N-Methylpyrrolidin-2-one hydrotribromide (MPHT) a mild reagent for selective bromination of carbonyl compounds: Synthesis of substituted 2-bromo-1-naphtols

Article abstract of DOI:10.1016/j.tetlet.2005.04.049

The reaction of the N-methylpyrrolidin-2-one hydrotribromide complex (MPHT) with substituted-1-tetralones has been investigated. This safety reagent proved to be successful for selective α,α-dibromination of tetralones. Moreover, under base-free conditions, several 2-bromo-1-naphtols were obtained from tetralones in a 'one pot' sequence in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2005.04.049

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4187–4191
N-Methylpyrrolidin-2-one hydrotribromide (MPHT) a mild
reagent for selective bromination of carbonyl compounds:
synthesis of substituted 2-bromo-1-naphtols
Alain Bekaert, Olivier Provot,* Olimihamina Rasolojaona,
*
Mouad Alami and Jean-Daniel Brion
ˆ
´ ´ ´
Laboratoire de Chimie Therapeutique, BioCIS-CNRS (UMR 8076), Universite Paris-Sud, Faculte de Pharmacie,
´ ˆ
rue J. B. Clement 92296 Chatenay-Malabry Cedex, France
Received 17 March 2005; revised 11 April 2005; accepted 13 April 2005
Available online 28 April 2005
Abstract—The reaction of the N-methylpyrrolidin-2-one hydrotribromide complex (MPHT) with substituted-1-tetralones has been
investigated. This safety reagent proved to be successful for selective a,a-dibromination of tetralones. Moreover, under base-free
conditions, several 2-bromo-1-naphtols were obtained from tetralones in a Ôone potÕ sequence in good to excellent yields.
ꢀ 2005 Published by Elsevier Ltd.
Bromination of carbonyl compounds is an important
transformation, as the resulting a-brominated products
are versatile intermediates in organic synthesis.1
Although the a-bromination of ketones is now well docu-
mented,2 the a,a-dibromination reaction has received
little attention. The most commonly used reagent for
this transformation requires elemental bromine,3 which
have several environmental drawbacks. The handling
of liquid bromine, due to its hazardous nature, is trou-
blesome and special equipment and care are needed
for the transfer of these materials in large scale. In order
to overcome these problems, alternative methods for
preparing a,a-dibromoketones have been developed
such as HBr–H2O2,4 1,3-dibromo-5,5-dimethylhydan-
toin,5 polymer supported brominating reagents,6 KBr–
KBrO3–Dowex7 or dioxane–dibromide–silica gel under
microwave irradiation.8 While these reactions are suit-
able methods, in the case of robust substrates, it would
be useful to have alternative sources of bromine that of-
fer advantages of safety, selectivity, mild reaction condi-
tions and stability.
halogenated carbonyl compounds,9 we had previously
improved the synthesis of a crystalline bromine complex
N-methylpyrrolidin-2-one hydrotribromide (MPHT,
[NMP]2HBr3) 1 (Fig. 1) and determined its structure
by means of single-crystal X-ray diffraction methods.10
This complex is insensitive to moisture and showed a
remarkable stability at room temperature. Even though
no decrease in free bromine titre could be detected when
exposed to air for several months, nothing is known
about its reactivity.
An important aspect of our ongoing research on the syn-
thetic utility of 1 as soft acting brominating reagent in
organic synthesis led us to investigate its reactivity with
carbonyl compounds. Herein, we report the results of
this study and the use of complex MPHT 1 for the
selective preparation of a,a-dibrominated tetralones 3
suitable substrates for the construction of substituted
2-bromo-1-naphtols 4.
CH3
N
As a part of our programme aimed at the development
of new and selective reagents for the preparation of a-
O
CH3
N
2
MeOH
Br2 + HBr
HBr3
O
HBr3
Keywords: Halogenation; MPHT; 1-Tetralones; 2-Bromo-1-naphtols.
2
*
Corresponding authors. Tel.: +33 14683 5847; fax: +33 14683 5828
(O.P.); tel.: +33 14683 5847; fax: +33 14683 5828 (M.A.); e-mail
addresses: olivier.provot@cep.u-psud.fr; mouad.alami@cep.u-psud.fr
MPHT 1
Figure 1. Synthesis of MPHT 1.
