A new access to efaroxan and its 5-amino derivatives

Article abstract of DOI:10.1016/j.tetlet.2007.11.108

The formal total synthesis of racemic efaroxan, a 2-disubstituted 2,3-dihydrobenzofuran having interesting therapeutic properties, and the preparation of some 5-amino derivatives were achieved using a convergent approach. The key intermediates of both syn

Full text of DOI:10.1016/j.tetlet.2007.11.108

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 715–718
A new access to efaroxan and its 5-amino derivatives
Thierry Lomberget *, Roland Barret
Laboratoire de Chimie The´rapeutique, Universite´ de Lyon, Lyon F-69003, France
Universite´ Lyon 1, ISPB, INSERM U-863, Hormones ste´ro¨ıdes et prote´ines de liaison, IFR 62,
8 Avenue Rockefeller, Lyon Cedex 08, F-69373, France
Received 25 September 2007; revised 19 November 2007; accepted 20 November 2007
Available online 23 November 2007
This Letter is dedicated to the memory of Charles Mioskowski who has brought an outstanding contribution
in all the fields of the Organic Chemistry, including efaroxan synthesis
Abstract
The formal total synthesis of racemic efaroxan, a 2-disubstituted 2,3-dihydrobenzofuran having interesting therapeutic properties,
and the preparation of some 5-amino derivatives were achieved using a convergent approach. The key intermediates of both syntheses
were obtained after a [3+2] cycloaddition reaction between two easily accessible partners.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: 2,3-Dihydrobenzofuran; Quinone imide; Hydrazone; Efaroxan
R1
R
Efaroxan (1), a 2,3-dihydrobenzofuranic derivative
5
2
HN
bearing an imidazoline ring, displays a range of interesting
biological activities. This compound in a racemic form was
originally designed as a powerful a2-adrenoceptor antago-
nist1 and further investigations have shown that biological
effects were related to the configuration of the asymmetric
centre at the 2-position (Fig. 1). The dextrorotatory enan-
tiomer2 was found to keep the selective a2-adrenergic
antagonist effect3 and was planned for the treatment of
neurodegenerative troubles such as Parkinson’s4 and
Alzheimer’s5 diseases.6 Its optical antipode isomer is
described as an imidazoline ligand7 that induces insulin
secretion, mediated by the blocking of ATP-sensitive
potassium channels in pancreatic b-cells, with a possible
application of treating diabetes.8
NH
O
N
O
CN
4
R = H : efaroxan 1
R = NR'2 : 5-amino derivatives 2
SO2R2
N
SO2R2
HN
+
N
N
O
N
N
O
6
5
Fig. 1.
5-amino analogues 2 (R ¼ NR02 where R0 could be H, alkyl,
aryl or sulfonyl groups) (Fig. 1).
Regarding to the potential clinical applications of efaro-
xan and to provide for medicinal chemists versatile syn-
thetic ways of this lead drug, we wish to describe herein a
new synthetic approach to racemic efaroxan as well as its
Although various 5-substituted efaroxan derivatives,
including 5-NH2,9 have been described in the literature,
we propose a new efficient convergent approach of com-
pounds 2 which could be useful for a fine-tuning of both
pharmacological activity and bioavailability of the parent
drug efaroxan.
*
Corresponding author. Tel.: +33 478 777 082; fax: +33 478 777 549.
E-mail address: thierry.lomberget@sante.univ-lyon1.fr (T. Lomberget).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.108

716
T. Lomberget, R. Barret / Tetrahedron Letters 49 (2008) 715–718
SO2R2
The direct precursor of the imidazoline-containing com-
SO2R2
HN
N
pound 1 is 2-ethyl-2,3-dihydrobenzofuran-2-carbonitrile
(3),10 as previously reported by many research groups.1a–c
This nitrile 3 is obtained from the corresponding 2-ethyl-
2,3-dihydrobenzofuran-2-carboxylic acid,11 usually using
a three step sequence: conversion of the acid into an acyl
chloride or an ester,12 formation of the amide which is sub-
mitted to dehydration under harsh conditions to give the
nitrile. In our synthetic approach, compound 3 could be
obtained after a deamination reaction of aniline 4
(R1 = H, Fig. 1) and the dimethylhydrazone functionality
in 2,3-dihydrobenzofuran 5 could be of prime interest for
the preparation of the cyano group via an oxidation step.
We have recently described an efficient synthesis of this
crucial intermediate 5, starting from phenylsulfonyl qui-
none monoimide 6 (R2 = Ph)13 and the appropriate azadi-
ene, 2-ethyl acrolein N,N-dimethylhydrazone (Fig. 1).14
With this efficient methodology in hand, we then
decided to apply this convergent approach to the 2,3-
dihydrobenzofuran core of efaroxan and its 5-amino
derivatives.
