Synthesis of 3-Aminochroman Derivatives by Radical Cyclization

Article abstract of DOI:10.1021/ol0353215

(Equation presented) Enantiomerically pure 5-acetyl-3-amino-3,4-dihydro-2H- 1-benzopyran and methyl 3-amino-3,4-dihydro-2H-1-benzopyran-5-carboxylate were successfully synthesized starting from D- or L-serine. The formation of the benzopyran ring involved a radical cyclization step. The enantiomeric purities of the final aminochroman derivatives were determined by capillary electrophoresis using β-cyclodextrins as a chiral selector.

Full text of DOI:10.1021/ol0353215

ORGANIC
LETTERS
2003
Vol. 5, No. 23
4253-4256
Synthesis of 3-Aminochroman
Derivatives by Radical Cyclization
Gre´goire Pave´,† Ste´phanie Usse-Versluys,† Marie-Claude Viaud-Massuard,‡ and
,†
Ge´rald Guillaumet*
Institut de Chimie Organique et Analytique, UMR CNRS 6005, UniVersite´ d’Orle´ans,
BP 6759, 45067 Orle´ans Cedex 2, France, and Groupe de Recherche en Chimie
He´te´rocyclique et The´rapeutique, EA 3247, UFR Sciences Pharmaceutiques,
UniVersite´ de Tours, 31 aVenue Monge, 37200 Tours, France
gerald.guillaumet@uniV-orleans.fr
Received July 17, 2003
ABSTRACT
Enantiomerically pure 5-acetyl-3-amino-3,4-dihydro-2H-1-benzopyran and methyl 3-amino-3,4-dihydro-2H-1-benzopyran-5-carboxylate were
successfully synthesized starting from D- or L-serine. The formation of the benzopyran ring involved a radical cyclization step. The enantiomeric
purities of the final aminochroman derivatives were determined by capillary electrophoresis using â-cyclodextrins as a chiral selector.
Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter
of the central nervous system. The identification of multiple
serotonin receptor subtypes has triggered the discovery of
new drugs that alter 5-HT neurotransmission.1 Due to its
neuroprotective properties2 and its key role in many (patho)
physiological processes,3 the 5-HT1A receptor is a major
target for neurobiological research and drug development.
The 5-HT7 receptor is the most recent addition to the
serotonin subfamily of G-protein-coupled receptors.4 At the
present time, the biological functions of this receptor are still
unknown. Recent reports suggest that it could be involved
in the control of circadian rhythms5 or in the etiology of
depression.6 Due to the role of 5-HT1A and 5-HT7 receptors
in anxiety and depression, the synthesis of agonists appears
to be very attractive. In our laboratory, previous works7 have
led to new potential therapeutic agents that demonstrated
promising affinity and high selectivity toward the 5-HT1A
and 5-HT7 receptors. For example, compound 1a (Figure 1)
showed 0.3 and 3.9 nmol affinities toward these receptors,
respectively.7c
(5) (a) Bard, J. A.; Zgombick, J.; Adham, N.; Vaysee, P.; Branchek, T.
A.; Weinshank, R. L. J. Biol. Chem. 1993, 268, 23422. Ruat, M.; Traiffort,
E.; Leurs, R.; Tardivel-Lacombe, J.; Diaz, J.; Arrang, J.-M.; Schwartz, J.
C. Proc. Natl. Acad. Sci. U. S. A. 1993, 90, 8547. (c) To, Z. P.; Bonhaus,
D. W.; Eglen, R. M.; Jakeman, L. B. Br. J. Pharm. 1995, 115, 107. (d)
Shen, Y.; Monsma, F. J.; Metcalf, M. A.; Jose, P. A.; Hamblin, M. W.;
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R. A.; Rea, M. A.; Foye, P. E.; Rucke, M.; Slone, A. L.; Siegel, B. W.;
Danielson, P. E.; Sutcliffe, J. G.; Erlander, M. G. Neuron 1993, 11, 449.
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Pfeiffer, B.; Renard, P.; Guillaumet, G. J. Med. Chem. 1994, 37, 1779. (b)
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. (c) Rezaie,
R.; Joseph, B.; Bremner, J. B.; Delagrange, P.; Kopp, C.; Misslin, R.;
Pfeiffer, B.; Renard, P.; Guillaumet, G. J. Pharm. Pharmacol. 2001, 53,
959-968. (d) Usse, S.; Guillaumet, G.; Viaud, M. C. J. Org. Chem. 2000,
65, 914. (e) Usse, S.; Pave´, G.; Guillaumet, G.; Viaud-Massuard, M.-C.
Tetrahedron: Asymmetry 2001, 12, 1689. (f) Pave´, G.; Le´ger, J.-M.; Jarry,
C.; Viaud-Massuard, M.-C.; Guillaumet, G. J. Org. Chem. 2003, 68, 1401.
† Universite´ d’Orle´ans.
‡ Universite´ de Tours.
(1) (a) Baumgarten, H. G.; Go¨thert, M. Serotoninergic Neurons and
5-HAT Receptors in the CNS; Springer-Verlag: Berlin, 1997; Vol. 129.
(b) Martin, G. R.; Eglen, R. M.; Hoyer, D.; Hamblin, M. W.; Yocca, F.
Annals of the New York Academy of Sciences; New York Academy of
Sciences: New York, 1998; Vol. 861.
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845, 232. (b) Kamei, K.; Maeda, N.; Ogino, R.; Koyama, M.; Nakajima,
M.; Tatsuoka, T.; Ohno, T. Inoue, T. Bioorg. Med. Chem. Lett. 2001, 11,
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10.1021/ol0353215 CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/16/2003

