Domino cyclization-alkylation protocol for the synthesis of 2,3-functionalized indoles from o-alkynylanilines and allylic alcohols

Article abstract of DOI:10.1039/c2ob25379h

A practical and efficient protocol for the one-pot synthesis of 2,3-substituted indoles was developed via a palladacycle catalyzed domino cyclization-alkylation reaction involving 2-alkynylanilines and allylic alcohols under mild conditions without any additives.

Full text of DOI:10.1039/c2ob25379h

View Article Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
Organic &
Biomolecular
Chemistry
Cite this: Org. Biomol. Chem., 2012, 10, 3875
www.rsc.org/obc
PAPER
Domino cyclization–alkylation protocol for the synthesis of 2,3-functionalized
indoles from o-alkynylanilines and allylic alcohols†
Chang Xu, Vinod K. Murugan and Sumod A. Pullarkat*
Received 22nd February 2012, Accepted 12th March 2012
DOI: 10.1039/c2ob25379h
A practical and efficient protocol for the one-pot synthesis of 2,3-substituted indoles was developed via a
palladacycle catalyzed domino cyclization–alkylation reaction involving 2-alkynylanilines and allylic
alcohols under mild conditions without any additives.
Introduction
We have recently reported the use of palladacycles I and IV
Fig. 1) as efficient promoters for P–H additions and for the
7
(
The development of facile, economical and environmentally
friendly synthetic methods targeting the generation of the indole
nucleus, a common structural motif in many bioactive natural
products and pharmaceuticals, has attracted continued research
interest. Numerous methods have also been developed for the
alkylation of 2-substituted indoles to yield 2,3-disubstituted
one-pot synthesis of 2-allylanilines from allylic alcohols respect-
ively. We herein report the results of our studies on the use of
palladacycle I to achieve the aforementioned domino sequence
towards 2,3-substituted indoles under mild conditions in one-pot
without the need for any additive or protecting agent.
8
1
indoles – a key synthetic task in the preparation of relevant mol-
2
ecules incorporating the indole nuclei. Recent literature reports
Results and discussion
show efforts being directed at developing methods that allow the
one-pot/sequential/domino formation of 2,3-disubstituted
indoles. Notable amongst these include the PdCl2 catalyzed
Transition metal catalyzed cyclization of 2-alkynylaniline deriva-
tives to 2-substituted indoles is an efficient approach for the syn-
domino-cyclization-Heck of 2-ethynylphenylcarbamates in the
9
thesis of indoles. Unfortunately, only a few such methods can
3
presence of reoxidant and excess Bu NF, a one-pot three com-
10
4
deal with unprotected primary 2-alkynylaniline. With the palla-
dacycle I in hand, we attempted the cyclization of unprotected 2-
ponent Sonogashira–Cacchi domino sequence involving 2-iodo-
N-triflouroacetylanilides, alkynes and arylbromides using Pd
(
phenylethynyl)aniline (1a) as our first step. Excellent yields (up
to 99%) of free NH 2-substituted indoles (2a) were obtained
Table 1).
4
(
OAc) and PPh , the PdBr (BINAP)-complex catalyzed reac-
2
3
2
5
tion of arylamines with α-diketones under reductive conditions
(
and the N-arylation and Fischer cyclization of N-tosylhydrazones
6
with benzyne.
Our aim was to develop a protocol that involves a domino cat-
alytic sequence consisting of cyclization of unprotected o-alky-
nylanilines (readily available via Sonogashira-type reactions) to
yield C-2 substituted indoles and their subsequent regioselective
alkylation at C-3 using allylic alcohols. The development of
such a one-pot reaction which allows low catalyst loading,
avoids use of protecting agents (at the risk of N-alkylated pro-
ducts) and tolerates the use of benign alcohols (as opposed to
conventional Lewis acids) as alkylating agents (in spite of their
acidic nature and poor leaving group behavior) is highly challen-
ging, yet desirable.
