Stannous chloride-mediated reductive cyclization - Rearrangement of nitroarenyl ketones

Article abstract of DOI:10.1021/jo0259921

Cyclization products are produced in excellent yields from using standard reaction conditions for nitroarene reduction to aminoarene with SnCl₂. Thus, 4-methyl-2-(2-nitrobenzyl)-2H-1,4-benzothiazin-3(4H)-one (2b) upon treatment with SnCl₂ in ethanol did not produce the expected aniline derivative. Instead, 6-methyl-11a, 12-dihydro-6H-quino[3,2-b][1,4]benzothiazine (3) was produced in excellent yield, presumably via novel Sn (IV)-mediated amidine formation from the initial aniline reduction product. Under identical reaction conditions, 2-(2-nitrophenyl)-thiochroman-4-one (6) produces ethyl 5,11-dihydrodibenzo[b,e][1,4]thiazepin-11-ylacetate (7). A novel semipinacol rearrangement is proposed to account for this extensive skeletal rearrangement. Aniline derivative (14) (from 6 treated with FeSO₄ · 7H₂O) forms 12-ethoxy-11,12-dihydro-6H-6,12-methanodibenzo[b,f][1,5]thiazocine (15) upon treatment with SnCl₂ in ethanol. Thiophene analogues of 6 and 14 (18 and 19, respectively) react similarly, forming the analogous thiazepine (20) and cyclic N,O-acetals (21), respectively.

Full text of DOI:10.1021/jo0259921

instance, heterocyclic nitrones4 or hydroxamic acids5 are
available from suitably substituted nitroarenes. Mecha-
nistically related intramolecular reactions with esters,6
anhydrides,7 and nitriles4c,8 are also reported to produce
a variety of heterocycles.
While investigating routes to novel precursors for the
sulfoxide electrophilic sulfenylation (SES) reaction,9 we
observed some unusual and synthetically useful reactions
of nitroarenes in the presence of stannous chloride in hot
alcoholic solvents which we report here.
Sta n n ou s Ch lor id e-Med ia ted Red u ctive
Cycliza tion -Rea r r a n gem en t of Nitr oa r en yl
Keton es†
Dallas K. Bates* and Kexue Li‡
Department of Chemistry, Michigan Technological
University, Houghton, Michigan 49931
dbates@mtu.edu
F or m a tion of Cyclic Am id in es. Reaction of o-ami-
nothiophenol with o-nitrocinnamic acid has been reported
to produce benzothiazepinone 1a as the sole product.10
However, we obtained not only the desired seven-
membered-ring product 1a , but also benzothiazinone 2a .
The two isomeric products could be cleanly separated by
column chromatography. The degree of conversion of
reactants and the ratio of the two products varied with
reaction conditions. Although not practical synthetically,
one run left for several months at room temperature
(after an initial 24 h at reflux in toluene) gave a combined
yield of 82% with 1a and 2a formed in a 1:1.3 ratio. By
comparison, after 24 h at reflux in toluene containing
piperidine, the yield was only 28% and the 1a to 2a ratio
was 1:2.6. Since the melting point of neither compound
matched the value of compound 1a reported in the
literature (lit.10 mp 176-178 °C, 1a mp 212-213 °C, 2a
mp 184-186 °C), we examined these compounds11 and
the literature12 more closely and conclude the structure
assignments for 1 and 2 shown below are correct.
Received May 30, 2002
Abstr a ct: Cyclization products are produced in excellent
yields from using standard reaction conditions for nitroarene
reduction to aminoarene with SnCl2. Thus, 4-methyl-2-(2-
nitrobenzyl)-2H-1,4-benzothiazin-3(4H)-one (2b) upon treat-
ment with SnCl2 in ethanol did not produce the expected
aniline derivative. Instead, 6-methyl-11a, 12-dihydro-6H-
quino[3,2-b][1,4]benzothiazine (3) was produced in excellent
yield, presumably via novel Sn (IV)-mediated amidine
formation from the initial aniline reduction product. Under
identical reaction conditions, 2-(2-nitrophenyl)-thiochroman-
4-one (6) produces ethyl 5,11-dihydrodibenzo[b,e][1,4]thiaze-
pin-11-ylacetate (7). A novel semipinacol rearrangement is
proposed to account for this extensive skeletal rearrange-
ment. Aniline derivative (14) (from 6 treated with FeSO4‚
7H2O) forms 12-ethoxy-11,12-dihydro-6H-6,12-methanodiben-
zo[b,f][1,5]thiazocine (15) upon treatment with SnCl2 in
ethanol. Thiophene analogues of 6 and 14 (18 and 19,
respectively) react similarly, forming the analogous thiaz-
epine (20) and cyclic N,O-acetals (21), respectively.
