A new, stereoselective, ring-forming reaction of 1,2-ethanedithiol with N-acylated indoles

Article abstract of DOI:10.1021/jo7013142

(Chemical Equation Presented) While attempting to prepare 2,5-dithiacyclopentyl derivatives from N-acyl 5-fluoroindole by reaction with 1,2-ethanedithiol we discovered that, instead of the expected product, annelation occurred to give a tricyclic compound containing a 3,6-dithiaazepine ring. This reaction is stereoselective and was found to be general for N-acylindoles, not being affected by substituents on the indole ring.

Full text of DOI:10.1021/jo7013142

SCHEME 1. Method of Preparation of the
C3-â-Conformationally Constrained Melatoninergic Indolic
A New, Stereoselective, Ring-Forming Reaction of
1,2-Ethanedithiol with N-Acylated Indoles
Andrew Tsotinis,*,† Andreas Eleutheriades,†
Lorenzo Di Bari,‡ and Gennaro Pescitelli‡
Faculty of Pharmacy, Department of Pharmaceutical Chemistry,
UniVersity of Athens, Panepistimioupoli-Zografou, 157 71
Athens, Greece, and Dipartimento di Chimica e Chimica
Industriale, Via Risorgimento 35, I-56126 Pisa, Italy
ethanedithiol and boron trifluoride etherate. Compound 3 was
a modest melatonin antagonist (pIC50 ) 4.96 nM)4 with some
selectivity (11-fold) for the MT2 receptor.5 In an attempt to
improve potency and receptor site selectivity we decided to
relocate the side chain from C3 to N1 (compound 8a, Scheme
2). This would require starting from compound 7a where,
however, the reactive carbonyl group is of the amide rather than
of the ketone type, making the synthesis of the dithiane unusual.
Nevertheless, a very recent report demonstrates that in a reaction
similar to ours, N-acylamides can add EtSH to give orthothioa-
mides.6
tsotinis@pharm.uoa.gr
ReceiVed July 2, 2007
However, when we reacted amide 7a with 1,2-ethanedithiol,
the spectroscopic data obtained for the compound isolated were
not in agreement with structure 8a. The LC-MS showed a
molecular mass of 328, in contrast to the expected value of 310.
Clearly, ethanedithiol addition did take place, but this was not
followed by water loss to give the dithiolane. 1H NMR revealed
that there were only three aromatic protons, with a coupling
pattern compatible with the trisubstituted benzene moiety, and
that addition to the pyrrole double bond and formation of an
indolidine had occurred. More detailed chemical shift, J-
coupling (COSY) and NOESY analysis (see ESI, Table 1)
showed the product to correspond to the structure 9a.
While attempting to prepare 2,5-dithiacyclopentyl derivatives
from N-acyl 5-fluoroindole by reaction with 1,2-ethanedithiol
we discovered that, instead of the expected product, anne-
lation occurred to give a tricyclic compound containing a
3,6-dithiaazepine ring. This reaction is stereoselective and
was found to be general for N-acylindoles, not being affected
by substituents on the indole ring.
While the initial reaction, thiol addition to an N-acyl indole
carbonyl, has been previously reported,6 the subsequent C2-
C3 addition of the thiol to the indole ring appears unprecedented
in the literature. It is noteworthy that Belhadj and Goekjian
report that the reaction of acylindole with EtSH in the presence
of BF3 leads only to the formation of orthothioamide, without
the formation of the C2-C3 addition product, even at high
temperature and after long reaction times; the effect of these
more rigorous conditions is the cleavage of the C-N bond.6
Clearly, the present exo-trig cyclization must be driven by a
favorable substrate stereochemistry,7a,b as also has been recently
observed in an analogous reaction reported by Clave´ et al.8
The two addition reactions that take place more or less
simultaneously at the carbonyl and at the pyrrole carbon pose
a further problem concerning the relative stereochemistry of the
newly formed stereogenic centers. GC data and the NMR spectra
clearly indicated the formation of only one diastereomer.
During studies on analogues of the pineal hormone melatonin
(N-acetyl-5-methoxytryptamine, 1)1,2 we wished to prepare
â-2,5-dithiacyclopentyl derivatives of melatonin as we had found
that the corresponding â-cyclopentyl compounds had an inter-
esting profile.3
We prepared the 4-fluoroindole analogue 3 (Scheme 1) in
40% yield by standard treatment of the ketone 2 with 1,2-
* Address correspondence to this author. Telephone +30 210-727-4812. Fax
+30 210-727-4811.
(4) Tsotinis, A.; Eleutheriades, A.; Davidson, K.; Sugden, D. Curr. Drug
DiscoVery Technol. 2007, 4, 198-207.
† University of Athens.
‡ University of Pisa.
(1) Sugden, D.; Davidson, K.; Hough, K. A.; Teh, M.-T. Pigm. Cell Res.
2004, 17, 454-460.
(2) Tsotinis, A.; Vlachou, M.; Papahatjis, D. P.; Nikas, S. P.; Sugden,
D. Lett. Org. Chem. 2007, 4, 92-95 and refs therein.
(3) Tsotinis, A.; Vlachou, M.; Papahatjis, D. P.; Calogeropoulou, T.;
Nikas, S.; Garratt, P. J.; Piccio, V.; Vonhoff, S.; Davidson, K.; Teh, M.-T.;
Sugden, D. J. Med. Chem. 2006, 49, 3509-3519.
(5) Reppert, S. M.; Weaver, D. R.; Cassone, V. M.; Godson, C.;
Kolakowski, L. F. Neuron 1995, 15, 1003-1015.
(6) Belhadj, T.; Goekjian, P. G. Tetrahedron Lett. 2005, 46, 8117-8120.
(7) (a) Baldwin, J. E. Chem. Commun. 1976, 734-736. (b) Baldwin, J.
E.; Cutting, J.; Dupont, W.; Kruse, L.; Silberman, L.; Thomas, R. C. Chem.
Commun. 1976, 736-738.
(8) Clave´, G.; Bernardin, A.; Massonneau, M.; Renard, P.-Y.; Romieu,
A. Tetrahedron Lett. 2006, 47, 6229-6233.
10.1021/jo7013142 CCC: $37.00 © 2007 American Chemical Society
Published on Web 10/17/2007
8928
J. Org. Chem. 2007, 72, 8928-8931