Division of Chemistry & Biological Chemistry, School of Physical and
Mathematical Sciences, Nanyang Technological University, Singapore
637371, Singapore. E-mail: sumod@ntu.edu.sg
†Electronic supplementary information (ESI) available. See DOI:
10.1039/c2ob25379h
Fig. 1 Palladacycle catalysts.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 3875–3881 | 3875

View Article Online
Subsequently the allylic alkylation of 2a with 1,3-diphenyl-2-
propenol (3a) was also attempted (Table 2). Such alkylations
with allylic alcohols to give C3- or N-substituted indoles, have
hitherto been achieved using Lewis acids, Brønsted acids, and
In order to test whether the two steps can be integrated into
one single operative procedure, we treated 1a, 3a and 10% cata-
lyst I in dichloroethane at 70 °C for 9 h, 4a was formed with a
yield of up to 98% (Table 3, entry 1). We further investigated the
other three palladacycles (Fig. 1) under the same conditions and
the summarized results are shown in Table 3. The results show
that catalyst I and II were much more effective than their benzyl
amine analogues III and IV, which is possibly indicative of the
difference in electronic influence of the Cnaphyl–Pd bond and
Cbenzyl–Pd bonds on the Pd center. From the results, I and II are
comparable, indicating that the anion effect does not play an
important role. We therefore chose the well characterized I as
our catalyst.
To further probe the general feasibility of this protocol,
various 2-alkynylanilines bearing different functional groups on
the aromatic ring were reacted with 1,3-diphenyl-2-propenol and
substituted 1,3-diphenyl-2-propenol (Table 4). The results show
that these 2-alkynylanilines can react with 1,3-diphenyl-2-prope-
nol very efficiently to afford the desired 2,3-substituted indoles
with excellent yields and regio-selectivities (Table 4, entries
11
iodine as catalysts via the Friedel–Crafts pathway and tran-
1
2
sition metal catalyzed alkylations. Recently, Hirashita et al.
reported that allylic alcohols reacted with indoles in the absence
1
3
of catalyst in ion-exchanged water at 220 °C. We were gratified
to find that the alkylation in low-coordinating solvents (toluene,
dichloroethane) gave clean conversion to 4a at only 70 °C. No
trace of N-allylic substituted indole was observed.
a
Table 1 Optimization of reaction conditions for the formation of 2a
1
–5). We further reacted the 2-alkynylanilines with the unsym-
b
Catalyst
Entry (mol%)
Yield
Solvent (%)
metrical allylic alcohol 3b. The results show that the reaction
can also afford the 2,3-substituted indole exclusively in excellent
yields but the product was a mixture of the isomers 4 and 4′.
The regioselectivity ratio however could not be determined accu-
rately due to the extensive overlap of the H NMR signals.
However the lack of regioselectivity is in line with the litera-
ture and indicated that the alkylation step maybe proceeding
via the Tsuji–Trost pathway rather than the Friedel–Crafts
pathway. It should be mentioned that the formation of trace
Temperature/°C
Time/h
1
2
3
4
5
6
7
8
9
10
20
5
10
10
10
10
10
10
110
110
110
110
90
80
80
24
24
24
9
24
24
9
Tol
Tol
Tol
Tol
ACN
DCE
DCE
DCE
DCE
91
78
93
91
97
91
99
98
90
1
14
70
60
9
9
1
amounts of black solid (no NMR signals in H NMR spectrum)
a
The reaction was carried out with 2-alkynlaniline (0.1 mmol, 1
equiv.), catalyst I (10 mol%) in 2 mL of specified solvent. Yields were
determined by H NMR spectroscopy using 1,3,5-trimethoxybenzene
on the sides of the reaction flask was observed upon completion
of the reaction, which is also consistent with the Tsuji–Trost
mechanism. However in order to confirm that the formation of
the black solid is not indicative of a palladium nanoparticle
b
1
as an internal standard.
a
Table 2 Optimization of reaction conditions for the formation of 4a
b
Entry
Catalyst (mol%)
Temperature/°C
Time/h
Solvent
Yield (%)
1
2
3
4
5
6
7
8
20
10
10
10
10
10
10
10
110
110
90
80
80
70
70
60
24
24
24
24
24
9
Tol
Tol
71
97
NR
80
84
91
91
NR
ACN
THF
DCE
Tol
DCE
DCE
9
9
a
b
The reaction was carried out with 2-alkynlaniline (0.1 mmol, 1 equiv.), catalyst I (10 mol%) in 2 mL of specified solvent. Yields were determined
1
by H NMR spectroscopy using 1,3,5-trimethoxybenzene as an internal standard.
