SEAr-SNAr couplings of indolizines and related pyrrole derivatives with superelectrophilic nitrobenzoxadiazoles

Article abstract of DOI:10.1016/j.tet.2009.11.071

The nucleophilic aromatic substitutions of 7-chloro-4,6-dinitrobenzofurazan (DNBZ-Cl) and 7-chloro-4,6-dinitrobenzofuroxan (DNBF-Cl) with a series of differently substituted indolizines (5a-f) and a series of dihyropyrroloisoquinolines (11a-f) have been i

Full text of DOI:10.1016/j.tet.2009.11.071

Tetrahedron 66 (2010) 995–1006
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
SEAr–SNAr couplings of indolizines and related pyrrole derivatives with
superelectrophilic nitrobenzoxadiazoles
a
a
a
b,
b
*
´
Artem Tatarov , Serguey Kurbatov , Gennady Borodkin , Regis Goumont , François Terrier
a Department of Chemistry, Southern Federal University, 7, Zorge Street, 344090 Rostov-on- Don, Russian Federation
b Institut Lavoisier, UMR CNRS 8180, University of Versailles, 45, Avenue des Etats-Unis, 78035 Versailles Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 October 2009
Received in revised form 13 November 2009
Accepted 16 November 2009
Available online 7 December 2009
The nucleophilic aromatic substitutions of 7-chloro-4,6-dinitrobenzofurazan (DNBZ-Cl) and 7-chloro-4,6-
dinitrobenzofuroxan (DNBF-Cl) with a series of differently substituted indolizines (5a–f) and a series of
dihyropyrroloisoquinolines (11a–f) have been investigated. In accord with previous reports emphasizing the
superelectrophilic character of these compounds in s-complexation processes, DNBZ-Cl and DNBF-Cl react
very readily and quantitatively with the weak carbon nucleophiles 5a–f and 11a–f at room temperature in
acetonitrile. In the case of DNBZ-Cl, the resulting products (7Z,a–f and 12Z,a–f) are those expected from the
displacement of the chlorine atom through a SEAr–SNAr mechanism. A significant result is that these
compounds, despite the lack of coplanarity of the two rings, are characterized by an intense intramolecular
charge transfer between the donor pyrrole-type moiety and the electron-deficient acceptor DNBZ moiety.
Contrasting with this behaviour, the DNBF-Cl reactions show a totally different pattern, proceeding with loss
of the N-oxide functionality and expansion of the pyrrole moiety to afford stable zwitterionic spiro adducts
(8F,a–f and 13F,a–f) of a so far unknown type. Rapid NMR recordings have revealed that the formation of
these adducts occurs after initial formation of the expected substitution products 7F,a–f and 12F,a–f. A
mechanism accounting for the overall rearrangement leading to the spirobenzofurazan adducts is sug-
gested. It is based on an initial nucleophilic attack of the oxygen atom of the N-oxide functionality at the
electron-deficient and strongly olefinic C–C coupling bond generated by the aforementioned intramolecular
charge transfer. This results in the formation of an unstable five-membered isoxazole ring whose de-
composition goes along with loss of the N-oxide functionality and enlargement of the pyrrole moiety into
a pyridine one. Also discussed are the factors accounting for the high thermodynamic stability of the spiro
adducts, and their relevance to the stability of previously reported spiro adducts.
Keywords:
Indolizine nucleophilicity
Pyrrole nucleophilicity
SEAr–SNAr couplings
Superelectrophilic nitrobenzoxadiazoles
Zwitterionic spiro adducts
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
s-adducts. The formation of the DNBF adducts 2a–k from various
indoles (1a–k) according to Eq. 1 is a prototype example. Altogether,
the results obtained have revealed that the neutral DNBF and DNBZ
molecules exhibit an electrophilic reactivity that compares well with
that of the positively charged 4-nitrobenzenediazonium cation.19
The ease of coupling of DNBF and DNBZ with very weak nucleophiles
has led to numerous synthetic, analytical and biological applica-
tions.8,20–22
The field of electrophile–nucleophile combinations has, during
the last few years, received a boost with the discovery of a class of
electron-deficient aromatic compounds that show increased re-
activity in the formation of
s-bonded (Meisenheimer) com-
plexes.1–14 The high susceptibility of 4,6-dinitrobenzofuroxan (DNBF,
4,6-dinitro-2,1,3-benzoxadiazole-1-oxide) and 4,6-dinitrobenzofur-
azan (DNBZ, 4,6-dinitro-2,1,3-benzoxadiazole) to react very readily
and quantitatively with water,10,11 or such weak carbon nucleophiles
Recently, we have found that the remarkable propensity of DNBF
and DNBZ to react in s-complexation processes extends to nucleo-
as benzenoid aromatics (phenols, anilines.)2,3b,15,16 or
heteroaromatics (indoles, pyrroles, thiophenes, furans.),
p
-excessive
philic aromatic substitutions of the SNAr type.23 While only strong
carbon bases of pKaꢀ9, e.g., 1,3,5-trispyrrolidinobenzene,24 react
satisfactorily with picryl chloride,25 the reactions of 7-chloro-4,6-
dinitrobenzofurazan (DNBZ-Cl) anddbenzofuroxan (DNBF-Cl) have
been found to proceed smoothly at room temperature with a large
set of indoles and 2-methylindoles (pKa values in the range ꢁ6 to
þ0.26), affording the related substituted products, i.e., 4Z and 4F, in
essentially quantitative yields (Scheme 1).23 An interesting struc-
tural property of these products is that a strong intramolecular
1,17,18
is
a nice illustration of this behaviour. In all of these reactions, covalent
addition of the carbon nucleophile takes place at C-7 of the carbo-
cyclic ring of DNBF and DNBZ to give very stable carbon-bonded
* Corresponding author. Tel.: þ33 1 39 25 66 56; fax: þ33 1 39 25 66 52.
E-mail address: goumont@chimie.uvsq.fr (R. Goumont).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.11.071

996
A. Tatarov et al. / Tetrahedron 66 (2010) 995–1006
Scheme 1.
charge transfer is taking place between the
zofuroxan or benzofurazan acceptor and the
p
p
-system of the ben-
-system of the aro-
this paper, we report on the SNAr reactivity of two families of
pyrrole derivatives. The first consists of a series of indolizines,
namely 5a–f, whose pKa values are known to lie in the range of the
most basic pyrroles, e.g., pKa¼3.94 for unsubstituted indolizine
versus pKa¼3.75 for 2,4-dimethyl-3-ethylpyrrole (krypto-
pyrrole).26–28 All pKa values presented relate to water as solvent
and give general indication of relative basicity. The second family
includes a series of pyrroloisoquinolines, 11a–f, whose C-basicity is
expected to be favoured by the 1,2-dialkylsubstitution of the
pyrrole ring. As will be seen, only the DNBZ-Cl reactions
matic or heteroaromatic donor, despite the fact that steric effects
preclude a full coplanarity of the two moieties.23 Similar couplings
with 1,2,5-trimethylpyrrole and azulene have also been carried
out.23 Accordingly, the resonance structures 4Z0 and 4F0 must play
a major role in determining the reactivity of 4Z and 4F.
