The synthesis of bicyclic 1,2,3,4-tetrahydro-1,4-benzodiazepin-5-ones from 2-(o-nitrobenzoyl)-1,2-thiazine-1-oxide precursors

Article abstract of DOI:10.1016/j.tet.2004.02.058

Sulfinylation of o-nitrobenzamide and subsequent hetero Diels-Alder reaction gave a series of 2-(o-nitrobenzoyl)-1,2-thiazine-1-oxides. The 2-(o-nitrobenzoyl)-1,2-thiazine-1-oxides undergo a ring opening reaction with phenyl magnesium bromide to give allylic sulfoxides, which, after [2,3]-sigmatropic rearrangement and desulfurisation, furnish unsaturated vicinal N-(o-nitrobenzoyl)-1,2-amino alcohols. Oxidation of the alcohol and reductive ring closure gave a series of bicyclic 1,2,3,4-tetrahydro-1,4- benzodiazepin-5-ones, a subset of the 'privileged' 1,4-benzodiazepine structure. A 4-hydroxy-1,2,5-benzothiadiazepin-1,1-dioxide was synthesised by the same route starting from o-nitrobenzenesulfonamide.

Full text of DOI:10.1016/j.tet.2004.02.058

Tetrahedron 60 (2004) 3349–3357
The synthesis of bicyclic 1,2,3,4-tetrahydro-1,4-benzodiazepin-5-
ones from 2-(o-nitrobenzoyl)-1,2-thiazine-1-oxide precursors
*
Karl Hemming and Christina Loukou
Department of Chemical and Biological Sciences, University of Huddersfield, Queensgate, Huddersfield, West Yorkshire HD1 3DH, UK
Received 23 January 2004; accepted 25 February 2004
Abstract—Sulfinylation of o-nitrobenzamide and subsequent hetero Diels–Alder reaction gave a series of 2-(o-nitrobenzoyl)-1,2-thiazine-
1-oxides. The 2-(o-nitrobenzoyl)-1,2-thiazine-1-oxides undergo a ring opening reaction with phenyl magnesium bromide to give allylic
sulfoxides, which, after [2,3]-sigmatropic rearrangement and desulfurisation, furnish unsaturated vicinal N-(o-nitrobenzoyl)-1,2-amino
alcohols. Oxidation of the alcohol and reductive ring closure gave a series of bicyclic 1,2,3,4-tetrahydro-1,4-benzodiazepin-5-ones, a subset
of the ‘privileged’ 1,4-benzodiazepine structure. A 4-hydroxy-1,2,5-benzothiadiazepin-1,1-dioxide was synthesised by the same route
starting from o-nitrobenzenesulfonamide.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
Synthetic approaches to the bicyclic 1,4-benzodiazepin-5-
ones most commonly involve formation of the 1,2 N–C
bond as the final step. This can be achieved either via the
intramolecular cyclisation of (o-aminobenzamido)carbo-
nyls11a,16a and acetals/thioacetals,16b reductive cyclisation
of (o-nitrobenzamido)carbonyls and (o-nitrobenzamido)-
acetals/thioacetals,14,17 intramolecular cycloadditions of
(o-azidobenzamido)alkenes and alkynes,8b,18 aza-Wittig
ring closure of [o-(iminophosphoranyl)benzamido]carbo-
nyls,5a,19 intramolecular Michael additions of (o-amino-
benzamido)enones,15,20 intramolecular cyclisation of
(o-aminobenzamido) p-allyl complexes obtained from
acylnitroso-derived Diels–Alder cycloadducts,21 or the
cyclisation of a-(o-aminobenzamido)nitriles.22 Construc-
tion of the 3,4 C–N bond as the final step is another
common approach and can be achieved via cyclodehydro-
chlorination of o-[(2-chloroethyl)amino]benzamides,12
cyclodehydrobromination of o-[(bromoalkyl)amino]aroyl-
hydrazines,23 and ozonolysis of o-(allylamino)benzamides,
followed by cyclisation.24 1,2 or 3,4 C–N bond formation
as the final step also occurs during in the reaction of
anthranilamide derivatives with cyanoester epoxides25 or
bromoacetaldehyde acetals,26 or reaction of methyl anthra-
nilate with aziridines.27 Other cyclisation methods include
1,7 N–C bond formation as a final step by intramolecular
aromatic nucleophilic displacement,28 4,5 C–N formation
via reduction of N-alkylnitrile substituted anthranilates and
subsequent ring closure,29 and 5,6 C–C bond formation via
treatment of b-anilino ethylisocyanates with aluminium
trichloride.27 1,4-Benzodiazepin-5-ones can also be
made from hydride reductions of 1,4-benzodiazepin-2,5-
diones,11e,30 Schmidt reaction between the azide anion and
1,2,3,4-tetrahydroquinolin-4-ones,31 ring expansion reac-
tions of chloromethyl quinazolin-4-ones,32 photolytic ring
The 1,4-benzodiazepine nucleus occupies a position as a
‘privileged’ structure within medicinal chemistry.1 The
most well-known sub-sets of this privileged set of structures
are the 1,4-benzodiazepin-2-ones2 and the 1,4-benzodiaze-
pin-2,5-diones,3 and these continue to attract enormous
interest, due to a broad and ever evolving spectrum of
biological activities.2,3 Relatively less well studied are the
1,4-benzodiazepin-5-ones, although interest in the synthesis
and biological activity even within this sub-set is consider-
able. Amongst the 1,4-benzodiazepin-5-ones, most attention
has been paid to tricyclic systems, such as the antitumour
pyrrolo-1,4-benzodiazepin-5-ones,4 the biologically active
quinazolino-fused circumdatin and asperlicin natural
products,5 the pyrido- and benzo- fused non-nucleosidic
reverse transcriptase inhibitors,6 muscarinic receptor
ligands,7 and the clinically used anti-depressant, cognition
enhancing imidazolo-fused flumazenil,8 and positron
emission tomography tracers derived from flumazenil.9
Bicyclic 1,4-benzodiazepin-5-ones have attracted attention
as simplified analogues and precursors of these tricyclic
systems,10–15 are of interest generally as members of the
privileged 1,4-benzodiazepine class, and are of specific
interest as anti-convulsants, anti-anxiety agents, anti-
depressants,10–13 sedatives, hypnotics, muscle relaxants,10,11
analgesics,12 anti-tumour agents14 and fibrinogenic receptor
antagonists.15
Keywords: Benzodiazepine; 1,2-Thiazine; Reductive ring closure; Diels–
Alder reaction; Sigmatropic rearrangement; Benzothiadiazepine.
*
Corresponding author. Tel.: þ44-1484-472188; fax: þ44-1484-472182;
e-mail address: k.hemming@hud.ac.uk
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.02.058

3350
K. Hemming, C. Loukou / Tetrahedron 60 (2004) 3349–3357
expansions of 4-azidoquinazolines,33 and ring expansions of
benzoxazines with subsequent cyclisation of the intermedi-
ate amidine carboxamides.5b In this paper we present a new
strategy for the synthesis of the bicyclic 1,2,3,4-tetrahydro-
1,4-benzodiazepin-5-one nucleus, which relies upon a novel
method for the synthesis of (o-nitrobenzamido)carbonyl
cyclisation precursors for 1,2 N–C bond formation.
Reductive cyclisation of these gives the desired 1,4-benzo-
diazepin-5-one nucleus. The method presented in this paper
is advantageous in allowing readily available 1,3-dienes
to be used as starting materials for the synthesis of
1,4-benzodiazepin-5-ones, only the second such method to
be published,21 and the first that utilises easily accessible
N-sulfinyl dienophiles.
Scheme 2. Synthesis of 1,4-benzodiazepin-5-ones 9 from 1,2-thiazine-1-
oxides 3. Reagents and Conditions: (i) SOCl2, pyridine, THF, room
temperature, 4 h. (ii) R1HCvvCH–CR2vCHR3, THF, room tempera-
ture, overnight. (iii) PhMgBr, THF, 240 8C, 3 h. (iv) Sat. NH4Cl(aq.). (v)
MeOH, P(OMe)3, 60 8C, 10–15 h. (vi) Dess–Martin periodinane, CH2Cl2,
room temperature, 1 h. (vii) H2, Pd/C, MeOH, room temperature, 16–20 h.
2. Results and discussion
We envisaged (see Scheme 1) that the 2-(o-nitroaroyl)-1,2-
thiazine-1-oxides 3 would be excellent precursors for the
synthesis of the (o-nitrobenzamido)carbonyl cyclisation
precursors 7 via the intermediate (o-nitrobenzamido)-
alcohols 6. The alcohols 6 would be formed from the
1,2-thiazine-1-oxides 3 via ring opening with a Grignard
reagent, [2,3]-sigmatropic rearrangement of the resultant
sulfoxide 4, and desulfurisation34 of the rearranged product,
the sulfenate ester 5. The requisite 2-(o-nitroaroyl)-1,2-
thiazine-1-oxides 3 would be made available via the hetero-
Diels–Alder reaction of the N-sulfinyl dienophile 2 with a
variety of dienes, where the N-sulfinyl compound should
easily be formed from the reaction of o-nitrobenzamide 1
with thionyl chloride.35
and was extremely unstable, undergoing facile hydrolysis
(over 10 to 15 min) in the air to liberate sulfur dioxide and
o-nitrobenzamide, the products of hydrolysis. However,
rapid analysis of the reaction mixture by infrared spectro-
scopy showed the total disappearance of the sulfonamide
–NH2 group after 4–5 h and the appearance of a band
(1176 cm21) characteristic35 of the –NvSvO group.
