Microwave-assisted preparation of aryltetrazoleboronate esters

Article abstract of DOI:10.1021/ol048896q

(Chemical Equation Presented) The addition of azido trimethylsilane to arylnitrileboronate esters is shown to proceed rapidly in dimethoxyethane to give aryltetrazoleboronate esters in moderate to good yields, with dibutyltin oxide as catalyst.

Full text of DOI:10.1021/ol048896q

ORGANIC
LETTERS
2004
Vol. 6, No. 19
3265-3268
Microwave-Assisted Preparation of
Aryltetrazoleboronate Esters
Mark J. Schulz,* Steven J. Coats, and Dennis J. Hlasta
Drug DiscoVery, Johnson & Johnson Pharmaceutical Research and DeVelopment,
L.L.C., Welsh and McKean Roads, Spring House, PennsylVania 19477-0776
mschulz@prdus.jnj.com
Received June 11, 2004
ABSTRACT
The addition of azido trimethylsilane to arylnitrileboronate esters is shown to proceed rapidly in dimethoxyethane to give aryltetrazoleboronate
esters in moderate to good yields, with dibutyltin oxide as catalyst.
The growing demand for fast organic transformations within
the synthetic community has resulted in considerable atten-
tion in the area of microwave-assisted organic synthesis.1
The rapid and homogeneous heating observed in microwave-
assisted organic synthesis is a clear advantage over conven-
tional thermal techniques. The dramatic reduction in reaction
time obtained with microwave heating has recently been
coupled with automation to further improve the preparative
efficiency of this powerful technique.
The tetrazole functional group is of particular interest in
medicinal chemistry due to its potential role as a bioisostere
of the carboxyl group.2 Tetrazoles can be regarded as nitrogen
analogues of carboxylic acids. Both groups have similar steric
requirements and pKa’s, which contribute to the overall
observed bioisosterism. Generally, a more favorable phar-
macokinetic profile (i.e., increased biological absorption and
greater metabolic stability) can be obtained by the bioisosteric
replacement of carboxylic acids with tetrazoles while still
retaining the desired pharmacological effect.
Several methods3 for the preparation of tetrazoles from
nitriles have been documented in the literature. Most methods
require long reaction times measured in hours or days.
However, Alterman and Hallberg4 have reported the micro-
wave-assisted preparation of tetrazoles from nitriles, requiring
only minutes for complete conversion.
In support of our therapeutic projects, we required a fast,
efficient route to aryltetrazoleboronic acids. It is well-known,
however, that boronic acids tend to be difficult to derivatize
by solution-phase methods. Difficulties can be attributed, in
part, to their troublesome isolation and purification. As a
result, chemical transformations on arylboronic acids5 are
(3) (a) Mihina, J. S.; Herbst, R. M. J. Org. Chem. 1950, 15, 1082-
1092. (b) Finnegan, W. G.; Henry, R. A.; Lofquist, R. J. Am. Chem. Soc.
1958, 80, 3908-3911. (c) Grzonka, Z.; Liberek, B. Rocz. Chem. 1971, 45,
967-980. (d) Dunica, J. V.; Pierce, M. E.; Santella, J. B., III. J. Org. Chem.
1991, 56, 2395-2400. (e) Ostrovskii, V. A.; Poplavskii, V. S.; Koldobskii,
G. I.; Erusalinkii, G. B. Khim. Geterotsikl. Soedin. 1992, 1214-1217. (f)
Huff, B. E.; Staszak, M. A. Tetrahedron Lett. 1993, 34, 8011-8014. (g)
Wittenberger, S. J.; Donner, B. G. J. Org. Chem. 1993, 58, 4139-4141.
(h) Kumar, A.; Narayanan, R.; Shechter, H. J. Org. Chem. 1996, 61, 4462-
4465. (i) Koguro, K.; Oga, T.; Mitsui, S.; Orita, R. Synthesis 1998, 910-
914. (j) Curran, D. P.; Hadida, S.; Kim, S.-Y. Tetrahedron 1999, 55, 8997-
9006. (k) Demko, D. P.; Sharpless, K. B. J. Org. Chem. 2001, 66, 7945-
7950.
