Coumarins from free ortho -hydroxy cinnamates by Heck-Matsuda arylations: A scalable total synthesis of (R)-tolterodine

Article abstract of DOI:10.1021/ol302923f

Free ortho-hydroxy cinnamate ester derivatives are evaluated in the synthesis of structurally diverse 4-aryl-coumarins via a tandem Heck-Matsuda cyclization reaction. Free phenolic groups were considered incompatible with such a reaction, which usually provide the corresponding diazo dyes. A concise and scalable route employing a ligand-free, Pd-catalyzed Heck-Matsuda arylation under aerobic conditions for the preparation of (R)-Tolterodine in high overall yield and ee is also presented.

Full text of DOI:10.1021/ol302923f

ORGANIC
LETTERS
2012
Vol. 14, No. 23
6036–6039
Coumarins from Free ortho-Hydroxy
Cinnamates by Heck-Matsuda Arylations:
A Scalable Total Synthesis of
(R)‑Tolterodine
Daniela A. Barancelli,† Airton G. Salles Jr.,† Jason G. Taylor,‡ and
Carlos Roque D. Correia*,†
´
Instituto de Quımica, Universidade Estadual de Campinas, UNICAMP, C.P. 6154,
CEP. 13084-971, Campinas, Sao Paulo, Brazil, and Departamento de Quımica, ICEB,
~
´
ꢀ
Universidade Federal de Ouro Preto, UFOP Campus Universitario Morro do Cruzeiro,
35400-000, Ouro Preto-MG, Brazil
roque@iqm.unicamp.br
Received October 23, 2012
ABSTRACT
Free ortho-hydroxy cinnamate ester derivatives are evaluated in the synthesis of structurally diverse 4-aryl-coumarins via a tandem Heck-Matsuda
cyclization reaction. Free phenolic groups were considered incompatible with such a reaction, which usually provide the corresponding diazo
dyes. A concise and scalable route employing a ligand-free, Pd-catalyzed Heck-Matsuda arylation under aerobic conditions for the preparation of
(R)-Tolterodine in high overall yield and ee is also presented.
Arylation methods are among the most important
reaction types in organic synthesis. Aryl groups are found
in an outstanding number of natural products and
pharmaceuticals.1 In recent years, our group and others
have been exploring the palladium-catalyzed coupling of
arenediazonium salts to olefins (Heck-Matsuda reaction)
as a convenient method to obtain arylated and diarylated
compounds of biological and medicinal interest.2 In this
context, coumarins might be considered representative
diarylated species of great interest due to their biological
properties. Their diverse physiological activity such as
disease prevention, growth modulation, antioxidant prop-
erties, bacteriostatic and antitumor activity makes these
compounds attractive core structures for further derivati-
zation, screening and development as novel therapeutic
agents.3 A simple procedure for the rapid synthesis of a
diverse array of 4-aryl-coumarins was reported in 2005 by
Tunge and co-workers operating on the basis of a se-
quential Pd(II)-Fujiwara-cycloisomerization of arylated
alkynoates followed by a Pd(0)-catalyzed cross coupling
reaction.4 In that same year, Cacchi reported an efficient
route to 4-aryl-coumarins from readily available methyl
† Universidade Estadual de Campinas.
‡ Universidade Federal de Ouro Preto.
(1) For reviews, see: (a) Alberico, D.; Scott, M. E.; Lautens, M.
(3) (a) Weber, U. S.; Steffen, B.; Siegers, C. P. Res. Commun. Mol.
Pathol. Pharmacol. 1998, 99, 193. (b) Egan, D.; James, P.; Cooke, D.;
O’Kennedy, R. Cancer Lett. 1997, 118, 201. (c) Cooke, D.; O’Kennedy,
R. Anal. Biochem. 1999, 274, 188. (d) Budzisz, E.; Brzezinska, E.;
Krajewska, U.; Rozalski, M. Eur. J. Med. Chem. 2003, 38, 597.
(4) Li, K.; Zeng, Y.; Neuenswander, B.; Tunge, J. A. J. Org. Chem.
2005, 70, 6515.
ꢀ
Chem. Rev. 2007, 107, 174. (b) Hassan, J.; Sevignon, M.; Gozzi, C.;
Schulz, E.; Lemaire, M. Chem. Rev. 2002, 102, 1359.
(2) For reviews, see: (a) Taylor, J. G.; Moro, A. V.; Correia, C. R. D.
Eur. J. Org. Chem. 2011, 1403. (b) Felpin, F.-X.; Nassar-Hardy, L.;
Callonnec, F. L.; Fouquet, E. Tetrahedron 2011, 67, 2815. (c) Roglans,
~
A.; Pla-Quintana, A.; Moreno-Manas, M. Chem. Rev. 2006, 106, 4622.
r
10.1021/ol302923f
Published on Web 11/28/2012
2012 American Chemical Society

