Metal-free synthesis of 1H-indole-2-carbaldehydes by N-iodosuccinimide- mediated cyclization of 1-(2′-anilinyl)prop-2-yn-1-ols in water. A formal synthesis of (R)-calindol

Article abstract of DOI:10.1016/j.tet.2013.06.032

A N-iodosuccinimide (NIS)-mediated method to prepare 1H-indole-2- carbaldehydes efficiently from cycloisomerization of 1-(2-aminophenyl)prop-2-yn- 1-ols is described. The reaction is operationally straightforward and accomplished in good to excellent yiel

Full text of DOI:10.1016/j.tet.2013.06.032

Accepted Manuscript
Metal-free synthesis of 1H-indole-2-carbaldehydes by N-iodosuccinimide-mediated
cyclization of 1-(2'-anilinyl)prop-2-yn-1-ols in water. A formal synthesis of (R)-calindol
Prasath Kothandaraman, Sherman Jun Liang Lauw, Philip Wai Hong Chan
PII:
S0040-4020(13)00962-9
10.1016/j.tet.2013.06.032
TET 24508
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 16 April 2013
Revised Date: 29 May 2013
Accepted Date: 10 June 2013
Please cite this article as: Kothandaraman P, Lauw SJL, Chan PWH, Metal-free synthesis of 1H-
indole-2-carbaldehydes by N-iodosuccinimide-mediated cyclization of 1-(2'-anilinyl)prop-2-yn-1-ols in
water. A formal synthesis of (R)-calindol, Tetrahedron (2013), doi: 10.1016/j.tet.2013.06.032.
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Metal-free synthesis of 1H-indole-2-
carbaldehydes by N-iodosuccinimide-
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mediated cyclization of 1-(2'-anilinyl)prop-2-
yn-1-ols in water. A formal synthesis of (R)-
calindol
Prasath Kothandaraman, Sherman Jun Liang Lauw and Philip Wai Hong Chan*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang
Technological University, Singapore 637371, Singapore
R
X = SO R
2
CHO
N
SO R
2
NIS
2.2 equiv)
HO
R
(
18 examples
51-91% yield
H
2
O/acetone
H
NHX
(25:1v/v), ∆, 24 h
R
R = H, alkyl, aryl
X = SO R, Ac
X = Ac
2
CHO
N
H
5
examples
48-72% yield

ACCEPTED MANUSCRIPT
1
Tetrahedron
journal homepage: www.elsevier.com
Metal-free synthesis of 1H-indole-2-carbaldehydes by N-iodosuccinimide-mediated
cyclization of 1-(2'-anilinyl)prop-2-yn-1-ols in water. A formal synthesis of (R)-
calindol
Prasath Kothandaraman, Sherman Jun Liang Lauw and Philip Wai Hong Chan*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore 637371,
Singapore
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A N-iodosuccinimide (NIS)-mediated method to prepare 1H-indole-2-carbaldehydes efficiently
from cycloisomerization of 1-(2-aminophenyl)prop-2-yn-1-ols is described. The reaction is
operationally straightforward and accomplished in good to excellent yields (48-91%) from a
wide range of alcohol substrates that are low cost, easily accessible and ecologically benign. The
utility of the approach as a potential scale-up strategy for the synthesis of the indole was
exemplified by the large-scale synthesis of one example in an excellent yield. The synthetic
utility of this chemistry was also demonstrated in a formal synthesis of (R)-calindol.
Available online
Keywords:
Cycloisomerization
N-Iodosuccinimide
2
009 Elsevier Ltd. All rights reserved.
1
H-Indole-2-carbaldehydes
Propargylic alcohols
Water
1. Introduction
Recently, we delineated a synthetic method which allowed for
the conversion of propargylic alcohols 1 to 2-oxindoles 2 and 3-
Over the years, indoles have been shown to be immensely
4-
2
oxindoles 3 when treated with NIS in MeNO (Scheme 1, eq 1).
valuable building blocks in a variety of synthetic strategies to
many natural products and bioactive compounds as well as in
7
In the course of this study, we noticed that when 1-phenyl-1-(2-
(
tosylamino)phenyl)prop-2-yn-1-ol (1a, R = Ph) was treated with
1
optoelectronic functional materials. For this reason, there has
2
NIS in non-distilled MeNO , 3-phenyl-1-tosyl-1H-indole-2-
been widespread interest in accessing this structural motif and
carbaldehyde 4a was obtained as the major adduct instead of the
anticipated 2-oxindole 2a (Scheme 1, eq 2). It also contrasted to
an earlier work by us on the gold(I)-catalyzed conversion of 1 to
1
-
this has led to a myriad of impressive methods being developed.
6
This has included synthetic routes to 1H-indole-2-
carbaldehydes that have typically relied on formylation of an
1H-indole-2-carbaldehydes that showed the analogous reaction of
1
,3
indole substrate under strongly acidic or basic conditions.
1
a with NIS in non-distilled acetone and in the absence of the
However, the main drawback of these synthetic approaches has
been the incompatibility of indole substrates containing
functional groups that cannot tolerate such harsh reaction
conditions. The use of stoichiometric or excess and often
environmentally unfriendly amounts of various reagents, such as
2e
metal catalyst gave only the recovery of the substrate. This
intriguing solvent effect on the reactivity of the alcohol toward
I
O
R
I
I or
(1)
O
POCl in the Vilsmeier-Haack reaction, is also typically required,
N
3
N
Ts
NIS
3 equiv)
Ts
HO
R
which can lead to the production of equimolar quantities of waste
products. Added to this is the need to introduce structural
elements to direct the formylation process to occur
regioselectively at the C2 position of the indole ring. In this
regard, it would be desirable to establish synthetic methods that
can sequentially construct the indole ring and aldehyde moiety
efficiently in a single operation from a wide variety of readily
accessible, low cost and simple acyclic substrates. This is all the
more so given synthetic approaches that simultaneously address
the preparation and derivatization of indoles are still far from
2
3
(
(
for R = H)
(for R = H)
MeNO2
∆, 24 h
NHTs
I
Ph
1
Ph
for R = Ph
I
O
R = H, alkyl, aryl
+
(2)
CHO
N
N
Ts
Ts
2a
4a
2
2% yield
61% yield
Scheme 1. NIS-mediated cyclization of 1-(2-(tosylamino)
phenyl)prop-2-yn-1-ols 1 in MeNO2.
1
-6
common.

*
    
Corresponding author. Tel: +65-6316-8760; fax: +65-6791-1961; e-mail: waihong@ntu.edu.sg

ACCEPTED MANUSCRIPT
2
Tetrahedron
the iodinating reagent prompted us to anticipate that NIS-
find that a product yield of 87% (0.86 g) could be reproduced
mediated cycloisomerization of 1 to 4 could be achieved by
when the reaction was repeated on a large scale with 1 g of 1a.
identifying the appropriate solvent medium and reaction
a
Table 1. Optimization of the reaction conditions
conditions, which would be attractive from
applications stand point.
a scale-up
Ph OH
Ph
Ph
OH
NIS
I
CHO +
2
d-2f
H2O, co-solvent
As part of our efforts to develop this type of reaction,
we
N
N
NHTs
∆, 24 h
Ts
Ts
6a
disclose herein our discovery that NIS can mediate the
1
a
4a
aminocyclization of propargylic alcohols of the type 1 with an
appropriately placed aniline moiety (Scheme 2) . Accomplished
b
8
Entry
1
NIS (equiv)
Co-solvent
-
Yield (%)
58
3
in an aqueous reaction medium under mild conditions, this
provides an expedient and low cost route to 1H-indole-2-
carbaldehydes that constructs both the nitrogen ring and aldehyde
moiety sequentially for a broad range of readily available
2
3
4
5
6
3
acetone
acetone
acetone
acetone
acetone
acetone
acetone
acetone
acetone
93
91
82
71
65
76
70
63
2.2
2
9
,10
1.5
1.2
2.2
2
substrates.
The approach also avoids the need for structural
elements to direct aldehyde formation to occur regioselectively at
the C-2 position of the indole ring. The application of this 1H-
indole-2-carbaldehyde formation process to the large-scale
synthesis of one example and formal synthesis of (R)-calindol in
c
7
c
8
c
9
1.5
1.2
2
11
c
d
10
-
a single step is also presented.
1
1
MeNO
THF
2
67
81
75
61
56
81
82
81
44
60
67
R1
R2
12
13
2
X = SO
2
CHO
R2
2
DMSO
MeCN
DMF
N
1
4
2
HO R1
NIS
2.2 equiv)
SO
2
(
4
15
16
2
H
2
O/acetone
2
2 2
CH Cl
NHX
(25:1v/v), ∆, 24 h
R1
1
7
2
CHCl
3
1
X = Ac
R1 = H, alkyl, aryl
X = SO
CHO
18
19
2
EtOAc
EtOH
2
2
R , Ac
N
H
5
2
c,e
20
21
-
acetone
acetone
acetone
acetone
e
f
Scheme 2. NIS-mediated cycloisomerizations of N-
substituted 1-(2-aminophenyl)prop-2-yn-1-ols in water and
acetone (25:1 v/v).
-
g
22
-
-
h
g
23
-
-
a
Unless otherwise stated, all reactions were performed with NIS at reflux for
2. Results and discussion
2
4 h with 0.132 mmol of 1a.
b
c
2
Reaction performed with H O:solvent ratio of 25:1 v/v. Reaction performed
We began by first examining the reaction of 1-phenyl-1-(2-
at room temperature for 24 h.
Compound 6a was obtained in 85% yield.
Reaction performed with 2 equiv of I .
2
Reaction performed with 2 equiv of NBS.
d
(
tosylamino)phenyl)prop-2-yn-1-ol 1a with 3 equiv of NIS in
e
f
water at reflux for 24 h and found 4a could be furnished in 58%
yield (Table 1, entry 1). Our studies subsequently showed that
when the reaction was repeated in water and acetone (25:1 v/v) as
a co-solvent, a further increase of 35% in product yield was
obtained (Table 1, entry 2). A similar product yield was afforded
on decreasing the amount of NIS from 3 to 2.2 equiv (Table 1,
entry 3). However, lower product yields were afforded when the
amount of NIS was further decreased to 2, 1.5 or 1.2 equiv
g
Recovery of 1a in 75% yield along with mixture of side products that could
not be identified based on H NMR analysis of the crude reaction mixture.
1
h
Reaction performed with 2 equiv of NCS.
We next turned our attention to the reactions of a variety of
propargylic alcohols to determine the scope of the present
procedure and the results are summarized in Table 2. We were
pleased to find that these experiments showed the reaction
conditions to be broad, providing a variety of substituted indole-
2-carbaldehydes in good to excellent yields. Substrates
containing an electron-donating group or electron-withdrawing
group or benzofused ring on the aniline moiety were found to be
well tolerated and afforded the corresponding products 4b-h in
54-85% yield. Notably, this included access to 4d and 4e, which
we had previously found could not be prepared in the analogous
reactions of the same substrates using gold catalysis. Likewise,
N-tosyl-indole-2-carbaldehydes 4i-l, in which the carbinol carbon
position is occupied by an aryl substituent with an electron-
donating or electron-withdrawing group at the ortho or para
position, were obtained in excellent yields of 75-91% from the
corresponding propargylic alcohols 1i-l. Changing the pendant
group at this position from an aryl to alkyl moiety was found to
have no influence on the course of the reaction with 4m and 4n
afforded in 89 and 91% yield, respectively. Similarly, the
secondary alcohols 1o and 1p provided the corresponding N-
tosyl-1H-indole-2-carbaldehydes 4o and 4p in 90 and 51% yield,
respectively, at room temperature or with 1.1 equiv NIS. As
(
Table 1, entries 4-6). A similar outcome was observed for the
analogous reactions of 1a with 1.5, 2 or 2.2 equiv of NIS at room
temperature (Table 1, entries 7-9). The only exception was the
control experiment of 1a with 1.2 equiv of NIS, which was found
to give the indolin-3-ol 6a in 85% yield (Table 1, entry 10). A
survey of other organic co-solvents was found to provide no
improvements in product yields (Table 1, entries 11-19). In these
latter reactions with 2 equiv of NIS, changing the co-solvent
2
e
from acetone to MeNO
CHCl , EtOAc or EtOH gave 4a in yields of 44-82%. Likewise,
control experiments with 2 equiv of I in place of NIS at room
2
, THF, DMSO, MeCN, DMF, CH
2
Cl
2
,
3
2
temperature or reflux provided product yields of 60 and 67%,
respectively (Table 1, entries 20 and 21). In our hands, changing
the halogenating source from NIS to either 2 equiv of NBS (N-
bromosuccinimide) or NCS (N-chlorosuccinimide) were the only
instances that led to the recovery of 1a in 75% yield along with a
mixture of decomposition products that could not be identified by
1
H NMR spectroscopy (Table 1, entries 22 and 23). On the basis
2
of the above results, reaction of 1a with 2.2 equiv of NIS in H O
and acetone (25:1 v/v) at reflux for 24 h provided the optimum
conditions. Using these optimized conditions, we were pleased to