In an attempt to expand the SNAr feasibility of C–C couplings,
we have become interested in looking at the reactivity of DNBF-Cl
and DNBZ-Cl towards various families of carbon nucleophiles. In

A. Tatarov et al. / Tetrahedron 66 (2010) 995–1006
997
proceeded to give the expected SNAr products. In the case of the
DNBF-Cl systems, the substitution products are not stable, un-
dergoing an unprecedented rearrangement, which is induced by
an intramolecular oxygen atom transfer from the N-oxide func-
tionality of the DNBF moiety. A possible mechanism for this
rearrangement will be discussed. To be noted is that a preliminary
communication dealing only with the reactivity of 2-(40-bromo-
phenyl)indolizine 5e and the X-ray determination of the resulting
products 7Ze and 7Fe has appeared.29
a reflection of this charge transfer, similar to the one observed in
the indole couplings (Scheme 1),23 there is a strong shift to low-
field of the H1 and C1 resonances of the pyrrole ring (
C1¼96.16 in 5e; H1¼7.06, C1¼104.66 in 7Ze) as well as of the H6,
H7 and H8 resonances of the pyridine ring: H7¼6.69,
H6¼6.53,
H8¼7.38 in 5e; H6¼6.91, H7¼7.24, H8¼7.79 in 7Ze. Con-
comitantly,the C6 and C7 resonances move significantly to low-field
e.g.,
dH1¼6.75,
d
d
d
d
d
d
d
d
d
dC6¼110.08,
d
C7¼117.78 in 5e;
d
C6¼113.44; C7¼123.89 in 7Ze.
d
These chemical shift variations suggest that the pyridine ring
contributes to a significant delocalization of the positive charge
generated on the nitrogen atom by the overall donor–acceptor in-
teraction (see Discussion). All 1H and 13C data pertaining to the
parent indolizines 5a–f and the resulting SNAr products 7Z,a–f are
collected in Tables 1 and 2.
O
O
a: CH3
R =
b: C6H5
c: 4'-H3CC6H4
d: 4'-H3COC6H4
e: 4'-BrC6H4
f: 4'-O2NC6H4
R
R
N
N
Table 1
1H NMR parameters for indolizines 5a–f and related substitution products 7Z,a–f,
7Fc and 7Fea,b
5
11
Substrate
H-500
H-1
H-5
H-6
H-7
H-8
2. Results
5a
7Za
5b
7Zb
5c
7Zc
7Fc
5d
7Zd
5e
7Ze
7Fe
5f
d
6.17
6.74
6.75
6.97
6.70
6.88
6.82
6.66
6.87
6.75
7.06
6.84
6.90
7.11
8.10
8.08
8.20
8.12
8.18
8.07
7.43
8.18
8.07
8.20
8.14
7.43
8.24
8.11
6.41
6.85
6.52
6.85
6.50
6.81
6.89
6.49
6.81
6.53
6.91
6.92
6.58
6.87
6.59
7.22
6.68
7.24
6.66
7.18
7.24
6.65
7.18
6.69
7.24
7.25
6.73
7.21
7.26
7.65
7.37
7.73
7.36
7.67
7.62
7.35
7.67
7.38
7.79
7.65
7.42
7.75
9.21
d
2.1. Reactions of DNBZ-Cl and DNBF-Cl with indolizines 5a–f
9.12
d
Treatment of DNBZ-Cl with 1 equiv of each of the indolizines
5a–f in CHCl3 solution produced deep blue-green crystals in rather
high yields. Confirming the results obtained previously with 2-(40-
bromophenyl)indolizine 5e,29 these solids correspond to the
expected SNAr substitution products 7Z,a–f Eq. 2. Of particular
significance is that 7Z,a–f exhibit an intense visible absorption at
very high wavelengths, e.g., lmax¼780 nm for 7Ze in CHCl3. This
points to a very strong intramolecular charge transfer from the
donor indolizine moiety to the 4,6-dinitrobenzofurazanyl acceptor
moiety, and therefore to an important contribution of the reso-
nance structure 7Z0,a–f to the stabilization of 7Z,a–f (Eq. 2). As
9.11
9.01
d
9.10
d
9.25
9.02
d
7Zf
9.15
a
Solvent: Me2SO-d6 for 7Z,a–f and CDCl3 for 7Fc and 7Fe;
d
in ppm, internal
reference Me4Si.
b
See structures and numbering of atoms in Eq. 2.
Table 2
13C NMR parameters for indolizines 5a–f and related substitution products 7Z,a–fa,b
Substrate
C-400
C-500
C-600
C-700
C-800
C-900
C-1
C-3
C-5
C-6
C-7
C-8
C-9
DNBZ-Cl
5a
7Za
5b
7Zb
5c
7Zc
5d
7Zd
5e
7Ze
5f
136.75
d
128.18
d
147.34
d
128.01
d
151.76
d
143.77
d
d
d
d
d
d
d
d
99.64
107.32
96.15
104.77
95.97
104.64
95.82
104.54
96.16
104.66
96.95
104.77
111.44
143.55
110.43
143.07
110.28
142.87
110.16
143.04
110.65
143.44
111.71
143.10
125.16
126.76
125.71
126.14
125.64
126.07
125.59
126.15
125.75
126.23
125.97
126.02
109.18
113.11
109.84
113.07
109.54
112.77
109.15
112.78
110.08
113.44
111.36
113.50
116.53
124.91
117.55
123.62
117.43
123.40
117.36
123.63
117.78
123.89
118.37
123.42
117.79
118.75
118.63
119.16
118.52
118.93
118.41
118.92
118.68
119.36
119.06
119.43
132.05
138.85
132.92
137.93
132.86
137.97
132.87
138.10
133.02
137.80
133.39
137.51
122.97
d
129.74
d
133.01
d
116.24
d
151.74
d
140.68
d
123.07
d
128.94
d
133.92
d
112.71
d
151.28
d
142.87
d
123.16
d
128.72
d
135.94
d
112.88
d
151.19
d
142.47
d
123.12
d
128.93
d
135.67
d
112.86
d
151.24
d
142.52
d
122.76
d
129.08
d
133.95
d
112.22
d
151.36
d
143.65
d
7Zf
122.50
128.71
133.51
112.32
151.34
143.83
a
Solvent: Me2SO-d6;
See Eq. 2 for the structures and the numbering of atoms.
d in ppm, internal reference Me4Si.