and butyl 3-(o-hydroxyaryl)acrylates with aryl iodides
and bromides in the presence of Pd(OAc)2.5 A similar
strategy to Cacchi’s was applied by Piccolo (2007) in the
enantioselective synthesis of a 4-arylcoumarin en route to
the asymmetric synthesis of (S)-Tolterodine.6
Scheme 2. Preparation of o-Hydroxy-cinnamate Ester
Substrates
Recently, we have demonstrated that various alkyl
cinnamates could be efficiently and stereoselectively ary-
lated with arenediazonium salts when using Pd(OAc)2
as catalyst in good to high yields.7 We envisioned that,
if successful, the application of this method to ortho-
hydroxy-cinnamate esters could lead to the straight-
forward synthesis of ortho-hydroxy-3,3-diaryl-acrylates
and their subsequent transformation to 4-aryl-coumar-
ins. In this context, we describe herein a feasible method
for the synthesis of 4-aryl-coumarins from free ortho-
hydroxy-cinnamate ester derivatives via a tandem Heck-
Matsuda cyclization procedure (Scheme 1). The generality
of the method is demonstrated by a concise and enantio-
selective total synthesis of (R)-tolterodine, an antimuscari-
nic drug used in the treatment of urinary incontinence8
(Scheme 5).
Therefore, we performed the same reaction in the pres-
ence of 1 equiv of CaCO3 as base. To our satisfaction and
surprise, the product yield of 6i was increased to 90%
(Scheme 3). Attempts to lower the catalyst loading from
10 to 5 mol % resulted in decreased yields (43%).
Scheme 1. Synthesis of 4-Aryl-coumarins via Tandem Heck
Arylation/Cyclization
Scheme 3. Heck Arylation/Cyclization of o-Hydroxy-
cinnamate Ester 3d
Cinnamate esters were prepared by either (E)-selective
one-pot Wittig reaction in aqueous media (a)9 or by
Horner-Wadsworth-Emmons reaction (b) using commer-
cially available benzaldehydes (Scheme 2). With the desired
cinnamates 3aÀ3f in hand, we started our investigation of
the Heck arylation/cyclization with the ortho-hydroxy-
cinnamate ester 3d using the same conditions described
previously for the arylation of cinnamate ester derivates.7
This procedure uses methanol as solvent and Pd(OAc)2 as
catalyst at 60 °C without an added base. The base-free
conditions seemed ideal to avoid the formation of pheno-
lates, which would be highly reactive toward arenediazo-
nium salts. However, under base-free conditions, the
4-aryl-coumarin 6i was obtained in only 29% yield. In view
of these rather disapointing results, we speculated that the
basicity of the reaction medium could be an important
factor in circumventing more detrimental Brønsted acid
promoted side reactions.
With these encouraging initial results in hand, we
decided to evaluate the scope of the arylation/cyclization
protocol to other ortho-hydroxy-cinnamate esters as well
as to investigate the compatibility of the arenediazonium
salts toward other functionalized free phenols. The pre-
valence of the Heck coupling over the well-known diazo-
nium coupling, leading to azo dyes, is striking since the
diazonium coupling is a very facile base-catalyzed process
(see Scheme 4).10 In most of the cases examined, the
corresponding coumarins were obtained in moderate to
good yields for several combinations of aryl diazonium
tetrafluoroborates and free phenol cinnamates (Table 1).
Many aryl diazonium salts possessing electron-neutral,
electron-donating (ED), and electron withdrawing groups
(EWG) were well-tolerated under the reaction conditions.
Entries 6, 7, 10, and 12 clearly indicate successful Heck
arylations involving diazo-coupling prone phenol deriva-
tives and highly electrophilic aryldiazonium salt bearing
electron withdrawing groups. However, some limitations
were observed. Cinnamates 3a, 3c and 3d failed to provide
the corresponding 4-aryl coumarins with aryldiazonium
salts bearing strong EWG such as p-NO2, p-Br or p-CF3.
(5) Battistuzzi, G.; Cacchi, S.; De Salve, I.; Fabrizi, G.; Parisi, L. M.
Adv. Synth. Catal. 2005, 347, 308.
(6) (a) Ulgheri, F.; Marchetti, M.; Piccolo, O. J. Org. Chem. 2007, 72,
6056. For a recent report on the synthesis of 4-aryl-coumarins using the
an oxidative Heck reaction, see: (b) Li, Y.; Qi, Z.; Wang, H.; Fu, X.;
Duan, C. J. Org. Chem. 2012, 77, 2053.
(7) Taylor, J. G.; Correia, C. R. D. J. Org. Chem. 2011, 76, 857.
(8) (a) Wefer, J.; Truss, M. C.; Jonas, U. World J. Urol. 2001, 19, 312.
(b) Rovner, E. S.; Wein, A. J. Eur. Urol. 2002, 41, 6.
(9) Wu, J.; Yue, C. Synth. Commun. 2006, 36, 2939.
(10) Hartwell, J. L.; Fieser, L. F. Org. Synth. 1943, 2, 145.
Org. Lett., Vol. 14, No. 23, 2012
6037

