One-pot desulfonylative alkylation of N-sulfonyl azacycles using alkoxides generated by phase-transfer catalysis

Article abstract of DOI:10.1055/S-0029-1218627

Sulfonamide heterocycles, specifically 3-acylindoles, undergo a deprotection/alkylation sequence in the presence of an appropriate alcohol when cesium carbonate or potassium carbonate and a phase-transfer catalyst are utilized. The outcome of the one-pot protocol was found to be significantly dependent on both the alcohol and sulfonamide heterocycle employed. Strictly anhydrous conditions are not necessary for this protocol. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/S-0029-1218627

PAPER
775
One-Pot Desulfonylative Alkylation of N-Sulfonyl Azacycles Using Alkoxides
Generated by Phase-Transfer Catalysis
One-Pot
D
u
esulfonylativ
s
e
A
lkylat
t
ion of
i
N
-Sulfo
n
nyl
A
zacycles R. Denton*
Chemical Research and Process Development, Obiter Research, 2809 Gemini Court, Champaign, IL 61822-9647, USA
Fax +1(217)3591626; E-mail: justin.denton@obires.com
Received 5 November 2009
acylindole 5 to synthesize analogues of the indole natural
Abstract: Sulfonamide heterocycles, specifically 3-acylindoles,
undergo a deprotection/alkylation sequence in the presence of an
appropriate alcohol when cesium carbonate or potassium carbonate
and a phase-transfer catalyst are utilized. The outcome of the one-
product pravadoline. Both reactions utilized a sodium
alkoxide generated from either sodium metal or sodium
hydride, and suffer from irregular yields of the desired N-
pot protocol was found to be significantly dependent on both the al- alkyl products and a limited substrate scope.
cohol and sulfonamide heterocycle employed. Strictly anhydrous
conditions are not necessary for this protocol.
N
Key words: phase-transfer catalysis, sulfonamides, heterocycles,
cleavage, alkylation
HO
H
O
O
N
H
H
O
O
2
N
t-BuOK THF
+
The N-H groups of indole and related heterocycles are
conveniently protected as their N-sulfonyl derivatives for
selective addition of electrophiles to the C-3 position and
for their tendency to form highly crystalline materials.1
Ultimately, the N-sulfonyl derivative has to undergo
cleavage to regenerate the N-H group, which can then un-
dergo further synthetic elaboration (N-alkylation, etc.).
Although new attractive protocols have been developed
for the removal of N-sulfonyl groups (KOH/CTAB2 or
M-SG materials3), the overall process is not atom-eco-
nomically effective especially if further N-elaboration is
needed.
88%
N
O
2/3 = 1:1
SO2Ph
O
H
1
N
N
3
Scheme 1 Intramolecular deprotection/alkylation reaction4
N
N
N
N
N
ROH, Na
THF, r.t.
N
R
O2S
N
(1)
Bosch and co-workers found that if N-sulfonylindole 1
was deprotected utilizing potassium tert-butoxide in tet-
rahydrofuran an unexpected intramolecular C-3 and N-1
alkylation occurred to produce a 1:1 mixture of cyclized
regioisomers 2 and 3 (Scheme 1).4 This unexpected result
can be rationalized by potassium tert-butoxide deprotona-
tion of the alcohol in indole 1, followed by attack of the
resulting alkoxide onto the sulfonamide group. The liber-
ated N anion can then displace the newly formed alkyl sul-
fonate group either through resonance to give the C-3
alkylated product 2 or directly to give the N-1 alkylated
product 3.
Katritzky and co-workers5 and Eissenstat and Weaver6 in
independent communications reported that this reaction
can occur in an intermolecular fashion (Scheme 2; equa-
tions 1 and 2, respectively). Katritzky’s group showed that
N-alkylbenzotriazoles could be prepared from the reac-
tion of sodium alkoxides with N,N¢-sulfonyldibenzotriaz-
ole 4. Eissenstat and Weaver investigated the plausibility
of this deprotection/alkylation sequence employing the 3-
+
10–74%
8 examples
N
N
N
N
R
N
4
OMe
OMe
(2)
O
O
ROH, NaH, K2CO3
toluene, reflux
11–90%
5 examples
N
N
SO2Me
R
5
Scheme 2 Previous intermolecular reactions of the deprotection/
alkylation sequence5,6
As we recently had need of an efficient, economical pro-
cess for the conversion of N-sulfonyl-protected heterocy-
cles into their N-alkyl counterparts, we decided to further
investigate the deprotection/alkylation sequence outlined
above to improve the general synthetic value of the reac-
tion. Herein, we disclose our initial results toward an
atom-economic deprotection/alkylation protocol for sul-
fonamide heterocycles utilizing cesium carbonate or po-
tassium carbonate with a phase-transfer catalyst.
