Synthesis of dihydronaphthalenes via aryne Diels-Alder reactions: Scope and diastereoselectivity

Article abstract of DOI:10.1021/ja055498p

Novel aryne Diels-Alder reactions with functionalized acyclic dienes are reported. These give useful cis-substituted dihydronaphthalene building blocks in good yield which are not easily accessible via other means, as demonstrated in the synthesis of sert

Full text of DOI:10.1021/ja055498p

Published on Web 10/05/2005
Synthesis of Dihydronaphthalenes via Aryne Diels-Alder Reactions: Scope
and Diastereoselectivity
Chris Dockendorff, Stefan Sahli, Madeline Olsen, Ludovic Milhau, and Mark Lautens*
DaVenport Laboratories, Department of Chemistry, UniVersity of Toronto, Toronto, Ontario, Canada M5S 3H6
Received August 11, 2005; E-mail: mlautens@chem.utoronto.ca
Table 1. Cycloadditions with Carbonyl-Substituted Dienesa
We have been developing approaches to hydronaphthalenes using
various stereo- and enantioselective ring-opening procedures. A
number of useful transformations have emerged but most are best
suited to preparing 1,2-substituted analogues.1 The need for methods
that directly form 1,4-substitution patterns is related to the diverse
biological activity observed with this “privileged” structural class.
Some methods are known,2-4 but simpler approaches are of interest.
A very attractive strategy is the Diels-Alder reaction between an
diene
R
X
Y
product
yieldb (%)
aryne (dehydrobenzene)5 and an acyclic diene (Scheme 1), but the
1a
1b
1c
1d
1e
1f
1g
1h
1i
Me
Ph
OEt
OEt
OEt
OBn
OH
OEt
OEt
N(i-Pr)2
OMe
OEt
H
H
H
H
H
H
H
H
2a
2b
2c
2d
2e
2f
2g
2h
2i
74
84
86
Scheme 1. Aryne Diels-Alder Reaction with Acyclic Dienes
3,4-ClPh
3,4-ClPh
3,4-ClPh
4-(MeO)Ph
4-(Me2N)Ph
Ph
78
(50)c
75
(0)d
54
Ph
Ph
Ph
Me
(0)e
80
1j
1k
Br
2j
2k
scope and utility of this approach have not been investigated in
depth since the first report by Wittig in the 1960s.6 Aryne Diels-
Alder (ADA) reactions with cyclic dienes are frequently utilized;
however, reactions with functionalized acyclic dienes are much less
common.7 A method leading to substituted 1,4-dihydronaphthalenes
would be highly desirable, especially if at least one of the
substituents could be a heteroatom or an easily manipulated
functional group. We now report a direct and stereoselective route
to cis-substituted dihydronaphthalenes via ADA reactions with
acyclic dienes and demonstrate the utility of the products with a
short synthesis of sertraline.
We began our study by reacting various acyclic 1,3-dienes with
benzyne generated from benzenediazonium-2-carboxylate (BDC)
using Friedman’s procedure.8 Ethyl sorbate 1a (1.2 equiv) and BDC
in 1,2-dichloroethane (DCE) at 60 °C gave the desired cycloadduct
2a cleanly by NMR (crude yield 60%). However, 2a and the excess
ethyl sorbate were inseparable by TLC and column chromatography.
We repeated the reaction using ethyl sorbate as the limiting reagent
with a slurry of an excess (∼2 equiv) of BDC in DCE at 60 °C to
provide 2a in 74% yield.9-11 Several other benzyne generation
methods were also investigated, all of which gave inferior results.9
We prepared a collection of functionalized dienes9 for screening
in the Diels-Alder reaction with benzyne (Table 1). Carbonyl-
substituted dienes were used since these are easy to synthesize via
Horner-Emmons-Wadsworth reactions. We observed that the
cycloaddition yields were consistently good, which is noteworthy
considering that reactions of cyclic dienes under similar conditions
with benzyne usually gave yields <70%. Dienyl esters and amides
(1h) gave clean reactions; however, dienyl acid 1e gave a complex
mixture, perhaps due to insertion into the O-H bond.5 Aryl
substituents with both electron-withdrawing and electron-donating
groups are tolerated (1c-f), except that the strongly electron-
donating dimethylamino group gave no trace of cycloadduct (1g).