b
8
7
9
1
6
N+
Cl
7''
N
8
R
R
2
1
4
5
O2N
8''
N
3
7
6
2
6''
O2N
+
O
R
O2N
N
N
O
N
7''
N
6''
5''
5''
N
8''
(2)
9''
O
4
5
3
4''
N
9''
NO2
4''
NO2
NO2
5a-f
7Z,a-f
7Z',a-f
DNBZ-Cl
3'
2'
1'
4'
with 5a : R = CH3
, 5b-f : R =
X
b : X = H, c : X = CH3, d : X = OCH3, e : X = Br, f : X = NO2

998
A. Tatarov et al. / Tetrahedron 66 (2010) 995–1006
00
comparison, the resonance of the related C7 carbons in DNBF or
Again in agreement with the results obtained in using 5e as the
nucleophilic reagent, DNBF-Cl reacted with all indolizines 5a–f to
afford the orange-red zwitterionic adducts 8F,a–f Eq. 3. In addition to
the X-ray structure of 8Fe,29 there are several significant features
supporting the proposed structures. A most important one deals
with the totally different chemical shift patterns characterizing the
DNBZ
s-adducts of type 2 appears at
d
¼30–31 ppm.1,19 Another ar-
gument supporting structures 8F,a–f comes from theoretical pre-
dictions that
s-complexation of a nitroaromatic or heteroaromatic
ring induces a negative charge at the ortho- and para-positions but
a
decrease in negative charge at the unsubstituted meta-
00
00
00
quaternary carbons C8 and C9 in the parent DNBF-Cl substrate and
the resulting adducts 8F,a–f (Table 3). As pointed out by several
authors, the electron-donatingþM effect of the N-oxide group has
positions.13,14,36–40 As shown inTable 3, the resonances of the C4 and
00
C6 carbonsof8F,a–f are atmuch higher fieldthan intheDNBZ-Cl and
DNBF-Cl substrates or the related DNBF or DNBZ molecules. At the
00
00
the effect to induce the presence of a negative charge on the C8
same time, the resonance of the C5 carbons moves appreciably to
carbon in a benzofuroxan structure, as depicted in the canonical form
B see Eq. 4. This causes a large upfield shift of the resonance of this
carbon, as compared with the situation in the benzofurazan se-
ries.30–35 As a matter of fact, it has been proposed that the chemical
low-field. To be noted is that the 13C resonances of the cyclo-
hexadienyl moiety of 8F,a–f are essentially the same as those
reported for all DNBF or DNBZ adducts so far descri-
bed.2,5,6,13e,14,16,20,41 A last noteworthy feature associated with the
formation of 8F,a–f is the enormous deshielding of the H1 resonance:
00
00
shift pattern of C8 and C9 be used as a diagnostic feature for dis-
criminating between benzofuroxan and benzofurazan skele-
d¼8.69 in 8Fe (Table S1) versus
d¼6.75 in 5e (Table 1).
tons.30,31,33 Here, the strong downfield shift of C8 observed on going
Due to the different patterns governing the reactivity of DNBZ-Cl
00
from DNBF-Cl to each of the spiro adducts 8F,a–f (Ddz33 ppm) is
obviously consistent with the loss of the N-oxide functionality dur-
ing the overall process.
and DNBF-Cl, there are significant differences in the physical
properties of the resulting products 7Z,a–f and 8F,a–f. Thus the
SNAr products 7Z,a–f have a high solubility in most organic sol-
vents, giving rise to deeply blue-green coloured solutions, which
reflect the importance of the intramolecular charge transfer men-
tioned above. Also worth noting is that 7Z,a–f exhibit a satisfactory
chromatographic mobility. In contrast, the dipolar spiro adducts
8F,a–f are poorly soluble in organic solvents, including in dipolar
aprotic solvents like Me2SO. Consistent with the presence of the
anionic cyclohexadienyl moiety, 8F,a–f show UV–visible absorption
1
9
10
R
2
3
Cl
8
7
O
8
5
N+
1
N+
O2N
6
7
6
O
O2N
2
5
N
(3)
7''
R
+
O
8''
6''
5''
N
O
N
4
3
N
9''
4''
NO2
N+
-
O
spectra, which are similar to those for all DNBF and DNBZ
s-adducts
O
5a-f
previously studied, i.e., lmax z470–480 nm.1–6,10,14,18,19,41
DNBF-Cl
8F,a-f
O
O
O
O
N+
N+
N+
N+
(4)
O
O
O
O
N
N
N
N
A
B
D
C
Table 3
Selected 13C NMR parameters for the spiro adducts 8F and 13Fa–d
Substrate
C-400
C-500
C-600
C-700 (C-4)
C-800
C-900
C-1
C-3
DNBZ-Cl
DNBZ
DNBF
DNBF-Cl
8Fa
8Fb
8Fc
8Fd
8Fe
136.75
137.88
137.96
136.18
111.69
111.76
111.72
111.70
111.80
111.90
112.84
112.96
112.91
112.86
113.00
113.14
128.18
124.50
125.83
129.07
135.43
135.54
135.52
135.53
135.53
135.56
136.52
136.55
136.56
136.55
136.52
136.51
147.34
148.80
144.85
144.04
122.11
121.83
121.87
121.93
121.71
121.57
120.99
121.35
121.41
121.47
121.26
121.18
128.01
122.22
119.53
127.35
71.05
71.84
71.78
71.72
71.86
72.00
70.53
71.25
71.23
71.14
71.25
71.37
151.76
150.23
116.12
115.79
149.86
149.61
149.62
149.64
149.52
149.47
151.12
151.28
151.34
151.39
151.23
151.16
143.77
143.62
144.65
145.39
143.79
143.83
143.83
143.83
143.82
143.84
146.21
146.27
146.28
146.29
146.27
146.27
d
d
d
d
d
d
d
d
111.69
111.76
111.72
111.70
111.80
111.90
112.84
112.96
112.91
112.86
113.00
113.14
135.43
135.54
135.52
135.53
135.53
135.56
136.52
136.55
136.56
136.55
136.52
136.51
8Ff
13Fa
13Fb
13Fc
13Fd
13Fe
13Ff
a
Solvent: Me2SO-d6 for 8F,a–f and nitrobenzene-d5 for 13F,a–f;
d in ppm, internal reference Me4Si.
b
c
See structures and numbering of atoms in Eq. 3 and structure 13F,a–f.
Values for DNBZ-Cl and DNBF-Cl in CD3CN-d3 determined in this work.
Values for DNBZ and DNBF taken from Ref. 31.
d
Other typical data in accord with the spiro structure are the car-
2.2. Reactions of DNBZ-Cl and DNBF-Cl with the
pyrroloisoquinolines 11a–f
bon chemical shifts assigned to the carbonyl group (dC3z135 ppm)
and to the sp3-hybridized spiro centre (
d
C7 z71 ppm). Being bonded
00
both to a carbonyl group and a positively charged nitrogen atom, this
centre is characterized by a relatively low-field resonance. For
A major finding emerging from the indolizine reactions de-
scribed above is that the formation of the spiro complexes 8F,a–f

A. Tatarov et al. / Tetrahedron 66 (2010) 995–1006
999
takes place with an expansion of the pyrrole ring. This made it of
interest to look at whether this rearrangement extends to other
pyrrolic structures. For this purpose, a series of 2-substituted-8,9-
dimethoxy-5,6-dihydropyrrolo[2,1-a]isoquinolines 11a–f, has been
investigated. These compounds were obtained in good to highyields
by carrying out the cyclizations in one stage, i.e., without isolating
the quaternary intermediates according tothe Tchichibabinprotocol
modified by Casagrande42 and other authors.43,44
As expected, the pyrroloisoquinolines 11a–f behave similarly to
the indolizines 5a–f, reacting with DNBZ-Cl and DNBF-Cl to give the
SNAr substitution products 12Z,a–f and the spiro adducts 13F,a–f,
respectively. The various arguments developed to account for the
formation of the indolizine products 7Z and 8F fully apply to the
recognition of structures 12Z,a–f and 13F,a–f so that there is no
need for many additional comments. Selected 1H and 13C data are
given in Tables S2 and S3 for 12Z,a–f and Tables 3 and S4 for 13F,a–f.
Regarding compounds 12Z,a–f, it may be further pointed out that
the strong intramolecular charge transfer is evidenced by the
O
O
9
strong shift to low-field of the H1 and C1 resonances, e.g.,
d
H1¼6.90,
O
O
10
11
dC1¼100.26 in 11e as compared with
dH1¼7.18,
dC1¼106.70 in 12Z,e
8
1
12
(Tables S2 and S3). Also worth noting is that the SNAr substitution
leading to 12Z,a–f causes a non-equivalence of the H5a and H5b
protons of the N-CH2 group with only the most deshielded one
appearing at lower field than in the parent pyrrole.