3876 | Org. Biomol. Chem., 2012, 10, 3875–3881
This journal is © The Royal Society of Chemistry 2012

View Article Online
a
Table 3 Optimization of reaction conditions for the formation of 4a
b
Entry
Catalyst (mol%)
Temperature/°C
Time/h
Yield (%)
1
2
3
4
5
6
7
8
I (10)
II (10)
III (10)
IV (10)
I (10)
I (10)
I (10)
I (5)
70
70
70
70
60
70
70
70
9
9
9
9
9
3
6
9
98
98
NR
18
NR
75
91
64
c
c
a
The reaction was carried out with 2-alkynlaniline (0.1 mmol, 1 equiv.), 1,3-diphenyl-2-propenol (0.1 mmol, 1 equiv.), catalyst, 2 mL of
b
1
c
dichloroethane. Yields were determined by H NMR spectroscopy using 1,3,5-trimethoxybenzene as an internal standard. Almost quantitative
amount of 2a was obtained together with un-reacted allylic alcohol.
catalyzed mechanism, we isolated the black solid and conducted
a fresh reaction. The solid however did catalyze neither the cycli-
zation nor the alkylation step. A blank experiment was also con-
ducted in the absence of the catalyst and it did not yield any
products. Palladium acetate as the catalyst under the reaction
conditions could catalyze the cyclization step but it could not
yield the alkylation product. We also attempted the reaction of 2-
alkynylanilines with 4-phenyl-3-buten-2-ol and cinnamyl
alcohol. Unfortunately, only cyclized products were obtained.
Although a detailed mechanism deserves further investi-
gations, based on the previously reported mechanistic studies a
reaction mechanism as described in Scheme 1 is proposed to
hereo cycle systems as well as work on an asymmetric protocol
are currently underway in our laboratory.
Experimental
All reactions and manipulations were carried out under dry,
oxygen-free nitrogen using the standard Schlenk technique.
NMR spectra were recorded on a Bruker AV 300 spectrometer
1
13
1
(
H at 300 MHz, C at 75 MHz) or a Bruker AV 400 ( H at
13
4
00 MHz, C at 100 MHz). Chemical shifts are given in ppm
and are referenced to the residual solvent peak in the respective
deutero-solvents. HR-MS spectra were obtained in the ESI mode
on a Waters Q-Tof Premier MS system. Solvents were degassed
prior to use when necessary. DCE, toluene, THF, acetone and
acetonitrile were purchased from TEDIA COMPANY (AR) and
used as supplied. Column chromatography was conducted on
Silica gel 60 (Merck).
9
a,15
rationalize the formation of 2,3-substituted indoles.
Firstly,
intramolecular nucleophilic attack by the amino group towards
the Pd-activated C–C triple bond occurs (5), leading to the for-
mation of a palladium intermediate (6). This palladium inter-
mediate undergoes a rapid proton–palladium exchange and
regenerates the catalyst with the formation of indole. Sub-
sequently, the indole as a nucleophile attacks the π-allylpalla-
The four palladacycles catalysts I–IV were prepared by treat-
ing the corresponding chloro-bridged dimeric palladium com-
1
5c
dium intermediate (7),
yielding the 2,3-substituted indole,
16
pounds with silver perchlorate–triflate in acetonitrile via a
which undergoes protonation to form the final product.
17
procedure reported previously. o-Alkynylanilines were pre-
18
pared according to the published procedure. All the other reac-
tants and reagents were used as supplied.
