Synthesis of heterocycles via ligand-free palladium catalyzed reductive Heck cyclization

Article abstract of DOI:10.1016/j.tetlet.2007.01.156

Synthesis of five and six membered heterocycles, indolines, 2,3-dihydrobenzofurans, chromans, isochromans, 1,2,3,4-tetrahydroquinolines, and 1,2,3,4-tetrahydroisoquinolines, in 70-99% yield by a ligand-free palladium catalyzed reductive Heck cyclization of phenyl bromides and chlorides, under mild conditions, is reported. Water was found to be essential for these reactions.

Full text of DOI:10.1016/j.tetlet.2007.01.156

Tetrahedron Letters 48 (2007) 2307–2310
Synthesis of heterocycles via ligand-free palladium
catalyzed reductive Heck cyclization
Pingli Liu,* Liang Huang, Yuelie Lu, Mina Dilmeghani, Jean Baum, Tingjian Xiang,
Jeff Adams, Andrew Tasker, Rob Larsen and Margaret M. Faul
Chemical Process R&D, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States
Received 22 December 2006; revised 25 January 2007; accepted 29 January 2007
Available online 2 February 2007
Abstract—Synthesis of five and six membered heterocycles, indolines, 2,3-dihydrobenzofurans, chromans, isochromans, 1,2,3,4-
tetrahydroquinolines, and 1,2,3,4-tetrahydroisoquinolines, in 70–99% yield by a ligand-free palladium catalyzed reductive Heck
cyclization of phenyl bromides and chlorides, under mild conditions, is reported. Water was found to be essential for these reactions.
Ó 2007 Elsevier Ltd. All rights reserved.
The presence of indoline, 2,3-dihydrobenzofuran, iso-
chroman, chroman, isochromene, 1,2,3,4-tetrahydro-
Reductive amination10 of aldehyde 1 with 2-methylallyl-
amine, in MeOH, followed by protection of the second-
ary amine with tert-butyl dicarboxylate afforded Boc
protected amines 2 in 86–90% overall yield.
quinoline, and 1,2,3,4-tetrahydroisoquinoline in
a
variety of natural products and therapeutic agents has
resulted in the development of several strategies for their
preparation.1 The most common synthetic methods
include2 Bronsted or Lewis acid catalyzed electrophilic
cyclizations on electronic rich aromatic rings,3 radical
cyclization,4 olefin metathesis,5 tetrahydrothiophene
catalyzed sulfonium ylide annulation,6 and metal cata-
lyzed cyclization.7 However, no general method to
access all these heterocycles is available, particularly
those containing quaternary carbon centers.
1]
H2N
Me
R1
R2
X
R1
R2
X
MeOH,rt
Boc
N
ð1Þ
2] NaBH4, MeOH
3] (Boc)2O, THF/NaOH
86 - 90%
CHO
Me
2, X = Br, Cl
3, X = H
1
Phenyl iodides are generally employed in the palladium
catalyzed Heck and reductive Heck cyclization reac-
tion.8 The use of readily available phenyl bromides or
chlorides to construct heterocyclic compounds by a
reductive Heck cyclization protocol would be attrac-
tive.9 In this manuscript, we report a practical, ligand-
free palladium catalyzed reductive cyclization reaction
on phenyl bromides and chlorides for the synthesis of
indoline, 2,3-dihydrobenzofuran, isochroman, chroman,
isochromene, 1,2,3,4-tetrahydroquinoline, and 1,2,3,4-
tetrahydroisoquinoline heterocycles. The reaction was
robust in the presence of water, and was successful with
electron-neutral, electron-donating and electron-defi-
cient groups on the aromatic ring.
Synthesis of cyclization precursors to prepare indolines,
2,3-dihydrobenzofurans, isochromans, chromans,
1,2,3,4-tetrahydroquinolines, and isochromene is repre-
sented in Eq. 2. Deprotonation of a carbamate, acetate,
phenol, benzenethiol, or benzyl alcohol 4 with base
(NaH, t-BuOK), followed by alkylation with an alkenyl
bromide or mesylate in DMF afforded 5 in 80–93% yield.