7
2
O
(5)
13
+
R
N
N
Br
6
4
3
R
5
9a-f
11a-f
10
3. Discussion
O
3.1. The SEAr–SNAr mechanism
O
9
O
8
10
11
10
As referred to in the introduction, DNBZ-Cl and DNBF-Cl have
been found to readily react with indoles. Besides a thorough
structural analysis, which has revealed that the resulting sub-
stitution products are subject to an intense intramolecular charge
transfer, a detailed kinetic investigation of the various substitutions
has been carried out.19,23 Based on the collected data and in par-
ticular the absence of a significant dependence of the rates of
coupling on the hydrogen or deuterium labelling at the reactive
centre of the nucleophiles, it has been unambiguously demon-
strated that the reactions take place through the SEAr–SNAr
mechanism depicted in Scheme 1. In this scheme, the initial
7
O
11
9
12
13
1
1
12
13
6
R
8
5
14
N
2
R
2
N+
4
7
Hb
6
3
O
O2N
Ha
3
5
N
O2N
7''
Y
8''
7''
6''
5''
6''
5''
8''
9''
O
O
N
9''
N
4''
4''
NO2
NO2
Y= N
Y= N+-O-
13Fa-f
12Z,a-f
12F,a-f
Scheme 2.

1000
A. Tatarov et al. / Tetrahedron 66 (2010) 995–1006
formation of the zwitterionic Wheland–Meisenheimer in-
termediate 3H takes place as the rate-limiting step of the overall
interaction. This is followed by fast rearomatization of the hetare-
as indoles, undergoing facile reactions with DNBZ-Cl and DNBF-Cl
to afford the substitution products (7Z,a–f, 7F,a–f and 12Z,a–f,
12F,a–f) according to the SEAr–SNAr mechanistic pattern outlined
in Scheme 2 for the indolizine systems. As a matter of fact, there is
little doubt that this scheme applies well to the DNBZ-Cl reactions.
Of particular significance for the characterization of the sub-
stitution products 7Z,a–f and 12Z,a–f is the X-ray structure
obtained for the 2-(40-bromophenyl)indolizine compound 7Z,e.29
nium moiety to give the anionic Meisenheimer s-complex 3. This
process is energetically assisted by the recovery of the aromaticity
of the indole nucleophile. Facile loss of chloride anionda good
leaving group (pKa¼ꢁ7)d45 from the adducts 3 then leads to the
substitution products. Importantly, DNBZ-Cl and DNBF-Cl are
reacting with similar rates with a given indole nucleophile, point-
ing out that the presence of the N-oxide functionality has very little
influence on the electrophilic reactivity of mono-nitro- and dinitro-
00
The twisting of the NO2 group located in the ortho position (C6 ) to
the reaction site is of only 26ꢂ, allowing an extensive conjugation
between the donor and acceptor moieties of the products 7Z,a–f.
This conjugation is reflected in the notable olefinic character of the
2,1,3-benzoxadiazoles in SNAr and related
processes.
s-complexation
00
C3–C7 bond (1.427 Å) and some typical NMR variations, e.g.,
Going to the present work, it was reasonable to anticipate that
a strong shift to low-field of the H1 and C1 resonances on going from
the indolizines 5a–f and the pyrroloisoquinolines 11a–f will behave
5e or 11e to 7Z,e and 12Z,e (see Tables 1, 2 and S2, S3).
Figure 1. 1H NMR spectra showing the formation of the transient SNAr substitution product 12F,e in the reaction of DNBF-Cl with 11e to give the spiro adduct 13Fe.

A. Tatarov et al. / Tetrahedron 66 (2010) 995–1006
1001
3.2. The DNBF rearrangement
counterparts (Tables 1 and S2). Also, the transient colour associated
with the formation of these SNAr products, namely 7F,b, 7F,e and
12F,b 12F,e, is the same as that characterizing the DNBZ-Cl ana-
logues. This implies an important contribution of the canonical
structures of type 7F0 and 12F0, thereby supporting the view that
a similar intramolecular charge transfer takes place between the
donor and acceptor moieties in both DNBF- and DNBZ-substitution
products.
Under the same experimental conditions as those used for the
DNBZ-Cl reactions, the interactions of DNBF-Cl with 5a–f and 11a–f
do not lead to the expected substitution products 7F,a–f and
12F,a–f. Instead, the zwitterionic spiro adducts 8F,a–f and 13F,a–f
are isolated. These have been structurally characterized by combining
the information provided by a X-ray structure of the (40-bromo-
phenyl)indolizine member (8F,e)29 with typical NMR and UV–vis-
ible data (see comments in the Results section as well as Tables 3,
S1 and S4). As the first peculiarity associated with the formation of
8F,a–f and 13F,a–f, there is the loss of the N-oxide functionality and
the overall conversion of the starting dinitrobenzofuroxan moiety
into a negatively charged dinitrobenzofurazan one. A second
noteworthy feature is that this conversion goes along with a skel-
etal rearrangement of the pyrrole fragment of the indolizine
nucleophile, resulting eventually in an enlargement of this five-
membered ring and the formation of a C–N spiro adduct.
Taking into account the essentially similar reactivity of DNBZ-Cl
and DNBF-Cl in the indole reactions, a reasonable mechanism ac-
counting for the overall formation of the spiro adducts 8F,a–f and
13F,a–f can be proposed. The starting point is the assumption that
DNBF-Cl must react initially as its DNBZ analogue to afford the
SEAr–SNAr substitution products 7F,a–f and 12F,a–f. As a matter of
fact, a rapid recording of the 1H NMR spectra after mixing of the
reagents has allowed the characterization of 7F and 12F as short-
lived species in the case of the indolizines 5b and 5e as well as the
dihydropyrroloisoquinolines 11b and 11e. This characterization is
illustrated in Figure 1, which shows the conversion of the initially
formed substitution product, here 12F,e, into the related spiro ad-
duct 13F,e. Since the final spirocyclic adduct 13F,e is poorly soluble
in chloroform, it was necessary to record spectrum of the pre-
cipitated product in deuterated nitrobenzene (Fig. 1). The related
NMR parameters compare well with those for the DNBZ-Cl
O
O
9
O
10
8
10
11
7
O
11
12
9
8
12
13
1
1
6
13
R
5
14
N
2
R
2
N+
4
7
Hb
6
3
O
O2N
Ha
3
5
N
O2N
7''
Y
8''
7''
6''
5''
6''
5''
8''
9''
O
O
N
9''
N
4''
4''
NO2
NO2
Y= N
Y= N+-O-
13Fa-f
12Z,a-f
12F,a-f
On the above grounds, we suggest that the charge transfer is the
key point determining the conversion of 7F and 12F into the spiro
adducts 8F and 13F. As shown in Scheme 3 with reference to the
indolizine systems, this transfer has the effect of generating a posi-
tively charged indolizinium moiety, thereby promoting nucleophilic
attack at the electron-deficient C3 centre by the negatively charged
oxygen atom of the N-oxide functionality. The result is the formation
of a five-membered ring (structure 14), which is prone to undergo
00
00
N1 –O1 and C3–N4 bond breakings, presumably through a concerted
Scheme 3.

