Direct conversion of aldehydes to amides, tetrazoles, and triazines in aqueous media by one-pot tandem reactions

Article abstract of DOI:10.1021/jo026407z

A variety of aldehydes reacted with iodine in ammonia water at room temperature to give the nitrile intermediates, which were trapped by addition of hydrogen peroxide, sodium azide, or dicyandiamide to produce their corresponding amides, tetrazoles, and 1,3,5-triazines in modest to high yields. The one-pot tandem reactions were conducted in water media, and the products were obtained simply by extraction or filtration.

Full text of DOI:10.1021/jo026407z

Dir ect Con ver sion of Ald eh yd es to Am id es,
Tetr a zoles, a n d Tr ia zin es in Aqu eou s
Med ia by On e-P ot Ta n d em Rea ction s
J iun-J ie Shie and J im-Min Fang*
Department of Chemistry, National Taiwan University,
Taipei, Taiwan 106
jmfang@ccms.ntu.edu.tw
Received September 6, 2002
5
pounds. It would be desirable that one could start with
Abstr a ct: A variety of aldehydes reacted with iodine in
ammonia water at room temperature to give the nitrile
intermediates, which were trapped by addition of hydrogen
peroxide, sodium azide, or dicyandiamide to produce their
corresponding amides, tetrazoles, and 1,3,5-triazines in
modest to high yields. The one-pot tandem reactions were
conducted in water media, and the products were obtained
simply by extraction or filtration.
the readily available aldehydes to carry out tandem
reactions, via the intermediacy of nitriles, in aqueous
media to furnish other nitrogen-containing functional
compounds of biological and material importance. In this
paper, we wish to demonstrate that this type of tandem
reaction in a one-pot procedure can provide an expedient
route to amides 3, triazoles 4, and tetrazines 5 (eqs 2-4).
The results are collected in Table 1.
When benzaldehyde (5 mmol) was treated with iodine
(5.5 mmol) in ammonia water (30 mL of 28% solution)
and THF (5 mL) at room temperature for 1 h, the dark
solution became colorless as iodine was consumed. A
practically pure product of benzonitrile (96% yield) was
In comparison with some inflammable and toxic or-
ganic solvents, water may serve as a superior solvent that
is safe to use in organic reactions. The low cost of water
1
renders the chemical processes more economical. In many
cases, water can be recycled to alleviate the problem of
solvent disposal. Furthermore, using water as a solvent
may also have advantages of simple operation and high
efficiency in many organic reactions that involve water-
2 2 3
obtained after charge with aqueous Na S O and extrac-
tion with ether.2 On the other hand, benzamide was
produced in 98% yield if the reaction mixture was
charged with aqueous H
two-step reaction sequence is mandatory to procure
amide products in high yields. If H was added together
with I to benzaldehyde in ammonia water, only a 35%
yield of benzamide was obtained. The decreased yield was
2 2
O (35% solution) for 2.5 h. The
1
soluble substrates and reagents. For example, we have
recently found a direct method for transformation of
2 2
O
aldehydes 1 to nitriles 2 by using iodine in ammonia
2
2
water (eq 1) instead of liquid ammonia or ammonia gas
6
saturated in alcohol solvents. This transformation is
completed within a short period (<1 h) at room temper-
ature. A variety of aldehydes, including aromatic, het-
erocyclic, aliphatic, conjugated, and polyhydroxy alde-
hydes, have thus been converted to their corresponding
nitriles in high yields (83-97%). This transformation
utilizes iodine as an appropriate oxidant and presumably
2 2 2
presumably due to a partial consumption of I by H O .
The presumed generation of hypoiodic acid might also
cause the side oxidations of aldehyde to other unidenti-
fied compounds.4 Benzaldehydes bearing either electron-
donating or electron-withdrawing substituents (e.g.,
4-methoxybenzaldehyde (1b) and 4-nitrobenzaldehdye
(1c)) gave the substituted benzamides (e.g., 3b and 3c)
in high yields by the similar reaction procedures. It is
known that nitrile compounds can be converted to their
corresponding amides by heating (e.g., 40-50 °C) with
alkaline hydrogen peroxide in organic solvents (e.g.,
c,f
3
,4e
proceeds with an intermediate of N-iodo aldimine (A),
which eliminates an HI molecule in ammonia solution
to afford the nitrile product. When compared to the
4
previously reported procedures that use various oxidants
7
and promoters in organic solvents, our method appears
to be simple, efficient, and environmentally benign.