0040-4039/$ - see front matter ꢀ 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2005.04.049

4188
A. Bekaert et al. / Tetrahedron Letters 46 (2005) 4187–4191
The synthesis of MPHT complex 1 was achieved readily
in 87% yield11 under a slightly modified DanielsÕ proce-
dure12 using a HBr solution (30% in acetic acid) instead
of gaseous HBr.
dibrominated tetralone 3a in very low yield (10%).
The effect of temperature was then examined and we
found that heating the reaction at 50 ꢁC provided the
expected tetralone 3a in 79% yield after stirring for
12 h. However, when the reaction was run at 80 ꢁC,
we were pleased to observe complete conversion of the
starting material 2a within 30 min and 3a was isolated
in 90% yield (Table 1, entry 1). Of the several solvents
tested, MeCN gave the highest yield of a,a-dibromi-
nated tetralone 3a. The other solvents including
CH2Cl2, toluene, dioxane and DMF gave unsatisfactory
yields of 3a.
The reactivity of the MPHT complex 1 was evaluated
with several 1-tetralones in order to prepare the a,a-
dibrominated compounds. First, we investigated this
reaction in CH3CN, solvent that we have previously
found to be efficient in a-iodination of ketones.9 Thus,
reaction of tetralone 2a with the MPHT complex 1
(2 equiv) at room temperature gave the desired a,a-
Table 1. Bromination of tetralones 2 with MPHT complex 1: synthesis of 2-bromo-1-naphtols 4
O
O
OH
MPHT
(2 equiv)
Br
Br
Br
NEt3
R
R
R
CH3CN, 80˚C,
30 min
CHCl3, 20˚C
2a-f
3a-f
4a-f
Entry
1
Tetralones 2
a,a-Dibrominated tetralones 3
Yielda,b (%) 2 ! 3
2-Bromo-1-naphtols 4
Yielda,b (%) 3 ! 4
OH
Br
O
O
Br
Br
90
91
2a
3a
4a
OH
Br
O
O
Br
Br
2
3
4
5
76
64
85
80
92
88
94
90
OCH3
OCH3
OCH3
2b
3b
4b
OH
O
O
Br
Br
Br
H3CO
H3CO
H3CO
H3CO
2c
3c
4c
OH
OH
O
O
O
H3CO
H3CO
Br
Br
Br
Br
2d
3d
4d
O
H3CO
H3CO
H3CO
Br
Br
H3CO
H3CO
H3CO
OCH3
OCH3
OCH3
2e
3e
4e
OH
O
O
Br
Br
Br
6
39c
56
Br
Br
Br
2f
3f
4f
a Isolated yield. All new compounds exhibited satisfactory spectral properties14 and microanalyses (C 0.40, H 0.31).
b a,a-Dibromotetralone and bromophenol derivatives synthesized are new compounds except those of entries 1 and 2.
c 20% of bromonaphtol 4f were also obtained.

A. Bekaert et al. / Tetrahedron Letters 46 (2005) 4187–4191
4189
OH
The results of the dibromination reaction of various
O
substituted tetralones 2 with the MPHT complex 1 in
CH3CN are summarized in Table 1. Under these opti-
mized conditions,13 good yields of dibrominated tetra-
lones 3 were obtained except when the reaction is
carried out from tetralone 2f. In this case, 39% of tetra-
lone 3f were isolated together with 20% of 2-bromo-
1-naphtol 4f.
Br
MPHT 2 equiv
R
R
CH3CN, 80˚C 18 h
2a R = H
4a 78%a
4b 70%a
4d 87 %a
2b R = 5-OMe
2d R = 7-OMe
Since 2-bromo-1-naphtol derivatives are interesting re-
agents for metal catalyzed coupling reaction15 and par-
ticularly for the synthesis of heterocyclic products,16 it
would be useful to transform the dibrominated tetra-
lones 3 into their corresponding 2-bromo-1-naphtols 4.
To this end, tetralones 3 were reacted for 30 min at
room temperature with an excess of Et3N (10 equiv) in
CHCl3, and the expected 2-bromo-1-naphtols 4 were
obtained in good to high yields (Table 1).