At this point, the appropriate diene [(E,E)-2,4-hexadiene,
(E)-1,3-pentadiene, isoprene or butadiene] was added into
the mixture. Hetero-Diels–Alder reaction proceeded
smoothly under anhydrous conditions, after which chroma-
tographic work-up yielded the required 2-(o-nitroaroyl)-1,2-
thiazine-1-oxides 3 in good to excellent yields for the
purified compounds over the two steps (4 examples, see
Table 1). Due to the fact that our target ketones 7 have only
one chiral centre, we did not need to confirm the
stereochemical outcome of the cycloaddition reaction.
However, those cycloadducts 3 with more than one chiral
centre, i.e. compounds 3a and 3b (see Table 1), were formed
as single diastereoisomers, an observation in keeping with
other N-sulfinyl cycloadditions.34,35
Next, also shown in Scheme 2, the purified 2-(o-nitro-
benzoyl)-1,2-thiazine-1-oxides 3 were treated with phenyl-
magnesium bromide in THF at low temperature (240 8C).
Aqueous work-up and treatment of the dried crude product
with hot methanolic trimethyl phosphite34 gave the
(o-nitrobenzamido)alcohols 6. The products 6 were con-
sistent with the thiazine 3 having undergone ring opening to
give the allylic sulfoxide 4, shown previously in Scheme 1,
followed by a thermally allowed (reversible) [2,3]-sigma-
tropic rearrangement to give intermediate sulfenate ester 5,
also shown in Scheme 1. Trimethyl phosphite mediated
Scheme 1. Proposed route to (o-nitrobenzamido)ketones 7.
Thus, as shown in Scheme 2, o-nitrobenzamide 1 was
reacted under anhydrous conditions with thionyl chloride
and pyridine in THF at room temperature for 4 h to give
N-sulfinyl compound 2. Compound 2 could not be purified
Table 1. % Yields for pure and isolated compounds 3, 6, 7 and 9
Entry
R1
R2
R3
% Yield of thiazine 3
(from 1)
% Yield of alcohol 6
(from 3)
% Yield of ketone 7
(from 6)
% Yield of benzodiazepine 9
(from 7)
a
b
c
d
Me
Me
H
H
H
Me
H
Me
H
H
77
81
75
72
88
74
85
76
82
75
72
70
47
58
29
40
H
H

K. Hemming, C. Loukou / Tetrahedron 60 (2004) 3349–3357
3351
(irreversible) desulfurisation of the intermediate sulfenate
esters 5 gave the (o-nitrobenzamido)alcohols 6. We made
no attempt to purify or characterise the intermediates 4 or 5
since the overall yields obtained for the purified (o-nitro-
benzamido)alcohols 6 were consistently excellent for this
three-step process (see Table 1). The relative stereo-
chemistry of compounds 6a and 6b (R1¼Me) was not
determined as, at the next stage, the alcohol chiral center
was to be oxidised. It is of interest to note, however, that
others have reported that this sequence of reactions proceeds
with a high degree of stereoselectivity when performed with
other substrates,34–36 a point reflected by the fact that we
found compounds 6a and 6b to be single diasteroisomers. In
the one case where it is appropriate, i.e. for compound 6a
(R2¼H, R3¼Me), the alkene geometry of compound 6 was
found to be (E). This can be explained34 by invoking a
5-membered ring envelope transition state for the [2,3]-
sigmatropic rearrangement, in which the methyl group that
occupies position 6 (see Scheme 3) is in a pseudo-equatorial
position leading to (E)-alkene geometry in the sulfenate
ester 5a and, subsequently, in the alcohol 6a.
Scheme 4. Synthesis of 4-hydroxy-1,2,5-benzothiadiazepin-1,1-dioxide 14.
Reagents and conditions: (i) (a) SOCl2, benzene, reflux, 72 h; (b) (E,E)-2,4-
hexadiene, room temperature, 14 h. (ii) (a) PhMgBr, THF, 240 8C, 2 h;
(b) Sat. NH4Cl(aq.); (c) P(OMe)3, MeOH, 60 8C, 5 h. (iii) Dess–Martin
periodinane, CH2Cl2, room temperature, 30 min. (iv) H2, Pd/C, MeOH,
room temperature, 4 h.
shown in Scheme 4, and subjected it to the same sequence of
reactions as was applied to the 2-(o-nitroaroyl)-1,2-thiazine-
1-oxides 3. This gave access to the 2-(o-nitrobenzenesul-
fonamido)alcohol 12 in 89% yield from the thiazine 11.
Dess–Martin periodinane oxidation proceeded in 84%
yield to give the 2-(o-nitrobenzenesulfonamido)ketone 13.
Compound 13 was treated with hydrogen and palladium
over activated carbon. Intriguingly, and anomalous to the
corresponding (o-nitrobenzamido) systems 7a–d, this gave
the carbinolamine 1,2,3,4-tetrahydro-4-hydroxy-1,2,5-
benzothiadiazepin-1,1-dioxide 14 in 45% yield. The product
was isolated as a single diastereoisomer. The stereo-
chemistry was assigned on the basis of nOe experiments
that showed a clear enhancement between the CH proton
at position 3 of the 1,2,5-benzothiadiazepine ring and the
C4-bound CH2 group of the C4 n-propyl substituent, but not
between the methyl group at position 3 and the same CH2
group.
Scheme 3. The formation of (E)-alkene 6a.
Oxidation of the purified alcohols 6, as per Scheme 2, was
best achieved with Dess–Martin periodinane, giving the
corresponding (o-nitrobenzamido)ketones 7 in good yields
(Table 1). Exposure of the (o-nitrobenzamido)ketones 7 to
hydrogenation at atmospheric pressure using 5% palladium
over activated carbon resulted in reduction of the nitro
group to the amine, ring closure to a cyclic imine followed
by reduction of imine bond, and accompanying reduction of
the exocyclic olefinic double bond. These four steps gave,
as the only isolated products, the 1,2,3,4-tetrahydro-1,4-
benzodiazepin-5-ones 9, as shown in Scheme 2. Where
relevant (i.e. for compounds 9a and 9b, R1¼Me, R2¼H,
R3¼Me/H), a single diastereoisomer was isolated, and the
relative stereochemistry of the groups at positions 2 and 3 of
the 1,4-benzodiazepin-5-one was assigned cis/syn on the
basis of nOe experiments. Thus, clear signal enhancements
were observed between the C3 R1 methyl protons and the
C2-bound CH2 group (R2¼H), but not between the C3 R1
methyl and the C2 proton, nor between the C3 proton and
the C2-bound CH2 group. The observed stereochemistry is
in line with the expected delivery of hydrogen to the face of
the imine bond in intermediate 8 that is opposite to the
existing methyl group at C3. The yields (Table 1) were fair
considering the four-step nature of the reaction and,
furthermore, considering that similar (o-nitrobenzamido)-
carbonyl reductive cyclisations reported in the literature
often give bicyclic 1,4-benzodiazepin-5-one yields in
approximately the same range.4,14,17
3. Conclusion
In summary, we have shown that 2-(o-nitrobenzoyl)-1,2-
thiazine-1-oxides, which are readily available from o-nitro-
benzamide and diene feedstocks, are easily transformed into
o-nitrobenzamido alkenones that are readily ring closed to
give 1,2,3,4-tetrahydro-1,4-benzodiazepin-5-ones in mod-
erate to good yield. This constitutes a new route to this
important sub-set of the ‘privileged’ 1,4-benzodiazepine
pharmacophore and adds to the diversity of structures
available. The method is also applicable to the synthesis of
1,2,5-benzothiadiazepines, although in this case, ring
closure gives the 4-hydroxy compound. We are currently
exploring this latter process further, together with other 1,2-
thiazine-1-oxide based routes to 1,2,5-benzothiadiazepin-
1,1-dioxides and will report our results in due course.
