Syntheses of the opioid substructures 1,2,3,4,5,6-hexahydro-2,6-methano-3- benzazocine and 2,3,4,5-tetrahydro-1,5-methano-1H-2-benzazepine

Article abstract of DOI:10.1016/j.tetlet.2010.12.072

Concise syntheses of 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine (12) and 2,3,4,5-tetrahydro-1,5-methano-1H-2-benzazepine (18) are described and involve an intramolecular Friedel-Crafts alkylation and an intramolecular Heck cyclization as their respec

Full text of DOI:10.1016/j.tetlet.2010.12.072

Tetrahedron Letters 52 (2011) 953–954
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Syntheses of the opioid substructures 1,2,3,4,5,6-hexahydro-2,6-methano-3-
benzazocine and 2,3,4,5-tetrahydro-1,5-methano-1H-2-benzazepine
⇑
Jotham W. Coe , Paige R. Brooks, Michael G. Vetelino, Crystal G. Bashore, Krista Bianco, Andrew C. Flick
Pfizer Global Research & Development, Neurosciences Chemistry, Eastern Point Rd., Groton, CT 06340, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Concise syntheses of 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine (12) and 2,3,4,5-tetrahydro-1,5-
methano-1H-2-benzazepine (18) are described and involve an intramolecular Friedel–Crafts alkylation
and an intramolecular Heck cyclization as their respective key ring-forming steps.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 23 November 2010
Revised 15 December 2010
Accepted 16 December 2010
Available online 23 December 2010
Natural products owe their existence to selection pressures that
confer advantages to their host, giving these structures a central
role in organic, natural product, and medicinal chemistry re-
search.1 Linking their pharmacological action to structure often in-
spires medicinal research to develop the safest and most beneficial
treatments for disease.
Ph
PhLi, THF
BnCl
N
CH3
N
CH3
N
CH3
Ph
12% from 1
1 → 5 (4%)
1
2
3
ref. 4
H3C
30%
N
PPA, heat
The 1970s witnessed considerable synthetic effort in the opioid
field intended to elucidate the structural features responsible for
morphine’s antinociceptive properties.2 The objective was and re-
mains to identify molecules capable of providing pain relief with
reduced reinforcement and addictive qualities. Advancing an
understanding of the distinct structure–pharmacology relation-
ships necessary for addiction and antinociception is central to this
research effort. The minimum structural requirements that elicit
the desired pharmacology are defined through the study of molec-
ular topology, ligand–receptor interactions, and biological systems
interactions.3 The continued study of these interrelationships re-
quires available sources of material for further experimentation.
To support this we describe herein efficient syntheses of two
known opioid substructures, benzomorphan, or 1,2,3,4,5,6-hexa-
hydro-2,6-methano-3-benzazocine (12) and 2,3,4,5-tetrahydro-
1,5-methano-1H-2-benzazepine (18).
Ph
N
H3C
H
4
5
74%
6
5
→
(59%)
this work
Ph
CH3I, EtOH
NaBH4
80%
Ph
Ph
N
CH3
N
N
CH
8
6
7
3
Scheme 1. Approaches to benzazocine 5.
which was reduced with NaBH4 to give
protocol (80%).5 It should be noted that May reported a similar
pyridinium salt reduction which gave a 4:1 mixture of the D3
and
4-isomers.6 In our hands, the 4-tetrahydropyridine was
D
4-isomer 8 in a one-pot
-
D
D
the only reduction product formed in this reaction. Friedel–Crafts
cyclization of alkene 8 in hot PPA furnished benzomorphan 5, com-
pleting a high-yielding and scalable preparation of this bicyclic
ring system. In further attempts to improve the cyclization yield
we investigated amide and carbamate N-protection to circumvent
doubly protonated intermediates (i.e., 4), which in theory would
reduce cyclization temperatures by enhancing the stability of reac-
tive intermediates. These reactions returned only complex mix-
tures or starting materials. Even the N-benzyl derivative of 7
failed to cyclize, possibly due to poor solubility in hot PPA. These
results suggest the facility of the Friedel–Crafts cyclization arises
from the highly reactive nature of dicationic species 4.
Our approach to benzomorphan 12 (Scheme 1) refines the ap-
proach described by Kanematsu involving an intramolecular Fri-
edel–Crafts alkylation to access N-methyl benzomorphan
5
(Scheme 1) by improving the yield from 4% to 59%.4 Kanematsu’s
key intramolecular cyclization of tetrahydropyridine 3 presumably
involves a dicationic 4-piperidinium species 4 that places the two
cations as remotely as possible. Kanematsu accessed intermediate
3 in low yield via Stevens rearrangement (2 ? 3).
Our related route to 5 involves alternative access to transition
structure 4 via tetrahydropyridine isomer 8 giving greatly en-
hanced overall yields (6 ? 8 ? 5, 59%). The alkylation of 2-benzyl-
pyridine 6 with iodomethane forms N-methyl pyridinium salt 7
N-Methyl benzomorphan 5 was demethylated via the trichloro-
ethyl carbamate (Troc) intermediate 11 (Scheme 2).7 Standard con-
ditions (Troc–Cl, DCE, 80 °C) gave a mixture of desired product and
a co-eluting material (M+14)+, the elimination product 10. Addi-
⇑
Corresponding author.
E-mail address: jwcoe@pfizer.com (J.W. Coe).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.12.072