For such reactions, we observed complex mixture of
colored compounds. We believe that in those cases diazo
coupling may be a competitive process with the Heck-
Matsuda reaction as illustrated in Scheme 4.
Table 1. Heck Arylation of o-Hydroxy-cinnamate Esters 3 with
Diazonium Salts 5a
Scheme 4. Possible Diazo Coupling
Gratifyingly, cinnamate esters containing electron-
donating (3b) or electron-withdrawing groups (3e, 3f) at
the 5 position of the aromatic ring were reactive with
neutral, electron-rich and electron-poor arenediazonium
salts providing 4-aryl-coumarins 6dÀg, 6jÀo in 41À88%
isolated yields (Table 1, entries 4À7 and 10À15).
We next turned our attention to the synthetic application
of this new Heck protocol. Our initial target was a concise
total synthesis of (R)-tolterodine. Different approaches
have been reported for the racemic and asymmetric synth-
esis of tolterodine over the last decades.6a
We envisioned a concise synthesis of tolterodine through
a Heck-Matsuda reaction between ortho-hydroxy-cinnamate
ester 3b (generated from commercially available 2-hydroxy-
5-methyl-benzaldehyde) and the arenediazonium salt 5d to
provided coumarin 6d, a known intermediate in a previously
reported total synthesis of tolterodine.6a The Heck-
Matsuda arylation/cyclization was performed on 1.4 g of
the ortho-hydroxy-cinnamate ester 3b with 4-bromobenze-
nediazonium tetrafluoroborate under our optimized condi-
tions to furnish 6-methyl-4-phenyl-coumarin 6d in 63%
isolated yield over two steps (Scheme 5).12 As expected,
the CÀBr bond underwent smooth debromination in situ to
afford the 4-aryl-coumarin 6d in good yield.13
Conjugate reduction mediated by a phosphine ligated
CuH species is known to be a powerful method for the
induction of chirality β to a carbonyl.14 Therefore, asym-
metric reduction of coumarin 6d was carried out using
similar conditions to those described by Lipshutz in
which Cu(OAc)2 (10 mol %), (R)-JOSIPHOS (10 mol %)
as ligand and excess DEMS (diethoxymethylsilane) are
employed.15 The resulting lactol 7 was isolated in 74%
yield. Reducing the amounts of copper and ligand from
€
(11) (a) Andersson, P. G.; Schink, H. E.; Osterlund, K. J. Org. Chem.
1998, 63, 8067. (b) De Castro, K. A.; Ko, J.; Park, D.; Park, S.; Rhee, H.
Org. Process Res. Dev. 2007, 11, 918. (c) De Castro, K. A.; Rhee, H.
Synthesis 2008, 1841. (d) Yoo, K.; Kim, H.; Yun, J. J. Org. Chem. 2009,
74, 4232. (e) Gallagher, B. D.; Taft, B. R.; Lipshutz, B. H. Org. Lett.
2009, 11, 5374.
(12) The same reaction when carried out on a smaller scale (0.3À0.5
mmol) gave the Heck product 6d in 92% yield (average of 3
experiments).
(13) Lower yields of the Heck product were obtained with benzene-
diazonium salt (entry 4, Table 1).
(14) For reviews, see: (a) Deutsch, C.; Krause, N.; Lipshutz, B. H.
ꢀ
Chem. Rev. 2008, 108, 2916. (b) Llamas, T.; Arrayas, R. G.; Carretero,
J. C. Angew. Chem., Int. Ed. 2007, 46, 3329. (c) Desrosiers, J.-N.;
Charette, A. B. Angew. Chem., Int. Ed. 2007, 46, 5955.
6038
Org. Lett., Vol. 14, No. 23, 2012

