Facile syntheses of substituted, conformationally-constrained benzoxazocines and benzazocines via sequential multicomponent assembly and cyclization

Article abstract of DOI:10.1016/j.tetlet.2011.10.022

A multicomponent assembly process (MCAP) was utilized to prepare versatile intermediates that are suitably functionalized for subsequent cyclizations via Ullmann and Heck reactions to efficiently construct substituted 2,6-methanobenzo[b][1,5]oxazocines an

Full text of DOI:10.1016/j.tetlet.2011.10.022

Tetrahedron Letters 52 (2011) 6855–6858
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Facile syntheses of substituted, conformationally-constrained
benzoxazocines and benzazocines via sequential multicomponent assembly and
cyclization
⇑
James J. Sahn, Stephen F. Martin
Department of Chemistry and Biochemistry, Texas Institute for Drug and Diagnostic Development, The University of Texas, Austin, TX 78712, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A multicomponent assembly process (MCAP) was utilized to prepare versatile intermediates that are
suitably functionalized for subsequent cyclizations via Ullmann and Heck reactions to efficiently con-
struct substituted 2,6-methanobenzo[b][1,5]oxazocines and 1,6-methanobenzo[c]azocines, respectively.
The intramolecular Ullmann cyclization was conducted in tandem with an intermolecular arylation that
enabled the rapid syntheses of a number of O-functionalized methanobenzoxazocines.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 25 August 2011
Revised 4 October 2011
Accepted 6 October 2011
Available online 15 October 2011
Keywords:
Benzoxazocine
Benzazocine
Multicomponent assembly process
Imine
Cyclization
An effective approach for discovering new lead compounds for
drug development programs and for identifying molecular probes
to study biological systems involves screening of chemical libraries
based upon privileged scaffolds.1 By varying the nature of periph-
eral substituents on these molecular frameworks, it is often possi-
ble to obtain hits across a wide range of biological targets. Toward
developing a general approach to the synthesis of heterocyclic
scaffolds comprising privileged substructures, we designed a novel
strategy for diversity-oriented synthesis (DOS) that featured a mul-
ticomponent assembly process (MCAP) involving Mannich-type
reactions to give substituted aryl methylamine derivatives.2–4
These adducts can be subjected to various cyclization reactions
that are enabled by selective functional group pairing to construct
substituted heterocyclic ring systems. We have demonstrated the
utility of this approach by applying it to syntheses of small libraries
of diversely substituted benzodiazepines,5 norbenzomorphans,6
aryl piperidines,7 and tetrahydroisoquinolines.8 We now report
the extension of this useful methodology to the facile preparation
of compounds having conformationally-constrained benzoxazo-
cines 1 and benzazocines 2 as key structural subunits (Fig. 1).
Methylene-bridged benzoxazocines and benzazocines have re-
ceived attention owing to their favorable biological profiles. For
example, benzoxazocines related to 5, which were prepared in five
steps from 4-methylpyridine (3) (Eq. 1), exhibit analgesic, hypo-
tensive, and CNS stimulating activities,9 whereas benzazocines
similar to 8, which have been prepared in a six-step sequence from
indene (6) (Eq. 2), have shown moderate antinociceptive activity
Figure 1. Generic structures of conformationally-constrained benzoxazocines 1
and benzazocines 2.
⇑
Corresponding author.
E-mail address: sfmartin@mail.utexas.edu (S.F. Martin).
Figure 2. Previous syntheses of benzoxazocine 5 and benzazocine 8.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.022

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J. J. Sahn, S. F. Martin / Tetrahedron Letters 52 (2011) 6855–6858
15 and tetrahydroazepine 16 were produced in excellent overall
yields from 12. Because these compounds serve as key intermedi-
ates, it is notable that they could be easily prepared on a multigram
scale.