4. Experimental
4.1. General instructions
1H NMR spectra were recorded on a Bruker AC-250
(250 MHz) or a Bruker Advance DPX-400 (400 MHz)
spectrometer using deuterochloroform as solvent with
tetramethylsilane as internal standard. 13C NMR spectra
were recorded on a Bruker AC-250 (63 MHz) or a Bruker
In an attempt to extend the scope of this methodology, we
also synthesised the 2-(o-nitrobenzenesulfonyl)-1,2-thiazine-
1-oxide 11 (60% yield from 10; single diastereoisomer), as

3352
K. Hemming, C. Loukou / Tetrahedron 60 (2004) 3349–3357
Advance DPX-400 (100 MHz) spectrometer using deutero-
chloroform as solvent, referencing to the deuterochloroform
lock. Coupling constants (J) are reported in Hertz (Hz). Low
resolution mass spectra were performed on a Micromass
Quattro II triple quadrupole mass spectrometer, and high
resolution mass spectra were recorded on a Finnegan MAT
900 XLT instrument operated at the EPSRC National Mass
Spectrometry Service Center, Swansea. Flash silica chroma-
tography was performed using Merck Kieselgel 60. Thin
layer chromatography was carried out with Camlab
0.25 mm silica gel (F254) coated plastic or aluminium
plates, using petroleum ether (40–608)/ethyl acetate as
eluent, and were visualised using ultraviolet light or a
vanillin stain. All reagents and reaction solvents were
purchased from Sigma-Aldrich and solvents for chroma-
tography were purchased from Merck. Petroleum ether and
ethyl acetate were purchased as AR grade and were used as
received. Reactions were routinely carried out under an
atmosphere of dry, oxygen-free, nitrogen, unless otherwise
stated. All new compounds were isolated by flash silica
chromatography as one spot pure compounds (TLC) and
150 (95%), 82 (100%), 76 (85%). HRMS (ESþ): found
MHþ 295.0755, C13H14N2SO4 requires MHþ 295.0753.
4.2.2. 3,6-Dihydro-3-methyl-2-(o-nitrobenzoyl)-1,2-thia-
zine-1-oxide 3b. Obtained, after column chromatographic
purification (single spot by TLC), as a pale yellow
solid (2.0961 g, 81%) from o-nitrobenzamide (1.5163 g,
9.13 mmol, 1.0 equiv.) and 1,3-pentadiene (d¼0.683,
1.46 ml, 14.60 mmol, 1.6 equiv.). Mp: 130–132 8C.
dH (250 MHz, CDCl3): 1.55 (d, 3H, J¼6.5 Hz, Me), 3.49
(dt, 1H, J¼3.0, 1.2 Hz, CHH), 3.55 (dd, 1H, J¼7.4, 1.2 Hz,
CHH), 4.97 (dquint, 1H, J¼6.4, 0.9 Hz, CHMe), 5.93 (ddd,
1H, J¼10.0, 7.4, 3.2 Hz, CvCH), 6.55 (ddd, 1H, J¼10.0,
6.2, 2.8 Hz, CvCH), 7.58–7.70 (m, 2H, 2£ArH), 7.78 (dt,
1H, J¼7.5, 1.2 Hz, 1£ArH), 8.25 (dd, 1H, J¼8.3, 1.1 Hz,
1£ArH). dC (63 MHz, CDCl3): 18.2 (CH3), 47.8 (CH2), 49.6
(CH), 115.0 (CH), 124.6 (CH), 129.5 (CH), 130.8 (CH),
131.5 (quat.), 134.7 (CH), 134.9 (CH), 145.1 (quat.), 168.7
(quat.). ymax (KBr disc, cm21): 3017, 1654, 1533, 1349,
1317, 1216, 1147, 1099, 859, 668. EI mass spectrum (m/z,
%): 281 (MþHþ, 1%), 233 (3%), 215 (20%), 150 (50%),
104 (35%), 82 (30%), 76 (100%). HRMS (ESþ): found
MHþ 281.0597, C12H12N2SO4 requires MHþ 281.0596.
1
were single pure compounds (.98% purity) by H NMR
and 13C NMR spectroscopy.
4.2. Synthesis of 2-(o-nitrobenzoyl)-1,2-thiazine-
1-oxides 3
4.2.3. 3,6-Dihydro-5-methyl-2-(o-nitrobenzoyl)-1,2-thia-
zine-1-oxide 3c. Obtained, after column chromatographic
purification (single spot by TLC), as a beige solid (1.9410 g,
75%) from o-nitrobenzamide (1.5419 g, 9.28 mmol,
1.0 equiv.) and isoprene (d¼0.681, 1.49 ml, 14.85 mmol,
1.6 equiv.). Mp: 128–130 8C.
A solution of o-nitrobenzamide (,9–9.3 mmol, 1.0 equiv.)
and anhydrous pyridine (6.0 equiv.) in anhydrous tetrahy-
drofuran (15 ml), under an atmosphere of dry nitrogen, was
prepared. To this solution was added, dropwise with stirring
over a period of 3–4 h, a solution of freshly distilled thionyl
chloride (1.5 equiv.) in anhydrous tetrahydrofuran (5 ml), to
yield the crude N-sulfinyl compound. The crude reaction
mixture was stirred for 30 min, followed by dropwise
addition of the appropriate 1,3-diene (1.6 equiv., except for
butadiene where 10 equiv. were condensed into the reaction
flask), and the whole was stirred at room temperature for
16 h, whilst being monitored by TLC. After completion of
the reaction, the solvent was removed in vacuo and the
crude product was purified by flash silica chromatography
(eluent PE/EtOAc 1:1). The following products were
obtained:
dH (250 MHz, CDCl3): 1.94 (s, 3H, Me), 3.23 (d, 1H, J¼
15.1 Hz, CHH), 3.41 (bd, 1H, J¼15.4 Hz, CHH), 4.14
(dt, 1H, J¼17.6, 1.2 Hz, CHH), 4.68 (bd, 1H, J¼17.8 Hz,
CHH), 5.86 (s, 1H, CvCH), 7.51 (d, 1H, J¼7.5 Hz,
1£ArH), 7.67 (dt, 1H, J¼8.2, 1.4 Hz, 1£ArH), 7.77 (dt, 1H,
J¼7.5, 1.1 Hz, 1£ArH), 8.15 (dd, 1H, J¼8.3, 1.1 Hz,
1£ArH). dC (63 MHz, CDCl3): 25.0 (CH3), 38.6 (CH2), 53.5
(CH2), 119.0 (CH), 123.0 (quat.), 125.1 (CH), 128.9 (CH),
131.1 (CH), 131.9 (quat.), 135.2 (CH), 145.6 (quat.), 167.5
(quat.). ymax (KBr disc, cm21): 3018, 1664, 1531, 1347,
1326, 1216, 1105, 1090, 850, 668. EI mass spectrum (m/z,
%): 281 (MþHþ, 1%), 233 (2%), 150 (20%), 104 (20%), 82
(30%), 76 (100%). HRMS (ESþ): found MHþ 281.0591,
C12H12N2SO4 requires MHþ 281.0596.
4.2.1. 3,6-Dihydro-3,6-dimethyl-2-(o-nitrobenzoyl)-1,2-
thiazine-1-oxide 3a. Obtained, after column chromato-
graphic purification (single spot by TLC), as a white
solid (2.0335 g, 77%) from o-nitrobenzamide (1.5000 g,
9.03 mmol, 1.0 equiv.) and 2,4-hexadiene (d¼0.720,
1.65 ml, 14.45 mmol, 1.6 equiv.). Mp: 154–156 8C.
4.2.4. 3,6-Dihydro-2-(o-nitrobenzoyl)-1,2-thiazine-1-
oxide 3d. Obtained, after column chromatographic
purification (single spot by TLC), as pale yellow prisms
(1.7418 g, 72%) from o-nitrobenzamide (1.5022 g,
9.04 mmol, 1.0 equiv.) and 1,3-butadiene (4.89 g,
10 equiv.). Mp: 136–138 8C.
dH (250 MHz, CDCl3): 1.30 (d, 3H, J¼7.2 Hz, Me), 1.68 (d,
3H, J¼6.4 Hz, Me), 3.45 (dquint, 1H, J¼7.2, 1.0 Hz,
CHMe), 4.72 (dquint, 1H, J¼5.7, 0.9 Hz, CHMe), 5.92
(ddd, 1H, J¼10.6, 7.2, 0.6 Hz, CvCH), 6.25 (dd, 1H, J¼
10.6, 4.8 Hz, CvCH), 7.61–7.70, (m, 2H, 2£ArH), 7.79
(dt, 1H, J¼7.7, 1.2 Hz, 1£ArH), 8.23 (dd, 1H, J¼7.3,
1.6 Hz, 1£ArH). dC (63 MHz, CDCl3): 15.7 (CH3), 20.7
(CH3), 48.9 (CH), 54.4 (CH), 119.6 (CH), 124.6 (CH), 128.1
(quat.), 129.5 (CH), 130.7 (CH), 131.5 (quat.), 132.4 (CH),
134.7 (CH), 145.5 (quat.), 170.4 (quat.). ymax (KBr disc,
cm21): 3019, 1677, 1532, 1350, 1216, 1092, 669. EI mass
spectrum (m/z, %): 295 (MþHþ, 1%), 269 (5%), 104 (45%),
dH (250 MHz, CDCl3): 3.46–3.52 (m, 2H, 2£CHH), 4.15
(dhextet, 1H, J¼18.5, 1.8 Hz, CHH), 4.84 (bd, 1H, J¼
18.1 Hz, CHH), 5.79–5.89 (m, 1H, CvCH), 6.23 (dd, 1H,
J¼8.1, 1.7 Hz, CvCH), 7.40 (d, 1H, J¼7.5 Hz, 1£ArH),
7.67 (ddd, 1H, J¼8.2, 7.6, 1.5 Hz, 1£ArH), 7.80 (dt, 1H,
J¼7.5, 1.2 Hz, 1£ArH), 8.24 (dd, 1H, J¼8.2, 1.2 Hz,
1£ArH). dC (63 MHz, CDCl3): 37.8 (CH2), 49.3 (CH2),
114.3 (CH), 124.8 (CH), 125.4 (CH), 128.5 (CH), 130.9
(CH), 131.4 (quat.), 134.8 (CH), 144.9 (quat.), 167.0 (quat.).