SYNTHESIS 2010, No. 5, pp 0775–0782
x
x
.
x
x
.2
0
1
0
Advanced online publication: 22.12.2009
DOI: 10.1055/s-0029-1218627; Art ID: M05709SS
© Georg Thieme Verlag Stuttgart · New York

776
J. R. Denton
PAPER
1-[1-(Phenylsulfonyl)-1H-indol-3-yl]ethanone (6)7 was
used as the prototypical substrate in the initial studies. 3-
Acetylindole 6 was subjected to known deprotection con-
ditions which gave only a minor amount of alkylated
product (Scheme 3).2 Reaction of 6 with methanol–water
and potassium carbonate at reflux led to a ~1:10 ratio of
the desired N-alkyl product 7 to the N-H product 8. It was
postulated that under anhydrous conditions the ratio of de-
sired product would increase. Therefore, 6 was dissolved
in anhydrous methanol–N,N-dimethylformamide8 with
potassium carbonate and refluxed. This led to a ~4:1 ratio
of desired N-alkyl product 7 to N-H product 8, but some
unidentified byproducts were also obtained. Encouraged
by the fact that potassium carbonate could affect the de-
sired deprotection/alkylation sequence in the absence of a
strong base, we carried out optimization studies. Specifi-
cally, phase-transfer catalysis (PTC)9 was explored as a
means for improving the yield of N-alkylated products.
O
O
a or b
reflux
R = Me, 7
R = H, 8
N
N
SO2Ph
R
6
Ratio (7/8)a
Conditions
~1:10
~4:1
a) MeOH, K2CO3, H2O, 4 h
b) MeOH, K2CO3, DMF, 4 h
a As judged from the 1H NMR spectrum of the
crude reaction mixture in acetone-d6
Scheme 3 Initial results toward the desired product
The findings of our PTC exploratory study can be found
in Table 1 (entries 1–13). Initial conditions utilizing 1-
pentanol10 (2.0 equiv) [instead of MeOH (10.0 equiv)]
with potassium carbonate (2.5 equiv) as the base resulted
in 60% yield of the desired N-alkylindole 9 (entry 1). In
Table 1 Optimization of the Deprotection/Alkylation Protocol
O
O
4 OH
R = (CH2)4Me, 9
R = H, 8
reflux
under N2
R = Me, 7
N
N
SO2Ph
R
6
Entry Solvent
Amount of
1-pentanol
Base
PTC
Time
(h)
Ratioa
(9/8/7/6)
Yieldb,c
(%) of 9
1
2
DMF
2.0 equiv
2.0 equiv
2.0 equiv
2.0 equiv
2.0 equiv
2.0 equiv
2.0 equiv
2.0 equiv
2.0 equiv
2.0 equiv
2.0 equiv
2.0 equiv
2.0 equiv
1.5 equiv
1.1 equiv
1.1 equiv
1.1 equiv
1.1 equiv
K2CO3 (2.5 equiv)
K2CO3 (2.5 equiv)
K2CO3 (2.5 equiv)
K2CO3 (2.5 equiv)
K2CO3 (2.5 equiv)
K2CO3 (2.5 equiv)
K2CO3 (2.5 equiv)
K2CO3 (2.5 equiv)
Na2CO3 (2.5 equiv)
Cs2CO3 (2.0 equiv)
Cs2CO3 (2.0 equiv)
Cs2CO3 (2.0 equiv)
Cs2CO3 (2.0 equiv)
Cs2CO3 (1.5 equiv)
Cs2CO3 (1.1 equiv)
Cs2CO3 (1.1 equiv)
Cs2CO3 (1.1 equiv)
Cs2CO3 (1.1 equiv)
none
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
8
65:35:0:0
0:0:0:100
87:1:11:0
>98:1:0:0
79:10:0:11
61:5:0:34
77:13:0:10
72:11:0:17
7:21:0:72
95:5:0:0
60
toluene
toluene
toluene
toluene
toluene
toluene
MeCN
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
none
–
3
CTAB (25 mol%)
TBAB (25 mol%)
TBAB (15 mol%)
TBAI (15 mol%)
[Me(CH2)7]4NBr (15 mol%)
TBAB (15 mol%)
TBAB (15 mol%)
TBAB (15 mol%)
TBAB (5 mol%)
TBAB (1 mol%)
none
86
4
98
5
ND
ND
ND
ND
ND
95
6
7
8
9
10
11
12
13
14
15
16
17
18
94:6:0:0
94
88:12:0:0
76:24:0:0
95:5:0:0
ND
ND
95
TBAB (5 mol%)
TBAB (5 mol%)
TBAB (5 mol%)
TBAB (5 mol%)
TBAB (5 mol%)
97:3:0:0
97
93:7:0:0
93d
93
93:7:0:0
4
81:8:0:11
ND
a As judged from the 1H NMR spectrum of the crude reaction mixture, in acetone-d6.
b Isolated yield after purification by column chromatography.
c ND = not determined.
d Reaction was conducted open to the atmosphere.
Synthesis 2010, No. 5, 775–782 © Thieme Stuttgart · New York

PAPER
One-Pot Desulfonylative Alkylation of N-Sulfonyl Azacycles
777
toluene, however, only starting material 6 was observed
after 24 hours at reflux (entry 2). In contrast, the PTC re-
action employing cetyltrimethylammonium bromide
(CTAB) led to 86% yield of 9, but with significant
amounts of byproduct 7 (entry 3). Byproduct 7 arises by
alkylation from the phase-transfer catalyst itself. The re-
action was then conducted utilizing 25 mol% of tetrabuty-
lammonium bromide (TBAB) and resulted in the desired
product 9 in 98% yield, with no evidence of any alkylation
from the phase-transfer catalyst (entry 4).
