Chemistry in the ambient field of the alkaloid epibatidine, 2: Triphenylarsine as an efficient ligand in the Pd-catalyzed synthesis of epibatidine and analogs

Article abstract of DOI:10.1055/s-1999-2528

The key-step in the original synthesis of the N-protected form 4 of the highly analgetic, but also toxic alkaloid epibatidine (1) via Pd-catalyzed Heck-type hydroarylation gave only a moderate yield. With triphenylarsine as a ligand we obtained 4 in 81% yield and some partly new analogs 5 - 8 in racemic form in 75 to 100% yield. Further attempts to optimize the ligand properties led to the combination of As and N donor centers. The N-protected pyrrolidine derivative 10 beating a diphenylarsino substituent provided 4 in 92% yield.

Full text of DOI:10.1055/s-1999-2528

114
LETTER
Chemistry in the Ambient Field of the Alkaloid Epibatidine, 2:
Triphenylarsine as an Efficient Ligand in the Pd-Catalyzed Synthesis of
Epibatidine and Analogs
Jan Christoph Namyslo and Dieter E. Kaufmann
Technische Universität Clausthal, Institut für Organische Chemie, Leibnizstr. 6, D-38678 Clausthal-Zellerfeld, Germany
Fax +49(0)5323/72-28 34
E-mail: dieter.kaufmann@tu-clausthal.de
Received 1 October 1998
novel alkaloid 1 and together with our preliminary pub-
Abstract: The key-step in the original synthesis of the N-protected
lished synthesis of the azabicyclic alkene 21, epibatidine 1
form 4 of the highly analgetic, but also toxic alkaloid epibatidine (1)
is now obtainable in 59% overall yield starting from
bis(trimethylsilyl)acetylene.
via Pd-catalyzed Heck-type hydroarylation gave only a moderate
yield. With triphenylarsine as a ligand we obtained 4 in 81% yield
and some partly new analogs 5 - 8 in racemic form in 75 to 100%
yield. Further attempts to optimize the ligand properties led to the
combination of As and N donor centers. The N-protected pyrroli-
dine derivative 10 bearing a diphenylarsino substituent provided 4
in 92% yield.
Apart from a few exceptions the use of arsine ligands in
Pd-catalyzed reactions is a new synthetic procedure. An
early application, for example, was published in 1989 by
Trost and co-workers who used triphenylarsine in a Pd-
mediated cyclization of an allylic enyne.5 Farina et al.6
found an acceleration of the Stille-coupling and other re-
cent examples also deal with Stille-7 and Suzuki-type8 cou-
pling reactions. The Pd-catalyzed cross-coupling reaction
between organozinc halides and vinyl or aryl halides has
been investigated by Rossi et al.9 During our investiga-
tions Shibasaki documented Heck reactions performed
with arsine ligands.10
Keywords: alkaloids, palladium, C-C coupling, heterocycles,
ligand
Epibatidine (1)1 was isolated from an Ecuadorian poison
frog and characterized by Daly in 1992.2 From a synthet-
ical viewpoint we have focused on a convergent synthesis
using the Pd-catalyzed Heck-type hydro(het)arylation of
an appropriate bicyclic alkene 2.
Using triphenylarsine as a ligand, the C-C coupling step of
2-chloro-5-iodopyridine (3) with 2 was completed within
2 hours.11 We were very pleased to note that the undesired
reduction of the aryl derivative3 was driven back in favour
of the reductive hetarylation. With different carbo-, aza-
and oxabicyclic alkenes we obtained the corresponding
racemic hydroarylation products 5 – 812 in yields ranging
from 75 to 100%13 (Scheme 2, Table 1).
Scheme 1
After we had shown that a broad variety of both aryl and
hetaryl components3 can be attached to the bicyclic alkene
norbornene by this reaction type we published recently the
high-yielding synthesis of the N-protected epibatidine 4
and of some analogs1 applying a modified hydroarylation
procedure of Clayton and Regan.4 For example, with
triphenylphosphine as a ligand in the key-step we ob-
tained N-methoxycarbonyl protected epibatidine 4 in up
to 77% yield. Herein, we report the synthesis of 4 in yields
up to 92% using ligands with arsine donor centers in the
hydroarylation procedure. To the best of our knowledge,
this synthetic pathway is hitherto the shortest route to the
Scheme 2
Thus, triphenylarsine is a soft ligand, suitable for Heck-
type hydro-arylations, which enables high yields and short
reaction times. We should emphasize that in the case of
the benzo-anellated azabicyclic compound 7 the prelimi-
Synlett 1999, No. 1, 114–116 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Pd-Catalyzed Synthesis of Epibatidine and Analogs
115
nary observed opening of the nitrogen bridge (accompa-
nied by rearomatization into a naphthylamine and in the
presence of a hydride source into a 1,2-dihydronaphthyl
derivative, respectively)14,15, did not occur using an arsine
ligand.