With 15 in hand, our next objective was to stereoselectively
introduce a hydroxyl group at C(4) of 15 cis to the aryl moiety
for the planned etherification reaction. Because hydroxyl groups
may be further derivatized by a number of refunctionalizations,
we elected to dihydroxylate 15 so that the product benzoxazocine
would contain a free hydroxyl group. Accordingly, tetrahydropyri-
dine 15 was subjected to Woodward’s dihydroxylation condi-
tions14 to form the vicinal diol 17 as a single diastereomer
(Scheme 3). The stereochemical outcome of this transformation
was presumably dictated by the pseudoaxial orientation of the aryl
group that results from A1,3-strain15 with the carbamate group.
Syn-dihydroxylation from the more hindered face of the olefin,
which is consistent with the mechanism of the Woodward dihydr-
oxylation, then gave 17 in 60% yield. We envisioned that the cycli-
zation of 17 by an intramolecular Ullmann reaction would also be
facilitated by A1,3-strain that would favorably position the aryl bro-
mide proximal to the hydroxyl group at C(4). Indeed, when diol 17
was heated with CuI, 3,4,7,8-tetramethyl-1,10-phenanthroline
(19), and Cs2CO3 in toluene according to the protocol of Buch-
wald,16 benzoxazocine 18 was obtained in 87% yield. The intramo-
lecular Ullmann cyclization of 17 represents a novel entry to this
bridged tricyclic scaffold.
Although the C(3) hydroxyl group of 18 might be employed in
bimolecular Ullmann coupling reactions, we were intrigued by
the more attractive possibility of accessing 3-O-arylated ben-
zoxazocines directly from diol 17. Specifically, we queried whether
it might be feasible to develop a one-pot transformation that
would feature both intra- and intermolecular Ullmann reactions.
Indeed, we discovered that when 18 was heated with an aryl io-
dide, base, CuI, and 19 in toluene (method A), a tandem double Ull-
mann reaction ensued to give aryl ethers 20 and 21 in 52% and 48%
yields, respectively (Table 1, entries 1 and 2). This procedure was
Scheme 1. General approaches to conformationally-constrained benzoxazocines 1
and benzazocines 2 from 2-bromobenzaldehydes 9.
(Fig. 2).10 Because routes to both of these scaffolds and their ana-
logs are rare,11 there is an unmet need for the development of flex-
ible approaches for their synthesis that enable facile diversification
for biological screening.
Although the routes depicted in Eqs. 1 and 2 do provide access
to analogs of 1 and 2, they are somewhat lengthy and not well sui-
ted for the facile syntheses of polysubstituted derivatives. Accord-
ingly, we envisioned a unified approach to both scaffolds might be
developed using an MCAP involving substituted bromobenzalde-
hydes 9 to assemble intermediates that could be readily trans-
formed into substituted piperidines 10 and azepines 11 by a ring
closing metathesis (RCM) (Scheme 1).12,13 Stereoselective vic-
dihydroxylation of 10 followed by an Ullmann cyclization would
lead to compounds of the general structure 1, whereas cyclization
of 11 via a Heck reaction followed by reduction would afford meth-
anobenzazocines 2. Since a vast array of substituted bromobenzal-
dehydes is readily available, it is conceivable that a more diverse
collection of compounds could be obtained. For example, we previ-
ously demonstrated that our MCAP/cyclization strategy may be ap-
plied to the preparation of scaffolds containing aryl chlorides,
which can be easily derivatized through various cross-coupling
reactions.6 We now report the reduction of the plan adumbrated
in Scheme 1 to practice as exemplified by the syntheses of deriva-
tives of 1 and 2 that incorporate functional handles that may be
exploited for further diversification reactions.
The first step toward implementing the plan outlined in Scheme
1 involved condensation of o-bromobenzaldehyde (12) with allyl-
amine, followed by treatment with methyl chloroformate and
allylzinc bromide to give 13 in 94% yield (Scheme 2). In a similar
fashion, 12 was treated sequentially with 1-amino-3-butene, ben-
zyl chloroformate, and allylzinc bromide to furnish 14 in 86% yield.