Conclusion
Typical procedure for the palladacycle catalyzed cyclization
of 1a
In conclusion, we have developed a very simple, clean and
atom-efficient protocol for the synthesis of 2,3-substituted
indoles from 2-alkynylanilines and allylic alcohols. The one-pot
domino cyclization–alkylation reaction proceeds under mild con-
ditions with no additives and provides an alternative method to
access 2,3-substituted indoles. The method more importantly
allows the incorporation of hithero unavailable substituents at the
C-3 position of C-2 substituted indoles which have potential for
further functionalization via the CvC bond. Further investi-
gations on the detailed reaction mechanism, extension to other
Compound 1a (19.3 mg, 0.1 mmol), catalyst I (4.9 mg, 10 mol
%), and 2 mL of varying solvents were placed in a 25 mL argon-
filled sealed Schlenk tube and stirred at the given temperature for
the stipulated reaction time. Upon completion of the reaction,
internal standard, 1,3,5-trimethoxybenzene, was added into the
mixture. The reaction mixture was then filtered through celite.
The filtrate was evacuated to dryness and the resulting residue
1
was dissolved in deuterated solvent and analyzed by H NMR
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 3875–3881 | 3877

View Article Online
a
Table 4 Palladacycle catalyzed domino cyclization–alkylation with o-alkynylanilines and allylic alcohols
b
Entry
1
R
1
R
2
Allylic alcohol
Product
Overall yield (%)
H
Ph
3a
98
95
90
94
90
91
2
3
4
5
6
Cl
CN
H
Ph
3a
3a
3a
3a
3b
Ph
4-MePh
4-MePh
Ph
Cl
H
7
Cl
Ph
3b
98
3878 | Org. Biomol. Chem., 2012, 10, 3875–3881
This journal is © The Royal Society of Chemistry 2012

View Article Online
Table 4 (Contd.)
b
Entry
8
R
1
R
2
Allylic alcohol
Product
Overall yield (%)
CN
Ph
3b
96
9
H
4-MePh
4-MePh
3b
3b
94
98
1
0
Cl
a
The reaction was carried out with 2-alkynlaniline (0.1 mmol, 1 equiv.), allylic alcohol (0.1 mmol, 1 equiv.), catalyst I (10 mol%) in 2 mL of
b
1
dichloroethane at 70 °C for 9 h. Overall yields (combined yields of two isomers for entries 6–10) were determined by H NMR spectroscopy using
,3,5-trimethoxybenzene as an internal standard.
1
Scheme 1 Proposed mechanism.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 3875–3881 | 3879

View Article Online
1
spectroscopy with 1,3,5-trimethoxybenzene as an internal stan-
4c: yellow paste (21.7 mg, 53%). H NMR (CDCl3,
300 MHz): δ 8.45 (s, 1H, NH), 7.72–7.26 (m, 18H, Ar), 6.82
(dd, 1H, J = 15.9, 7.2 Hz, CHvCHPh), 6.40 (d, 1H, J = 15.9
dard. The signals due to product 2a were confirmed by compari-
1
9
sons with values obtained from the literature.
13
Hz, CHvCHPh), 5.29 (d, 1H, J = 7.2 Hz, CHCHvCH);
NMR (CDCl , 75 MHz): δ 142.7, 137.9, 137.8, 137.0, 131.8,
31.8, 131.1, 129.1, 128.9, 128.6, 128.6, 128.5, 128.0, 127.6,
27.5, 126.6, 126.5, 126.4, 125.2, 120.8, 114.8, 111.8, 102.9,
C
3
Typical procedure for the palladacycle catalyzed allylic
alkylation of 2a with 3a
1
1
4
+
4.7. HRMS (ESI): calcd for C H N [M + H] : 411.1861;
30 23 2
Compound 2a (19.3 mg, 0.1 mmol), 3a (21.0 mg, 0.1 mmol),
catalyst I (4.9 mg, 10 mol%), and 2 mL of varying solvents were
placed in a 25 mL argon-filled sealed Schlenk tube and stirred at
the given temperature for the stipulated reaction time. Upon
completion of the reaction time, internal standard, 1,3,5-tri-
methoxybenzene, was added and dissolved in the mixture. The
reaction mixture was then filtered through celite. The filtrate was
evacuated to dryness and the resulting residue was dissolved in
found: 411.1859.