The reaction can also proceed with some trisubstituted dienes. An
electron-withdrawing ester group in the 3-position gave quantitative
OMe
CO2Et
85f
a All reactions were performed according to the optimized conditions
detailed in the Supporting Information. b Isolated yield (NMR yield with
acetone or dichloromethane as standard is in parentheses). Unless otherwise
noted, all diene starting material was consumed. c Complex mixture. d No
reaction. e No reaction, but diene was consumed. f Isomerization of the
product occurred with flash chromatography.
yields by NMR (1k), though the product was unstable to column
chromatography with silica gel. A diene with a methyl group in
the 3-position (1i) was consumed in the reaction but gave no desired
product by NMR.12 The best result was obtained with a bromo group
(1j), which gave the product in 80% isolated yield. The expected
cis stereochemistry from a concerted [4+2] process was confirmed
by an X-ray structure of product 2h.9
Cycloadditions with NC-, NO2-, and O-substituted dienes are
also possible.9 Particularly with O-substituted diene 3, the ADA
reaction proceeds efficiently under the standard conditions with
BDC to generate 4 in 77% yield,13 or alternatively with benzyne
generated from 2-(trimethylsilyl)phenyl triflate and CsF in CH3-
CN (Scheme 2).14
Scheme 2. Cycloaddition with Heterosubstituted Diene
We have also adapted the ADA reaction to the preparation of
enantiomerically enriched products. Our first approach was to attach
a chiral auxiliary to a diene carbonyl group. Poor to moderate
diastereoselectivities (1:1 to 3.5:1) were obtained using several
different auxiliaries under our standard conditions with BDC.
However, excellent diastereoselectivities (>19:1) are obtained with
9
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J. AM. CHEM. SOC. 2005, 127, 15028-15029
10.1021/ja055498p CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
N-methylated and deprotected with a water-soluble Pd(0) catalyst16
to give sertraline, with NMR spectrum consistent with that reported
by workers at Pfizer.17
Table 2. Highly Diastereoselective Aryne Cycloadditions
In conclusion, we have reported that the aryne Diels-Alder
reaction with acyclic dienes is a useful method for the synthesis of
functionalized 1,4-dihydronaphthalenes. Reactions with electron-
withdrawing substituents on the diene generally proceed favorably,
indicating that an inverse electron-demand Diels-Alder pathway
might be operating in these cases. The first diastereoselective aryne
Diels-Alder reaction to provide enantiomerically enriched cy-
cloadducts was developed.
diene
R
X
Y
product
yield (%)
Acknowledgment. We thank AZRCM, NSERC, the ORDCF,
and the University of Toronto for funding of this research. C.D.
thanks the W. C. Sumner Foundation for a postgraduate fellowship.
S.S. thanks the Swiss National Science Foundation for a postdoc-
toral fellowship. L.M. thanks IUT Castres for an exchange visit to
Toronto. We also thank Dr. Alex Young for MS analysis, Dr. Alan
Lough for X-ray analysis, Dr. Tim Burrow for assistance with NMR
instruments, and Perkin-Elmer Canada for lending us an Isco
Companion automated chromatography system.
1l
Me
Ph
H
H
H
H
H
H
H
H
2l
60
48
40
45
51
1m
1n
1o
1l
2m
2n
2o
2p
3,4-ClPh
3,4,5-(MeO)Ph
Me
-OCH2O-
Oppolzer’s sultam, specifically when using benzyne generated from
2-(trimethylsilyl)phenyl triflate and CsF in CH3CN (Table 2). The
assignment of the diastereomers 2l and 2m is based upon ROESY
NMR measurements. In addition, this method was successfully
extended to cycloadditions with substituted arynes (2p, Table 2).