3-hydroxybenzaldehyde provided ethers 3a-c in 90% yield
(R ) COCH3), 70% yield (R ) COOCH3), and 27% yield
(R ) CHO), respectively (Scheme 2). Cleavage of the
Scheme 2
Figure 1.
Parallel to our works, Johansson et al.8 achieved the
racemic syntheses of several 3-aminochroman derivatives
possessing a carbonyl group (ketone, ester, and amide) at
their C-5 position. These compounds were also used as
ligands for the serotoninergic receptors 5-HT1A. In this study,
enantiomerically pure amines were obtained by resolution
with tartric acid. Dixneuf et al. reported also an easy access
to 3-aminochroman derivatives by way of ruthenium-
catalyzed enantioselective hydrogenation of enamides9 and
ene carbamate.10 As the enantioselectivities observed in the
asymmetric hydrogenation were sometimes relatively low,
it appears to us that this methodology was not general enough
to be applied successfully to the synthesis of enantiopure
3-aminochromans.
In a previous paper,7e we reported the synthesis of both
enantiomers (-)-1b and (+)-1b starting from Garner’s
aldehyde and an appropriate electrophile. This reaction
involved an anionic step that could not be used due to the
presence of the carbonyl group.
isopropylidene protective group was accomplished by ad-
dition of p-toluenesulfonic acid on 3a-c in methanol at room
temperature. This reaction furnished the expected alcohols
4a-c in 81% yield (R ) COCH3), 66% yield (R )
COOCH3), and 38% yield (R ) CHO), respectively.
To realize the ring closure of alcohols 4 into their
corresponding 3-aminochroman derivatives by a radical
cyclization reaction, different activated compounds were
synthesized (Scheme 3). According to the literature,12 iodide
Scheme 3
Herein, we wish to report a stereocontrolled synthesis of
compound 1a and methyl 3-amino-3,4-dihydro-2H-1-ben-
zopyran-5-carboxylate (1c), a promising intermediate for the
synthesis of several C-5-functionalized 3-aminochroman
derivatives.8
Our synthesis began with the preparation of the chiral
alcohol 2 obtained in four steps starting from L-serine
(Scheme 1).11
Scheme 1
derivatives are more reactive than other halogeno com-
pounds. Then, the next step involved the replacement of the
hydroxyl group with an halogen and more interestingly by
an iodide.
Treatment of alcohols 4a-c with triphenylphosphine,
imidazole, and iodide in a mixture of toluene and acetonitrile
Treatment of the chiral alcohol 2 with triphenylphosphine
and diethyl azodicarboxylate at 80 °C in toluene with 1-(3-
hydroxy-phenyl)-ethanone, methyl 3-hydroxybenzoate, or
(10) Dupau, P.; Bruneau, C.; Dixneuf, P. H. Tetrahedron: Asymmetry
1999, 10, 3467.
(11) See Supporting Information and also: (a) Garner, P.; Park, J. M.
Org. Synth. 1992, 70, 18. (b) Dondoni, A.; Perrone, D. Synthesis 1997, 5,
527.
(8) Hammarberg, E.; Nordvall, G.; Leideborg, R.; Nylo¨f, M.; Hanson,
S.; Johansson, L.; Thorberg, S.-O.; Tolf, B.-O.; Jerning, E.; Svantesson, G.
T.; Mohell, N.; Ahlgren, C.; Westlind-Danielsson, A.; Cso¨regh, I.; Johans-
son, R. J. Med. Chem. 2000, 43, 2837.
(9) Dupau, P.; Le Gendre, P.; Bruneau, C.; Dixneuf, P. H. Synlett 1999,
11, 1832.
(12) Curran, D. P. In ComprehensiVe Organic Synthesis; Pergamon
Press: Elmsford, NY, 1991; Vol. 4, pp 715-831.
4254
Org. Lett., Vol. 5, No. 23, 2003