Although the stated yields for carbamates 13 and 14 are for puri-
fied materials, it is important from a practical standpoint that they
are of sufficient purity to use directly in the next step. When the
dienes 13 and 14 were subjected to ring closing metathesis
(RCM) using Grubbs 2nd generation catalyst, tetrahydropyridine
A1,3–strain
4
Br
i) I2, AgOAc, AcOH
ii) H2O
OH
4
OH
Br
O
N
N
CO2Me iii) KOH, MeOH
60%
15
OMe
17
30 mol % CuI
60 mol % 19
O
OH
N
N
Cs2CO3, toluene, Δ
3
O
N
87%
OMe
19
18
Scheme 3. Synthesis of benzoxazocine 18 via Ullmann reaction.
H2N
i)
O
n
RO2C
n
N
n
4 Å MS, CH2Cl2
Grubbs II
CH2Cl2
N
ii) ROCOCl, –78 o
iii) allylzinc bromide
C
CO2R
Br
Br
Br
12
13: n = 1, R = Me (94%)
14: n = 2, R = Bn (86%)
15: n = 1, R = Me (96%)
16: n = 2, R = Bn (91%)
Scheme 2. Multicomponent assembly processes followed by RCM reactions.

J. J. Sahn, S. F. Martin / Tetrahedron Letters 52 (2011) 6855–6858
6857
Table 1
the syntheses of 24–27 (Scheme 4). For example, benzylation and
acylation of the free OH group in 18 with 28 and 29, respectively,
afforded the corresponding ether 24 and ester 25. Propargylation of
18 followed by a Huisgen [3+2] cycloaddition with the aryl azide
30 delivered triazole 26 in 97% overall yield from 18. Finally, a SNAr
reaction between 18 and 2-chloropyrimidine (31) provided the O-
arylated benzoxazocine 27.
The relative orientation of the substituents on 17 is well suited
to the purpose of appending additional fused rings as illustrated by
the use of 17 in two different ring forming reactions to deliver no-
vel heterocyclic scaffolds. Bis-O-allylation of 17 gave a diene inter-
mediate that underwent a RCM reaction in the presence of Grubbs
2nd generation catalyst to form the piperidino-1,4-dioxocine 32
(Scheme 5). Alternatively, when a mixture of 17 and 2,3-dichloro-
pyrazine was treated with NaH in DMF, the fused tricycle 33 was
obtained via a double SNAr reaction in 51% yield.
One-pot synthesis of O-arylated benzoxazocines from diol 17.
OH
OH
ArX
O
OAr
N
N
O
CuI, Cs2CO3,19
toluene, Δ
CO2Me
OMe
Br
17
20-23
Entry
1
ArX
Method
a
Compound
Yield (%)
MeO
I
20
52
48
2
a
21
I
Having developed a facile entry to several bridged benzoxazo-
cines, we turned our attention to the preparation of the bridged
benzazocine 36. Toward this goal, 16 was subjected to an intramo-
lecular Heck cyclization in the presence of Bu4NCl4a,17 to provide a
readily separable mixture (1.3:1.0) of benzazocine isomers 34 and
35 in 79% yield. Although attempts to isomerize 35 to the thermo-
dynamic enecarbamate product 34 were unsuccessful,18,6 the iso-
mers were successfully converged to 36 via complementary
reducing conditions. Namely, ionic reduction19 of 34 employing
Et3SiH and TFA and catalytic hydrogenation of 35 with Adam’s cat-
alyst gave 36 in 59% and 96% yields, respectively (Scheme 6). Con-
strained benzazocine 36 is well suited for analog synthesis via N-
derivatization. Moreover, we have shown that the use of chlori-
nated bromobenzaldehyde inputs in the MCAP leads to benzoxazo-
cines possessing aromatic functional handles, thereby enabling a
broad range of diversification reactions.6
In summary, we have extended our original MCAP/cyclization
strategy to generate intermediates that can be quickly elaborated
into conformationally constrained benzoxazocines and benzazo-
cines. Our approach to O-arylated benzoxazocines was improved
through the development of a one-pot double Ullmann reaction,
in which functionalized benzoxazocines were obtained in only four
steps from commercially available starting materials. Furthermore,
CN
Cl
3
4
b
b
22
23
53
54
Me
N
N
Br
efficacious for aryl iodide coupling partners, but we found that
such reactions with halopyridines proceeded to give 22 and 23 in
only about 30% yields. This decrease in yield is attributed to com-
petitive intermolecular bis-arylation of diol 17, a process that was
observed to a much lesser extent with aryl iodide coupling part-
ners. We soon discovered that the undesired bis-arylation could
be avoided if the halopyridine component was introduced after
the initial cyclization was complete. Accordingly, diol 17, CuI, 19
and base were heated in toluene until 17 had been consumed
(TLC), whereupon the appropriate halopyridine was added (meth-
od B). In this manner 22 and 23 were obtained in 53% and 54%
yields, respectively (entries 3 and 4).