(4) Alterman, M.; Hallberg, A. J. Org. Chem. 2000, 65, 7984-7989.
(5) (a) Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 2719-2724. (b)
Chen, D.; Qing, F.; Huang, Y. Org. Lett. 2002, 4, 1003-1005. (c) Gravel,
M.; Thompson, K. A.; Zak, M.; Berube, C.; Hall, D. G. J. Org. Chem.
2002, 67, 3-15. (d) Spencer, J.; Burd, A. P.; Goodwin, C. A.; Merette, S.
A. M.; Scully, M. F.; Adatia, T.; Deadman, J. J. Tetrahedron 2002, 58,
1551-1556. (e) Holland, R.; Spencer, J.; Deadman, J. J. Synthesis 2002,
16, 2379-2382.
(1) For recent reviews, see: (a) Perreux, L.; Loupy, A. Tetrahedron 2001,
57, 9199-9223. (b) Lidstrom, P.; Tierney, J.; Wathey, B.; Westman, J.
Tetrahedron 2001, 57, 9225-9283. (c) Lew, A.; Krutzik, P. O.; Hart, M.
E.; Chamberlin, A. R. J. Comb. Chem. 2002, 4, 95-105. (d) Santagada,
V.; Perissutti, E.; Caliendo, G. Curr. Med. Chem. 2002, 9, 1251-1283. (e)
Mavandadi, F.; Lidstrom, P. Curr. Top. Med. Chem. 2004, 4, 773-792.
(2) (a) Singh, H.; Chawla, A. S. C.; Kapoor, V. K.; Paul, D.; Malhotra,
R. K. Prog. Med. Chem. 1980, 17, 151-183. (b) Hodges, J. C.; Hamby, J.
M.; Blankley, C. J. Drugs Future 1992, 17, 575-593. (c) Wittenberger, S.
J. Org. Prep. Proced. Int. 1994, 26, 499-531. (d) Herr, R. J. Bioorg. Med.
Chem. 2002, 10, 3379-3393.
10.1021/ol048896q CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/17/2004

quite limited in scope. Therefore, we deemed a contribution
in this area appropriate.
O-B-C links.6a,9 We were led to investigate this reaction
in greater detail because of our belief that formation of these
adducts would be reversible under our tetrazole-forming
reaction conditions and thus not explain the incomplete
conversion to tetrazole 2. Our model system, to this end,
involved the reaction of 4-cyanophenylboronic acid 3 with
dibutyltin oxide (Scheme 1).
Initially, we investigated the reaction of 3-cyanophenyl-
boronic acid 1 with azidotrimethylsilane in the presence of
dibutyltin oxide. Several sets of conditions were screened
under microwave heating, and the results are summarized
in Table 1. Among the conditions tested, entries 5 and 6
Scheme 1. Preparation of Dibutylaryltin Trifluoroacetate 4
Table 1. Optimization of Reaction Conditions
TMSN3
(equiv)
Bu2Sn(O)
(equiv)
T
time
convna
(%)
entry
(°C)
(min)
We quickly discovered that a one-to-one ratio of 3 to the
tin oxide was necessary for complete consumption of the
boronic acid. Although the reaction was quite clean by LC/
MS analysis, the mass spectra were not consistent with any
expected products and we were unable to isolate the purified
product of this reaction by recrystallization, silica, or Florosil
chromatography. A further complication was that the crude
1
2
3
4
5
6
1
2
2
2
2
2
0.05
2.00
0.10
0.10
0.10
0.10
110
110
110
130
150
160
10
10
10
10
10
10
25
31
55
55
60
60
a Determined by integration of an HPLC total absorption chromatogram
from 190 to 360 nm.
1
compound slowly decomposed as determined by H NMR
analysis under ambient conditions.
We were surprised to find that preparative reversed-phase
chromatography provided a clean stable compound, which
allowed us to obtain full characterization data. It was not
until we completed a single-crystal X-ray diffraction analysis
that we became confident in the structure assigned to 4
(Figure 1).
were found to be the most effective. The conversion of 1 to
3-tetrazolephenylboronic acid 2 was improved from 25%
(Table 1, entry 1) to 55% (entry 3) at 110 °C by using 2
equiv of TMSN3 and 10 mol % Bu2Sn(O). A slight
improvement was realized with increasing temperature,
resulting in 60% conversion at 150 °C (entry 5).