led to the expected iodide derivatives 5a in 79% yield (R )
COCH3), 5b in 73% yield (R ) COOCH3), and 5c in 37%
yield (R ) CHO).13 Compound 8c was obtained with a poor
overall yield. The cyclization step starting from this com-
pound was not envisaged. Starting from alcohol 4a, the
chloride derivative 5d was synthesized by addition of
triphenylphosphine and carbon tetrachloride in acetonitrile
in 45% yield. According to the high reactivity of xanthate
derivatives,14 their numerous advantages (e.g., no heavy or
toxic metals, concentrated solutions, etc.) and their known
utility as an easy and convenient source of radicals, xanthate
analogues of alcohols 4a,b were also obtained. The displace-
ment of iodide with the potassium salt of O-ethylxanthic acid
in acetonitrile at room temperature furnished the xanthate
derivatives 5e and 5f in 98 and 88% yields, respectively.
At this stage, several comments on the radical cyclization
can be made in anticipation of the results that will be shortly
described. As shown in Scheme 4, three compounds could
reduction of the radical is also possible and leads to
compound 8.
According to our strategy, the activated compounds
5a,b,d-f were involved in the radical cyclization step
(Scheme 5). As shown in Table 1, slow addition of tributyltin
Scheme 5
Scheme 4
hydride on the iodide derivative 5a gave the best overall
yield of cyclized aminochromans 6 and 9 (entries 1 and 2;
37 and 47% yields, respectively). Starting from the chloride
derivative 5c (less reactive than the corresponding iodide
compound), we noticed that the reduced compound 8 was
obtained preferentially in 47% yield (entry 3). When tribu-
tyltin chloride15 (5 equiv) was added to the reaction (entry
4), aminochroman 7 was obtained preferentially in 35% yield.
Indeed, as expected, this result is due to coordination between
the carbonyl group of the C-5 substituent and tributyltin
chloride as a Lewis acid. A steric repulsion occurs. We also
used tris(trimethylsilyl)silane16 (TTMSS) as a free-radical
mediator because this reagent has kinetic and thermodynamic
properties comparable to tributyltin hydride (entry 5). Then,
with the iodide derivative 5a, addition of TTMSS led to the
expected 3-aminochroman in 36% yield. Finally, starting with
xanthate 5e, addition of dilauroyl peroxide (DLP, 1.5 equiv)
in refluxing chlorobenzene led to cyclized products (89%),
including our expected bicyclic derivative 6 in 69% yield.
The favored formation of the 3-aminochroman derivative 6
may be explained by a reversible and degenerated pathway
into the catalytic cycle of the radical reaction.14 As described
for the generation of compound 6, xanthate 5f was involved
be generated starting from 5. After the formation of the
radical moiety, ring closure occurred between two positions.
On one hand, it can link between both substituents following
path A. This sequence leads to the expected 3-aminochroman
derivative 6 having the substitution in its C-5 position. On
the other hand, if the cyclization occurs on the other
accessible position (path B), the 3-aminochroman derivative
7 substituted in its C-7 position could be formed. Finally,
Table 1. Radical Cyclization: Conditions and Results
entry
R
X
conditions
compounds (yields)
6 + 7 or 9 + 10
1a
2b
3b
4b
5
COCH3
COCH3
COCH3
COCH3
COCH3
COCH3
COOCH3
I
I
Cl
I
I
Bu3SnH, AIBN, PhH, reflux
Bu3SnH, AIBN, PhH, reflux
Bu3SnH, AIBN, PhH, reflux
Bu3SnH, Bu3SnCl, AIBN, PhH, reflux
(Me3Si)3SiH, AIBN, PhCH3, reflux
DLP, PhCl, 80 °C
6 (23%)
6 (31%)
6 (21%)
6 (33%)
6 (36%)
6 (69%)
9 (56%)
7 (14%)
7 (16%)
7 (12%)
7 (35%)
7 (18%)
7 (20%)
8 (32%)
8 (34%)
8 (47%)
8 (23%)
8 (12%)
8 (<5%)
37%
47%
33%
68%
54%
89%
73%
6
7c
SCSOEt
SCSOEt
DLP, PhCl, 80 °C
10 (17%)
11 (<5%)
a Manual addition of Bu3SnH. b Syringe pump addition of Bu3SnH. c Yield determined by NMR.
Org. Lett., Vol. 5, No. 23, 2003
4255

