A new method of bromination of aromatic rings by an iso-amyl nitrite/HBr system

Article abstract of DOI:10.1016/j.tet.2008.03.085

A mixture of iso-amyl nitrite/HBr is shown to be a mild and efficient reagent for electrophilic aromatic bromination. The reaction succeeds with slightly activated arenes and heterocyclic compounds. By using HCl instead of HBr, chlorination can also be performed in few cases. The i-amONO₂/HBr mixture can also be utilized for bromination in the α-position of electron withdrawing groups. A possible mechanism is briefly discussed.

Full text of DOI:10.1016/j.tet.2008.03.085

Tetrahedron 64 (2008) 4999–5004
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Tetrahedron
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A new method of bromination of aromatic rings by an iso-amyl
nitrite/HBr system
a
a
a,
b,
*
*
ˆ
´
Laurent Gavara , Thomas Boisse , Benoıt Rigo , Jean-Pierre Henichart
a Ecole des Hautes Etudes d’Inge´nieur, EA 2692, 13 rue de Toul, 59046 Lille, France
b Institut de Chimie Pharmaceutique Albert Lespagnol, EA 2692, Universite´ de Lille 2, rue du Professeur Laguesse, 59006 Lille, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A mixture of iso-amyl nitrite/HBr is shown to be a mild and efficient reagent for electrophilic aromatic
bromination. The reaction succeeds with slightly activated arenes and heterocyclic compounds. By using
HCl instead of HBr, chlorination can also be performed in few cases. The i-amONO2/HBr mixture can also
be utilized for bromination in the a-position of electron withdrawing groups. A possible mechanism is
briefly discussed.
Received 15 February 2008
Received in revised form 18 March 2008
Accepted 26 March 2008
Available online 29 March 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Oxybromination
iso-Amyl nitrite
Atom economy
Bromo indolizinones
1. Introduction
To the best of our knowledge, no aromatic halogenation method
using a hydrohalide acid as a reagent and an organic nitrite as a co-
Recently, a mishmash between some experimental results from
our students led us to describe that a mixture of indolizine 1, 37%
HCl and iso-amyl nitrite yielded nitroso product 2.1 Actually, when
we tried to repeat this reaction, we observed that the isolated solid
was not the nitroso pyridone 2, but chlorinated triester 3, and that
the compound subjected to elemental analysis was the impure
reagent had been depicted: only a ‘bromination impurity at the 5-
position of the thiophene ring’ was reported during the oxidation of
2-thiophene carbinol into its corresponding ketone by a mixture
of tert-butyl nitrite, HBr, oxygen and TEMPO2 (oxidation of a variety
of alcohols to ketones is possible with these reagents;2 in addition,
iso-amyl nitrite has already been reported to give nitroso aromatic
products3).
Halogenated compounds can be found in many pharmaceutical
products4 or are used as key intermediates for organic reactions
such as metal-catalyzed carbon–carbon bond formations5 and
nucleophilic substitution reactions.6 Aryl bromides are usually
synthesized by electrophilic substitution of arenes with molecular
bromine,7 sometimes with transition metal catalysts. These re-
actions involve several environmental drawbacks because of the
toxic nature of the reagents and the formation of HBr as a by-
product.7–9 Moreover, when using bromine, only half of the Br
atoms are utilized and the others turn into hydrohalic acid,
reducing the atom efficiency by 50%. Brominating agents such as
quaternary ammonium salts of trihalides10 or NBS11 in the presence
of Bro¨nsted12 or Lewis acid13 have been developed to facilitate
handling, but their synthesis still requires bromine.
nitro analogs
4 (a product synthesized by another reaction
sequence1). By a similar procedure using 48% HBr instead of 37%
HCl, bromopyridone 5 was obtained in a very good yield of 98%
(Scheme 1).
3, 74%
(i) or (ii)
MeO2C
MeO2C
MeO2C
MeO2C
CO2Me
CO2Me
or
N
N
5, 98%
O
O
X
2 X = NO
3 X = Cl
4 X = NO2
5 X = Br
1
Scheme 1. Reaction conditions: (i) iso-amyl nitrite (3.4 equiv), 37% HCl (1.2 equiv),
THF, 20 ꢀC, 15 h; (ii) iso-amyl nitrite (2 equiv), 48% HBr (1.5 equiv), CH2Cl2, 20 ꢀC, 3 h.
New methods of bromination have been developed to overcome
these problems, involving in situ preparation of Brþ by oxidation of
the halogen anion. These approaches are bromine atom economic,
and can be realized by using non-pollutant oxidizing agents. The
bromine sources are generally an inorganic bromide,14–18
* Corresponding authors. Tel.: þ33 3 28 38 48 58; fax: þ33 3 28 38 48 04.
E-mail address: rigo@hei.fr (B. Rigo).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.03.085

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L. Gavara et al. / Tetrahedron 64 (2008) 4999–5004
R4NþBrꢁ16,19,20 or HBr,16,21–25 and the oxidant can be H2O2,19,21–25
Table 2
TBHP,22 NaNO2/O2,26 Oxone,27 NaBO3,14 Fe(NO3)3$1.5N2O4/C,15
Oxybromination of selected substrates
CAN,28 (R4Nþ)2$S2O82ꢁ 18 PhI(OAc)2,17 IBX amide resin,20 methyl-
,
Entry
Substrates
Yielda (%) Time (h)
Products
trioxorhenium,29 or HNO3,16 sometimes in the presence of catalyst
such as V2O5,19 R4NþBrꢁ,20,21 or ammonium molybdate.14 The use
of t-BuOCl or t-BuOBr in the presence of zeolites has also been
described.30–32
Br
O
O
O
1
100
84
4
O
Br
Since iso-amyl nitrite is a readily accessible, stable and non-
polluting agent, and because of the novelty of its use in conjunction
with a hydrohalic acid to achieve halogenation, we decided to in-
vestigate the potential of this reagent as an oxidant in oxy-
halogenation reactions.