Nitrile compounds are viable precursors for prepara-
tion of a variety of nitrogen-containing functional com-
acetone, ethanol, dioxane, THF, and DMSO). The hydra-
tion of nitrile is initiated by a nucleophilic addition of
-
OOH ion to the cyano group, giving an intermediate
peroxycarbaximidic acid (B), which is then reduced by
2 2
H O (or DMSO) to produce carboxamide along with
7
(
1) (a) Reichardt, C. In Solvents and Solvent Effects in Organic
Chemistry; VCH: Weinheim, Germany, 1988. (b) Li, C. J . Chem. Rev.
993, 93, 2023. (c) Li, C. J . In Organic Reactions in Aqueous Media;
Wiley: New York, 1997. (d) Lindstr o¨ m, U. M. Chem. Rev. 2002, 102,
751.
2) Talukdar, S.; Hsu, J .-L.; Chou, T.-K.; Fang, J .-M. Tetrahedron
Lett. 2001, 42, 1103.
3) Misono, A.; Osa, T.; Koda, S. Bull. Chem. Soc. J pn. 1967, 40,
875.
4) (a) Brackman, W.; Smit, P. J . Recl. Trav. Chim. 1963, 82, 757.
b) Parameswaran, K. N.; Friedman, O. M. Chem. Ind. (London) 1965,
dioxygen (or dimethyl sulfone). We have mentioned that
-
I ion was generated during the reaction of aldehyde with
1
2 3
I /aq NH to form a nitrile product. Thus, a facilitated
degradation of the peroxycarbaximidic acid intermediate,
2
(
(
(5) (a) Mowry, D. T. Chem. Rev. 1948, 42, 250. (b) Friedrich, K.;
Wallensfels, K. In The Chemistry of Cyano Group; Rappoport, Z., Ed.;
Wiley-Inter Science: New York, 1970. (c) North, M. In Comprehensive
Organic Functional Group Transformations; Katritzky, A. R., Meth-
Conn, O., Rees, C. W., Eds.; Pergamon: 1995; pp 617-618.
(6) Ball, J . M.; Hnatiw, J . B. Can. J . Chem. 2001, 79, 304.
(7) (a) Wiberg, K. B. J . Am. Chem. Soc. 1953, 75, 3961. Sawaki, Y.;
Ogata, Y. Bull. Chem. Soc. J pn. 1981, 54, 793. (b) Katritzky, A. R.;
Pilarski, B.; Urogdi, L. Synthesis 1989, 949.
2
(
(
9
8
1
88. (c) Misono, A.; Osa, T.; Koda, S. Bull. Chem. Soc. J pn. 1966, 39,
54. (d) Sato, R.; Itoh, K.; Nishina, H.; Goto, T., Saito, M. Chem. Lett.
984, 1913. (e) Okimoto, M.; Chiba, T. J . Org. Chem. 1988, 53, 218. (f)
Erman, M. B.; Snow, J . W.; Williams, M. J . Tetrahedron Lett. 2000,
1, 6749.