X2
R3
n
n = 1, 2
R1
R2
X1
Y
R1
R2
X1
Y
X2 = Br, OMs
Z
base, DMF,rt
80 - 93%
( )n R3
ð2Þ
4
5
R3 = H, CH3; X1 = Br, Cl
Y = O; NHBoc; NHAc; Z = CH2
Y = CH2; Z = O; n = 1,0
Y = OH; CH2OH;
NHBoc; NHAc
Synthesis of the cyclization precursors to prepare
1,2,3,4-tetrahydroisoquinolines is represented in Eq. 1.
*
Corresponding author. E-mail: pliu@amgen.com
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.01.156

2308
P. Liu et al. / Tetrahedron Letters 48 (2007) 2307–2310
The reductive cyclization reaction was initially evaluated
with olefin 2a (Eq. 3, Table 1, entry 1) using Jeffery’s
conditions9a and HCO2Na as reducing agent. Treatment
of 2a with Pd(OAc)2 (0.5 mol %),11 NaOAc (2.5 equiv),
HCO2Na (1.2 equiv), and Et4NClÆH2O (1.2 equiv) in
N,N-dimethylformamide at 85–95 °C under nitrogen
for 1–4 h provided tert-butyl 4,4-dimethyl-3,4-dihydro-
iso-quinoline-2(1H)-carboxylate 6a in 95% isolated
yield. Et4NClÆH2O was better than n-Bu4NCl and n-
Bu4NBr. In the absence of Et4NClÆH2O, the reaction
afforded <10% 6a. Water was essential for the reaction
and up to 5% water in DMF was tolerated. Excess water
was detrimental to the cyclization. Using 25% water in
DMF the reaction was sluggish and unknown impurities
were generated. Under anhydrous conditions, the major
product was the reductive dehalogenation compound 3.
Pd(OAc)2 0.5 mol % proved optimal, since with high
palladium loading (10 mol %) the reaction sometimes
stalled and palladium black precipitated from the reac-
tion mixture. These results are in accordance with gener-
ation of palladium nano-particles that are the actual
palladium pre-catalysts for the reductive Heck reac-
tion.12 Ammonium salts are reported as palladium
nano-particle stabilizing agents.13
substrates 2d and 5c was presumably due to the strong
electron-withdrawing effect of the p-nitro group on the
Ar–Cl bond that accelerates the rate of palladium oxida-
tive insertion, since reaction of 5d, the nitro free analog
of 5c, only gave ca. 6% conversion to 7d (entry 4).
To address the low reactivity of phenyl chlorides under
reductive Heck conditions in the absence of an activating
group on the aromatic ring, we evaluated the phosphine
free catalyst system reported by Buchwald that has
proved effective in coupling activated olefins with both
electron-donating and electron-deficient phenyl iodides
and bromides.15 Application of these conditions to 5d,
provided 7d in 87% yield (Table 2, entry 5). Upon further
development of this chemistry we found that the
palladium-phosphinous acid complexes [(t-Bu)2P(OH)]2-
PdCl2, [(t-Bu)2P(OH)(t-Bu)]2PdCl2, and [(t-Bu)2P(OH)-
PdCl2]2,16,17 developed by Li, afforded a 99% yield of
7d (entry 6). This chemistry was also successful in prep-
aration of 2,3-dihydrobenzofuran 7e in 70% yield from
5e (entry 7). Attempts to prepare benzo[b]thiophene 7f
failed, presumably due to poisoning of palladium by
sulfur (entry 8).18
R1
R2
Me
R1
R2
X
Y
The same reaction conditions were successfully applied
to the synthesis of substituted 1,2,3,4-tetrahydroiso-
quinolines 6b–d in 72–92% yield (Table 1, entries 2–4).
