Heck arylations of N-acyl-3-pyrroline and N-acyl-1,2,5,6-tetrahydropyridine with aryldiazonium salts. Short syntheses of aryl γ- and δ-lactams, baclofen, homobaclofen and analogues

Article abstract of DOI:10.1016/S0040-4039(01)02267-5

Heck arylation of N-acyl-3-pyrrolines and an N-acyl-tetrahydropyridine with aryldiazonium tetrafluoroborates under phosphine-free conditions proceeded smoothly to give α-hydroxycarbamates (hemiaminals) or α-alkoxycarbamates which were oxidized to the desi

Full text of DOI:10.1016/S0040-4039(01)02267-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 741–744
Heck arylations of N-acyl-3-pyrroline and
N-acyl-1,2,5,6-tetrahydropyridine with aryldiazonium salts.
Short syntheses of aryl g- and d-lactams, baclofen,
homobaclofen and analogues
Marcos Jose´ S. Carpes and Carlos Roque D. Correia*
Instituto de Qu´ımica, Universidade Estadual de Campinas, UNICAMP, C.P. 6154, CEP 13083-970, Campinas, Sa˜o Paulo,
Brazil
Received 19 November 2001; accepted 28 November 2001
Abstract—Heck arylation of N-acyl-3-pyrrolines and an N-acyl-tetrahydropyridine with aryldiazonium tetrafluoroborates under
phosphine-free conditions proceeded smoothly to give a-hydroxycarbamates (hemiaminals) or a-alkoxycarbamates which were
oxidized to the desired g- and d-lactams. Acidic hydrolysis of the g-lactams produced a series of arylated GABA derivatives,
including baclofen, a useful therapeutic drug, in only three steps with an overall yield of 63–76%. Starting from N-acyl-tetra-
hydropyridine, aryl-d-lactams and higher homologues of baclofen can be obtained. © 2002 Elsevier Science Ltd. All rights
reserved.
forward and phosphine-free Heck arylation protocol.3
Despite the fact that Heck arylations of 3-pyrrolines
and tetrahydropyridines were already described in the
literature, these traditional Heck protocols employing
aryl triflates and aryl iodides require large excesses of
the olefin to ensure good yields of the arylated products
and frequently lead to mixtures of arylated and isomer-
ized Heck adducts.4 Recently, we applied the Heck
The Heck arylation reaction has a prominent place
among the key organic reactions leading to the con-
struction of CꢀC bonds.1 This has been the result of an
enormous effort in the last two decades to develop this
versatile reaction promoted by catalytic Pd. Most of the
Heck procedures call for the use of phosphines in order
to stabilize the active Pd(0), in which cases oxygen-free
conditions should be applied. Moreover, the amount of
phosphine added should be carefully monitored to
maintain reasonable rates of the catalytic cycle. Despite
their critical role in catalytic asymmetric synthesis,2
there are occasions when the use of phosphines is
undesirable. For this reason, Heck reactions under
conditions avoiding the use of phosphines (phosphine-
free conditions) has been an area of intensive investiga-
tion and much synthetic interest, not only for its
practical aspects, but also for its economics.1a
O
H3CO
G
O
O
N
H
N
H
1
2: rolipram
We have been exploring the Heck arylation of endo-
cyclic enecarbamates and pyrrolines with aryldiazonium
salts as a feasible alternative to introduce aryl sub-
stituents into pyrrolidine and piperidine rings. Aryldia-
zonium tetrafluoroborates are stable intermediates that
have been used as effective electrophiles in a straight-
( )n
CO2H
H2N
RO2C
Cl
N
H
3: n = 1, baclofen
4: n = 2, homobaclofen
5
* Corresponding author. Tel.: 55 019 7883086; fax: 55 019 7883023;
e-mail: roque@iqm.unicamp.br
Figure 1.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02267-5