2
48
Br
80/20
Br
3
4
85
8
2. Results and discussion
HO
2.1. Influence of the solvent
Mixture of many
unidentified products
100
16
Investigation on the influence of the solvent was realized by
reacting 1,3-benzodioxole 6 with 2 equiv of iso-amyl nitrite and
1.5 equiv of 48% HBr, at room temperature for 3 h (Table 1). All the
solvents lead to pure 4-bromobenzodioxole 7 without detectable
impurities; as shown in Table 1, dichloromethane leading to 90% of
7 proves to be the best solvent and was thus selected to perform
oxybrominations described in the next part of this paper.33
OH
Br
N
OH
N
5
100
16
72
Br
70% b
N
6
7
NR
Mixture of many
unidentified products
2.2. Oxybromination of various substrates
100
Me2N
The arenes that we have chosen for the oxybrominations was
listed in Table 2. They are representative of activated and inacti-
vated aromatics, as well as compounds of moderate activity or
taken from our laboratory library. All reactions were realized at
room temperature, by using 2 equiv of iso-amyl nitrite and
1.5 equiv of 48% HBr. In these conditions, no regioselectivity was
observed for electron rich N,N-dimethylaniline or phenols, which
led to mixture of mono and poly-brominated products (entries 4, 5
and 7). 1,2-Methylenedioxybenzene gave a quantitative amount of
4-bromobenzodioxole 7 (entry 1) (71% from LiBr/PhI(OAc)2/THF17),
and reaction of less activated naphthalene yielded 85% of 1-bro-
monaphthalene in 8 h (entry 3). This needs to be compared with
the result of other literature reactions: no reaction from Et4NþBrꢁ/
IBX amide resin/CH2Cl2,20 60% yield from the mixture HBr/H2O2/
CH2Cl2/H2O23 or 52% from HBr/HNO3/TBAC/dichloroethane,16 while
with NaBr/Fe(NO3)3$1.5N2O4/C/CH2Cl2 20% of 1-nitronaphthalene
goes with 70% of the bromo product.15 The reaction concerning
toluene is very instructive; indeed it led to 84% of an 80/20 mixture
of para/ortho bromotoluene. These yields and selectivity are supe-
rior to those described in literature for rather similar reactions: no
bromination occurred with LiBr or Et4NþBrꢁ and hypervalent
8
9
NR
NR
72
48
Cl
O
N
H
O
O
10
11
100
98
16
5
Decomposition
MeO2C
CO2Me
MeO2C
MeO2C
CO2Me
N
N
O
O
O
O
MeO2C
Br
8
9
MeO2C
MeO2C
CO2Me
CO2Me
MeO2C
MeO2C
CO2Me
CO2Me
N
N
N
12
98
84
3
5
Br
1
5
iodine compounds17,20 or (R4Nþ)2$S2O28ꢁ 18
while yields were only
,
40% (para/ortho: 66/34) with HBr/HNO3/TBAC/dichloroethane,16
Br
N
13
O
O
Table 1
MeO2C
Br
MeO2C
Oxybromination of benzodioxole in different solvents
Br
10
O
O
O
O
11
1H NMR yields.
a
b
Accompanied by 15% of ortho and 15% of para monobromo compounds.
6
7
and selectivity was only 60/40 with PyHþBrCl2ꢁ/MeOH10b or
NaBr/Fe(NO3)3$1.5N2O4/C/CH2Cl2.15
Entry
Solventsa
Conversionb (%)
1
2
3
4
CH2Cl2
MeCN
EtOH
THF
90
77
69
62
On the other hand, less reactive arenes such as chlorobenzene or
4-methoxyacetanilide did not react in these conditions (entries 8
and 9). As for the lack of reactivity of quinoline (entry 6), it probably
indicates the formation of inert hydrobromide ammonium salt.
Acid sensitive 2-methylfuran was entirely decomposed, leading to
a mixture of unidentified products (entry 10).
a
Reaction conditions: iso-amyl nitrite (2 equiv), HBr (1.5 equiv), 1 mmol/mL of
solvent, 3 h, rt.
b
1H NMR yields.

L. Gavara et al. / Tetrahedron 64 (2008) 4999–5004
5001
Perhaps the more interesting result was the easiness of forma-
NO
NO2
O
O
O
O
O
O
[O]
(i)
tion and very good yields obtained starting from the functionalized
indolizinones described in entries 11–13. Indeed, bromopyridone 5
was obtained in the same 96% yield as from Br2/KHCO3/CH2Cl2/H2O
method (Scheme 1),1a and its ethyl analogue 81a led only to 80% of
less pure product 9 when subjected directly to Br2 versus 98% by
using our HBr/iso-amyl nitrite system (Scheme 2) (see Section 4).
Moreover, the bromination of indolizinone 10 led to 84% yield of
dibromo compound 11 with 2 equiv of HBr. Using 1 equiv of HBr,
the same reaction leads to 78% of para bromo compound 12 ac-
companied with 13% of an unidentified unbrominated product
(Scheme 2).
6
14 80%
15
Scheme 3. Reaction conditions: (i) iso-amyl nitrite (2 equiv), 40% HF (3 equiv), CH2Cl2,
20 ꢀC, 3 days.
