furnish the desired tetrazole products 4a, 7c, and 7d in 80%,
7%, and 82% yields, respectively. The direct conversion of
the tryptophan-derived primary alcohol 8e was similarly per-
formed, albeit by using a larger quantity of NaN3 (18 equiv)
and ZnBr2 (9 equiv) for a longer period (45 min), to obtain a
did not encounter any incidents in this study, one should avoid
using excess reagents or high concentrations of iodine-ammonia
water and sodium azide in the following procedures.
7
General Procedure for Direct Conversion of Aldehydes to
Triazines Using Microwave Irradiation. A solution of aromatic
aldehyde (1a-e, 1 mmol) and iodine (1.1 mmol) in ammonia water
7
0% yield of the tryptophan tetrazole 7e with concomitant
(9 mL of 28% solution) and THF (1 mL) was placed in a round-
removal of the Boc group. The cycloaddition of the tryptophan
nitrile generated from 8e was more sluggish presumably as a
result of its low solubility in the reaction conditions. The
R-aminotetrazoles 7a-e prepared as such showed only minimal
racemerization (3.5-6%) during the microwave-assisted one-
pot tandem reactions according to the HPLC analyses on a chiral
column (see Supporting Information).
bottomed flask equipped with a condenser. The dark solution was
stirred for 1 h at room temperature and became colorless at the
end of the reaction. After addition of dicyandiamide (1.1 mmol),
the mixture was irradiated in a single mode microwave reactor (100
W power) at approximately 80 °C (as indication of the reactor’s
temperature setting) for 15-30 min. The reaction mixture was
2
cooled; the precipitates were filtered and rinsed with Et O to give
the desired pure product 6-aryl-2,4-diamino-1,3,5-triazine (3a-e)
in 69-83% yields (Table 1). The physical and spectroscopic
properties of 3a-e were in agreement with those data previously
reported (see Supporting Information).
General Procedure for Direct Conversion of Aldehydes to
Tetrazoles Using Microwave Irradiation. A solution of R-ami-
noaldehyde (5a, 1 mmol) and iodine (1.1 mmol) in ammonia water
We have demonstrated an expedient microwave-assisted
method for the direct transformation of primary alcohols and
aldehydes into triazines and tetrazoles in aqueous media. The
alcohols and aldehydes reacted with iodine in ammonia water
to provide the corresponding nitrile intermediates (e.g., 2a-e,
6
a-c, and 6f), which readily underwent [2 + 3] cycloadditions
with dicyandiamide and sodium azide on exposure to microwave
irradiation to give the corresponding 4-aryl-2,6-diamino-1,3,5-
triazines (3a-e), 5-aryl-1,2,3,4-tetrazoles (4a-e), N-Cbz-R-
aminotetrazoles (7a-c), and dipeptidyl tetrazole (7f) in a one-
pot operation. This method circumvents the problem in prior
preparation of nitrile compounds from halides and toxic
cyanides. The one-pot tandem reactions were conducted in
aqueous media, and the products (triazines and tetrazoles) were
obtained simply by extraction or filtration. In comparison with
the previously reported heating methods, microwave irradiation
has an advantage in the acceleration of reactions. No caustic
KOH was required in the microwave-accelerated synthesis of
triazines.
(
8 mL of 28% solution) and THF (2 mL) was stirred at room
temperature for 1-2 h. The dark solution became colorless at the
end of reaction. NaN (4 mmol) and ZnBr (2 mmol) were then
3
2
added sequentially. The reaction mixture was exposed to microwave
irradiation (80 W) at 80 °C for 30 min. The reaction mixture was
cooled, aqueous HCl (1 M solution) and EtOAc were added, and
the mixture was vigorously stirred until no solid was present. The
organic layer was separated, and the aqueous layer was extracted
with EtOAc (2×). The combined organic layers were dried over
4
MgSO , filtered, and concentrated under reduced pressure. The
desired (S)-N-Cbz-R-aminotetrazole 7a was obtained in 88% yield
by crystallization from EtOAc/Et O solution.