ACCEPTED MANUSCRIPT
3
expected, starting alcohols 1q and 1r, with a pendant Ms or Ns
protecting group on the nitrogen center, were also found to
proceed well under the reaction conditions, giving the
of NIS in the water/acetone solvent system, at a ratio of 6:1 v/v
due to the poorer solubility of the substrate, at reflux for 24 h
gave the deprotected indole product 5s in 70% yield. A similar
outcome was obtained on applying these slightly modified
conditions to 1t-w, with the corresponding 1H-indole-2-
carbaldehyde adducts 5t-w furnished in 52-72% yield.
corresponding
N-sulfonyl-1H-indole-2-carbaldehydes
in
respective yields of 83 and 85%.
Table 2. NIS-mediated cycloisomerization of 2-tosylamino
a
phenylprop-2-yn-1-ols 1b-r in H O
Table 3. NIS-mediated cycloisomerization of 2-acylamino
2
a
Substrate
2
phenylprop-2-yn-1-ols 1s-w in H O
Entry
Substrate
HO Ph
Product
Yield (%)
70
HO Ph
HO Ph
HO Ph
NHTs
HO Me
NHTs
R1
Ph
1
O
O
CHO
NHTs
NHTs
N
H
Me
NHAc
1
b, R1 = Me
1f
1g
1h
1s
5s
1
1
1
1
c, R = OMe
HO Me
Me
1
2
3
4
72
62
57
d, R = Cl
1
e, R = Br
CHO
R2
N
H
5t
NHAc
OH
HO CH2R4
NHTs
Me
1t
HO
HO
R1
R3
HO Ph
Ph
NHTs
NHTs
Me
1o
CHO
NHTs
N
Me
Cl
NHAc
Me
i, R2 = Me
1k, R1 = H, R3 = Me
1l, R1 = Cl, R3 = F
OH
1m, R4 = H
1n, R4 = Me
HO Ph
H
1
1
1u
5u
2
j, R = Cl
HO Ph
Ph
Cl
CHO
NHSO2R5
NHAc
N
NHTs
p
H
1
1
1
q, R5 = Me
r, R = p-NO2C6H4
1v
5v
5
5
52
Product
HO
Cl
Cl
Cl
Cl
Ph
Ph
Ph
R1
CHO
NHAc
N
CHO
CHO
CHO
H
N
1w
N
N
5w
Ts
Ts
Ts
Me
4f (83%)
a
All reactions were performed at reflux for 24 h with 0.19 mmol of 1 and
0.41 mmol of NIS in H O/acetone (6:1 v/v)
4b (85%)
4c (77%)
4d (84%)
4e (84%)
4g (54%)b
2
R2
A tentative mechanism for the present NIS-mediated reaction
to form 1H-indole-2-carbaldehydes is put forward in Scheme 3.
This could involve nucleophilic addition of the aniline group to
the alkyne moiety of the substrate and concomitant quenching of
the resultant cycloadduct to give 6. Activation of the hydroxyl
group of the resultant indolin-3-ol intermediate by another
molecule of NIS would then give the coordinated species I.
Nucleophilic substitution of this newly formed activated adduct
R1
Me
O
O
R3
CHO
CHO
N
CHO
N
N
Ts
Ts
Ts
4h (65%)
4i (91%)
j (90%)
4k (91%)
4l (75%)
4
CH2R4
Me
CHO
CHO
N
2
by H O would result in the formation of iodomethanol adduct II,
Ts
N
Ts
Me
which subsequently eliminates HI to deliver 4. Presumably, in
cycloadducts containing an Ac protecting group at the nitrogen
center, the aqueous acidic conditions promote a facile deacylation
process to produce 5. While it remains unclear whether the
4
m (89%)
n (91%)
4o (90%)c
4
Ph
substitution step proceeds in an S
N
1' or S
N
2' manner, the added
CHO
CHO
O
N
N
SO2R
O
Ts
p (51%)d
5
N
N
H
I
R
OH
R
OH
R
O
4
4q (83%)
r (85%)
I
O
O
I
4
I
a
Unless otherwise stated all reactions were performed at reflux for 24 h with
−NHS
N
NHX
X
N
X
H2O
0
2
.13 mmol of 1 and 0.29 mmol of NIS in H O/acetone (25:1 v/v) Values in
1
6
I
parentheses denote product yields.
b
−HOI
Starting material recovered in 32% yield.
−
NHS
c
d
Reaction performed at room temperature. Reaction performed with 1.1
equiv of NIS.
R
R
R
O
I
H
CHO
CHO
Interestingly, the NIS reactions with substrates in which an
acyl substituent was employed as the nitrogen protecting group,
as in 1s-1w shown in Table 3, did not give the expected N-acetyl-
−AcOH
−HI
N
N
N
H
(for X = Ac)
X
X
5
4
II
Scheme 3. Proposed mechanism.
1H-indole-2-carbaldehydes. We found subjecting 1s to 2.2 equiv

ACCEPTED MANUSCRIPT
4
Tetrahedron
role of NIS in making 6 susceptible to nucleophilic attack by
4. Experimental section
H
2
O would be consistent with our earlier findings showing
4
.1. General remarks
formation of only this adduct when 1.2 equiv of the iodinating
reagent was used under the conditions described in Table 1, entry
Unless specified, all reagents and starting materials were
6. This is further supported by the conversion of 6a to 4a in 89%
purchased from commercial sources and used as received.
Solvents were purified following standard literature procedures.
Analytical thin layer chromatography (TLC) was performed
using pre-coated silica gel plate. Visualization was achieved by
UV light (254 nm) Flash chromatography was performed using
silica gel (230-400 mesh) and gradient solvent system (EtOAc:n-
yield when it was re-subjected to 1.2 equiv of NIS under the
conditions depicted in Scheme 4.
HO
Ph
Ph
I
NIS (1.2 equiv)
CHO
H2O/acetone
(25:1 v/v)
N
N
1
13
Ts
Ts
4a
9% yield
hexane as eluent). H and C NMR spectra were measured on a
00, 400, and 500 MHz spectrometer. Chemical shifts (ppm)
∆
, 24 h
6
a
3
8
were recorded with tetramethylsilane (TMS) as the internal
reference standard. Multiplicities are given as: s (singlet), brs
Scheme 4. Nucleophilic substitution of 6a by water mediated
by NIS.
(
broad singlet), d (doublet), t (triplet), dd (doublet of doublets) or
m (multiplet). The number of protons (n) for a given resonance is
indicated by nH and coupling constants are reported as a J value
in Hz. Infrared spectra were recorded on a FTIR spectrometer.
Solid samples were examined as a thin film between NaCl salt
plates. Low resolution mass spectra were determined on a mass
spectrometer and reported in units of mass to charge (m/z) High
resolution mass spectra (HRMS) were obtained on a LC/HRMS
TOF spectrometer using simultaneous electrospray (ESI) Optical
rotations were measured in CHCl3 on a polarimeter with a
sodium vapor lamp at 589 nm and 10 cm cell (c given in g/100
mL)
Having established an efficient route to 1H-indole-2-
carbaldehydes, we applied this new strategy to the formal
synthesis of the bioactive indole alkaloid (R)-calindol (Scheme
5
). At room temperature, reductive amination of 4p with (R)-1-
1-naphthyl)ethylamine in the presence of 3 equiv of NaBH in
MeOH gave (R)-N-tosylcalindol 7 in 90% yield and as a single
(
4
1
1d
enantiomer.
As (R)-N-tosylcalindol 7 has been previously
converted into (R)-calindol by removal of the N-tosyl protecting
1
1b
group,
this route constitutes a formal synthesis of the
enantiopure indole alkaloid.
4
.2. General experimental procedure for the preparation of
NaBH
3 equiv)
4
(
N-protected aniline substituted propargylic alcohols (1a, d, h,
i, j, m, o and p)
aminophenyl)-ketone or -aldehyde (1.1 mmol) in pyridine (0.4
mL) was added p-toluenesulfonyl chloride (1.6 mmol) at room
temperature under a nitrogen atmosphere. The resulting solution
was stirred for 4 h at room temperature. On completion, the
CHO
+
2e,f
HN
N
To a solution of the appropriate 1-(2-
MeOH, r.t.
3.5 h
Me
Ts
H
2
N
Me
N
Ts
4
p
(R)-1-(1-naphthyl)ethylamine
7
9
0% yield
2
reaction mixture was quenched by adding H O (5 mL) and
ref 11b
filtered. The resulting solid was dried and then used directly for
the next step. The solid (0.51 mmol) was dissolved in anhydrous
THF (8 mL) and a solution of ethynylmagnesium bromide (0.5 M
THF solution; 1.5 mmol) was added at room temperature. The
resulting mixture was allowed to reflux for 3 h. On completion,
the reaction mixture was cooled to room temperature and treated
HN
Me
N
H
(
R)-calindol
Scheme 5. A formal synthesis (R)-calindol.
with saturated NH Cl (7 mL). After additional stirring at room
4
3
. Conclusion
temperature for 10 min, EtOAc (15 mL) was added and phases
were separated. The aqueous phase was extracted with EtOAc (3
x 5 mL) and the combined organic layers were washed with brine
(10 mL), dried over anhydrous Na SO and concentrated under
reduced pressure. Purification by flash column chromatography
on silica gel (10% EtOAc/n-hexane as eluent) gave the title
compound.
In summary, we have described an efficient synthetic method
for the preparation of 1H-indole-2-carbaldehydes from NIS-
mediated cycloisomerization of N-substituted 1-(2-aminophenyl)
prop-2-yn-1-ols in water. The attractiveness of the synthetic
approach lies in the fact that both the indole ring and aldehyde
functional group are sequentially formed from the cyclization
process. Previous synthetic methods to this immensely important
member of the indole family of compounds have mainly relied on
formylation of the nitrogen heterocycle and structural elements to
direct the functional group transformation to occur
regioselectively at the C2 position of the substrate. Our approach
also offers a potential scale-up strategy for the synthesis of the
indole, which was demonstrated by the large-scale synthesis of
one example in an excellent yield. This is notable as the present
method makes use of a wide range of inexpensive and easily
accessible alcohol substrates in combination with the low cost
and green credentials often associated with such metal-free
mediated systems. The synthetic utility of this chemistry was also
demonstrated in a formal synthesis of (R)-calindol.
2
4
4
.3. General experimental procedure for the preparation of
13a,b
propargylic alcohols (1b, c, e, f, g, k, l and n)
To a solution
O/THF
2:1 v/v, 9 mL) was added triethylamine (0.30 g, 0.42 mL, 3.0
of the appropriate 2-aminobenzoic acid (1.0 mmol) in H
(
2
mmol) at room temperature followed by p-toluenesulfonyl
chloride (0.23 g, 1.2 mmol) at 0 °C. The resulting mixture was
stirred at room temperature for 3 h. On completion, THF was
removed and the aqueous solution was washed with diethyl ether
(
5 mL). The diethyl ether layer was discarded while the aqueous
layer was acidified with hydrochloric acid (2 M, pH 2) and
extracted with EtOAc (3 x 5 mL). The combined organic layers
were washed with brine (10 mL), dried over anhydrous Na SO4
2
and concentrated under reduced pressure. The resulting solid was
dried under vacuum for 16 h and used directly for the next step.
2 2
The solid (0.8 mmol) was dissolved in CH Cl (10 mL) and
cooled to 0 °C under a nitrogen atmosphere. The solution was
then treated with N,O-dimethylhydroxylamine.HCl (DMHA) (0.9
mmol) followed by N-methylmorpholine (NMM, 0.26 mL, 2.4