742
M. J. S. Carpes, C. R. D. Correia / Tetrahedron Letters 43 (2002) 741–744
(C) 2 mol% of Pd(OAc)2 in a biphasic system CCl4/H2O
(1:1, v/v). The protocol using aqueous acetonitrile (1:1,
v/v) was the most practical one providing slightly
higher yields of the lactamols 7a–e. To avoid losses
during the purification process, the lactamols were
directly oxidized using either (i) RuCl3/NaIO4 (G=
NO2, Cl); (ii) PCC (G=OMe, diOMe, naphthyl) or (iii)
CrO3/acetone (Jones reagent) to yield the correspond-
ing arylated lactams 8a–e in good overall yields (Table
1).
arylation of 3-pyrrolines and five-membered endocyclic
enecarbamates with aryldiazonium salts for the con-
struction of more elaborated 4-aryl enecarbamates5 and
the total stereoselective synthesis of the pyrrolidine
alkaloid (−)-codonopsinine.6 The Heck arylation using
aryldiazonium salts were very fast, regioselective, and
did not require an excess of the olefins to warrant good
yields.
With the objective of extending this methodology to the
synthesis of other pharmacological active compounds
and to probe the scope of the Heck arylation with
diazonium salts, we pursued the concise syntheses of (i)
4-aryl-g-lactams, such as 1, from which rolipram (2), a
phosphodiesterase inhibitor used as an anti-asthma
drugs is a representative example;7 (ii) a short synthesis
of the g-amino acid baclofen 38 and some aromatic
analogues; (iii) the synthesis of the homobaclofen 4,
and (iv) the synthesis of aryl-d-lactams that might be
used as precursors to arylpiperidines (Fig. 1). Of partic-
ular interest was the short synthesis of baclofen, a
GABAB receptor agonist used to treat spasms caused
by spinal cord injuries and which shows some potential
as treatment for cocaine addiction.9 Arylpiperidines,
such as 5, has been attracting much attention due to its
pronounced pharmacological activity as inhibitors of
dopamine and serotonine reuptake systems, and consti-
tutes a common pharmacophore to many active com-
pounds, such as morphine, pentazocine, etc.10
Oxidation employing RuCl3/NaIO4 or Jones’ reagent
(CrO3/acetone) of lactamols 7a, 7c and 7e led to lower
yields of the corresponding lactams, probably due to
partial oxidation of the electron-rich aromatic rings.
Oxidation with pyridinium chlorochromate (PCC) in
CH2Cl2 worked well for all lactamols 7a–e, providing
the corresponding lactams in good overall yields (75–
90%), thus performing as our oxidant of choice in this
study.
Preparation of the g-amino acids from the arylated
lactams was straightforward (Eq. (1)). Acidic hydrolysis
(6N HCl/reflux) of the arylated lactams 8a–e occurred
smoothly to provide the corresponding g-amino acids 3,
and 9a–d in good yields (84–95%). This procedure
permitted the synthesis of ( )-baclofen 3 and a number
of new analogues bearing electron-withdrawing and
electron-donating substituents in the aromatic ring
(Table 2).
G
We started by preparing the known N-Boc-3-pyrroline
6 from the N-Boc-bisallyl amine according to the pro-
cedure of Grubbs in 80% yield.11 The Heck arylation of
3-pyrroline 6 was carried out with several aryldiazo-
nium tetrafluoroborates (Scheme 1) under three differ-
ent conditions: (A) 2 mol% of Pd(OAc)2 in aqueous
acetonitrile; (B) 2 mol% of Pd(OAc)2 in methanol or
Cl
H3N
OH
(1)
O
HCl 6N
O
N
reflux, 18h
Boc
G
3, 9a-d
8a-e
N2 BF4
G
N
G
G
oxidation
Pd(OAc)2 (2 mol%)
N
O
OH
N
CCl4/H2O
2-4 h
Boc
6
Boc
Boc
8a-e
7a-e
Scheme 1.
Table 1. b-Aryl-g-lactams from Heck arylation of N-Boc-
3-pyrroline
Table 2. g-Amino acids (AA) from acidic hydrolysis of
lactams 8a–e
Entry
Diazonium salt
Lactam (yield, %)a
Entry
Diazonium salt
AA (yield, %)a
1
2
3
4
5
G=3,4-diOMe
G=4-Cl
G=4-OMe
G=4-NO2
2-Naphthyl
8a (76)
8b (75)
8c (75)
8d (90)
8e (70)b
1
2
3
4
5
G=3,4-diOMe
G=Cl
G=OMe
G=NO2
9a (86)
3 (90)
9b (84)
9c (85)
9d (95)
2-Naphthyl
a Yield of purified compound over two steps.
b Reaction performed in CH3CN/H2O (1:1 ratio, v/v).
a Yield of purified product.

