Palladium-catalyzed cyclization/cyclopropanation reaction for the synthesis of fused N-containing heterocycles

Article abstract of DOI:10.1016/j.tetlet.2009.09.156

Palladium-catalyzed cyclization/cyclopropanation can be used to convert a range of substituted cyclic N-aryl allyl/methallyl amines efficiently and selectively to the corresponding fused tetrahydropyridine/cyclopropane-fused isoquinoline derivatives via β

Full text of DOI:10.1016/j.tetlet.2009.09.156

Tetrahedron Letters 50 (2009) 6993–6997
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Palladium-catalyzed cyclization/cyclopropanation reaction for the synthesis
of fused N-containing heterocycles
*
Sukla Nandi, Jayanta K. Ray
Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 16 July 2009
Revised 23 September 2009
Accepted 26 September 2009
Available online 1 October 2009
Palladium-catalyzed cyclization/cyclopropanation can be used to convert a range of substituted cyclic
N-aryl allyl/methallyl amines efficiently and selectively to the corresponding fused tetrahydropyridine/
cyclopropane-fused isoquinoline derivatives via b-hydrogen elimination or a domino sequence.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Heterocycles
Tetrahydropyridine
Cyclopropanation
Intramolecular Heck reaction
Among numerous approaches towards the synthesis of hetero-
cycles as well as carbocycles, the palladium-catalyzed cyclization/
cyclopropanation has proven to be a novel and versatile method.1–3
Since several reactions take place in a sequential fashion, cyclo-
propanation can be used for the synthesis of polycyclic organic
molecules. Fused cyclopropane moiety is a basic unit of biologi-
cally active natural products such as CC-1065 and duocarmycin.4
The construction of substituted pyridine frameworks has also been
used by numerous groups in the total synthesis of alkaloids and
other nitrogen containing natural products such as decumbenine
B,5 carnegine,6 antidesma7 and krukovine.8 Lamellarin D, which is
one of the most potent lead candidates for anticancer chemother-
apy and is an inhibitor of topoisomerase I, can also be synthesized
using the Heck reaction.9
Based on these reports we have developed a methodology for
the synthesis of fused tetrahydropyridine derivatives via a palla-
dium-catalyzed intramolecular Heck reaction10 of substituted
cyclic derivatives of N-aryl allyl amine (5a–5j) and cyclopropane-
fused isoquinoline derivatives via palladium-catalyzed cyclopropa-
nation11–14 of N-aryl methallyl amines (6a–6f).
get bromomethylvinyl bromides 3. On the other hand monoallyla-
tion of aniline derivatives was achieved from 4-substituted ani-
lines and allyl bromides by using KF-Celite in CH3CN at reflux
temperature. After this, bromomethylvinyl bromides 3 were alkyl-
ated with monoallylated aniline derivatives 4 in the presence of
Et3N in DMF at 60 °C to get the precursors 5 and 6 for the Heck
reaction (Scheme 1).
The precursors 5a–5j on reaction with Pd(OAc)2 (10 mol %),
PPh3 (0.25 equiv) and Cs2CO3 (1.2 equiv) in DMF (6 mL) at 90–
100 °C yielded the fused tetrahydropyridine derivatives 7a–7j
(Table 1) in excellent yield15 via 6-exo-trig cyclization (Scheme 2).
But when N-methallylated derivatives 6a–6f were subjected to
the Heck reaction under the same reaction conditions15 they gave
cyclopropa[d]fused isoquinoline derivatives 8a–8f (Scheme 3,
Table 2).
A plausible rationale for the formation of the products (8a–8f) is
shown in Scheme 4. At first an alkenyl palladium intermediate is
formed by oxidative addition of Pd(0) to the sp2 C–Br bond which
undergoes addition to the unactivated double bond to produce an
alkylpalladium which is again added to the unactivated double
bond followed by b-H elimination to afford the cyclopropane-fused
compounds16–18 (Scheme 4).
Both electron-donating and electron-withdrawing substituents
are compatible with this reaction except the nitro group. These reac-
tions can also be performed with acetonitrile as a solvent and Et3N as
a base. A reaction temperature of 100 °C and a time of 5–6 h were
found to be optimum. Lower temperatures and shorter reaction
times lead to incomplete conversion of the starting materials to
the products.
The starting materials for this palladium-catalyzed reaction
were prepared by alkylation of bromomethylvinyl bromides 3 with
monoallylated aniline derivatives 4. At first the bromovinyl alde-
hydes 1 were reduced to get bromomethylvinyl alcohols 2 with
NaBH4 in CH3CN at room temperature (25–30 °C). Then these bro-
momethylvinyl alcohols 2 were brominated using PBr3 in CCl4 to
* Corresponding author.
E-mail address: jkray@chem.iitkgp.ernet.in (J.K. Ray).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.156