Indeed, no bromination occurred when HBr was changed for
KBr. Thus, an initial oxidation of Brꢁ by iso-amyl nitrite to give Brþ
then Br2 can be excluded. Another possibility is formation of nitrous
acid and iso-amyl bromide. This can then react either as a bromo-
nium ion source or give the radical Brꢂ. Moreover, by using a Dra¨ger
tube, it was observed that the brown vapours formed in the be-
ginning of the reaction are not bromine or chlorine. In the same
way as for analogue reactions,22 the absence of halogenation of the
methyl group of toluene (Table 2, entry 2) is indicative for an
electrophilic mechanism of the reaction more than a radical path-
way. However, this needs to be nuanced because when heterocycle
1634 was subjected to the reaction, a mixture of mono and dibro-
minated products 17 and 18 was obtained in 70% yield (Scheme 4).
O
O
MeO2C
MeO2C
X
N
N
CO2Me
CO2Me
Me2OC
Me2OC
8
(i) 9 X = Br 98%
(ii) 13 X = Cl 60%
(iii)
O
O
O
O
MeO2C
MeO2C
MeO2C
MeO2C
X2
(i)
N
N
N
N
CO2Me
CO2Me
N
N
Br
X
X1
17 X = H 32%
18 X = Br 38%
16
10 94%
(iv) 11 X1= Br, X2 = Br 84%
(v) 12 X1= Br, X2= H 78%
Scheme 4. Reaction conditions: (i) iso-amyl nitrite (3 equiv), 48% HBr (0.9 equiv),
CH2Cl2, 20 ꢀC, 12 h.
Scheme 2. Reaction conditions: (i) iso-amyl nitrite (2 equiv), 48% HBr (1.5 equiv),
CH2Cl2, 20 ꢀC, 5 h; (ii) iso-amyl nitrite (3 equiv), 37% HCl (1.5 equiv), THF, 20 ꢀC, 7 days;
(iii) (a) 48% HBr, reflux, 5 h; (b) MeOH, MeSO3H, CHCl3, molecular sieves 3 Å, reflux,
48 h; (iv) iso-amyl nitrite (2 equiv), 48% HBr (2 equiv), CH2Cl2, 20 ꢀC, 5 h; (v) iso-amyl
nitrite (2 equiv), 48% HBr (1 equiv), CH2Cl2, 20 ꢀC, 4 h.
There are many differences in the kinetics and regioselectivity
between this bromination of arenes and the one realized with free
bromine. Thus, it is likely that the postulated iso-amyl bromide
reacted as a Brþ cation equivalent. The following reactions go in the
same direction: a-bromination of acetophenones in dioxane, with
HBr and TBHP22 at 60 ꢀC, or with H2O2 at reflux35 has been de-
scribed in literature; in the latter, a mixture containing mainly the
dibromoketone was formed, and the reaction was thought to pro-
cess from the enol form of the ketone.35 The new HBr/iso-amyl
nitrite system led to 61% of a-bromoacetophenone 19 in 48 h at
room temperature (Scheme 5). In the same way, methyl cyano-
malonate yielded quantitatively to dibromo product 20. A possible
2.3. Other attempted halogenation of arenes with the
iso-amyl nitrite/HX system
Direct and regioselective halogenation of arenes has recently
been described by using the NaI/Fe(NO3)3$1.5 N2O4/C/CH2Cl2 sys-
tem.15 This led us to try iodination of the majority of compounds of
Table 2 by the method of HI/iso-amyl nitrite/CH2Cl2. However, no
reaction was observed even with 3 equiv of reagent. In the same
way, oxidation of HCl with H2O2 has been reported for oxy-
chlorination of activated aromatics22,23 but 3 equiv of HCl/iso-amyl
nitrite in CH2Cl2 at room temperature did not allow halogenation
of compounds of Table 2. Even the very reactive 1,2-dimethoxy-
benzene did not react; only chlorination of indolizines 1 and 8 was
successful, but 1 week was necessary to obtain 60% of chloropyr-
idone 13 when 1.5 equiv of reagent was utilized (Scheme 2). Under
the same conditions, chloropyridone 3 was obtained with 74% yield
after only one night (Scheme 1).
mechanism is the formation of
a
cyclic bromonium ion
O
O
Br
(i)
19 61%
(ii)
MeO2C
CN
MeO2C
CN
It was evidently not expected that fluorination could be realized
by using these methods. Nevertheless, when benzodioxole 6 was
subjected to 40% HF/iso-amyl nitrite/CH2Cl2 for 3 days, 4-nitro-
benzodioxole 14 was formed in 80% NMR yield (Scheme 3). Even by
using only a few amount of iso-amyl nitrite, we were not able to
observe the possible nitroso intermediate 15 that was oxidized in
situ to give 14.
Br Br
20 98%
Br
Br
Br
O
(ii)
(ii)
(iii)
O
21
O
O
O
O
O
23 92%
O
O
Br
Br
(iii)
Br
2.4. Other reactions of the HBr/iso-amyl nitrite system and
possible mechanisms
O
O
O
O
O
O
25
22
24 80%
Some other bromination reactions were performed with this
system, which allowed suggesting
mechanism.
a part of the reaction
Scheme 5. Reaction conditions: (i) iso-amyl nitrite (2 equiv), HBr (1.5 equiv), 48 h, rt;
(ii) iso-amyl nitrite (3 equiv), HBr (2 equiv), 48 h, rt; (iii) DBU (1.5 equiv), CH2Cl2, 1 h, rt.

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L. Gavara et al. / Tetrahedron 64 (2008) 4999–5004
intermediate on the double bond of enolized carbonyl compounds,
followed by attack of unoxidized bromide ion and then elimination
of HBr. That is comforted by the formation of dibromocoumarine 21
and dibromopyranone 22 (characterized by 1H NMR) from the
corresponding heterocycles. These compounds were not purified
but subjected to the action of DBU to give 92% of bromocoumarine
23 and 80% of 24. It is important to note that direct addition of
bromine on aldehyde 2536 led to complex mixture from which,
according to 1H NMR, only few amount of 22 formed, pointing
against formation of Br2 from the HBr/iso-amyl nitrite mixture.