Stannous chloride in concentrated hydrochloric acid is
one of the classic reagents for reduction of nitroarenes
to the corresponding aminoarene.1 More recent modifica-
tions use water or ethanol as solvent with no added acid.2
Reduction of the nitro group followed (in situ) by interac-
tion of a reduction intermediate with functionality in an
ortho-substituted arene is a well-trodden pathway to
heterocyclic compounds. In addition to examples of cy-
clization of fully reduced aniline species such as the
Reissert sequence (o-nitrotoluene condensation with ethyl
oxalate followed by reduction to ethyl indole-2-carboxy-
late),3 intramolecular capture of an intermediate hy-
droxylamine is also a well-established process. For
Methylation of 1a and 2a utilizing Gaino’s method14
yielded 1b and 2b, respectively. Reduction of 2b using
Bellamy’s procedure15 (SnCl2 in hot ethanol) did not
(4) (a) Baik, W.; Kim, D. I.; Lee, H. J .; Chung, W.; Kim, B. H.; Lee,
S. W. Tetrahedron Lett. 1997, 38, 4579-4580. (b) Battistoni, P.; Bruni,
P.; Fava, G. Tetrahedron 1979, 35, 1771-1775. (c) Makosza, M.;
Kmiotek-Skarzynska, I.; J awdosiuk, M. Synthesis 1977, 56-58. (d)
Delpierre, G. R.; Lamchen, M. Quart. Rev. 1965, 329-349.
(5) (a) Stephensen, H.; Zaragoza, F. Tetrahedron Lett. 1999, 40,
5799-5802. (b) Tennant, G.; Wallis, C. J .; Weaver, G. W. J . Chem.
Soc., Perkin Trans. 1 1999, 629-640. (c) Coutts, R. T.; Peel, H. W.;
Smith, E. M. Can. J . Chem. 1965, 43, 3221-3231.
(6) (a) Watabe, Y.; Kondo, T.; Akazome, M. J pn. Kokai Tokkyo Koho
J P 05,239,036 [93,239,036]; Chem. Abstr. 1994, 120, 217719x. (b)
Konstantinova, A. V.; Mikhalina, T. V.; Fokin, E. P. Izv. Sib. Otd. Akad.
Nauk SSSR, Ser. Khim. Nauk 1989, 57; Chem. Abstr. 1990, 112,
98352v.
* Author to whom correspondence should be addressed: Voice
mail: (906) 487 2059. Fax: (906) 487 2061.
† A portion of this work was presented at the 221th National Meeting
of the American Chemical Society, San Diego, CA, April 1-5, 2001;
ORGN-180. Structures for 7 and 20 were assigned incorrectly in this
presentation.
‡ Current address: Tularik, Inc.; 2 Corporate Drive; South San
Francisco, CA 94080.
(1) Fieser, L. F.; Fieser, M. Reagents for Organic Synthesis; Wiley:
New York, 1967; pp 1113-1116.
(2) Faul, M. M. Tin (II) Chloride. In Encyclopedia of Reagents for
Organic Synthesis; Paquette, L. A., Ed.; Wiley: New York, 1995; Vol.
7, p 4893.
(3) Tyson, F. T. Organic Syntheses; Wiley: New York, 1955; Collect.
Vol. III, p 479. See also: Preston, P. N.; Tennant, G. Chem. Rev. 1972,
72, 627-677.
(7) Bourdais, J . Compt. Rend., Ser. C 1966, 262, 1701-1704.
(8) Varney, M. D.; Palmer, C. L.; Deal, J . G. PCT Int. Appl. WO 96
02,502; Chem. Abstr. 1996, 125, 10624v.
(9) Bates, D. K.; Xia, M. J . Org. Chem. 1998, 63, 9190-9196.
(10) Levai, A. Pharmazie 1980, 35, 680-681.
