Remarkable electronic effect on the diastereoselectivity of the Heck reaction of methyl cinnamate with arenediazonium salts: Formal total synthesis of (±)-indatraline and (±)-sertraline

Article abstract of DOI:10.1002/adsc.200900032

An efficient and stereoselective protocol for the preparation of β,β-disubstituted acrylates in good to high yields by means of a Heck-Matsuda arylation was accomplished. The method employs a base- and ligand-free Heck arylation reaction of methyl cinnamate using both electron-deficient and electron-rich arenediazonium salts as electrophiles. The Heck reaction displays a remarkable electronic dependence regarding the diastereoselectivity of the arylation process, which correlates with the electronic nature of the arenediazonium salts employed. A rationale for the observed diastereoselectivity is presented. The overall methodology provides a convenient route to 3-arylindanones and 4aryltetralones allowing the concise formal total syntheses of the therapeutically important psychoactive compounds (± )-indatraline and (± )-sertraline.

Full text of DOI:10.1002/adsc.200900032

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DOI: 10.1002/adsc.200900032
Remarkable Electronic Effect on the Diastereoselectivity of the
Heck Reaction of Methyl Cinnamate with Arenediazonium Salts:
Formal Total Synthesis of (Æ)-Indatraline and (Æ)-Sertraline
Julio Cezar Pastrea and Carlos Roque Duarte Correiaa,*
a
Instituto de Quꢀmica, Universidade Estadual de Campinas, UNICAMP, C.P. 6154, 13083-970 Campinas, S¼o Paulo, Brazil
Fax : (+55)-19-3521-3023; e-mail: roque@iqm.unicamp.br
Received: January 15, 2009; Revised: April 10, 2009; Published online: June 2, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900032.
Abstract: An efficient and stereoselective protocol
for the preparation of b,b-disubstituted acrylates in
good to high yields by means of a Heck–Matsuda
arylation was accomplished. The method employs a
base- and ligand-free Heck arylation reaction of
methyl cinnamate using both electron-deficient and
electron-rich arenediazonium salts as electrophiles.
The Heck reaction displays a remarkable electronic
dependence regarding the diastereoselectivity of
the arylation process, which correlates with the
electronic nature of the arenediazonium salts em-
ployed. A rationale for the observed diastereoselec-
tivity is presented. The overall methodology pro-
vides a convenient route to 3-arylindanones and 4-
aryltetralones allowing the concise formal total syn-
theses of the therapeutically important psychoactive
compounds (Æ)-indatraline and (Æ)-sertraline.
exceptional tool for the synthesis of complex organic
structures.[3]
Among the several arylating agents available to
perform the Heck reaction, arenediazonium salts are
probably the least explored ones (the Heck–Matsuda
reaction), in spite of the fact that they offer consider-
able advantages (economical and environmental) over
traditional electrophiles, such as aryl halides and aryl
triflates.[4] First, Heck arylations employing arene-
AHCTUNGTREGdNNUN iazonium salts do not require the use of phosphanes
(“ligand-free conditions”), so reactions can be carried
out under aerobic conditions making them much
easier to handle than traditional protocols. Second,
the arenediazonium salts are more reactive than the
corresponding aryl halides in the palladium-catalyzed
Heck reactions. Third, the Heck–Matsuda reactions
can be carried out at lower temperature than the typi-
cal Heck reactions (usually over 1008C), without
added base or salt (such as silver chloride or thallium
ethoxide), which extend the reaction scope to sub-
strates with sensitive functional groups. Fourth, al-
though certain aryl halides and triflates are difficult
to synthesize, most arenediazonium salts can be easily
generated from the corresponding aniline in high
Keywords: arenediazonium salts; Heck reaction; in-
datraline; methyl cinnamate; palladium; sertraline
The palladium-catalyzed C C coupling reactions con- yields.[5] This is a significant consideration for combi-
stitute an important methodology in current organic natorial synthesis. Thus, application of arenediazoni-
À
synthesis.[1] Among the palladium-catalyzed C C cou- um salts in the metal-catalyzed coupling reactions
À
plings, the Heck reaction[2] (Scheme 1) of aryl halides/ could potentially simplify the synthesis of certain
triflates and alkenes holds a prominent position in types of advanced intermediates, as well as reduce the
view of its exceptional versatility, thus making it an number of steps involved in the synthesis of pharma-
ceuticals and agrochemicals.[6]
The Heck arylation of unsubstituted acrylates em-
ploying aryl halides/triflates or even arenediazonium
salts is a well-established process.[3g] It has been used
extensively as a benchmark protocol for the discovery
of new palladium catalysts and/or to demonstrate new
advances in the Heck arylation processes. However,
reports on the use of more complex substituted acryl-
ates are scarce in the literature. Usually these sub-
Scheme 1. Heck reaction of aryl halides/triflates with al-
kenes.