Table 2 Reactivity of Different Alcohols and Sulfonyl Groups
O
O
R1OH
(1.5 equiv)
TBAB (5 mol%)
Cs2CO3 (1.1 equiv)
toluene, reflux, 24 h
N
N
R1
SO2R2
under N2
Entry Substrate R2
Product R1
Yielda (%)
52
1
2
3
4
6
6
6
6
Ph
Ph
Ph
Ph
7
7
Me
The influence of the catalyst loading as well as the catalyst
employed in the reaction was then investigated (Table 1,
entries 5–8). It was found that the loading of the catalyst
had a significant impact on the outcome of the reaction
(entry 5). When the loading of TBAB was decreased to 15
mol% the efficiency of the reaction decreased and after
workup led to a mixture of starting material 6, N-H indole
8, and desired product 9. Attempts were then made to cir-
cumvent this problem by changing the phase-transfer cat-
alyst (entries 6 and 7). Unfortunately, of the catalysts
screened, none improved the outcome of the reaction. The
reaction medium was then changed to a more polar sol-
vent (MeCN), but this did not improve the ratio of prod-
ucts obtained (entry 8).
Me
95b
i-Pr
(20)c
96
10a
CH2CH2OMe
5
6
Ph
(<5)c
6
7
6
6
Ph
i-Bu
(55)c
96
Ph
10b
10c
10d
9
CH2CH2CHMe2
Bn
8
6
Ph
95
9
6
Ph
CH2CH=CH2
(CH2)4Me
(CH2)4Me
91b
94
The next series of experiments evaluated the effect of dif-
ferent carbonate bases on the reaction (Table 1, entries 5,
9, and 10). These experiments were conducted using 15
mol% of TBAB and it was found that the base had a sig-
nificant effect on the outcome of the reaction. If sodium
carbonate (2.5 equiv) was employed, the reaction proved
sluggish (entry 9); however, if cesium carbonate (2.0
equiv) was employed, the desired product 9 was isolated
in 95% yield. Subsequently, it was found that by employ-
ing cesium carbonate as the base, the catalyst loading
could be decreased to 5 mol% without a significant de-
crease in efficiency (24 h, 94% yield; entry 11). Surpris-
ingly, if the reaction was conducted without a phase-
transfer catalyst, only the desulfonated products 8 and 9
were observed (entry 13).
10
11
11
p-Tol
Me
12
9
(55)c
a Isolated yield after purification by column chromatography.
b Reaction was conducted at the boiling point of the alcohol.
c Estimated conversion based on the 1H NMR spectrum of the crude
reaction mixture, in acetone-d6.
underwent the desired transformation in high yield
(>90%) as long as the reaction was conducted around their
boiling points (entries 1, 2, and 9). 2-Methoxyethanol and
benzyl alcohol also gave their respective products in high
yield (>95%, entries 4 and 8). The latter reaction could be
considered an efficient protecting group interconversion,
since the benzenesulfonamide 6 is directly converted into
benzyl derivative 10c.
Next, an optimization study was performed in regards to
equivalence of 1-pentanol and cesium carbonate used in
the reaction as well as to how long the reaction was con-
ducted (Table 1, entries 14–18). The optimal conditions
were found to be the following: 1-pentanol (1.1 equiv) and
cesium carbonate (1.1 equiv) with 5 mol% of TBAB for
24 hours in refluxing toluene under a nitrogen atmo-
sphere, which produced 9 in 97% yield (entry 15). Inter-
estingly, if the reaction was conducted open to the
atmosphere, the outcome was similar (93% vs 97% yield,
entries 16 and 15). It was also found that the reaction time
played a significant role in the outcome of the reaction
(entries 15, 17, and 18).
Alcohols congested at either the a- or b-position led to a
significant decrease in the desired product (Table 2, en-
tries 3, 5, and 6). In the case of 1-adamantanemethanol, no
1
detectable N-alkyl product could be observed in the H
NMR spectrum of the crude reaction mixture (entry 5).
The major components observed in these reactions were
the starting material 6 and the desulfonylated product 8.
Steric hindrance, however, could be tolerated in the g-po-
sition, as demonstrated by the use of 3-methyl-1-butanol
(96% yield, entry 7).
