Synthesis of hexahydrochromeno[4,3-b]azepine derivatives

Article abstract of DOI:10.1016/S0040-4039(03)00890-6

Synthesis of optically pure (6aR,11aS)-7,8,9,10,11,11a-hexahydro-5-oxa-11- azacyclohepta[a]naphthalen-6a-ylamine from 2-cyano-6-oxazolopiperidine is described via the CN(R,S) strategy. The lithium aluminium hydride involves a one-pot reduction and a ring-

Full text of DOI:10.1016/S0040-4039(03)00890-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4219–4222
Synthesis of hexahydrochromeno[4,3-b]azepine derivatives
Gre´goire Pave´,a Jean-Michel Le´ger,b Christian Jarry,b Marie-Claude Viaud-Massuardc and
Ge´rald Guillaumeta,*
aInstitut de Chimie Organique et Analytique, UMR CNRS 6005, Universite´ d’Orle´ans, BP 6759, 45067 Orle´ans Cedex 2, France
bEA 2962 Pharmacochimie, UFR de Pharmacie, Universite´ Victor Segalen Bordeaux 2, 33076 Bordeaux Cedex, France
cGroupe de Recherche en Chimie Heterocyclique et The´rapeutique, EA 3247, UFR Sciences Pharmaceutiques,
Universite´ de Tours, 31 avenue Monge, 37200 Tours, France
Received 3 March 2003; revised 1 April 2003; accepted 4 April 2003
Abstract—Synthesis of optically pure (6aR,11aS)-7,8,9,10,11,11a-hexahydro-5-oxa-11-azacyclohepta[a]naphthalen-6a-ylamine
from 2-cyano-6-oxazolopiperidine is described via the CN(R,S) strategy. The lithium aluminium hydride involves a one-pot
reduction and a ring-enlargement process. Absolute configuration of the tricyclic derivative is unambiguously established by X-ray
crystal structure analyses. © 2003 Published by Elsevier Science Ltd.
1. Introduction
The stereoselective alkylation of the anion derived from
(3R,5S,8aR)-2-cyano-6-phenyloxazolopiperidine
with 1-bromo-2-(chloromethoxy)benzene
34
Several compounds owning the 3-aminochroman skele-
ton, synthesized in our laboratory, have shown a good
affinity and a good selectivity toward the serotoninergic
receptors 5-HT1A and 5-HT7.1 Due to the potential of
1,2-diamines2 as medicinal agents, we were attracted to
prepare compounds owning a 3-aminochromanic skele-
ton incorporating the 1,2-diamine functionality.
2
(LDA,
THF, −78°C) led to the bromo derivative 4 (Scheme 2).
This compound 4 was isolated as a single isomer in 75%
yield after flash chromatography on silica gel. The
absolute configuration at C-5 was (S) according to the
CN(R,S) strategy.3 Compound 4 was then involved in a
We report here the synthesis of (6aR,11aS)-7,8,
9,10,11,11a-hexahydro-5-oxa-11-azacyclohepta[a]naph-
thalen-6a-ylamine derivatives achieved through the
CN(R,S) strategy developed by Husson et al.3
Scheme 1.
2. Results and discussion
The electrophile 2 was obtained in a two-step procedure
starting from the commercially available 2-bromophe-
nol. Then, action of sodium hydride on this phenol in
solution in 1,2-dimethoxyethane followed by the addi-
tion of the chloromethylmethylsulfide led to the O,S-
acetal 1 in 84% yield (Scheme 1). Compound 2 was
obtained quantitatively from thiocompound 1 by action
of sulfuryl chloride in dichloromethane at room
temperature.
* Corresponding author. Tel.: (+33)-(0)2-3841-7073; fax: (+33)-(0)2-
3841-7281; e-mail: gerald.guillaumet@univ-orleans.fr
Scheme 2.
0040-4039/03/$ - see front matter © 2003 Published by Elsevier Science Ltd.
doi:10.1016/S0040-4039(03)00890-6

