Microwave-assisted NBS bromination of p-iminotoluenes: Preparation of new alcohol, mercapto, and amino protection groups

Article abstract of DOI:10.1080/00397911.2010.517378

A simple, efficient, safe, high-yielding and rapid microwave-assisted method for the preparation of protected p-bromomethyl and p- dibromomethylanilines was developed as new alcohol, thiol, and amine protection groups. The procedure involves microwave-assisted N-bromosuccinimide (NBS) radical bromination of readily available N-protected p-toluidine. The microwave-assisted radical bromination was found to be superior to the conventional NBS radical bromination. Copyright

Full text of DOI:10.1080/00397911.2010.517378

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Microwave-Assisted NBS Bromination of
p-Iminotoluenes: Preparation of New
Alcohol, Mercapto, and Amino Protection
Groups
Sunil K. Upadhyay a & Branko S. Jursic a b
a Department of Chemistry , University of New Orleans , New
Orleans , Louisiana , USA
b Stepharm , New Orleans , Louisiana , USA
Published online: 27 Jul 2011.
To cite this article: Sunil K. Upadhyay & Branko S. Jursic (2011) Microwave-Assisted NBS Bromination
of p-Iminotoluenes: Preparation of New Alcohol, Mercapto, and Amino Protection Groups, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
41:21, 3177-3185, DOI: 10.1080/00397911.2010.517378
To link to this article: http://dx.doi.org/10.1080/00397911.2010.517378
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Synthetic Communications1, 41: 3177–3185, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.517378
MICROWAVE-ASSISTED NBS BROMINATION OF
p-IMINOTOLUENES: PREPARATION OF NEW
ALCOHOL, MERCAPTO, AND AMINO
PROTECTION GROUPS
Sunil K. Upadhyay1 and Branko S. Jursic1,2
1Department of Chemistry, University of New Orleans, New Orleans,
Louisiana, USA
2Stepharm, New Orleans, Louisiana, USA
GRAPHICAL ABSTRACT
Abstract A simple, efficient, safe, high-yielding and rapid microwave-assisted method for
the preparation of protected p-bromomethyl and p-dibromomethylanilines was developed
as new alcohol, thiol, and amine protection groups. The procedure involves
microwave-assisted N-bromosuccinimide (NBS) radical bromination of readily available
N-protected p-toluidine. The microwave-assisted radical bromination was found to be
superior to the conventional NBS radical bromination.
Keywords Benzyl bromides; microwave-assisted reactions; NBS bromination; radical
bromination
In the course of our preparations of the total synthesis of the naturally occurring
antifungal C-27 steroidal saponins,[1–5] tetramic acid–based antibiotics,[6–9] and
cysteine-tyrosine–based antioxidants,[10–12] we were faced with a significant problem
involving the protection of hydroxyl, 1,3-dihydroxy, and thio groups. While there
are numerous protection groups that are efficiently applied in the preparations of
complex organic molecules,[13,14] our target molecules required additional functional
properties that are not commonly associated with the traditional protection groups;
namely, they must alter the physical properties of the protected molecules to produce
intermediates that could be purified, characterized, and subjected to harsh reaction
conditions. Additionally, we proposed that these protecting groups should also be
Received August 11, 2010.
Address correspondence to Branko S. Jursic, Department of Chemistry, University of New
Orleans, New Orleans, LA 70148, USA. E-mail: bsjstepharm@ymail.com
3177

3178
S. K. UPADHYAY AND B. S. JURSIC
resistant to most reagents required for the preparation of our targeted natural pro-
ducts, allowing their convenient removal at the very end of the synthetic procedure.
We selected cyclic imides of p-aminobenzyl and p-aminobenzylidene bromides
as ideal protection groups for the purposes of our natural product syntheses (Fig. 1).