EtOH
5
+
0 °C
N
N
N
O
N
O
R2 = Ph : 6a
R2 = (CH2)2SiMe3 : 6b
90 %
83 %
5a
5b
Scheme 2.
the corresponding 2,3-dihydrobenzofuran 5b was isolated
in a very good 83% yield (Scheme 2).
The hydrazone moiety was converted into a nitrile with
the oxidative reagent magnesium bis(monoperoxyphtalate)
(MMPP)21 and the cleavage of the SES group in compound
7b was carried out using caesium fluoride, in DMF. For
this deprotection, the heating at 140 °C was necessary to
ensure a fast and complete conversion of the substrate into
the corresponding aniline in a very good 93% isolated yield
(Scheme 3).22
Although the phenylsulfonyl amide (R2 = Ph) could be
helpful in terms of solid-supported synthesis,15 the removal
of such group appears to be somewhat troublesome since it
requires a three step sequence.16 Indeed, the preparation of
efaroxan from intermediate 4 requires the removal of the
sulfonamide. A good alternative for the phenylsulfonyl
group lies in the use of 2-trimethylsilyl ethylsulfonyl
(SES) group which is easily cleaved by fluoride-promoted
b-elimination.17
The synthesis of the SES-protected quinone monoimide
6b was then realized in two steps: first N-sulfonylation with
SES chloride18 in dimethylformamide (DMF) in the pres-
ence of pyridine as a base and subsequent oxidation of
the sulfonamide with lead tetracetate in acetic acid in an
excellent 97% yield (Scheme 1).19
This protecting group opens up also a possible applica-
tion of our methodology for the elaboration of analogues
libraries since the water-soluble SES-functionalized poly-
ethylene glycol (PEG) polymer has been developed and
applied for the preparation of different compounds.20
The reaction between the quinone imide 6b, having a
SES group instead of a phenylsulfonyl one, proceeded well
under the developed conditions (slow addition of an alco-
holic solution of the quinone imide on the azadiene) as
A diazotation reaction of the aromatic free amine
followed by an in situ reductive step with sodium bisulfite
in ethanol23 afforded then 2-ethyl-2,3-dihydrobenzofuran-
2-carbonitrile 3 in a good global yield (36% yield from
p-aminophenol).24 The nitrile is the direct precursor of
the imidazoline ring of efaroxan 1: our strategy allowed
us to achieve a new formal total synthesis of this com-
pound (Scheme 3).
The synthesis of the 5-amino derivatives of this lead
compound was completed using a similar strategy, starting
from intermediates 5a,b.
After oxidation of the dimethylhydrazone functionality
with MMPP (MeOH, 0 °C, 30 min) into a cyano group
in very good yields (quantitative yield for 7a where
R2 = Ph), the sulfonamides were protected with a benzyl
group (Scheme 4). The synthesis of the target compounds
was completed by the formation of the imidazoline ring,
according to Chapleo’s method.1a This step was realized
SES
HN
SES
HN
c
N
97%
O
O
CN
CN
O
N
O
7b
5b
H2N
d
e
SO2
SO2
64%
93%
NH2
OH
HN
N
O
CN
3
a
b
SiMe3
SiMe3
ref. 1a
efaroxan 1
78%
97%
6b
OH
Scheme 1. Reagents and conditions: (a) Me3Si(CH2)2SO2Cl 1.0 equiv,
pyridine/DMF 1:2, 0 °C to rt, then rt for 2 h; (b) Pb(OAc)4 1 equiv, glacial
AcOH, rt, 1 h.
Scheme 3. Reagents and conditions: (c) MMPP 2 equiv, MeOH, 0 °C,
30 min; (d) CsF 4 equiv, DMF, 140 °C, 19 h; (e) NaNO2, AcOH/EtOH,
0 °C and then NaHSO3 solution in water, 0 °C, 2 h.

T. Lomberget, R. Barret / Tetrahedron Letters 49 (2008) 715–718
717
6. For a study on the effect of (+)-efaroxan on acetylcholine release in
the rat cortex, see: Tellez, S.; Colpaert, F.; Marien, M. Eur. J.
Pharmacol. 1995, 277, 113.
SO2R2
SO2R2
N
HN
f
Bn
5
7. For reviews on imidazoline binding sites, see: (a) Regunathan, S.;
Reis, D. J. Annu. Rev. Pharmacol. Toxicol. 1996, 36, 511; (b) Eglen, R.