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narrow triplet, attributed to the bridgehead proton, was
1
observed at l 5.03 (J=2.1 Hz) in the H NMR spec-
trum of compound 5.
As shown in our previous paper,1f reduction of imine 5
with sodium cyanoborohydride in acidic conditions
afforded hemiaminal 6 and/or hemiacetal 7 according
to the chosen solvent (Fig. 1).
Figure 1. Reduction of imine 5 with NaBH3CN.
Different results were observed when the reduction of
imine 5 was performed with lithium aluminium hydride.
Although we still noticed an important influence of the
solvent choice. Indeed, as shown in Scheme 3, when the
reaction was performed in THF at −10°C, only reduc-
tion of the imine moiety into its corresponding amine
function occurred, leading to a 65/356 diastereoisomeric
mixture of compound 8 in 80% yield. On the other
hand, when this sequence was realized in Et2O at
−10°C, only diaminoalcohol 97 was isolated in 88%
yield. Such ring enlargement was recently discovered
and explained by Husson et al. in a less constrained
system.8
Scheme 3.
Finally, we had to cleave the chiral appendage. Thus,
treatment of compound 9 under classical hydrogenoly-
sis conditions furnished the desired diamine 109 in 68%
yield (Scheme 4).
The structure of the diamino derivative 10 was unam-
biguously established using X-ray crystallography (Fig.
2). The spatial group (P21) indicated that there is only
one isomer. This result can be used, in conjunction with
the previous datum concerning C-5 of compound 5, to
establish the (6aR,11aS) absolute configuration of 10.
Scheme 4.
A preliminary study of the reactivity of the 1,2-diamino
derivative 10 was achieved (Scheme 5). Thus, when 10
was treated with 1 equiv. of acetic anhydride in pyri-
dine, only the amide 11a was formed (Table 1, entry 1).
With regard to the sulfonylation, two cases were con-
sidered. When the reaction was performed in methylene
chloride with triethylamine and using 1 equiv. of sulfo-
nyl chloride derivatives, a separable mixture of mono-
sulfonamides on both positions was obtained in
moderate yield. On the other hand, when the reaction
was realized in pyridine using 1 equiv. of 4-bromoben-
Figure 2. ORTEP diagram of diamine 10.
Scheme 5.
halogen/metal exchange reaction using n-BuLi in THF
at −78°C. The lithiated intermediate led to a single
isomer of imine 5, isolated in 91% yield.
Table 1. Synthesis of amide 11a and sulfonamide 11b
Entry
Conditions
R
11
According to the literature,5 the formation of com-
pound 5 can be explained by the attack of an intermedi-
ate imine salt on the potential iminium ion at C-8a. A
1
2
Ac2O, pyridine
4-BrC6H4SO2Cl, pyridine
Ac
11a 87%
11b 81%
4-BrC6H4SO2

