Microwave-assisted suzuki cross-coupling reaction, a key step in the synthesis of polycyclic aromatic hydrocarbons and their metabolites

Article abstract of DOI:10.1021/jo701665j

(Chemical Equation Presented) A highly efficient and general method for Suzuki cross-coupling reaction en route to the synthesis of polycyclic aromatic hydrocarbons (PAHs) and their metabolites has been developed. Microwave irradiation of aryl bromides 1

Full text of DOI:10.1021/jo701665j

TABLE 1. Optimization of Reaction Conditions
Microwave-Assisted Suzuki Cross-Coupling
Reaction, a Key Step in the Synthesis of
Polycyclic Aromatic Hydrocarbons and Their
Metabolites
entry
reaction conditions
time/temp (°C)
conv (%)
1
2
Pd(PPh3)4, CsF, DME
Pd(OAc)2, K2CO3,
1 h/120
20 min/120
90
85
dioxane/water (5:1)
Pd EnCat 30 (5 mol %),
Bu4NH4OAc, EtOH
Pd EnCat 30 (10 mol %),
Bu4NH4OAc, EtOH
3
4
10 min/120
20 min/ 120
90
Arun K. Sharma,* Krishnegowda Gowdahalli,
Jacek Krzeminski, and Shantu Amin
>98
Department of Pharmacology, Chemical Carcinogenesis and
ChemopreVention Program of Penn State Cancer Institute, Penn
State College of Medicine, 500 UniVersity DriVe,
Hershey, PennsylVania 17033
chrysene (B[g]C), dibenzo[a,l]pyrene (DB[a,l]P), and dibenzo-
[c,mno]chrysene (DB[c,mno]C)] and those having a methyl
group in the bay region4 [e.g., 7,12-dimethylbenz[a]anthracene
(DMBA)] are relatively potent carcinogens. In connection with
metabolism study and determination of mutagenicity and
tumorigenicity, the synthetic standards of PAHs and their
metabolites are required. This need has led to a continuous
development of new and efficient methods for their synthesis.
Most prominent methods commonly used involve Suzuki cross-
coupling reactions5-13 and photochemical reactions.1,10,13,14 The
former has recently been used extensively because it allows for
a larger scale and is by far the most versatile synthetic method
for the generation of biaryl compounds.15 We have previously
reported the successful use of Suzuki cross-coupling reactions
to generate key intermediates for the synthesis of PAHs and
their metabolites.9-13 However, this coupling is associated with
extended reaction times and requires up to 24 h of refluxing.
In pursuit of our previous investigations toward developing more
efficient methods for the synthesis of PAH derivatives, we
optimized the Suzuki reaction conditions under microwave
irradiation. It was envisaged that the microwave irradiation
would enhance the rate of reaction, thereby reducing time.
The conditions were optimized for the reaction of 9-bro-
mophenanthrene with 2-formylphenylboronic (2) (Table 1).
Microwave irradiation resulted in 90% conversion16 in 1 h at
120 °C, using Pd(PPh3)4 and CsF in DME (entry 1), the reaction
aks14@psu.edu
ReceiVed July 30, 2007
A highly efficient and general method for Suzuki cross-
coupling reaction en route to the synthesis of polycyclic
aromatic hydrocarbons (PAHs) and their metabolites has been
developed. Microwave irradiation of aryl bromides 1 and
boronic acids (2 and 3) using polyurea microencapsulated
palladium catalyst (Pd EnCat 30) gave the coupling adducts
4 and 5 in excellent yields in just 20 min compared to ∼24
h under thermal conditions, corresponding to a ∼72-fold
increase in reaction rate.
Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous
environmental pollutants1 that require metabolic activation to
electrophilic reactive species in order to exert their mutagenic
and tumorigenic activity.2 The diol epoxides derived from PAHs
having a sterically hindered fjord region3 [e.g., benzo[c]-
phenanthrene (B[c]P), benzo[c]chrysene (B[c]C), benzo[g]-
(4) (a) Huggins, C. B.; Pataki, J.; Harvey, R. G. Proc. Natl. Acad. Sci.
U.S.A. 1967, 58, 2253. (b) DiGiovanni, J.; Diamond, L.; Harvey, R. G.;
Slaga, T. J. Carcinogenesis 1983, 4, 403. (c) Hecht, S. S.; Amin, S.; Huie,
K.; Melikan, A. A.; Harvey, R. G. Cancer Res. 1987, 47, 5310. (d) Iyer, R.
P.; Lyga, J. W.; Secrist, J. A., III; Daub, G. H.; Slaga, T. J. Cancer Res.