4
1
0.1021/jo026407z CCC: $25.00 © 2003 American Chemical Society
Published on Web 12/20/2002
1
158
J . Org. Chem. 2003, 68, 1158-1160

TABLE 1. Rea ction s of Ald eh yd es w ith Iod in e in Am m on ia Wa ter a F ollow ed by Tr ea tm en ts w ith Hyd r ogen P er oxid e,
Sod iu m Azid e, or Dicya n d ia m id e, Givin g Am id es 3, Tetr a zoles 4, a n d Tr ia zin es 5
entry
aldehydes
C6H5CHO (1a )
4-MeOC6H4CHO (1b)
4-O2NC6H4CHO (1c)
2-NCC6H4CHO (1d )
4-OHCC6H4CHO (1e)
2-furaldehyde (1f)
thiophene-2-carbaldehyde (1g)
1-methylpyrrole-2-carbaldehyde (1h )
CH3(CH2)3CHO (1i)
treatments
35% H2O2
35% H2O2
35% H2O2
35% H2O2
35% H2O2
35% H2O2
35% H2O2
conditions
product (yield, %)
1
2
3
4
5
6
7
8
9
r.t., 2.5 h
r.t., 4 h
r.t., 3 h
r.t., 2.5 h
r.t., 2.5 h
r.t., 2 h
r.t., 3.5 h
r.t., 2 h
amide 3a (98)
amide 3b (95)
amide 3c (81)
amide 3d (93)
amide 3e (95)
amide 3f (94)
amide 3g (81)
amide 3h (93)
amide 3i (91)
35% H2O2
35% H2O2
r.t., 3.5 h
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
Me3CCHO (1j)
C6H5CHO (1a )
35% H2O2
NaN3, ZnBr2
NaN3, ZnBr2
NaN3, ZnBr2
NaN3, ZnBr2
NaN3, ZnBr2
NaN3, ZnBr2
NaN3, ZnBr2
dicyandiamide, KOH
dicyandiamide, KOH
dicyandiamide, KOH
dicyandiamide, KOH
dicyandiamide, KOH
dicyandiamide, KOH
dicyandiamide, KOH
r.t., 2.5 h
amide 3j (91)
reflux, 24 h
reflux, 48 h
reflux, 17 h
reflux, 24 h
reflux, 14 h
reflux, 12 h
reflux, 48 h
reflux, 24 h
reflux, 48 h
reflux, 24 h
reflux, 24 h
reflux, 24 h
reflux, 18 h
reflux, 18 h
tetrazole 4a (81)
tetrazole 4b (72)
tetrazole 4c (89)
tetrazole 4f (79)
tetrazole 4g (87)
tetrazole 4k (82)
tetrazole 4l (84)
triazine 5a (78)
triazine 5b (56)
triazine 5c (72)
triazine 5f (80)
triazine 5g (82)
triazine 5k (80)
triazine 5l (70)
4-MeOC6H4CHO (1b)
4-O2NC6H4CHO (1c)
2-furaldehyde (1f)
thiophene-2-carbaldehyde (1g)
pyridine-2-carbaldehyde (1k )
C6H5CHdCHCHO (1l)
C6H5CHO (1a )
4-MeOC6H4CHO (1b)
4-O2NC6H4CHO (1c)
2-furaldehyde (1f)
thiophene-2-carbaldehyde (1g)
pyridine-2-carbaldehyde (1k )
C6H5CHdCHCHO (1l)
a
A small amount of THF was used as the cosolvent. The aldehydes were allowed to react with iodine in ammonia water at room
temperature for 1 h before the subsequent addition of H2O2, NaN3/ZnBr2, or dicyandiamide/KOH.
9
derived by addition of H
2
O
2
to the transient nitrile
alkylsilicon, and alkyltin azides. The formation of tet-
product in basic ammonia solution, could be achieved by
razoles is accelerated by microwave irradiation of a
mixture of NaN , nitrile, and NH Cl in DMF solution.
3 4
-
10
I
ion.
In this operation, one should take precautions on the
built-up high pressure and the sublimed ammonium
azide that may explode in dry form.9 As DMF is not a
preferable solvent for industrial use, the reaction in
b,d
1
aqueous media is more appealing. Sharpless and co-
workers have recently carried out the addition reactions
of nitrile compounds with sodium azide in water by the
promotion of zinc salts.11 The high heat capacity of water
is able to mitigate the explosion hazards on using sodium
azide.9 In our study, benzaldehyde was successfully
converted to 5-phenyltetrazole (4a ) by tandem reactions
b,d
with I
reflux. The optimal conditions applying 1.2 equiv of NaN
and 1.5 equiv of ZnBr afforded an 81% yield of tetrazole
a . ZnI was an equally efficient promoter, but ZnCl
Et NHCl, or Al(OMe) were inferior. By the similar
procedures, substituted benzaldehydes (4-methoxyben-
zaldehyde and 4-nitrobenzaldehyde) and heterocyclic
aromatic aldehydes (2-furaldehyde, thiophene-2-carbal-
dehyde, and pyridine-2-carbaldehyde) also underwent the
2 3 3 2
/aq NH at room temperature and NaN /ZnBr at
Treatments of 2-cyanobenzaldehyde sequentially with
I /aq NH and H O yielded a bisamide 3d (phthalamide),
2 3 2 2
3
2
whereas the similar treatments of terephthaldehyde
afforded a bisamide 3e (terephthamide). Heterocyclic and
aliphatic aldehdyes such as 2-furaldehyde, thiophene-2-
carbaldehyde, 1-methylpyrrole-2-carbaldehyde, valer-
aldehyde, and pivalaldehyde were also transformed into
their corresponding amides 3f-j in high yields (81-94%)
4
2
2
,
3
3
by conducting the tandem reactions with I
in a one-pot procedure.