K. Hemming, C. Loukou / Tetrahedron 60 (2004) 3349–3357
3353
y
max (KBr disc, cm21): 3019, 1682, 1531, 1348, 1311, 1152,
3,6-dihydro-3,6-dimethyl-2-(o-nitrobenzoyl)-1,2-thiazine-
1-oxide 3a (1.0000 g, 3.40 mmol, 1.0 equiv.).
1100, 1095, 669. EI mass spectrum (m/z, %): 267 (MþHþ,
2%), 219 (25%), 150 (100%), 104 (35%), 82 (30%), 76
(40%). HRMS (ESþ): found MHþ 267.0441, C11H10N2SO4
requires MHþ 267.0439.
dH (400 MHz, CDCl3): 1.30 (d, 3H, J¼6.6 Hz, Me), 1.74
(dd, 3H, J¼6.4, 1.1 Hz, Me), 2.27 (bs, 1H, OH), 4.05–4.25
(m, 2H, CHMe and CHOH), 5.61 (ddd, 1H, J¼14.6, 6.0,
1.5 Hz, vCHCHOH), 5.77 (dq, 1H, J¼14.8, 6.2 Hz,
vCHMe), 6.18 (bd, 1H, J¼8.0 Hz, NH), 7.49 (dd, 1H,
J¼7.3, 1.7 Hz, ArH), 7.56 (dt, 1H, J¼7.8, 1.6 Hz, ArH),
7.66 (dt, 1H, J¼7.4, 1.3 Hz, ArH), 8.04 (dd, 1H, J¼8.1,
1.2 Hz, ArH). dC (100 MHz, CDCl3): 17.3 (CH3), 17.8
(CH3), 50.2 (CH), 75.2 (CHOH), 124.5 (CH), 128.7 (CH),
129.2 (CH), 130.4 (CH), 130.6 (CH), 133.1 (quat.), 133.6
(CH), 146.5 (quat.), 166.4 (quat.). ymax (NaCl plates, neat,
cm21): 3380 (broad), 3268, 2978, 2932, 1645, 1532, 1450,
1349, 1260, 1146, 1112, 1093, 972, 788, 702. EI mass spec-
trum (m/z, %): 265 (MHþ, 1%), 193 (25%), 150 (100%),
121 (25%), 104 (35%), 76 (30%). HRMS (ESþ): found
MHþ 265.1188, C13H16N2O4 requires MHþ 265.1188.
4.2.5. 3,6-Dihydro-3,6-dimethyl-2-(o-nitrobenzenesulfon-
yl)-1,2-thiazine-1-oxide 11. o-Nitrobenzenesulfonamide
(1.0000 g, 4.95 mmol, 1.0 eq) and thionyl chloride
(1.5 equiv.) were heated in anhydrous benzene (15 ml) at
reflux for 72 h. The mixture was cooled to room temperature
and the solvent and excess thionyl chloride were removed
in vacuo. The residue was dissolved in freshly distilled
anhydrous THF (10 ml). 2,4-Hexadiene (d¼0.720, 0.90 ml,
7.91 mmol, 1.6 equiv.) was added, and the mixture was
stirred at room temperature for 14 h. The crude product was
purified by flash silica chromatography (eluent PE/EtOAc
6:5) to give the pure product as a pale yellow solid
(0.9830 g, 60%). Mp: 110–112 8C.
dH (400 MHz, CDCl3): 1.39 (d, 3H, J¼7.4 Hz, Me), 1.56
(d, 3H, J¼7.0 Hz, Me), 3.29–3.41 (m, 1H, CHMe), 4.57
(dquint, 1H, J¼6.8, 3.4 Hz, CHMe), 5.45 (ddd, 1H, J¼11.0,
2.5, 2.0 Hz, CvCH), 5.96 (ddd, 1H, J¼11.0, 3.4, 2.9 Hz,
CvCH), 7.71–7.91 (m, 3H, 3£ArH), 8.19 (dd, 1H, J¼8.3,
1.1 Hz, 1£ArH). dC (100 MHz, CDCl3): 15.7 (CH3), 23.5
(CH3), 51.8 (CH), 53.1 (CH), 119.5 (CH), 124.8 (CH), 129.5
(CH), 131.3 (CH), 132.5 (CH), 133.0 (quat), 134.8 (CH),
147.6 (quat.). ymax (KBr disc, cm21): 3019, 1531, 1332,
1311, 1156, 1106, 1095, 753, 669. EI mass spectrum (m/z,
%): 331 (MþHþ, 2%), 282 (2%), 229 (35%), 186 (20%), 82
(100%), 67 (85%). HRMS (CIþ[NH3]): found MHþ
331.0419, C12H14N2O5S2 requires MHþ 331.0422.
4.3.2. 4-(o-Nitrobenzamido)-pent-1-en-3-ol 6b. Obtained,
after column chromatographic purification (single spot
by TLC), as a yellow oil (0.3300 g, 74%) from 3,6-di-
hydro-3-methyl-2-(o-nitrobenzoyl)-1,2-thiazine-1-oxide 3b
(0.5000 g, 1.78 mmol, 1.0 equiv.).
dH (400 MHz, CDCl3): 1.36 (d, 3H, J¼6.6 Hz, Me), 5.26
(dq, 1H, J¼9.8, 1.5 Hz, CHMe), 5.40 (qt, 1H, J¼8.6,
1.2 Hz, CHOH), 5.89 (dd, 1H, J¼16.0, 5.2 Hz,
HHCvCHCHOH), 5.97 (ddd, 1H, J¼15.9, 5.4, 1.1 Hz,
vCHCHOH), 6.04 (m, 1H, HHCvCHCHOH), 6.15 (bs,
1H, NH), 7.51–7.68 (m, 3H, 3£ArH), 8.07 (dd, 1H, J¼8.1,
1.2 Hz, ArH). dC (100 MHz, CDCl3): 17.1 (CH3), 54.2
(CH), 76.4 (CH), 122.8 (CH), 124.1 (CH), 126.0 (CH),
128.6 (CH), 129.1 (quat.), 130.2 (CH), 132.3 (CH), 142.6
(quat.), 167.4 (quat.). ymax (NaCl plates, neat, cm21): 3388
(broad), 3318 (broad), 2925, 2870, 1651, 1537, 1454, 1377,
1349, 1261, 1216, 1041, 699. EI mass spectrum (m/z, %):
251 (MHþ, 1%), 193 (35%), 150 (100%), 104 (15%), 76
(20%). HRMS (ESþ): found MHþ 251.1032, C12H14N2O4
requires MHþ 251.1032.
4.3. Synthesis of (o-nitrobenzamido)alkenols 6
A solution of phenylmagnesium bromide (3 M solution in
ether, 2.0 equiv.) was added with stirring to a solution of
the 2-(o-nitrobenzoyl)-3,6-dihydro-1,2-thiazine-1-oxide
(1.5–3.5 mmol, 1.0 equiv.) in anhydrous tetrahydrofuran
(10 ml) at 278 8C under an atmosphere of dry nitrogen. The
reaction mixture was kept at low temperature (,240 8C)
for 3 h, whilst being monitored by TLC. Upon completion
of the reaction, the mixture was quenched at 220 8C with
saturated ammonium chloride solution (15 ml) and allowed
to warm to room temperature. The mixture was extracted
with ethyl acetate (2£10 ml) and washed with water
(2£10 ml) and brine (10 ml). The organic phase was
collected, dried (MgSO4), filtered and the solvent evapo-
rated off to yield the allylic sulfoxide, which was not
purified further. To a solution of this crude allylic sulfoxide
in anhydrous methanol (10 ml) was added trimethyl
phosphite (d¼1.052, 2.0 equiv.), under an atmosphere of
dry nitrogen, and the whole was heated under reflux for a
total of 10–15 h, and was monitored by TLC. Upon
completion of the reaction, the solvent was removed in
vacuo and the crude product was purified by column
chromatography (eluent: PE/EtOAc 3:2) to yield the
(o-nitrobenzamido)alkenols as follows:
4.3.3. 2-Methyl-4-(o-nitrobenzamido)-but-1-en-3-ol 6c.