ACCEPTED MANUSCRIPT
5
mmol). The hydrochloride salt of 1-ethyl-3-(3-dimethylamino
propyl)carbodiimide (EDCI⋅HCl, 0.17 g, 0.9 mmol) was then
added portion-wise over a 15 min period. The reaction mixture
was allowed to stir for further 3 h at 0 °C and an additional 15 h
at room temperature. On completion, the reaction mixture was
treated with saturated sodium bicarbonate solution (7 mL). The
organic and aqueous phases were separated and the aqueous
phase was extracted with EtOAc (3 x 5 mL). The combined
organic layers were washed with 10% citric acid solution (5 mL)
4.5. General procedure for the NIS-Mediated cycloisomeri-
zation of 1-(2-(sulfonylamino)phenyl)prop-2-yn-1-ols to 1H-
indole-2-carbaldehydes (4) To a solution of NIS (66 mg, 0.29
mmol) in water (2.5 mL) was added dropwise a solution of 1
(0.13 mmol) in acetone (0.1 mL) at room temperature. The
addition was performed under an ambient atmosphere. The
resulting mixture was stirred at reflux for 24 h. On completion,
the reaction mixture was cooled to room temperature, quenched
2 2 3 2
with 10% Na S O .5H O solution (5 mL) and extracted with
followed by brine solution (5 mL), dried over anhydrous Na
2
SO
4
EtOAc (2 x 5 mL). The combined organic layers were washed
and concentrated under reduced pressure. The solid product was
washed with a mixture of 5% EtOAc/n-hexane solution and the
resulting Weinreb amide solid was dried under vacuum for 16 h.
After drying, the solid (0.6 mmol) was dissolved in anhydrous
THF (5 mL) followed by the addition of the respective bromide
of the Grignard reagent (0.5, 1 M or 2 M THF solution, 2.1
mmol) at room temperature under a nitrogen atmosphere. The
resulting mixture was stirred for another 18 h at room
temperature. On completion, the reaction mixture was treated
with brine (10 mL), dried over anhydrous Na SO4 and
2
concentrated under reduced pressure. Purification by flash
column chromatography on silica gel (9% EtOAc/n-hexane as
eluent) gave the title compound.
4
.6. General procedure for the NIS-mediated cycloiso
merization of 1-(2-(acetylamino)phenyl)prop-2-yn-1-ols to
1
H-indole-2-carbaldehydes (5) To a solution of NIS (93 mg,
0.41 mmol) in water (2.5 mL) was added dropwise a solution of 1
(
0.19 mmol) in acetone (0.4 mL). The addition was performed at
4
with saturated NH Cl or 2 M aqueous HCl solution (7 mL) and
room temperature under an ambient atmosphere. The resulting
mixture was stirred at reflux for 24 h. On completion, the
reaction mixture was cooled to room temperature, quenched with
the resulting mixture was stirred at room temperature for 15 min
before EtOAc (15 mL) was added. The phases were separated
and the aqueous phase was extracted with EtOAc (3 x 5 mL). The
combined organic layers were washed with brine solution (15
1
0% Na S O .5H O solution (5 mL) and extracted with EtOAc (2
2 2 3 2
x 5 mL). The combined organic layers were washed with brine
2 4
mL), dried over anhydrous Na SO and concentrated under
(
10 mL), dried over anhydrous Na SO and concentrated under
2
4
reduced pressure to afford the 1-(2-tosylaminophenyl)ketone
adduct that was then dried under reduced pressure for 5 h. The
ketone (0.51 mmol) was dissolved in anhydrous THF (8 mL) and
a solution of ethynylmagnesium bromide (0.5 M THF solution;
reduced pressure. Purification by flash column chromatography
on silica gel (10% EtOAc/n-hexane as eluent) gave the title
compound.
1
.5 mmol) was added at room temperature. The resulting mixture
4
.7. Experimental procedure for the synthesis of (R)-N-tosyl
was allowed to reflux for 3 h. On completion, the reaction
mixture was cooled to room temperature and treated with
saturated NH Cl (7 mL). After additional stirring at room
4
temperature for 10 min, EtOAc (15 mL) was added and the
phases were separated. The aqueous phase was extracted with
EtOAc (3 x 5 mL) and the combined organic layers were washed
11d
calindol (7) To a solution of N-tosylindole-2-carbaldehyde
0.017 g, 0.056 mmol) in MeOH (2 mL) was added (R)-1-(1-
(
naphthyl)ethylamine (0.010 g, 0.061 mmol) at room temperature
under a nitrogen atmosphere. The reaction mixture was stirred for
3
h until the aldimine formation was completed based on TLC
analysis. Upon confirmation, NaBH (6.4 mg, 0.17 mmol) was
4
with brine (10 mL), dried over anhydrous Na
2
SO
4
and
added to the reaction mixture and stirred for another 0.5 h before
quenching with 1 M NaOH (1 mL). The product was extracted
with diethyl ether (2 x 5 mL). The diethyl ether extract was
washed with brine (10 mL), dried over anhydrous Na SO and
concentrated under reduced pressure. Purification by flash
column chromatography on silica gel (10% EtOAc/n-hexane as
eluent) gave the title compound.
2
4
concentrated under reduced pressure. The solvent was evaporated
to give the crude product. Purification by flash column
chromatography on silica gel (20% EtOAc/n-hexane as eluent)
gave the title compound (0.023g, 90% yield).
4
.4. General experimental procedure for the preparation of
2e,f,13b
propargylic alcohols (1s-w)
To a solution of the
appropriate 1-(2-aminophenyl)ketone (1.0 mmol) and pyridine
0.48 mL, 6.0 mmol) in dichloromethane (5 mL) was added
(
acetyl chloride (1.2 mmol) in dichloromethane (2 mL) in a
dropwise manner at 0 °C under a nitrogen atmosphere. The
resulting solution was stirred for 0.25 h at 0 °C and then brought
up to room temperature slowly and monitored to completion by
TLC analysis. After 3 h, the reaction mixture was quenched with
4
.8. Characterization of compounds
2e,f
4.8.1. 1-Phenyl-1-(2-(tosylamino)phenyl)prop-2-yn-1-ol (1a)
Yield 87%; 0.166 g; colorless solid; R
f
(10% EtOAc/n-hexane)
1
0
.25; H NMR (CDCl , 400 MHz) δ 8.47 (1H, brs), 7.54 (1H, dd,
3
1
0% aqueous HCl solution and the aqueous solution was
J = 8.32Hz, 12.4 Hz), 7.38 (2H, d, J = 6.6 Hz), 7.29-7.36 (5H,
extracted with dichloromethane (3 x 10 mL). The combined
organic layers were washed with brine (10 mL), dried over
m), 7.21 (1H, d, J = 7.48 Hz), 7.05 (2H, d, J = 8.0 Hz), 6.98 (1H,
t, J = 7.64 Hz) 3.22 (1H, brs), 2.90 (1H, s), 2.33 (3H, s);
NMR (CDCl , 100 MHz) δ 143.4, 142.2, 136.3, 135.8, 130.1,
13
C
2 4
anhydrous Na SO and concentrated under reduced pressure to
3
afforded the 1-(2-acetylaminophenyl)ketone adduct which was
dried under reduced pressure for 5 h. The ketone (0.51 mmol)
was dissolved in anhydrous THF (8 mL) and a solution of
ethynylmagnesium bromide (0.5 M THF solution; 1.5 mmol) was
added at room temperature. The resulting mixture was allowed to
reflux for 3 h. On completion, the reaction mixture was cooled to
1
29.6, 129.4, 128.8, 128.7, 128.3, 127.3, 125.8, 122.8, 119.0,
+
84.4, 77.8, 74.9, 21.5; MS (ESI) m/z 400 [M+Na] .
4.8.2. 1-(5-Methyl-2-(tosylamino)phenyl)-1-phenylprop-2-yn-1-ol
(1b) Yield 80%; 0.190 g; colorless solid; R (10% EtOAc/n-
hexane) 0.25; H NMR (CDCl
2
e,f
f
1
3
, 400 MHz) δ 8.46 (1H, brs), 7.43
4
room temperature and treated with saturated NH Cl (7 mL). After
(
1H, d, J = 8.2 Hz), 7.24-7.36 (8H, m), 7.00 (3H, dd, J = 6.9 Hz,
13
additional stirring at room temperature for 10 min, EtOAc (15
mL) was added and the phases were separated. The aqueous
phase was extracted with EtOAc (3 x 5 mL) and the combined
organic layers were washed with brine (10 mL), dried over
7
.6 Hz), 3.77 (1H, s), 2.87 (1H, s), 2.31 (3H, s), 2.24 (3H, s);
, 100 MHz) δ 143.3, 142.4, 136.4, 133.2, 132.6,
30.2, 130.1, 129.5, 129.4, 128.6, 128.2, 127.4, 125.9, 119.3,
C
NMR (CDCl
3
1
8
2
4.7, 77.6, 74.9, 21.5, 20.9; IR (NaCl, neat) ν: 3419, 3305, 3021,
113, 1647, 1635, 1497, 1392, 1330, 1157, 1091, 844, 813 cm ;
anhydrous Na
2
SO
4
and concentrated under reduced pressure.
-1
Purification by flash column chromatography on silica gel (10%
EtOAc/n-hexane as eluent) gave the title compound.
+
MS (ESI) m/z 414 [M+Na] .