Altering the sulfonamide group had an unexpected influ-
ence on the outcome of the reaction (Table 2, entries 10
and 11). N-(p-Tolylsulfonyl)indole 11 gave the desired
product in a similar yield to N-(phenylsulfonyl)indole 6
(94% vs 97%). As for N-(methylsulfonyl)indole 12, the
efficiency of the protocol decreased, producing a mixture
of starting material 12, desulfonated product 8, and N-
The deprotection/alkylation protocol for 3-acetylindole 6
was then expanded to a range of alcohols and the results
are summarized in Table 2 (entries 1–9). It was found that
more sterically hindered alcohols led to lower yields of
the desired N-alkyl products.11 Methanol and allyl alcohol
Synthesis 2010, No. 5, 775–782 © Thieme Stuttgart · New York

778
J. R. Denton
PAPER
Table 3 Scope of the Protocol: Different N-(Phenylsulfonyl) Heterocycles
MeO
R2
OH
R2
R1
(1.5 equiv)
R1
N
N
TBAB (5 mol%)
Cs2CO3 (1.1 equiv)
toluene, reflux
(CH2)2OMe
SO2Ph
Entry
Substrate
Product
Time (h)
Yield (%)
1
2
24
72
(40)a
(65)a
N
N
SO2Ph
(CH2)2OMe
13a
MeO
MeO
3
24
(50)a
N
N
SO2Ph
(CH2)2OMe
13b
4
5
6
24
24
24
(55)a
N
N
N
N
SO2Ph
(CH2)2OMe
13c
N
N
N
N
97b
SO2Ph
(CH2)2OMe
13d
14a
14b
N
N
N
N
N
N
75b
SO2Ph
(CH2)2OMe
13e
O
c
c
7
8
–
24
72
–
–
c
c
N
–
SO2Ph
13f
a Estimated conversion based on the 1H NMR spectrum, in CDCl3.
b Isolated yield after purification by column chromatography.
c No reaction based on the 1H NMR spectrum of the crude reaction mixture, in CDCl3.
alkylated product 9 after 24 hours. This result is striking, ance was the starting material 13a–c and the desulfonated
since Eissenstat and Weaver reported that the methylsul- N-H products.
fonyl derivative was more reactive than the phenylsulfo-
At this stage of the investigation, we postulated that in or-
der to effect an efficient deprotection/alkylation sequence
utilizing the described PTC conditions employing other
nyl analogue in their study employing the 3-acylindole 5
(Scheme 2, equation 2).6
The scope of the deprotection/alkylation protocol was N-(phenylsulfonyl) heterocycles, the acidity of the N-het-
then extended to a range of N-(phenylsulfonyl) heterocy- erocycle had to be increased. Therefore, N-(phenylsul-
cles 13a–f and the results are depicted in Table 3. Reac- fonyl)imidazole 13d was subjected to the deprotection/
tion of the N-(phenylsulfonyl) heterocycles 13a–c lacking alkylation protocol and this resulted in a high-yielding re-
the keto substituent in the C-3 position with 2-methoxy- action after 24 hours (97%; Table 3, entry 5). Likewise,
ethanol and cesium carbonate gave significantly lower the reaction of N-(phenylsulfonyl)triazole 13e gave the
yields of the desired N-alkylated products (40–65%, en- desired N-1 alkylated product, but only in 75% yield (en-
tries 1–4). Conducting the reaction for a longer period of try 6). The remainder of the mass balance for this reaction
time (72 vs 24 h) did increase the conversion of the overall was the N-2 alkylated benzotriazole.5,12 Similarly, it was
sequence, but only from 40% to 65% (entries 1 and 2). In expected that if the basicity of the N-heterocycle was sig-
each of these experiments the remainder of the mass bal- nificantly increased the PTC reaction would not be effec-
tive at all. This was indeed found to be true as the reaction
Synthesis 2010, No. 5, 775–782 © Thieme Stuttgart · New York

PAPER
One-Pot Desulfonylative Alkylation of N-Sulfonyl Azacycles
779
Table 4 Synthesis of 16, a Potent Cannabimimetic Indole
O
O
TBAB (5 mol%)
toluene, reflux
open to the atmosphere
N
N
SO2Ph
(CH2)4Me
16
15
Entry
Conditions
Yielda (%) of 16
1
1-pentanol (1.1 equiv), Cs2CO3 (1.1 equiv), 24 h
93
(80)b
94
2
1-pentanol (1.1 equiv), Cs2CO3 (1.1 equiv), 8 h; then, 1-pentanol (0.1 equiv), PhSO2Cl (0.1 equiv), 16 h
1-pentanol (1.1 equiv), Cs2CO3 (1.1 equiv), 24 h; then, 1-pentanol (0.1 equiv), PhSO2Cl (0.1 equiv), 8 h
1-pentanol (1.1 equiv), Cs2CO3 (1.1 equiv), 24 h; then, 1-bromopentane (0.1 equiv), 8 h
1-pentanol (1.1 equiv), Cs2CO3 (1.1 equiv), 24 h; then, 1-bromopentane (0.1 equiv), 8 h
3
4
99
5c
98
a Isolated yield after purification by column chromatography.
b Estimated conversion based on the 1H NMR spectrum, in acetone-d6.
c Optimized reaction conditions were repeated on a gram scale.
of N-(phenylsulfonyl)morpholine (13f) with 2-methoxy- In conclusion, a one-pot desulfonylative alkylation of N-
ethanol (1.5 equiv) and cesium carbonate (1.1 equiv) in sulfonyl azacycles utilizing cesium carbonate or potassi-
refluxing toluene for 24 or 72 hours gave no observed re- um carbonate and a phase-transfer catalyst has been de-
action (entries 7 and 8).
veloped. The outcome of the one-pot protocol was found
to be significantly dependent on both the alcohol and the
sulfonamide heterocycle employed. Sterically congested
alcohols at either the a- or b-position led to a significant
decrease in the desired N-alkyl products. N-(Phenylsul-
fonyl) heterocycles that are too basic do not undergo the
deprotection/alkylation sequence, whereas less basic N-
(phenylsulfonyl) heterocycles (3-acetylindole, benzimi-
dazole, etc.) undergo the desired transformation with high
efficiency. Ultimately, the efficiency of the deprotection/
alkylation protocol could be improved to near quantitative
yield when a corresponding electrophilic alkyl reagent
was also added. Future endeavors will focus on expanding
the scope of the N-sulfonyl heterocycles employed, in-
cluding intramolecular reactions, as well as on physical
chemical aspects of the reaction.