2f R = 5-Br
2f R = 5-Br
4f 60 %a
4f 95 %b
Scheme 1. One pot synthesis of 2-bromo-1-naphtols under base-free
conditions. aIsolated yield (Ref. 17). bIsolated yield after irradiation in
microwave for 1 h at 140 ꢁC.
lated yield (90%). This result clearly indicated that in the
case of dibromination–dehydrobromination process, the
MPHT complex acted first, as a safe and selective bro-
minating agent and subsequently, the NMP liberated
in the media promoted the thermal dehydrobromination
step, when reactions were performed for a prolongated
reaction time (80 ꢁC). Under these thermal and base-free
conditions (2 equiv of 1), it should be noted that no
products resulting from bromination of activated aro-
matic ring could be detected.
In order to simplify this transformation from the point
of view of the synthetic chemist, our aim was also to
obtain a-bromonaphtol derivatives 4 in a one-pot proce-
dure without isolation of the intermediate a,a-dibromi-
nated products 3. Thus, we investigated the reaction of
tetralone 2a with MPHT complex (2 equiv) in acetoni-
trile in the presence of an excess of Et3N (3 mL/1 mmol
of tetralone 2a) at 80 ꢁC for 18 h. Under these condi-
tions, the dibromination–dehydrobromination process
does not occurred and starting material was recovered
unchanged, probably owing to an undesirable reaction
between NEt3 and electrophilic MPHT. However, by
adding Et3N in the media after completion of the dibro-
mination step (disappearance of tetralone 2a after
30 min as judged by TLC) we were pleased to observe
that, the expected 2-bromo-1-naphtol 4a was isolated
in 76% isolated yield after stirring for 30 min at room
temperature.
Interestingly, we showed if an excess of MPHT was
used, selective electrophilic aromatic bromination on
the aryl ring occurred. Thus, reaction of 7-methoxytetra-
lone 2d with the MPHT complex 1 (3 equiv) in acetoni-
trile at 80 ꢁC for a night, provided selectively 2,6-
dibromo-7-methoxy-1-naphtol 4g in 83% yield. The
MPHT complex acted this time at first, as a a,a-dibromi-
nating agent, then assisted the dehydrobromination
step and finally permitted the bromination of the inter-
mediary naphtol derivative 4d (Fig. 2).
To examine if the presence of Et3N is necessary for the
dehydrobromination step, we performed the reaction of
tetralone 2a with the MPHT complex 1 (2 equiv) in boil-
ing CH3CN for a prolongated reaction time (18 h). In
these base-free conditions, we observed a fully dehydro-
bromination of the intermediate a,a-dibrominated tetra-
lone 3a to give the expected 2-bromo-1-naphtol 4a in
a one-step sequence in 78% yield. These base-free condi-
tions have been applied successfully to the preparation
a-bromonaphtol derivatives 4 from tetralones 2 (Scheme
1).
Finally, it is noteworthy that the use of a stoichiometric
amount of the MPHT complex 1, exclusively monobro-
mination of tetralones 2 occurred. Thus, in CH2Cl2, a-
bromination of 2a with the MPHT complex 1 (1 equiv)
provided the corresponding a-bromoketone at room
temperature in 80% yield, comparable with those ob-
tained to bromination with elemental bromine (e.g.,
72!99%).18
In summary, we have examined the synthetic potential
of the MPHT complex 1 in the bromination reactions
of various tetralones. This complex, which could be pre-
pared in large amounts (multi-moles scale) and could be
stored several months at room temperature, permitted
Moreover, we were pleased to observe that tetralone 2f
has been transformed successfully (95% vs 60%) into
its corresponding bromonaphtol 4f under microwave
irradiation.
For a complete understanding of this dehydrobromina-
tion reaction, we have stirred the a,a-dibrominated tetra-
lone 3a in CH3CN for 18 h at 80 ꢁC. The result of this
experiment showed a partial thermal dehydrobromina-
tion of 3a producing 4a in only 25% yield. However, if
the experiment is carried out in CH3CN in the presence
of N-methyl-2-pyrrolidin-2-one (4 equiv), the expected
2-bromo-1-naphtol 4a was obtained in an excellent iso-
OH
O
H3CO
Br
Br
H3CO
MPHT 3 equiv
CH3CN 80˚C 18 h
4g 83%
2d
Figure 2. A one-pot synthesis of 4g from 2d.