ACCEPTED MANUSCRIPT
6
Tetrahedron1
4
.8.3. 1-(5-Methoxy-2-(tosylamino)phenyl)-1-phenylprop-2-yn-
3
0.25; H NMR (CDCl , 500 MHz) δ 8.49 (1H, brs), 7.50 (1H, d, J
2
e,f
1
-ol (1c) Yield 75%; 0.185 g; beige solid; R
f
(10% EtOAc/n-
= 7.5 Hz), 7.47 (1H, dd, J = 1.35 Hz, 7.85 Hz), 7.28 (2H, d, J =
8.4 Hz), 7.18-7.12 (3H, m), 7.02 (2H, d, J = 8.1 Hz), 6.98 (2H, d,
J = 8.15 Hz), 6.92-6.89 (1H, m), 2.78 (1H, s), 2.29 (3H, s), 2.25
1
hexane) 0.25; H NMR (CDCl , 400 MHz) δ 8.04 (1H, brs), 7.49
3
(
7
1H, d, J = 8.8 Hz), 7.26-7.40 (7H, m), 7.13 (1H, d, J = 2.8 Hz),
.06 (2H, d, J = 8.8 Hz), 6.76 (1H, dd, J = 2.8 Hz, 8.9 Hz ), 3.72
13
3
(3H, s); C NMR (CDCl , 125 MHz) δ 143.3, 139.4, 138.1,
136.4, 135.8, 130.2, 129.5, 129.3, 128.8, 127.3, 125.7, 122.8,
119.0, 84.6, 77.5, 74.8, 21.5, 21.2; MS (ESI) m/z 414 [M+Na] .
1
3
(
(
3H, s), 3.30 (1H, s), 2.87 (1H, s), 2.35 (3H, s); C NMR
CDCl , 100 MHz) δ 155.4, 143.3, 142.2, 136.5, 132.7, 129.4,
+
3
1
7
1
28.7, 128.6, 128.3, 127.3, 125.8, 121.6, 115.4, 113.7, 84.6, 77.5,
4
.8.10. 1-(4-Chlorophenyl)-1-(2-(tosylamino)phenyl)prop-2-yn-
2e,f
4.7, 55.4, 21.5; IR (NaCl, neat) ν: 3392, 3292, 3020, 2113,
-
1
+
1
-ol (1j)
Yield 80%; 0.167 g; pale-yellow solid; R
f
(10%
153, 1089, 1035, 844, 812 cm ; MS (ESI) m/z 430 [M+Na] ;
1
+
EtOAc/n-hexane) 0.25; H NMR ((CD
3
)
2
CO, 300 MHz) δ 9.02
HRMS (ESI) calcd. for C H NO SNa (M +Na) 430.1089,
found: 430.1082.
2
3
21
4
(
1H, brs), 7.71 (1H, dd, J = 1.5 Hz, 3.8 Hz), 7.68 (1H, dd, J = 1.6
Hz, 4.3 Hz), 7.34 (2H, d, J = 8.3 Hz), 7.32 (1H, d, J = 1.8 Hz),
4
.8.4. 1-(5-Chloro-2-(tosylamino)phenyl)-1-phenylprop-2-yn-1-ol
7.27 (4H, d, J = 5.9 Hz), 7.14 (2H, d, J = 8.0 Hz), 7.03 (1H, td, J
= 1.2 Hz, 7.7 Hz), 3.52 (1H, s), 2.33 (3H, s); C NMR
2
e,f
13
(1d) Yield 84%; 0.175 g; pale-yellow solid; R
f
(10% EtOAc/n-
1
hexane) 0.25; H NMR (CDCl , 400 MHz) δ 8.52 (1H, brs), 7.55
((CD ) CO, 75 MHz) δ 143.7, 142.6, 136.7, 136.3, 133.4, 130.3,
3
3 2
(
1H, s), 7.49 (1H, d, J = 8.6 Hz), 7.16-7.37 (8H, m), 7.03 (2H, d,
129.5, 129.4, 128.9, 128.4, 127.3, 126.9, 122.7, 118.4, 84.6, 78.5,
74.1, 20.7; MS (ESI) m/z 434 [M+Na] .
13
+
J = 7.3 Hz), 3.81 (1H, s), 2.91 (1H, s), 2.33 (3H, s); C NMR
CDCl , 100 MHz) δ 143.6, 141.6, 135.8, 134.4, 131.9, 129.5,
29.4, 128.8, 128.7, 128.6, 128.3, 127.3, 125.8, 120.2, 83.8, 78.3,
4.4, 21.5; IR (NaCl, neat) ν: 3406, 3302, 3018, 2113, 1637,
(
3
4
.8.11. 1-o-Tolyl-1-(2-(tosylamino)phenyl)prop-2-yn-1-ol (1k)
1
7
1
Yield 82%; 0.195 g; colorless solid; m.p. 98-101 °C; R (10%
EtOAc/n-hexane) 0.25; H NMR (CDCl , 300 MHz) δ 8.60 (1H,
3
f
1
-
1
+
485, 1332, 1157, 1089, 813 cm ; MS (ESI) m/z 434 [M+Na] ;
+
s), 7.78 (1H, d, J = 7.2 Hz), 7.59 (1H, d, J = 8.1 Hz), 7.45 (1H, d,
J = 8.4 Hz), 7.28-7.15 (4H, m), 7.09 (3H, d, J = 8.1 Hz), 6.91-
HRMS (ESI) calcd. for C22
found: 434.0598.
3
H18ClNO SNa (M +Na) 434.0594,
6
.85 (1H, m), 3.46 (1H, s), 2.83 (1H, s), 2.31 (3H, s), 1.96 (3H,
13
4
.8.5. 1-(5-Bromo-2-(tosylamino)phenyl)-1-phenylprop-2-yn-1-ol
3
s); C NMR (CDCl , 100 MHz) δ 143.6, 139.2, 137.0, 136.5,
2
e,f
(1e) Yield 77%; 0.213 g; pale-brown solid; R
f
(10% EtOAc/n-
, 400 MHz) δ 8.46 (1H, brs), 7.72
1H, d, J = 2.1 Hz), 7.44 (1H, d, J = 8.8 Hz), 7.26-7.38 (8H, m),
136.0, 132.9, 129.9, 129.4, 129.4, 128.9, 128.9, 127.5, 126.7,
1
hexane) 0.25; H NMR (CDCl
(
3
126.1, 123.2, 119.7, 83.8, 78.0, 75.5, 21.5, 21.2; IR (NaCl, neat)
-
1
ν: 3421, 3304, 3019, 2120, 1653, 1480, 1339, 1159, 928 cm ;
+
7
.04 (2H, d, J = 8.1 Hz), 3.58 (1H, s), 2.93 (1H, s), 2.34 (3H, s);
MS (ESI) m/z 392 [M+H] ; HRMS (ESI) calcd. for C23
H22NO
3
S
13
+
C NMR (CDCl
3
, 100 MHz) δ 143.8, 141.5, 135.8, 135.0, 132.5,
(M +H) 392.1320, found: 392.1317.
1
32.1, 131.5, 129.5, 128.9, 128.6, 127.4, 125.8, 120.5, 115.8,
+
4
.8.12.
1-(5-Chloro-2-(tosylamino)phenyl)-1-(2-fluorophenyl)
83.8, 78.4, 74.4, 21.5; MS (ESI) m/z 478 [M+Na] .
prop-2-yn-1-ol (1l) Yield 76%; 0.193 g; pale-brown solid; m.p.
116-118 °C; R (10% EtOAc/n-hexane) 0.25; H NMR (CDCl ,
f 3
300 MHz) δ 8.46 (1H, brs), 7.51 (1H, s), 7.41 (2H, d, J = 8.4 Hz),
7.31 (3H, d, J = 8.1 Hz), 7.05-7.12 (1H, m), 7.00 (3H, d, J = 8.1
Hz), 6.91 (1H, dd, J = 8.4 Hz, 11.4 Hz), 4.60 (1H, brs), 2.83 (1H,
1
4.8.6. 1-(3-Methyl-2-(tosylamino)phenyl)-1-phenylprop-2-yn-1-ol
2
e,f
(1f) Yield 78%; 0.185 g; light brown solid; m.p. 124-127 °C;
1
f
R (10% EtOAc/n-hexane) 0.25; H NMR (CDCl3, 300 MHz)
7
7
.65 (2H, d, J = 8.1 Hz), 7.55 (1H, s), 7.52-7.49 (2H, m), 7.34-
.28 (4H, m), 7.22 (2H, d, J = 8.1 Hz), 7.13-7.03 (2H, m), 4.58
13
3
s), 2.25 (3H, s); C NMR (CDCl , 75 MHz) δ 161.6, 158.2,
1
3
(
(
1
7
1
1H, s), 2.90 (1H, s), 2.38 (3H, s), 1.93 (3H, s); C NMR
CDCl , 75 MHz) δ 143.6, 143.6, 139.4, 138.3, 137.8, 133.4,
32.1, 129.2, 128.4, 128.2, 127.8, 127.2, 126.5, 126.5, 86.1, 77.2,
4.5, 21.62, 19.93; IR (NaCl, neat) ν: 3412, 3302, 3018, 1599,
143.9, 136.1, 134.5, 130.9, 130.8, 130.6, 129.6, 129.1, 129.0,
128.8, 128.7, 128.5, 127.3, 127.2, 127.1, 124.4, 124.3, 120.6,
116.8 (d, JC-F = 22.5 Hz) 82.4, 77.9, 72.7, 21.5. IR (NaCl, neat) ν:
3682, 3576, 3302, 3019, 2122, 1599, 1487, 1389, 1335, 1262,
1161, 1091, 930, 910, 887 cm ; MS (ESI) m/z 430 [M+H] ;
HRMS (ESI) calcd. for C22
found: 430.0690.
3
-
1
+
-1
+
429, 1329, 1153, 1092, 908 cm . MS (ESI) m/z 392 [M+H] ;
+
+
HRMS (ESI) calcd. for C23
H22NO
3
S (M +H) 392.1320, found:
3
H18ClFNO S (M +H) 430.0680,
392.1320.
2
e,f
4
.8.7. 1-(Naphthalen-2-yl)-1-(2-(tosylamino)phenyl)prop-2-yn-1-
4.8.13. 2-(2-(Tosylamino)phenyl)but-3-yn-2-ol (1m)
90%; 0.150 g; colorless solid; R (10% EtOAc/n-hexane) 0.25; H
NMR (CDCl , 300 MHz) δ 9.19 (1H, brs), 7.74 (2H, d, J = 8.3
Yield
2
e,f
1
ol (1g) Yield 80%; 0.207 g; colorless solid; R
f
(10% EtOAc/n-
, 300 MHz) δ 8.65 (1H, brs), 7.80
2H, d, J = 6.4 Hz), 7.69 (4H, dd, J = 7.5 Hz, 8.7 Hz), 7.48 -7.67
2H, m), 7.34 (1H, dd, J = 1.9 Hz, 8.7 Hz), 7.29 (1H, dd, J = 1.5
f
1
hexane) 0.25; H NMR (CDCl
(
(
3
3
Hz), 7.53 (2H, d, J = 8.0 Hz), 7.20 (3H, d, J = 8.3 Hz), 6.97 (1H,
td, J = 1.0 Hz, 7.7 Hz), 3.62 (1H, s), 2.69 (1H, s), 2.35 (3H, s),
1.67 (3H, s); C NMR (CDCl , 75 MHz) δ 143.8, 137.0, 135.7,
3
1
3
Hz, 7.5 Hz), 7.06 (2H, d, J = 8.3 Hz), 7.02 (1H, dd, J = 0.9 Hz,
.6 Hz), 6.57 (2H, d, J = 8.1 Hz), 3.67 (1H, s), 2.93 (1H, s), 2.15
7
130.9, 129.7, 129.1, 127.3, 127.2, 123.5, 119.9, 85.7, 74.7, 71.6,
1
3
+
(
3H, s); C NMR ((CD ) CO, 75 MHz) δ 143.3, 140.9, 136.5,
31.2, 21.5; MS (ESI) m/z 338 [M+Na] .
3
2
1
1
2
36.3, 133.1, 133.0, 130.6, 129.3, 129.1, 129.0, 128.4, 128.3,
2
e,f
4
5
.8.14. 2-(2-(Tosylamino)phenyl)pent-3-yn-2-ol (1n)
5%; 0.105 g; colorless solid; R (10% EtOAc/n-hexane) 0.25; H
, 500 MHz) δ 9.09 (1H, brs), 7.73 (2H, d, J = 6.8
Yield
27.6, 126.8, 126.5, 124.0, 123.9, 122.6, 118.1, 84.9, 78.4, 74.6,
1
+
0.5; MS (ESI) m/z 450 [M+Na] .
f
NMR (CDCl
3
4
.8.8. 2-(5-(Tosylamino)benzo[d][1,3]dioxol-6-yl)but-3-yn-2-ol
Hz), 7.60 (1H, dd, J = 1.0 Hz, 8.25 Hz), 7.55 (1H, dd, J = 1.5 Hz,
7.9 Hz), 7.23-7.19 (3H, m), 7.01-6.98 (1H, td, J = 1.1 Hz, 7.75
Hz), 3.26 (1H, brs), 2.76 (1H, s), 2.35 (3H, s), 1.28-1.75 (1H, m),
1.69-1.61 (1H, m), 0.75 (3H, t, J = 7.4 Hz); C NMR (CDCl ,
3
125 MHz) δ 143.7, 137.5, 135.6, 129.7, 129.6, 129.0, 128.6,
2
e,f
(
1h) Yield 88%; 0.160 g; yellow solid; R
f
(10% EtOAc/n-
, 300 MHz) δ 8.97 (1H, brs), 7.72
2H, d, J = 8.4 Hz), 7.24 (2H, d, J = 8.2 Hz), 7.12 (1H, s), 7.03
1H, s), 5.90 (2H, s), 3.55 (1H, brs), 2.68 (1H, s), 2.36 (3H, s),
1
hexane) 0.25; H NMR (CDCl
(
(
3
13
13
1
1
7
.55 (3H, s); C NMR (CDCl
36.9, 129.8, 129.6, 127.2, 125.0, 107.3, 102.6, 101.6, 85.8, 74.5,
1.2, 31.3, 21.5; MS (ESI) m/z 360 [M+H] .
3
, 75 MHz) δ 147.7, 143.8, 143.8,
127.1, 123.3, 120.3, 84.3, 76.4, 76.1, 35.6, 21.4, 8.9; MS (ESI)
+
m/z 352 [M+Na] .
+
4
.8.15.
1-(3,5-Dimethyl-2-(tosylamino)phenyl)prop-2-yn-1-ol
2
e,f
4.8.9. 1-p-Tolyl-1-(2-(tosylamino)phenyl)prop-2-yn-1-ol (1i)
(1o) Yield 78%; 0.130 g; pale-brown solid; m.p. 160-162 °C; Rf
(10% EtOAc/n-hexane) 0.25; H NMR (CDCl , 300 MHz) δ 7.58
3
1
Yield 82%; 0.163 g; colourless gum; R
f
(10% EtOAc/n-hexane)