One of the most significant discoveries found from the
earlier experimentations involving 3-acetylindole 6 was
that anhydrous conditions are not necessary for the depro-
tection/alkylation protocol. Therefore, we wanted to opti-
mize and showcase this methodology employing
nonanhydrous conditions in the synthesis of naphthalen-
1-yl(1-pentyl-1H-indol-3-yl)methanone (16), a very po-
tent cannabimimetic indole.13,14 The findings can be found
in Table 4.
Reaction of N-(phenylsulfonyl)indole 15 using the previ-
ously described conditions led to 93% yield of the desired
N-alkylindole 16 (entry 1). Since the remainder of the
mass balance in the reaction was the desulfonated N-H
product, it was hypothesized that addition of an electro-
philic pentyl reagent would increase the yield of the reac-
tion. In situ generation of a pentyl sulfonate intermediate
utilizing 1-pentanol and benzenesulfonyl chloride did not
significantly improve the yield of the reaction and led to
the formation of the desired product 16 and the starting
material 15 after 24–32 hours (entries 2 and 3). Therefore,
1-bromopentane was implemented as the electrophilic
pentyl reagent and it was found that upon reaction of 15
using the deprotection/alkylation conditions, followed by
addition of 1-bromopentane at reflux for 8 hours, 16 was
synthesized in near quantitative yield with no evidence of
the desulfonated N-H product by TLC (entry 4). The reac-
tion was then repeated on a gram scale (entry 5), which
confirmed the increase in yield when 1-bromopentane is
utilized.
Reagents were purchased at the highest purity available from com-
mercial suppliers and used without further purification. Toluene
was distilled from CaH2 and kept under a N2 atmosphere over 4 Å
molecular sieves until used. All reactions were run under a N2 atmo-
sphere unless otherwise noted. Melting points were determined on
1
a Büchi capillary melting point apparatus and are uncorrected. H
and 13C NMR spectra were recorded at 400 and 100 MHz, respec-
tively, on a Varian 400 instrument. Chemical shifts are reported in
ppm (d) and coupling constants, J, are reported in hertz. Infrared
spectra (IR) peaks are reported in cm–1. Analytical TLC was per-
formed on 0.25 mm E. Merck silica gel plates using UV light for vi-
sualization.
N-Sulfonyl Protection; General Procedure
60% NaH in paraffin (1.10 equiv) was added in two portions to a
stirred soln of the N-heterocycle (1.00 equiv) in anhyd THF at
<5 °C (ice bath). The ice bath was then removed and the mixture
Synthesis 2010, No. 5, 775–782 © Thieme Stuttgart · New York

780
J. R. Denton
PAPER
was aged at r.t. for 1 h. Benzenesulfonyl chloride (1.10 equiv) was
then added dropwise to the mixture. The reaction mixture was aged
at r.t. for another 1 h, and was then poured into dil aq NaHCO3 and
extracted with EtOAc (3 ×). The extracts were combined, dried
(Na2SO4), filtered, and concentrated under reduced pressure. The
product was then purified by column chromatography and/or re-
crystallization. The pure isolated N-(phenylsulfonyl) heterocycles
were kept over P2O5 in a vacuum desiccator until used in the depro-
tection/alkylation protocol.
1-(Phenylsulfonyl)-1H-benzimidazole (13d)2
Compound 13d was purified by column chromatography (silica gel,
20% → 30% EtOAc in hexanes) to give a white solid. The physical
and spectroscopic data were identical to those reported for this com-
pound.
1H NMR (400 MHz, CDCl3): d = 7.35–7.44 (m, 2 H), 7.52–7.56 (m,
2 H), 7.63–7.66 (m, 1 H), 7.78 (d, J = 8.0 Hz, 1 H), 7.88 (d, J = 8.0
Hz, 1 H), 8.01 (d, J = 8.0 Hz, 2 H), 8.40 (s, 1 H).
1-(Phenylsulfonyl)-1H-1,2,3-benzotriazole (13e)19
Compound 13e was purified by column chromatography (silica gel,
20% → 30% EtOAc in hexanes) to give a white solid. The physical
and spectroscopic data were identical to those reported for this com-
pound.
1H NMR (400 MHz, CDCl3): d = 7.48–7.57 (m, 3 H), 7.65–7.70 (m,
2 H), 8.09–8.15 (m, 4 H).
1-[1-(Phenylsulfonyl)-1H-indol-3-yl]ethanone (6)1a
Compound 6 was purified by column chromatography (silica gel,
30% EtOAc in hexanes) followed by recrystallization (i-PrOH) to
give a white solid. The physical and spectroscopic data were identi-
cal to those reported for this compound.