Obtained, after column chromatographic purification (single
spot by TLC), as a yellow oil (0.6050 g, 85%) from 3,6-di-
hydro-5-methyl-2-(o-nitrobenzoyl)-1,2-thiazine-1-oxide 3c
(0.8000 g, 2.85 mmol, 1.0 equiv.).
dH (400 MHz, CDCl3): 1.79 (s, 3H, Me), 2.18 (bs, 1H, OH),
3.36 (ddd, 1H, J¼13.8, 7.6, 4.9 Hz, CHH), 3.81 (ddd, 1H,
J¼13.8, 6.8, 3.4 Hz, CHH), 4.33 (dd, 1H, J¼7.5, 3.4 Hz,
CHOH), 4.97 (s, 1H, CvCH2), 5.10 (s, 1H, CvCH2), 6.39
(bs, 1H, NH), 7.50–7.64 (m, 2H, 2£ArH), 7.66 (dt, 1H,
J¼7.4, 1.3 Hz, ArH), 8.04 (dd, 1H, J¼8.0, 1.3 Hz, ArH). dC
(100 MHz, CDCl3): 18.6 (CH3), 44.2 (CH2), 73.8 (CH),
111.9 (CH2), 124.6 (CH), 128.8 (CH), 130.5 (CH), 132.9
(quat.), 133.7 (CH), 144.8 (quat.), 146.8 (quat.), 167.1
(quat.). ymax (NaCl plates, neat, cm21): 3396 (broad), 3304
(broad), 3087, 2921, 1654, 1532, 1442, 1350, 1314, 1083,
1055, 907, 858, 789, 699. EI mass spectrum (m/z, %):
251(MHþ, 1%), 151 (70%), 150 (100%), 121 (45%), 104
(40%), 76 (72%). HRMS (CIþ[NH3]): found MHþ
251.1036, C12H14N2O4 requires MHþ 251.1032.
4.3.1.
(E)-5-(o-Nitrobenzamido)-hex-2-en-4-ol
6a.
Obtained, after column chromatographic purification (single
spot by TLC), as a yellow oil (0.7900 g, 88%) from

3354
K. Hemming, C. Loukou / Tetrahedron 60 (2004) 3349–3357
4.3.4. 4-(o-Nitrobenzamido)-but-1-en-3-ol 6d. Obtained,
after column chromatographic purification (single spot
by TLC), as a yellow oil (0.3370 g, 76%) from 3,6-di-
hydro-2-(o-nitrobenzoyl)-1,2-thiazine-1-oxide 3d (0.5000 g,
1.88 mmol, 1.0 equiv.).
(o-nitrobenzamido)-hex-2-en-4-ol 6a (0.5000 g, 1.89 mmol,
1.0 equiv.).
dH (400 MHz, CDCl3): 1.54 (d, 3H, J¼7.1 Hz, Me), 1.99
(dd, 3H, J¼6.9, 1.5 Hz, Me), 5.05 (quint., 1H, J¼7.0 Hz,
CHMe), 6.26 (dq, 1H, J¼15.7, 1.6 Hz, MeHCvCHCO),
6.88 (bs, 1H, NH), 7.11 (dq, 1H, J¼15.5, 6.9 Hz,
MeHCvCH), 7.52–7.72 (m, 3H, 3£ArH), 8.10 (d, 1H,
J¼8.0 Hz, ArH). dC (100 MHz, CDCl3): 18.2 (CH3), 18.6
(CH3), 52.8 (CH), 124.6 (CH), 127.8 (CH), 128.7 (CH),
130.6 (CH), 132.7 (quat.), 133.7 (CH), 146.3 (quat.), 146.6
(CH), 165.7 (quat.), 197.0 (quat). ymax (NaCl plates, neat,
cm21): 3321 (broad), 3018, 2928, 1654, 1532, 1444, 1349,
1217, 1078, 970, 667. EI mass spectrum (m/z, %): 263
(MHþ, 2%), 193 (25%), 150 (100%), 104 (15%), 76 (15%),
69 (35%). HRMS (ESþ): found MHþ 263.1030,
C13H14N2O4 requires MHþ 263.1032.
dH (400 MHz, CDCl3): 2.55 (bs, 1H, OH), 3.31 (ddd, 1H,
J¼13.8, 7.7, 5.1 Hz, CHH), 3.78 (ddd, 1H, J¼13.8, 7.6,
3.5 Hz, CHH), 4.39–4.46 (m, 1H, CHOH), 5.24 (dt,
1H, J¼10.5, 1.4 Hz, CvCH2), 5.38 (dt, 1H, J¼17.2,
1.4 Hz, CvCH2), 5.89 (ddd, 1H, J¼17.2, 10.5, 5.5 Hz,
H2CvCHCHOH), 6.58 (bs, 1H, NH), 7.54 (dt, 1H, J¼7.3,
1.5 Hz, ArH), 7.59–7.70 (m, 2H, 2£ArH), 8.05 (dd, 1H,
J¼8.0, 1.3 Hz, ArH). dC (100 MHz, CDCl3): 45.5 (CH2),
71.4 (CH), 116.6 (CH), 124.6 (CH), 128.8 (CH), 130.5
(CH), 133.7 (quat.), 133.8 (CH), 137.6 (CH), 146.5 (quat.),
167.2 (quat.). ymax (NaCl plates, neat, cm21): 3360 (broad),
3309 (broad), 3086, 3013, 2929, 1651, 1530, 1349, 1313,
1048, 930, 857, 788, 698. EI mass spectrum (m/z, %): 237
(MHþ, 2%), 151 (25%), 152 (65%), 121 (20%), 104 (50%),
76 (100%), 57 (54%). HRMS (ESþ): found MHþ 237.0875,
C11H12N2O4 requires MHþ 237.0875.
4.4.2.
4-(o-Nitrobenzamido)-pent-1-en-3-one
7b.
Obtained, after column chromatographic purification (single
spot by TLC), as a yellow oil (0.2225 g, 75%) from 4-(o-
nitrobenzamido)-pent-1-en-3-ol 6b (0.3000 g, 1.20 mmol,
1.0 equiv.).
4.3.5. (E)-5-(o-Nitrobenzenesulfamido)-hex-2-en-4-ol 12.
This was obtained by the identical procedure except that, at
the trimethyl phosphite stage, the reaction was noted to be
complete after 5 h. Chromatographic purification gave the
product (single spot by TLC) as a yellow oil (0.8100 g,
89%) from 3,6-dihydro-3,6-dimethyl-2-(o-nitrobenzene-
sulfonyl)-1,2-thiazine-1-oxide 11 (1.0000 g, 3.03 mmol,
1.0 equiv.).
dH (400 MHz, CDCl3): 1.56 (d, 3H, J¼7.1 Hz, Me), 5.14
(quint., 1H, J¼7.1 Hz, CHMe), 6.02 (dd, 1H, J¼8.1, 3.5 Hz,
CvCH), 6.49–6.52 (m, 2H, 2£CvCH), 6.84 (bs, 1H, NH),
7.52–7.73 (m, 3H, 3£ArH), 8.09 (dd, 1H, J¼8.0, 1.3 Hz,
ArH). dC (100 MHz, CDCl3): 18.0 (CH3), 52.1 (CH), 124.7
(CH), 128.7 (CH), 130.6 (CH), 131.3 (CH), 132.5 (CH),
133.8 (CH), 134.0 (quat.), 143.3 (quat.), 168.2 (quat.), 197.6
(quat.). ymax (NaCl plates, neat, cm21): 3324 (broad), 2924,
1650, 1531, 1349, 1075, 852, 789, 699. EI mass spectrum
(m/z, %): 249 (MHþ, 2%), 193 (35%), 150 (100%), 76
(65%), 55 (90%). HRMS (CIþ[NH3]): found MNH4þ
266.1140, C12H12N2O4 requires MNHþ4 266.1141.
dH (400 MHz, CDCl3): 1.15 (d, 3H, J¼6.7 Hz, Me), 1.58
(dd, 3H, J¼6.4, 1.5 Hz, Me), 1.82 (bs, 1H, OH), 3.49
(dquint, 1H, J¼6.7, 5.0 Hz, CHMe), 3.95 (dd, 1H, J¼7.3,
5.0 Hz, CHOH), 5.35 (ddq, 1H, J¼15.2, 7.4, 1.6 Hz,
HCvCHMe), 5.61 (bd, 1H, J¼7.9 Hz, NH), 5.70 (qdd,
1H, J¼15.2, 6.5, 0.8 Hz, HCvCHMe), 7.72–7.78 (m, 2H,
2£ArH), 7.85–7.90 (m, 1H, ArH), 8.13–8.17 (m, 1H, ArH).
dC (100 MHz, CDCl3): 17.8 (CH3), 18.2 (CH3), 55.1 (CH),
75.5 (CH), 125.3 (CH), 129.6 (CH), 130.4 (CH), 130.7
(CH), 132.8 (CH), 133.3 (CH), 134.7 (quat.), 149.0 (quat.).
4.4.3. 2-Methyl-4-(o-nitrobenzamido)-but-1-en-3-one 7c.