4
1
d: pale yellow paste (22.7 mg, 57%). H NMR (CDCl3,
00 MHz): δ 8.04 (s, 1H, NH), 7.43–6.96 (m, 18H, Ar), 6.88
dd, 1H, J = 15.9, 7.2 Hz, CHvCHPh), 6.40 (d, 1H, J = 15.9
Hz, CHvCHPh), 5.27 (d, 1H, J = 7.2 Hz, CHCHvCH), 2.40
s, 3H, Me); C NMR (CDCl , 75 MHz): δ 143.6, 138.0, 137.6,
36.2, 135.7, 132.4, 131.0, 130.1, 129.6, 128.5, 128.5, 128.3,
3
(
13
(
3
1
1
128.3, 127.1, 126.3, 126.1, 122.0, 121.2, 119.7, 113.6, 110.9,
5.2, 21.3. HRMS (ESI): calcd for C H N [M + H] :
30 26
deuterated solvent and analyzed by H NMR spectroscopy with
+
4
1
,3,5-trimethoxybenzene as an internal standard. The signals due
4
00.2065; found: 400.2067.
to product 4a were confirmed by comparisons with values
1
2
0
4e: pale yellow paste (23.4 mg, 54%). H NMR (CDCl3,
00 MHz): δ 8.09 (s, 1H, NH), 7.42–7.09 (m, 18H, Ar), 6.82
obtained from the literature.
4
(dd, 1H, J = 15.6, 7.2 Hz, CHvCHPh), 6.39 (d, 1H, J = 15.6
Typical procedure for the palladacycle catalyzed domino
cyclization–alkylation of 1a with 3a
Hz, CHvCHPh), 5.23 (d, 1H, J = 7.2 Hz, CHCHvCH), 2.41
13
(s, 3H, Me); C NMR (CDCl
1
1
, 100 MHz): δ 143.1, 138.4,
37.4, 137.2, 134.5, 131.7, 131.4, 129.6, 129.6, 129.0, 128.5,
28.5, 128.4, 128.2, 127.2, 126.4, 126.3, 125.2, 122.3, 120.3,
13.4, 111.9, 45.0, 21.3. HRMS (ESI): calcd for C H NCl
3
1
a (19.3 mg, 0.1 mmol), 3a (21.0 mg, 0.1 mmol), an appropriate
amount of varying catalyst as shown in Table 3, as well as 2 mL
of dichloroethane were placed in a 25 mL argon-filled sealed
Schlenk tube and stirred at the given temperature for the stipu-
lated reaction time. Upon completion of the reaction, internal
standard, 1,3,5-trimethoxybenzene, was added and dissolved
into the mixture. The reaction mixture was then filtered through
celite. The filtrate was evacuated to dryness and the resulting
1
30 25
+
[M + H] : 434.1676; found: 434.1679.
1
4
f/f′: pale yellow paste (20.0 mg, 50%). H NMR (CDCl ,
3
3
6
00 MHz): δ 8.10 (s, 1H, NH), 7.55–6.92 (m, 18H, Ar),
.89–6.79 (m, 1H, CHvCHPh), 6.42–6.35 (m, 1H,
CHvCHPh), 5.28–5.23 (m, 1H, CHCHvCH), 2.30 (s, 3H,
13
Me); C NMR (CDCl , 75 MHz): δ 143.6, 140.4, 137.6, 136.9,
3
1
residue was dissolved in deuterated solvent and analyzed by H
NMR spectroscopy with 1,3,5-trimethoxybenzene as an internal
1
1
1
36.3, 135.6, 134.7, 133.0, 132.5, 131.3, 131.0, 130.9, 129.1,
29.0, 128.8, 128.6, 128.4, 128.3, 128.2, 128.2, 128.0, 128.0,
27.1, 126.3, 126.2, 126.1, 122.1, 121.3, 121.3, 120.0, 114.1,
standard. The signals due to the product 4a were confirmed by
2
0
comparisons with values obtained from the literature.
1
10.9, 45.1, 44.8, 21.1, 21.0. HRMS (ESI): calcd for C H N
30 26
+
[M + H] : 400.2065; found: 400.2073.