Interestingly under the ligand-free reductive cyclization
conditions, electron-neutral (entry 1), electron-donating
(entry 2), and electron-deficient (entries 3 and 4) sub-
strates, all gave good to excellent yields of the desired
products 6. Incorporation of a p-NO2 group on the
aromatic ring, substrate 2d afforded 6d in 92% yield
(entry 4). This reaction has been reproduced on a 10 g
scale.
Pd-Cat,
Me
Me
ð4Þ
Base/HCO2Na
Y
7a-f
Y = NAc, NBoc, O
5a-f
X = Br, Cl
Y = NAc, NBoc, O, S
Table 2. Synthesis of indolines and 2,3-dihydrobenzofuran 7 (Eq. 4)a
Entry
5
X
Y
R1, R2
Yield 7b (%)
1
2
3
4
5
6
7
8
a
b
c
d
d
d
e
f
Br
Br
Cl
Cl
Cl
Cl
Br
Br
NBoc
NAc
NAc
NAc
NAc
NAc
O
H, H
90
94
92
6
87c
99d
70
H, NO2
H, NO2
H, H
H, H
H, H
Pd(OAc)2
Me Me
NaOAc/HCO2Na
R1
R2
X
R1
Et4NCl. H2O
Me
ð3Þ
NBoc
NBoc
DMF
R2
H, H
H, H
85 oC ~ 95 oC
S
Mixture
2a-d
6a-d
a Reactions were performed with 0.5–2.0 g of substrates in 5–20 mL
DMF [0.1 g/mL] under nitrogen. All products exhibit satisfactory
spectroscopic and physical properties.
Table 1. Synthesis of 1,2,3,4-tetrahydroisoquinoline 6 (Eq. 3)a
Entry
2
X
R1, R2
Yield 6b (%)
b Isolated yield of purified products.
c Reaction performed using Pd(OAc)2, Cy2NMe, Et4NCl, HCO2Na,
DMAc, 100 °C, 2 h.
1
2
3
4
a
b
c
Br
Br
Br
Cl
H, H
–O(CH2)2O–
H, F
95
72
83
92
d Reaction performed using [(t-Bu)2P(OH)PdCl2]2, Cs2CO3, HCO2Na,
DMAc, 100 °C, 4 h.
d
H, NO2
a Reactions were performed with 0.5–2.0 g of substrate in 5–20 mL
DMF [0.1 g/mL] under nitrogen. All products exhibit satisfactory
spectroscopic and physical properties.
Finally the reaction scope was expanded to the synthesis
of chromans, isochromans, and 1,2,3,4-tetrahydroquino-
lines in 91–97% yield (Eq. 5, Table 3, entries 1–6).
Again, the reductive cyclization of 5 afforded the desired
product 7 regardless of whether the substrate was elec-
tron-neutral, electron-donating or electron-deficient.19
b Isolated yield of purified products.
Indolines and 2,3-dihydrobenzofurans were also pre-
pared using similar conditions (Eq. 4, Table 2). The
NBoc derivative 5a afforded 7a in 90% yield (entry 1).
Similarly the N-acetyl analog 5b, derived from 2-bromo-
nitro aniline, afforded 7b in 94% yield (entry 2). As
observed with 2d, this reaction was also successful with
the corresponding chloro analog 5c, affording 7c in 92%
yield (entry 3).14 The high reactivity observed with
Pd(OAc)2
Me Me
NaOAc/HCO2Na
Et4NCl. H2O
R1
R2
Br
Y
R1
ð5Þ
Z
Z
DMF
Me
R2
Y
85 oC ~ 95 oC
5g-l
7g-l

P. Liu et al. / Tetrahedron Letters 48 (2007) 2307–2310
2309
Table 3. Synthesis of chromans and 1,2,3,4-tetrahydroquinolines 7
L. E. Chem. Rev. 2003, 103, 2945–2964; (c) Geen, G. R.;
Evans, J. M.; Vong, A. K. In Comprehensive Heterocyclic
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(Eq. 5)a
Entry
5
Y
Z
R1, R2
Yield 7b (%)
1
2
3
4
5
6
g
h
i
NHBoc
O
O
CH2
CH2
CH2
CH2
CH2
CH2
O
O
O
H, H
H, H
CN, H
H, H
–O(CH2)2O–
H, F
96
91
96
91
97
97
j
k
l
a Reactions were performed with 0.5 g of substrate in 5 mL of DMF
[0.1 g/mL] under nitrogen. All products exhibit satisfactory spec-
troscopic and physical properties.
b Yield refers to isolated yield of purified products.