Acknowledgment
We thank the DEGUSSA AG, Frankfurt, for a generous supply of
palladium salts, as well as the BAYER AG, Leverkusen, and the
Fonds der chemischen Industrie for financial support. We gratefully
acknowledge Dr. G. Remberg (Universität Göttingen) for HRMS
measurements.
References and Notes
(1) A. Otten, J. C. Namyslo, D. E. Kaufmann, Eur. J. Org. Chem.
1998, 1997-2001.
(2) T. F. Spande, H. M. Garaffo, M. W. Edwards, H. J. C. Yeh, L.
Pannell, J. W. Daly, J. Am. Chem. Soc. 1992, 114, 3475-3478.
(3) J. C. Namyslo, D. E. Kaufmann, Chem. Ber./Recueil 1997,
130, 1327-1331.
(4) S. C. Clayton, A. C. Regan, Tetrahedron Lett. 1993, 34, 7493-
7496.
(5) B. M. Trost, E. D. Edstrom, M. B. Carter-Petillo, J. Org. Chem.
1989, 54, 4489-4490.
(6) (a) V. Farina, B. Krishnan, J. Am. Chem. Soc. 1991, 113,
9585-9595 (b) V. Farina, G. P. Roth, Tetrahedron Lett. 1991,
32, 4243-246.
(7) (a) F. Bellina, A. Carpita, D. Ciucchi, M. De Santis, R. Rossi,
Tetrahedron 1993, 49, 4677-4698 (b) F. Bellina, A. Carpita,
M. De Santis, R. Rossi, Tetrahedron 1994, 50, 12029-12046
(c) Y. Obora, Y. Tsuji, M. Kobayashi, T. Kawamura, J. Org.
Chem. 1995, 60, 4647-4649 (d) M. A. Armitage, D. C. Lath-
bury, J. B. Sweeney, Tetrahedron Lett. 1995, 36, 775-776 (e)
V. Jeanneret, L. Meerpoel, P. Vogel, Tetrahedron Lett. 1997,
38, 543-546.
(8) (a) T. Gillmann, T. Weber, Synlett 1994, 649-650 (b) Y.-Q.
Mu, R. A. Gibbs, Tetrahedron Lett. 1995, 36, 5669-5672.
(9) (a) R. Rossi, F. Bellina, A. Carpita, R. Gori, Synlett. 1995,
344-346 (b) R. Rossi, F. Bellina, A. Carpita, F. Mazzarella,
Tetrahedron 1996, 52, 4095-4110 (c) R. Rossi, F. Bellina, D.
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Lett. 1997, 38, 3459-3460 (b) Y. Cho, M. Shibasaki, Tetrahe-
dron Lett. 1998, 39, 1773 -1776.
(11) General procedure for hydroarylation reactions: 5.6 mg (25
µmol) palladium(II) acetate and 55 µmol of the arsine ligand
were dissolved in 1.5 ml dry dimethylsulfoxide and stirred at
65 °C for 15 min. 1.00 mmol of the bicyclic alkene, 1.50 mmol
of the aryl compound, 488 µl (3.60 mmol) triethylamine, and
3.00 mmol of formic acid were added rapidly in one portion.
After stirring until conversion was completed (usually 2 hrs)
the reaction mixture was partioned between water and ethyl
acetate. The aqueous layer was extracted three times with
ethyl acetate. The resulting organic layer was dried over ma-
gnesium sulfate and the solvent finally evaporated. The crude
products 4 - 8 were purified by flash column chromatography
(SiO2, 40-64 µm).
These results prompted us to develop arsine ligands with
a chiral backbone to render the reductive coupling enan-
tioselective. Although numerous arsine ligands with a
chiral arsine donor atom are known, arsine ligands with a
chiral backbone are rare.16 One of the latter kind is
DIARSOP17, the arsino pendant to Kagan’s DIOP.18 Very
recent examples of chiral arsine ligands were published by
Shibasaki, who worked with BINAP-like, atropisomeric
arsine ligands.10 We have introduced a diphenylarsino
center into chiral aliphatic systems using an appropriate
organic bromide 9 and lithium diphenylarsenide.19,20 It is
noteworthy that the organoarsines with phenyl groups are
more stable than the corresponding phosphines, although
the tendency of the higher homologues to be oxidized in-
creases in the case of aliphatic substituents.21 The known
optically pure (S)-prolinol bismesylate22 gave the N-pro-
tected bromide 9 by Finkelstein reaction which afterwards
was converted into the new ligand (S)-Ms-ProDPAs 10.