Cyclic imides are compounds that crystallize well and are relatively stable in acidic,
neutral, and dry basic reaction media.[15] When these groups are part of the protected
compound either in the ether, thioether, or amine form, they are relatively stable in
the mentioned reaction conditions. The major advantage of these benzyl-based pro-
tection groups over others that their acid sensitivity can be significantly increased by
removal of imide protection using hydrazine or a base. The resulting p-amino benzyl
ethers, thioethers, or amines are easily cleaved with moderate acids. For alcohols, the
corresponding phenylmethyl bromide 1 is an ideal protection group, whereas for 1,2-
and 1,3-diols the phenylmethylene dibromide 2 is the ideal protection group. Finally,
for thiols and amines, the triphenylmethyl bromide 3 is the ideal protection group
(Fig. 1).[16–18]
One of the requirements for broad use of these protection groups in natural
product synthesis is that they be available in large amounts, either commercially
or through simple preparation procedures. The classical approach to prepare benzyl
bromides and benzylidene dibromides is through the direct bromination of the
benzylic methyl or through deoxybromination of benzylic alcohol or benzaldehyde
derivatives.[19] The latter route implies a multistep synthesis, which is often
time-consuming. Alternatively, the two-step bromination method, via the generation
of the methyl anion developed by Fraser,[20,21] appears attractive. However, this
method is incompatible with the presence of nucleophile-sensitive functional groups
on the molecule, such as an ester group.
Radical-mediated bromination is frequently used to achieve selective activation
of the benzyl and allyl positions of an organic molecule.[22] The reaction is normally
carried out using N-bromosuccinimide (NBS) in tetrachloromethane with various
radical initiators.[23] However, tetrachloromethane presents relatively high toxicity
and carcinogenicity, which restricts its use in general synthesis.[24] Tetrachloro-
methane can be replaced by other solvents, such as methyl acetate, in light and some
microwave-assisted benzylic brominations,[25] but to avoid using tetrachloro-
methane, Golding and coworkers[26] used (trifluoromethyl)benzene as a solvent in
Figure 1. New alcohol, thiol, and amino protection groups.

MICROWAVE-ASSISTED BROMINATION OF p-IMINOTOLUENES
3179
the benzylic bromination with NBS. Subsequently, Ulrich and coworkers found that
dichloromethane and benzene are better solvents for radical bromination than
carbontetrachloride.[27]
In a recent approach, radical benzyl bromination was performed using H2O2-
HBr. This is a promising synthetic procedure,[28] but the reagent pair is still some-
what aggressive. The softer and simplest route to prepare these compounds remains
the free radical bromination with NBS.[29–31] Nonetheless, some of these bromina-
tions require long reaction times (more than 20 h of refluxing) that cause product
decomposition and the formation of a dibromo by-product that is often difficult
to separate from the product. Nevertheless, we selected NBS radical bromination
of cyclic imides protected p-toluidene as our method of choice to prepare our neces-
sary reagents (compounds 1–3, Fig. 1). Two major recent developments enabled us
to properly explore this reaction. First, we developed a laboratory microwave reac-
tor that can be used as standard laboratory equipment for reactions that require high
energy, and second, this equipment was recently used to prepare large quantities of
cyclic imides in short reaction times and good yields.[32] Because of these two
advances in our laboratory, the starting material for the preparation of new protec-
tion groups was already available in large quantities.
Considering that the NBS radical benzyl bromination usually requires longer
reaction times, there have been previous attempts to shorten the NBS benzyl bromin-
ation and increase the bromination selectivity. As mentioned previously, there were
other attempts to perform microwave-assisted benzyl bromination in methyl acet-
ate.[25] However, the isolated yields of the reaction were, at best, moderate
(30–60%). On the other hand, Goswami and coworkers reported microwave-assisted
benzyl bromination without solvent and a radical initiatior.[33] This reaction was
performed using a microwave magnetron power of 450 W for several minutes. The
reported yields for this experimental procedure were around 40%. In another recent
report, the microwave-assisted benzyl bromination was compared to ultrasound-
assisted benzyl bromination.[34] In this experiment, the microwave reaction con-
ditions were strenuous (microwave temperature 150 ꢀC, time 4 min, pressure
3.5 bar, and microwave magnetron power 200 W) and clearly results in the reactant
decomposition and poor yields of the brominated product. Subsequently, the
bromination reaction mixture contained substantial amounts of the dibromination
product, causing additional problems with purification. Using the microwave reactor
developed in our laboratory, we were able to extend the reaction times associated
with organic reactions by controlling the temperature and adding magnetic stirring
and a water-cooled condenser. In doing these simple modifications, we were able to
extend the length of the reaction time to several days if necessary, below or at solvent
refluxing temperature.