2 3
/aq NH and
2 2
H O
(8) (a) Butler, R. N. In Comprehensive Heterocyclic Chemistry;
Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon:
Oxford, 1966; Vol. 4. (b) Singh, H.; Chawla, A. S.; Kapoor, V. K.; Paul,
D.; Malhotra, R. K. Prog. Med. Chem. 1980, 17, 151. (c) Ostrovskii, V.
A.; Pevzner, M. S.; Kofmna, T. P.; Shcherbinin, M. B.; Tselinskii, I. V.
Targets Heterocycl. Syst. 1999, 3, 467. (d) Pevzner, M. S. Adv.
Heterocycl. Chem. 1999, 75, 1. (e) Zabrocki, J .; Marshall, G. R. Methods
Mol. Med. 1999, 23, 417. (f) Zubarev, V. Y.; Ostrovskii, V. A. Chem.
Heterocycl. Compd. 2001, 36, 759.
(
9) (a) Dunica, J . V.; Pierce, M. E.; Santella, J . B., III. J . Org. Chem.
Tetrazoles play important roles in coordination chem-
1
3
991, 56, 2395. (b) Huff, B. E.; Staszak, M. A. Tetrahedron Lett. 1993,
4, 8011. (c) Wittenberger, S. J . Org. Prep. Proced. Intl. 1994, 26, 499.
(d) Koguro, K.; Oga, T.; Mitsui, S.; Orita, R. Synthesis 1998, 910. (e)
Curran, D. P.; Hadida, S.; Kim, S.-Y. Tetrahedron 1999, 55, 8997.
istry, as useful ligands, and in medicinal chemistry, as
8
stable isosteres of carboxylic acids. Tetrazoles can be
obtained by addition of azide ion to nitriles. The conven-
tional methods require either drastic reaction conditions
or use of unconventional reagents of alkylaluminum,
(
(
10) Alterman, M.; Hallberg, A. J . Org. Chem. 2000, 65, 7984.
11) (a) Demko, Z. P.; Sharpless, K. B. Org. Lett. 2001, 3, 4091. (b)
Demko, Z. P.; Sharpless, K. B. J . Org. Chem. 2001, 66, 7945.
J . Org. Chem, Vol. 68, No. 3, 2003 1159

one-pot tandem reactions with I
to give reasonable yields (72-89%) of 5-aryltetrazoles
2
/aq NH
3
and NaN
3
/ZnBr
2
The advantageous features of this method, including
simple operation, high yielding, and solvent reuse, pro-
vide an excellent opportunity for parallel synthesis and
industrial production. This method can also circumvent
the problem in prior preparation of nitrile compounds
from halides and toxic cyanides.
(
entries 12-16). Cinnamaldehyde was also converted to
the corresponding tetrazole 4l (84%) with the CdC double
bond retained.
Exp er im en ta l Section
CAUTION: It is known that iodine reacts with ammonia
water under certain conditions to give a black powder of nitrogen
1
5
triiodide monoamine (NI
3
3
‚NH ). The dry powder explodes
readily by mechanical shock, heat, or irradiation. Although we
did not have any incidents when handling the reactants in this
study, one should avoid using excess reagent.
Diamino-1,3,5-triazines are a class of compounds pos-
sessing diverse bioactivities such as anti-inflammation,
antiallergy, and protective effect against gastric lesions.12
Diaminotriazines are also applicable to material design
via assembly of the multiple hydrogen-bonded com-
plexes.13 Among a number of synthetic methods for 2,4-
diaminotriazines, the most convenient approach utilizes
the addition reactions of nitrile compounds with dicyan-
diamide (also called cyanoguanidine). The reaction is
catalyzed by base. In our present study, benzonitrile
resulted in situ from the reaction of benzaldehyde with
Rep r esen ta tive P r oced u r e for Tr a n sfor m a tion of Ald e-
h yd es in to Am id es. A solution of appropriate aldehyde (1a -j,
5
mmol) and iodine (5.5 mmol) in ammonia water (30 mL of 28%
solution) and THF (5 mL) was stirred at room temperature for
h. The dark solution became colorless at the end of reaction.