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Table 1. Pd-catalyzed Heck arylation of methyl cinnamate with 4-methoxybenzenediazonium tetrafluoroborate.
Entry[a] Pd Cat. (mol%) Solvent
Base (3 equiv.)
T
t [h] Conversion [%] Yield [%][b] E/Z ratio[c]
1
2
3
4
5
6
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
U
MeCN
MeOH
EtOH
–
–
–
–
–
–
–
–
reflux
reflux
reflux
reflux
1008C
r.t.
reflux
reflux
reflux
r.t.
8
2
6
6
2
5
4
6
4
14
6
2
4
100
100
100
29
100
100
40
64:36
70:30
–
68:32
60:40
80:20
71:29
–
98:02
97:03
98:02
78:22
98:02
86
[d]
iPrOH
83
57
67
1,2-propanediol
MeOH
MeOH
MeCN
MeOH
MeOH
EtOH
7
G
E
76
90
8[f]
9
[e]
[d]
NaOAc
NaOAc
NaOAc
2,6-DTMP
TBAA
80
88
55
100
75
66
63
40
35
56
10
11
12[g]
13[h]
reflux
reflux
reflux
MeOH
MeOH
[a]
Reaction conditions: unless mentioned otherwise, 1.0 mmol of methyl cinnamate and 1.2 equiv. of 4-methoxybenzene-
ACHTUNGTRENNUNGdiazonium tetrafluoroborate in 6 mL of solvent were used.
[b]
[c]
[d]
[e]
[f]
Yields were calculated after flash chromatography and were based on the recovering of the starting material.
1
Diastereoselectivities were determined by GC and GC/MS analysis, and confirmed by H NMR.
Complex mixture.
Low conversion.
2.0 equiv. of the arenediazonium salt were used.
2,6-DTMP=2,6-di-tert-butyl-4-methylpyridine; product of Michael addition of MeOH to 1 isolated in 53% yield.
TBAA=n-tetrabutylammonium acetate.
[g]
[h]
strates are more resistant to Heck arylations, requir- allow introduction of an electron-rich aryl group,
ing relatively harsh reaction conditions to reach com- which is considerably less efficient when employing
plete conversion and/or high yields of the desired traditional Heck protocols. Some selected examples
adduct. From the synthetic standpoint this is a consid- are presented in Table 1.
erable limitation to the potential of the Heck reac-
tions and poses a challenge to be addressed.
We first evaluated the effect of the solvent on the
Heck reaction of methyl cinnamate using Pd(OAc)2
ACHTUNGTRENNUNG
In particular for the arylation of cinnamic esters, as pre-catalyst, without addition of bases. Arylations
several protocols have been developed during the last were screened using common organic solvents usually
decades.[7] These protocols often require high temper- employed in our laboratory for this type of reaction
atures,[7d,e,h,i] the use of DMF,[7c,d] DMA[7e] or TBAB[7h,i] (like MeCN and alcohols). Arylation was observed in
as solvents, as well as the use of hindered tertiary almost all solvents tested (Table 1). However, these
amines as bases.[7e,g] As far as stereochemistry is con- were more efficient and faster in refluxing MeOH
cerned, high stereoselectivity has been obtained only (entry 2). Heck arylations in ethanol, isopropyl alco-
in a few cases. Therefore, the development of a gener- hol and 1,2-propanediol resulted in more complex
al, simple and highly stereoselective process that oper- mixtures or low yields due to a rather fast transesteri-
ates under mild reaction conditions constitutes an im- fication (entries 3, 4 and 5). Arylations were complet-
portant synthetic objective.
ed in 2 h to provide the corresponding b,b-diarylpro-
In view of an increasing awareness of the synthetic pionic ester 1 in good yields. Tendency for thermody-
advantages of the arenediazonium salts in the Heck namic equilibration of the Heck adducts was observed
reaction, we decided to investigate the feasibility of when the reactions were followed by capillary GC –
the Heck arylation of cinnamic esters.
the ratio between adducts decreased with time. Based
For the Heck arylation of the commercially avail- on this observation, we carried out the reaction at
able methyl cinnamate, 4-methoxybenzenediazonium room temperature and the desired Heck adduct was
tetrafluoroborate was chosen as the initial arylating isolated in a higher diastereoselectivity, favoring the
agent due to its exceptional thermostability and to (E) Heck adduct (entry 6). Also noteworthy is the
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Remarkable Electronic Effect on the Diastereoselectivity of the Heck Reaction
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Table 2. Pd-catalyzed Heck arylation of methyl cinnamate with various arenediazonium salts.
