Photodesulfonylation of indoles initiated by electron transfer from triethylamine

Article abstract of DOI:10.1016/j.tetlet.2006.01.152

N-Sulfonyl indoles can be easily deprotected by a photoinduced electron transfer reaction with triethylamine. By using an equivalent amount of n-Bu₃SnH in the photolysis medium, it is possible to suppress the competitive photo-Fries like rearrangement by scavenging the phenylsulfonyl radical.

Full text of DOI:10.1016/j.tetlet.2006.01.152

Tetrahedron Letters 47 (2006) 2409–2412
Photodesulfonylation of indoles initiated by
electron transfer from triethylamine
*
´
´
Xuechuan Hong, Jose M. Mejıa-Oneto, Stefan France and Albert Padwa
Department of Chemistry, Emory University, Atlanta, GA 30322, USA
Received 26 November 2005; revised 27 January 2006; accepted 30 January 2006
Available online 17 February 2006
Abstract—N-Sulfonyl indoles can be easily deprotected by a photoinduced electron transfer reaction with triethylamine. By using an
equivalent amount of n-Bu3SnH in the photolysis medium, it is possible to suppress the competitive photo-Fries like rearrangement
by scavenging the phenylsulfonyl radical.
Ó 2006 Elsevier Ltd. All rights reserved.
The kopsifolines (3) represent a new group of hexacyclic
N
N
H
H
monoterpenoid indoline alkaloids that were obtained
from a Malayan Kopsia species and their structures were
established on the basis of extensive NMR studies.1
While no biological activity has yet been reported for
this alkaloid family, the kopsifolines are structurally
intriguing compounds, related to and possibly derived
from an aspidosperma-type alkaloid precursor 1. A pos-
sible biogenetic pathway to the kopsifolines from 1
could involve an intramolecular epoxide-ring opening
followed by loss of H2O as shown in Scheme 1.
O
O
N
N
H
CO2Me
CO2Me
4
5
O
O
N
N
O
O
O
O
Our approach toward the synthesis of the kopsifoline
skeleton derives from a program underway in our labo-
ratory that is designed to exploit the rhodium(II)-cata-
lyzed cyclization/cycloaddition cascade of a-diazo
carbonyl compounds for the purposes of natural prod-
uct synthesis.2,3 Our retrosynthetic analysis of 1 is
shown in Scheme 2 and proceeds by a 1,3-dipolar cyclo-
N2
O
O
N
N
R
H
CO2Me
CO2Me
R
7
6
Scheme 2.
addition of a carbonyl ylide dipole derived from diazo
ketoester 7 across the indole p-bond.4 Reductive ring
opening of the resulting cycloadduct 6 followed by de-
hydration and N-deprotection would lead to the key
precursor 5 necessary for the final F-ring closure.
D
H
N
N
C
N
H
H+
O
H
E
A
OH
B
F
+
N
R
R
N
N
H
R
CO2Me
CO2Me
H
We first carried out a model study using diazo amide 10
in order to test the feasibility of the key dipolar cyclo-
addition/ring opening sequence. Compound 10 was
easily prepared by adding acid chloride 8 to diazo amide
CO2Me
2
3; R = H or OMe
1; R = H or OMe
Kopsifolines
Scheme 1.
˚
9 in the presence of 4 A molecular sieves at room tem-
perature. Gratifyingly, heating a sample of 10 with
Rh2(OAc)4 in benzene at 80 °C afforded cycloadduct
11 in 94% yield as a single diastereomer (Scheme 3).
*
Corresponding author. Tel.: +1 404 727 0283; fax: +1 404 727
6629; e-mail: chemap@emory.edu
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.01.152