6994
S. Nandi, J. K. Ray / Tetrahedron Letters 50 (2009) 6993–6997
CHO
Br
Br
OH
NaBH4 (2 equiv.)
CH3CN, rt.
PBr3 (0.5 equiv.)
CCl4, rt.
(1 mmol)
Cl
Br
Br
1
3
2
85-95%
90-95%
TEA
(1.2 mmol),
N
DMF, 60 oC
2 h
R
R
NH2
N
R
Br
HN
(1 mmol),
Br
R
R
5 R = H
6 R = Me
80-85%
+
KF-celite (1.25 mmol),
CH3CN, reflux
R = H, Me
(1 mmol)
4
X
X
10%
X
90%
X = Cl, CH3, F
1.2 mmol
Scheme 1. Alkylation of bromomethylvinyl bromides with monoallylated aniline derivatives.
Table 1
Pd(0)-catalyzed intramolecular reaction of N-aryl allyl derivative 5
Entry
Substrate
Product
Time (h)
Yield (%)
82
Br
N
Cl
1
5
N
Cl
7a
5a
Br
N
2
5.5
80
N
7b
5b
Cl
Cl
N
N
3
4
5
6
5
90
85
88
80
Br
5c
7c
CH3
CH3
N
N
5
Br
5d
7d
Br
6
N
Cl
N
Cl
7e
5e
Br
N
5.5
N
7f
5f

S. Nandi, J. K. Ray / Tetrahedron Letters 50 (2009) 6993–6997
6995
Table 1 (continued)
Entry
Substrate
Product
Time (h)
Yield (%)
Br
7
5
90
N
N
7g
Cl
Cl
5g
Cl
Cl
Br
N
N
8
6
81
80
85
7h
5h
CH3
CH3
Br
N
N
9
6
7i
5i
Cl
N
Cl
N
10
5.5
Br
7j
5j
X
X
N
Pd(OAc)2, PPh3
Cs2CO3, DMF
N
In conclusion, we have developed a general methodology for the
synthesis of fused tetrahydropyridine derivatives and cyclopro-
pane-fused compounds by a palladium-catalyzed domino reaction.
This methodology can also be used for the synthesis of various
types of nitrogen containing natural products and other heterocy-
clic compounds.
Br
90-100 o
C
5
7
80-90%
X = Cl, CH3
Scheme 2. Pd(0)-catalyzed intramolecular cyclization of N-aryl allyl derivative 5.
X
X
R1
R1
N
Pd(OAc)2, PPh3
N
Br
Cs2CO3, DMF
90-100 oC
R1 = H, Me
X = F, Cl
6
8
70-80%
Scheme 3. Pd(0)-catalyzed intramolecular cyclization of N-aryl methallyl derivative 6. Reagents and conditions: 5a–5j (1 equiv), Pd(OAc)2 (10 mol %), PPh3 (0.25 equiv),
Cs2CO3 (1.2 equiv), DMF, 90–100 °C.