The inability to realize complete conversion to tetrazole
2, despite higher dibutyltin oxide loading, forced us to
consider whether the dibutyltin oxide was consumed by
reaction with the boronic acid. Consumption of dibutyltin
oxide would presumably result in the premature termination
of the catalytic cycle since it is proposed3h to be operative
in the addition of trimethylsilyl azide to nitriles. The most
obvious possible products from this reaction would be
insertion of the tin oxide into the boronic acid cyclic trimer
to form a trioxastannadiborinane6 or formation of a four
membered diorganotin borate.7
Heterocycles that contain an Sn-O-B-C bonding ar-
rangement are known,8 but their chemical behavior has not
been extensively studied. In fact, the thermally driven
reaction of dialkyltin oxides with arylboronic acids has been
shown to provide three different products, each with Sn-
Figure 1. X-ray crystal structure of 4.
(6) (a) Brown, P.; Mahon, M. F.; Molloy, K. C. J. Chem. Soc., Dalton
Trans. 1992, 24, 3503-3509. (b) For a related compound, see: Beckmann,
J.; Jurkschat, K.; Pieper, N.; Schurmann, M. Chem. Commun. 1999, 12,
1095-1096.
It appears that under the microwave conditions 3 under-
goes ipso replacement of boron by dibutyltin oxide. The
resulting tin hydroxide, of limited stability,10 is converted11
to the trifluoroacetate during reversed-phase purification. To
our knowledge, this ipso replacement of boron by tin is
unreported in the chemical literature.
(7) Tanaka, K.; Tanikawa, H.; Kitamori, N.; Kukimoto, T.; Uchiyama,
M.; Mitsuhashi, Y. EP 216295 April 1, 1987.
(8) (a) Coles, S. J.; Hibbs, D. E.; Hursthouse, M. B.; Beckett, M. A.;
Owen, P.; Varma, K. S. Acta Crystallogr., Sect. E: Struct. Rep. Online
2002, E58, m65-67. (b) Beckett, M.; Owen, P.; Varma, K. S. J. Organomet.
Chem. 1999, 588, 107-112.
3266
Org. Lett., Vol. 6, No. 19, 2004

The disordered trifluoroacetate group as well as a coor-
dinated water molecule are clearly visible from the X-ray
structure (Figure 1). The Sn-O bond lengths of 2.220 and
2.344 Å correlate well with related structures.12 In addition,
the Sn-C bond lengths range from 2.131 to 2.140 Å, which
also compares well to related compounds. The crystal
structure also implies a hydrogen-bonding network of the
water molecule to a neighboring molecules’ nitrogen atom
and another neighboring molecules’ trifluoroacetate carbonyl
oxygen.
microwave heating cycle (150 °C, 10 min) to complete the
reaction. Interestingly, the N-(trimethylsilyl)tetrazole species
that is associated with the reaction between nitriles and
alkylsilyl azide reagents was never observed; only the 1H-
tetrazole was detected, most likely due to a trace amount of
water present in the reaction.
For comparison, the reaction outlined in Scheme 2 was
also conducted under conventional thermal techniques.
Utilizing the same conditions as the microwave-assisted
reaction [i.e., 150 °C (sealed tube), 10 min, 2 cycles] we
observed similar percent conversion (90%) conventionally
as compared to the reaction when it was conducted with
microwave heating (99%). However, under refluxing condi-
tions the reaction required more than 22 h for complete
conversion. Overall, these comparisons demonstrated that
microwave heating was a more effective and convenient
method than conventional thermal techniques.
