Palladium-catalyzed alkylation-alkenylation reactions: Rapid access to tricyclic mescaline analogues

Article abstract of DOI:10.1055/s-2006-941583

A norbornene-mediated palladium-catalyzed sequence is described in which two alkyl-aryl bonds and one alkenyl-aryl bond are formed in one pot. A variety of symmetrical and unsymmetrical tricyclic heterocycles were synthesized in good yields from a Heck ac

Full text of DOI:10.1055/s-2006-941583

LETTER
2969
Palladium-Catalyzed Alkylation–Alkenylation Reactions: Rapid Access to
Tricyclic Mescaline Analogues
P
alladium-Catalyz
i
e
d
A
lk
nonylationReactionsAlberico, Mark Lautens*
Davenport Research Laboratories, Department of Chemistry, University of Toronto, Toronto, Ontario, M5S 3H6, Canada
Fax +1(416)9468185; E-mail: mlautens@chem.utoronto.ca
Received 16 February 2006
reaction, based upon modified Catellani conditions,3 for
the synthesis of fused aromatic carbocycles and heterocy-
cles from aryl iodides and functionalized alkyl bromides.4
We also described a three-component reaction employing
Abstract: A norbornene-mediated palladium-catalyzed sequence is
described in which two alkyl–aryl bonds and one alkenyl–aryl bond
are formed in one pot. A variety of symmetrical and unsymmetrical
tricyclic heterocycles were synthesized in good yields from a Heck
acceptor and an aryl iodide containing two tethered alkyl bromides. an iodoarene containing a tethered alkyl halide, an exter-
nal alkyl halide, and a Heck acceptor.5 We now report a
This methodology was applied to the synthesis of a tricyclic mesca-
line analogue.
new approach to tricyclic heterocycles from an aryl iodide
Key words: palladium, annulations, Heck reaction, mescaline,
microwave irradiation
containing two tethered alkyl bromides and an external
Heck acceptor (Table 1). Using this approach, both sym-
metrical and unsymmetrical substituted tricyclic hetero-
cycles can be easily prepared from readily accessible
Multicomponent carbon–carbon bond-forming reactions starting materials and three C–C bonds are formed in one
continue to evolve as a powerful method for the synthesis pot. Compounds with these motifs are widely found in
of complex molecules from simple building blocks.1 In natural products exhibiting notable biological and phar-
particular, great attention has been given to the develop- maceutical properties.6,7
ment of sequential reactions involving metal-catalyzed
processes.2 Previously, we reported a palladium-catalyzed
Table 1 Norbornene-Mediated Palladium-Catalyzed Alkylation–Alkenylationa
X
I
Pd(OAc)2, PPh3, Cs2CO3,
Y
norbornene, DME,
MW, 190 °C
X
Y
m
n
+
Br
Br
n
O
O
m
O
O
1, 7, 9, 11
2–6, 8, 10, 12
Entry
1
Substrate
Heck acceptor H2C=CXY
Product
Yield (%)b
CO2t-Bu
1
CO2t-Bu
m = 1
n = 1
85
O
O
2
C(O)NHt-Bu
O
1
2
m = 1
n = 1
61
NHt-Bu
O
O
3
SYNLETT 2006, No. 18, pp 2969–2972
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Advanced online publication: 29.06.2006
DOI: 10.1055/s-2006-941583; Art ID: S01906ST
© Georg Thieme Verlag Stuttgart · New York

2970
D. Alberico, M. Lautens
LETTER
Table 1 Norbornene-Mediated Palladium-Catalyzed Alkylation–Alkenylationa (continued)
X
I
Pd(OAc)2, PPh3, Cs2CO3,
Y
norbornene, DME,
MW, 190 °C
X
Y
m
n
+
Br
Br
n
O
O
m
O
O
1, 7, 9, 11
2–6, 8, 10, 12
Entry
3
Substrate
Heck acceptor H2C=CXY
Product
Yield (%)b
CO2Me
NHAc
1
AcHN
CO2Me
m = 1
n = 1
42
O
O
4
Ph
1
4
5
m = 1
n = 1
77
57
O
O
5
C5H4N
1
N
m = 1
n = 1
O
O
6
CO2t-Bu
7
CO2t-Bu
6
7
m = 1
n = 2
80c
O
O
8
CO2t-Bu
9
CO2t-Bu
m = 2
n = 2
70c
O
O
10
CO2t-Bu
11
m = 3
n = 3
CO2t-Bu
8
68d
O
O
12
a All reactions were run under the following conditions unless otherwise specified: iodoarene (0.20 mmol, 1 equiv), Pd(OAc)2 (10 mol%), PPh3
(22 mol%), Cs2CO3 (5 equiv), norbornene (3 equiv), and Heck acceptor (5 equiv) in DME (4 mL) were exposed to microwave irradiation for
5 min at 190 °C.
b Isolated yield.
c The reaction was carried out for 10 min.
d The reaction was carried out for 20 min.
We initially explored the synthesis of 5,6,5-ring systems acceptor (5 equiv) in dimethoxyethane (0.05 M) under mi-
from 1 and various Heck acceptors using iodoarene (1 crowave irradiation8 for 5 minutes at 190 °C (entries 1–5,
equiv), Pd(OAc)2 (10 mol%), triphenylphosphine (22 Table 1). While use of an acrylate afforded the corre-
mol%), Cs2CO3 (5 equiv), norbornene (3 equiv), and Heck sponding product in a good yield (entry 1), acrylamides
Synlett 2006, No. 18, 2969–2972 © Thieme Stuttgart · New York