2410
X. Hong et al. / Tetrahedron Letters 47 (2006) 2409–2412
metalating agent.7 In addition, the product N-sulfona-
O
HN
mides are often crystalline and stable to a variety of
reaction conditions (e.g., alkaline hydrolysis and cata-
lytic reduction). A corollary of the stability of the N-sulfon-
yl bond is the difficulty encountered in the removal
of this type of protecting group. Harsh deprotection
conditions are often required, which limit the synthetic
usefulness of these compounds. Thus, arylsulfonamides
are cleaved by sodium in liquid ammonia,8 sodium
naphthalenide, or anthracenide,9 heating to reflux in
strong acid10 and reaction with highly nucleophilic11
or reducing12 reagents. These harsh conditions have
led to the development of new methods for the deprotec-
tion of N-sulfonamides. This has included deprotection
by using SmI2,13 TiCl4/Zn,14 Mg in methanol,15
TBAF,16 iodotrimethylsilane,17 or electrolysis.18
Cl
+
O
OBn
N
N2
O
SO2Ph
CO2Et
8
9
o
4 A
sieves
O
O
N
N
O
O
OBn
Rh(II)
94%
OBn
N2
O
N
O
N
CO2Et
H
CO2Et
SO2Ph
R
10
hv
NEt3
11; R = SO2Ph
12; R = H
While the desulfonylation of several alkyl N-sulfonyl
amides has been achieved photochemically,19 the related
reaction using indoles has not been reported in the liter-
ature. Since the serendipitous deprotection reaction that
we encountered with indoline 11 proceeded in such high
yield and under very mild conditions, we set out to fur-
ther explore the generality and scope of the photodesulf-
onylation of a series of related indoles. The photolysis of
indoles 13 was carried out in the presence of 5.0 equiv of
Et3N and CH3CN in a quartz vessel using 254 nm lamps
for 1 h under a nitrogen atmosphere. Column chroma-
tography of the crude residue followed by removal of
the solvent gave the desired desulfonylated indoles 14
in 48–77% yield based on recovered starting material
(Table 1, entries 1–5). Interestingly, we also observed
the formation of both the ortho- and para-photo Fries
like rearrangement products 15 and 16 in varying quan-
tities (8–24%) depending on the particular system. In
most cases the para-rearrangement product was the
major isomer formed, suggesting leakage from a radical
cage.
Scheme 3.
Having established a viable route to cycloadduct 11,
efforts were next centered on the reductive opening of
the oxido bridge. In 1991, Cossy and co-workers
reported that a photoinduced electron transfer reaction
from Et3N to 7-oxabicyclo-[2.2.1]heptan-2-ones easily
generated the corresponding 3-hydroxycyclohexanone
derivatives.5 The reduction relies on the intermediacy
of a ketyl radical anion6 derived from the oxabicyclo-
heptane under the photochemical conditions. With this
result in mind, our initial attempts to carry out the
reductive ring opening of 11 employed Cossy’s photo-
reductive approach. We found, however, that the irradi-
ation of 11 in the presence of NEt3 (5 equiv) using
CH3CN as the solvent only furnished the desulfonylated
indoline 12 in 90% yield.
The ready photodesulfonylation of indoline 11
prompted us to carry out a broader study of this depro-
tection reaction since substituted N-sulfonyl-indoles are
commonly employed in organic synthesis. The powerful
electron-withdrawing property of the sulfonyl group
coupled with its ortho-directing effect has been exten-
sively utilized for selective metalation at the C2-position
of the indole ring without having to use a large excess of
Encouraged by these positive results, we studied the
effect of adding different additives in order to capture
the initially produced sulfonyl radical and thereby
enhance the yield of the desulfonylated indole. The use
of tert-butyl mercaptan as a radical scavenger showed
Table 1. Photodesulfonylation of indoles
R2
R2
R2
R2
PhO2S
+
hv
R1 +
R1
R1
SO2Ph
13 (a-e)
R1
N
N
N
N
H
H
H
SO2Ph
15 (a-e)
14 (a-e)
16 (a-e)
Entry
R1
R2
Product + yield (%)
14
15
16
13a
13b
13c
13d
13e
H
Me
H
Me
H
48
55
57
77
60
11
11
19
4
8
11
5
4
—
CH2CH2OTBS
CO2Me
COMe
H
CH2OH
—

X. Hong et al. / Tetrahedron Letters 47 (2006) 2409–2412
2411
no improvement in the overall yield of the desulfony-
lated indole 14. However, in the presence of 1.0 equiv
of n-Bu3SnH, the photoreaction of 13d afforded indole
14d in 96% yield (based on recovered starting material)
with no signs of the rearranged aryl sulfones 15d and
16d. The more highly activated tin hydride (weaker
Sn–H bond) allows for capture of the sulfonyl radical
thereby suppressing attack at the ortho- and para-
positions.
Further studies directed toward the synthesis of the
kopsifoline alkaloid family are currently underway and
will be described in a forthcoming publication.
Acknowledgments
We appreciate the financial support provided by the
National Institutes of Health (GM 059384) and the
National Science Foundation (Grant CHE-0132651).
More than likely, the photodesulfonylation reaction can
be attributed to a photoinduced electron transfer as out-
lined in Scheme 4. Amines are well known to undergo
such a transfer with electronically excited carbonyl
groups.20 The reaction is initiated by single electron
transfer from NEt3 to the electronically excited indole
with formation of the radical cation of triethylamine
(18) and the radical anion of the indole (17). Formation
of 17 weakens the N-SO2Ph bond and facilitates bond
cleavage.21 Proton transfer from the radical cation of
NEt3 (18) would lead to the observed desulfonylated in-
dole 14. In competition with this process, the phen-
ylsulfonyl radical can undergo addition to the
aromatic framework of the indole anion 19 producing
radical anion 20 as a transient species. A subsequent
electron transfer from 20 to 18 would afford the
rearranged indole 15 (and/or 16). In the presence of
n-Bu3SnH, the phenylsulfonyl radical undergoes bimole-
cular hydrogen atom transfer and is no longer available
to add to the aromatic ring.22
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In summary, N-sulfonyl indoles can be easily deprotec-
ted by a photoinduced electron transfer reaction with
triethylamine. By using an equivalent amount of n-
Bu3SnH in the photolysis medium, it is possible to sup-
press the competing photo-Fries like rearrangement by
scavenging the phenylsulfonyl radical. It is anticipated
that the mild and chemoselective nature of this deprotec-
tion reaction should lead to its application in synthesis.
*
-
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.
.
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NEt3
+
NEt3
N
N
18
SO2Ph
SO2Ph
17 (a-e)
-PhSO2
13 (a-e)
.
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N
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15 (a-e)
14 (a-e)
Scheme 4.

2412
X. Hong et al. / Tetrahedron Letters 47 (2006) 2409–2412
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22. In the case of indoles 13a–c, which are devoid
of an electron-withdrawing substituent at the 2-position
of the ring, no significant effect on the yield of the
desulfonylated indole 14 was noticed when n-Bu3SnH
was added to the reaction mixture. We assume that with
these systems the initially formed indolyl anion (i.e.,
19a–c) is simply more reactive and therefore under-
goes reaction with the phenylsulfonyl radical at
a
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faster rate than bimolecular hydrogen transfer with
n-Bu3SnH.