6996
S. Nandi, J. K. Ray / Tetrahedron Letters 50 (2009) 6993–6997
Table 2
Pd(0)-catalyzed intramolecular reaction of N-aryl methallyl derivative 6
Entry Substrate
Product
Time (h)
Yield (%)
Cl
Cl
N
N
1
5
80
Br
6a
8a
2
3
4
5
6
2.5
73
75
70
65
66
N
N
N
Br
Br
6b
8b
8c
F
F
N
5
6c
Cl
Cl
H3C
H3C
N
N
6
Br
6d
8d
H3C
H3C
6
N
N
N
Br
6e
8e
8f
F
F
H3C
H3C
N
5.5
Br
6f
N
Pd(0)
N
N
Br
PdBr
BrPd
PdBr
-Pd(0)
-HBr
N
N
Scheme 4. A plausible rationale for the Pd(0)-catalyzed cyclopropanation reaction. Reagents and conditions: 6a–6f (1 equiv), Pd(OAc)2 (10 mol %), PPh3 (0.25 equiv), Cs2CO3
(1.2 equiv), DMF, 90–100 °C.

S. Nandi, J. K. Ray / Tetrahedron Letters 50 (2009) 6993–6997
6997
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Acknowledgements
12. Brown, D.; Grigg, R.; Sridharan, V.; Tambyrajah, V.; Trornton-Pett, M.
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Financial support from CSIR is gratefully acknowledged. D.S.T. is
also thanked for providing funds for the project and creating
400 MHz NMR facility under the IRPHA programme.
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Supplementary data
15. Typical experimental procedure for the Heck reaction: Compounds
5 or 6
(1 equiv), Pd(OAc)2 (10 mol %), PPh3 (0.25 equiv), Cs2CO3 (1.2 equiv) and DMF
(6 mL) were placed in a two-neck round-bottomed flask. After degassing with
N2, the mixture was heated at 90–100 °C for 5 h. After cooling, the reaction
mixture was diluted with cold water and extracted with ether (30 mL Â 3) and
the combined organic layers were dried over anhydrous Na2SO4. The solvent
was evaporated and the crude product was purified by preparative thin layer
chromatography.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.09.156.
References and notes
Spectral data of representative compounds: 2-(4-Chloro-phenyl)-4-methylene-
1,2,3,4,5,6-hexahydro-benzo[h]isoquinoline (7j): Yellow liquid, 1H NMR
(CDCl3, 200 MHz) d: 2.50 (t, 2H, J = 8.4 Hz), 2.84 (t, 2H, J = 8.2 Hz), 4.01 (s,
2H), 4.23 (s, 2H), 5.05 (s, 1H), 5.25 (s, 1H), 6.97 (dd, 2H, J1 = 2.0 Hz, J2 = 8.8 Hz),
7.18–7.25 (m, 6H); 13C NMR (CDCl3, 100 MHz) d: CH2 at 22.25, 27.77, 50.04,
53.36, 109.05, CH at 117.65 (2C), 121.84, 126.50, 127.27, 127.50, 128.94 (2C),
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3-(4-Chloro-phenyl)-1a-methyl-1,1a,2,3,4,6,7,8-octahydro-3-aza-cyclopropa[d]naph-
thalene (8a): Yellow liquid, 1H NMR (CDCl3, 200 MHz) d: 0.29 (d, 1H, J = 4.6 Hz),
1.16 (d, 1H, J = 4.6 Hz), 1.19 (s, 3H), 1.68–1.78 (m, 4H), 2.09 (br s, 2H), 3.07 (d,
1H, J = 12 Hz), 3.51 (t, 2H, J = 11.6 Hz), 3.82–3.92 (m, 1H), 5.59–5.63 (m, 1H),
6.63 (dd, 2H, J1 = 2.0 Hz, J2 = 7 Hz), 7.15 (dd, 2H, J1 = 2.2 Hz, J2 = 6.8 Hz); 13C
NMR (CDCl3, 100 MHz) d: CH3 at 17.28, CH2 at 21.84, 22.20, 25.27, 28.96, 51.0,
51.96, CH at 113.97 (2C), 121.36, 128.72 (2C), qC at 23.90, 25.40, 121.53,
134.24, 148.48; Anal. Calcd for C17H20ClN: C, 74.57; H, 7.36; N, 5.12. Found: C,
74.69; H, 7.49; N, 4.99; HRMS calcd for C17H21ClN [M++H]: 274.1363, found:
274.1355.
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