M.; Hudson, A. L.; Kendall, D. A.; Nutt, D. J.; Morgan, N. G.;
Wilson, V. G.; Dillon, M. P. Trends Pharmacol. Sci. 1998, 19, 381; (c)
Darbonville, C.; Rozas, I. Med. Res. Rev. 2004, 24, 639.
CN
O
O
CN
R2 = Ph
7a
7b
8a 90%
8b 96%
R2 = (CH2)2SiMe3
8. (a) See Ref. 3a; For a deeper overview of interactions of (S)-(ꢀ)-
efaroxan with the putative subtype imidazoline I3 receptor: (b)
Morgan, N. G.; Chan, S. L. F.; Mourtada, M.; Monks, L.; Ramsden,
C. A. Ann. NY Acad. Sci. 1999, 881, 217; (c) Morgan, N. G. Exp.
Opin. Invest. Drugs 1999, 8, 575.
9. (a) Clews, J.; Morgan, N. G.; Ramsden, C. J. Heterocycl. Chem. 2001,
38, 519; The interest of 5-amino efaroxan derivative for the isolation
of imidazoline binding proteins was outlined in the literature: (b)
Chan, S. L. F.; Pallett, A. L.; Clews, J.; Ramsden, C. A.; Chapman, J.
C.; Kane, C.; Dunne, M. J.; Morgan, N. G. Eur. J. Pharmacol. 1998,
355, 67; (c) Monks, L. K.; Cosgrove, K. E.; Dunne, M. J.; Ramsden,
C. A.; Morgan, N. G.; Chan, S. L. F. FEBS Lett. 1999, 447, 61.
10. The formation of the imidazoline ring of efaroxan could also be
achieved from an ester, by using ethylene diamine in the presence of a
strong Lewis acid, AlMe3, in toluene: see Ref. 1d.
SO2R2
N
g
Bn
5
5-amino Efaroxan
derivatives
NH
O
N
R2 = Ph
2a 74%
2b 77%
R2 = (CH2)2SiMe3
Scheme 4. Reagents and conditions: (f) NaH 1.1 equiv, DMF, 50 °C,
BnBr 1.05 equiv, 1 h 30; (g) (1) 0.5 equiv MeONa, MeOH, 21 h, rt; (2)
1.3 equiv ethylenediamine, then 1.3 equiv HCl (1 M in MeOH), 0 °C to rt,
18 h.
11. (a) For the synthesis of racemic 2-ethyl-2,3-dihydrobenzofuran-2-
carboxylic acid, see: Ref. 1a–d; (b) Couture, K.; Gouverneur, V.;
Mioskowski, C. Biorg. Med. Chem. Lett. 1999, 9, 3023; (c) Mayer, P.;
Imbert, T.; Couture, K.; Gouverneur, V.; Mioskowski, C. PCT Int.
Appl. WO 00/02836, 2000; For the preparation of this acid in an
enantioenriched form by resolution of the racemate: (d) Imbert, T.;
Mayer, P. PCT Int. Appl. WO 96/35682, 1996.; For enantioselective
syntheses of this acid, see: Ref. 11c; (e) de Carvalho e Silveira, G. P.;
Coelho, F. Tetrahedron Lett. 2005, 46, 6477.
by first, formation of an imidate intermediate by alkaline
treatment of the nitrile with sodium methoxide in methanol
and then the reaction with a slight excess of ethylene di-
amine in the presence of hydrogen chloride. Compounds
2 were then obtained as their free base, after an alkaline
work-up with sodium bicarbonate, in good isolated yields
(Scheme 4).25
To conclude with this work, we have described an effi-
cient formal synthesis of racemic efaroxan and a versatile
approach to the corresponding 5-amino derivatives. After
the present validation of this synthetic pathway, further
developments of the described methodology for the prepa-
ration of enantioenriched compounds 3 and 2 are actually
under investigation and will be reported in due course.
12. For a synthesis of ( )-efaroxan involving nitrile 3, obtained from an
ester, see: Mioskowski, C.; Gouverneur, V.; Couture, K.; Lesimple,
P.; Autret, J.-M. PCT Int. Appl. WO 00/15624.
13. For several references on synthetic applications of arylsulfonylated
quinone monoimides, see: (a) Engler, T. A.; Chai, W.; Lynch, K. O.
Tetrahedron Lett. 1995, 36, 7003; (b) Engler, T. A.; Chai, W.;
LaTessa, K. O. J. Org. Chem. 1996, 61, 9297; (c) Engler, T. A.;
LaTessa, K. O.; Iyengar, R.; Chai, W.; Agrios, K. Bioorg. Med.
Chem. 1996, 4, 1755; (d) England, D. B.; Kerr, M. A. J. Org. Chem.