Our microwave-assisted NBS bromination was performed in benzene as sol-
vent instead of tetrachloromethane with only 1 equivalent of NBS. The reaction
was basically over in less than 2 h, and the isolated yields were greater than 80%
(Table 1). By comparison, if the reaction was performed under conventional meth-
ods (refluxing of benzene), then the reaction required a reaction time 3–10 times
longer. Longer reaction times generate more by-products that hamper the isolation
and purification of the final product, resulting in lower isolated yields. In addition,
for conventional NBS bromination, more than 1 equivalent (1.3–1.5 eq.) of NBS

3180
S. K. UPADHYAY AND B. S. JURSIC
Table 1. Preparation of benzyl bromides
Microwave
Conventional
Time (min) Yield (%)
Product
Time (min)
Yield (%)
4a
4b
4c
4d
4e
30
40
60
40
90
85
83
87
80
82
190
300
180
240
300
72
75
65
67
78
is required for full conversion (disappearance of starting material). On the other
hand, if carbon tetrachloride was used as a solvent, then the required reaction time
was more than doubled in comparison with benzene as a solvent. For instance, 17 h
was required for the preparation of 4a in benzene (Table 1). For example, to shorten
reaction times to 2 h for compound 4a (Table 1) using more conventional reaction
conditions, a combination of both carbon tetrachloride refluxing and ultraviolent
radiation was used.[35] These examples only emphasize superiority of microwave-
assisted NBS benzyl bromination in benzene as a solvent (Table 1).
Microwave-assisted NBS dibromination is as effective as monobromination
(Table 2), and this method again is superior, considering that the usual isolated
yields for dibromination are between 5% to 40%.[36] Furthermore, using conven-
tional methods, the reaction mixture always contains mixture of dibromo and mono-
bromo products and requires more than 1 day to complete and at least 3 equivalents
of NBS. In the case of conventional heating, the benzene solution was refluxed for at
least 12 h and a small amount of monobrominated product was still present. The iso-
lated yields are somewhere between 60% and 70%.[37] Microwave-assisted reaction
requires only a few hours with more than 95% conversion into dibromo product,
Table 2. Isolated yields of benzylidine bromides
Microwave
Conventional
Product
Time (h)
Yield (%)
Time (h)
Yield (%)
5a
5b
5c
1
3
3
88
83
92
12
24
24
70
65
66

MICROWAVE-ASSISTED BROMINATION OF p-IMINOTOLUENES
3181
and the isolated yields are between 80% and 90% (Table 2). This is the cleanest, sim-
plest, shortest, and the highest-yielding procedure for preparation of dibromomethy-
larene derivatives from methylarenes.
Finally, benzyl NBS bromination can be performed in environmentally friendly
solvents such as ethyl acetate and diethyl carbonate.[23] For instance, if NBS radical
bromination was performed in ethyl acetate instead of benzene for 4a (Table 2), then
the required reaction time was slightly longer (1 h), and the isolated yield is moder-
ately lower (75%). However, if the NBS bromination was performed in dimethylfor-
maide (DMF) as a reaction media, then the reaction was completed in 10 min but
isolated yield was only 60%.
In conclusion, it can be stated that with using this new NBS radical benzyl
bromination method, desirable bromomethyl and dibromomethylarenes can be pre-
pared from readily available methylarenes in good quantities and short reaction
times coupled with almost quantitative isolated yields. This synthetic approach
was proven to be superior to conventional NBS bromination.[38,39]
EXPERIMENTAL
Thin-layer chromatographic analysis (TLC) was performed using silica gel on
1
glass plates and was detected under ultraviolet (UV) light. The H and 13C NMR
spectra were run on Varian 300-MHz Gemini2000 and on Varian 400-MHz Unity
instruments in CDCl3 solvent and internal standards. The mass spectra were
recorded on a Micromass Quattro 2 Triple Quadrupole mass spectrometer. All
reagents and solvents were purchased from Aldrich and were analytical grade. The
laboratory version of our microwave has a cavity size of 21.6 cm high, 17.30 cm wide,
and 25.4 cm deep with two 2.54-cm holes on the top of the microwave for the con-
denser and thermometer. The magnetron (700 W) was directly wired to a variable
electronic autotransformer for control of the magnetron power. An ECM meter
(10 amps) was wired to the magnetron transformer to control the microwave power.
The magnetic stirrer was installed beneath the cavity for stirring the reaction mix-
ture. The reaction temperature was measured directly with a thermometer inserted
into the reaction mixture.