in the radical cyclization step using DLP in refluxing
chlorobenzene. This reaction led to the 3-aminochroman 9
with the ester function on C-5.
Unfortunately, carbamate 9 could not be isolated by flash
chromatography and was obtained in an unseparable mixture
of compounds 10 and 11.
The tert-butoxycarbonyl group of compounds 6 and 9 was
removed with trifluoroacetic acid in methylene chloride to
give the desired aminochroman (S)-12 in 78% yield (Scheme
6). Amine 1c was easily isolated by flash chromatography
The enantiomeric purities of aminochromans 12 and 1c
were determined by capillary electrophoresis using â-cyclo-
dextrin as a chiral selector. In each case, we obtained the
desired enantiomer with an ee >99%.17
In conclusion, the syntheses of enantiomerically pure (3S)-
5-acetyl-3-amino-3,4-dihydro-2H-1-benzopyran (S)-12 and
(3S)-3-amino-3,4-dihydro-2H-1-benzopyran-5-carboxylic acid
methyl ester 1c were accomplished starting from alcohol 2
obtained from L-serine. The (R)-12 was synthesized using
an analogous route starting from D-serine with similar overall
yield. The key step of our synthesis was the radical
cyclization of the xanthate derivative into the 3-aminochro-
man skeleton.
Scheme 6
Acknowledgment. The authors thank Camille Dicke for
her help during this work and the Ministe`re de la Jeunesse,
de l’Education Nationale et de la Recherche for a grant (G.P.
and S.U.). The authors are very grateful to Professor P. Morin
and S. Zubrzycki (ICOA, Universite´ d’Orle´ans) for perform-
ing the capillary electrophoresis analyses.
Supporting Information Available: Characterization for
compounds 2 to 12. This material is available free of charge
via the Internet at http://pubs.acs.org.
in 43% yield (in two steps starting from 5f). The final step,
leading to the (+)-1a derivative, involved N,N-dialkylation
of compound (S)-12.7a
OL0353215
(13) Garegg, P. J.; Samuelsson, B. J. Chem. Soc., Chem. Commun. 1979,
979.
(14) Zard, S. Z. Angew. Chem., Int. Ed. Engl. 1997, 36, 672.
(15) Ishibashi, H.; Matsukida, H.; Toyao, A.; Tamura, O.; Takeda, Y.
Synlett 2000, 10, 1497.
(16) Ikeda, M.; Hamada, M.; Yamashita, T.; Matsui, K.; Sato, T.;
Ishibashi, H. J. Chem. Soc., Perkin Trans. 1 1999, 1949.
(17) Enantiomeric excess was determined by comparison of each
enantiomer with a racemic mixture of the corresponding amine.
(3R)-5-Acetyl-3-amino-3,4-dihydro-2H-1-benzopyran (R)-
12 was prepared according to the same synthetic pathway
starting from D-serine. All compounds were fully character-
1
ized (IR, H, 13C NMR, mass, and specific rotation), and
physical data are identical to those described for their
enantiomers.
4256
Org. Lett., Vol. 5, No. 23, 2003