1980, 40, 1073.
(5) (a) Zhang, F. J.; Cortez, C.; Harvey, R. G. J. Org. Chem. 2000, 65,
3952. (b) Rice, J. E.; Cai, Z.-W. J. Org. Chem. 1993, 58, 1415. (c) Kumar,
S. J. Chem. Soc., Perkin Trans. 1 1998, 3157.
* To whom correspondence should be addressed. Phone: (717) 531-0003
ext 285016. Fax: (717) 531-0244.
(6) Kumar, S. J. Chem. Soc., Perkin Trans. 1 2001, 1018.
(7) Kumar, S. J. Org. Chem. 1997, 62, 8535.
(8) Kumar, S. Synthesis 2001, 841.
(1) Harvey, R. G. Polycyclic Aromatic Hydrocarbons: Chemistry and
Carcinogenicity; Cambridge University Press: Cambridge, England, 1991.
(2) (a) Gelboin, H. V. Physiol. ReV. 1980, 34, 1107. (b) Conney, A. H.
Cancer Res. 1982, 42, 4875. (c) Cooper, C. S.; Grover, P. L.; Sims, P.
Prog. Drug. Metab. 1983, 7, 295. (d) Guengerich, F. P. Carcinogenesis
2000, 21, 345-351. (e) Cavalieri, E. L.; Rogan, E. G. One-electron oxidation
in aromatic hydrocarbon carcinogenesis. In Polycyclic Hydrocarbons and
Carcinogenesis; Harvey, R. G., Ed.; American Chemical Society: Wash-
ington, DC, 1985; pp 289-305. (f) Penning, T. M.; Burczynski, M. E.;
Hung, C-F.; McCoull, K. D.; Palackal, N. T.; Tsuruda, L. S. Chem. Res.
Toxicol. 1999, 12, 1.
(9) Sharma, A. K.; Kumar, S.; Amin, S. J. Org. Chem. 2004, 69, 3979.
(10) Desai, D.; Sharma, A. K.; Lin, J.-M.; Krzeminski, J.; Pimental, M.;
El-Bayoumy, K.; Nesnow, S.; Amin, S. Chem. Res. Toxicol. 2002, 15, 964.
(11) Sharma, A. K.; Amin, S.; Kumar, S. Polycyclic Aromat. Compd.
2002, 22, 277.
(12) Desai, D.; Sharma, A. K.; Lin, J.-M.; El-Bayoumy, K.; Amin, S.;
Pimentel, M.; Nesnow, S. Polycyclic Aromat. Compd. 2002, 22, 267.
(13) Sharma, A. K.; Lin, J-M.; Desai, D.; Amin, S. J. Org. Chem. 2005,
70, 4962.
(3) (a) Hecht, S. S.; El-Bayoumy, K.; Rivenson, A.; Amin, S. Cancer
Res. 1994, 54, 21. (b) Levin, W.; Wood, A. W.; Chang, R. L.; Ittah, Y.;
Croisy-Delcey, M.; Yagi, H.; Jerina, D. M.; Conney, A. H. Cancer Res.
1980, 40, 3910-3914. (c) Amin, S.; Desai, D.; Dai, W.; Harvey, R. G.;
Hecht, S. S. Carcinogenesis 1995, 16, 2813. (d) Amin, S.; Krzeminski, J.;
Rivenson, A.; Kurtzke, C.; Hecht, S. S.; El-Bayoumy, K. Carcinogenesis
1995, 16, 1971. (e) Amin, S.; Lin, J. M.; Krzeminski, J.; Boyiri, T.; Desai,
D.; El-Bayoumy, K. Chem. Res. Toxicol. 2003, 16, 227. (f) Nelson, G.;
Ross, J. A.; Pimentel, M.; Desai, D.; Sharma, A. K.; Amin, S.; Nesnow, S.
Cancer Lett. 2007; 247, 309.
(14) (a) Krzeminski, J.; Lin, J.-M.; Amin, S.; Hecht, S. S. Chem. Res.
Toxicol. 1994, 7, 125. (b) Desai, D.; Krzeminski, J.; Lin, J.-M.; Jerina, D.;
Amin, S. Polycyclic Aromat. Compd. 1999, 13, 301. (c) Misra, B.; Amin,
S. J. Org. Chem. 1990, 55, 4478. (c) Liu, L.; Yang, B.; Katz, T. J.;
Poindexter, M. K. J. Org. Chem. 1991, 56, 3769.