Typical Procedure for Preparation of Monobromoarene 4
Benzene (10 ml) solution of methyl benzene derivative (5 mmol), N-
bromosuccinamide (0.89 g; 5 mmol), and benzoylperoxide (0.12 g; 0.5 mmol) was
refluxed under microwave heating (magnetron power 600 W). After reaction was
completed (see Table 1) the solvent was evaporated; the solid residue was dissolved

3182
S. K. UPADHYAY AND B. S. JURSIC
in dichloromethane (100 ml) and washed with saturated water solution of sodium
bicarbonate (3 ꢁ 15 ml) and water (3 ꢁ 15 ml). Dichloromethane was evaporated,
and the solid residue was purified by silica-gel column chromatography with
hexane–dichloromethane as an eluent.
Selected Data for 4a–4e
2-(4-(Bromomethyl)phenyl)isoindoline-1,3-dione (4a). Isolated yield
1
(85%). H NMR d 7.98 (2H, m), 7.80 (2H, m), 7.55 (2H, d, J ¼ 8 Hz), 7.45 (2H, d,
J ¼ 8 Hz), and 4.55 (2H, s) ppm. 13C NMR d 167, 140, 138, 135, 132, 130, 127,
124, and 33 pm. C15H10BrNO2 (MW 316.15). MS (m=z) 317.99 (10%), 314.99
(100%), and 316.99 (95%).
1-(4-(Bromomethyl)phenyl)pyrrolidine-2,5-dione (4b). Isolated yield
1
83%. H NMR d 7.51 (2H, d, J ¼ 7.6 Hz), 7.32 (2H, d, J ¼ 7.6 Hz), 4.48 (2H, s)
ppm. 13C-NMR d 176, 138, 130, 127, 126, 33, and 28 ppm. C11H10BrNO2 (MW
268.11). MS (m=z) 269.99 (8%), 268.99 (95%), 266.99 (100%).
2-(4-(Bromomethyl)phenyl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (4c). Iso-
lated yield (87%). 1H NMR d 8.65 (2H, d, J ¼ 7.2 Hz), 8.27 (2H, d, J ¼ 8.4 Hz), 7.80
(2H, t, J ¼ 7.2 Hz), 7.58 (2H, d, J ¼ 8.4 Hz), 7.30 (2H, d, J ¼ 8.4 Hz), and 4.57 (2H, s)
ppm. 13C NMR d 164, 138, 135, 134, 131, 130, 129, 127, 123, and 33 ppm.
C19H12BrNO2 (MW 366.21) m=z: 368.01 (15%), 367.00 (100%), 365.01 (100.0%),
366.01 (10%).
N-(4-(Bromomethyl)phenyl)-N-methylbenzamide (4d). Isolated yield
1
(80%). H NMR d 7.28 (2H, d, J ¼ 7.8 Hz), 7.25 (7H, m), 7.02 (2H, d, J ¼ 7.8 Hz),
4.40 (2H, s), and 3.47 (3H, s) pp. 13C-NMR d 171, 145, 136, 135, 130, 129, 128,
127, 39, and 33 ppm. C15H14BrNO (MW 304.18). MS (m=z) 306.03 (10%) 305.02
(90%), 303.03 (100).
2-(2-(Bromomethyl)phenyl)isoindoline-1,3-dione (4e). Isolated yield
1
(82%). H NMR d 7.98 (2H, m), 7.80 (2H, m), 7.30 (4H, m), and 4.46 (2H) ppm.
13CNMR d 167, 136, 135, 132, 131, 130, 129, 128, 124, and 30 ppm. C15H10BrNO2
(Mw 316.15). MS (m=z) 317.99 (10%), 316.99 (95%), 314.99 (100%).
Typical Procedure for Preparation of Dibromoarene 5
Benzene (10 ml) mixture of the methylbenzene derivative (3.3 mmol), N-
bromsucinimide (1.8 g; 10 mmol), and benzoylperoxide (75 mg; 0.31 mmol) was
refluxed for 3 h under microwave radiation (magnetron power 600 W). The solvent
was evaporated under reduced pressure, and the solid residue was dissolved in
dichloromethane (100 ml). Dichloromethane solution was washed with saturated
sodium bicarbonate (3 ꢁ 15 ml), and water (3 ꢁ 20 ml) and dried over anhydrous
sodium sulfate. The solvent was evaporated, and the residue was purified by
filtration through a short silica-gel column with hexane–dichloromethane as solvent.