1H NMR (400 MHz, CDCl3): d = 2.59 (s, 3 H), 7.34–7.42 (m, 2 H),
7.50–7.65 (m, 3 H), 7.94–7.98 (m, 3 H), 8.22 (s, 1 H), 8.33–8.36 (m,
1 H).
4-(Phenylsulfonyl)morpholine (13f)20
Compound 13f was purified by recrystallization (EtOH–H2O) to
give a white solid. The physical and spectroscopic data were identi-
cal to those reported for this compound.
1H NMR (400 MHz, CDCl3): d = 3.02 (t, J = 4.0 Hz, 4 H), 3.76 (t,
J = 4.0 Hz, 4 H), 7.56–7.60 (m, 2 H), 7.63–7.67 (m, 1 H), 7.76–7.79
(m, 2 H).
1-[1-(p-Tolylsulfonyl)-1H-indol-3-yl]ethanone (11)15
p-Toluenesulfonyl chloride was used instead of benzenesulfonyl
chloride. Compound 11 was purified by column chromatography
(silica gel, 20% → 30% EtOAc in hexanes) to give a white solid.
The physical and spectroscopic data were identical to those reported
for this compound.
1H NMR (400 MHz, CDCl3): d = 2.38 (s, 3 H), 2.58 (s, 3 H), 7.28–
7.40 (m, 4 H), 7.85 (d, J = 12.0 Hz, 2 H), 7.92–7.94 (m, 1 H), 8.22
(s, 1 H), 8.33–8.35 (m, 1 H).
Naphthalen-1-yl[1-(phenylsulfonyl)-1H-indol-3-yl]methanone
(15)
Compound 15 was purified by recrystallization (i-PrOH–toluene,
1:1) to give a white solid.
1-[1-(Methylsulfonyl)-1H-indol-3-yl]ethanone (12)16
Methanesulfonyl chloride was used instead of benzenesulfonyl
chloride. Compound 12 was purified by column chromatography
(silica gel, 30% → 35% EtOAc in hexanes) to give a white solid.
The physical and spectroscopic data were identical to those reported
for this compound.
Mp 158–160 °C.
IR (neat): 3133, 3060, 1644, 1532, 1380, 1176, 967, 684 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.42–7.62 (m, 8 H), 7.73 (dd,
J = 1.2, 7.2 Hz, 1 H), 7.85–7.90 (m, 3 H), 7.95–8.01 (m, 2 H), 8.06
(d, J = 8.4 Hz, 1 H), 8.19 (d, J = 8.4 Hz, 1 H), 8.45–8.49 (m, 1 H).
13C NMR (100 MHz, CDCl3): d = 113.1, 122.3, 123.2, 124.5, 125.1,
125.4, 126.1, 126.6, 127.06, 127.11, 127.2, 128.1, 128.4, 129.6,
130.5, 131.4, 133.8, 134.6, 134.7, 135.1, 137.0, 137.2, 192.3.
1H NMR (400 MHz, CDCl3): d = 2.59 (s, 3 H), 3.27 (s, 3 H), 7.43–
7.49 (m, 2 H), 7.88–7.90 (m, 1 H), 8.10 (s, 1 H), 8.43–8.46 (m, 1 H).
1-(Phenylsulfonyl)-1H-indole (13a)17
HRMS (ES+): m/z [M + H]+ calcd for C25H18NO3S: 412.1007;
found: 412.1007.
Compound 13a was purified by column chromatography (silica gel,
10% → 30% EtOAc in hexanes) followed by recrystallization (i-
PrOH) to give a white solid. The physical and spectroscopic data
were identical to those reported for this compound.
Deprotection/Alkylation Protocol; General Procedure
The appropriate alcohol (1.10–1.50 equiv) was added in one por-
tion to a stirring slurry of the N-(phenylsulfonyl) heterocycle (100
mg, 1.00 equiv), TBAB (5 mol%), and Cs2CO3 (1.10 equiv) in tol-
uene (5 mL) at r.t. A condenser was attached and the slurry was
brought to reflux. The slurry was held at reflux for 24 h and then
cooled to r.t. H2O (10 mL) and EtOAc (10 mL) were then added.
The layers were separated and the aqueous layer was extracted with
EtOAc (2 × 10 mL). The organic extracts were combined, dried
(Na2CO3), filtered, and concentrated under reduced pressure. The
product was then purified by column chromatography.
1H NMR (400 MHz, CDCl3): d = 6.67 (d, J = 4.4 Hz, 1 H), 7.21–
7.34 (m, 2 H), 7.42–7.46 (m, 2 H), 7.51–7.55 (m, 2 H), 7.57 (d,
J = 3.6 Hz, 1 H), 7.87–7.90 (m, 2 H), 8.00 (d, J = 9.2 Hz, 1 H).
5-Methoxy-1-(phenylsulfonyl)-1H-indole (13b)17
Compound 13b was purified by recrystallization (EtOH) to give a
white solid. The physical and spectroscopic data were identical to
those reported for this compound.