(CDCl3, 200 MHz) d 2.18–2.60 (m, 2H, CH2CH2CH), 3.36–3.49 (m, 2H,
CH2CH2CH), 3.67 (s, 3H, CO2CH3), 3.73 (s, 3H, CO2CH3), 3.76 (s, 3H,
CO2CH3), 4.12 (s, 2H, CH2), 5.12 (dd, J¼9.7, 3.2 Hz, 1H, CH2CH2CH);
13C NMR: (CDCl3, 50 MHz) d 25.4 (CH2), 33.2 (CH2), 37.6 (CH2), 51.8
(CH3), 52.1 (CH3), 52.8 (CH3), 53.3 (CH3), 62.6 (CH), 107.0 (C),
125.2 (C), 143.3 (C), 153.8 (C), 156.4 (C), 165.1 (C), 169.5 (C); IR:
n cmꢁ1 1740, 1730, 1720, 1590, 1500, 1430, 1200. Anal. Calcd for
C15H16BrO7N: C, 44.80; H, 4.01; N, 3.48. Found: C, 44.97; H, 4.19; N;
3.44.
4.4. General procedure of oxybromination
3. Conclusion
Arene (5 mmol) was dissolved in 5 mL of dichloromethane. A
solution of aq 48% HBr (7.5 mmol, 0.85 mL) was added followed by
iso-amyl nitrite (10 mmol, 0.4 mL). The reaction mixture was stirred
at room temperature for necessary time then aqueous NaHCO3
(5 mL) was added and the mixture was extracted with dichloro-
methane (2ꢃ10 mL). The combined organic layers were dried then
evaporated. The crude products were identified according to the 1H
NMR spectra of pure compounds, or from literature data.
We have presented our results towards an environmentally safe
procedure for the bromination of different compounds using
a simple reaction protocol. The positive bromine reagent is pre-
pared in situ from aqueous hydrobromic acid and iso-amyl nitrite as
oxidant. The method is practically feasible, and safer than bromi-
nation with molecular bromine.
4. Experimental section
4.1. General
4.4.1. 5-Bromo-1,3-benzodioxole
Yield 100%; 1H NMR (CDCl3, 200 MHz): d 5.95 (s, 2H, CH2), 6.66
(d, J¼8.8 Hz, 1H, ArH), 6.92 (m, 2H, ArH).
Melting points were determined using an Electrothermal ap-
paratus and are uncorrected. 1H and 13C NMR spectra were
obtained on a Varian Gemini 2000 at 200 and 50 MHz, respectively.
IR spectra were obtained in ATR mode on a FTIR Bruker Tensor 27.
Thin layer chromatographies were performed on precoated Kie-
selgel 60F254 plates. APCIþ (atmospheric pressure chemical ioni-
zation) mass spectra were obtained on an LC–MS system Thermo
Electron Surveyor MSQ. Microanalyses were performed by the
4.4.2. 1-Bromo-4-methylbenzene
Yield 67%; 1H NMR (CDCl3, 200 MHz): d 2.28 (s, 3H, CH3), 7.02 (d,
J¼8.1 Hz, 2H, ArH), 7.37 (d, J¼8.4 Hz, 2H, ArH).
4.4.3. 1-Bromo-2-methylbenzene
Yield 17%; 1H NMR (CDCl3, 200 MHz): d 2.38 (s, 3H, CH3), 7.04
(m, 1H, ArH), 7.13–7.22 (m, 2H, ArH), 7.48–7.52 (m, 1H, ArH).
´
‘Service de Microanalyses’ of LSEO, Universite de Bourgogne, Dijon,
France. All products are obtained as mixtures of diastereoisomers.
4.4.4. 1-Bromonaphthalene
Yield 85%; 1H NMR (CDCl3, 200 MHz): d 7.24 (t, J¼8.1 Hz, 1H,
ArH), 7.42–7.57 (m, 2H, ArH), 7.71–7.79 (m, 3H, ArH), 8.2 (d,
J¼8.4 Hz, 1H, ArH).
4.2. Dimethyl 6-chloro-7-methoxycarbonylmethyl-5-oxo-
1,2,3,5-tetrahydro-indolizine-3,8-dicarboxylate (3)
A mixture of 1 (0.21 g, 0.65 mmol), and iso-amyl nitrite (0.3 mL,
2.23 mmol) in 37% hydrochloric acid (0.1 mL, 0.78 mmol) and tet-
rahydrofuran (3 mL) was stirred at room temperature for 15 h. The
mixture was extracted with dichloromethane (2ꢃ50 mL). The
combined organic layers were dried (sodium sulfate), filtered and
evaporated. The residue was then subjected to flash chromatogra-
phy (ethyl acetate/heptane, 70/30) to give 3. Yellow oil; 74% yield;
TLC Rf (AcOEt)¼0.65; 1H NMR: (CDCl3, 200 MHz) d 2.22–2.64 (m,
2H, CH2CH2CH), 3.43–3.56 (m, 2H, CH2CH2CH), 3.72 (s, 3H, CO2CH3),
3.80 (s, 3H, CO2CH3), 3.82 (s, 3H, CO2CH3), 4.14 (s, 2H, CH2), 5.19 (dd,
J¼9.5, 3.2 Hz, 1H, CH2CH2CH); 13C NMR: (CDCl3, 50 MHz) d 28.4
(CH2), 36.2 (CH2), 40.6 (CH2), 54.9 (CH3), 55.1 (CH3), 55.9 (CH3), 56.3
(CH), 65.6 (C),110.1 (C),128.2 (C),146.3 (C),156.8 (C),159.4 (C),168.1
(C), 172.5 (C); IR: n cmꢁ1 1750, 1720, 1670, 1580, 1520, 1440, 1200.