MICROWAVE-ASSISTED BROMINATION OF p-IMINOTOLUENES
3183
Selected Data for 5a–5c
2-(4-(Dibromomethyl)phenyl)isoindoline-1,3-dione (5a). Isolated yield
1
(88%). H NMR d 7.98 (2H, m), 7.82 (2H, m), 7.72 (2H, d, J ¼ 8.0 Hz), 7.51 (2H,
d, J ¼ 8.0 Hz), and 6.68 (1H, s) ppm. 13C-NMR d 167, 141, 135, 133, 131, 128,
127, 124, and 40 ppm. C15H9Br2NO2 (MW 395.05). MS (m=z) 396.90 (50%),
395.90 (10%), 394.90 (100%), 392.90 (50%).
1-(4-(Dibromomethyl)phenyl)pyrrolidine-2,5-dione (5b). Isolated yield
1
(83%). H NMR d 7.68 (2H, d, J ¼ 7.4 Hz), 7.32 (2H, d, J ¼ 7.4 Hz), 6.64 (1H, s),
and 2,99 (4H, s) ppm. 13C NMR d 178, 133, 128, 127, 126, 40, and 28 ppm.
C11H9Br2NO2 (MW 347.00) m=z 348.90 (50%), 347.90 (10%), 346.90 (100%),
344.90 (50%).
2-(4-(Dibromomethyl)phenyl)-1H-benzo[de]isoquinoline-1,3(2H)-dione
(5c). Isolated yield (92%). 1H NMR d 8.82 (2H, t, J ¼ 8 Hz), 8.48 (2H, d, J ¼ 8 Hz),
7.83 (2H, t, J ¼ 8 Hz), 7.75 (2H, d, J ¼ 7.8 Hz), 7.36 (2H, d, J ¼ 7.8 Hz), and 6.72 (1H,
s) ppm. 13C NMR (CDCl3, 400 MHz) d 164, 142, 137, 135, 132, 129, 128, 127, 123,
and 40 ppm. C19H11Br2NO2 (MW 445.10). MS (m=z) 447.91 (10%), 446.9 (50%)
445.9 (20%), 444.9 (100%), 443.9 (10%). 442.9 (50%).
ACKNOWLEDGMENT
We thank the National Science Foundation for financial support (CHE-
0611902) for this work.
REFERENCES
1. Hostettmann, K.; Marston, A. Saponins: Chemistry & pharmacology of natural products;
Cambridge University Press: Cambridge, 2005.
2. Tasleem, A. T.; Bhosale, J. D.; Kumar, N.; Mandal, T. K.; Bendre, R. S.; Lavekar, G. S.;
Dabur, R. Natural products: Antifungal agents derived from plants. J. Asian Nat. Prod.
Res. 2009, 11, 621–638.
3. Sautour, M.; Mitaine-Offer, A. C.; Lacaille-Dubois, M. A. The Dioscorea genus: A review
of bioactive steroid saponins. J. Nat. Med. 2007, 61, 91–101.
4. Yang, C. R.; Zhang, Y.; Jacob, M. R.; Khan, S. I.; Zhang, Y. J.; Li, X. C. Antifungal
activity of C-27 steroidal saponins. Antimicrob. Agents Ch. 2006, 50, 1710–1714.
5. De Lucca, A. J.; Klich, M.; Boue, S.; Cleveland, T. E.; Sien, T.; Walsh, T. J. Fungicidal
activity of plant saponin CAY-1 for fungi isolated from diseased Vitis fruit and stems. Am.
J. Enol. Vitic. 2008, 59, 67–72.
6. Lowery, C. A.; Park, J.; Gloeckner, C.; Meijler, M. M.; Mueller, R. S.; Boshoff, H. I.;
Ulrich, R. L.; Barry, C. E.; Bartlett, D. H.; Kravchenko, V. V.; Kaufmann, G. F.; Janda,
K. D. Defining the mode of action of tetramic acid antibacterials derived from pseudomo-
nasaeruginosa quorum sensing signals. J. Am. Chem. Soc. 2009, 131, 14473–14479.