SCHEME 2. Preparation of the x-Substituted 5-(Alkanamidomethyl)-2,3,11,12-tetrahydro-5H-1,5,3-dithiazepino[3,2-a]indol-5-ol
Derivatives 9a-c and Their Congeners 12a,b
To confirm the structure and to determine the relative
stereochemistry of compound 9a, we ran ROESY experiments
at 600 MHz, in conjunction with molecular mechanics confor-
mational searches (MMFF force field, Spartan ’06, Wavefunc-
tion, Inc., Irvine, CA). The results of ROESY are pictorially
summarized in Figure 1.
The ROE between the methylene protons at 3.87 ppm and
the methine at 4.67 ppm is the first indication of their cis
arrangement. Moreover, the rest of the ROE network is fully
compatible with the low-energy MMFF conformations found
for the (R,R)/(S,S) diastereomer, but in total disagreement with
the (R,S)/(S,R) diastereomer. Thus, the signal at 3.87 ppm also
exhibits a NOE with that for the aromatic proton at 7.29 ppm.
The two simultaneous NOEs observed for the methylene signal
are in accord with the lowest-energy MMFF structure for the
(R,R)/(S,S) diastereomer (Figure 2), but with none of the low-
energy MMFF structures for the (R,S)/(S,R) diastereomer (within
3 kcal/mol from the absolute minimum).
Wishing to establish the synthetic generality of this remark-
ably facile 7-exo-trig cyclization, we subjected a variety of 4-
or 5-substituted 1-(alkanamidoacetyl) indoles (Scheme 2) to the
same experimental protocol and found that, in each case, the
annulation proceeded smoothly over 24 h at ambient temperature
to produce their respective 9- or 10-substituted 5-(alkanami-
domethyl)-2,3,11,12-tetrahydro-5H-1,5,3-dithiazepino[3,2-a]in-
dol-5-ol derivatives 9b,c9 (Scheme 2). Analogous products were
obtained (12a and 12b9) when the X group in compounds 11a
(9) Satisfactory analytical data and attributable NMR spectra were
obtained for all new compounds.
(10) Ottoni, O.; Cruz, R.; Alves, R. Tetrahedron 1998, 54, 13915-13928.
(11) Ikeda, M.; Uno, T.; Homma, K.; Ohno, K.; Tamura, Y. Synth.
Commun. 1980, 10, 437-450.
J. Org. Chem, Vol. 72, No. 23, 2007 8929