1002
A. Tatarov et al. / Tetrahedron 66 (2010) 995–1006
process, to afford the 7-substituted-4,6-dinitrobenzofurazans 15. In
a last step, intramolecular nucleophilic addition of the basic pyridine
this respect, there is strong experimental evidence that a protonated
amine nitrogen exhibits a very high nucleofugality in -complexa-
s
tion processes.13,14,59–61 For example, the rate constant k&minus1 for
spontaneous opening of the dioxolan ring of the picryl adduct 18 Eq.
6 is about 107 times lower than that for opening of the ethylenedi-
amine ring of the adduct 19 Eq. 7 in aqueous solution.59,61,62 In as
much as the acidity common iminium ions (pKaz7)63,64 do not
differ very much from that of common ammonium ions, e.g.,
pKa¼8.36 for morpholine, and pKa¼5.17 for pyridine, the positive
charge located on the nitrogen atom is not at all a favourable factor
contributing to the thermodynamic stability of adducts 8F and 13F.
One can therefore raise the question of whether the large de-
localization of the negative charge through the dinitrobenzofurazan
moiety can be the only factor contributing to this stability.
00
nitrogen atom of 15, takes place at C7 . This process is facilitated by
the superelectrophilic character of the 4,6-dinitrobenzofurazan
structure, leading to the stable spiro adducts 8F. In the case of the
pyrroloisoquinolines 11a–f, a similar mechanism will operate, the
only difference with the indolizine systems being that the last step
includes cyclization through nucleophilic attack by an imino nitro-
gen. The intermediates 16F and 17F involved in the rearrangement of
the substitution products 12F,a–f into the spiro adducts 13F,a–f are
shown below.
O
O
O
O
OH
O
O
O
N
..
N+
O
O
O
O
O
O2N
NO2
+
O2N
NO2
O2N
NO2
O
O
k1
Fast
R
R
N
RO-
(6)
k-1
-ROH
N
O2N
O2N
O
N+
O
NO2
NO2
-
N
N
10
18
N+
N+
-
-
O
O
O
16F,a-f
17F,a-f
H
N
3.3. Enlargement of the pyrrole ring
N+
H
NO2
Each of the individual steps of Scheme 3 deserves further com-
ment. Deoxygenation of a N-oxide functionality is a relatively
common process in heterocyclic chemistry where it often occurs via
formal elimination of a water molecule. Deoxygenative nucleophilic
substitutions of hydrogen of azaactivated compounds bearing
a N-oxide group are prototype examples.14,46–50 Ring transformations
induced by oxygen migration have also been reported.51,52 The
conversion of 1,2,4-triazine 4-oxides into pyridazines upon reaction
with substituted acetonitriles is a representative example.51 In this
work, it is noteworthy that the oxygen transfer goes through
opening of the five-membered isoxazole and pyrrole rings of the
intermediates 14F or 16F. Thus, after cyclization, the pyrrole moiety
of the starting nucleophilic reagents is replaced by a six-membered
ring. While there have been many reports of pyrrole/pyridine or
indole/quinoline interconversions, none of these rearrangements
take place via a mechanism of the type depicted in Scheme 3. The
fact that the present rearrangements are induced by the dipolar
nature of the substitution products with an attack of the strongly
N
N
O2N
O2N
NO2
k1
(7)
k-1
N+
NO2
-
O
O
19
A possible explanation of the ease of formation and stability of
8F and 13F emerges when considering the canonical structures
shown below in Eqs. 8 and 9. As can be seen, the positive charge of
these adducts is subject to a strong delocalization through either
the pyridine ring (8F) or the dimethoxyphenyl ring (13F), resulting
in a favourable resonance stabilization of their positive moiety. In
particular, this delocalization has the effect to remote the positive
00
charge from the C7 –N5 bond, which becomes less prone to spon-
taneous breaking. As a matter of fact, there is experimental evi-
dence supporting this proposal. Thus, the resonances of the H6, H7
and H8 protons of the pyridine ring move strongly downfield upon
formation of 8F (see Tables 1 and S1). Similarly, the formation of
13F is associated with a large deshielding of the H8 and H11 protons
of the dimethoxyphenyl ring (Table S4), while the resonance of the
H1 proton, which is now remote from the positive charge is only
slightly affected. These variations are clearly consistent with a dis-
persion of the positive charge. It is this dispersion coupled with that
of the negative charge of the anionic moiety, which will account for
the observed stability of 8F and 13F.
00
deactivated C7 –C3 double bond by the oxygen atom of the N-oxide
function is a further remarkable manifestation of the exceptional
electrophilic character of a DNBF moiety. So far, reports of an en-
largement of a pyrrole ring have derived from radical rearrange-
ments or treatment of methylindoles and 2,5-dimethylpyrrole
under strong basic conditions.53–58
3.4. How to account for the stability of the spiro adducts 8F
and 13F? A re-examination of previously reported spiro
adducts
R
R
R
+
There are several significant features to highlight regarding the
formation of 8F and 13F as the stable products of the DNBF-Cl re-
N+
N
O
N
O
+
O
O2N
O
O2N
O
O2N
N
N
N
N
N
actions. First, no example is known to us of a spiro s-adduct with
(8)
O
O
O
a sp3 centre combining a C–C and a C–N coupling.13,14 8F and 13F are
therefore original structures in the field of Meisenheimer com-
plexes, especially because their dipolar character goes with the
presence of a positively charged pyridinium or iminium moiety. In
N
N+
N+
N+
-
-
-
O
O
O
O
8F,a-f

A. Tatarov et al. / Tetrahedron 66 (2010) 995–1006
1003
of DNBZ-Cl or DNBF-Cl. The resulting solution turned rapidly green,
becoming either deeply blue (7Z,a–f) or brown (8F,a–f) after a few
minutes. After stirring the solution for 1 h, the resulting pre-
cipitates were collected by filtration. The purification of 7Z,a–f was
achieved by column chromatography. Because of their low solu-
bility, compounds 8F,a–f were simply washed with copious
amounts of ethyl alcohol and dried under vacuum. Analytical and
spectral data for these compounds are given below. As the great
O
O
O+
O
R
R
N+
N
O
O
O2N
O
O2N
N
N
N
N
(9)
O
O
N+
N+
-
-
majority of s-adducts isolated so far, 8a–f decomposed prior to
O
O
O
melting.1–3,15–21
12Fa-f
4.3.1. Compounds 7Z,a–f. See Eq. 2 in the text for the numbering
of the various atoms.
Based on the above conclusion, it is of interest to return to pre-
viously reported dipolar spiro adducts such as 20, 21 and 22.65–67 In
all of these species, the negative charge is delocalized through
a 4,6-dinitrobenzofuroxan moiety, which is known to be as electron
withdrawing as a 4,6-dinitrobenzofurazan analogue.14,68 A most
important feature is therefore that the positive charge of the three
types of adducts is subject to strong dispersion through either a tro-
pone ring, a benzimidazole ring or an isoquinoline ring. Obviously, it
is the same potentiality of delocalization of both their positive and
negative charges, which governs the stabilityofdipolar spiro adducts.