1
4
g/g′: pale yellow paste (20.8 mg, 48%). H NMR (CDCl ,
3
Typical procedure for the palladacycle catalyzed domino
cyclization–alkylation of o-alkynlanilines with allylic alcohols
4
6
00 MHz): δ 8.13 (s, 1H, NH), 7.54–7.08 (m, 18H, Ar),
.84–6.74 (m, 1H, CHvCHPh), 6.41–6.35 (m, 1H,
o-Alkynylaniline (0.1 mmol,
1
equiv.), allylic alcohol
CHvCHPh), 5.24–5.20 (m, 1H, CHCHvCH), 2.32–2.32 (m,
13
(0.1 mmol, 1 equiv.), catalyst I (10 mol%), and 2 mL of dichloro-
3H, Me); C NMR (CDCl , 100 MHz): δ 143.2, 139.9, 137.4,
3
ethane were placed in a 25 mL argon-filled sealed Schlenk tube
and stirred at 70 °C for 9 h. Upon completion of the reaction
time, internal standard, 1,3,5-trimethoxybenzene, was added and
dissolved into the mixture. The reaction mixture was then filtered
through celite. The filtrate was evacuated to dryness and the
resulting residue was dissolved in deuterated solvent and ana-
137.1, 137.0, 137.0, 135.8, 134.6, 134.6, 132.5, 131.9, 127.2,
126.4, 126.3, 125.2, 122.5, 120.5, 120.4, 113.9, 111.9, 44.9,
+
44.6, 21.2, 21.0. HRMS (ESI): calcd for C H NCl [M + H] :
30 25
434.1676; found: 434.1688.
1
4h/h′: yellow paste (17.8 mg, 42%). H NMR (CDCl3,
400 MHz): δ 8.43 (s, 1H, NH), 7.73–7.09 (m, 18H, Ar),
6.83–6.73 (m, 1H, CHvCHPh), 6.41–6.35 (m, 1H,
CHvCHPh), 5.28–5.23 (m, 1H, CHCHvCH), 2.33–2.32 (m,
1
lyzed by H NMR spectroscopy with 1,3,5-trimethoxybenzene
as an internal standard. The analytically pure products were
13
obtained by flash chromatography using hexane–DCM.
3H, Me); C NMR (CDCl , 100 MHz): δ 142.8, 139.5, 137.9,
3
1
4
b: pale yellow paste (25.9 mg, 62%). H NMR (CDCl3,
137.7, 137.7, 137.3, 137.1, 136.1, 134.3, 131.8, 131.7, 131.6,
131.4, 130.1, 129.3, 129.3, 129.1, 128.8, 128.6, 128.6, 128.5,
128.3, 128.1, 127.9, 127.7, 127.4, 126.6, 126.6, 126.4, 126.3,
126.0, 125.1, 120.8, 120.8, 115.0, 111.8, 102.8, 102.8, 44.7,
3
00 MHz): δ 8.14 (s, 1H, NH), 7.53–7.11 (m, 18H, Ar), 6.83
(
dd, 1H, J = 15.9, 7.5 Hz, CHvCHPh), 6.41 (d, 1H, J = 15.8
13
Hz, CHvCHPh), 5.25 (d, 1H, J = 7.2 Hz, CHCHvCH);
C
+
NMR (CDCl , 75 MHz): δ 143.0, 137.3, 137.0, 134.6, 132.5,
44.4, 21.2, 21.0. HRMS (ESI): calcd for C H N [M + H] :
3
31 25
2
1
1
31.6, 131.5, 128.9, 128.6, 128.5, 128.4, 128.2, 127.3, 126.4,
425.2018; found: 425.2030.
4i/i′: pale yellow paste (21.5 mg, 52%). H NMR (CDCl ,
300 MHz): δ 8.11 (s, 1H, NH), 7.49–7.02 (m, 18H, Ar),
1
25.3, 122.5, 120.4, 113.7, 111.9, 44.9. HRMS (ESI): calcd for
3
+
C H NCl [M + H] : 420.1519; found: 420.1527.
2
9 23
3880 | Org. Biomol. Chem., 2012, 10, 3875–3881
This journal is © The Royal Society of Chemistry 2012

View Article Online
6
.90–6.84 (m, 1H, CHvCHPh), 6.43–6.39 (m, 1H,
6 D. McAusland, S. Seo, D. G. Pintori, J. Finlayson and M. F. Greaney,
Org. Lett., 2011, 13, 3667–3669.