ACCEPTED MANUSCRIPT
7
o
1
(
(
2H, d, J = 8.4 Hz), 7.49 (1H, s), 7.26 (2H, d, J = 8.1 Hz), 6.93
1H, s), 6.35 (1H, s), 5.64 (1H, dd, J = 2.3 Hz, 5.3 Hz), 3.26 (1H,
f 3
C; R (10% EtOAc/n-hexane) 0.25; H NMR (CDCl , 300
MHz) δ 8.34 (1H, brs), 7.79 (1H, s), 7.60 (1H, d, J = 8.1 Hz),
d, J = 5.4 Hz), 2.61 (1H, d, J = 2.4 Hz), 2.43 (3H, s), 2.33 (3H,
7.46 (2H, d, J = 6.6 Hz), 7.37-7.29 (3H, m), 6.95 (1H, d, J = 8.1
13
13
s), 1.76 (3H, s); C NMR (CDCl
3
, 75 MHz) δ 139.4, 138.6,
36.8, 132.3, 129.8, 128.6, 127.7, 127.3, 83.2, 74.8, 60.8, 21.6,
1.1, 18.0. IR (NaCl, neat) ν: 3688, 3304, 3018, 2135, 1599,
Hz), 3.56 (1H, s), 2.94 (1H, s), 2.34 (3H, s), 1.78 (3H, s);
C
1
2
1
NMR (CDCl
3
, 75 MHz) δ 168.1, 162.3, 142.8, 139.6, 135.8,
128.6, 128.3, 127.9, 125.6, 125.1, 124.6, 84.9, 77.2, 74.3, 24.2,
-
1
521, 1474, 1419, 1379, 1325, 1161, 1091, 1018, 927 cm ; MS
21.3; IR (NaCl, neat) ν: 3420, 3275, 3019, 2102, 1668, 1531,
+
-1
(
ESI) m/z 330 [M+H] ; HRMS (ESI) calcd. for C18
H20NO
3
S
1472, 1418, 1335, 1300, 1121, 1059, 984, 826 cm ; MS (ESI)
+
+
+
(
M +H) 330.1164, found: 330.1158.
m/z 280 [M+H] ; HRMS (ESI) calcd. for C18
80.1338, found: 280.1338.
2
H18NO (M +H)
2
2
e,f
4
9
.8.16. 1-(2-(Tosylamino)phenyl)prop-2-yn-1-ol (1p)
Yield
1
0%; 0.137 g; yellow oil; R (10% EtOAc/n-hexane) 0.25; H
4.8.22. 1-(4-Methyl-2-(acetylamino)phenyl)-1-phenylprop-2-yn-
f
NMR (CDCl3, 400 MHz) δ 7.92 (1H, brs), 7.67 (2H, d, J = 8.0
Hz), 7.52 (1H, d, J = 7.6 Hz), 7.32 (2H, d, J = 8.1 Hz), 7.24 (2H,
dd, J = 8.0 Hz, 13.2 Hz), 7.13 (1H, t, J = 7.6 Hz), 5.33 (1H, d, J =
1-ol (1v) Yield 77%; 0.117 g; light-brown solid; m.p. 182-185
C; R (10% EtOAc/n-hexane) 0.25; H NMR (CDCl , 300 MHz)
f 3
δ 8.30 (1H, brs), 7.94 (1H, d, J = 8.7 Hz), 7.75 (1H, d, J = 2.4
o
1
13
2
.4 Hz), 3.61 (1H, brs), 2.64 (1H, d, J = 2.1 Hz), 2.36 (3H, s);
C
Hz), 7.47-7.44 (2H, m), 7.40-7.32 (4H, m), 3.55 (1H, s), 3.00
1
3
NMR (CDCl
3
, 100 MHz) δ 144.2, 136.5, 135.2, 131.4, 129.7,
3
(1H, s), 1.80 (3H, s); C NMR (CDCl , 75 MHz) δ 168.4, 141.9,
1
29.6, 128.4, 127.3, 125.6, 123.4, 81.6, 76.4, 62.3, 21.6; MS
134.5, 133.7, 129.2, 129.1, 128.7, 128.6, 127.8, 125.5, 84.0, 77.9,
+
(
ESI) m/z 324 [M+Na] .
74.0, 24.1; IR (NaCl, neat) ν: 3358, 3227, 3019, 2112, 1665,
-
1
1
533, 1396, 1317, 1169, 1047, 887, 829 cm ; MS (ESI) m/z 300
+
+
4.8.17. 1-Phenyl-1-(2-(mesylamino)phenyl)prop-2-yn-1-ol (1q)
[
M+H] ; HRMS (ESI) calcd. for C17
2
H15ClNO (M +H) 300.0791,
o
Yield 73%; 0.111 g; colorless solid; m.p. 148-151 C; R
f
(10%
, 300 MHz) δ 8.18 (1H,
brs), 7.85 (1H, dd, J = 1.4, 7.84 Hz), 7.74 (1H, d, J = 8.16 Hz),
.55 (2H, d, J = 1.4 Hz), 7.42-7.21 (4H, m), 7.19 (1H, t, J = 6.64
found: 300.0788.
1
EtOAc/n-hexane) 0.25; H NMR (CDCl
3
4.8.23. 1-(5-Chloro-2-(tosylamino)phenyl)-1-(2-chlorophenyl)
7
prop-2-yn-1-ol (1w) Yield 80%; 0.157 g; light-brown solid; m.p.
1
3
o
1
Hz), 3.61 (1H, s), 3.04 (1H, s), 2.16 (3H, s); C NMR (CDCl
3
,
179-182 C;
R
f
(10% EtOAc/n-hexane) 0.25;
H NMR
7
1
3
5 MHz) δ 143.1, 135.8, 132.3, 130.0, 128.8, 128.3, 125.8,
((CD CO, 300 MHz) δ 8.64 (1H, brs), 8.19 (1H, d, J = 8.7),
3 2
)
24.0, 120.9, 84.5, 78.0, 74.4, 38.0; IR (NaCl, neat) ν: 3414,
7.84-8.0 (2H, m), 7.52-7.45 (1H, m), 7.41-7.32 (2H, m), 6.84
-
1
13
281, 3019, 2120, 1584, 1489, 1323, 1267, 1148, 970, 926 cm .
(1H, s), 3.56 (1H, s), 2.91 (1H, brs); 1.81 (3H, s); C NMR
+
MS (ESI) m/z 302 [M+H] ; HRMS (ESI) calcd. for C16
H16NO
3
S
3 2
((CD ) CO, 75 MHz) δ 167.6, 139.7, 134.9, 134.1, 131.6, 129.8,
129.2, 128.3, 128.0, 127.6, 126.8, 125.8, 82.9, 77.62, 72.6, 23.2;
+
(
M +H) 302.0851, found: 302.0857.
IR (NaCl, neat) ν: 3385, 3273, 3019, 2118, 1668, 1518, 1310,
-
1
+
4
.8.18. 1-Phenyl-1-(2-(nosylamino)phenyl)prop-2-yn-1-ol (1r)
1
171, 991, 889, 833 cm ; MS (ESI) m/z 334 [M+H] ; HRMS
o
+
Yield 70%; 0.145 g; brown solid; m.p. 166-168 C; R (10%
EtOAc/n-hexane) 0.25; H NMR (CDCl
brs), 7.92 (2H, d, J = 8.7 Hz), 7.60-7.53 (2H, m), 7.26 (2H, d, J =
f
17 14 2 2
(ESI) calcd. for C H Cl NO (M +H) 334.0402, found:
1
3
, 300 MHz) δ 8.84 (1H,
334.0408.
13
2e,f
8.7 Hz), 7.24-7.11 (6H, m), 7.02-6.97 (1H, m), 2.81 (1H, s);
C
4.8.24. 3-Phenyl-1-tosyl-1H-indole-2-carbaldehyde (4a) Yield
1
NMR (CDCl , 75 MHz) δ 149.8, 144.8, 142.3, 135.0, 130.8,
91%; 0.045 g; yellow solid; R (8% EtOAc/n-hexane) 0.42; H
3
f
1
8
1
29.9, 129.3, 128.7, 128.4, 128.3, 125.6, 124.0, 123.9, 119.4,
3
NMR (CDCl , 400 MHz) δ 10.22 (1H, s), 8.30 (1H, d, J = 8.5
4.3, 78.1, 74.6; IR (NaCl, neat) ν: 3420, 3302, 3019, 2119,
Hz), 7.83 (2H, d, J = 8.3 Hz), 7.52-7.58 (2H, m), 7.45 (5H, m),
-1
13
637, 1531, 1410, 1348, 1165, 1091, 930, 855 cm ; MS (ESI)
7.26 (1H, m), 7.24 (2H, d, J = 6.5 Hz), 2.36 (3H, s); C NMR
+
+
m/z 409 [M+H] ; HRMS (ESI) calcd. for C H N O S (M +H)
(CDCl , 100 MHz) δ 182.4, 145.3, 138.2, 135.8, 135.2, 132.5,
2
1
17
2
5
3
4
09.0858, found: 409.0860.
130.5, 130.4, 129.7, 129.3, 129.2, 129.0, 128.4, 127.2, 124.6,
+
122.6, 115.7, 21.7; MS (ESI) m/z 376 [M+H] .
4
.8.19. 1-Phenyl-1-(2-(acetylamino)phenyl)prop-2-yn-1-ol (1s)
o
Yield 75%; 0.10 g; light-brown solid; m.p. 136-139 C; R
f
(10%
4.8.25.
(4b)
5-Methyl-3-phenyl-1-tosyl-1H-indole-2-carbaldehyde
1
2e,f
EtOAc/n-hexane) 0.25; H NMR (CDCl , 300 MHz) δ 8.53 (1H,
brs), 7.94 (1H, d J = 7.9), 7.73 (1H, d, J = 7.8 Hz), 7.46 - 7.43
Yield 85%; 0.042 g; yellow gum; R (8% EtOAc/n-
3
f
1
hexane) 0.42; H NMR (CDCl
3
, 400 MHz) δ 10.21 (1H, s), 8.17
(
2H, m), 7.36-7.25 (4H, m), 7.14 (1H, t, J = 7.5 Hz), 4.31 (1H, s),
.91 (1H, s), 1.75 (3H, s); C NMR (CDCl , 75 MHz) δ 168.3,
3
(1H, d, J = 8.6 Hz), 7.79 (2H, d, J = 8.2 Hz), 7.45 (5H, m), 7.36
(1H, d, J = 7.0 Hz), 7.22-7.29 (3H, m), 2.38 (3H, s), 2.36 (3H, s);
1
3
2
1
1
3
9
13
62.3, 142.8, 136.1, 132.1, 129.4, 128.5, 128.2, 127.9, 125.6,
24.3, 123.9, 84.8, 74.4, 24.2; IR (NaCl, neat) ν: 3397, 3302,
019, 2119, 1682, 1587, 1520, 1447, 1304, 1163, 1040, 988, 928,
C NMR (CDCl , 100 MHz) δ 182.5, 145.2, 136.5, 135.6, 135.1,
3
134.6, 132.6, 130.6, 130.5, 129.7, 129.6, 129.5, 129.0, 128.4,
+
127.2, 122.1, 115.5, 21.7, 21.3; MS (ESI) m/z 390 [M+H] .
-
1
+
01 cm ; MS (ESI) m/z 288 [M+Na] ; HRMS (ESI) calcd. for
+
4
.8.26. 5-Methoxy-3-phenyl-1-tosyl-1H-indole-2-carbaldehyde
C H NO Na (M +Na) 288.1000, found: 288.1012.
1
7
15
2
2e,f
(4c)
Yield 77%; 0.038 g; yellow solid; R (8% EtOAc/n-
f
1
4
0
.8.20. 2-(2-(Acetylamino)phenyl)but-3-yn-2-ol (1t) Yield 78%;
hexane) 0.42; H NMR (CDCl , 400 MHz) δ 10.23 (1H, s), 8.19
3
o
.080 g; light-brown solid; m.p. 158-160 C; R
f
(10% EtOAc/n-
, 300 MHz) δ 9.28 (1H, brs), 8.14
1H, d, J = 8.1), 7.65 (1H, d, J = 7.8 Hz), 7.33 (1H, t, J = 7.2 Hz),
(1H, d, J = 9.2 Hz), 7.76 (2H, d, J = 8.3 Hz), 7.43 (5H, m), 7.22
(2H, d, J = 8.0 Hz), 7.16 (1H, dd, J = 2.6 Hz, 9.2 Hz), 6.86 (1H,
1
hexane) 0.25; H NMR (CDCl
(
3
13
d, J = 2.4 Hz), 3.76 (3H, s), 2.36 (3H s); C NMR (CDCl , 100
3
7
1
1
.10 (1H, t, J = 7.5 Hz), 3.37 (1H, s), 2.77 (1H, s), 2.15 (3H, s),
MHz) δ 182.6, 157.3, 145.2, 135.4, 134.9, 133.1, 132.8, 130.6,
1
3
.89 (3H, s); C NMR (CDCl
3
, 100 MHz) δ 168.4, 136.2, 131.3,
130.4, 129.7, 128.9, 128.4, 127.1, 119.2, 116.9, 103.4, 55.7, 21.6;
+
29.0, 126.3, 123.9, 123.5, 85.8, 74.4, 71.1, 30.4, 25.0; IR (NaCl,
MS (ESI) m/z 406 [M+H] .
neat) ν: 3340, 3294, 3019, 2110, 1658, 1581, 1520, 1449, 1366,
-
1
+
4
.8.27.
5-Chloro-3-phenyl-1-tosyl-1H-indole-2-carbaldehyde
(8% EtOAc/n-hexane)
, 300 MHz) δ 10.21 (1H, s), 8.25 (1H, d, J
9.8 Hz), 7.81 (2H, d, J = 8.3 Hz), 7.51-7.41 (7H, m), 7.26 (2H,
1
306, 1184, 1042, 955, 878 cm ; MS (ESI) m/z 226 [M+Na] ;
+
(4d) Yield 84%; 0.041 g; yellow gum; R
f
2
HRMS (ESI) calcd. for C12H13NO Na (M +Na) 226.0844, found:
1
0.42; H NMR (CDCl
3
226.0844.
=
13
4.8.21. 1-(4-Methyl-2-(acetylamino)phenyl)-1-phenylprop-2-yn-
d, J = 8.1 Hz), 2.36 (3H, s); C NMR (CDCl , 75 MHz) δ 182.3,
3
1-ol (1u) Yield 82%; 0.109 g; light-brown solid; m.p. 167-169
162.3, 145.7, 136.3, 134.9, 134.4, 133.3, 130.6, 130.5, 129.9,