(15) For recent reviews, see: (a) Hassan, J.; Sevignon, M.; Gozzi, C.;
Schulz, E.; Lamaire, M. Chem. ReV. 2002, 102, 1359. (b) Kotha, S.; Lahiri,
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2201. (e) Bellina, F.; Carpita, A.; Rossi, R. Synthesis 2004, 2419.
10.1021/jo701665j CCC: $37.00 © 2007 American Chemical Society
Published on Web 10/16/2007
J. Org. Chem. 2007, 72, 8987-8989
8987

TABLE 2. Microwave-Assisted Suzuki Cross-Coupling Reactions Using Pd EnCat 30 (Method C) or Pd(PPh3)4 (Method A) as Catalysts
a All the products (except 4a) were characterized by comparison with the published data.7-11 b See the Experimental Section.
conditions that we9-13 and others5c,6-8 have used earlier under
conventional thermal conditions. The conversion could not be
improved even after keeping the reaction for longer time at
140 °C or by using 1.5 equiv of boronic acid 2. In an attempt
to achieve better conversion in less time, we investigated the
use of Pd(OAc)2 in the presence of K2CO3 in dioxane/water
5:1 (entry 2). Under these conditions, the reaction went to about
85% conversion in 20 min at 120 °C. The TLC showed
additional spots of impurities compromising the yield of the
reaction. Next, we exploited the use of palladium-microencap-
(16) (a) The conversion percentage was determined by normal phase
HPLC monitored at 254 nm (solvent system: THF/hexanes (5:95) at 1.0
mL min-1; column: LiChrosorb Si 60 10 µm (250 × 4 mm)]. (b) The
isolated yield of this reaction after column purification was 82%.
8988 J. Org. Chem., Vol. 72, No. 23, 2007

SCHEME 1
sulated catalyst, Pd EnCat 30, in the presence of tetrabutylam-
monium acetate in ethanol.17 Using 5 mol % of Pd EnCat 30
(entry 3) with these reagents at 120 °C, the reaction showed
90% conversion in 10 min. The percentage conversion could
not be improved by enhancing the reaction time, temperature
or by using excess of boronic acid. However, using 10 mol %
of Pd EnCat 30 in the presence of tetrabutylammonium acetate
in ethanol led to up to 95% conversion in 10 min. Increasing
the reaction time to 20 min under the above conditions led to
>98% conversion (entry 4). The compound was purified by
silica gel column chromatography to yield the product in 89%
yield. The product was characterized on the basis of NMR and
MS. In all of the above cases, the workup procedures consisted
of only filtration followed by purification by silica gel column
chromatography.
To demonstrate the versatility of the Pd EnCat 30 catalyzed
Suzuki coupling among boronic acids, we performed a few
reactions with the reverse combination, i.e., the reaction of
2-bromobenzaldehyde with aryl boronic acids (Scheme 1) in
place of 2-formylphenylboronic acid (2) with aryl bromides (1)
as described above (Table 2). The reactions of naphthalene-1-
boronic acid, phenanthrene-9-boronic acid, and pyrene-1-boronic
acid10 with 2-bromobenzaldehyde using method C led to g97%
conversion and gave isolated yields of 4b, 4d, and 4f similar to
those obtained earlier (Table 2).
In conclusion, an efficient method has been developed for
the microwave-assisted Suzuki cross-coupling reaction using Pd
EnCat 30 as a catalyst. The products 4 and 5 are the key
intermediates for the syntheses of PAHs 6 and PAH-diol
epoxides 7, and these transformations have been reported
previously.7-11 These results establish for the first time the
application of microwave irradiation in the synthesis of envi-
ronmental pollutant PAHs and their ultimate carcinogens.