4190
A. Bekaert et al. / Tetrahedron Letters 46 (2005) 4187–4191
and the solution was stirred for 10 min. Then, N-methyl-
pyrrolidin-2-one, 250 mL, was added by the dropping
funnel (two drops per second). The mixture was stirred for
1 h at 10 ꢁC and orange crystals were collected, washed
with Et2O (4 · 50 mL) and dried under vacuum to give
440 g of MPHT 1 as orange crystals (yield = 87%). Mp
122–124 ꢁC. 1H NMR (CDCl3, 200 MHz): d 2.25 (m, 4H),
2.90 (t, 4H, J = 8 Hz), 3.00 (s, 6H), 3.75 (t, 4H,
J = 7.2 Hz), 14.6 (br s, 1H). 13C NMR (CDCl3,
200 MHz): d 18.3, 31.4, 33.3, 52.8, 178.3. IR cmꢀ1: 3339,
1640, 1420, 1228.
the selective mono- and/or dibromination of various
substituted tetralones. Moreover, under base-free condi-
tions, in boiling CH3CN, the N-methylpyrrolidin-2-one
liberated in the media assisted and completed the ther-
mal dehydrobromination of intermediary dibrominated
tetralones to lead in a one-pot sequence to the expected
2-bromo-1-naphtol derivatives.
The ease of MPHT use in selective bromination(s) and
subsequent dehydrobromination(s) together with its
crystalline state, make it very attractive in organic chem-
istry. Other selective bromination reactions with ali-
phatic ketones and electrophilic aromatic bromination
are now in progress in our laboratory.
12. Daniels, W. E.; Chaddix, M. E.; Glickman, S. A. J. Org.
Chem. 1963, 28, 573–574.
13. General procedure for the a,a-dibromination of tetralones
with MPHT 1: In a round bottomed flask, a solution of
tetralone 2 (1 mmol) in CH3CN (10 mL) was stirred in an
oil bath at 80 ꢁC and then MPHT (2 mmol) was added
dropwise (each drop was added only after the previous
drop had completely decolourized). The mixture was then
stirred for 30 additional minutes at this temperature. The
reaction mixture was cooled to 20 ꢁC and treated with a
saturated Na2S2O3 solution. The organic layer was washed
with HCl 10% (3 · 10 mL) and dried over MgSO4.
Removal of the solvent yielded a crude product, which
was purified by silica gel flash chromatography to afford 3
(see Table 1 for yields).
Acknowledgements
The CNRS is gratefully acknowledged for financial sup-
port of this research. We wish to thank also la Ligue
Contre le Cancer for a doctoral fellowship to O.R.
1
14. All new compounds were characterized by H, 13C NMR
References and notes
and IR.
Compound 3c: Mp 85 ꢁC. 1H NMR (CDCl3, 200 MHz): d
2.90 (s, 4H), 3.70 (s, 3H), 6.65 (d, 1H, J = 2.1 Hz), 6.85
(dd, 1H, J = 8.3, 2.1 Hz), 8.05 (d, 1H, J = 8.3 Hz). 13C
NMR (CDCl3, 200 MHz): d 29.5, 46.0, 55.6, 67.8, 112.3,
114.5, 120.2, 132.4, 144.7, 164.4, 183.0. IR cmꢀ1: 1684,
1596, 1494.
1. (a) Bolton, R. In Bromine Compounds: Chemistry and
Applications; Price, D., Iddon, B., Wakefield, B. J., Eds.;
Elsevier: Amsterdam, 1988, p 151; (b) De Kimpe, N.;
´
Verhe, R. In The Chemistry of a-Haloketones, a-Haloal-
dehydes and a-Haloimines; Patai, S., Rappoport, Z., Eds.;
Wiley, 1988.