Entry[a]
R1
R2
X
T [8C]
t [h]
Compound (yield [%][b])
E/Z ratio[c]
À
1
2
3
4
5
6
7
8
OCH3
F
Cl
Cl
NO2
Cl
Br
OH
H
H
OCH3
H
H
Cl
Cl
H
H
H
H
BF4À
BF4À
BF4À
BF4À
BF4À
BF4À
BF4
reflux
reflux
reflux
r.t.
reflux
reflux
reflux
reflux
reflux
r.t.
2
2
1
3
2
1
1
2
1 (86)
2 (67)
3 (70)
3 (79)
4 (98)
5 (95)
6 (94)
7 (93)
8 (93)
9 (86)
10 (58)
70:30
94:06
92:08
97:03
96:04
95:05
81:19
70:30
97:03
–
À
CF3ÀCO2
BF4À
BF4À
BF4
9
NO2
H
OCH3
0.5
24
2
10[d]
11
reflux
60:40
[a]
Reaction conditions: unless mentioned otherwise, 1.0 mmol of methyl cinnamate, 1.2 equiv. of arenediazonium
tetrafluoroborate, and 10 mol% of Pd(OAc)2 in 6 mL of MeOH were used.
Yields were calculated after flash chromatography.
Diastereoselectivities were determined by GC and GC/MS analysis and confirmed by H NMR.
3.0 equiv. of the arenediazonium salt was added in small portions.
G
ACHTUNGTRENNUNG
[b]
[c]
[d]
1
fact that Pd
cient than Pd
complex mixtures (entries 7 and 8).
G
In order to evaluate the scope of this reaction, we
ACHTUNGTRENNUNG
Regarding the stereochemical outcome, the stereo- ate to excellent yields of coupling products were ob-
isomers are probably generated through the well- tained, with the diastereoselectivity depending on the
known elimination-reverse addition-elimination of the nature of the arenediazonium salt used. Notably, dia-
cationic PdH species. The low stereoselectivity ob- stereoselectivity was much higher with salts bearing
served in such systems has also been previously ex- electron-withdrawing groups than with electron-do-
plained as a base-catalyzed isomerization (addition- nating groups (compare entries 1 and 5). These results
elimination), leading to the preferred formation of are very interesting since they demonstrate for the
the thermodynamic product. However, the use of first time a remarkable dependence of the diastereo-
bases in the Heck–Matsuda arylation of methyl cinna- selectivity of the Heck arylation of cinnamates on the
mate with 4-methoxybenzenediazonium tetrafluoro- nature of the arenediazonium salts employed.[9] Fur-
borate (entries 9–13) led to excellent diastereoselec- thermore, these results strongly suggest that the lower
tivities (>97:03) in most cases, despite a significant stereoselectivity observed for the Heck arylation of
drop in substrate conversion.[8]
methyl cinnamate with electron-rich arenediazonium
The replacement of acetate bases by a soluble or- salts results from re-addition of [PdH]+ to the double
ganic base such as 2,6-di-tert-butyl-4-methylpyridine bond of the Heck enoates (Scheme 2).
led to a sharp decrease in the stereoselectivity with
By contrast, recently Nꢃjera developed an oxime-
formation of the Heck adducts in a lower diastereo- derived palladacycle and applied it to preparation of
meric ratio (78:22, entry 12), along with 53% of the trisubstituted olefins by a Heck arylation. However,
product of methanol Michael addition to the enoate. when coupling ethyl cinnamate with either electron-
We hypothesize that the more soluble and hindered poor and electron-rich aryl iodides, at 120 to 1408C,
pyridine base is less effective in abstracting a proton the Heck adducts were obtained as a ca. 3:1 mixture
from the cationic hydropalladium intermediate ligated of isomers.[7m] This example highlights the advantages
to the olefin. On the other hand, acetate located at of performing Heck arylations of cinnamates under
the coordinating shell of palladium could act as an ef- milder reaction conditions.
fective base by intramolecular neutralization of
It is also worth mentioning that p-nitro- and m-ni-
[PdH]+ through a five-membered transition state, as trobenzenediazonium tetrafluoroborate were equally
proposed by Calꢂ and co-workers.[7i]
suitable for the Heck arylation of methyl cinnamate
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Scheme 2. Rationale for the stereoselectivity of the Heck arylation of methyl cinnamate.