Obtained, after column chromatographic purification (single
spot by TLC), as a yellow oil (0.2500 g, 72%) from
2-methyl-4-(o-nitrobenzamido)-but-1-en-3-ol 6c (0.3500 g,
1.40 mmol, 1.0 equiv.).
y
max (NaCl plates, neat, cm21): 3389 (broad), 3327 (broad),
3045, 2996, 1547, 1449, 1346, 1287, 1180, 1108, 1027, 780,
662. EI mass spectrum (m/z, %): 301 (MHþ, 3%), 229
(33%), 218 (20%), 186 (100%), 109 (55%), 84 (41%), 76
(20%). HRMS (CIþ[NH3]): found MNHþ4 318.1129,
C12H14N2O5S requires MNHþ4 318.1125.
dH (270 MHz, CDCl3): 1.93 (s, 3H, Me), 4.69 (d, 1H, J¼
4.4 Hz, CH2), 5.94 (d, 1H, J¼1.5 Hz, CvCHH), 6.12 (s,
1H, CvCHH), 6.91 (bs, 1H, NH), 7.56–7.61 (m, 2H,
2£ArH), 7.68 (dt, 1H, J¼7.5, 1.2 Hz, ArH), 8.05 (dd, 1H,
J¼8.0, 0.8 Hz, ArH). dC (63 MHz, CDCl3): 17.2 (CH3),
46.0 (CH2), 124.5 (CH), 126.5 (CH2), 128.7 (CH), 130.6
(CH), 132.4 (quat.), 133.6 (CH), 142.0 (quat.), 146.5 (quat.),
166.3 (quat.), 195.0 (quat.). ymax (NaCl plates, neat, cm21):
3306 (broad), 2927, 1657, 1532, 1349, 1075, 1052, 857,
789, 699. EI mass spectrum (m/z, %): 249 (MHþ, 2%), 193
(35%), 150 (100%), 120 (20%), 104 (25%), 76 (65%).
HRMS (CIþ[NH3]): found MNHþ4 266.1140, C12H12N2O4
requires MNHþ4 266.1141.
4.4. Synthesis of (o-nitrobenzamido)alkenones 7
To a solution of Dess–Martin periodinane (1.1 equiv.) in
dry dichloromethane (10 ml) was added a solution of the
allylic alcohol (1–2 mmol, 1 equiv.) in dry dichloro-
methane (5 ml) at room temperature. The reaction mixture
was stirred at room temperature for 0.5–1 h, whilst being
monitored by TLC. The solvent was evaporated off and the
crude product was purified by column chromatography
(eluent: PE/EtOAc 3:2) to yield the following products:
4.4.4. 4-(o-Nitrobenzamido)-but-1-en-3-one 7d. Obtained,
after column chromatographic purification (single spot by
TLC), as a yellow oil (0.1736 g, 70%) from 4-(o-nitrobenz-
amido)-but-1-en-3-ol 6d (0.2500 g, 1.06 mmol, 1.0 equiv.).
4.4.1. (E)-5-(o-Nitrobenzamido)-hex-2-en-4-one 7a.
Obtained, after column chromatographic purification (single
spot by TLC), as a yellow oil (0.4070 g, 82%) from (E)-5-
dH (400 MHz, CDCl3): 4.62 (d, 2H, J¼4.4 Hz, CH2), 6.07 (t,

K. Hemming, C. Loukou / Tetrahedron 60 (2004) 3349–3357
3355
1H, J¼3.8 Hz, CvCH), 6.46 (d, 2H, J¼3.8 Hz, 2£
CvCH), 6.79 (bs, 1H, NH), 7.56–7.65 (m, 2H, 2£ArH),
7.71 (dt, 1H, J¼7.4, 1.3 Hz, ArH), 8.11 (dd, 1H, J¼8.1,
1.2 Hz, ArH). dC (100 MHz, CDCl3): 47.6 (CH2), 124.7
(CH2), 127.1 (quat.), 128.7 (CH), 130.8 (CH), 133.6 (CH),
133.8 (CH), 134.8 (CH), 148.8 (quat.), 166.2 (quat.), 193.8
(quat.). ymax (NaCl plates, neat, cm21): 3301 (broad), 2925,
1654, 1530, 1349, 1260, 856, 790, 699. EI mass spectrum
(m/z, %): 235 (MHþ, 3%), 177 (45%), 166 (25%), 150
(30%), 121 (35%), 105 (70%), 91 (97%), 77 (100%). HRMS
(CIþ[NH3]): found MNHþ4 252.0990, C11H10N2O4 requires
MNHþ4 252.0984.
(CH2), 33.2 (CH2), 50.6 (CH), 60.6 (CH), 117.5 (CH), 118.0
(CH), 126.1 (quat.), 132.7 (CH), 133.3 (CH), 145.5 (quat.),
169.8 (quat.) ymax (KBr disc, cm21): 3283, 3126, 2970,
2927, 1628, 1527, 1441, 1260, 1089, 1023, 803. EI mass
spectrum (m/z, %): 219 (MHþ, 10%), 218 (50%), 203
(10%), 175 (30%), 147 (25%), 133 (60%), 132 (65%), 119
(100%), 105 (35%), 91 (55%), 77 (30%), 65 (25%), 57
(35%), 45 (50%). HRMS (ESþ): found MHþ 219.1498,
C13H18N2O requires MHþ 219.1497.
4.5.2. 2-Ethyl-1,2,3,4-tetrahydro-3-methyl-1,4-benzodi-
azepin-5-one 9b. Obtained, after column chromatographic
purification (single spot by TLC), as a yellow oil (0.0716 g,
58%) from 4-(o-nitrobenzamido)-pent-1-en-3-one 7b
(0.1500 g, 0.6043 mmol).
4.4.5. (E)-5-(o-Nitrobenzenesulfamido)-hex-2-en-4-one
13. Obtained, after column chromatographic purification
(single spot by TLC), as a yellow oil (0.4170 g, 84%)
from (E)-5-(o-nitrobenzenesulfamido)-hex-2-en-4-ol 12
(0.5000 g, 1.67 mmol, 1.0 equiv.).
dH (400 MHz, CDCl3): 0.97 (t, 3H, J¼7.4 Hz, Me), 1.15 (d,
3H, J¼6.9 Hz, Me), 1.43–1.52 (m, 1H, CH2), 1.96–2.02
(m, 1H, CH2), 3.24 (t, 1H, J¼6.8 Hz, CH), 3.65 (quint., 1H,
J¼6.2 Hz, CHMe), 4.88 (bs, 1H, NH), 6.53 (d, 1H, J¼
8.17 Hz, ArH), 6.69 (t, 1H, J¼7.4 Hz, ArH), 7.16 (bs, 1H,
NH), 7.40 (t, 1H, J¼7.0 Hz, ArH), 7.96 (d, 1H, J¼8.0 Hz,
ArH). dC (100 MHz, CDCl3): 10.9 (CH3), 16.7 (CH3), 24.0
(CH2), 50.6 (CH), 62.5 (CH), 117.5 (CH), 118.0 (CH), 124.0
(quat.), 132.7 (CH), 133.2 (CH), 145.5 (quat.), 169.5 (quat.).
ymax (NaCl plates, neat, cm21): 3341, 3155, 2960, 2926,
2855, 1626, 1464, 1262, 1216, 1088, 1022, 668. EI mass
spectrum (m/z, %): 205 (MHþ, 10%), 204 (65%), 189
(15%), 175 (20%), 161 (55%), 147 (30%), 133 (90%), 132
(100%), 118 (30%), 104 (75%), 77 (40%), 57 (35%), 44
(40%). HRMS (ESþ): found MHþ 205.1339, C12H16N2O
requires MHþ 205.1341.
dH (270 MHz, CDCl3): 1.42 (d, 3H, J¼7.2 Hz, Me), 1.91
(dd, 3H, J¼6.9, 1.7 Hz, Me), 4.42 (quint., 1H, J¼7.2 Hz,
CHMe), 6.15 (dq, 1H, J¼15.6, 1.6 Hz, HCvCHMe), 6.47
(bd, J¼7.2 Hz, NH), 6.94 (dq, 1H, J¼15.6, 6.9 Hz,
CvCHMe), 7.67–7.75 (m, 2H, 2£ArH), 7.87–7.90 (m,
1H, ArH), 8.03–8.07 (m, 1H, ArH). dC (63 MHz, CDCl3):
18.6 (CH3), 19.6 (CH3), 56.6 (CH), 125.6 (CH), 127.0 (CH),
129.5 (quat.), 130.3 (CH), 132.8 (CH), 133.6 (CH), 134.4
(quat.), 146.3 (CH), 195.8 (quat.). ymax (NaCl plates, neat,
cm21): 3319 (broad), 3021, 2989, 1660, 1552, 1447, 1348,
1318, 1287, 1216, 1180, 1108, 1077, 796, 700, 669. EI mass
spectrum (m/z, %): 299 (MHþ, 1%), 229 (47%), 186 (95%),
109 (20%), 76 (15%), 69 (100%). HRMS (CIþ[NH3]):
found MNHþ4 316.0965, C12H14N2O5S requires MNHþ4
316.0967.
4.5.3. 1,2,3,4-Tetrahydro-2-isopropyl-1,4-benzodiaze-
pin-5-one 9c. Obtained, after column chromatographic
purification (single spot by TLC), as a yellow oil (0.0239 g,
29%) from 2-methyl-4-(o-nitrobenzamido)-but-1-en-3-one
7c (0.1000 g, 0.4028 mmol, 1.0 equiv.).