ACCEPTED MANUSCRIPT
8
Tetrahedron
129.8, 129.4, 129.2, 128.8, 128.6, 127.2, 121.9, 116.9, 21.7; IR
(1H, d, J = 8.4 Hz), 7.76 (2H, d, J = 8.1 Hz), 7.55 (1H, t, J = 7.5
(
1
[
NaCl, neat) ν: 3019, 2926, 1686, 1597, 1543, 1491, 1443, 1373,
Hz), 7.26-7.20 (6H, m), 7.10 (2H, d, J = 7.2 Hz), 2.35 (3H, s),
-
1
13
265, 1171, 1090, 1022, 928, 912, 812 cm ; MS (ESI) m/z 410
1.97 (3H, s); C NMR (CDCl , 75 MHz) δ 182.5, 145.4, 138.1,
3
+
+
M+H] ; HRMS (ESI) calcd. for
C
22
H
17ClNO
3
S
(M +H)
137.3, 135.4, 134.9, 132.8, 130.4, 130.2, 130.0, 129.9, 129.7,
4
10.0618, found: 410.0615.
129.2, 128.8, 127.1, 125.6, 124.8, 122.7, 115.9, 21.6, 19.8; IR
(
1
NaCl, neat) ν: 3019, 2920, 1684, 1599, 1543, 1489, 1443, 1373,
-
1
4.8.28. 5-Bromo-3-phenyl-1-tosyl-1H-indole-2-carbaldehyde (4e)
263, 1175, 1090, 922, 910, 805 cm ; MS (ESI) m/z 390
+
+
Yield 84%; 0.041 g; yellow gum; R (8% EtOAc/n-hexane) 0.42;
f
23 20 3
[M+H] ; HRMS (ESI) calcd. for C H NO S (M +H) 390.1164,
1
H NMR (CDCl
3
, 300 MHz) δ 10.21 (1H, s), 8.19 (1H, d, J = 9.3
found: 390.1163.
Hz), 7.81 (2H, d, J = 8.4 Hz), 7.66-7.62 (2H, m), 7.49-7.41 (5H,
m), 7.27 (2H, d, J = 7.8 Hz), 2.38 (3H, s); C NMR (CDCl
MHz) δ 182.3, 162.3, 145.6, 136.7, 134.9, 134.3, 133.1, 132.0,
1
3
3
, 75
4.8.35. 5-Chloro-3-(2-fluorophenyl)-1-tosyl-1H-indole-2-carbal
o
dehyde (4l) Yield 75%; 0.037 g; colorless solid; m.p. 110-111 C;
1
1
1
1
31.0, 130.4, 129.9, 129.7, 129.2, 128.6, 127.2, 125.0, 118.2,
17.2, 21.7; IR (NaCl, neat) ν: 3019, 2920, 1686, 1600, 1541,
491, 1439, 1375, 1265, 1171, 1090, 1022, 928, 910, 810 cm ;
R
f
(8% EtOAc/n-hexane) 0.42; H NMR (CDCl
3
, 300 MHz) δ
10.39 (1H, s), 8.23 (1H, d, J = 8.9 Hz), 7.73 (2H, d, J = 8.4 Hz),
-1
7.51-7.42 (2H, m), 7.36-7.31 (2H, m), 7.28-7.17 (4H, m), 2.37
+
13
MS (ESI) m/z + 454 [M+H] ; HRMS (ESI) calcd. for
C
(3H, s); C NMR (CDCl , 75 MHz) δ 182.6, 145.8, 135.9, 134.4,
3
22
H17NO
3
SBr (M +H) 454.0113, found: 454.0116.
134.0, 131.9, 131.1, 131.0, 130.8, 130.4, 130.0, 129.3, 127.0,
1
26.4, 124.2, 124.1, 121.8, 116.8, 116.1 (d, JC-F = 22.5 Hz), 21.7;
4
.8.29. 7-Methyl-3-phenyl-1-tosyl-1H-indole-2-carbaldehyde (4f)
IR (NaCl, neat) ν: 3019, 2960, 1688, 1599, 1545, 1493, 1445,
o
-
1
Yield 83%; 0.041 g; colorless solid; m.p. 173-175 C; R
EtOAc/n-hexane) 0.42; H NMR (CDCl , 300 MHz) δ 10.04
f
(8%
1377, 1263, 1171, 1090, 926, 849 cm ; MS (ESI) m/z 428
1
+
+
3
22 16 3
[M+H] ; HRMS (ESI) calcd. for C H ClFNO S (M +H)
(
(
(
1
1
1
1H, s), 7.71 (2H, d, J = 8.4 Hz), 7.47-7.44 (3H, m), 7.38-7.25
428.0523, found: 428.0521.
13
3H, m), 7.23-7.18 (4H, m), 2.66 (3H, s), 2.37 (3H, s); C NMR
CDCl , 75 MHz) δ 182.5, 162.3, 144.9, 140.5, 140.0, 136.1,
34.3, 132.8, 132.6, 132.5, 130.1, 129.2, 128.9, 127.5, 125.9,
20.6, 21.6, 21.5; IR (NaCl, neat) ν: 3019, 2920, 1682, 1597,
558, 1494, 1445, 1362, 1283, 1171, 1088, 1007, 928, 910, 810
2
e,f
3
4.8.36. 3-Methyl-1-tosyl-1H-indole-2-carbaldehyde (4m) Yield
89%; 0.044 g; colorless solid; R (8% EtOAc/n-hexane) 0.42; H
NMR (CDCl , 300 MHz) δ 10.61 (1H, s), 8.20 (1H, d, J = 8.5
3
Hz), 7.55 (3H, d, J = 8.2 Hz), 7.50 (1H, dd, J = 1.1 Hz, 8.4 Hz),
7.29 (1H, dd, J = 0.7 Hz, 7.9 Hz), 7.12 (2H, d, J = 8.1 Hz), 2.51
(3H, s), 2.30 (3H, s); C NMR (CDCl , 75 MHz) δ 185.3, 145.3,
1
f
-
1
+
cm ; MS (ESI) m/z 390 [M+H] ; HRMS (ESI) calcd. for
C H NO S (M +H) 390.1164, found: 390.1166.
+
13
2
3
20
3
3
1
37.5, 134.2, 133.0, 132.1, 130.6, 129.8, 129.1, 126.7, 124.6,
+
4
.8.30.
3-Phenyl-1-tosyl-1H-benzo[f]indole-2-carbaldehyde
121.6, 115.8, 21.6, 10.5; MS (ESI) m/z 314 [M+H] .
2
e,f
(
4g) Yield 54%; 0.026 g; yellow solid; R
f
(8% EtOAc/n-
1
2e,f
hexane) 0.42; H NMR (CDCl
3
, 400 MHz) δ 10.33 (1H, s), 8.71
4.8.37. 3-Ethyl-1-tosyl-1H-indole-2-carbaldehyde (4n) Yield
91%; 0.045 g; colorless gum; R (8% EtOAc/n-hexane) 0.42; H
1
(
1H, s), 8.04 (1H, d, J = 8.4 Hz), 7.97 (1H, s), 7.83 (1H, d, J =
f
8
8
1
1
1
.3 Hz), 7.74 (2H, d, J = 8.3 Hz), 7.44 (7H, m), 7.16 (2H, d, J =
3
NMR (CDCl , 400 MHz) δ 10.58 (1H, s), 8.22 (1H, d, J = 8.5
13
.2 Hz), 2.30 (3H, s); C NMR (CDCl
3
, 100 MHz) δ 183.0,
Hz), 7.59-7.49 (4H, m), 7.33 (1H, t, J = 7.5 Hz), 7.14 (2H, d, J =
8.2 Hz), 2.99 (2H, q, J = 7.5 Hz), 2.30 (3H, s), 1.18 (3H, t, J =
45.2, 136.4, 135.7, 134.7, 134.3, 133.8, 131.0, 130.6, 130.2,
30.0, 129.7, 129.2, 128.5, 128.4, 127.2, 126.8, 125.5, 122.1,
13
7.5 Hz); C NMR (CDCl , 100 MHz) δ 184.9, 145.2, 138.4,
3
+
13.3, 21.6; MS (ESI) m/z 426 [M+H] .
137.8, 134.1, 132.3, 129.7, 129.6, 128.9, 126.7, 124.6, 121.4,
+
1
16.0, 21.5, 18.1, 14.4; MS (ESI) m/z 328 [M+H] .
4
.8.31. 7-Methyl-5-tosyl-5H-[1,3]dioxolo[4,5-f]indole-6-carbal
2
e,f
dehyde (4h) Yield 65%; 0.032 g; colorless gum; R
f
(8%
4.8.38. 5,7-Methyl-1-tosyl-1H-indole-2-carbaldehyde (4o) Yield
1
o
EtOAc/n-hexane) 0.42; H NMR (CDCl , 400 MHz) δ 10.50 (1H,
s), 7.71 (1H, s), 7.58 (2H, d, J = 8.2 Hz), 7.19 (2H, d, J = 8.2
90%; 0.044 g; pale-brown solid; m.p. 110-113 C; R (8%
3
f
1
EtOAc/n-hexane) 0.42; H NMR (CDCl
3
, 400 MHz) δ 10.24 (1H,
13
Hz), 6.87 (1H, s) 6.07 (2H, s), 2.45 (3H, s), 2.35 (3H, s);
NMR (CDCl , 100 MHz) δ 184.3, 150.3, 146.3, 145.2, 134.2,
33.5, 132.7, 129.8, 126.7, 125.2, 102.0, 99.1, 96.7, 21.6, 10.8;
C
s), 7.38 (2H, d, J = 8.2 Hz), 7.27 (1H, s), 7.10 (4H, d, J = 7.1
13
3
3
Hz), 2.68 (3H, s), 2.33 (3H, s), 2.31 (3H, s); C NMR (CDCl ,
1
100 MHz) δ 183.4, 145.0, 141.6, 138.5, 135.9, 134.0, 133.1,
131.9, 129.3, 127.0, 123.2, 121.4, 21.6, 21.5, 20.9; IR (NaCl,
neat) ν: 3019, 2920, 1682, 1600, 1555, 1473, 1460, 1400, 1368,
+
MS (ESI) m/z 358 [M+H] .
2
e,f
-
1
+
4.8.32. 3-p-Tolyl-1-tosyl-1H-indole-2-carbaldehyde (4i) Yield
1
169, 1090, 999, 876, 810 cm ; MS (ESI) m/z 328 [M+H] ;
1
+
9
f
1%; 0.045 g; yellow solid; R (8% EtOAc/n-hexane) 0.42; H
HRMS (ESI) calcd. for C H NO S (M +H) 328.1007, found:
1
8
18
3
NMR (CDCl , 300 MHz) δ 10.2 (1H, s), 8.29 (1H, d, J = 8.4 Hz),
3
328.1002.
7.82 (2H, d, J = 8.4 Hz), 7.52 (2H, d, J = 7.8 Hz), 7.32 (2H, d, J
13
2e,f,12a
=
8.1 Hz), 7.23 (5H, m), 2.42 (3H, s), 2.36 (3H, s); C NMR
, 75 MHz) δ 182.4, 145.2, 139.0, 138.3, 136.1, 135.2,
4.8.39. 1-Tosyl-1H-indole-2-carbaldehyde (4p)
Yield 51%;
1
(
CDCl
3
0.025 g; colorless solid; R (8% EtOAc/n-hexane) 0.42; H NMR
f
1
32.5, 130.4, 129.7, 129.3, 129.1, 127.2, 124.6, 122.7, 115.7,
(CDCl , 400MHz) δ = 10.53 (1H, s), 8.23 (1H, dd, J = 0.4 Hz,
8.4 Hz), 7.65 (2H, d, J = 8.4 Hz), 7.62 (1H, dd, J = 1.2 Hz, 8.0
Hz), 7.52 (1H, ddd, J = 1.2 Hz, 7.2 Hz, 7.2 Hz,), 7.46 (1H, s),
3
+
79.5, 21.6, 21.4; MS (ESI) m/z 390 [M+H] .
4
.8.33.
3-(4-Chlorophenyl)-1-tosyl-1H-indole-2-carbaldehyde
(8% EtOAc/n-
hexane) 0.42; H NMR (CDCl , 300 MHz) δ 10.31 (1H, s), 8.29
7
.31 (1H, ddd, J = 0.8 Hz, 7.2 Hz, 7.2 Hz), 7.18 (2H, d, J = 8.4
2
e,f
13
(4j) Yield 90%; 0.044 g; colorless solid; R
f
Hz), 2.32 (3H, s); C NMR (CDCl , 100 MHz) δ = 183.3, 145.6,
3
1
3
138.4, 137.7, 134.6, 129.9, 128.8, 128.1, 126.6, 124.8, 123.6,
+
(
1H, d, J = 8.6 Hz), 7.77 (2H, d, J = 8.4 Hz), 7.54 (1H, td, J = 1.2
1
18.8, 115.3, 21.6; MS (ESI) m/z 300 [M+H] .
Hz, 8.5 Hz), 7.38-7.49 (5H, m), 7.29-7.33 (2H, m), 7.23 (1H, d, J
1
3
=
9.3 Hz), 2.36 (3H, s); C NMR (CDCl
3
, 75 MHz) δ 182.6,
4.8.40. 3-Phenyl-1-mesyl-1H-indole-2-carbaldehyde (4q) Yield
o
162.3, 145.5, 137.8, 135.0, 134.8, 133.6, 132.5, 131.8, 129.8,
83%; 0.041 g; colorless solid; m.p. 126-129 C; R (8% EtOAc/n-
f
1
129.3, 129.1, 128.9, 128.6, 127.1, 124.9, 122.3, 115.7, 21.7; MS
hexane) 0.42; H NMR (CDCl
3
, 300 MHz) δ 9.84 (1H, s), 8.19
+
(
ESI) m/z 410 [M+H] .
(1H, d, J = 8.7 Hz), 7.65 (1H, d, J = 8.1 Hz), 7.58-7.54 (6H, m),
13
7
3
.33 (1H, t, J = 7.8 Hz), 3.78 (3H, s); C NMR (CDCl , 75 MHz)
4
.8.34. 3-o-Tolyl-1-tosyl-1H-indole-2-carbaldehyde (4k) Yield
δ 181.9, 162.3, 139.0, 138.6, 132.8, 130.6, 130.0, 129.7, 129.3,
129.9, 128.0, 124.3, 122.6, 115.6, 43.7; IR (NaCl, neat) ν: 3019,
o
9
1%; 0.045 g; colorless solid; m.p. 98-101 C; R (8% EtOAc/n-
f
1
3
hexane) 0.42; H NMR (CDCl , 300 MHz) δ 10.24 (1H, s), 8.31