1H NMR (400 MHz, acetone-d6): d = 2.60 (s, 3 H), 7.33–7.44 (m, 2
H), 7.62–7.76 (m, 3 H), 8.01 (d, J = 8.4 Hz, 1 H), 8.14 (d, J = 8.8
Hz, 2 H), 8.28 (d, J = 8.4 Hz, 1 H), 8.62 (s, 1 H).
1-(1-Pentyl-1H-indol-3-yl)ethanone (9)
Compound 9 was purified by column chromatography (silica gel,
20% → 30% EtOAc in hexanes) to give a light yellow oil; yield:
0.075 g (97%).
IR (neat): 3105, 2931, 1644, 1527, 1390, 1224, 931, 747 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.91 (t, J = 6.8 Hz, 3 H), 1.26–
1.41 (m, 4 H), 1.90 (quintet, J = 7.2 Hz, 2 H), 2.55 (s, 3 H), 4.16 (t,
J = 7.2 Hz, 2 H), 7.28–7.39 (m, 3 H), 7.75 (s, 1 H), 8.37–8.41 (m, 1
H).
1-(Phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (13c)18
Compound 13c was purified by column chromatography (silica gel,
20% → 30% EtOAc in hexanes) to give a white solid. The physical
and spectroscopic data were identical to those reported for this com-
pound.
1H NMR (400 MHz, CDCl3): d = 6.60 (d, J = 4.0 Hz, 1 H), 7.18 (dd,
J = 5.2, 8.0 Hz, 1 H), 7.48 (t, J = 8.0 Hz, 2 H), 7.55–7.59 (m, 1 H),
7.73 (d, J = 4.0 Hz, 1 H), 7.85 (dd, J = 1.6, 7.6 Hz, 1 H), 8.20 (d,
J = 8.8 Hz, 2 H), 8.43 (dd, J = 1.6, 4.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 13.8, 22.1, 27.5, 28.9, 29.5, 49.0,
109.7, 116.7, 122.3, 122.5, 123.0, 126.2, 134.7, 136.6, 192.9.
Synthesis 2010, No. 5, 775–782 © Thieme Stuttgart · New York

PAPER
One-Pot Desulfonylative Alkylation of N-Sulfonyl Azacycles
781
HRMS (ES+): m/z [M + H]+ calcd for C15H20NO: 230.1545; found:
1-(2-Methoxyethyl)-1H-1,2,3-benzotriazole (14b)
230.1546.
Compound 14b was purified by column chromatography (silica gel,
50% EtOAc in hexanes) to give a light yellow oil; yield: 0.051 g
(75%).
1-(1-Methyl-1H-indol-3-yl)ethanone (7)21
The reaction was conducted at the boiling point of MeOH by utiliz-
ing an oil bath. Compound 7 was purified by column chromatogra-
phy (silica gel, 30% → 50% EtOAc in hexanes) to give a white
solid; yield: 0.055 g (95%). This reaction was monitored by TLC,
and on one occasion the reaction was not complete until ~36 h. The
physical and spectroscopic data were identical to those reported for
this compound.
IR (neat): 2930, 1615, 1455, 1231, 1121, 747 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.31 (s, 3 H), 3.90 (t, J = 4.0 Hz,
2 H), 4.82 (t, J = 4.0 Hz, 2 H), 7.38 (t, J = 8.0 Hz, 1 H), 7.50 (t,
J = 8.0 Hz, 1 H), 7.64 (d, J = 8.0 Hz, 1 H), 8.06 (d, J = 8.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 48.3, 58.9, 71.1, 110.1, 119.6,
123.7, 127.2, 133.6, 145.8.
1H NMR (400 MHz, CDCl3): d = 2.53 (s, 3 H), 3.86 (s, 3 H), 7.28–
7.37 (m, 3 H), 7.72 (s, 1 H), 8.36–8.39 (m, 1 H).
HRMS (ES+): m/z [M + H]+ calcd for C9H12N3O: 178.0980; found:
178.0977.
1-[1-(2-Methoxyethyl)-1H-indol-3-yl]ethanone (10a)22
Compound 10a was purified by column chromatography (silica gel,
30% → 50% EtOAc in hexanes) to give a clear oil; yield: 0.070 g
(96%). The physical and spectroscopic data were identical to those
reported for this compound.
1H NMR (400 MHz, CDCl3): d = 2.53 (s, 3 H), 3.32 (s, 3 H), 3.73
(t, J = 5.2 Hz, 2 H), 4.31 (t, J = 5.2 Hz, 2 H), 7.27–7.37 (m, 3 H),
7.81 (s, 1 H), 8.36–8.41 (m, 1 H).