M. J. S. Carpes, C. R. D. Correia / Tetrahedron Letters 43 (2002) 741–744
743
With the underlining objective of comparing the Heck
arylation of non-symmetrical double bonds with aryldi-
azonium salts, we also carried out an investigation into
the Heck arylation of a tetrahydropyridine derivative as
an alternative synthetic entry to arylpiperidines. Heck
arylation of tetrahydropyridine substrates with aryl
iodides were carried out previously by Hallberg and
co-workers with quite interesting results and the basic
idea here was to test how diazonium salts compare with
aryl iodides as electrophiles.12 We started our studies by
converting the commercially available 1,2,5,6-tetra-
hydropyridine into the N-Cbz tetrahydropyridine 10
using standard procedures (Cbz-Cl, Et3N, CH2Cl2, 90%
yield). Heck arylation of tetrahydropyridine 10 with
p-Cl-benzenediazonium tetrafluoroborate was then per-
formed under conditions similar to those used for the
Heck arylation of pyrroline 6 (Scheme 2). Thus, Heck
arylation with Pd(OAc)2/CH3CN–H2O led to three
products as analyzed by Cap. GC. Although these
compounds could be separated by chromatography on
silica gel, lactamol 11 and 12 proved rather unstable.13
Therefore, the reaction mixture was directly oxidized
after workup with tetrapropylammonium perruthenate
(TPAP) to provide a mixture of lactams 14 and 15
together with a minor amount of the olfefinic com-
pound 13 in an overall yield of 66% over the two steps.
Compounds 14, 15 and 13 were obtained in a ratio of
50:36:13 after flash chromatography. Lactams 14 and
15 are known compounds and both have been used
as precursors to the synthesis of isomeric homobac-
lofens.14
Acidic hydrolysis of the isolated major lactam 14, car-
ried out as applied for compounds 8a–e, furnished
homobaclofen 4 in 97% yield (Scheme 3).
The Heck arylation of 1,2,5,6-tetrahydropyridine 10
with diazonium salts was demonstrated to be milder
than the one employing aryl iodides, did not require
excess of the olefin to attain reasonable yields, but
provided the Heck adduct in slightly lower yields than
those reported by Hallberg and co-workers (72%
yield).12 An interesting aspect of the Heck arylation
with diazonium salts was the overall regioselectivity of
the process (1.7:1), very similar to the one reported by
Hallberg. We made no attempts to obtain the six-mem-
bered enecarbamate directly from the Heck arylation
with diazonium salts in view of their instability under
acidic conditions. However, these enecarbamates can be
easily obtained from the intermediate lactamols with
the use of trifluoroacetic anhydride, as previously
described by us.5 Heck arylation of 10 using 2 mol%
Pd(OAc)2 in MeOH provided results similar to the ones
described in Scheme 2, but contrary to the six-mem-
bered lactamols 11 and 12 the a-methoxy carbamates
were quite stable.
In summary, Heck arylation of N-acyl pyrrolines with
several aryldiazonium salts proceeded in a fast and
exothermic process to competently produce the corre-
sponding Heck adducts. In view of their instability
these Heck a-hydroxy carbamates products were
directly oxidized to the corresponding lactams in good
overall yields. The key p-Cl-aryl-g-lactam 8b was effec-
tively converted into the therapeutically valuable drug
baclofen in a three-step process with an overall yield of
67% from pyrroline 6. Heck arylation of tetra-
hydropyridine 10 followed by oxidation of the lactamol
intermediates provided the corresponding p-Cl-phenyl-
d-lactams 14 and 15 in a 60% overall yield in a ratio of
ꢀ1.5:1. The major regioisomeric p-Cl-phenyl-d-lactam
14 was converted to the 5-amino-4-(4-chlorophenyl)-
pentanoic acid 4, a higher homologue of baclofen.
Compounds 3 (baclofen) and 4 (homobaclofen) were
prepared in a concise manner using a new synthetic
Ar
Ar
Ar
a
+
OH
+
N
N
HO
N
N
Cbz
Cbz
10
Cbz
Cbz
11
12
13
Ar
Ar
Ar
b
+
+
strategy.
The
synthesis
of
other
g-lactams
N
O
N
N
O
(pyrrolidones) and d-lactams are in progress in our
laboratory.
Cbz
Cbz
Cbz
14
15
13
Ar = p-Cl-C6H5
Acknowledgements
Scheme 2. (a) p-ClC6H4N2BF4, 2 mol% Pd(OAc)2, CH3CN/
,
H2O (2:1 ratio, v/v); (b) TPAP, NMO, CH2Cl2, 4 A MS (66%
over two steps).
This work was supported by a grant from the Research
Supporting Foundation of the State of Sa˜o Paulo
(FAPESP 99/06566-7). We also thank CNPq and
FAPESP for fellowships.
Cl
Cl
6M HCl
.HCl
reflux, 18 h
N
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O
Boc
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Scheme 3.

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