ACCEPTED MANUSCRIPT
9
-
1
2
916, 1678, 1604, 1543, 1445, 1368, 1172, 1022, 968, 926 cm ;
128.2, 127.6, 127.3, 126.0, 125.6, 125.3, 116.6, 82.9, 65.9,
21.7; MS (ESI) m/z 504 [M+H] .
+
+
MS (ESI) m/z 300 [M+H] ; HRMS (ESI) calcd. for C16
H14NO
3
S
+
(
M +H) 300.0694, found: 300.0694.
4
.8.48. (R)-N-Tosylcalindol (7) Yield 90%; 0.023 g; colorless
solid: m.p. 102-105 °C; R (20% EtOAc/n-hexane) 0.17; H
f
1
4
.8.41. 3-Phenyl-1-nosyl-1H-indole-2-carbaldehyde (4r) Yield
o
8
5%; 0.042 g; colorless solid; m.p. 151-153 C; R
f
(8% EtOAc/n-
, 300 MHz) δ 9.92 (1H, s), 8.34
3H, d, J = 9.3 Hz), 8.24 (2H, d, J = 9.1 Hz), 7.65-7.60 (2H, m),
NMR (CDCl3, 400 MHz) δ 8.17 (1H, d, J = 8.3 Hz), 8.07 (1H, d,
J = 8.0 Hz), 7.88 (1H, d, J = 7.76 Hz), 7.75-7.77 (2H, m), 7.56
(2H, d, J = 8.3 Hz), 7.37-7.51 (4H, m), 7.19-7.30 (2H, m), 7.04
(2H, d, J = 8.3 Hz), 6.35 (1H, s), 4.69 (1H, q, J = 6.4 Hz), 4.16
(1H, d, J = 15.4 Hz), 3.97 (1H, d, J = 15.4 Hz), 2.50 (1H, br s),
2.25 (3H, s), 1.49 (3H, d, J = 6.52 Hz); C NMR (CDCl3, 100
MHz) δ 144.7, 140.5, 139.6, 137.4, 135.7, 134.0, 131.3, 129.7,
129.4, 128.9, 127.2, 126.2, 125.8, 125.7, 125.3, 124.4, 123.6,
1
hexane) 0.42; H NMR (CDCl
3
(
7
13
.50 (5H, s), 7.38 (1H, t, J = 8.1 Hz); C NMR (CDCl
δ 181.3, 162.3, 150.6, 144.3, 138.7, 138.4, 132.5, 130.5, 130.0,
29.6, 128.9, 128.8, 128.7, 125.1, 124.2, 123.0, 115.6; IR (NaCl,
neat) ν: 3019, 1684, 1603, 1533, 1420, 1350, 1261, 1182, 1090,
3
, 75 MHz)
1
3
1
-1
+
1
022, 968, 928, 855 cm ; MS (ESI) m/z 407 [M+H] ; HRMS
+
(
4
ESI) calcd. for
07.0698.
C
21
H
15
N
2
O
5
S
(M +H) 407.0702, found:
123.2, 123.0, 120.6, 114.7, 111.3, 51.7, 44.9, 23.8, 21.5; MS
+
(ESI) m/z 455 [M+H] ; HRMS (ESI) calcd. for C28
(
H
27
N
2
O
2
S
+
22
M +H) 455.1793, found: 455.1791; [α]D −30.05° (c = 0.51,
1
2c
4
0
.8.42. 3-Phenyl-1H-indole-2-carbaldehyde (5s) Yield 70%;
CHCl ).
3
1
.029 g; colorless solid; R
, 400 MHz) δ 9.88 (1H, s), 9.33 (1H, brs), 7.82 (1H,
d, J = 8.1 Hz), 7.62 (1H, d, J = 8.4 Hz), 7.56-7.41 (6H,m), 7.20
f
(10% EtOAc/n-hexane) 0.32; H
NMR (CDCl
3
Acknowledgments
1
3
(
1H, t, J = 6.9 Hz); C NMR (CDCl , 75 MHz) 182.9, 137.3,
32.0, 131.8, 130.6, 129.6, 128.9, 128.1, 127.8, 126.8, 122.3,
3
This work is supported by a College of Science Start-Up
Grant from Nanyang Technological University and a Science and
Engineering Research Council Grant (092 101 0053) from
A*STAR, Singapore.
1
+
121.5, 112.5; MS (ESI) m/z 222 [M+H] .
1
2b
4
0
.8.43. 3-Methyl-1H-indole-2-carbaldehyde (5t) Yield 71%;
1
.028 g; colorless solid; R (10% EtOAc/n-hexane) 0.32; H
f
NMR (CDCl
3
, 300 MHz) δ 10.0 (1H, s), 9.56 (1H, brs), 7.67 (1H,
Supplementary data
d, J = 8.1 Hz), 7.42-7.33 (2H, m), 7.12 (1H, t, J = 7.8 Hz), 2.60
13
1
13
(
1
3H, s); C NMR (CDCl
3
, 100 MHz) δ 180.8, 137.9, 132.2,
Copies of H and C NMR spectra for all starting materials
and products. This material is available free of charge via the
Internet at
28.1, 127.7, 125.3, 121.3, 120.4, 112.5, 8.4; MS (ESI) m/z 160
+
[
M+H] .
4
.8.44. 6-Methyl-3-phenyl-1H-indole-2-carbaldehyde (5u) Yield
References and notes
6
2%; 0.026 g; colorless solid; m.p. 167-169 °C; R (10%
f
1
EtOAc/n-hexane) 0.32; H NMR ((CD ) CO, 300 MHz) δ 10.92
3
2
1
.
For selected reviews: (a) Sharma,V.; Kumar, P.; Pathak, D. J. Heterocycl.
Chem. 2010, 47, 491; (b) Amat, M.; Checa, B.; Llor, N.; Molins E.;
Bosch, J. Chem. Commun. 2009, 2935 and references therein; (c)
Barluenga, J.; Rodríguez, F.; Fańanás, F. J. Chem. Asian J. 2009, 4, 1036.
(
1H, brs), 9.84 (1H, s), 7.67 (3H, d, J = 8.1 Hz), 7.57 (2H, t, J =
7
2
1
1
1
.2 Hz), 7.49-7.44 (1H,m), 7.10 (1H, s), 7.05 (1H, d, J = 8.4 Hz),
.47 (3H, s); C NMR ((CD ) CO, 75 MHz) δ 181.57, 138.29,
3 2
37.35, 132.51, 131.88, 130.43, 128.8, 128.19, 127.7, 124.6,
23.3, 121.3, 112.3, 21.2; IR (NaCl, neat) ν: 3447, 2850, 1643,
13
(
d) Miyata, O.; Takeda, N.; Naito, T. Heterocycles 2009, 78, 843; (e)
Krüger (née Alex), K.; Tillack, A.; Beller, M. Adv. Synth. Catal. 2008,
350, 2153; (f) Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006, 106,
2875; (g) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873; (h)
Sundberg, R. J. Indoles; Academic Press: New York, 1996.
-
1
522, 1435, 1375, 1339, 1009, 928 cm ; MS (ESI) m/z 236
+
+
[
M+H] ; HRMS (ESI) calcd. for C16
H
14NO (M +H) 236.1075,
found: 236.1078.
2
.
For recent examples: (a) Zhan, F.; Liang, G. Angew. Chem. Int. Ed. 2013,
1
2c
5
2, 1266; (b) Wang, Y.; Liu, L.; Zhang, L. Chem. Sci. 2013, 4, 739; (c)
4.8.45. 5-Chloro-3-phenyl-1H-indole-2-carbaldehyde (5v)
Cera, G.; Piscitelli, S.; Chiarucci, M.; Fabrizi, G.; Goggiamani, A.;
Ramón, R. S.; Nolan, S. P.; Bandini, M. Angew. Chem. Int. Ed. 2012, 51,
Yield 57%; 0.024 g; colorless solid; R
f
(10% EtOAc/n-hexane)
1
0
7
7
1
1
.32; H NMR (CDCl3, 300 MHz) δ 9.87 (1H, s), 9.20 (1H, brs),
.78 (1H, s), 7.74 (1H, d, J = 7.2 Hz), 7.59-7.54 (4H, m), 7.41-
.39 (2H, m); C NMR ((CD ) CO, 75 MHz) δ 182.0, 141.6,
3 2
31.7, 130.4, 129.0, 128.5, 128.0, 127.5, 127.2, 127.1, 126.4,
9
891; (d) Mothe, S.R.; Kothandaraman, P.; Lauw, S. J. L.; Chin, S. M.
W.; Chan, P. W. H. Chem. Eur. J. 2012, 18, 6133; (e) Kothandaraman,
P.; Mothe, S. R.; Toh, S. S. M.; Chan, P. W. H. J. Org. Chem. 2011, 76,
7633; (f) Kothandaraman, P.; Rao, W.; Foo, S. J.; Chan, P. W. H. Angew.
Chem., Int. Ed. 2010, 49, 4619; (g) Bandini, M.; Eichholzer, A. Angew.
Chem. Int. Ed. 2009, 48, 9533; (h) Sato, S.; Shibuya, M.; Kanoh, N.;
Iwabuchi, Y. Chem. Commun. 2009, 6264. (i) Yamane, Y.; Liu, X.;
Hamasaki, A.; Ishida, T.; Haruta, M.; Yokoyama, T.; Tokunaga, M. Org.
Lett. 2009, 11, 5162.
1
3
+
20.6, 114.6; MS (ESI) m/z 256 [M+H] .
4
.8.46. 5-Chloro-3-(2-chlorophenyl)-1H-indole-2-carbaldehyde
(
(
(
(
5w) Yield 52%; 0.022 g; colorless solid; m.p. 164-169 °C; R
10% EtOAc/n-hexane) 0.32; H NMR (CDCl3, 300 MHz) δ 9.71
1H, s), 9.37 (1H, brs), 7.61-7.58 (1H, m), 7.51 (1H, s), 7.49-7.36
5H, m); C NMR (CDCl , 75 MHz) δ 182.4, 135.2, 134.4,
f
1
3
.
For recent examples: (a) Okuro, K.; Gurnham, J.; Alper, H. J. Org.
Chem. 2011, 76, 4715; (b) Lopchuk, J. M.; Gribble, G. W. Heterocycles,
2011, 82, 1617 and references therein; (c) Jones, S. B.; Simmons, B.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2009, 131, 13606; (d) Hari, Y.;
Kanie, T.; Miyagi, T.; Aoyama, T. Synthesis 2006, 8, 1249; (e)
Kolhatkar, R. B.; Ghorai, S. K.; George, C.; Reith, M. E. A.; Dutta, A. K.
J. Med. Chem. 2003, 46, 2205.
13
3
1
1
1
33.1, 132.9, 130.3, 130.2, 130.0, 128.1, 127.3, 127.0, 124.9,
21.6, 113.7; IR (NaCl, neat) ν: 3445, 2860, 1653, 1551, 1494,
475, 1419, 1430, 1373, 1339, 1294, 1072, 1055, 1003, 955, 930
-
1
+
cm . MS (ESI) m/z 290 [M+H] ; HRMS (ESI) calcd. for
+
4. Kothandaraman, P.; Koh, B. Q.; Limpanuparb, T.; Hirao, H.; Chan, P. W.
C
15
H10Cl
2
NO (M +H) 290.0139, found: 290.0137.
H. Chem. Eur. J. 2013, 19, 1978.
5
.
For recent reviews on haloamination of π bonds: (a) Parvatkar, P. T.;
Parameswaran, P. S.; Tilve, S. G. Chem. Eur. J. 2012, 18, 5460; (b)
Godoi, B.; Schumacher, R. F.; Zeni, G. Chem. Rev. 2011, 111, 2937; (c)
Yamamoto, Y.; Gridnev, I. D.; Patil, N. T.; Jin, T. Chem. Commun. 2009,
5075; (d) Mphahlele, M. J. Molecules 2009, 14, 4814; (e) Stavber, S.;
Jereb, M.; Zupan, M. Synthesis 2008, 1487; (f) Togo, H.; Iida, S. Synlett
4
.8.47.
(E)-2-(Iodomethylene)-3-phenyl-1-tosylindolin-3-ol
2
e,f
(6a) Yield 85%; 0.056 g; yellow solid; m.p. 84-86 °C; R
f
(12%
1
EtOAc/n-hexane) 0.3; H NMR (CDCl 400 MHz) δ 7.91 (1H, d,
3
,
J = 8.3 Hz), 7.58 (2H, d, J = 8.2 Hz), 7.31 (2H, d, J = 8.2 Hz),
.24 (2H, d, J = 8.1 Hz), 7.12 (3H m), 7.01 (3H, m), 6.95 (1H, d,
7
13
2
006, 2159. (f) Larock, R. C. In Acetylene Chemistry. Chemistry,
J = 7.5 Hz), 2.65 (1H, s), 2.41 (3H, s); C NMR (CDCl
MHz) δ 148.0, 145.3, 142.3, 139.7, 135.1, 133.6, 130.2, 129.8,
3
, 100
Biology, and Material Science; Diederich, F., Stang, P. J., Tykwinski, R.
R., Eds.; Wiley-VCH: New York, 2005; Ch. 2, pp 51.