4.5. Synthesis of 1,4-benzodiazepin-5-ones 9
A solution of the allylic ketone (0.3–0.8 mmol) in dry
methanol (10 ml) at room temperature was treated with 5%
palladium on charcoal (,0.1 g) and a slow stream of
hydrogen was allowed to pass from a balloon into the
reaction mixture. The reaction was monitored by TLC and
was showed to be complete after 16–20 hrs, except for
compound 14, the formation of which was complete after
4 h. The reaction mixture was filtered (celite) to remove the
catalyst, the solvent was evaporated off and the residue was
purified by column chromatography (PE:EtOAc, 1:2). Thus
obtained were the following 1,4-benzodiazepin-5-ones:
dH (400 MHz, CDCl3): 0.90 (d, 3H, J¼6.8 Hz, Me), 0.96 (d,
3H, J¼6.7 Hz, Me), 1.81 (octet, 1H, J¼6.6 Hz, CHCHMe2),
3.27 (dd, 1H, J¼5.8, 1.9 Hz, CH2), 3.28–3.36 (m, 2H, CH2
and CHCHMe2), 6.55 (d, 1H, J¼8.2 Hz, ArH), 6.75 (t, 1H,
J¼7.5 Hz, ArH), 7.16 (dd, 1H, J¼6.9, 1.6 Hz, ArH), 7.29
(bs, 1H, NH), 7.49 (d, 1H, J¼7.3 Hz, ArH), 7.79 (dd, 1H,
J¼6.5, 1.5 Hz, ArH), 8.03 (dd, 1H, J¼7.1, 1.5 Hz, ArH). dC
(100 MHz, CDCl3): 18.3 (CH3). 18.9 (CH3), 29.7 (CH),
42.8 (CH2), 65.0 (CH), 118.2 (CH), 118.9 (CH), 128.3
(quat.), 132.5 (CH), 132.9 (CH), 145.1 (quat.), 172.1 (quat.).
ymax (NaCl plates, neat, cm21): 3328, 3166, 2963, 2927,
1637, 1609, 1466, 1264, 1098, 1047, 796. EI mass spectrum
(m/z, %): 205 (MHþ, 5%), 204 (20%), 161 (60%), 133
(45%), 132 (40%), 84 (100%), 104 (20%), 91 (40%), 77
(40%), 57 (45%), 49 (85%). HRMS (ESþ): found MHþ
205.1338, C12H16N2O requires MHþ 205.1341.
4.5.1. 1,2,3,4-Tetrahydro-3-methyl-2-(n-propyl)-1,4-ben-
zodiazepin-5-one 9a. Obtained, after column chromato-
graphic purification (single spot by TLC), as a white
crystalline solid (0.0782 g, 47%) from (E)-5-(o-nitrobenz-
amido)-hex-2-en-4-one 7a (0.2000 g, 0.7626 mmol). Mp:
193–195 8C.
dH (400 MHz, CDCl3): 0.97 (t, 3H, J¼6.9 Hz, Me), 1.22 (d,
3H, J¼6.9 Hz, Me), 1.25–1.63 (m, 4H, CH2CH2), 3.39 (dd,
1H, J¼8.8, 2.5 Hz, CHN), 3.70 (quint., 1H, J¼7.1 Hz,
CMeHN), 6.29 (bd, 1H, J¼8.5 Hz, NH), 6.58 (dd, 1H, J¼
8.2, 1.0 Hz, ArH), 6.76 (dt, 1H, J¼7.3, 1.0 Hz, ArH), 7.23,
(dt, 1H, J¼7.6, 1.6 Hz, ArH), 8.03 (dd, 1H, J¼8.1, 1.6 Hz,
ArH). dC (100 MHz, CDCl3): 14.0 (CH3), 16.8 (CH3), 19.6
4.5.4. 2-Ethyl-1,2,3,4-tetrahydro-1,4-benzodiazepin-5-
one 9d. Obtained, after column chromatographic purifi-
cation (single spot by TLC), as a yellow oil (0.0325 g, 40%)
from 4-(o-nitrobenzamido)-but-1-en-3-one 7d (0.1000 g,
0.4270 mmol, 1.0 equiv.).
dH (400 MHz, CDCl3): 1.10 (t, 3H, J¼7.4 Hz, Me), 1.60

3356
K. Hemming, C. Loukou / Tetrahedron 60 (2004) 3349–3357
Anderson, P. S.; Chang, R. S. L.; Lotti, V. J.; Cerino, D. J.;
Chen, T. B.; Kling, P. J.; Kunkel, K. A.; Springer, J. P.;
Hirschfield, J. J. Med. Chem. 1988, 31, 2235. (b) Patchett,
A. A.; Nargund, R. P. Annu. Rep. Med. Chem. 2000, 35, 289.
´ ´
(c) Herrero, S.; Garcıa-Lopez, M. T.; Herranz, R. J. Org.
Chem. 2003, 68, 4582.
(hextet, 1H, J¼7.3 Hz, CHCH2Me), 2.00–2.05 (m, 1H, J¼
7.2 Hz, CHCH2Me), 3.24–3.35 (m, 1H, CHN), 3.40 (dd,
1H, J¼5.7, 2.3 Hz, CH2N), 3.57 (dd, 1H, J¼6.6, 2.3 Hz,
CH2N), 4.95 (bs, 1H, NH), 6.60 (d, 1H, J¼8.2 Hz, NH),
6.81 (t, 1H, J¼7.5 Hz, ArH), 7.41 (d, 1H, J¼7.5 Hz, ArH),
7.91 (dd, 1H, J¼7.8, 1.6 Hz, ArH), 8.10 (dd, 1H, J¼7.2,
1.3 Hz, ArH). dC (100 MHz, CDCl3): 14.1 (CH3), 22.7
(CH2), 31.9 (CH2), 44.9 (CH), 118.7 (CH), 119.3 (CH),
128.1 (CH), 129.7 (quat.), 132.9 (CH), 139.8 (quat.), 161.9
(quat.). ymax (NaCl plates, neat, cm21): 3307, 3149, 2966,
2925, 1633, 1444, 1260, 1096, 1035, 798, 698. EI mass
spectrum (m/z, %): 191 (MHþ, 10%), 190 (75%), 161
(100%), 133 (55%), 132 (80%), 118 (20%), 104 (45%), 77
(35%), 57 (25%). HRMS (ESþ): found MHþ 191.1188,
C11H14N2O requires MHþ 191.1184.
2. See, for example: (a) Sternbach, L. H. J. Med. Chem. 1979, 22,
1. (b) Sternbach, L. H. Prog. Drug. Res. 1978, 22, 229.
(c) Showell, G. A.; Bourrain, S.; Neduvelil, J. G.; Fletcher,
S. R.; Baker, R.; Watt, A. P.; Fletcher, A. E.; Freedman, S. B.;
Kemp, J. A.; Marshall, G. R.; Patel, S.; Smith, A. J.; Matassa,
V. G. J. Med. Chem. 1994, 37, 719. (d) Bunin, B. A.; Plunkett,
M. J.; Ellman, J. A. Proc. Natl. Acad. Sci. USA 1994, 91, 4708.
3. See, for example: (a) Wright, W. B.; Brabander, H. J.;
Greenblatt, E. N.; Day, I. P.; Hardy, R. A. J. Med. Chem. 1978,
21, 1087. (b) Boojamra, C. G.; Burow, K. M.; Thompson,
L. A.; Ellman, J. A. J. Org. Chem. 1997, 62, 1240. (c) Keating,
T. A.; Armstrong, R. W. J. Org. Chem. 1996, 61, 8935.
(d) Webb, R. R.; Barker, P. R.; Baier, M.; Reynolds, M. E.;
Robarge, K. D.; Blackburn, B. K.; Tichler, M. H.; Weese, K. J.
Tetrahedron Lett. 1994, 35, 2113.
4.5.5. 2,3,4,5-Tetrahydro-4-hydroxy-3-methyl-4-(n-pro-
pyl)-1,2,5-benzothiadiazepin-1,1-dioxide 14. Obtained, as
a single spot by TLC, by the identical procedure via column
chromatography (eluent PE:EtOAc, 1:1) as a yellow oil
(0.0408 g, 45%) from (E)-5-(o-nitrobenzenesulfamido)-
hex-2-en-4-one 13 (0.1000 g, 0.3352 mmol, 1 equiv.).
4. (a) Thurston, D. E.; Bose, D. S. Chem. Rev. 1994, 94, 433.
´
´
(b) Molina, P.; Dıaz, I.; Tarraga, A. Tetrahedron 1995, 51,
5617. (c) O’Neil, I. A.; Thompson, S.; Murray, C. L.;
Kalindjian, S. B. Tetrahedron Lett. 1998, 39, 7787.
(d) Cooper, N.; Hagan, D. R.; Tiberghien, A.; Ademefun, T.;
Matthews, C. S.; Howard, P. W.; Thurston, D. E. Chem.
Commun. 2002, 1784.
dH (400 MHz, CDCl3): 0.76 (t, 3H, J¼7.4 Hz, Me), 1.30
(d, 3H, J¼7.2 Hz, Me), 1.42 (hextet, 2H, J¼7.4 Hz,
CH2CH2Me), 2.18 (dt, 1H, J¼17.4, 7.1 Hz, CH2CH2Me),
2.37 (dt, 1H, J¼17.6, 7.0 Hz, CH2CH2Me), 3.88 (quintet,
1H, J¼7.1 Hz, CHMe), 4.89 (bs, 2H, OH and NH), 5.89
(d, 1H, J¼6.8 Hz, NH), 6.71–6.80 (m, 2H, 2£ArH), 7.30
(t, 1H, J¼7.4 Hz, ArH), 7.66 (d, 1H, J¼7.9 Hz, ArH). dC
(100 MHz, CDCl3): 13.4 (CH3), 16.8 (CH3), 19.0 (CH2),
29.1 (CH), 40.9 (CH2), 57.0 (quat.), 117.7 (CH), 118.0
(CH), 127.3 (quat.), 127.5 (quat.), 129.3 (CH), 134.3 (CH).
ymax (NaCl plates, neat, cm21): 3401, 3377, 3265, 3038,
2960, 1600, 1483, 1455, 1332, 1156, 1024, 753. EI mass
spectrum (m/z, %): 271 (MHþ, 20%), 270 (95%), 199
(80%), 182 (50%), 156 (75%), 108 (35%), 92 (100%), 65
(40%). HRMS (CIþ[NH3]): found MNHþ4 288.1379,
C12H18N2O3S requires 288.1381.