To circumvent the above-mentioned impediments, it was
clear that an alternate approach would be needed. We
envisioned that protection of the boronic acid as the pinacol
ester may help to alleviate the problem at hand. The
pinacolboronate ester was readily prepared by allowing the
boronic acid in DME to react with a slight excess of pinacol
in the presence of magnesium sulfate. Filtration of this
reaction slurry provides a solution of the boronate ester,
which could be used directly in our tetrazole formation
reactions. Indeed, when the pinacol ester 5b was subjected
to the conditions found in entry 5 of Table 1 the formation
of the tin-containing byproduct was not observed and the
percent conversion was improved to 78% (Scheme 2). After
Ten different arylnitrile boronates 5 were selected as
starting materials and utilized for the synthesis of a set of
aryltetrazole boronates. The nitrile boronates were either
commercially available or prepared from the requisite
bromide by one of the following methods: (1) metal-
halogen exchange and trapping with 2-isopropoxypinacol
borolane14 or (2) palladium-catalyzed boronation with bis-
(pinacolato)diboron.15 The crude reaction mixtures were
analyzed via HPLC with a 0.05% formic acid modifier.16
Scheme 2. Preparation of Aryltetrazole Boronatea
All of the nitrile boronates were smoothly converted to
the corresponding tetrazoles in moderate to good yields
(Table 2). However, in the case of 2-hydroxybenzonitrile,
pinacol ester 6h, it was discovered that three reaction cycles
were required for complete conversion. Although there was
no clear correlation between the aryl substituents and the
reaction outcome, the reaction did prove to tolerate a variety
of functionalities.
a Percent conversion determined by integration of an HPLC total
absorption chromatogram from 190 to 360 nm.
Product isolation was accomplished by either Florisil flash
chromatography or aqueous workup.17 Florisil chromatog-
raphy was found to be our preferred method of isolation. It
allowed the complete reaction solution to be directly loaded
further investigation, it was found that when the reaction
was subjected to a second reaction cycle greater than 99%
conversion could be obtained. In a typical experiment,13
a
(13) General Procedure. A microwave vial was charged with (3-
cyanophenyl)boronic acid, pinacol ester (344 mg, 1.5 mmol), azidotri-
methylsilane (0.40 mL, 3.0 mmol), dibutyltin oxide (37 mg, 0.15 mmol),
and DME (2.2 mL). The reaction mixture was heated to 150 °C for 10 min
in a CEM Explorer microwave. After the mixture was cooled to room
temperature, additional azidotrimethylsilane (0.40 mL, 3.0 mmol) and
dibutyltin oxide (37 mg, 0.15 mmol) were added, and the mixture was
reheated for 10 min at 150 °C. The reaction solution was loaded onto a
Florisil column (35 g) and eluted with 20% CH2Cl2/heptane f 10%
methanol/CH2Cl2 to furnish the product (3-tetrazolephenyl)boronic acid,
pinacol ester 6b (342 mg, 83%). 1H NMR (DMSO-d6): δ 8.37 (s, 1H),
8.16 (d, 1H, J ) 7.9 Hz), 7.80 (d, 1H, J ) 7.2 Hz), 7.58 (t, 1H, J ) 7.6
Hz), 1.34 (s, 12H). 13C NMR (DMSO-d6): δ 156.5, 136.1, 132.6, 129.6,
128.8, 125.6, 83.9, 24.7. HRMS: m/z (M + H)+ calcd for C13H17BN4O2
273.1523, found 273.1519.
(14) Garg, N. K.; Sarpong, R.; Stoltz, B. M. J. Am. Chem. Soc. 2002,
124, 13179-13184.
(15) Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60,
7508-7510.
(16) The use of 0.05% trifluoroacetic acid as a modifier resulted in
hydrolysis of the pinacol ester functionality, during HPLC analysis.
(17) Typical Aqueous Workup. After completion of the reaction, the
solvent was removed and the residue was taken up in ether. The ether was
extracted with 2 N NaOH, and the combined aqueous layers were washed
with ether. The aqueous layer was then acidified to pH 4, and the resulting
precipitate was collected.
mixture of 2 equiv of TMSN3 and 5b in DME was irradiated
at 150 °C for 10 min in the presence of 10 mol % Bu2Sn(O).
After the addition of an additional 2 equiv of TMSN3 and
10 mol % Bu2Sn(O), the mixture was subjected to another
(9) Chaturvedi, V.; Bhal, L.; Tandon, J. P Indian J. Chem., Sect. A 1985,
24A, 1039-1041.