Compound 3d: Mp 88–90 ꢁC. 1H NMR (CDCl3,
200 MHz): d 2.90 (m, 4H), 4.10 (s, 3H), 7.40 (m, 2H),
7.85 (d, 1H, J = 1 Hz). 13C NMR (CDCl3, 200 MHz): d
28.4, 46.0, 55.5, 67.3, 111.5, 123.0, 128.0, 129.8, 134.6,
158.8, 184.1. IR cmꢀ1: 1498, 1283.
2. For recent advances on a-bromination of carbonyl com-
pounds, see: (a) Tanemura, K.; Suzuki, T.; Nishida, Y.;
Satsumabayashi, K.; Horaguchi, T. Chem. Commun. 2004,
470–471; (b) Lee, J. C.; Park, J. Y.; Yoon, S. Y.; Bae, Y.
H.; Lee, S. J. Tetrahedron Lett. 2004, 45, 191–193; (c) Lee,
J. C.; Bae, Y. H.; Chang, S.-K. Bull. Korean Chem. Soc.
2003, 24, 407–408; (d) Choi, H. Y.; Chi, D. Y. Org. Lett.
2003, 5, 411–413.
3. (a) House, H. O.; McDaniel, W. C. J. Org. Chem. 1977,
42, 2155–2160; (b) Lambert, C.; No¨ll, G.; Schma¨lzlin, E.;
Meerholz, K.; Bra¨uchle, C. Chem. Eur. J. 1998, 4, 2129–
2135; (c) Hatzigrigoriou, E.; Spyroudis, S.; Vargolis, A.
Liebigs Ann. Chem. 1989, 167–170; (d) Plieninger, H.;
Vo¨lkl, A. Chem. Ber. 1976, 109, 2121–2125.
4. Tillu, V. H.; Shinde, P. D.; Bedekar, A. V.; Wakharkar, R.
D. Synth. Commun. 2003, 33, 1399–1403.
5. Spitulnik, M. J. Synthesis 1985, 299–300.
6. Sket, B.; Zupan, M. Synth. Commun. 1989, 19, 2481–
2487.
7. Kosmrlj, J.; Kocevar, M.; Polanc, S. Synth. Commun.
1996, 26, 3583–3592.
8. Satya, P.; Gupta, V.; Gupta, R.; Loupy, A. Tetrahedron
Lett. 2003, 44, 439–442.
Compound 3e: Mp 83 ꢁC. 1H NMR (CDCl3, 200 MHz): d
2.95 (m, 4H), 3.80 (s, 3H), 3.82 (s, 3H), 3.90, (s, 3H), 7.40
(s, 1H). 13C NMR (CDCl3, 200 MHz): d 23.1, 45.6, 56.0,
60.6, 60.8, 67.2, 107.4, 122.2, 129.9, 145.6, 149.8, 152.8,
185.1. IR cmꢀ1: 1691, 1589, 1485.
Compound 3f: 1H NMR (CDCl3, 200 MHz): d 3.30 (m,
4H), 7.50 (t, 1H, J = 8 Hz), 8.00 (dd, 1H, J = 8, 1 Hz), 8.35
(dd, 1H, J = 8, 1 Hz). 13C NMR (CDCl3, 200 MHz): d
30.0, 44.3, 65.6, 124.2, 128.5, 129.0, 129.1, 138.0, 140.9,
183.1. IR cmꢀ1: 1699, 1586, 1559.
Compound 4c: Mp 87 ꢁC. 1H NMR (CDCl3, 200 MHz): d
3.85 (s, 3H), 5.80 (br s, 1H), 6.95 (d, 1H, J = 2 Hz), 7.05
(m, 2H), 7.25 (d, 1H, J = 8.5 Hz), 8.05 (d, 1H, J = 8.5 Hz).
13C NMR (CDCl3, 200 MHz): d 55.2, 101.6, 105.7, 118.4,
119.6, 120.1, 123.9, 128.9, 135.2, 148.2, 158.3. IR cmꢀ1
:
3530, 1622, 1595.
1
Compound 4d: Mp 60 ꢁC. H NMR (CDCl3, 200 MHz):
d 3.95 (s, 3H), 5.35 (br s, 1H), 7.10–7.25 (m, 3H), 7.45
(d, 1H, J = 2 Hz), 7.70 (d, 1H, J = 9 Hz). 13C NMR
(CDCl3, 200 MHz): d 55.3, 100.5, 104.7, 119.5, 121.0,
125.5, 125.8, 128.8, 129.1, 147.0, 157.9. IR cmꢀ1: 3497,
1626, 1591.