4.3.1.1. 2-Methyl-3-(400,600-dinitro-200,100,300-benzoxadiazol-700-yl)-
indolizine 7Za. Dark-blue solid; yield 78%; mp 212–213 ꢂC. Anal.
calcd for C15H9N5O5: C, 53.10; H, 2.67; N, 20.64. Found: C, 53.28; H,
2.67; N, 20.59%. 1H NMR (250 MHz, DMSO-d6):
d 2.25 (s, 3H, 2-CH3),
6.74 (s, 1H, H-1), 6.85 (dd, J¼7.0, 6.8 Hz, 1H, H-6), 7.22 (dd, J¼8.6,
6.8 Hz, 1H, H-7), 7.65 (d, J¼8.6 Hz, 1H, H-8), 8.08 (d, J¼7.0 Hz, 1H, H-
5), 9.21 (s, 1H, H-500); 13C NMR (62.9 MHz, DMSO-d6):
d 13.27 (2-
CH3), 107.32 (C-1), 113.11 (C-6), 116.24 (C-700), 118.75 (C-8), 122.97
(C-400), 124.91 (C-7), 126.76 (C-5), 129.74 (C-500), 131.65 (C-2), 133.01
(C-600), 138.85 (C-9), 140.68 (C-900), 143.55 (C-3), 151.74 (C-800).
R
Me
4.3.1.2. 2-Phenyl-3-(400,600-dinitro-200,100,300-benzoxadiazol-700-yl)-
indolizine 7Zb. Dark-blue solid; yield 81%; mp 189–190 ꢂC. Anal.
calcd for C20H11N5O5: C, 59.86; H, 2.76; N, 17.45. Found: C, 60.06; H,
Me
+
Ph
SO2
H
N
R
R
Ph
O
N+
N+
O
2.77; N, 17.41%. 1H NMR (250 MHz, DMSO-d6):
d
6.85 (dd, J¼6.7,
O
O
O
O
N
O
N
O
N+
O
O2N
+
N
+
N
O2N
O2N
6.6 Hz, 1H, H-6), 6.97 (s, 1H, H-1), 7.24 (dd, J¼8.8, 6.7 Hz, 1H, H-7),
7.24–7.28 (m, 5H, H-20, H-30, H-40), 7.73 (d, J¼8.8 Hz, 1H, H-8), 8.12
(d, J¼6.6 Hz, 1H, H-5), 9.12 (s, 1H, H-500); 13C NMR (62.9 MHz,
O
O
O
N
N
N
N+
20
N+
N+
d
104.77 (C-1), 112.71 (C-700), 113.07 (C-6), 119.16 (C-8),
-
DMSO-d6):
-
-
O
O
123.07 (C-400), 123.62 (C-7), 126.14 (C-5), 127.07 (C-40), 128.49 (C-20),
128.54 (C-30), 128.94 (C-500), 132.71 (C-2), 133.92 (C-600), 135.65 (C-
10), 137.93 (C-9), 142.87 (C-900), 143.07 (C-3), 151.28 (C-800).
21
22
4. Experimental
4.1. General
4.3.1.3. 2-(40-Methylphenyl)-3-(400,600-dinitro-200,100,300-benzox-
adiazol-700-yl)-indolizine 7Zc. Dark-blue solid; yield 73%; mp
233–234 ꢂC. Anal. calcd for C21H13N5O5: C, 60.73; H, 3.15; N,
16.86. Found: C, 60.82; H, 3.15; N, 16.80%. 1H NMR (250 MHz,
Melting points were determined on a Reichert-type microscope
and are uncorrected. 1H and 13C NMR spectra were recorded on
either a Bruker DPX-250 MHz spectrometer or a Varian Unity-
300 MHz spectrometer. The peaks are characterized by s (singlet),
br s (broad singlet), d (doublet), dd (doublet of doublet) and t
(triplet). Mass spectra were obtained using a LCQ DecaXPMAX (ESI,
1.8 kV, 180 ꢂC) instrument. Elemental analyses were determined by
the Institute of Physical and Organic Chemistry of the Southern
Federal University in Rostov on Don.
DMSO-d6):
d
2.29 (s, 3H, 40-CH3), 6.81 (dd, J¼7.0, 6.7 Hz, 1H, H-6),
6.88 (s, 1H, H-1), 7.01 (d, J¼8.0 Hz, 2H, H-30), 7.13 (d, J¼8.0 Hz, 2H,
H-20), 7.18 (dd, J¼8.8, 6.7 Hz, 1H, H-7), 7.67 (d, J¼8.8 Hz, 1H, H-8),
8.07 (d, J¼7.0 Hz, 1H, H-5), 9.11 (s, 1H, H-500); 13C NMR (62.9 MHz,
DMSO-d6): d
20.66 (40-CH3), 104.64 (C-1), 112.77 (C-6), 112.88 (C-700),
118.93 (C-8), 123.16 (C-400), 123.40 (C-7), 126.07 (C-5), 128.36 (C-20),
128.72 (C-500),129.02 (C-30),131.06 (C-10),132.46 (C-2),135.94 (C-600),
136.20 (C-40), 137.97 (C-9), 142.47 (C-900), 142.87 (C-3), 151.19 (C-800).
4.3.1.4. 2-(40-Methoxyphenyl)-3-(400,600-dinitro-200,100,300-benzox-
adiazol-700-yl)-indolizine 7Zd. Dark-blue solid; yield 73%; mp
217–218 ꢂC. Anal. calcd for C21H13N5O6: C, 58.47; H, 3.04; N, 16.24.
Found: C, 58.64; H, 3.05; N, 16.18%. 1H NMR (250 MHz, DMSO-d6):
4.2. Materials
7-Chloro-4,6-dinitrobenzofurazan (DNBZ-Cl) and 7-chloro-4,6-
dinitrobenzofuroxan (DNBF-Cl) were prepared according to the pro-
cedures described by Sharnin et al.69 and Norris et al.70 Indolizines
5a–f were long known compounds, which were synthesized fol-
lowing reported protocols.71–78 Adding to the structural data so far
available, a detailed 1H and 13C NMR characterizationof5a–f has been
made. The results are provided in pages-in the Supplementary data.
d
3.73 (s, 3H, 40-OCH3), 6.74 (d, J¼8.8 Hz, 2H, H-30), 6.81 (dd, J¼7.0,
6.7 Hz, 1H, H-6), 6.87 (s, 1H, H-1), 7.17 (d, J¼8.8 Hz, 2H, H-20), 7.18
(dd, J¼8.8, 6.7 Hz, 1H, H-7), 7.67 (d, J¼8.8 Hz, 1H, H-8), 8.07 (d,
J¼7.0 Hz, 1H, H-5), 9.10 (s, 1H, H-500); 13C NMR (62.9 MHz, DMSO-
d6):
d
54.71 (40-OCH3), 104.54 (C-1), 112.78 (C-6), 112.86 (C-700),
113.95 (C-30), 118.92 (C-8), 123.12 (C-400), 123.63 (C-7), 126.15 (C-5,
C-10), 128.93 (C-500), 129.70 (C-20), 132.43 (C-2), 135.67 (C-600), 138.10
(C-9), 142.52 (C-900), 143.04 (C-3), 151.24 (C-800), 158.47 (C-40).
4.3. Couplings of DNBZ-Cl and DNBF-Cl with indolizines 5a–f.
General procedure
4.3.1.5. 2-(40-Bromophenyl)-3-(400,600-dinitro-200,100,300-benzox-
adiazol-700-yl)-indolizine 7Ze. Dark-blue solid; yield 87%; mp
244–245 ꢂC. Anal. calcd for C20H10BrN5O5: C, 50.02; H, 2.10; N,14.58.