(Table 2, entries 5 and 9). This observation is signifi- angiotensin II antagonists,[11] the platelet-activating
cant in view of the low yields of coupling products ob- factor antagonists,[12] and the SRS-A antagonists
tained by both Kikukawa[4b] and Sengupta[10] when (slow-reacting substance of anaphylaxis).[13]
employing these nitro-based diazonium salts in their
ligand-free palladium-catalyzed coupling reactions.
To highlight the versatility of the procedure devel-
oped herein, our planning also included the applica-
In entry 8, p-hydroxybenzenediazonium trifluoro- tion of these Heck arylations in the synthesis of phar-
ACHTUNGTRENNUNG
methoxy-substituted salt.
indatraline and sertraline, respectively.
Benzenediazonium tetrafluoroborate was a chal-
Indatraline 11 (Lu 19-005, Figure 1) is a potent psy-
lenge for the Heck arylation of methyl cinnamate, choactive compound with high binding and inhibitory
probably due to its low thermostability. To overcome activity for neuronal monoamine reuptake sites, in-
this difficulty, the reaction was conducted at room cluding dopamine and serotonin transporters.[16] In
temperature and the salt was added in small portions vivo dialysis and behavioral studies have indicated a
to ensure complete conversion. To our delight, the de- potent dopaminergic mechanism of action for indatra-
sired Heck adduct was obtained in a good 86% yield line[17] with a long period of action.[18] In addition,
(entry 10).
studies in monkeys indicated that indatraline reduced
The development of an efficient process for the cocaine self administration.[19] Sertraline 12 (marketed
Heck arylation of b-aryl acrylates is of significant util- as Zoloftꢄ) acts on the central nervous system as a se-
ity since b,b-diarylpropionic esters are key intermedi- lective serotonin reuptake inhibitor (SSRI)[20] and is
ates in the synthesis of many important drugs, like the an important commercial drug for the treatment of
Figure 1. Chemical structures of indatraline and sertraline.
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Remarkable Electronic Effect on the Diastereoselectivity of the Heck Reaction
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Scheme 3. Formal total synthesis of (Æ)-indatraline.
depression, dependency, and other anxiety-related dis- subjected to the Wolff rearrangement using silver
orders.[21] In spite of several available methodologies benzoate under ultrasound irradiation. Next, hydroly-
for preparing indatraline and sertraline, there is the sis of the methyl ester 17 with aqueous KOH gave the
need for new strategies to prepare the 3-arylindane corresponding acid homologue 18 in 99% yield. Final-
and 4-aryltetrahydronaphthalene systems displayed ly, cyclization with chlorosulfonic acid afforded the
by this class of compounds.
tetralone 19 in 87% yield, which can be converted to
We first turned our attention to the synthesis of the (Æ)-sertraline using conditions described in the litera-
precursor of indatraline. Thus, methyl cinnamate was ture.[23]
subjected to the Heck arylation with 3,4-dichloroben-
zenediazonium tetrafluoroborate at room tempera- stereoselective method for the preparation of b,b-di-
ture followed by an in situ catalytic hydrogenation of arylacrylates in good to high yields by means of a
In conclusion, we have developed an efficient and
AHCTUNGTRENNUNG
the Heck adduct 3 (Scheme 3), to provide the saturat- Heck reaction with arenediazonium tetrafluorobo-
ed b,b-diarylated product 13 in 85% yield (over 2 rates. This method is applicable to the coupling of
steps). Control of the hydrogenation step is crucial both electron-deficient and electron-rich arenediazo-
since we identified the formation of dehalogenated nium salts and displays a remarkable diastereoselec-
by-products under GC/MS analysis after one hour. tivity dependence on the electronic nature of the are-
Next, hydrolysis of the ester function with aqueous nediazonium salts. These results corroborate the hy-
KOH gave the corresponding acid 14 in 91% yield. pothesis of isomerization of the Heck adduct by a
Subsequent cyclization using polyphosphoric acid PdH re-addition to the double bond. Moreover, we
(PPA) or chlorosulfonic acid afforded the known pre- describe concise and convenient routes for the prepa-
cursor of (Æ)-indatraline 15 in 38% and 70% yields, ration of 3-arylindanones and 4-aryltetralones em-
respectively, whose spectroscopic data were identical ploying a base- and ligand-free, palladium-catalyzed
to those described in the literature (Scheme 3).[22]
Heck arylation of methyl cinnamate as the key step.