LETTER
Palladium-Catalyzed Alkylation–Alkenylation Reactions
2971
and acetamidoacrylates bearing a free NH gave only mod- Our synthesis began with the methylation of commer-
est yields (entries 2 and 3). We note that 4 is of particular cially available 2,4,6-triiodophenol (17) in 98% yield
interest as subsequent asymmetric hydrogenation and (Scheme 1). Selective halogen–lithium exchange fol-
allows access to a variety of phenylalanine analogues.9 lowed by quenching with trimethyl borate and subsequent
Vinyl aromatic Heck acceptors were also compatible oxidation with peracetic acid solution resulted in 77%
under the reaction conditions (entries 4 and 5).
yield of diol 16.14 Alkylation of 16 with 1,2-dibromo-
ethane provided 15 in 84% yield. The one-pot palladium-
catalyzed bis-intramolecular ortho-alkylation of 15 and
subsequent Heck reaction with tert-butyl acrylate afford-
ed the tricyclic heterocycle 19 in 81% yield. Catalytic hy-
drogenation of 19 afforded the aryl propionate 20 in 98%
yield, which was converted to the desired carboxylic acid
21 in 87% yield by treatment with trifluoroacetic acid.
Conversion of 21 to the mescaline analogue 14·HCl was
the achieved by a Curtius rearrangement15 followed by
hydrogenolysis and treatment with HCl (1 M in Et2O) in
62% yield over two steps.
The successful preparation of compounds containing the
5,6,5-ring system prompted us to extend the reaction
scope to include other ring sizes. Reaction of 7 with tert-
butyl acrylate resulted in a good yield of an unsymmetri-
cal compound having a 5,6,6-ring system (entry 6). Com-
pounds with 6,6,6-ring systems (entry 7) and 7,6,7-ring
systems (entry 8) were also isolated in good yields. The
primary difference as the ring size was varied was an in-
crease in the reaction time.
To demonstrate the synthetic potential of this reaction, we
carried out a synthesis of tricyclic mescaline analogue 14
(Figure 1); first synthesized by Nichols,6 and later by
Bergman and Ellman.10 Mescaline (13), which is the ac-
tive component in the hallucinogenic plant Peyote,11 has
served as a prototype for structure–activity relationship
(SAR) studies linking molecular structure to hallucino-
genic activity.12 The behavioral effects produced by mes-
caline have been used as a standard against which other
hallucinogenic compounds are measured. Its behavioral
effects primarily occur through interactions with 5-
hydroxytryptamine2 (5-HT2) receptors.13 The mescaline
analogue 14, containing tetrahydrobenzodifuran function-
alities as rotationally restricted bioisosteres of the aromat-
ic methoxy groups in mescaline, showed an enhanced
affinity for 5-HT2 receptors with decreased hallucino-
genic activity. Hence, the mescaline analogue 14 and
other rotationally restricted analogues may be valuable in
SAR studies of hallucinogenic agents.
I
I
[i] n-BuLi, Et2O, –78 °C, 1 h
[ii] B(OMe)3, –78 °C to r.t., 16 h
[iii] peracetic acid/AcOH,
0 °C, 30 min
I
I
HO
OH
OH
OMe
MeI, K2CO3,
acetone,
reflux, 3 h
98%
17
16
77%
18
CO2t-Bu
Pd(OAc)2, PPh3,
Br
Br
I
Cs2CO3, norbornene,
K2CO3,
acetone,
reflux, 36 h
tert-butyl acrylate, DME,
MW, 190 °C,
Br
Br
5 min
O
O
O
O
84%
OMe
OMe
81%
15
19
Pd/C, H2(g),
MeOH–EtOAc,
r.t., 12 h
CO2t-Bu
CO2H
O
TFA, CH2Cl2,
r.t., 12 h
98%
87%
O
O
O
OMe
OMe
20
21
NH2
NH2
O
[i] Pd(OH)2/C, H2(g),
MeOH, 12 h
[ii] HCl (1 M Et2O),
r.t., 2 h
NH2·HCl
DPPA, Et3N,
benzyl alcohol,
toluene,
NHCbz
O
O
MeO
OMe
OMe
OMe
reflux, 18 h
O
O
O
96%
13
14
OMe
14
65%
OMe
22
Figure 1 Mescaline and tricyclic mescaline analogue
Scheme 1 Synthesis of Tricyclic Mescaline Analogue
The proposed disconnection is illustrated in Figure 2. The
key step is the bis-alkylation–Heck reaction sequence
involving aryl iodide 15 and a Heck acceptor.
In summary, we have shown that tricyclic symmetrical
and unsymmetrical heterocycles can be easily prepared
from a Heck acceptor and an aryl iodide containing two
tethered alkyl bromides via a palladium-catalyzed in-
tramolecular bis-alkylation–intermolecular alkenylation
reaction. In addition, application of this methodology to
the synthesis of mescaline analogue 14 was obtained in
27% yield over eight steps with an average yield per step
of 85%. The value of this approach is that a variety of ro-
tationally restricted mescaline analogues with varying
ring sizes can be easily prepared. We are currently explor-
ing the application of this methodology to the synthesis
other tricyclic hetero- and carbocycles.
I
NH2·HCl
I
Br
O
Br
Y
+
O
O
HO
OH
O
OMe
OMe
OMe
14
15
16
Figure 2 Retrosynthetic analysis
Synlett 2006, No. 18, 2969–2972 © Thieme Stuttgart · New York