(10) (a) Chambers, R. F.; Scherer, P. C. J. Am. Chem. Soc. 1926, 48,
1054-1062. (b) Ha¨nssgen, D.; Reuter, P.; Do¨llein, G. J. Organomet. Chem.
1986, 317, 159-165. (c) Blunden, S. J.; Hill, R. J. Organomet. Chem. 1987,
333, 317-321.
(11) (a) Alcock, N. W.; Roe, S. M. J. Chem. Soc., Dalton Trans. 1989,
8, 1589-1598. (b) Ali, S.; Khokhar, M. N.; Bhatti, M. H.; Mazhar, M.;
Masood, M. T.; Shahid, K.; Badshah, A. Synth. React. Inorg. Met.-Org.
Chem. 2002, 32, 1373-1392. (c) Gielen, M.; Dalil, H.; Mahieu, B.;
Biesemans, M.; Willem, R. Appl. Organomet. Chem. 1998, 12, 855-
859.
(12) (a) Srivastava, T. N.; Siddiqui, M. A.; Singh, J. D.; Srivastava, S.
Indian J. Chem., Sect. A 1987, 26A, 158-161. (b) Chee, C. F.; Lo, K. M.;
Ng, S. W. Acta Crystallogr., Sect. E: Struct. Rep. Online 2003, E59, m205-
206. (c) Chee, C. F.; Lo, K. M.; Ng, S. W. Acta Crystallogr., Sect. E:
Struct. Rep. Online 2002, E58, m661-662.
Org. Lett., Vol. 6, No. 19, 2004
3267

onto the column, thus minimizing contact to toxic tin-
containing compounds. In some cases, hydrolysis of the
pinacol ester on Florisil was observed, which resulted in
troublesome product recovery. In those cases, standard
aqueous workup conditions were employed to isolate the free
boronic acid.
Table 2. Synthesis of Aryltetrazole Boronates 6
This rapid method was easily transferred to larger scale
applications. We found that the reaction could be run at
higher concentration in a sealed 80 mL microwave vessel.
In fact, when the reaction was scaled up to 15 mmol and
conducted under identical microwave conditions the desired
product, 3-tetrazolephenylboronic acid, was isolated in nearly
quantitative yield.
To demonstrate the synthetic utility of these boronic acids
we also conducted a palladium-catalyzed Suzuki coupling
(Scheme 3). To our knowledge, previously reported cou-
Scheme 3. Suzuki Coupling of Unprotected Tetrazole
plings18 with tetrazole-containing boronic acids required
protection at the N-2 position. Apparently, in these cases
tetrazole protection was deemed necessary as the free
tetrazole acted as a poison with palladium catalysts. In our
unprotected case, however, 3-tetrazolephenylboronic acid
was coupled with 4-bromoacetanilide in the presence
of Pd(dppf)Cl2 to provide 7 in 74% unoptimized isolated
yield.
In conclusion, we have developed a convenient method
for the preparation and isolation of aryltetrazoleboronates.
As part of our study, we demonstrated that protection of the
boronic acid functionality as the pinacol ester greatly
increased preparative efficiency. Furthermore, the use of
microwave irradiation was shown to provide rapid access to
aryltetrazoleboronate derivatives.
Supporting Information Available: Experimental pro-
cedures and characterization data (1H and 13C NMR) for all
compounds, including X-ray data for compound 4. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL048896Q
(18) (a) Larsen, R. D.; King, A. O.; Chen, C. Y.; Corley, E. G.; Foster,
B. S.; Roberts, F. E.; Yang, C.; Lieberman, D. R.; Reamer, R. A.; Tschaen,
D. M.; Verhoeven, T. R.; Reider, P. J.; Lo, Y. S.; Rossano, L. T.; Brookes,
A. S.; Meloni, D.; Moore, J. R.; Arnett, J. F. J. Org. Chem. 1994, 59, 6391-
6394. (b) Yagupolskii, L. M.; Fedyuk, D. V. Tetrahedron Lett. 2000, 41,
2265-2267.
a Compounds 6a-f were isolated by Florisil flash chromatography.
Compounds 6g-k were isolated by aqueous workup as free boronic acids.
3268
Org. Lett., Vol. 6, No. 19, 2004