17. Murugesan, N.; Gu, Z.; Stein, P. D.; Bisaha, S.; Spergel, S.; Girotra, R.; Lee, V. G.;
Lloyd, J.; Misra, R. N.; Schmidt, J.; Mathur, A.; Stratton, L.; Kelly, Y. F.; Bird, E.;
Waldron, T.; Liu, E. C.-K.; Zhang, R.; Lee, H.; Serafino, R.; Abboa-Offei, B.;
Mathers, P.; Giancarli, M.; Seymour, A. A.; Webb, M. L.; Moreland, S.; Barrish, J.
C.; Hunt, J. T. J. Med. Chem. 1998, 41 5198e521816.
ded 41 (55 mg, 75%) as
a
colourless crystalline solid.
Mp¼208e210 ꢀC (EtOAc); Rf¼0.30 (c-Hex-EtOAc; 3:1); vmax¼2924,
2851, 1582, 1539, 1489, 1459, 1416, 1315, 1284, 1153,1045, 844 cmꢂ1
;
HRMS (ESI): calcd for [(C16H17NO4SþNa)]þ 342.0776, found
342.0781; 1H NMR (400 MHz, CDCl3) 7.11 (1H, s, CH), 6.84 (1H, s,
CH), 6.06 (1H, s, CH), 3.98 (3H, s, CH3), 3.91 (3H, s, CH3), 2.83e2.89
(2H, m, CH2), 2.39e2.44 (2H, m, CH2), 1.71e1.86 (4H, m, CH2) ppm;
13C NMR (100 MHz, CDCl3) 154.0, 148.5, 129.4, 127.9, 127.6, 125.5,
123.0, 104.5, 104.1, 102.3, 56.4, 56.35, 23.1, 22.7, 22.3, 21.3 ppm;
Anal. found (Calcd) for C16H17NO4S: C, 60.11% (59.98%); H, 5.37%
(5.35%); N, 4.10% (4.37%). Recrystallisation from EtOAc gave crystals
suitable for X-ray crystallography.
18. O’Sullivan, S.; Doni, E.; Tuttle, T.; Murphy, J. A. Angew. Chem., Int. Ed. 2014, 53,
474e478.
19. So, C. M.; Kume, S.; Hayashi, T. J. Am. Chem. Soc. 2013, 135, 10990e10993.
20. Clavier, H.; Nolan, S. P. Chem.dEur. J. 2007, 13, 8029e8036.
Acknowledgements
21. Hu, S.; Wang, D.; Liu, J.; Li, X. Org. Biomol. Chem. 2013, 11, 2761e2765.
22. Geoghehgan, K.; Smullen, S.; Evans, P. J. Org. Chem. 2013, 78, 10443e10451.
Lenka Fujakova is thanked for the synthesis of dihydropyrrole 15
ꢁ
~
23. Cerezo, S.; Cortes, J.; Moreno-Manas, M.; Pleixats, R.; Roglans, A. Tetrahedron
1998, 54, 14869e14884.
€
and Helge Muller-Bunz is thanked for X-ray crystallography.
24. Fuchigami, R.; Namba, K.; Tanino, K. Tetrahedron Lett. 2012, 53, 5725e5728.
25. Fukada, T.; Sudo, E.; Shimokawa, K.; Iwao, M. Tetrahedron 2008, 64, 328e338.
26. Dondas, H. A.; Clique, B.; Cetinkaga, B.; Grigg, R.; Kilner, C.; Morris, J.; Sridharan,
V. Tetrahedron 2005, 61, 10652e10666.
27. Noland, W. E.; Etienne, C. L.; Lanzatella, N. P. J. Heterocycl. Chem. 2011, 48,
381e388.
References and notes
€
1. For reviews concerning pyrrole chemistry see: (a) Furstner, A. Angew. Chem., Int.
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Soc. Rev. 2010, 39, 4402e4421; (d) Domagala, A.; Jarosz, T.; Lapkowski, M. Eur. J.
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