7. Schobert, R.; Schlenk, A. Tetramic and tetronic acids: An update on new derivatives and
biological aspects. Bioorg. Med. Chem. 2008, 16, 4203–4221.
8. Yoshinari, T.; Ohmori, K.; Schrems, M. G.; Pfaltz, A.; Suzuki, K. Total synthesis and
absolute configuration of macrocidin A, a cyclophane tetramic acid natural product.
Angew. Chem. Int. Ed. 2009, 49, 881–885.

3184
S. K. UPADHYAY AND B. S. JURSIC
9. Sorokina, I. K.; Alekseeva, L. M.; Parshin, V. A.; Granik, V. G. Functional derivatives of
tetramic acid: New approaches to the synthesis of heterotricyclic compounds. Pharm.
Chem. J. 2007, 41, 543–548.
10. Jongberg, S.; Carlsen, C. U.; Skibsted, L. H. Peptides as antioxidants and carbonyl
quenchers in biological model systems. Free Radical Res. 2009, 43, 932–942.
11. Berndt, C.; Lillig, C. H.; Holmgren, A. Thiol-based mechanisms of the thioredoxin and
glutaredoxin systems: Implications for diseases in the cardiovascular system. Am. J.
Physiol. Heart Circ. Physiol. 2007, 292, H1227–H1236.
12. Bielicki, J. K. Cysteine-containing peptides having antioxidant properties. US Patent
7,601,802, October 13, 2009.
13. Wuts, P. G. M.; Greene, T. W. Protective Groups in Organic Synthesis, 4th ed.; Wiley and
Sons: New York, 2006.
14. Kocienski, P. J. Protecting Groups, 3rd ed.; Thieme: Stuttgart, 2005.
15. Chen, Y.; Li, H.; Cai, S. Luminescent N-arylphthalimidino derivatives 2- and 4-(1-oxo-
1H-2,3-dihydroisoindol-2-yl)benzoic acid: Examples of a new class of reaction induced
crystallization for an organic compound. Chem. Commun. 2009, 5392–5393.
16. Chan, W. C.; Bycroft, B. W.; Evans, D. J.; White, P. D. A novel 4-aminobenzyl
ester-based carboxy-protecting group for synthesis of atypical peptides by Fmoc-But
solid-phase chemistry. Chem. Commun. 1995, 2209–2210.
17. Sekine, M.; Hata, T. Synthesis of short oligoribonucleotides bearing a 30- or 50-terminal
phosphate by use of 4,40,400-tris(4,5-dichlorophthalimido)trityl as a new 50-hydroxyl
protecting group. J. Am. Chem. Soc. 1986, 108, 4581–4586.
18. Dubowchik, G. M.; Radia, S. Monomethoxytrityl (MMT) as a versatile amino protecting
group for complex prodrugs of anticancer compounds sensitive to strong acids, bases, and
nucleophiles. Tetrahedron Lett. 1997, 38, 5257–5260.
19. Funeriu, D. P.; Lehn, J. M.; Baum, G.; Fenske, D. Double subroutine self-assembly:
Spontaneous generation of a nanocyclic dodecanuclear Cu1 inorganic architecture. Chem.
Eur. J. 1997, 3, 99–104.
20. Smith, A.; Lamba, J. J. S.; Fraser, C. L. Effective synthesis of halomethyl-2,20-bipyridines:
4,40-Bis(chloromethyl)-2,20-bipyridine. Org. Synth. 2002, 78, 82–90.
21. Fraser, C. L.; Anastasi, N. R.; Lamba, J. J. S. Synthesis of halomethyl and other pipyri-
dine derivatives by reaction of 4,40-bis[(trimethylsilyl)methyl]-2,20-bipyridine with electro-
philes in the presence of fluoride ion. J. Org. Chem. 1997, 62, 9314–9317.
22. Jereb, M.; Zupan, M.; Stavber, S. Visible-light-promoted Wohl–Ziegler functionalization
of organic molecules with N-bromosuccinimide under solvent-free reaction conditions.
Helv. Chim. Acta 2009, 92, 555–566.
23. Virgil, S. C.; Jenkins, P. R.; Wilson, A. J.; Romero, M. D. G. N-Bromosuccinimide.
Encyclopedia of Reagents for Organic Synthesis 1995, 1, 768–772.
24. McGregor, D.; Lang, M. Carbon tetrachloride: Genetic effects and other modes of action.
Mutat. Res.-Rev Mutat. 1996, 366, 181–195.