The benzoxazocine scaffold 18 was an excellent embarkation
point for other O-derivatization processes as is exemplified by
O
O
1. NaH, DMF
propargyl bromide
28
O
O
N
N
CO2Me
MeO2C
NaH, DMF
76%
2. 30, CuI,
Na ascorbate
N
N
N
97%
(2 steps)
24
O
O
MeO
26
18
O
O
29
31
O
N
O
O
N
N
NEt3, CH2Cl2
76%
NaH, DMF
89%
CO2Me
MeO2C
N
25
27
Ph
O
N3
N
Cl
O
Cl
Br
N
O
Ph
MeO
28
29
30
31
Scheme 4. Syntheses of benzoxazocine derivatives 24–27.

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J. J. Sahn, S. F. Martin / Tetrahedron Letters 52 (2011) 6855–6858
N
N
N
N
Cl
Cl
O
1. allyl bromide
NaH, DMF
O
N
OH
N
O
OH
O
Br
88%
N
2. Grubbs II
CH2Cl2, Δ
NaH, DMF
51%
CO2Me
CO2Me
CO2Me
Br
Br
51%
32
17
33
Scheme 5. Fused scaffolds from diol 17.
V. J.; Cerino, D. J.; Chen, T. B.; Kling, P. J.; Kunkel, K. A.; Springer, J. P.; Hirshfield,
J. J. Med. Chem. 1988, 31, 2235–2246; (b) DeSimone, R. W.; Currie, K. S.; Darrow,
J. W.; Mitchell, S. A.; Pippin, D. A. Comb. Chem. High Throughput Screening 2004,
7, 473–493; (c) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003, 103,
893–930; (d) Constantino, L.; Barlocco, D. Curr. Med. Chem. 2006, 13, 65–85.
2. For the first example of this process, see: Martin, S. F.; Benage, B.; Hunter, J. E. J.
Am. Chem. Soc. 1988, 110, 5925–5927.
3. For a review of such strategies, see: Sunderhaus, J. D.; Martin, S. F. Chem. Eur. J.
2009, 15, 1300–1308.
4. (a) Sunderhaus, J. D.; Dockendorff, C.; Martin, S. F. Org. Lett. 2007, 9, 4223–
4226; (b) Sunderhaus, J. D.; Dockendorff, C.; Martin, S. F. Tetrahedron 2009, 65,
6454–6469.
5. Donald, J. R.; Martin, S. F. Org. Lett. 2011, 13, 852–855.
6. Sahn, J. J.; Su, J. Y.; Martin, S. F. Org. Lett. 2011, 13, 2590–2593.
7. Hardy, S.; Martin, S. F. Org. Lett. 2011, 13, 3102–3105.
8. Granger, B. A.; Kaneda, K.; Martin, S. F. Org. Lett. ASAP.
9. Raj, K. R.; Harry, G. P. Beecham Group LTD, DE 1908324-(A1), 19690911.
10. Mazzocchi, P. H.; Stahly, B. C. J. Med. Chem. 1981, 24, 457–462.
11. For benzo-fused analogs of 8, see: (a) Confalone, P. N.; Huie, E. M. J. Org. Chem.
1987, 52, 79–83; (b) Stein, R. P.; Delecki, D. J. American Home Prod.; US
19770817392 19770720.; (c) Houlihan, W.; Nadelson, J. Sandoz; US D3781270
19710913.