10.1021/jo0259921 CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/30/2002
8662
J . Org. Chem. 2002, 67, 8662-8665

SCHEME 1a
SCHEME 2a
a
Reagents: (a) (CO)2Cl2, CH2Cl2; (b) SnCl4, CH2Cl2 (70%, 2
steps); (c) 5 equiv of SnCl2, EtOH, reflux (>97%).
aniline product under tin catalysis, perhaps in the form
of a tin amidate, could account for the product. The
intermediacy of aniline 4 in this process is supported by
reduction of 2b using FeSO4‚7H2O in refluxing MeOH/
H2O.19 This reaction provided the aniline derivative (4)
in excellent yield as the sole product. Exposure of 4 to
SnCl2 in hot ethanol produces 3 in 92% yield.
a
Reagents: (a) 5 equiv of SnCl2, EtOH, reflux, 2 h; (b) 10 equiv
of FeSO4‚7H2O, MeOH/H2O, reflux, 1.5 h.
produce the corresponding aniline as expected. Instead,
cyclic amidine 3 was isolated in nearly quantitative yield
(Scheme 1).16
Treatment of benzothiazepinone 1b with SnCl2 pro-
duced only a very poorly soluble solid, which could not
be characterized. This reaction was not pursued further.
A Novel Sem ip in a col Rea r r a n gem en t a n d Re-
la ted N,O-Aceta l F or m a tion . To explore this unex-
pected chemistry further we prepared the thiochro-
manone analogue of 2 (i.e., 6) using the general procedure
of Ponticello (Scheme 2).20
Treatment of 6 with SnCl2 in refluxing ethanol repro-
ducibly gave a single product in nearly quantitative yield.
However, the product was not an aniline or an amidine,
as expected from the results obtained from 2b. NMR
spectral data show incorporation of an ethoxy group and
the presence of an ester carbonyl and an exchangeable
hydrogen. An apparent triplet at δ 4.57 is attributed to
the proton attached to a methine carbon adjacent to
the sulfur atom. This triplet signal is coupled to non-
equivalent hydrogen atoms on an adjacent methylene
group (δ 2.77 and 2.70). Further NMR analysis (1H-1H
COSY, 1H-13C COSY, DEPT, and HMBC) as well as
interpretation of the IR and LRMS suggests the product
is 7.
Formation of amidines by reaction of amines and
amides with prior amide activation by electrophilic
reagents is a very common synthetic protocol,17 but
formation from nitroarene reduction or from reaction of
an amide and an amine in the presence of SnCl2 is
novel.18 No reaction takes place in the absence of SnCl2.
In this case amidine formation from the intermediate
(11) Additional structural confirmation was obtained from the 13C
chemical shifts of methine and methylene carbon atoms in seven- and
six-membered ring compounds 1a , 1b, 2a , 2b, and 4. Seven-membered
ring compounds show a CH peak at δ 45-46 and a CH2 peak at δ
39-40 [1H-13C COSY correlation to methine and methylene protons
at δ 5.51 and δ 2.84-2.98, respectively, in 1a ]. Six-membered-ring
compounds show a CH peak at δ 42-43 and a CH2 peak at δ 31-33
[1H-13C COSY correlation to methine and methylene protons at δ 3.71
and δ 2.70/3.20 (AB quartet), respectively, in 4]. These 13C chemical
shifts are in accord with the assignment of seven- and six-membered-
ring skeletons to 1 and 2, respectively.
(12) There is only one report of 1a in the literature (ref 10) and no
reports of 2a . The benzothiazepinone skeleton is generally prepared
by reacting o-aminobenzenethiol with an R,â-unsaturated carboxylic
acid (e.g., cinnamic acid) at high temperature (160-180 °C) for several
hours10,12a while the benzothiazinone skeleton is generally prepared
from an R-bromoacid (e.g., 2-bromo-3-phenylpropanoic acid).12b,c As a
product of initial direct Michael addition, 1 is expected to be the kinetic
product. However, after 1 has formed and under conditions allowing
equilibration through retro-Michael addition, even though anti-Michael
addition product 2 is disfavored kinetically it could begin to appear in
the reaction mixture since it may be favored thermodynamically. This
analysis is consistent with the 1a :2a ratio observed in our reactions.
Also, the rate of anti-Michael addition is enhanced with Michael
(16) Confirmation of structure 3 by X-ray diffraction will be reported
separately. The only impurity isolated (in very small quantity) is i,
acceptors containing
a â-group capable of stabilizing a negative
charge.12d,e All of this may mean that some compounds assigned the
benzothiazepinone skeleton in the literature may in fact be the
corresponding benzothiazinone analogue (especially when the phenyl
ring is replaced by 2-nitrophenyl, a pyridine ring or other π-deficient
heteroaromatic moieties). This is an important point because many of
the reports of applications of these reactions discuss the products as
potential therapeutic targets.10,12c,13 (a) Mills, W. H.; Whitworth, J . B.
J . Chem. Soc. 1927, 2738-2753. (b) Unger, R.; Graf, G. Chem. Ber.