To a solution of the indolizine reagent (1 mmol) in ethyl alcohol
or chloroform (10–15 ml) at room temperature was added 1 equiv

1004
A. Tatarov et al. / Tetrahedron 66 (2010) 995–1006
Found: C, 49.83; H, 2.09; N, 14.63%. 1H NMR (300 MHz, DMSO-d6):
yield 80%; mp 178–179 ꢂC (dec). Anal. calcd for C21H13N5O6: C,
58.47; H, 3.04; N, 16.24. Found: C, 58.57; H, 3.05; N, 16.18%. 1H NMR
d
6.91 (dd, J¼7.0, 6.8 Hz, 1H, H-6), 7.06 (s, 1H, H-1), 7.24 (dd, J¼8.8,
6.8 Hz, 1H, H-7), 7.28 (d, J¼7.8 Hz, 2H, H-20), 7.38 (d, J¼7.8 Hz, 2H, H-
30), 7.79 (d, J¼8.8 Hz, 1H, H-8), 8.14 (d, J¼7.0 Hz, 1H, H-5), 9.25 (s, 1H,
(250 MHz, DMSO-d6):
d
2.37 (s, 3H, 40-CH3), 7.35 (d, J¼7.7 Hz, 2H, H-
30), 7.61 (d, J¼7.7 Hz, 2H, H-20), 8.00 (dd, J¼7.0, 6.7 Hz, 1H, H-7), 8.51
(d, J¼7.7 Hz, 1H, H-9), 8.62 (s, 1H, H-1), 8.74 (dd, J¼7.7, 7.0 Hz,1H, H-
8), 9.13 (s,1H, H-500), 9.15 (d, J¼6.7 Hz,1H, H-6); 13C NMR (62.9 MHz,
H-500); 13C NMR (75.43 MHz, DMSO-d6): 104.66 (C-1),112.22 (C-700),
d
113.44 (C-6), 119.36 (C-8), 120.83 (C-40), 122.76 (C-400), 123.89 (C-7),
126.23 (C-5), 129.08 (C-500), 130.64 (C-20), 131.69 (C-30), 133.21 (C-10),
133.30 (C-2), 133.95 (C-600), 137.80 (C-9), 143.44 (C-3), 143.65 (C-).
DMSO-d6):
d
21.02 (40-CH3), 71.78 (C-700), 111.72 (C-400), 121.87 (C-
600), 128.24 (C-2), 128.77 (C-7), 128.92 (C-20), 129.48 (C-30), 130.63
(C-9), 133.19 (C-1), 135.52 (C-500), 137.34 (C-40), 141.10 (C-10), 143.08
(C-10), 143.83 (C-900), 145.75 (C-6), 148.16 (C-8), 149.62 (C-800),
185.65 (C-3).
4.3.1.6. 2-(40-Nitrophenyl)-3-(400,600-dinitro-200,100,300-benzox-
adiazol-700-yl)-indolizine 7Zf. Dark-blue solid; yield 80%; mp
238–239 ꢂC. Anal. calcd for C20H10N6O7: C, 53.82; H, 2.26; N, 18.83.
Found: C, 54.00; H, 2.26; N, 18.76%. 1H NMR (250 MHz, DMSO-d6):
4.3.2.4. 2-(40-Methoxyphenyl)-400,600-dinitro-3-oxo-3H-spi-
ro(200,100,300-benzoxadiazole-700,4-quinolizine) 8Fd. Dark-brown solid;
yield 83%; mp 230–231 ꢂC (dec). Anal. calcd for C21H13N5O7: C,
56.38; H, 2.93; N, 15.65. Found: C, 56.45; H, 2.94; N, 15.59%. 1H NMR
d
6.87 (dd, J¼7.0, 6.8 Hz, 1H, H-6), 7.11 (s, 1H, H-1), 7.21 (dd, J¼8.8,
6.8 Hz, 1H, H-7), 7.57 (d, J¼8.8 Hz, 2H, H-20), 7.75 (d, J¼8.8 Hz, 1H,
H-8), 8.04 (d, J¼8.8 Hz, 2H, H-30), 8.11 (d, J¼7.0 Hz, 1H, H-5), 9.15 (s,
1H, H-500); 13C NMR (62.9 MHz, DMSO-d6):
d
104.77 (C-1),112.32 (C-
(250 MHz, DMSO-d6):
d
3.83 (s, 3H, 40-OCH3), 7.10 (d, J¼8.4 Hz, 2H,
700),113.50 (C-6), 119.43 (C-8),122.50 (C-400), 123.42 (C-7), 123.53 (C-
30), 126.02 (C-5), 128.71 (C-500), 129.48 (C-20), 132.49 (C-2), 133.51
(C-600), 137.51 (C-9), 140.95 (C-10), 143.10 (C-3), 143.83 (C-900), 146.04
(C-40), 151.34 (C-800).
H-30), 7.72 (d, J¼8.4 Hz, 2H, H-20), 7.97 (dd, J¼7.0, 6.3 Hz, 1H, H-7),
8.49 (d, J¼7.7 Hz, 1H, H-9), 8.58 (s, 1H, H-1), 8.72 (dd, J¼7.7, 7.0 Hz,
1H, H-8), 9.12 (d, J¼6.3 Hz, 1H, H-6), 9.13 (s, 1H, H-500); 13C NMR
(62.9 MHz, DMSO-d6): d
55.52 (40-OCH3), 71.72 (C-700),111.70 (C-400),
114.47 (C-30), 121.93 (C-600), 123.19 (C-2), 128.41 (C-7), 130.41 (C-9),
130.78 (C-20), 131.87 (C-1), 135.53 (C-500), 136.84 (C-10), 143.38 (C-
10), 143.83 (C-900), 145.48 (C-6), 148.01 (C-8), 149.64 (C-800), 161.59
(C-40), 185.85 (C-3).
4.3.1.7. 2-(40-Methylphenyl)-3-(400,600-dinitro-300-oxido-200,100,300-
benzoxadiazol-700-yl)-indolizine 7Fc (transient species). 1H NMR
(250 MHz, chloroform-d1):
d
2.32 (s, 3H, 40-CH3), 6.82 (s, 1H, H-1),
6.89 (dd, J¼7.0, 6.7 Hz, 1H, H-6), 7.05 (d, J¼8.8 Hz, 2H, H-30), 7.09 (d,
J¼8.8 Hz, 2H, H-20), 7.24 (dd, J¼8.8, 6.7 Hz, 1H, H-7), 7.43 (d,
J¼7.0 Hz, 1H, H-5), 7.62 (d, J¼8.8 Hz, 1H, H-8), 9.01 (s, 1H, H-500).
4.3.2.5. 2-(40-Bromophenyl)-400,600-dinitro-3-oxo-3H-spi-
ro(200,100,300-benzoxadiazole-700,4-quinolizine) 8Fe. Dark-purple solid;
yield 78%; mp 204–205 ꢂC (dec). Anal. calcd for C20H10BrN5O6: C,
48.41; H, 2.03; N, 14.11. Found: C, 48.27; H, 2.03; N, 14.13%. 1H NMR
4.3.1.8. 2-(40-Bromophenyl)-3-(400,600-dinitro-300-oxido-200,100,300-
benzoxadiazol-700-yl)-indolizine 7Fe (transient species). 1H NMR
(250 MHz, DMSO-d6):
d
7.64 (d, J¼7.8 Hz, 2H, H-30), 7.74 (d,
(250 MHz, chloroform-d1):
d
6.84 (s, 1H, H-1), 6.92 (dd, J¼6.8,
J¼7.8 Hz, 2H, H-20), 8.03 (dd, J¼6.8, 6.6 Hz, 1H, H-7), 8.53 (d,
J¼8.8 Hz,1H, H-9), 8.69 (s,1H, H-1), 8.76 (dd, J¼8.8, 6.8 Hz,1H, H-8),
9.13 (s, 1H, H-500), 9.17 (d, J¼6.6 Hz, 1H, H-6); 13C NMR (62.9 MHz,
DMSO-d6): 71.86 (C-700), 111.80 (C-400), 121.71 (C-600), 124.66 (C-40),
129.18 (C-7), 130.24 (C-2), 130.98 (C-9, C-20), 131.92 (C-30), 134.56
(C-1), 135.53 (C-500), 136.17 (C-10), 142.63 (C-10), 143.82 (C-900),
146.07 (C-6), 148.30 (C-8), 149.52 (C-800), 185.31 (C-3).