Conversion of aldehydes 1a-e, 5b, 5c, and 5f to the corre-
sponding tetrazoles 4a-e, 7b, 7c, and 7f using microwave
irradiation was carried out by the procedure described for 7a. The
2
The optically active R-aminotetrazoles, e.g., 7c derivative of
L-proline, have been employed as versatile chiral catalysts in
physical and spectroscopic properties of tetrazoles 4a-e and 7a-c
1
6
were in agreement with the previously reported data.5,14
organic reactions. Because the tetrazole products have a
striking structural resemblance to their triazole analogues, our
method for an easy access to optically active R-aminotetrazoles
in aqueous media may have a growing impact on drug discovery
similar to that demonstrated by the click chemistry of alkynes
with azides.17
General Procedure for Direct Conversion of R-Amino Alco-
hols to R-Aminotetrazoles Using Microwave Irradiation. A
solution of (S)-(benzyloxycarbonyl)prolinol 8c (3 mmol) and iodine
(
(
12 mmol) in ammonia water (12 mL of 28% solution) and THF
3 mL) was placed in a round-bottomed flask equipped with a
condenser. The mixture was stirred for 5 min at room temperature
and exposed to microwave irradiation in a single mode microwave
reactor (100 W) at 60 °C (as indication of the reactor’s temperature
setting) for 15-30 min. The mixture was cooled to room temper-
Experimental Section
CAUTION: Iodine may react with ammonia water under certain
3 2
ature, NaN (12 mmol) and ZnBr (6 mmol) were added sequen-
conditions to give the explosive powder nitrogen triiodide monoam-
tially, and the mixture was again subjected to microwave irradiation
at 80 °C for 30 min. The reaction mixture was cooled, aqueous
HCl (1 M solution) and EtOAc were added, and the mixture was
vigorously stirred until no solid was present. The organic layer was
separated, and the aqueous layer was extracted with EtOAc (2×).
18
ine (NI
3
‚NH
3
), and the reaction of sodium azide may release a
). Although we
minute amount of hazardous hydrazoic acid (HN
3
(
16) Hartikka, A.; Arvidsson, P. I. Tetrahedron: Asymmetry 2004, 15,
831-1834.
17) (a) Kolb, H. C.; Sharpless, K. B. Drug DiscoVery Today 2003, 8,
1
1
4
The combined organic layers were dried over MgSO , filtered,
(
concentrated, and chromatographed on a silica gel column to give
the desired (S)-tetrazole product 7c (77% yield, 93% ee).
128-1137. (b) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem.,
Int. Ed. 2001, 40, 2004-2021. (c) Prescher, J. A.; Bertozzi, C. R. Nat.
Chem. Biol. 2005, 1, 13-21. (d) Van Swieten, P. F.; Leeuwenburgh,
M. A.; Kessler, B. M.; Overkleeft, H. S. Org. Biomol. Chem. 2005, 3, 20-
Conversion of benzyl alcohol (8a) and the tyrosine- and
tryptophan-derived primary alcohols 8d and 8e using microwave
irradiation was carried out by the procedure described for 8c, giving
the tetrazoles 4a (80% yield), 7d (82% yield, 92% ee), and 7e (70%
yield, 88% ee), respectively. The physical and spectroscopic
properties of 7c and 7e are listed in Supporting Information.
HPLC Analysis. The enantiomeric purity of tetrazoles 7a-e was
determined by HPLC analysis on a Chiralcel OD-H column (0.46
cm i.d. × 25 cm) at 30 °C. The tetrazole sample (5.0 mg/mL in
2
7. (e) Lewis, W. G.; Green, L. G.; Grynszpan, F.; Radic, Z.; Carlier,
P. R.; Taylor, P.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed.
002, 41, 1053-1057. (f) Lee, L. V.; Mitchell, M. L.; Huang, S.-J.; Fokin,
V. V.; Sharpless, K. B.; Wong, C.-H. J. Am. Chem. Soc. 2003, 125, 9588-
589. (g) Krasinski, A.; Radic, Z.; Manetsch, R.; Raushel, J.; Taylor, P.;
Sharpless, K. B.; Kolb, H. C. J. Am. Chem. Soc. 2005, 127, 6686-6692.
h) Whiting, M.; Muldoon, J.; Lin, Y.-C.; Silverman, S. M.; Lindstrom,
2
9
(
W.; Olson, A. J.; Kolb, H. C.; Finn, M. G.; Sharpless, K. B.; Elder, J. H.;
Fokin, V. V. Angew. Chem., Int. Ed. 2006, 45, 1435-1439.
2
-propanol) was prepared, and 20 µL was loaded for each analysis.
(
18) (a) Southwick, P. L.; Christman, D. R. J. Am. Chem. Soc. 1952,
7
4, 1886-1891. (b) Roesky, H. W.; M o¨ ckel, K. In Chemical Curiosities;
VCH: Weinheim, Germany 1996; pp 292-293.
The mobile phase of hexane/2-propanol (85:15, v/v) with a flow
rate of 0.5 mL/min was applied, and the signals of the sample were
J. Org. Chem, Vol. 72, No. 8, 2007 3143