TABLE 1. 1H NMR Chemical Shifts of Thioorthoamides
Annulation Products
SCHEME 3. Proposed Mechanism for the Conversion of 7
and 11 into 9 and 12, Respectively
cmpd
H12
H11a-b
H10
H9
9a
4.67
3.08
-
7.01
9b
4.78
3.19
8.19
-
8.10
12a
4.70
3.04
7.26
7.11
7.19
12b
4.77
3.09
7.36
7.22
7.27
H8
7.25
H7
7.29
7.92
7.31
7.30
H2-H3
OH
3.18-3.27
9.42
3.18-3.27
9.24
3.20-3.22
9.34
3.14-3.25
9.96
3.87(CH2)
8.28(NH)
1.89(CH3)
3.95
8.29
1.89
2.2(CH3)
7.95(2H, o)
7.53(2H, m)
7.60(1H, p)
X
the amide carbon leads to the formation of the chiral semi-
thioketal 13. The second mercapto group of 1,2-ethanedithiol
is added to the C2-C3 double bond of the indolic analogue 14
to give the indolino intermediate 15 and finally the new tricyclic
nuclei 9a,b,c and 12a,b.
FIGURE 1. Compound 9a: ROESY proton spatial interactions.
This new cyclization proceeds with very high stereoselective
control to afford an N1-C2 annulated indoline as a single
diastereomer. We are now examining the application of this
reaction to other N-heterocycles and are investigating the
reactions of these dithiazepines, which represents a relatively
unknown system.12,13 Their biological activity will be described
elsewhere.
Experimental Section
Typical Experimental Procedure: Synthesis of 5-(Acetami-
domethyl)-10-fluoro-2,3,11,11a-tetrahydro-5H-1,5,3-dithiazepino-
[3,2-a]indol-5-ol (9a). Chloroacetylchloride (3.3 mL, 41.4 mmol)
was added dropwise to a solution of 4-fluoroindole (4a) (0.56 g,
4.11 mmol) in anhydrous benzene (15 mL). The mixture was heated
at reflux for 5.5 h and then treated with 50 mL of aqueous NaOH
(8%). The organic phase was separated, and the aqueous was
extracted with CH2Cl2 (3 × 50 mL). The combined organics were
washed with brine, the solvent was removed in vacuo, and the
FIGURE 2. Lowest-energy MMFF structure computed for (R,R)-9a
(some hydrogens have been removed for clarity).
and 11b was methyl and phenyl, respectively (Scheme 2). It
seems, therefore, that the proposed cyclization is not affected
by the nature of the N-acylating group, nor by the electron-
releasing or electron-withdrawing character and/or position of
the indole substituent.
A plausible pathway for the conversion of analogues 7 and
11 into 9 and 12, respectively, is outlined in Scheme 3.
According to the proposed mechanism, the catalyst (BF3‚Et2O)
is complexed with 7 and 11 to form an electrophilic substrate
for 1,2-ethanedithiol. The nucleophilic attack of the latter on
(12) Bailey, P. D.; Baker, S. R.; Boa, A. N.; Clayson, J.; Rosaira, G. M.
Tetrahedron Lett. 1998, 39, 7755-7758.
(13) Wolfgang, H.; Gu¨nther, H.; Mautner, H. G. J. Am. Chem. Soc. 1960,
82, 2762-2765.
8930 J. Org. Chem., Vol. 72, No. 23, 2007