(12) With comparable amounts of triphenylphosphine 7 was obtai-
ned in 18% yield: J. Klinge, Diploma thesis, TU Clausthal
1997. The aforementioned conditions gave 8 in 50% yield: H.-
M. Richter, Ph.D. thesis, TU Clausthal 1998.
Scheme 3
(13) Selected data for the epibatidine analogs 5, 7, 8, and the pyr-
rolidine-As,N ligand 10: 2-(6’-Chloro-3’-pyridyl)-nor-borna-
ne (5): m.p. 86 °C; Rf = 0.46 (SiO2, petroleum ether/ AcOEt
10:1); 1H NMR (400 MHz, CDCl3) δ = 1.15–1.65 (m, 7 H),
1.78 (ddd, J = 12.3, 9.0, 1.8 Hz, 1 H, 3-Hendo), 2.31 and 2.36
(s, 2 H, 1,4-H), 2.69 (dd, J = 8.8, 5.5 Hz, 1 H, 2-Hendo), 7.19 (d,
J = 8.0 Hz, 1 H, 5’-Hpyridyl), 7.45 (dd, J = 8.0, 2.4 Hz, 1 H,
4’-Hpyridyl), 8.20 (d, J = 2.4 Hz, 1 H, 2’-Hpyridyl); 13C NMR (100
MHz, CDCl3) δ = 28.6 (–), 30.3 (–), 35.9 (–), 36.8 (+), 38.9
With this As,N ligand in hand we obtained the protected
epibatidine 4 in 92% yield. Unfortunately, the asymmetric
induction was low (11 % ee). The results of further studies
on arsine ligands, in particular with chiral backbones, will
be published soon.
Synlett 1999, No. 1, 114–116 ISSN 0936-5214 © Thieme Stuttgart · New York

116
J. C. Namyslo, D. E. Kaufmann
LETTER
(–), 42.6 (+), 44.2 (+), 123.6 (+, Cpyridyl-5’), 137.2 (+, Cpyri-
dyl-4’), 141.5 (Cquat., Cpyridyl-3’), 148.3 (+, Cpyridyl-2’), 148.7
(Cquat., Cpyridyl-6’); MS (70 eV), m/z (%) = 207 (46) [M+], 164
fonyl-pyrrolidine, (S)-Ms-ProDPAs (10): 500 mg (64%); m.p.
23
97 °C; Rf = 0.23 (SiO2, petroleum ether/AcOEt 2:1); [α]D
=
–104.2° (c = 1.12, CHCl3); 1H NMR (400 MHz, CDCl3) δ =
1.77–2.09 (m, 4 H, CH2CH2), 2.20 (dd, J = 12.7, 10.7 Hz, 1
H, HCHAs), 2.72 (s, 3 H, SO2CH3), 2.77 (dd, J = 12.7, 3.7 Hz,
1 H, HCHAs), 3.29–3.42 (m, 2 H, NCH2), 3.85–3.93 (m, 1 H,
NCH), 7.28–7.38 (m, 6 H, Haryl), 7.40–7.45 (m, 2 H, Haryl),
7.51–7.56 (m, 2 H, Haryl); 13C NMR (100 MHz, CDCl3)
δ = 24.7 and 32.7 (–, 2 C, CH2CH2), 35.4 (–, CH2As), 35.7 (+,
SO2Me), 48.9 (–, NCH2), 58.9 (+, CHN), 128.4, 128.6, 128.7,
132.8, and 133.2 (+, 10 C, Caryl), 138.9 and 140.3 (Cquat., 2 C,
+
(11), 153 (7), 140 (100) [ClPy–CH=CH2 ], 127 (27), 114 (12),
104 (16); HRMS C12H14ClN requires: 207.0815; found:
207.0815. N-(Methoxycarbonyl)-2,3-benzo-5-(6’-chloro-3’-
pyridyl)-7-aza-bicyclo[2.2.1]hept-2-ene (7): m.p. 165 °C; Rf=
0.28 (SiO2 petroleum ether/AcOEt 3:1); 1H NMR (400 MHz,
CDCl3) δ = 1.98 (dd, J = 11.7, 8.7 Hz, 1 H, 6-Hendo), 2.13 (dd,
J = 12.2, 4.6 Hz, 1 H, 6-Hendo), 2.85 (dd, J = 8.7, 4.1 Hz, 1 H,
5-Hendo), 3.60 (s, 3 H, OCH3), 5.07 (br s, 1 H, 4-H), 5.33 (br s,
1 H, 1-H), 7.18–7.22 (m, 2 H, Haryl), 7.28–7.36 (m, 3 H, Haryl),
7.74 (dd, J = 8.3, 2.3 Hz, 1 H, 4’-Hpyridyl), 8.31 (d, J = 2.0 Hz,
1 H, 2’-Hpyridyl); 13C NMR (100 MHz, CDCl3) δ = 37.9 (–, C–
6), 42.7 (+, C–5), 52.7 (+, OMe), 61.3 (+, C-1), 67.0 (+, C-4),
119.9 and 120.2 (+, 2 C, Caryl), 124.3 (+, Cpyridyl-5’), 126.9 and
127.1 (+, 2 C, Caryl), 137.3 (+, Cpyridyl-4’), 138.6 (Cquat., Cpyri-
dyl-3’), 144.8 and 145.4 (Cquat., 2 C, C-2,3), 149.0 (+, Cpyri-
dyl-2’), 149.7 (Cquat., Cpyridyl-6’), 156.5 (Cquat., C=O); MS (70
eV), m/z (%) = 15 (100) [M+ +1], 176 (26) [M+ –ClPy–
Caryl); C18H22AsNO2S (391.36): calcd.