954
J. W. Coe et al. / Tetrahedron Letters 52 (2011) 953–954
OCH2CCl3
O
O
CCl3
I
HN
N
O
N
H3C
N
H3C
I
conditions
Zn, AcOH
55%
H
H
Cl
5
9
11
12
fragmentation
conditions
10
11
CH3
N
o
2.5 eq. Troc-Cl, DCE, 80
C
40%
5%
60%
95%
O
CCl3
o
1.1 eq. Troc-Cl, n-Bu NI, DCE, 80
C
4
O
o
1.5 eq. Troc-Cl, NaI, acetone , 40
C
0%
96%
10
Scheme 2. Troc-mediated N-demethylation of 5.
Acknowledgments
Pcy3
Ru
Pcy3
Ph
O
Cl
Cl
O
J.W.C. thanks Bertrand L. Chenard and Art Nagel for helpful sug-
gestions inspiring these approaches.
F3C
O
N
N
F3C
1) allylamine, MeOH
2) allylMgBr, Et2O
3) TFAA
2% Grubbs cat.
86 - 99%
H
100%
Supplementary data
Br
Br
Br
13
14
15
Supplementary data (experimental procedures and supporting
data for all compounds) associated with this article can be found
at doi:10.1016/j.tetlet.2010.12.072.
O
O
Pd(OAc)2, P(o-tol)3
F3C
N
F3C
N
HN
TEA, DMF
Na2CO3
65%
H2, Pd/C
91%
80 oC, 16 h
87%
References and notes
16
17
18
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Scheme 3. Metathesis–Heck route to bicyclic 18.
tional Troc–Cl was necessary to completely consume 5, as the HCl
formed in the pathway to 10 presumably protonates the starting
amine thereby protecting it from reaction with Troc–Cl. To en-
hance the nucleophilic pathway to 11 we introduced iodide ion,
which successfully circumvented the elimination pathway under
two conditions (see table, Scheme 2).8 Both reactions were com-
plete in less than 1 h with no elimination observed under the Fin-
kelstein conditions.9 Troc removal under standard conditions (Zn,
AcOH) provided 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazo-
cine (12) in four synthetic operations from 1 in 31% yield overall.
Benzazepine (18), a homolog of benzomorphan (12), was pre-
pared by a Heck-based sequence to generate the bicyclic core
(Scheme 3).10 The original preparation of 18 proceeded in eight-
steps and 3% yield overall.11 In our synthesis, 2-bromobenzalde-
hyde 13 was condensed with allylamine in MeOH and stripped of
solvent. After dissolving the residue in Et2O, the mixture was
cooled to À78 °C and then treated with allylMgBr. The resulting
salt was trapped in situ with trifluoroacetic anhydride to generate
14 in quantitative yield. Ring-closing metathesis converted this
crude material to tetrahydropyridine 15 reproducibly in excellent
yield. Standard Heck conditions afforded [3.2.1]-bicyclic adduct
16. The enamide was reduced by hydrogenation and the trifluoro-
acetamide was removed to give 2,3,4,5-tetrahydro-1,5-methano-
1H-2-benzazepine (18) in five steps and 50% overall yield for the
sequence.
4. Kanematsu, K.; Takeda, M.; Jacobson, A. E.; May, E. L. J. Med. Chem. 1969, 12,
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Ohmiya, H.; Yorimitsu, H.; Oshima, K. Chem. Lett. 2004, 33, 1240–1241; (c)
Panizzon, L. Helv. Chim. Acta 1944, 27, 1748–1756; (d) Yamashita, S.; Kurono,
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M.; Woodworth, G. F.; Morgan, B. P.; Coe, J. W. J. Org. Chem. 1999, 64, 9719–
9721.
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10948.
We used these compounds to examine their pharmacology as
described in the original work of the 1970s2 and in our effort to
discover varenicline.2a By modifying the original approach to ben-
zomorphan 12 and applying modern methodology to the prepara-
tion of benzazocine 19, efficient syntheses have been realized.
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Jacobsen, A. E.; Mokotoff, M. J. Med. Chem. 1970, 13, 7–9.