ACCEPTED MANUSCRIPT
1
0
Tetrahedron
6
.
For reviews on alcohol proelectrophiles: (a) Bandini, M. Angew.
10. Approximate price of commercially available 1-tosyl-1H-indole-2-
carbaldehyde (4p): US$ 300 for 500 mg (source: Matrix Scientific;
Catalogue No: 064706; page no. 7151) Cost of 4p by our method: S$
11.05 for 500 mg.
Chem. Int. Ed. 2011, 50, 994; (b) Biannic, B.; Aponick, A. Eur. J. Org.
Chem. 2011, 6605; (c) Bandini, M.; Tragni, N. Org. Biomol. Chem. 2009,
7
6
, 1501; (d) Ljungdahl, N.; Kann, N. Angew. Chem. Int. Ed. 2009, 48,
42; (e) Muzart, J. Tetrahedron 2008, 64, 5815; (f) Muzart, J. Eur. J.
Org. Chem. 2007, 3077; (g) Muzart, J. Tetrahedron 2005, 61, 4179; (h)
Tamaru, Y. Eur. J. Org. Chem. 2005, 2647.
For examples of halogen-mediated aminocyclization of propargylic
alcohols: (a) Ali, S.; Zhu, H.-T.; Xia, X.-F.; Ji, K.-G.; Yang, Y.-F.; Song,
X.-R.; Liang, Y.-M. Org. Lett. 2011, 13, 2598; (b) Zhu, Y.; Yin, G.;
Hong, D.; Lu, P.; Wang, Y. Org. Lett. 2011, 13, 1024; (c) Kim, K.; Kim,
I. J. Comb. Chem. 2010, 12, 379; (d) Choi, J.; Lee, G. H.; Kim, I. Synlett,
11. (a) Dodd, R.; Beaumard, F.; Kiefer, L.; Pages, J.-M.; Chevalier, J.;
Ahner, F. PCT Int. Appl. 2012, WO 2012/084971; (b) Ohta, Y.; Chiba,
H.; Oishi, S.; Fujii, N.; Ohno, H. J. Org. Chem. 2009, 74, 7052; (c)
Kessler, A.; Faure, H.; Petrel, C.; Ruat, M.; Dauban, M.; Dodd, R. H.
Bioorg. Med. Chem. Lett. 2004, 14, 3345; (d) Abdel-Magid, A. F.;
Carson, K. G.; Harris, B. D.; Maryanoff, C. A.; Shah, R. D. J. Org.
Chem.1996, 61, 3849.
12. (a) Karadeolian, A.; Kerr, M. A. Angew. Chem. Int. Ed. 2010, 49, 1133;
(b) Wilson, R. M.; Hengge, A. J. Org. Chem. 1987, 52, 2699; (c)
Metlesics, W.; Silverman, G.; Sternbach, L. H. J. Org. Chem. 1964, 29,
1621.
7
.
2
008, 1243; (e) Knight, D. W.; Rost, H. C.; Sharland, C. M.; Singhornrat,
J. Tetrahedron Lett. 2007, 48, 7906; (f) Hessian, K. O.; Flynn, B. L. Org.
Lett. 2006, 8, 243.
8
9
.
.
A provisional U.S. patent application of this work has been filed,
application no. 61/684,344.
Approximate number of commercially available 2-aminoketone
substrates ~1000 (source: Scifinder Scholar)
13. (a) Unthank, M. G.; Tavassoli B.; Aggarwal, V. K. Org. Lett. 2008, 10,
1501; (b) Park K. K.; Lee, J. J. Tetrahedron 2004, 60, 2993; (c) Luca, L.
D.; Giacomelli G.; Taddei, M. J. Org. Chem. 2001, 66, 2534.

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Supporting Information
Metal-free synthesis of 1H-indole-2-carbaldehydes
by N-iodosuccinimide-mediated cyclization of 1-(2'-
Anilinyl)prop-2-yn-1-ols in water. A formal
synthesis of (R)-Calindol
Prasath Kothandaraman, Sherman Jun Liang Lauw and Philip Wai Hong Chan*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical
Sciences, Nanyang Technological University, Singapore 637371, Singapore.
waihong@ntu.edu.sg
S1

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Table of Contents
Page
S3
1
1
1
1
1
13
H and C NMR Spectra of 1-(2-(Tosylamino)phenyl)prop-2-yn-1-ols (1)
13
H and C NMR Spectra of 1H-Indole-2-carbaldehydes (4)
S20
S45
S44
S50
S51
13
H and C NMR Spectra of 1H-Indole-2-carbaldehydes (5)
13
H and C NMR Spectra of (E)-2-(Iodomethylene)indolin-3-ols (6a)
13
H and C NMR Spectra of (R)-N-Tosylcalindol (7)
Specific Optical Rotation Value of (R)-N-Tosylcalindol (7)
S2

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Figure S1. H and C NMR Spectra of 1-Phenyl-1-(2-(tosylamino)phenyl)prop-2-yn-1-ol
(1a)
S3

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Figure S2. H and C NMR Spectra of N-(2-(1-Hydroxy-1-phenylprop-2-ynyl)-4-
methylphenyl)-4-methylbenzene sulfonamide (1b)
S4

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Figure S3. H and C NMR Spectra of N-(2-(1-Hydroxy-1-phenylprop-2-ynyl)-4-
methoxyphenyl)-4-methylbenzene sulfonamide (1c)
S5

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Figure S4. H and C NMR Spectra of N-(4-Chloro-2-(1-hydroxy-1-phenylprop-2-
ynyl)phenyl)-4-methylbenzene sulfonamide (1d)
S6

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Figure S5. H and C NMR Spectra of N-(4-Bromo-2-(1-hydroxy-1-phenylprop-2-
ynyl)phenyl)-4-methylbenzene sulfonamide (1e)
S7

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Figure S6. H and C NMR Spectra of 1-(3-Methyl-2-(tosylamino)phenyl)-1-phenylprop-2-
yn-1-ol (1f)
S8

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Figure S7. H and C NMR Spectra of N-(3-(1-Hydroxy-1-phenylprop-2-ynyl)naphthalen-2-
yl)-4-methylbenzene sulfonamide (1g)
S9

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Figure S8. H and C NMR Spectra of 2-(5-(Tosylamino)benzo[d][1,3]dioxol-6-yl)but-3-yn-
2-ol (1h)
S10

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Figure S9. H and C NMR Spectra of 1-p-Tolyl-1-(2-(tosylamino)phenyl)prop-2-yn-1-ol
(
1i)
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Figure S10. H and C NMR Spectra of 1-(4-Chlorophenyl)-1-(2-(tosylamino)phenyl) prop-
2
-yn-1-ol (1j)
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Figure S11. H and C NMR Spectra of 1-o-Tolyl-1-(2-(tosylamino)phenyl)prop-2-yn-1-ol
(
1k)
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Figure S12. H and C NMR Spectra of 1-(5-Chloro-2-(tosylamino)phenyl)-1-(2-
fluorophenyl)prop-2-yn-1-ol (1l)
S14

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Figure S13. H and C NMR Spectra of 2-(2-(Tosylamino)phenyl)but-3-yn-2-ol (1m)
S15

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Figure S14. H and C NMR Spectra of 3-(2-(Tosylamino)phenyl)pent-1-yn-3-ol (1n)
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Figure S15. H and C NMR Spectra of 1-(3,5-Dimethyl-2-(tosylamino)phenyl)prop-2-yn-1-
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Figure S16. H and C NMR Spectra of 1-(2-(Tosylamino)phenyl)prop-2-yn-1-ol (1p)
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