G. Pa6e´ et al. / Tetrahedron Letters 44 (2003) 4219–4222
4221
Supplementary Material
Analytical data for compounds 1, 2, 4–12 (this material
is available from the author) and description of crystal-
lographic methods. Further crystallographic data for
the structure 10 have been deposited with the Cam-
bridge Crystallographic Centre as supplementary publi-
cation number CCDC-205276. Copy of data can be
obtained free of charge on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK (fax: (+44)-
1223-336-033; e-mail: deposit@ccdc.cam.ac.uk).
Scheme 6.
zenesulfonyl chloride only the mono-sulfonamide 11b
was isolated (entry 2).
Acknowledgements
Such results enlighten the influence of the experimental
conditions on the behaviour of both amine centres
towards these reactions. But at the present time, no
explanation of this reactivity difference can be founded.
The authors thank the Ministe`re de la Jeunesse, de
l’Education Nationale et de la Recherche for a grant
(G.P.).
´
1
In order to prove the structure of compound 11, the H
References
NMR data of each compound could be consider.
Indeed, the H-11a signal of compound 10 (l=3.29
ppm) is very close to compounds 11 (l=3.39 ppm).
Moreover, the influence of the amide or sulphonyl
group on the primary amine involves a downfield shift
of one H-6 proton and one H-7 proton of compounds
11. Let us take for example, the case of the amide 11a.
H-6 protons of this compound represent two doublets
at l=3.83 and l=4.66 ppm. While for compound 10,
H-6 protons represent two doublet at l=3.31 and
l=3.64 ppm. The same analysis can be carried out for
the H-7 protons. Indeed, a H-7 proton of compound
11a is moved of l=1.80 ppm to l=2.59 ppm. These
observations indicate us that it is the primary amine
function which reacts under these condition. For sul-
fonamide 11b, the same remarks were observed.
1. (a) Podona, C.; Guardiola-Lemaˆıtre, B.; Caignard, D.-H.;
Adam, G.; Pfeiffer, B.; Renard, P.; Guillaumet, G. J. Med.
Chem. 1994, 37, 1779–1793; (b) Usse, S.; Pave´, G.; Guil-
laumet, G.; Viaud-Massuard, M.-C. Tetrahedron: Assym-
metry 2001, 12, 1689–1694; (c) Rezaie, R.; Joseph, B.;
Bremner, J. B.; Delagrange, P.; Kopp, C.; Misslin, R.;
Pfeiffer, B.; Renard, P.; Guillaumet, G. J. Pharm. Pharma-
col. 2001, 53, 959–968; (d) Comoy, C.; Marot, C.; Podona,
T.; Baudin, M.-L.; Morin-Allory, L.; Guillaumet, G.;
Pfeiffer, B.; Caignard, D.-H.; Renard, P.; Rettori, M.-C.;
Adam, G.; Guardiola-Lemaˆıtre, B. J. Med. Chem. 1996,
39, 4285–4298; (e) Usse, S.; Guillaumet, G.; Viaud, M. C.
J. Org. Chem. 2000, 65, 914–917; (f) Pave´, G.; Le´ger,
J.-M.; Jarry, C.; Viaud-Massuard, M.-C.; Guillaumet, G.
J. Org. Chem. 2003, 68, 1401–1408.
2. Lucet, D.; Le Gall, T.; Mioskowski, C. Angew. Chem., Int.
Ed. 1998, 37, 2580–2627 and references cited therein.
3. Husson, H.-P.; Royer, J. J. Chem. Soc. Rev. 1999, 28,
383–394 and references cited therein.
4. Bonin, M.; Grierson, D. S.; Royer, J.; Husson, H.-P. Org.
Synth. 1992, 70, 54–58.
A reductive amination of amine 10 was although per-
formed. Benzaldehyde, molecular sieves, and sodium
cyanoborohydride were added in a solution of 10 in
methanol (Scheme 6). A separable mixture of mono-
and dialkylated compounds was obtained when 1 equiv.
of the aldehyde was used. On the other hand, when 2
equiv. of the reactant were used, only dialkylated
derivative 12 was generated in 89% yield.
5. Froelich, O.; Desos, P.; Bonin, M.; Quirion, J.-C.; Husson,
H.-P. J. Org. Chem. 1996, 61, 6700–6705.
1
6. Ratio determined by H NMR.
7. Typical procedure for imine reduction. Preparation of 9: to
a suspension of LiAlH4 (0.36 g, 9.6 mmol) at −10°C in
diethylether (30 mL), imine 7 (0.4 g, 1.2 mmol) was added
portionwise. After stirring for 18 h, the solution was
hydrolyzed by NaOH (1N, 0.4 mL) and water (1.2 mL).
The mixture was stirred again for 18 h and filtrated
through celite pad. After concentration, the residue was
purified by flash chromatography (SiO2, CH2Cl2/MeOH
98:2) to furnish diaminoalcohol 9 as a white foam in 88%
yield (0.36 g).
8. Cutri, S.; Bonin, M.; Micouin, L.; Froelch, O.; Quirion,
J.-C.; Husson, H.-P. Tetrahedron Lett. 2000, 41, 1179–
1182.
9. Diamine (−)-10. Colourless crystal. mp=74°C. MS: 219
(M+1)+, 202 (M−NH2)+; [h]D20=−151 (c 1.0, CHCl3). 1H
NMR (250 MHz, CDCl3) (l, ppm; J, Hz): 1.31–1.87 (m,
3. Conclusion
In conclusion, synthesis of (6aR,11aS)-7,8,9,10,11,11a-
hexahydro-5-oxa-11-azacyclohepta[a]naphthalen-6a-
ylamine 10 was performed in four steps via the
CN(R,S) strategy in 41% overall yield, starting from
the 2-cyano-6-phenyloxazolopiperidine 3. The key step
involved an one-pot reduction and a ring-enlargement
process occurring in a highly regio- and stereoselective
way. The absolute configuration of diamine 10 was
unambiguously established by X-ray crystallography
(Fig. 2). A preliminary study of the reactivity of this
new diamine was realized.

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G. Pa6e´ et al. / Tetrahedron Letters 44 (2003) 4219–4222
ppm): 20.8, 32.2, 37.1, 52.7, 53.0, 65.0, 70.8, 116.2, 120.7,
9H), 2.94 (td, 1H, J=12.2, 2.8), 3.27 (d, 1H, J=2.2),
123.4, 128.2, 130.7, 152.8. Anal. calcd for C13H18N2O: C,
71.53; H, 8.31; N, 12.83. Found: C, 71.28; H, 8.34; N,
12.97%.
3.27–3.34 (m, 1H), 3.64 (dd, 1H, J=10.7, 2.2), 3.91 (d,
1H, J=10.7), 6.85 (d, 1H, J=8.1), 6.91 (td, 1H, J=8.1,
1.3), 7.12–7.22 (m, 2H); 13C NMR (62.5 MHz, CDCl3, l,