Anal. Calcd for C15H16ClO7N: C, 50.26; H, 4.51; N, 3.92. Found: C,
49.94; H, 4.61; N; 3.86.
4.4.5. 2,4-Dibromo-1-naphthol
Yield 70%; 1H NMR (CDCl3, 200 MHz): d 7.56 (m, 1H, ArH), 7.92
(s, 1H, ArH), 8.44–8.51 (m, 1H, ArH), 8.8–8.85 (m, 1H, ArH).
4.4.6. 2-Bromo-1-phenylethanone
Yield 61%; 1H NMR (CDCl3, 200 MHz): d 4.48 (s, 2H, CH2Br), 7.45–
7.67 (m, 3H, ArH), 7.95–8.04 (m, 2H, ArH).
4.4.7. Methyl dibromo(cyano)acetate
Yield 98%; 1H NMR (CDCl3, 200 MHz): d 4.02 (s, 3H, CO2CH3).
4.5. Dimethyl 7-(1-(methoxycarbonyl)propyl)-1,2,3,5-tetra-
hydro-6-bromo-5-oxoindolizine-3,8-dicarboxylate (9)
Pyridone
8 (1.5 g, 4.4 mmol) was dissolved in 44 mL of
dichloromethane. Solution of aq 48% HBr (0.75 mL, 6.6 mmol) was
added follow by iso-amyl nitrite (1.22 mL, 8.8 mmol). The reaction
mixture was stirred at room temperature for 6 h, and then aqueous
NaHCO3 (60 mL) was added and the mixture was extracted by
dichloromethane (2ꢃ100 mL). The combined organic layers were
dried then evaporated. The residue was purified by chromatogra-
phy on SiO2 (heptane/EtOAc, 100/0% to 0/100%), to give compound
9. Yellow oil; 98% yield; TLC Rf (AcOEt)¼0.5; 1H NMR: (CDCl3,
200 MHz) d 0.95, 0.97 (2t, J¼7.4 Hz and J¼8.2 Hz, 3H, CHCH2CH3),
1.50–1.75 (m, 1H, CHCH2CH3), 2.24–2.63 (m, 3H, CHCH2CH3 and
CH2CH2CH), 3.36–3.54 (m, 2H, CH2CH2CH), 4.43, 4.45 (2d, J¼8.2 Hz
and J¼7.2 Hz, 1H, CHCH2CH3), 5.17, 5.19 (2dd, J¼9.7, 5.8 Hz and
J¼9.6, 5.4 Hz, 1H, CH2CH2CH); 13C NMR: (CDCl3, 50 MHz) d 10.9
4.3. Dimethyl 6-bromo-7-methoxycarbonylmethyl-5-oxo-
1,2,3,5-tetrahydro-indolizine-3,8-dicarboxylate (5)
Pyridone 1 (300 mg, 0.92 mmol) was dissolved in 1 mL of
dichloromethane. A solution of aq 48% HBr (1.3 mmol, 0.16 mL) was
added followed by iso-amyl nitrite (1.8 mmol, 0.1 mL). The reaction
mixture was stirred at room temperature for necessary time (Table
2), then aqueous NaHCO3 (5 mL) was added and the mixture was
extracted with dichloromethane (2ꢃ10 mL). The combined organic
layers were dried and then evaporated. White powder; 98% yield;
TLC Rf (heptane/AcOEt: 50/50)¼0.2; mp (AcOEt) 110 ꢀC; 1H NMR:

L. Gavara et al. / Tetrahedron 64 (2008) 4999–5004
5003
(CH3), 22.1 (CH2), 23.9 (CH2), 31.1 (CH2), 50.2 (CH3), 50.3 (CH3), 50.7
(CH), 51.3 (CH3), 61.2 (CH), 105.5 (C), 117.0 (C), 148.8 (C), 152.2 (C),
155.2 (C), 163.8 (C), 168.0 (C), 170.1 (C); IR: n cmꢁ1 1738, 1719, 1654,
1436, 1259, 1209. Anal. Calcd for C17H20BrNO7: C, 47.46; H, 4.69; N,
3.26. Found: C, 47.25; H, 4.77; N; 3.20.
CO2CH3), 3.81, 3.82 (2s, 3H, CO2CH3), 4.42, 4.43 (2dd, J¼8, 3.6 Hz
and J¼8.2, 3.7 Hz, 1H, CHCH2CH3), 5.14–5.23 (m, 1H, CH2CH2CH);
13C NMR: (CDCl3, 50 MHz) d 12.4 (CH3), 23.4 (CH2), 25.6 (CH2), 32.8
(CH2), 49.1 (CH), 51.8 (CH3), 51.9 (CH3), 52.9 (CH3), 62.6 (CH), 106.8
(C),125.3 (C),148 (C),153 (C),156.6 (C),165.4 (C),169.6 (C),171.8 (C);
IR: n cmꢁ1 1738, 1717, 1654, 1432, 1262, 1209. Anal. Calcd for
4.6. Methyl 6,8-dibromo-7-[1-(methoxycarbonyl)propyl]-
5-oxo-1,2,3,5-tetrahydroindolizine-3-carboxylate (11)
C17H20ClNO7: C, 52.93; H, 5.23; N, 3.63. Found: C, 53.08; H, 5.34; N,
3.81.