Once the reaction conditions were optimized, they were used
for coupling of several aryl bromides 1 with 2-formylphenyl-
boronic acid (2) and 2-formyl-5-methoxyphenylboronic acid6
(3) to obtain the key intermediates (4 and 5) for the synthesis
of DMBA (6a) B[c]P (6b), B[c]C (6c), B[g]C (6d), DB[a,l]P
(6e), DB[c,mno]C (6f) and their corresponding ultimate car-
cinogens, the diol epoxides 7a-f. The experimental details,
results, and the literature data comparison are summarized in
Table 2. The reaction conditions using Pd EnCat 30 with Bu4-
NH4OAc (method C) worked extremely well (>98% conver-
sion) for all of the substrates except for the reactions of 7-bromo-
5,6-dihydro-4H-benz[de]anthracene (1e) and 2-bromo-1,4-di-
methylnaphthalene (1a). We determined that the reactions of
1e with boronic acids 2 and 3 by method C gave only 25-30%
conversion. The conversion percentage was not improved even
after the reaction mixture was irradiated for up to 1 h at 140 °C
under these conditions. Altering the reaction conditions using
Pd EnCat 30 in the presence of K2CO3 in a mixture of toluene/
water/EtOH (4:2:1)17 did not improve the conversion percentage
significantly. In an attempt to enhance the yield, we tried the
reactions of 1e with boronic acids 2 and 3 with Pd(OAc)2 or
Pd(PPh3)4 as catalysts. The use of Pd(OAc)2 (method B) resulted
in even diminished conversion (∼10%) and more sloppy
reactions. The best results were obtained by conducting the
coupling using Pd(PPh3)4 as a catalyst in the presence of CsF
in DME (method A). Under these conditions, a satisfactory
90% conversion was achieved in about 1 h leading to about
76-80% isolated yields (Table 2, entries 9 and 10). Similarly,
the reactions of 2-bromo-1,4-dimethylnaphthalene (1a) with
boronic acids 2 and 3 worked best (∼90% conversion) when
Pd(PPh3)4 was employed as a catalyst in the presence of CsF
in DME. The coupling reactions in the presence of Pd EnCat
30 (60-70% conversion) or Pd(OAc)2 (40-50% conversion)
Experimental Section
General Method for Suzuki Cross-Coupling Reactions. Method
A. The aryl halide (0.5 mmol) and boronic acid (0.55 mmol) were
dissolved in ethylene glycol dimethyl ether (5 mL) in a microwave
vial. Pd(PPh3)4 (0.02 mmol) and cesium fluoride (1.25 mmol) were
added, and the reaction mixture was irradiated in a microwave
apparatus at 120 °C, 250 W for 1 h. After the reaction mixture
was cooled to ambient temperature, the product was filtered, the
filtrate was concentrated, and the crude mixture was purified by
silica gel column chromatography using hexane/ethyl acetate (96/
4) as eluent.
Method B. The aryl halide (0.5 mmol) and boronic acid (0.55
mmol) were dissolved in dioxane/water (5:1, 5 mL) in a microwave
vial. Palladium acetate (0.02 mmol) and potassium carbonate (1.25
mmol) were added, and the reaction mixture was irradiated in a
microwave apparatus at 120 °C, 250 W for 20 min. After the
reaction mixture was cooled to ambient temperature, the product
was purified as described in method A.
Method C. The aryl halide (0.5 mmol) and boronic acid (0.55
mmol) were dissolved in ethanol (5 mL) in a microwave vial. Pd
EnCat 30 (10 mol %) and tetrabutylammonium acetate (1.5 mmol)
were added, and the reaction mixture was irradiated in a microwave
apparatus at 120 °C, 250 W for 20 min. The product was purified
as described in method A.
1
were less efficient. All the products were characterized by H
NMR and MS and by comparison of the spectral data and
melting points with the literature values.
1
2-(2-Formylphenyl)-1,4-dimethylnaphthalene (4a): H NMR
The use of Pd EnCat 30 has led to substantial reduction in
reaction time (20 min) compared to the reported conventional
thermal conditions (up to 24 h), corresponding to up to 72-fold
rate increase. The reactions were also more expeditious and
cleaner than the other microwave conditions tried herein. The
reaction yields were better than or comparable to those reported
under thermal conditions (see Table 2). In addition to signifi-
cantly facilitating the Suzuki coupling reaction, the advantages
of Pd EnCat 30 are that it can be recycled and reused, thus
reducing the expense and palladium-related toxicity especially
at a larger scale.17
(500 MHz, CDCl3) δ 2.47 (s, 3H), 2.73 (s, 3H), 7.23 (s, 1H), 7.40
(d, J ) 7.5 Hz, 1H), 7.56 (t, J ) 7.5 Hz, 1H), 7.62-7.67 (m, 2H),
7.70 (dt, J ) 7.5 and 1.5 Hz, 1H), 8.09-8.16 (m, 3H), 9.82 (s,
1H); HRMS (EI) calcd for C19H16O 260.1187, found 260.1194.
Acknowledgment. This study was supported by NCI
Contract NO2-CB-56603 and by the Penn State Cancer Institute
of the Penn State College of Medicine.
Supporting Information Available: Copies of 1H NMR spectra
for compounds 4a, 5a, 4b, 5b, 4c, 5c, 4d, 5d, 4e, 5e, 4f, and 5f.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(17) Baxendale, I. R.; Griffiths-Jones, C. M.; Ley, S. V.; Tranmer, G.
K. Chem. Eur. J. 2006, 12, 4407 and references cited therein.
JO701665J
J. Org. Chem, Vol. 72, No. 23, 2007 8989