CHvCHPh), 5.30–5.26 (m, 1H, CHCHvCH), 2.45 (s, 3H,
Me), 2.35 (s, 3H, Me); C NMR (CDCl , 75 MHz): δ 143.7,
7
Y. Huang, S. A. Pullarkat, Y. Li and P. H. Leung, Chem. Commun., 2010,
46, 6950–6952.
1
3
3
1
1
1
1
40.5, 138.0, 137.7, 136.8, 136.2, 135.7, 135.6, 135.5, 134.8,
32.6, 131.4, 130.9, 130.8, 130.1, 129.5, 129.1, 129.0, 128.5,
28.4, 128.3, 128.2, 128.2, 128.0, 127.0, 126.3, 126.2, 126.0,
21.9, 121.2, 121.2, 119.6, 113.7, 110.8, 45.2, 44.9, 21.3, 21.2,
8 K. Chen, Y. Li, S. A. Pullarkat and P. H. Leung, Adv. Synth. Catal., 2011,
54, 83–87.
3
9
For selected reviews see: (a) G. R. Humphrey and J. T. Kuethe, Chem.
Rev., 2006, 106, 2875–2911; (b) S. Cacchi and G. Fabrizi, Chem. Rev.,
2005, 105, 2873–2920.
+
2
1.0. HRMS (ESI): calcd for C H N [M + H] : 414.2222;
10 For some selected examples see: (a) N. Sakai, K. Annaka and
T. Konakahara, Org. Lett., 2004, 6, 1527–1530; (b) X. Li,
A. R. Chianese, T. Vogel and R. H. Crabtree, Org. Lett., 2005, 7, 5437–
3
1 28
found: 414.2222.
1
4
j/j′: pale yellow paste (22.4 mg, 50%). H NMR (CDCl ,
3
5
440; (c) R. A. Widenhoefer and X. Han, Eur. J. Org. Chem., 2006,
4555–4563; (d) Y. Zhang, J. P. Donahue and C.-J. Li, Org. Lett., 2007, 9,
27–630; (e) K. Okuma, J.-I. Seto, K.-I. Sakaguchi, S. Ozaki,
N. Nagahora and K. Shioji, Tetrahedron Lett., 2009, 50, 2943–2945.
3
6
00 MHz): δ 8.09 (s, 1H, NH), 7.41–7.10 (m, 18H, Ar),
.80–6.73 (m, 1H, CHvCHPh), 6.41–6.34 (m, 1H,
6
CHvCHPh), 5.23–5.18 (m, 1H, CHCHvCH), 2.41 (s, 3H,
Me), 2.32 (s, 3H, Me); C NMR (CDCl , 75 MHz): δ 143.2,
1
1
1
1
1 For selected reviews see: (a) M. Bandini, A. Melloni and A. Umani-
Ronchi, Angew. Chem., Int. Ed., 2004, 43, 550–556; (b) M. Bandini,
A. Melloni, S. Tommasi and A. Umani-Rochi, Synlett, 2005, 1199–1222;
1
3
3
40.0, 138.3, 137.1, 137.1, 137.0, 135.7, 134.6, 134.5, 132.0,
31.3, 131.2, 130.7, 129.6, 129.2, 129.1, 129.0, 128.5, 128.3,
28.2, 128.0, 127.2, 126.3, 126.2, 125.1, 122.3, 120.3, 113.5,
(c) S.-L. You, Q. Cai and M. Zeng, Chem. Soc. Rev., 2009, 38, 2190–
2201; (d) M. Zeng and S.-L. You, Synlett, 2010, 1289–1301.
1
2 For selected examples see: (a) J. C. Antilla, A. Klapars and
S. L. Buchwald, J. Am. Chem. Soc., 2002, 124, 11684–11688;
(b) M. Kimura, M. Futamata, R. Mukai and Y. Tamaru, J. Am. Chem.
Soc., 2005, 127, 4592–4593; (c) Z. Liu, L. Liu, Z. Shafiq, Y.-C. Wu,
D. Wang and Y.-J. Chen, Tetrahedron Lett., 2007, 48, 3963–3967;
111.8, 44.9, 44.6, 21.3, 21.2, 21.0. HRMS (ESI): calcd for
+
C H NCl [M + H] : 448.1832; found: 448.1835.