The pyrrolopyridone 10 (600 mg, 2 mmol) was dissolved in
10 mL of dichloromethane. Solution of aq 48% HBr (6 mmol, 0.7 mL)
was added followed by iso-amyl nitrite (4 mmol, 0.9 mL). The re-
action mixture was stirred at room temperature for 6 h then
aqueous NaHCO3 (10 mL) was added and the mixture was extracted
by dichloromethane (2ꢃ20 mL). The combined organic layers were
dried then evaporated. The product was isolated by crystallization
and recrystallized in a mixture of ethyl acetate and ether. Yellow
powder; 84% yield; TLC Rf (AcOEt)¼0.7; mp (AcOEt) 69–70 ꢀC; 1H
NMR: (CDCl3, 200 MHz) d 0.97, 0.98 (2t, J¼7.3 Hz and J¼7.3 Hz, 3H,
CHCH2CH3), 1.87–2.15 (m, 2H, CHCH2CH3), 2.25–2.7 (m, 2H,
CH2CH2CH), 3.15–3.27 (m, 2H, CH2CH2CH), 3.7(s, 3H, CO2CH3), 3.82,
3.83 (2s, 3H, CO2CH3), 4.27–4.46 (br s, 1H, CHCH2CH3), 5.24, 5.25
(2dd, J¼9.5, 3.5 Hz and J¼9.5, 3.3 Hz, 1H, CH2CH2CH); 13C NMR:
(CDCl3, 50 MHz) d 11.9 (CH3), 22.5 (CH2), 25.4 (CH2), 33.7 (CH2), 52.5
(CH, CH3), 53.9 (CH3), 64.1 (CH), 148.9 (C), 150.4 (C), 156.5 (C), 168.0
(C),169.7 (C),171.4 (C); IR: n cmꢁ11738,1729,1642,1590,1549,1530,
1204. Anal. Calcd for C15H17Br2O5N$1⁄2 H2O: C, 39.16; H, 3.94; N,
3.04. Found: C, 39.31; H, 3.81; N; 3.16.
4.8. 5-Nitro-1,3-benzodioxole (14)
To a stirred solution of arene (5 mmol) and aq solution of HF 40%
(0.6 mL, 15 mmol) in a Teflon flask was added iso-amyl nitrite
(2 mmol, 0.4 mL). The mixture was stirred at room temperature for
3 days and the solvent was evaporated. The residue was diluted
with dichloromethane (10 mL) and washed with satd aqueous
NaHCO3 (5 mL). The aqueous phase was extracted with dichloro-
methane (2ꢃ10 mL) and the combined organic layers were dried
(MgSO4). The residue obtained upon evaporation was analyzed by
1H NMR and identified according to the literature data. 80% yield;
1H NMR: (CDCl3, 200 MHz) d 3.97, 3.99 (2s, 6H, OCH2O), 6.93 (d,
J¼8.9 Hz, 1H, ArH), 7.75 (d, J¼2.7 Hz, 1H, ArH), 7.92 (dd, J¼8.9,
2.7 Hz, 1H, ArH).
4.9. Brominated pyrroloquinazolinones
To a solution of compound 16 (1.0 g, 4.1 mmol) in dichloro-
methane (10 mL) were slowly added iso-amyl nitrite (1.6 mL,
8.0 mmol), then a solution of aq 48% HBr (1 mL, 3.6 mmol). The
reaction mixture was stirred at room temperature for 12 h. A sat-
urated aqueous solution of NaHCO3 was then added, and the mix-
ture was extracted with dichloromethane. The combined organic
layers were washed with water, then dried upon MgSO4 and
evaporated. The dark residue was then separated by HPLC using
a gradient of ethyl acetate in heptane to yield to cis and trans
monobrominated products 17 and dibrominated product 18.
4.6.1. Methyl 8-bromo-7-[1-(methoxycarbonyl)propyl]-5-oxo-
1,2,3,5-tetrahydroindolizine-3-carboxylate (12)
The pyrrolopyridone 10 (600 mg, 2 mmol) was dissolved in
10 mL of dichloromethane. Solution of aq 48% HBr (6 mmol, 0.7 mL)
was added followed by iso-amyl nitrite (4 mmol, 0.9 mL). The re-
action mixture was stirred at room temperature for 6 h then
aqueous NaHCO3 (10 mL) was added and the mixture was extracted
by dichloromethane (2ꢃ20 mL). The combined organic layers were
dried then evaporated. The residue was purified by chromatogra-
phy on SiO2 (heptane/EtOAc, 100/0% to 0/100%). Yellow oil; 78%
yield; TLC Rf (AcOEt)¼0.6; 1H NMR: (CDCl3, 200 MHz) d 0.96, 0.98
(2t, J¼7.4 and J¼7.3 Hz, 3H, CHCH2CH3), 1.66–2.14 (m, 2H,
CHCH2CH3), 2.24–2.67 (m, 2H, CH2CH2CH), 3.16–3.26 (m, 2H,
CH2CH2CH), 3.70, 3.71 (2s, 3H, CO2CH3), 3.75 (m, 1H, CHCH2CH3),
3.80, 3.81 (2s, 3H, CO2CH3), 5.19 (dd, J¼9.7, 3.4 Hz, 1H, CH2CH2CH),
6.43 (s, 1H, ArH); 13C NMR: (CDCl3, 50 MHz) d 11.0 (CH3), 25.3 (CH2),
25.6 (CH2), 33.0 (CH2), 51.0 (CH), 52.2 (CH3), 52.5 (CH3), 62.7 (CH),
97.5 (C), 116.9 (CH), 148.0 (C), 151.9 (C), 160 (C), 170 (C), 172 (C); IR:
n cmꢁ1 1738, 1670, 1596, 1533, 1438, 1339, 1210. Anal. Calcd for
4.9.1. Methyl 3-bromo-9-oxo-1,2,3,9-tetrahydropyrrolo[2,1-b]quin-
azoline-1-carboxylate (17)
4.9.1.1. Cis isomer. Grey powder; 10% yield; mp 124–126 ꢀC; TLC Rf
(EtOAc/Hept 50/50)¼0.26; 1H NMR: (CDCl3, 200 MHz) d 2.92 (dt,
J¼15.2, 1.5 Hz, 1H, CH–CH2–CHBr), 3.20 (ddd, J¼15.2, 9.4, 7.2 Hz, 1H,
CH–CH2–CHBr), 3.84 (s, 3H, CO2CH3), 5.22 (dd, J¼7.2,1.5 Hz,1H, CH–
CH2–CHBr), 5.29 (dd, J¼9.4, 1.5 Hz, 1H, CH–CH2–CHBr), 7.54 (dd,
J¼8.0, 6.1 Hz, 1H, Har), 7.79 (d, J¼8.2 Hz, 1H, Har), 7.81 (ddd, J¼8.2,
6.1, 1.5 Hz, 1H, Har), 8.33 (ddd, J¼8.0, 1.5, 0.7 Hz, 1H, Har); 13C NMR
(CDCl3, 50 MHz): d ppm 28.7 (CH2), 41.6 (CH3), 52.2 (CH), 56.7 (CH),
119.9 (C), 125.8 (CH), 126.6 (CH), 126.9 (CH), 133.8 (CH), 147.8 (C),
155.7 (C),158.9 (C), 167.8 (C); IR: n cmꢁ1 1751, 1667, 1631, 1214, 695;
1H NMR (CDCl3, 200 MHz). Anal. Calcd for C13H11BrN2O3$3⁄4 H2O: C,
46.38; H, 3.74; N, 8.32. Found: C, 46.06; H, 3.79; N, 8.67.