1897, 30, 2387. (c) Trapani, G.; Latrofa, A.; Franco, M.; Liso, G.
Farmaco 1995, 50, 107-112. (d) Martin, V.; Molines, H.; Wakselman,
C. J . Org. Chem. 1992, 57, 5530-5532. (e) Klumpp, G. W.; Mierop, A.
J .; Vrielink, J . J .; Brugman, A.; Schakel, M. J . Am. Chem. Soc. 1985,
107, 6740-6742.
perhaps formed from an acid- or tin-catalyzed attack of ethanol on the
intermediate hydroxylamine (with loss of water) followed by amidine
formation from the derived aniline derivative. For physical and spectral
properties of i see the Experimental Section.
(17) (a) Via imidoyl triflates: Charette, A. B.; M. Grenon Tetrahe-
dron Lett. 2000, 41, 1677-1680. (b) Via imidoyl chlorides: Kraft. A.
J . Chem. Soc., Perkin Trans. 1 1999, 705-714. Benincori, T.; Sannicolo,
F. J . Heterocycl. Chem. 1988, 25, 1029-1033. (c) Via imidoesters:
Roger, R.; Neilson, D. G. In The Chemistry of Imidates; Patai, S., Ed.;
Wiley: New York, 1960; p 179.
(18) Amidine formation in a one-pot reductive cyclization of ni-
troarenes containing a cyano group is known: see refs 4c and 8.
Amidines from addition of amines to nitriles are well-known: Ogonor,
J . I. Tetrahedron 1981, 37, 2909-2910.
(13) (a)Bartch, H.; Erker, T. J . Heterocyl. Chem. 1988, 25, 1151-
1154. (b) Kori, M.; Itoh, K.; Sugihara, H. Chem. Pharm. Bull. J pn.
1987, 35, 2319-2324. (c) Slade, J .; Stanton, J . L.; Ben-David, D.;
Mazzenga, G. C. J . Med. Chem. 1985, 28, 1517-1521. (d) Carr, J . B.
J . Heterocycl. Chem. 1971, 8, 511-516. (e) Krapcho, J .; Turk, C. F. J .
Med. Chem. 1966, 9, 191-195. (f) Krapcho, J .; Spitzmiller, E. R.; Turk,
C. F. J . Med. Chem. 1963, 6, 544-546. (g) Kirchner, F. K.; Alexander,
E. J . J . Am. Chem. Soc. 1959, 81, 1721-1726.
(19) Kugita, H.; Inoue, H.; Ikezaki, M.; Takeo, S. Chem. Pharm. Bull.
1970, 18, 2028-2037.
(20) Ponticello, S. P.; Freedman, M. B.; Habecker, C. N.; Holloway,
M. K.; Amato, J . S.; Conn, R. S.; Baldwin, J . J . J . Org. Chem. 1988,
53, 9-13.
(14) Gaino, M.; Iijima, I.; Nishimoto, S.; Ikeda, K.; Fujii, T. J pn.
Kakai 1983, 58-99471; Chem. Abstr. 1983, 99, 175819v.
(15) Bellamy, F. D.; Ou, K. Tetrahedron Lett. 1984, 25, 839-842.
J . Org. Chem, Vol. 67, No. 24, 2002 8663

SCHEME 3a
SCHEME 6
SCHEME 7a
a
Reagents: (a) MeI (5 equiv), t-BuOK (2.2 equiv), THF, rt, 19
h; (b) NaOMe (2 equiv), MeOH, reflux, 15 h.
SCHEME 4
a
Reagents: (a) 10 equiv of FeSO4‚7H2O, MeOH/H2O, reflux, 2
SCHEME 5a
h (98%); (b) 5 equiv of SnCl2, ROH, reflux, 2 h (98%); (c) 5 equiv
of SnCl2, EtOH, reflux, 2 h (99%).
ratio) in excellent yield (Scheme 5). Treatment of 14 with
SnCl2 in refluxing ethanol produced a single compound
in nearly quantitative yield to which we assign structure
15.23
Formation of 15 may be mechanistically similar to
formation of 7. With the reduced nucleophilicity of the
nitrogen atom in 14 (compared to the R-effect enhanced
11), the reaction pathway could proceed slightly differ-
a
Reagents: (a) 10 equiv of FeSO4‚7H2O, MeOH/H2O, reflux, 2
h (>98%); (b) 5 equiv of SnCl2, EtOH, reflux, 2 h (>99%).