3
1 27
(
2
d) N. Kagawa, J. P. Malerich and V. H. Rawal, Org. Lett., 2008, 10,
381–2384; (e) T. Hoshi, K. Sasaki, S. Sato, Y. Ishii, T. Suzuki and
Acknowledgements
H. Hagiwara, Org. Lett., 2011, 13, 932–935.
3 T. Hirashita, S. Kuwahara, S. Okochi, M. Tsuji and S. Araki, Tetrahedron
Lett., 2010, 51, 1847–1851.
We gratefully acknowledge the Ministry of Education, Singapore
for financial support (MOE2009-T2-2-065) and the Nanyang
Technological University for a research scholarship to XC.
1
14 A. V. Malkov, S. L. Davis, I. R. Baxendale, W. L. Mitchell and
P. K očovský, J. Org. Chem., 1999, 64, 2751–2764.
5 (a) X. Li, J.-Y. Wang, W. Yu and L.-M. Wu, Tetrahedron, 2009, 65,
1
1
6
140–1146; (b) S. Norsikian and C.-W. Chang, Curr. Org. Synth., 2009,
, 264–289; (c) M. Kimura, M. Futamata, R. Mukai and Y. Tamaru,
J. Am. Chem. Soc., 2005, 127, 4592–4593.
References
1
(a) G. R. Humphrey and J. T. Kuethe, Chem. Rev., 2006, 106, 2875–
911; (b) S. Cacchi and G. Fabrizi, Chem. Rev., 2005, 105, 2873–2920.
(a) M. Bandini, A. Melloni and A. Umani-Ronchi, Org. Lett., 2004, 6,
199–3202; (b) S. Whitney, R. Grigg, A. Derrick and A. Keep, Org.
2
16 For the synthesis of corresponding dimeric palladium complex of I and
II, see: (a) D. G. Allen, G. M. McLaughlin, G. B. Robertson,
W. L. Steffen, G. Salem and S. B. Wild, Inorg. Chem., 1982, 21, 1007–
1014. However, using non-chiral amine instead of chiral amine as starting
material. For the synthesis of corresponding dimeric palladium complex
of III and IV, see: (b) A. C. Cope and E. C. Friedrich, J. Am. Chem. Soc.,
1968, 90, 909–913.
17 S. Y. M. Chooi, P.-H. Leung, C. C. Lim, K. F. Mok, G. H. Quek,
K. Y. Sim and M. K. Tan, Tetrahedron: Asymmetry, 1992, 3, 529–
532.
18 A. S. K. Hashmi, T. D. Ramamurthi and F. Rominger, Adv. Synth. Catal.,
2010, 352, 971–975.
19 A. Carpita, A. Ribecai and P. Stabile, Tetrahedron, 2010, 66, 7169–7178.
20 H. Y. Cheung, W.-Y. Yu, F. L. Lam, T. T.-L. Au-Yeung, Z. Zhou,
T. H. Chan and A. S. C. Chan, Org. Lett., 2007, 9, 4295–4298.
2
3
Lett., 2007, 9, 3299–3302; (c) S. Baehn, S. Imm, K. Mevius, L. Neubert,
A. Tillack, J. M. J. Williams and M. Beller, Chem.–Eur. J., 2010, 16,
3
590–3593; (d) R. Sanz, D. Miguel, A. Martínez, M. Gohain, P. García-
García, M. A. Fernández-Rodríguez, E. Álvarez and F. Rodríguez,
Eur. J. Org. Chem., 2010, 7027–7039; (e) Y. L. Hu, H. Jiang and M. Lu,
Green Chem., 2011, 13, 3079–3087.
3
4
5
A. Yasuhara, Y. Takeda, N. Suzuki and T. Sakamoto, Chem. Pharm.
Bull., 2002, 50, 235–238.
B. Z. Lu, W. Zhao, H.-X. Wei, M. Dufour, V. Farina and
C. H. Senanayake, Org. Lett., 2006, 8, 3271–3274.
A. Cabrera, P. Sharma, M. Ayala, L. Rubio-Perez and M. Amézquita-
Valencia, Tetrahedron Lett., 2011, 52, 6758–6762.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 3875–3881 | 3881