C
15H18BrNO5, H2O: C, 46.17; H, 5.17; N, 3.59. Found: C, 46.58; H,
4.85; N, 3.82.
4.7. Dimethyl 7-(1-(methoxycarbonyl)propyl)-1,2,3,5-tetra-
hydro-6-chloro-5-oxoindolizine-3,8-dicarboxylate (13)
A solution of 8 (300 mg, 0.85 mmol) in THF (4 mL), 37% hydro-
chloric acid (0.1 mL, 1.16 mmol) and iso-amyl nitrite (0.4 mL,
2.89 mmol) was stirred at room temperature for 1 week. The
mixture was neutralized by satd aqueous NaHCO3 (50 mL) and the
aqueous phase was extracted with dichloromethane (3ꢃ30 mL)
and the combined organic layers were dried (MgSO4) then evapo-
rated. The residue was purified by chromatography on SiO2 (hep-
tane/EtOAc,100/0% to 0/100%) to give compound 14. Yellow oil; 60%
yield; TLC Rf (AcOEt)¼0.6; 1H NMR: (CDCl3, 200 MHz) d 0.94, 0.95
(2t, J¼7.3 and J¼7.4 Hz, 3H, CHCH2CH3), 1.52–1.83 (m, 1H,
CHCH2CH3), 2.25–2.65 (m, 3H, CHCH2CH3 and CH2CH2CH3), 3.39–
3.51 (m, 2H, CH2CH2CH), 3.66 (m, 3H, CO2CH3), 3.79, 3.8 (2s, 3H,
4.9.2. Trans isomer
Grey powder; 22% yield; mp 132–134 ꢀC; TLC Rf (EtOAc/Hept 50/
50)¼0.41; 1H NMR (CDCl3, 200 MHz): d 2.91 (dd, J¼7.2, 5.8 Hz, 2H,
CH–CH2–CHBr), 3.85 (s, 3H, CO2CH3), 5.17 (t, J¼7.2 Hz, 1H, CH–CH2–
CHBr), 5.34 (t, J¼7.2 Hz, 1H, CH–CH2–CHBr), 7.52 (ddd, J¼7.9, 7.2,
1.9 Hz, 1H, Har), 7.78 (dd, J¼8.3, 1.9 Hz, 1H, Har), 7.80 (ddd, J¼8.3,
7.2, 1.1 Hz, 1H, Har), 8.29 (ddd, J¼7.9, 1.1 Hz, 1H, Har); 13C NMR
(CDCl3, 50 MHz): d ppm 28.7 (CH2), 41.6 (CH3), 52.2 (CH), 56.7 (CH),
119.9 (C), 125.8 (CH), 126.6 (CH), 126.9 (CH), 133.8 (CH), 147.8 (C),
155.7 (C),158.9 (C), 167.8 (C); IR: n cmꢁ1 1751, 1667, 1631, 1214, 695.
Anal. Calcd for C13H11BrN2O3$3⁄4 H2O: C, 46.38; H, 3.74; N, 8.32.
Found: C, 46.22; H, 3.72; N, 8.02.

5004
L. Gavara et al. / Tetrahedron 64 (2008) 4999–5004
4.10. Methyl 3,3-dibromo-9-oxo-1,2,3,9-tetrahydropyrrolo-
References and notes
[2,1-b]quinazoline-1-carboxylate (18)
1. (a) Makecki, N.; Houssin, R.; He´nichart, J. P.; Couturier, D.; Petra, F.; Legentil, L.;
Rigo, B. J. Heterocycl. Chem. 2003, 40, 45; (b) For some nitration in these series,
see: Gavara, L.; Rigo, B.; Couturier, D.; Goossens, L.; He´nichart, J. P. Tetrahedron
2007, 63, 9556.
2. Xie, Y.; Mo, W.; Xu, D.; Shen, Z.; Sun, N.; Hu, B.; Hu, X. J. Org. Chem. 2007, 72,
4288.
3. Holschbach, M.; Wutz, W.; Olsson, R. Tetrahedron Lett. 2002, 44, 41.
4. Butler, A.; Walker, J. Chem. Rev. 1993, 93, 1937.
5. Diederich, F.; Stang, P. Metal-Catalyzed Cross-Coupling Reactions; Wiley: New
York, NY, 1997; p 1.
6. Winterfeldt, E. Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: New York, NY, 1991; Vol. 6, p 1.
7. De la Mare, P. B. Electrophilic Halogenation; Cambridge University Press:
Cambridge, 1976; Vol. 5, p 1.