Aiming at intercepting a known advanced inter- Application of this protocol allowed the concise
mediate for the synthesis of sertraline, the diarylated formal total syntheses of (Æ)-indatraline and (Æ)-ser-
acid 14 was subjected to the corresponding homologa- traline. Furthermore, thanks to the high degree of ste-
tion process using the Arndt–Eistert protocol reoselectivity of the Heck arylation when using the di-
(Scheme 4). Preparation of diazo ketones via mixed chloro-based arenediazonium salt, we are now in a
carbonic anhydride proved ineffective in our sub- position to explore the asymmetric synthesis of both
strate. However, treatment of the corresponding acyl indatraline and sertraline, via an enantioselective re-
chloride with diazomethane gave the desired a-diazo duction of the Heck adduct. These results will be re-
ketone 16 in high yields (88–95%), which was then ported in due course.
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Scheme 4. Formal total synthesis of (Æ)-sertraline.
Wiley-VCH, Weinheim, 2004; e) V. Farina, Adv. Synth.
Catal. 2004, 346, 1553–1582; f) A. F. Littke, G. C. Fu,
Org. Synth. 2004, 81, 63–76; g) K. C. Nicolaou, P. G.
Bulger, D. Sarlah, Angew. Chem. 2005, 117, 4516–
4563; Angew. Chem. Int. Ed. 2005, 44, 4442–4489.
[2] a) T. Mizoroki, K. Mori, A. Ozaki, Bull. Chem. Soc.
Jpn. 1971, 44, 581–584; b) R. F. Heck, J. P. Nolley, J.
Org. Chem. 1972, 37, 2320–2322.
[3] For reviews of the Heck reaction, see: a) G. T. Crisp,
Chem. Soc. Rev. 1998, 27, 427–436; b) I. P. Beletskaya,
A. V. Cheprakov, Chem. Rev. 2000, 100, 3009–3066;
c) J. G. de Vries, Can. J. Chem. 2001, 79, 1086–1092;
d) N. J. Whitcombe, K. K. M. Hii, S. E. Gibson, Tetrahe-
dron 2001, 57, 7449–7476; e) J. Hassan, M. Sꢅvignon,
C. Gozzi, E. Schulz, M. Lemaire, Chem. Rev. 2002, 102,
1359–1469; f) A. B. Dounay, L. E. Overman, Chem.
Rev. 2003, 103, 2945–2963; g) F. Alonso, I. P. Belet-
skaya, M. Yus, Tetrahedron 2005, 61, 11771–11835;
h) N. T. S. Phan, M. Van der Sluys, C. W. Jones, Adv.
Synth. Catal. 2006, 348, 609–679; i) K. KÅhler, S. S.
Prçckl, W. Kleist, Curr. Org. Chem. 2006, 10, 1585–
1601; j) A. F. Schmidt, A. Al Halaiqa, V. V. Smirnov,
Synlett 2006, 2861–2878.
[4] For some seminal publications, see: a) K. Kikukawa, T.
Matsuda, Chem. Lett. 1977, 159–162; b) K. Kikukawa,
K. Nagira, F. Wada, T. Matsuda, Tetrahedron 1981, 37,
31–36. For a recent review on arenediazonium salts as
substrates in palladium-catalyzed cross-coupling reac-
tions, see: c) A. Roglans, A. Pla-Quintana, M. Moreno-
MaÇas, Chem. Rev. 2006, 106, 4622–4643.
[5] For the preparation of arenediazonium salts, see:
a) M. F. W. Dunker, E. B. Starkey, G. L. Jenkins, J. Am.
Chem. Soc. 1936, 58, 2308–2309; b) A. Roe, Org.
React. 1949, 5, 193–228; c) M. P. Doyle, W. J. Bryker, J.
Org. Chem. 1979, 44, 1572–1574; d) A. I. Vogel, B. S.
Furniss, A. J. Hannaford, P. W. G. Smith, A. R. Tatchell,
Experimental Section
Typical Experimental Procedure
To a solution of methyl cinnamate (161 mg; 1.0 mmol) in
6.0 mL of methanol was added, at once, a mixture of the
arenediazonium salt (1.2 mmol; 1.2 equiv.) and palladi-
ACHTUNGTRENNUNGum(II) acetate (24 mg; 10 mol%). The reaction mixture was
immersed in an oil bath and heated at reflux until TLC and
GC analyses indicated complete consumption of the methyl
cinnamate. After cooling, the mixture was filtered through a
pad of Celite and purified by flash column chromatography
(ethyl acetate/hexane) to give the corresponding Heck
adduct in the yields and diastereoselectivities shown in
Table 1 and Table 2.
Acknowledgements
We thank the Research Supporting Foundation of the State of
S¼o Paulo (FAPESP) for financial support of this work. We
also thank CNPq (CRDC) and FAPESP (JCP, grant 05/
01614-6) for fellowships.
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