2005, 70, 6519; (e) England, D. B.; Magolan, J.; Kerr, M. A. Org.
Lett. 2006, 8, 2209; (f) Ganton, M. D.; Kerr, M. A. J. Org. Chem.
2007, 72, 574; (g) Jackson, S. K.; Kerr, M. A. J. Org. Chem. 2007, 72,
1405; (h) Lebold, T. P.; Kerr, M. A. Org. Lett. 2007, 9, 1883.
14. Lomberget, T.; Baragona, F.; Fenet, B.; Barret, R. Org. Lett. 2006, 8,
3919.
Acknowledgement
The authors would like to thank Dr. Denis BOUCHU
for his promptness in determining HRMS of compound 2a.
15. For a reference on the interest of resin-bound phenyl sulfonyl chloride
for solid-supported synthesis: ten Holte, P.; van Esseveldt, B. C. J.;
Thijs, L.; Zwanenburg, B. Eur. J. Org. Chem. 2001, 2965.
References and notes
16. The deprotection of phenyl sulfonamide into an amine was described
in the literature: first protection of the sulfonamide with a tert-
butoxycarbonyl group, then cleavage of the phenyl sulfonyl group
using sodium/anthracene and finally deprotection of the BOC group
with an acidic hydrolysis: Engler, T. A.; Chai, W. Tetrahedron Lett.
1996, 37, 6969.
1. (a) Chapleo, C. B.; Myers, P. L. Eur. Pat. Appl. EP 0071368, 1983; (b)
Chapleo, C. B.; Myers, P. L.; Butler, R. C. M.; Davis, J. A.; Doxey, J.
C.; Higgins, S. D.; Myers, M.; Roach, A. G.; Smith, C. F. C.;
Stillings, M. R.; Welbourn, A. P. J. Med. Chem. 1984, 27, 570; (c)
Edwards, C.; Readhead, M. J.; Tweddle, N. J. J. Heterocycl. Chem.
1987, 24, 495; (d) Mayer, P.; Brunel, P.; Imbert, T. Biorg. Med. Chem.
Lett. 1999, 9, 3021.
17. For an excellent review on the preparation and synthetic uses of SES
`
amides: Ribiere, P.; Declerck, V.; Martinez, J.; Lamaty, F. Chem. Rev.
2006, 106, 2249.
2. For the determination of the absolute stereochemistry of (R)-(+)-
efaroxan, see: Belin, C.; Chauvet, A.; Leloup, J. M.; Ribet, J. P.;
Maurel, J. L. Acta Crystallogr., Sect. C 1995, 51, 2439.
3. (a) Chapleo, C. B.; Doxey, J. C.; Stillings, M. R. PCT Int. Appl. WO
92/05171, 1992. For a review on a2-adrenoceptor antagonists, see: (b)
Mayer, P.; Imbert, T. IDrugs 2001, 4, 662.
18. (a) Weinreb, S. M.; Demko, D. M.; Lessen, T. A. Tetrahedron Lett.
1986, 27, 2099; (b) Weinreb, S. M.; Chase, C. E.; Wipf, P.;
Venkatraman, S. Org. Synth. 1997, 75, 161; (c) Parker, L. L.;
Gowans, N. D.; Jones, S. W.; Robins, D. J. Tetrahedron 2003, 59,
10165.
19. Although the following reference suggests the use of chloroform as
the reaction solvent, we found acetic acid better for this oxidation:
Parker, K. A.; Mindt, T. L. Org. Lett. 2002, 4, 4265. Experimental
procedure for the preparation of 6b: To a solution of SES N-protected
4. Colpaert, F.; Briley, M.; Imbert, T. PCT Int. Appl. WO 95/00145,
1995.
5. Colpaert, F.; Briley, M.; Imbert, T. PCT Int. Appl. WO 95/01791,
1995.

718
T. Lomberget, R. Barret / Tetrahedron Letters 49 (2008) 715–718
para-aminophenol (820 mg, 3.0 mmol) in 10 mL of glacial acetic acid
24. When the diazotation reaction was carried out under classical
conditions (6 M HCl/NaNO2/0 °C followed by a reductive step with
H3PO2), a complex mixture was obtained among which traces of the
deaminated compound 3 were observed.