Table 1. continued
Scheme 5. Synthesis of (R)-Tolterodine
provided (R)-tolterodine in 75% yield in only four steps
from cinnamate 3b in an overall yield of 30%.
In summary, we have described an efficient, mild and
operationally simple method for the synthesis of 4-aryl-
coumarins from free ortho-hydroxy-cinnamate ester deri-
vatives via a tandem Heck arylation/cyclization procedure
employing arenediazonium salts under palladium cataly-
sis. The Heck-Matsuda reaction proceeds under aerobic
conditions requiring only a few hours to go to completion
to afford the corresponding 4-aryl-coumarin derivatives in
moderate to good yields. Furthermore, the 6-methyl-4-
phenyl-coumarin obtained in the current protocol was
used as an intermediate for a concise (4 steps) asymmetric
total synthesis of (R)-tolterodine in 30% overall yield and
98% ee.
a Reactions performed in the presence of o-hydroxy-cinnamate ester
3 (0.3 mmol), arenediazonium salt 5 (0.6 mmol), Pd(OAc)2 (10 mol %),
CaCO3 (0.3 mmol), MeOH (1.8 mL) at 60 °C. b Yields of 6aÀo are given
for isolated products.
10 to 5 mol % provided a significant lower 57% yield of the
desired lactol 7. In order to evaluate the enantioselectivity
of the CuÀH reduction step, lactol 7 was oxidized with
PCC to the corresponding lactone (72% yield). Chiral CG
analysis indicated a 98% ee for lactone 8.
Finally, aiming at synthesizing (R)-tolterodine, we car-
ried out the reductive amination reaction of lactol 7.
Stirring lactol 7 in the presence of diisopropylamine
(DIPA), AcOH and NaHB(OAc)3 at room temperature
Acknowledgment. We thank the Research Supporting
~
Foundation of the State of Sao Paulo (FAPESP) for
financial support and the Brazilian National Research
Council (CNPq) for financial support and fellowships.
Supporting Information Available. Experimental pro-
cedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(15) Similar results were obtained with (S)-JOSIPHOS, which was
employed in the synthesisof the enantiomeric lactol 7 (7b), lactone 8 (8b),
and (S)-tolterodine. For procedures and spectral data for these com-
pounds see the Supporting Information.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 23, 2012
6039