12. For reviews of applications of RCM to the synthesis of heterocycles and natural
products, see: (a) Deiters, A.; Martin, S. F. Chem. Rev. 2004, 104, 2199–2238; (b)
Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4490–
4527.
13. For some applications of RCM to alkaloid synthesis, see: (a) Martin, S. F.; Liao,
Y.; Wong, Y.; Rein, T. Tetrahedron Lett. 1994, 35, 691–694; (b) Martin, S. F.;
Chen, H. J.; Courtney, A. K.; Liao, Y.; Pätzel, M.; Ramser, M. N.; Wagman, A. S.
Tetrahedron 1996, 52, 7251–7264; (c) Fellows, I. M.; Kaelin, D. E., Jr.; Martin, S.
F. J. Am. Chem. Soc. 2000, 122, 10781–10787; (d) Kirkland, T. A.; Colucci, J.;
Geraci, L. S.; Marx, M. A.; Schneider, M.; Kaelin, D. E., Jr.; Martin, S. F. J. Am.
Chem. Soc. 2001, 123, 12432–12433; (e) Humphrey, J. M.; Liao, Y.; Ali, A.; Rein,
T.; Wong, Y.-L.; Chen, H.-J.; Courtney, A. K.; Martin, S. F. J. Am. Chem. Soc. 2002,
124, 8584–8592; (f) Washburn, D. G.; Heidebrecht, R. W., Jr.; Martin, S. F. Org.
Lett. 2003, 5, 3523–3525; (g) Neipp, C.; Martin, S. F. J. Org. Chem. 2003, 68,
8867–8878; (h) Brenneman, J. B.; Machauer, R.; Martin, S. F. Tetrahedron 2004,
60, 7301–7314; (i) Andrade, R. B.; Martin, S. F. Org. Lett. 2005, 7, 5733–5735; (j)
Kummer, D. A.; Brenneman, J. B.; Martin, S. F. Tetrahedron 2006, 62, 11437–
11449; (k) Simila, S. T. M.; Martin, S. F. J. Org. Chem. 2007, 72, 5342–5349; (l)
Deck, J. A.; Martin, S. F. Org. Lett. 2010, 12, 2610–2613; (m) Cheng, B.;
Sunderhaus, J. D.; Martin, S. F. Org. Lett. 2010, 12, 3622–3625.
14. Woodward, R. B.; Brutcher, F. V. J. Am. Chem. Soc. 1958, 80, 209–211.
15. For reviews on A1,3-strain, see: (a) Johnson, F. Chem. Rev. 1968, 68, 375–413; (b)
Hoffmann, R. F. Chem. Rev. 1989, 89, 1841–1860.
Scheme 6. Bridged benzazocine 36 from an intramolecular Heck reaction.
diol 17 proved to be a versatile intermediate that could be diverted
toward novel, fused heterocyclic ring systems. Further applications
of this and related approaches to the syntheses of unique com-
pound libraries are in progress, and the results of these investiga-
tions will be reported in due course.
Acknowledgments
We thank the National Institutes of Health (GM 24539 and
86192) and the Robert A. Welch Foundation (F-0652) for their gen-
erous support of this work.
Supplementary data
Supplementary data (detailed experimental procedures and
characterization data of compounds 14, 16, 20–23, 24, 26, 27, 33,
and 36) associated with this article can be found, in the online ver-
sion, at doi:10.1016/j.tetlet.2011.10.022.
16. Altman, R. A.; Shafir, A.; Choi, A.; Lichtor, P. A.; Buchwald, S. L. J. Org. Chem.
2008, 73, 284–286.
17. Jeffrey, T. Tetrahedron Lett. 1985, 26, 2667–2670.
References and notes
18. Painter, F. F.; Wanner, K. T. Tetrahedron 1994, 50, 3113–3122.
19. Comins, D. L.; Weglarz, M. A. J. Org. Chem. 1991, 56, 2506–2512.
1. (a) Evans, B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R. M.; Freidinger, R. M.;
Whitter, W. L.; Lundell, G. F.; Veber, D. F.; Anderson, P. S.; Chang, R. S. L.; Lotti,