9. Bekaert, A.; Barberan, O.; Gervais, M.; Brion, J.-D.
Tetrahedron Lett. 2000, 41, 2903–2905.
10. Bekaert, A.; Barberan, O.; Kaloun, E. B.; Danan, A.;
Brion, J.-D.; Lemoine, P.; Viossat, B. Z. Kristallogr. NCS
2001, 216, 1–2.
1
Compound 4e: Mp 75 ꢁC. H NMR(CDCl3, 200 MHz): d
3.90 (s, 3H), 3.92 (s, 3H), 3.94 (s, 3H), 5.00–5.50 (br s, 1H),
7.15 (s, 1H), 7.20 (d, 1H, J = 9 Hz), 7.40 (d, 1H, J = 9 Hz).
13C NMR (CDCl3, 200 MHz): d 55.8, 60.1, 61.4, 97.2,
105.2, 115.2, 124.5, 126.0, 129.1, 152.1, 152.6, 152.9, 162.2.
IR cmꢀ1: 3497, 1629, 1590.
11. Preparation of MPHT: To a 2 L round bottomed flask,
cooled in an ice bath and equipped with a dropping funnel
and a condenser, were added, successively, 200 mL of
MeOH and 250 mL (one drop per second) of HBr (30% in
acetic acid) while maintaining the internal temperature
between 10 and 15 ꢁC. Elemental bromine, 60 mL, was
then added by the dropping funnel (two drops per second)
Compound 4f: Mp 70–72 ꢁC. 1H NMR (CDCl3,
200 MHz): d 6.05 (s, 1H), 7.30 (dd, 1H, J = 8.5, 8.0 Hz),

A. Bekaert et al. / Tetrahedron Letters 46 (2005) 4187–4191
4191
7.55 (d, 1H, J = 9 Hz), 7.70 (d, 1H, J = 9 Hz), 7.80 (dd,
1H, J = 8, 1 Hz), 8.20 (d, 1H, J = 8.5 Hz). 13C NMR
(CDCl3, 200 MHz): d 105.2, 120.5, 122.2, 122.6, 125.6,
126.3, 129.4, 130.8, 132.4, 148.2. IR cmꢀ1: 3406, 1616,
1583.
16. Jiang, Y.-Y.; Li, Q.; Lu, W.; Cai, J.-C. Tetrahedron Lett.
2003, 44, 2073–2075.
17. General procedure for the synthesis of 2-bromo-1-naphtols
under base-free conditions: In a round bottomed flask, a
solution of tetralone 2 (1 mmol) and MPHT (2 mmol) in
CH3CN (10 mL) was stirred in an oil bath at 80 ꢁC for
18 h. The reaction mixture was cooled and treated as
above (Ref. 13).
18. (a) Mosettig, E.; Everette, L. M. J. Org. Chem. 1940, 5,
528–536; (b) Brewster, W. K.; Nichols, D. E.; Watts, V. J.;
Riggs, R. M.; Mottola, D.; Mailman, R. B. J. Med. Chem.
1995, 38, 318–327; (c) Hulme, A. H.; Henry, S. S.; Meyers,
A. I. J. Org. Chem. 1995, 60, 1265–1270.
1
Compound 4g: Mp 142 ꢁC. H NMR (CDCl3, 200 MHz):
d 3.90 (s, 3H), 5.80 (br s, 1H), 7.05–7.20 (dd, 1H, J = 9,
2.5 Hz), 7.45 (d, 1H, J = 2.5 Hz), 7.55 (s, 1H), 7.85–7.95
(d, 1H, J = 9 Hz). 13C NMR (CDCl3, 200 MHz): d 55.4,
101.0, 103.7, 113.1, 120.4, 126.0, 126.7, 128.4, 128.7, 146.9,
158.3. IR cmꢀ1: 3441, 1585, 1497.
15. Brimble, M. A.; Brenstrum, T. J. J. Chem. Soc., Perkin
Trans. 1 2001, 1624–1631.