C 55.24 H 5.67 N 3.58 S 8.19 found C 55.33 H 5.79 N 3.30
S 8.00.
(14) C. Moinet, J.-C. Fiaud, Tetrahedron Lett. 1995, 36, 2051-
2052.
(15) J.-P. Duan, C.-H. Cheng, Organometallics 1995, 14, 1608-
1618.
(16) S. B. Wild, (Ed.: S. Patai) in The Chemistry of Organic Arse-
nic, Antimony and Bismuth Compounds, pp. 89-152, Wiley,
Chichester 1994.
+
+
CH=CH2 ], 140 (18) [ClPy–CH=CH2 ]; HRMS
C17H15ClN2O2 requires: 314.0822; found: 314.0822. 2-(6’-
Chloro-3’-pyridyl)-7-oxabicyclo[2.2.1]heptane (8): m.p. 74.5
°C; Rf = 0.32 (SiO2, petroleum ether/AcOEt 3:1); 1H NMR
(400 MHz, CDCl3) δ = 1.48–1.84 (m, 5 H), 2.09 (dd, J = 12.2,
8.9 Hz, 1 H, 3-Hendo), 2.88 (dd, J = 8.9, 4.5 Hz, 1 H, 2-Hendo),
4.38–4.42 (m, 1 H, 1-H), 4.68–4.78 (m, 1 H, 4-H), 7.23 (d, J =
8.2 Hz, 1 H, 5’-Hpyridyl), 7.67 (dd, J = 8.2, 2.4 Hz, 1 H, 4’-Hpy-
ridyl), 8.23 (d, J = 2.4 Hz, 1 H, 2’-Hpyridyl); 13C NMR (100 MHz,
CDCl3) δ = 29.5 (–), 30.1 (–), 41.8 (–), 45.6 (+), 76.3 (+), 82.3
(17) (a) A. D. Calhoun, W. J. Kobos, T. A. Nile, C. A. Smith, J. Or-
ganomet. Chem. 1979, 170, 175-179 (b) B. A. Murrer, J. M.
Brown, P. A. Chaloner, P. N. Nicholson, D. Parker, Synthesis
1979, 350-352.
(18) H. B. Kagan, T.-P. Dang, J. Am. Chem. Soc. 1972, 94, 6429-
6433.
(19) G. O. Doak, L. D. Freedman, Synthesis 1974, 328-338.
(20) We found that under ultrasonic conditions lithium pellets sus-
pended in a solution of triphenylarsine in THF were dissolved
within 8 hours.
(+), 124.2 (+, Cpyridyl-5’), 137.5 (+, Cpyridyl-4’), 140.8 (Cquat.
,
Cpyridyl-3’), 148.5 (+, Cpyridyl-2’), 149.2 (Cquat., Cpyridyl-6’); MS
(70 eV), m/z (%) = 209 (22) [M+], 180 (7) [M+ –C2H5], 165
(100), 130 (45); HRMS C11H12ClNO requires: 209.0607;
found: 209.0607.(S)-2-(Diphenylarsinomethyl)-1-methylsul-
(21) C. Elschenbroich, A. Salzer, in Organometallchemie, p. 191,
Teubner, Stuttgart 1990.
22. G. F. Cooper, Synthesis 1991, 859-860.
Synlett 1999, No. 1, 114–116 ISSN 0936-5214 © Thieme Stuttgart · New York