25. Amijs, C. H. M.; van Klink, G. P. M.; van Koten, G. Carbon tetrachloride free benzylic
brominations of methyl aryl halides. Green Chem. 2003, 5, 470–474.
26. Suarez, D.; Laval, G.; Tu, S.-M.; Jiang, D.; Robinson, C. L.; Scott, R.; Golding, B. T.
Benzylic brominations with N-bromosuccinimide in (trifluoromethyl)benzene. Synthesis
2009, 1807–1810.
27. Bedel, S.; Ulrich, G.; Picard, C. Alternative approach to the free radical bromination of
oligopyridine benzylic-methyl group. Tetrahedron Lett. 2002, 43, 1697–1700.
28. Podgorsek, A.; Stavber, S.; Zupan, M.; Iskra, J. Environmentally benign electrophilic and
radical bromination ‘‘on water’’: H2O2–HBr system versus N-bromosuccinimide. Tetra-
hedron 2009, 65, 4429–4439.

MICROWAVE-ASSISTED BROMINATION OF p-IMINOTOLUENES
3185
29. Xu, W.-T.; Jin, N.; Xu, J.; Xu, Y. G.; Wang, Q. J.; You, Q. D. Design, synthesis, and
biological evaluation of novel substituted benzoylguanidine derivatives as potent Naþ=
Hþ exchanger inhibitors. Bioorg. Med. Chem. Lett. 2009, 19, 3283–3287.
30. Kharkar, P. S.; Deodhar, M. N.; Kulkarni, V. M. Design, synthesis, antifungal activity,
and ADME prediction of functional analogues of terbinafine. Med. Chem. Res. 2009,
18, 421–432.
31. Sechi, M.; Carta, F.; Sannia, L.; Dallocchio, R.; Dessi, A.; Al-Safi, R. I.; Neamati, N.
Design, synthesis, molecular modeling, and anti-HIV-1 integrase activity of a series of
photoactivatable diketo acid-containing inhibitors as affinity probes. Antivir. Res. 2009,
81, 267–276.
32. Upadhyay, S. K.; Pingali, S. R.K.; Jursic, B. S. Comparison of microwave-assisted and
conventional preparation of cyclic imides. Tetrahedron Lett. 2010, 51, 2215–2217.
33. Goswami, S. P.; Dey, S.; Jana, S.; Adak, A. K. Side chain bromination of mono and
dimethyl heteroaromatic and aromatic compounds by solid phase N-bromosuccinimide
reaction without radical initiator under microwave. Chem. Lett. 2004, 33, 916–917.
34. Heropoulos, G. A.; Cravotto, G.; Screttas, C. G.; Steele, B. R. Contrasting chemoselec-
tivities in the ultrasound and microwave assisted bromination reactions of substituted
alkylaromatics with N-bromosuccinimide. Tetrahedron Lett. 2007, 48, 3247–3250.
35. Baker, B. R.; Kozma, J. A. Irreversible enzyme inhibitors. XCV. 8-(m-Bromoacetamido-
benzylthio)hypoxanthine, an active-site-directed irreversible inhibitor of xanthine oxidase.
J. Med. Chem. 1967, 10, 682–685.
36. Mataka, S.; Liu, G. B.; Sawada, T.; Kurisu, M.; Tashiro, M. Photothermal side-chain
bromination of methyl-, dimethyl-, and trimethylbenzenes with N-bromosuccinimide. B.
Chem. Soc. Jpn. 1994, 67, 1113–1119.
37. Luzzio, F. A.; Wlodarczyk, M. T. Preparation of benzoheterocyclic carbaldeydes. Tetra-
hedron Lett. 2009, 50, 580–583.
38. Stover, J. S.; Shi, J.; Jin, W.; Vogt, P. K.; Boger, D. L. Discovery of inhibitors of aberrant
gene transcription from libraries of DNA binding molecules: Inhibition of LEF-1-
mediated gene transcription and oncogenic transformation. J. Am. Chem. Soc. 2009,
131, 3342–3348.
39. Khoumeri, O.; Montana, M.; Terme, T.; Vanelle, P. First TDAE approach in quinonic
series: Synthesis of new 2-substituted 1,4-dimethoxy-9,10-anthraquinones. Tetrahedron
2008, 64, 11237–11242.