6.5 Hz, 1H, H-6), 7.06 (d, J¼7.7 Hz, 2H, H-20), 7.25 (dd, J¼8.6, 6.5 Hz,
1H, H-7), 7.42 (d, J¼7.7 Hz, 2H, H-30), 7.43 (d, J¼6.8 Hz,1H, H-5), 7.65
(d, J¼8.6 Hz, 1H, H-8), 9.02 (s, 1H, H-500).
4.3.2. Compounds 8F,a–f. See Eq. 3 in the text for the numbering of
the various atoms.
4.3.2.1. 2-Methyl-400,600-dinitro-3-oxo-3H-spiro(200,100,300-benzox-
adiazole-700,4-quinolizine) 8Fa. Brown solid; yield 85%; mp
234–235 ꢂC (dec). Anal. calcd for C15H9N5O6: C, 50.71; H, 2.55; N,
19.71. Found: C, 50.80; H, 2.55; N, 19.65%. 1H NMR (250 MHz,
4.3.2.6. 2-(40-Nitrophenyl)-400,600-dinitro-3-oxo-3H-spiro(200,100,300-
benzoxadiazole-700,4-quinolizine) 8Ff. Brown solid; yield 75%; mp
186–187 ꢂC (dec). Anal. calcd for C20H10N6O8: C, 51.96; H, 2.18; N,
18.18. Found: C, 52.11; H, 2.18; N, 18.11%. 1H NMR (250 MHz, DMSO-
DMSO-d6):
d
2.18 (s, 3H, 2-CH3), 7.97 (dd, J¼7.4, 6.7 Hz, 1H, H-7),
d6):
d
7.96 (d, J¼8.9 Hz, 2H, H-20), 8.08 (dd, J¼7.0, 6.7 Hz, 1H, H-7),
8.28 (s, 1H, H-1), 8.39 (d, J¼7.7 Hz, 1H, H-9), 8.71 (dd, J¼7.7, 7.4 Hz,
8.37 (d, J¼8.9 Hz, 2H, H-30), 8.58 (d, J¼7.7 Hz, 1H, H-9), 8.80 (dd,
1H, H-8), 9.09 (s, 1H, H-500), 9.10 (d, J¼6.7 Hz, 1H, H-6); 13C NMR
J¼7.7, 7.0 Hz, 1H, H-8), 8.84 (s, 1H, H-1), 9.13 (s, 1H, H-500), 9.22 (d,
(62.9 MHz, DMSO-d6):
d
15.11 (2-CH3), 71.05 (C-700), 111.69 (C-400),
J¼6.7 Hz, 1H, H-6); 13C NMR (62.9 MHz, DMSO-d6):
d
72.00 (C-700),
122.11 (C-600), 128.68 (C-7), 129.61 (C-9), 134.32 (C-1), 135.43 (C-500),
138.05 (C-2),142.69 (C-10),143.79 (C-900),145.89 (C-6),148.43 (C-8),
149.86 (C-800), 187.09 (C-3).
111.90 (C-400), 121.57 (C-600), 123.90 (C-30), 129.76 (C-7), 130.48 (C-
20), 131.49 (C-9), 135.26 (C-1), 135.56 (C-500), 136.63 (C-10), 137.30 (C-
2), 142.09 (C-10), 143.84 (C-900), 146.48 (C-6), 148.48 (C-8, C-40),
149.47 (C-800), 185.07 (C-3).
4.3.2.2. 2-Phenyl-400,600-dinitro-3-oxo-3H-spiro(200,100,300-benzox-
adiazole-700,4-quinolizine) 8Fb. Brown solid; yield 88%; mp
176–177 ꢂC (dec). Anal. calcd for C20H11N5O6: C, 57.56; H, 2.66; N,
16.78. Found: C, 57.75; H, 2.66; N, 16.72%. 1H NMR (250 MHz,
4.3.3. 2-Substituted 5,6-dihydropyrrolo[2,1-a]isoquinolines 11a–f.
Numbering of the various atoms is shown in the structures drawn
in the main text.
DMSO-d6):
d
7.53 (t, J¼4.2 Hz, 1H, H-40), 7.54 (d, J¼4.2 Hz, 2H, H-20),
The dihydropyrroloisoquinolines 11a–f were obtained following
the Tchichibabin procedure modified by Casagrande42 and other au-
thors.43,44 Equimolar amounts of 6,7-dimethoxy-1-methyl-3,4-
dihydroisoquinoline (10)44 and of the appropriate bromide (9a–f)
were mixed in the presence of 3 equiv NaHCO3. After addition of
a minimal amount of n-butanoldCasagrande et al. used ethanol–to
achieve a complete dissolution of the reagents42dthe resulting
mixture was refluxed for about 30 min. All cyclizations were thus
carried out in one stage without isolating the quaternary in-
termediates. A TLC control showed that the reactions proceeded
satisfactorily, affording the requested pyrroloisoquinolines 11a–f in
7.68 (t, J¼4.2 Hz, 2H, H-30), 8.03 (dd, J¼7.4, 6.3 Hz, 1H, H-7), 8.54 (d,
J¼7.7 Hz, 1H, H-9), 8.66 (s, 1H, H-1), 8.76 (dd, J¼7.7, 7.4 Hz, 1H, H-8),
9.14 (s, 1H, H-500), 9.17 (d, J¼6.3 Hz, 1H, H-6); 13C NMR (62.9 MHz,
DMSO-d6): d
71.84 (C-700), 111.76 (C-400), 121.83 (C-600), 128.89 (C-20),
129.00 (C-30, C-7), 130.82 (C-9), 130.90 (C-2), 131.12 (C-40), 134.20
(C-1), 135.54 (C-500), 137.43 (C-10), 142.86 (C-10), 143.83 (C-900),
145.94 (C-6), 148.26 (C-8), 149.61 (C-800), 185.55 (C-3).
4.3.2.3. 2-(40-Methylphenyl)-400,600-dinitro-3-oxo-3H-spi-
ro(200,100,300-benzoxadiazole-700,4-quinolizine) 8Fc. Dark-brown solid;

A. Tatarov et al. / Tetrahedron 66 (2010) 995–1006
1005
good yields after cooling of the reaction mixture at 0 ꢂC. Compounds
11b–e were recrystalized in butanol while 11a and 11f were purified
by column chromatography (silica, CHCl3). Analytical and spectral
data for the six compounds are given in pages S8–S9 in Supplemen-
tary data. To be noted is that only 11a and 11e were previously
reported.44
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The synthesis of the coupling products 12Z,a–f and 13F,a–f has
been completed, including the purification, under the same ex-
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1H and 13C NMR data pertaining to compounds 8F,a–f, 11a–f,
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