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D. Alberico, M. Lautens
LETTER
General Procedure for the Alkylation–Alkenylation Reaction
3-(2,3,5,6-Tetrahydrobenzo[1,2-b;5,4-b¢]difuran-4-yl)acrylic
Acid tert-Butyl Ester (2)
Microwave-assisted reactions were preformed in a Emrys Liberator
model from Biotage (formerly Personal Chemistry) using Biotage
Microwave Vials (2–5 mL). Microwave irradiation time was con-
ducted using ramp time and hold time at the final temperature.
(3) (a) Catellani, M.; Frignani, F.; Rangoni, A. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 119. (b) Catellani, M.; Mealli, C.;
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Chem. Soc. 2002, 124, 4336. (c) Catellani, M. Synlett 2003,
298. (d) Catellani, M. Top. Organomet. Chem. 2005, 14, 21.
(4) (a) Lautens, M.; Piguel, S. Angew. Chem. Int. Ed. 2000, 39,
1045. (b) Lautens, M.; Paquin, J.-F.; Piguel, S.; Dahlmann,
M. J. Org. Chem. 2001, 66, 8127. (c) Lautens, M.; Paquin,
J.-F.; Piguel, S. J. Org. Chem. 2002, 67, 3972. (d)Alberico,
D.; Paquin, J.-F.; Lautens, M. Tetrahedron 2005, 61, 6283.
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2005, 127, 13148.
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To a microwave reaction vessel were added Cs2CO3 (323 mg, 1.00
mmol, 5 equiv), norbornene (56.0 mg, 0.600 mmol, 3 equiv),
Pd(OAc)2 (4.50 mg, 0.0200 mmol, 10 mol%), PPh3 (11.5 mg,
0.0440 mmol, 22 mol%), aryl iodide 1 (90.0 mg, 0.200 mmol, 1
equiv) and tert-butyl acrylate (146 mL, 1.00 mmol, 5 equiv). The
vessel was sealed and flushed with N2. Through the septa was added
degassed dry DME (4 mL). The reaction vessel was subjected to mi-
crowave irradiation at 190 °C for 5 min. The mixture was diluted
with Et2O (4 mL) and quenched with H2O (4 mL). The aqueous lay-
er was extracted with Et2O (3×) and the combined organic layers
were washed with brine, dried with anhyd MgSO4 and filtered.
Removal of the solvent and purification by flash chromatography
using 10% EtOAc–hexanes as eluant resulted in 2 (49.1 mg, 85%)
as a pale yellow solid; mp 108–109 °C. Rf = 0.35 (silica gel, 10%
EtOAc–hexanes). IR (neat). n = 1707, 1593, 1440, 1293, 1154 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.66 (d, J = 16.3 Hz, 1 H), 6.32 (s,
1 H), 6.17 (d, J = 16.4 Hz, 1 H), 4.61 (t, J = 8.6 Hz, 4 H), 3.25 (t,
J = 8.6 Hz, 4 H), 1.53 (s, 9 H). 13C NMR (75 MHz, CDCl3): d =
166.6, 160.9, 140.4, 127.3, 123.2, 118.4, 94.3, 81.0, 72.2, 29.6,
28.4. HRMS: m/z calcd for C17H20O4 [M]+: 288.1363; found:
288.1361.
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Acknowledgment
We gratefully acknowledge the financial support of the Natural
Sciences and Engineering Research Council (NSERC) of Canada,
the Merck Frosst Centre for Therapeutic Research for an Industrial
Research Chair, and the University of Toronto.
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Synlett 2006, No. 18, 2969–2972 © Thieme Stuttgart · New York