5. (a) Sugimori, T.; Okawa, T.; Eguchi, S.; Kakehi, A.; Yashima,
E.; Okamoto, Y. Tetrahedron 1998, 54, 7997. (b) Witt, A.;
Bergman, J. J. Org. Chem. 2001, 66, 2784.
6. Artico, M.; Silvestri, R.; Pagnozzi, E.; Stefancich, G.; Massa,
S.; Loi, A. G.; Putzolu, M.; Corrias, S.; Spiga, M. G.; La Colla,
P. Bioorg. Med. Chem. 1996, 4, 837, and references cited
therein.
7. Novelli, F.; Sparatore, A.; Tass, B.; Sparatore, F. Bioorg. Med.
Chem. Lett. 1999, 9, 3031, and references cited therein.
ˆ
¨
8. (a) Frostl, W.; Maıtre, L. Pharmacopsych. 1989, 22, 54.
(b) Broggini, G.; Molteni, G.; Terraneo, A.; Zecchi, G.
Tetrahedron 1999, 55, 14803.
9. Gru¨nder, G.; Siessmeier, T.; Lange-Asschenfeldt, C.;
Vernaleken, I.; Buchholz, H.-G.; Stoeter, P.; Drzezga, A.;
Acknowledgements
¨
Lu¨ddens, H.; Rosch, F.; Bartenstein, P. Eur. J. Nucl. Med.
2001, 28, 1463.
We thank the EPSRC for a standard research grant and
project studentship (to C.L.); the University of Huddersfield
for facilities, NMR spectroscopy (Dr. Neil McLay), mass
spectroscopy (Ms. Lindsay Harding) and funding, and the
EPSRC National Service for Mass Spectrometry at the
University of Wales Swansea for mass spectra and for all
accurate mass measurements. Thanks are due to Ms.
Amanda Aley of Aventis Cropscience for repeating the
synthesis of cycloadducts 3, to Dr. Philip Evans for
technical assistance with the hydrogenations, and to the
late Division of Chemistry at the University of Hertfordshire
for NMR spectroscopy (Mr. David Clarke) and low
resolution mass spectroscopic facilities (Mr. Mark Scott).
10. Walser, A.; Fryer, R. I. In Chemistry of heterocyclic
compounds. Bicyclic diazepines; Taylor, E. C., Weissberger,
A., Eds.; Wiley: Chichester, UK, 1991; Vol. 50, p 431
Chapters V–VIII.
11. (a) Meguro, K.; Kuwada, Y. Tetrahedron Lett. 1970, 10, 4039.
(b) Mohiuddin, G.; Reddy, P. S.; Ahmed, K.; Ratnam, C. V.
Heterocycles 1986, 24, 3489. (c) Santilli, A. A.; Osdene, T. S.
U.S. Patent 3,336,330, 1967; Chem. Abstr. 68, 21972.
(d) Hester, J. B. U.S. Patent 3,896,109, 1975; Chem. Abstr.
84, 17440. (e) Osman, A. N.; El-Gendy, A. A.; Omar, R. H.;
Wagdy, L.; Omar, A. H. Ind. J. Chem. (B) 2002, 41B, 871.
12. Santilli, A. A.; Osdene, T. S. U.S. Patent 3,457,258; Chem.
Abstr. 1969, 71, 101898.
13. Hester, J. B.; Rudzik, A. D.; Kamadar, B. V. J. Med. Chem.
1971, 14, 1078.
References and notes
14. Kaneko, T.; Wong, H.; Doyle, T. W.; Rose, W. C.; Bradner,
W. T. J. Med. Chem. 1985, 28, 388.
1. (a) Evans, B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R. M.;
Freidinger, R. M.; Whitter, W. L.; Lundell, G. F.; Veber, D. F.;
15. Keenan, R. M.; Callahan, J. F.; Samanen, J. M.; Bondinell,
W. E.; Calvo, R. R.; Chen, L.; DeBrosse, C.; Eggleston, D. S.;

K. Hemming, C. Loukou / Tetrahedron 60 (2004) 3349–3357
3357
Haltiwanger, R. C.; Hwang, S. M.; Jakas, D. R.; Ku, T. W.;
Miller, W. H.; Newlander, K. A.; Nichols, A.; Parker, M. F.;
Southhall, L. S.; Uzinskas, I.; Vasko-Moser, J. A.; Venslavsky,
J. W.; Wong, A. S.; Huffman, W. F. J. Med. Chem. 1999, 42,
545.
25. Ammadi, F.; Boukhris, S.; Souizi, A.; Coudert, G.
Tetrahedron Lett. 1999, 40, 6517.
26. Yoo, H. W.; Lee, J. W.; Suh, M. E. Yakhak Hoechi 1989 33,
246; Chem. Abstr. 112, 216885.
27. Corral, C.; Madron˜ero, R.; Vega, S. J. Heterocycl. Chem.
1977, 14, 99.
16. (a) Santilli, A. A.; Osdene, T. S. J. Org. Chem. 1965, 30, 2100.
(b) Matsunaga, N.; Harada, H.; Aoyama, T.; Shioiri, T.
Heterocycles 1992, 33(1), 235.
28. Abrous, L.; Hynes, Jr. J.; Friederich, S. R.; Smith, III., A. B.;
Hirschmann, R. Org. Lett. 2001, 3, 1089.
17. (a) Miyamoto, M.; Kondo, S.; Naganawa, H.; Maeda, K.;
Ohno, M.; Umezawa, H. J. Antibiot. 1977, 30, 340. (b) Weber,
K.-H. Arch. Pharmaz. 1969, 302, 584.
29. Bauer, A.; Weber, K.-H. Z. Naturforsch. 1974, 29b, 670.
30. Thurston, D. E.; Kaumaya, P. T. P.; Hurley, L. H. Tetrahedron
Lett. 1984, 25, 4706.
18. (a) Santagada, V.; Perissutti, E.; Fiorino, F.; Vivenzio, B.;
Caliendo, G. Tetrahedron Lett. 2001, 42, 2397. (b) Molteni,
G.; Broggini, G.; Pilati, T. Tetrahedron: Asymmetry 2002, 13,
2491.
31. (a) Wu¨nsch, K. H.; Stahnke, K. H.; Gomoll, P. Z. Chem. 1970,
10, 219. (b) Ittyerah, P. I.; Mann, F. G. J. Chem. Soc. 1958,
467. (c) Misiti, D.; Gatta, F.; Landi-Vittory, R. J. Heterocycl.
Chem. 1971, 8, 231. (d) Grunewald, G. L.; Dahanukar, V. H.;
Ching, P.; Criscione, K. R. J. Med. Chem. 1996, 39, 3539.
32. (a) Field, G. F.; Zally, W. J.; Sternbach, L. H. J. Org. Chem.
1971, 36, 777. (b) Yamada, Y.; Oine, T.; Inoue, I. Bull. Chem.
Soc. Jpn 1974, 47(2), 339.
19. (a) Anwar, B.; Grimsey, P.; Hemming, K.; Krajniewski, M.;
Loukou, C. Tetrahedron Lett. 2000, 41, 10107. (b) Eguchi, S.;
Yamashita, K.; Matsushita, Y. Synlett 1992, 295.
20. White, J. D.; Haefliger, W. E.; Dimsdale, M. J. Tetrahedron
1970, 26, 233.
33. Hollywood, F.; Khan, Z. U.; Scriven, E. F. V.; Smalley, R. K.;
Suschitzky, H.; Thomas, D. R.; Hull, R. J. Chem. Soc., Perkin
Trans. 1 1982, 431.
21. Surman, M. D.; Mulvihill, M. J.; Miller, M. J. Org. Lett. 2002,
4, 139.
22. Julia, M.; Hurion, N.; Huynh, D. T. Chimica Therapeutica
1970, 5, 343.
34. Weinreb, S. M. Acc. Chem. Res. 1988, 21, 313.
¨
35. Bussas, R.; Kresze, G.; Mu¨nsterer, H.; Schwobel, A. Sulfur
23. Pedrazzoli, A.; Dall’Asta, L.; Ferrario, P. Bull. Soc. Chim.
France 1968, 407.
Rep. 1983, 2, 215.
36. Evans, D. A.; Andrews, G. C. Acc. Chem. Res. 1974, 7, 147.
24. Wang, T.; Lui, A. S.; Cloudsdale, I. S. Org. Lett. 1999, 1,
1835.