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Pd
O
Pd(OAc)2
NaOAc/HCO2Na
Et4NCl.H2O
Br
Reduction
slow
O
O
DMF
85 - 95oC
74%
8
8a
8b
8d
fast
β-H elimination
Pd
isomerization
O
O
8c
Scheme 1.
Interestingly, substrate 8 provided Heck product 8d,
rather than the reductive cyclization product 8b, even
with HCO2Na as reducing agent (Scheme 1).20 Product
8b could not be detected in the reaction mixture. We
speculated that 8 first underwent palladium catalyzed
oxidative addition and subsequently palladium migra-
tory insertion to afford 8a; the b-hydride elimination
of 8a to provide 8c was faster than competing hydride
reduction of 8a–8b. The exo-alkene intermediate 8c
isomerized under the reaction conditions to give the
thermodynamically more stable 8d as the final product
in 74% isolated yield. Without HCO2Na, palladium cat-
alyzed Heck cyclization of 8 afforded 8d but with a
slower reaction rate. We speculate that HCO2Na might
serve as the reducing agent facilitating the generation of
palladium(0) nano-particles from Pd(OAc)2 under the
reaction conditions.
In summary, we have developed a general ligand-free
palladium catalyzed reductive Heck reaction that can
be applied to the synthesis of a variety five and six
membered heterocycles in 70–99% yield. The chemistry
is robust and easy to perform on scale.
Acknowledgments
Dr. Michael Martinelli, Dr. John Ng, and Dr. Shawn
Eisenberg are acknowledged for providing helpful sug-
gestions. Dr. Paul Schnier and Mr. Samuel Thomas
are acknowledged for their assistance in obtaining
HRMS.
References and notes
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2310
P. Liu et al. / Tetrahedron Letters 48 (2007) 2307–2310
11. For small scale reactions 1 mol % Pd(OAc)2 was employed
due to ease in measuring this amount of material.
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19. Typical reductive Heck cyclization procedure: A mixture
of 3-bromo-4-(3-methylbut-enyloxy)benzene 5h (0.5 g,
1.9 mmol), NaOAc (0.43 g, 5.0 mmol), HCO2Na (0.15 g,
2.4 mmol), Et4NClÆH2O (0.41 g, 2.4 mmol), and Pd(OAc)2
(4.7 mg, 0.02 mmol) in DMF (5 mL) was degassed and
refilled with nitrogen three times. The mixture was heated
to 85–95 °C (oil bath) for 1–4 h. Completion of the
reductive cyclization was monitored by HPLC and GC.
After completion, the reaction mixture was cooled to
room temperature. Water (15 mL) was added and the
mixture filtered through a Celite bed and washed with tert-
butyl methyl ether (25 mL). The organic phase was
separated and concentrated to give an oily residue that
was filtered through silica gel with eluent (EtOAc/hexane
1/20) to give the desired product 3,4-dimethyl-3,4-di-
1
hydro-2H-chromene 7h as colorless oil (0.31 g, 91%). H
NMR (400 MHz, CDCl3, d): 1.33, (s, 6H); 1.83, (t,
J = 5.5 Hz, 2H); 4.19 (t, J = 5.5 Hz, 2H); 6.75–6.80 (m,
1H); 6.83–6.91 (m, 1H); 7.02–7.10 (m, 1H); 7.23–7.28 (m,
1H); 13C NMR (400 MHz, CDCl3, d): 30.56, 31.10, 37.70,
64.04, 116.89, 120.40, 126.91, 131.64, 153.59. Exact mass
(M+H): 163.11174. Found: 163.11242.
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