Naphthalen-1-yl(1-pentyl-1H-indol-3-yl)methanone (16)24
1-Pentanol (0.73 mL, 6.7 mmol) was added in one portion to a stir-
ring slurry of indole 15 (2.50 g, 6.1 mmol), TBAB (0.098 g, 5
mol%), and Cs2CO3 (2.18 g, 6.7 mmol) in toluene (25 mL) at r.t. and
open to the atmosphere. A condenser was attached and the slurry
was brought to reflux. After 24 h at reflux, the slurry was allowed
to cool to r.t. and the condenser was rinsed with toluene (10 mL). At
r.t., 1-bromopentane (0.08 mL, 0.6 mmol) was added in one portion
and the slurry was brought to reflux. After 8 h at reflux, the slurry
was cooled to r.t., and H2O (25 mL) and EtOAc (25 mL) were then
added. The resulting bilayer soln was separated and the aqueous
layer was extracted with EtOAc (2 × 25 mL). The organic extracts
were combined, dried (Na2SO4), filtered, and concentrated under re-
duced pressure. The gummy residue was then purified by column
chromatography (silica gel, 20% → 30% EtOAc in hexanes). The
collected fractions were concentrated under reduced pressure, dried
under vacuum, and placed in a freezer (–20 °C) overnight to give a
white crystalline solid; yield: 2.03 g (98%). The physical and spec-
troscopic data were identical to those reported for this compound.
1-[1-(3-Methylbutyl)-1H-indol-3-yl]ethanone (10b)
Compound 10b was purified by column chromatography (silica gel,
20% → 30% EtOAc in hexanes) to give a light brown oil; yield:
0.074 g (96%).
IR (neat): 3106, 2958, 1645, 1528, 1389, 1198, 929, 746 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.00 (d, J = 6.4 Hz, 6 H), 1.59–
1.68 (m, 1 H), 1.79 (q, J = 7.6 Hz, 2 H), 2.54 (s, 3 H), 4.17 (t, J = 7.6
Hz, 2 H), 7.26–7.38 (m, 3 H), 7.75 (s, 1 H), 8.35–8.39 (m, 1 H).
13C NMR (100 MHz, CDCl3): d = 22.2, 25.6, 27.5, 38.5, 45.2,
109.7, 116.7, 122.3, 122.4, 123.0, 126.2, 134.6, 136.6, 192.8.
Mp 65–67 °C.
HRMS (ES+): m/z [M + H]+ calcd for C15H20NO: 230.1545; found:
230.1541.
1H NMR (400 MHz, CDCl3): d = 0.85 (t, J = 6.8 Hz, 3 H), 1.21–
1.33 (m, 4 H), 1.81 (quintet, J = 7.2 Hz, 2 H), 4.07 (t, J = 7.2 Hz, 2
H), 7.35–7.55 (m, 7 H), 7.66 (dd, J = 1.2, 6.8 Hz, 1 H), 7.91 (d,
J = 7.6 Hz, 1 H), 7.98 (d, J = 8.0 Hz, 1 H), 8.19 (d, J = 8.8 Hz, 1 H),
8.47–8.52 (m, 1 H).
1-(1-Benzyl-1H-indol-3-yl)ethanone (10c)21
Compound 10c was purified by column chromatography (two sep-
arate columns: silica gel, 20% → 30% EtOAc in hexanes; then silica
gel, CH2Cl2–hexanes–MeOH, 6:3:1) to give a white solid; yield:
0.079 g (95%). The physical and spectroscopic data were identical
to those reported for this compound.
1H NMR (400 MHz, CDCl3): d = 2.52 (s, 3 H), 5.35 (s, 2 H), 7.16–
7.40 (m, 8 H), 7.76 (s, 1 H), 8.37–8.43 (m, 1 H).
Acknowledgment
Dr Bill Boulanger, the owner of Obiter Research, is thanked for his
financial contribution.
1-(1-Allyl-1H-indol-3-yl)ethanone (10d)15
References
The reaction was conducted at the boiling point of allyl alcohol by
utilizing an oil bath. Compound 10d was purified by column chro-
matography (silica gel, 20% → 30% EtOAc in hexanes) to give a
yellow oil; yield: 0.061 g (91%). The physical and spectroscopic
data were identical to those reported for this compound.
1H NMR (400 MHz, CDCl3): d = 2.54 (s, 3 H), 4.77–4.79 (m, 2 H),
5.18 (d, J = 19.6 Hz, 1 H), 5.31 (d, J = 11.6 Hz, 1 H), 5.98–6.07 (m,
1 H), 7.28–7.36 (m, 3 H), 7.75 (s, 1 H), 8.37–8.40 (m, 1 H).
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1-(2-Methoxyethyl)-1H-benzimidazole (14a)23
Compound 14a was purified by column chromatography (silica gel,
100% EtOAc → 100% acetone) to give a light yellow oil; yield:
0.066 g (97%). The physical and spectroscopic data were identical
to those reported for this compound.
1H NMR (400 MHz, CDCl3): d = 3.31 (s, 3 H), 3.72 (t, J = 4.0 Hz,
2 H), 4.33 (t, J = 4.0 Hz, 2 H), 7.26–7.32 (m, 2 H), 7.40–7.42 (m, 1
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782
J. R. Denton
PAPER
(8) N,N-Dimethylformamide was chosen as the solvent for its
ability to increase the solubility of the base (K2CO3) and for
its high boiling point.
(9) For information on phase-transfer catalysis, see the
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Synthesis 2010, No. 5, 775–782 © Thieme Stuttgart · New York