brownish residue was purified by recrystallization from methanol
to afford 0.40 g (49%) of pure 1-chloroacetyl-4-fluoroindole (5a).
Mp 52-54 °C; 1H NMR (400 MHz, CDCl3) δ 4.57 (s, 2H, COCH2-
Cl), 6.80-6.81 (d, J ) 4.0 Hz, 1H, Harom), 6.97-7.01 (t, J ) 8.9
Hz, 1H, Harom), 7.28-7.34 (m, 1H, Harom), 7.39-7.40 (d, J ) 4.0
Hz, 1H, Harom), 8.19-8.21 (d, J ) 8.1 Hz, 1H, Harom).
To a solution of R-chloroketone 5a (0.40 g, 1.90 mmol) in
chloroform (2.5 mL) was added dropwise a solution of hexameth-
ylenetetramine (0.50 g, 3.57 mmol) in absolute ethanol (25 mL).
The mixture was stirred at ambient temperature for 10 min and
then treated with sodium iodide (0.32 g, 2.13 mmol). The resulting
suspension was stirred for 24 h at room temperature and then chilled
to 0 °C. The precipitate formed was filtered, washed with cold
absolute ethanol, and dried in vacuo. The solid was then dissolved
in absolute ethanol (18 mL) and treated dropwise with concd HCl
(1.5 mL) at 0 °C. The mixture was then allowed to thaw, stirred at
room temperature for 4 h and at reflux for 2 more hours. The
resulting solid was filtered and washed with cold absolute ethanol
to give 6a, which was used as such in the next reaction.
To a solution of 7a (30.0 mg, 0.14 mmol) in 1,2-ethanedithiol
(1.5 mL) a catalytic quantity of freshly distilled BF3‚Et2O (10 drops)
was added dropwise at room temperature, and the mixture was
stirred for 24 h. The crude product was dissolved in EtOAc (50
mL) and washed with a saturated aqueous solution of sodium
bicarbonate and brine. The organic phase was dried (Na2SO4) and
the solvent removed under reduced pressure to give a residue, which
was purified by flash column chromatography (silica gel; eluent
5% MeOH/EtOAc) to afford 5-(acetamidomethyl)-10-fluoro-2,3,-
11,11a-tetrahydro-5H-1,5,3-dithiazepino[3,2-a]indol-5-ol (9a) (yield
20 mg, 44%) as a white solid. Mp 118-120 °C (ethanol); 1H NMR
(600 MHz, DMSO, data referred to the residual solvent shift at δ
2.49 ppm) δ 1.89 (s, 3H, CH3), 3.08 (d, J ) 7.9 Hz, 2H, H11),
3.18-3.27 (m, 4H, H2-H3) 3.87 (d, J ) 4.9 Hz, CH2), 4.67 (t, J
) 7.9 Hz, H12), 7.01 (t, J ) 8.5 Hz, H9), 7.25 (t, J ) 7.3 Hz, H8),
7.29 (d, J ) 7.3 Hz, H7), 8.28 (bt, J ) 4.2 Hz, NH) 9.42 (s, OH);
13C NMR (150 MHz, CDCl3) δ 21.6, 23.3, 31.5, 34.6, 43.6, 52.9,
60.6, 112.7, 113.2, 122.4, 128.8, 138.5, 169.3, 170.8. MS: M+
)
328. Anal. calcd for C14H17FN2O2S2 (%) C, 51.20; H, 5.22; N, 8.53;
found (%) C, 51.16; H, 5.19; N, 8.49.
To a stirred, chilled (0 °C) solution of 6a in H2O (4 mL) was
sequentially added acetic anhydride (0.2 mL) and an aqueous
solution (2 mL) of sodium acetate (0.32 g, 3.9 mmol). The resulting
suspension was allowed to thaw, stirred at ambient temperature
for 1 h, and acidified by the cautious addition of concd HCl. The
mixture was then extracted with CH2Cl2 (3 × 25 mL), the combined
organic phases were washed with brine and dried (Na2SO4), and
the solvent was removed under reduced pressure to give a beige
solid. The solid was triturated with EtOAc (1 mL) to afford pure
1-(acetamidoacetyl)-4-fluoroindole (7a) as a white solid (yield 45
mg, 44%). Mp 66-68 °C; 1H NMR (400 MHz, CDCl3) δ 2.12 (s,
3H, COCH3), 4.66-4.67 (d, J ) 3.3 Hz, 2H, CH2NH), 6.50 (bs,
1H, NHCO), 6.78-6.80 (d, J ) 2.9 Hz, 1H, Harom), 6.93-7.02 (t,
J ) 8.4 Hz, 1H, Harom), 7.27-7.31 (m, 1H, Harom), 7.37-7.38 (d,
Acknowledgment. The University of Athens group thanks
EPEAEK II Program Pythagoras II - Support of UniVersities
Research Groups (KA: 70/3/7993) for financial support.
Note Added after ASAP Publication. Since the October 17,
2007 published version refs 7 and 8 have been modified to
include an additional journal citation; the modified version was
published October 24, 2007.
Supporting Information Available: NMR spectra and spectral
data for selected compounds and elemental analysis data for key
target compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
J ) 2.6 Hz, 1H, Harom), 8.13-8.17 (d, J ) 8.4 Hz, 1H, Harom); 13
C
NMR (100 MHz, CDCl3) δ 23.0, 43.1, 106.3, 109.6, 110.0, 112.4,
123.1, 126.5, 126.6, 153.2, 167.1, 170.3. Anal. calcd for C12H11-
FN2O2 (%) C, 61.53; H, 4.73; N, 11.96; found (%) C, 61.47; H,
4.65; N, 11.85.
JO7013142
J. Org. Chem, Vol. 72, No. 23, 2007 8931