(21) Less strained analogues of 12 (Scheme 4) are intermediates in
the standard route to nitrones. Nitrones and oxaziranes equilibrate
photochemically or thermally (ref 4). In this case, ii/iii
Chemical evidence also supports structure 7. Treat-
ment of compound 7 with t-BuOK and MeI in THF both
N-methylates the nitrogen atom and induces retro-
Michael addition giving products 8 and 9 (Scheme 3).
Interestingly, under these reaction conditions the ethyl
ester is replaced by a methyl ester. Ethyl ester 7 could
also be converted to the corresponding methyl ester (10)
by MeONa in refluxing MeOH, but under these condi-
tions no retro-Michael product was isolated.
could form from attack of the hemiaminal hydroxyl at nitrogen with
Sn-assisted displacement of the N-hydroxyl group. Although rear-
The mechanism of formation of 7 most likely involves
an intermediate hydroxylamine (11) (Scheme 4). Nucleo-
philic addition of the hydroxylamine to the ketonic
carbonyl leads to 12, which may undergo a tin-mediated
pinacol-type rearrangement with preferred migration of
the phenyl substituent to produce amide 13. Ethanolysis
of the amide generates the observed product (7).21 Such
a semipinacol rearrangement22 of an N-hydroxyhemi-
aminal has not been reported previously.
rangement of oxaziranes to amides is
a well-know process, this
pathway to 13 seems less likely due to steric strain in the intermedi-
ates: (a) J ust, G.; Cunningham, M. Tetrahedron Lett. 1972, 1151-
1153. (b) Hamar, J .; Macaluso, A. Chem. Rev. 1964, 64, 473-495. (c)
Umezawa, B. Chem. Pharm. Bull. J pn. 1960, 8, 967-975. (d) Bonnett,
R.; Clark, V. M.; Todd, A. J . Chem. Soc. 1959, 2102-2104. (e) Krimm,
H. Chem. Ber. 1958, 91, 1057-1068. (f) Kroehnke, F. Ann. 1957, 604,
203-207.
(22) Coveney, D. J . The Semipinacol and Other Rearrangements.
In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: New York, 1991; Vol. 3, pp 777-801.
(23) N,O-Acetal formation catalyzed by SnCl2 has some prece-
dence: 2,3-dimethylindole reacts with benzaldehydes in the presence
of SnCl2 in ethanol-stabilized dicholoromethane to form N,O-acetals
(Pindur, U.; Schiffl, E. Monatsh. Chem. 1986, 117, 1461-1463).
Reduction of nitroarene 6 by FeSO4‚7H2O in refluxing
MeOH/H2O was uneventful, producing the corresponding
aniline derivative (14) as a mixture of conformers (7:3
8664 J . Org. Chem., Vol. 67, No. 24, 2002

ently, providing initially the hemiacetal 16, by attack of
ethanol rather than the proximate amino group. Under
Sn catalysis 16 could form an oxenium ion (17) with
subsequent intramolecular attack providing N,O-acetal
15 (Scheme 6). In the absence of SnCl2, no reaction takes
place.
To begin to investigate the generality of these reac-
tions, thiophene analogues 18 and 19 were prepared as
described above for 6 and 14, respectively. Reduction of
18 with SnCl2 in hot ethanol gave the benzothienothi-
azepine 20a in excellent yield (Scheme 7). Changing the
alcohol used as the reaction solvent to methanol or 2-bu-
tanol provided the corresponding methyl and sec-butyl
esters 20b and 20c, respectively. Treatment of 19 with
SnCl2 in ethanol gave N,O-acetal 21 in excellent yield.
In conclusion, three reaction pathways for intermedi-
ates in processes in which tin may serve as a reducing
agent or Lewis acid, or both, are reported. One of these
pathways, a novel semipinacol rearrangement, may be
useful for the preparation of novel heterocycles not
readily available by other approaches.
Ack n ow led gm en t. The authors thank the NSF for
an equipment grant (CHE-9512445). K. Li thanks the
Graduate School and Chemistry Department of Michi-
gan Technological University for the Outstanding Gradu-
ate Fellowships and Alumni Summer Fellowships. Mr.
J erry L. Lutz is also thanked for NMR instrumental
assistance, and Mr. Shane Crist’s help with numerous
computer issues related to SI material preparation was
invaluable.
Su p p or tin g In for m a tion Ava ila ble: Full experimental
details, characterization of new compounds, and 1H and 13C
spectra of compounds 1a b, 2a b, 3-10, 14, 15, 18, 19, 20a ,b,c,
and 21. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O0259921
J . Org. Chem, Vol. 67, No. 24, 2002 8665