To demonstrate the utility of the alkoxycarbonyl-substituted 1,4-
dihydronaphthalenes as precursors to medicinally important prod-
ucts, a Curtius rearrangement was utilized as a key step in a
synthesis of racemic sertraline15 (Scheme 3). Moreover, 2n, which
Supporting Information Available: Experimental procedures,
additional data tables, characterization data, and 1H and 13C NMR
spectra for new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
References
(1) See for example: (a) Lautens, M.; Fagnou, K.; Hiebert, S. Acc. Chem.
Res. 2003, 36, 48 and references therein. (b) Lautens, M.; Fagnou, K.;
Yang, D. J. Am. Chem. Soc. 2003, 125, 14884. (c) Lautens, M.;
Dockendorff, C. Org. Lett. 2003, 5, 3695.
Scheme 3. Synthesis of Sertraline
(2) Via dissolving metal reductions: (a) See for example: Rabideau, P. W.;
Husted, C. A.; Young, D. M. J. Org. Chem. 1983, 48, 4149. (b) For a
review, see: Rabideau, P. W.; Marcinow, Z. Organic Reactions; John
Wiley and Sons Inc.: New York, 1992; Vol. 42.
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Chem. 2004, 69, 2257 and references therein.
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Am. Chem. Soc. 2000, 122, 571.
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Int. Ed. 2003, 42, 502.
(6) Wittig, G.; Du¨rr, H. Justus Liebigs Ann. Chem. 1964, 672, 55.
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Schmidt, R. Angew. Chem., Int. Ed. Engl. 1979, 18, 304. For a recent
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(8) Logullo, F. M.; Seitz, A. H.; Friedman, L. Org. Synth. 1968, 48, 12.
(9) See Supporting Information for details.
(10) DCE was previously reported to be a preferred solvent for the generation
of benzyne from BDC: Heaney, H.; Buxton, P. C.; Fensome, M.; Mason,
K. G. Tetrahedron 1995, 51, 2959.
(11) The addition of a catalytic amount of BHT as a radical inhibitor gave no
improvement in the yield.
(12) This substrate may be prone to, e.g., an ene reaction, which could lead to
a complex mixture of products. See for example ref 6.
(13) Cycloadduct 4 is made as mixture of diastereomers (∼2:1).
(14) We were inspired to try these conditions by a recent report by Mori and
co-workers: Sato, Y.; Tamura, T.; Mori, M. Angew. Chem., Int. Ed. 2004,
43, 2436.
is obtained almost diastereomerically pure in 40% (unoptimized)
yield, is a precursor for the corresponding asymmetric synthesis.
The Diels-Alder reaction between benzyne and dienyl ester 1d
proceeded in good yield using the standard protocol. Cycloadduct
2d was hydrogenated and deprotected in one pot without epimer-
ization or loss of the aryl chlorides to give acid 5. The benzyl ester
was essential, since the analogous ethyl ester could not be
hydrolyzed under basic conditions (KOH, THF/water, 60 °C; K2-
CO3, MeOH/water, room temperature) without epimerization of the
sensitive benzylic center alpha to the carbonyl group.
(15) For recent industrially relevant syntheses of sertraline, see for example:
(a) Vukics, K.; Fodor, T.; Fischer, J.; Fellegva´ri, I.; Le´vai, S. Org. Process
Res. DeV. 2002, 6, 82. (b) Colberg, J. C.; Taber, G.; Pfisterer, D. M. Org.
Process Res. DeV. 2004, 8, 385.
The Curtius rearrangement of 5 was best conducted by formation
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slow addition to a hot solution (90 °C) of allyl alcohol in toluene.
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(16) Geneˆt, J. P.; Lemaire-Audoire, S.; Savignac, M.; Blart, E.; Bernard, J.-
M. Tetrahedron Lett. 1997, 2955.
(17) DeNinno, M. P.; Eller, C.; Etienne, J. B. J. Org. Chem. 2001, 66, 6988.
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