8. Dear, K. M. Top. Curr. Chem. 1993, 164, 115.
9. Clark, J. H. Chemistry of Waste Minimisation; Chapman and Hall: London,
1995; p 1.
Grey crystals; 38% yield; mp (AcOEt) 128–130 ꢀC; TLC Rf (EtOAc/
Hept 60/40)¼0.7; 1H NMR (CDCl3, 200 MHz): d 3.55 (dd, J¼14.8,
4.6 Hz, 1H, CH–CH2–CBr2), 3.69 (dd, J¼14.8, 7.8 Hz, 1H, CH–CH2–
CBr2), 3.86 (s, 3H, CO2CH3), 5.15 (dd, J¼7.8, 4.6 Hz, 1H, CH–CH2–
CBr2), 7.57 (ddd, J¼7.9, 6.6, 1.7 Hz, 1H, Har), 7.84 (ddd, J¼8.2, 6.6,
1.5 Hz, 1H, Har), 7.92 (ddd, J¼8.2, 1.7, 0.7 Hz, 1H, Har), 8.32 (ddd,
J¼7.9, 1.5, 0.7 Hz, 1H, Har); 13C NMR (CDCl3, 50 MHz): d ppm 49.3
(CH2), 53.2 (CH3), 55.8 (CH), 62.3 (C), 120.5 (C), 126.6 (CH), 127.9
(CH), 128.1 (CH), 134.8 (CH), 148.3 (C), 155.5 (C), 159.3 (C), 167.6 (C);
IR: n cmꢁ1 1747, 1680, 1616, 1224, 693. Anal. Calcd for
C
13H10Br2N2O3$1⁄2 H2O: C, 37.99; H, 2.70; N, 6.82. Found: C, 37.92;
H, 2.78; N, 6.80.
10. (a) Forlani, L. Synthesis 1980, 487; (b) Kajigaeshi, S.; Kakinami, T.; Moriwaki, M.;
Tanaka, T.; Fujisaki, S.; Oramoto, T. Bull. Chem. Soc. Jpn. 1989, 62, 439; (c) Negoro,
T.; Ikeed, Y. Bull. Chem. Soc. Jpn. 1984, 57, 2116; (d) Muathen, H. A. Synthesis
2002, 169.
4.11. Bromination of coumarine or pyranone 25
11. Smith, M. B.; March, J. March’s Advanced Organic Chemistry; Wiley: New York,
NY, 2001; p 704.
12. (a) Prakash, G. K. S.; Mathew, T.; Hoole, D.; Esteves, P. M. J. Am. Chem. Soc. 2004,
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Coumarine or pyranone 25 (1.1 mmol) was dissolved in 3 mL of
dichloromethane. A solution of aq 48% HBr (2 mmol, 0.23 mL) was
added followed by iso-amyl nitrite (3.2 mmol, 0.72 mL). The re-
action mixture was stirred at room temperature for 2 days giving
dibromo intermediate.
4.11.1. 3,4-Dibromochroman-2-one (21)
1H NMR: (CDCl3, 200 MHz) d 4.97 (d, J¼2.5 Hz, 1H, CHBr), 5.35
(d, J¼2.5, 1H, CHBr), 7.15–7.29 (m, 2H, ArH), 7.36–7.51 (m, 2H, ArH).
20. Kim, D.-K.; Chung, W.-J.; Lee, Y.-S. Synlett 2005, 279.
21. Dakka, J.; Sasson, Y. Chem. Commun. 1987, 1421.
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4.11.2. 2,3-Dibromo-5-ethyl-6-oxo-3,6-dihydro-2H-pyran-4-
carbaldehyde (22)
1H NMR: (CDCl3, 200 MHz) d 1.28 (q, J¼7.4 Hz, 3H, CH2CH3), 2.94
(t, J¼7.4 Hz, 2H, CH2CH3), 5.33 (d, J¼1.5 Hz, 1H, CHBr), 6.77 (s,
J¼1.5 Hz, 1H, CHBr), 10.25 (s, 1H, CHO).
ˇ
24. Podgorsek, A.; Stavber, S.; Zupan, M.; Iskra, J. Tetrahedron Lett. 2006, 47, 7245.
DBU (1.6 mmol, 0.3 mL) was added and the reaction mixture
was stirred for 1 h. Solvents were then evaporated under reduced
pressure. The residue was dissolved in dichloromethane (50 mL)
and washed with distilled water (2ꢃ50 mL). The combined organic
layers were dried (Na2SO4) and then evaporated.
25. Khan, A.; Parvin, T.; Choudhury, L. H.; Ghosh, S. Tetrahedron Lett. 2007, 48, 2271.
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34. Synthesis of this compound will be described in the near future.
35. Terent’ev, A. O.; Khodykin, S. V.; Krylov, I. B.; Ogibin, Y. N.; Nikishin, G. I.
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4.11.3. 4-Bromo-2H-chromen-2-one (23)
Yield 92%; 1H NMR: (CDCl3, 200 MHz) d 7.26–7.39 (m, 2H, ArH),
7.45–7.64 (m, 2H, ArH), 8.13 (s, 1H, ArH).
4.11.4. 5-Bromo-3-ethyl-2-oxo-2H-pyran-4-carbaldehyde (24)
Yellow oil; 80% yield; TLC Rf (AcOEt)¼0.6; 1H NMR: (CDCl3,
200 MHz) d 1.21 (t, J¼7.4 Hz, 3H, CH2CH3), 2.72 (q, J¼7.4 Hz, 2H,
CH2CH3), 7.6 (s, 1H, ArH), 10.18 (s, 1H, COH).
36. Akue´-Ge´du, R.; He´nichart, J. P.; Couturier, D.; Rigo, B. Tetrahedron Lett. 2004,
45, 9197.