was added 95% lead tetracetate Pb(OAc)4 (1.40 g, 3.0 mmol) in one
portion. The colourless solution faded to orange. The resulting
mixture was allowed to stir at room temperature for 1 h, after which
ethylene glycol (1 mL) was added. After a 10 min stirring, water
(40 mL) and ethyl acetate (50 mL) were added. After decantation, the
organic phase was washed with water (2 ꢁ 50 mL) and brine (50 mL),
dried over anhydrous sodium sulfate. After filtration, removal of
AcOEt in vacuo and drying, the quinone monoimide 6b was obtained
as a yellow powder (786 mg, 97%); mp 65–66 °C. 1H NMR (300 MHz,
CDCl3, ppm): d = 0.10 (9H, s), 1.13–1.19 (2H, m), 3.22–3.28 (2H, m),
6.64 (1H, dd, J = 10.6, 2.3 Hz), 6.72 (1H, dd, J = 10.2, 2.3 Hz), 7.03
(1H, dd, J = 10.2, 2.6 Hz), 8.01 (1H, dd, J = 10.6, 2.6 Hz). 13C NMR
(75 MHz, CDCl3, ppm): d = ꢀ1.9, 9.8, 51.5, 130.7, 135.0, 135.7,
140.2, 164.8, 185.9. HRMS (CI): m/z calcd for C11H18NO3SSi:
272.0777 [MH+]; found: 272.0778.
25. Typical experimental procedure for the preparation of 5-sulfonamido
efaroxan derivative 2a: To a solution of the cyano compound 8a
(150 mg, 0.36 mmol) in 2 mL of anhydrous methanol was added
sodium methoxide (10 mg, 0.18 mmol). After a 21 h stirring at room
temperature, the mixture was cooled down to 0 °C and an ethylene
diamine (31 lL, 0.464 mmol) solution in MeOH (0.5 mL) was added
dropwise. After a 5 min stirring, a 1 M HCl solution in MeOH
(470 lL, 0.466 mmol) was added dropwise at 0 °C. The mixture was
allowed to warm to room temperature and was stirred for an
additional 18 h. After this time, the volatiles were removed under
reduced pressure and the residue was taken up into 10 mL of
NaHCO3 saturated aqueous solution. Two extractions were realized
on the aqueous phase with dichloromethane (2 ꢁ 15 mL) and the
organic phases were washed with water (10 mL), dried over Na2SO4,
filtered and the solvents were removed under reduced pressure. The
crude product was purified by flash chromatography (silica gel,
CH2Cl2/MeOH 1:1) to give compound 2a as an off-white powder
(123 mg, 74%); mp 53–55 °C (dec.). 1H NMR (300 MHz, DMSO-d6,
ppm): d = 0.79 (3H, t, J = 7.4 Hz), 1.86 (2H, q, J = 7.4 Hz), 2.97 (1H,
d, J = 16.2 Hz), 3.42 (4H, br s), 3.59 (1H, d, J = 16.2 Hz), 4.69 (1H, d,
J = 15.1 Hz), 4.75 (1H, d, J = 15.1 Hz), 6.60 (1H, d, J = 8.7 Hz), 6.69
(1H, dd, J = 8.7, 2.3 Hz), 6.86 (1H, d, J = 2.3 Hz), 7.18–7.30 (5H, m),
7.59–7.75 (5H, m). 13C NMR (75 MHz, DMSO-d6, ppm): d = 7.9,
31.5, 37.6, 49.5, 54.2, 89.7, 108.8, 125.8, 127.1, 127.4, 127.4, 128.0,
128.2, 128.3, 129.3, 131.3, 133.1, 136.5, 138.1, 157.5, 168.3. HRMS
(ESI): m/z calcd for C26H28N3O3S: 462.1851 [MH+]; found: 462.1853.
20. Cyclic a-aminoacids: (a) Varray, S.; Lazaro, R.; Martinez, J.; Lamaty,
`
F. Eur. J. Org. Chem. 2002, 2308; Benzazepines: (b) Ribiere, P.;
Declerck, V.; Ne´dellec, Y.; Yadav-Bhatnagar, N.; Martinez, J.;
`
Lamaty, F. Tetrahedron 2006, 62, 10456; b-Aminoesters: (c) Ribiere,
P.; Enjalbal, C.; Aubagnac, J.-L.; Yadav-Bhatnagar, N.; Martinez, J.;
Lamaty, F. J. Comb. Chem. 2004, 6, 464.
21. For an excellent review on the transformation of N,N-dialkylhydra-
zones into various functional groups, including cyano group, see:
Enders, D.; Wortmann, L.; Peters, R. Acc. Chem. Res. 2000, 33, 157.
22. After a 48 h reaction time at 95 °C, the aniline was obtained in a 45%
isolated yield, together with the unreacted SES-protected
dihydrobenzofuran 7b (52% isolated yield).
23. Geoffroy, O. J.; Morinelli, T. A.; Meier, G. P. Tetrahedron Lett. 2001,
42, 5367.