Aqueous H (3 mL of 35% solution) was then added dropwise.
1
2
O
2
1
4
The reaction mixture was stirred for 2-4 h and extracted with
CH Cl . The organic phase was washed with brine, dried (Na -
2
2
2
SO
4
), and concentrated in vacuo. The residue was rinsed with
hexane/EtOAc (1:3) to give a pure amide product (3a -j, 81-
9
8% yields). Amides 3a -j are characterized by their physical
and spectral properties that are consistent with known com-
pounds (see Supporting Information).
2 3
I /aq NH was treated with dicyandiamide (1.1 equiv) and
KOH (2.2 equiv) at refluxing temperature for 24 h to
afford 2,6-diamino-4-phenyl-1,3,5-triazine (5a ) in 78%
yield. A control reaction of benzonitrile with dicyandi-
Rep r esen ta tive P r oced u r e for Tr a n sfor m a tion of Ald e-
h yd es in to Tetr a zoles. CAUTION: Although a study has
shown this protocol only releases a minute amount of hydrazoic
1
1
3
acid (HN ), one should still avoid using excess amounts or high
amine (1.1 equiv) and KOH (2.2 equiv) in aq NH
3
/THF
concentrations of sodium azide in the following procedure.
A solution of appropriate aldehyde (1 mmol) and iodine (1.1
mmol) in ammonia water (9 mL of 28% solution) and THF (1
mL) was stirred at room temperature for 1 h. The dark solution
3
(9:1) yielded 82% of 5a . Without ammonia, the reaction
of benzonitrile (1.1 equiv) and KOH (2.2 equiv) in
aqueous THF at refluxing temperature for 24 h gave 5a
in 69% yield. Using a smaller amount of KOH (1.1 equiv)
decreased the yield of 5a (64%). Omission of KOH gave
an even lower yield of 5a (42%) after refluxing for a
prolonged period (48 h). It appeared that our current one-
pot tandem reaction in ammonia water was the method
of choice for the direct conversion of aldehyde to triazines.
Thus, a series of 2,4-diaminotriazines were synthesized
by the one-pot tandem reactions using appropriate alde-
hydes as the starting materials (entries 18-24).
became colorless at the end of reaction. A mixture of NaN (1.2
2
mmol) and ZnBr (1.5 mmol) was then added. The reaction
mixture was heated at reflux for 12-48 h with vigorous stirring.
HCl (10 mL of 1 M solution) and EtOAc (50 mL) were added,
and vigorous stirring was continued until no solid was present
and the aqueous layer had a pH of 1. The organic phase was
concentrated in vacuo, and the remaining solids were rinsed with
EtOAc (20 mL) to give a pure tetrazole product (4a -c, f, g, k , l,
72-89% yields). These 5-substituted tetrazoles are characterized
by their physical and spectral properties that are consistent with
known compounds (see Supporting Information).
Rep r esen ta tive P r oced u r e for Tr a n sfor m a tion of Ald e-
h yd es in to Tr ia zin es. A solution of appropriate aldehyde (1
mmol) and iodine (1.1 mmol) in ammonia water (9 mL of 28%
solution) and THF (1 mL) was stirred at room temperature for
1 h. The dark solution became colorless at the end of the reaction.
A mixture of dicyandiamide (1.1 mmol) and KOH (2.2 mmol)
was then added. The reaction mixture was heated at reflux for
In summary, we have explored a new methodology
using one-pot tandem reactions for the direct conversion
of aldehydes to amides, tetrazoles, and triazines, via
2 2 3
addition of H O , NaN /ZnBr2, and dicyandiamide/KOH
to the intermediate nitriles. These reactions are con-
ducted smoothly in aqueous media, and the desired
products are obtained simply by extraction or filtration.
1
2-48 h. The suspended solid products were filtered and rinsed
with Et O to give a pure diaminotriazine (5a -c, f, g, k , l, 56-
2% yields). These 6-substituted 2,4-diamino-1,3,5-triazines are
2
(12) (a) Hasegawa, Y.; Yanagisawa, T.; Okui, Y.; Sato, T.; Hosaka,
8
K.; Chin, M.; Mitsuhashi, H. Chem. Pharm. Bull. 1991, 39, 3180. (b)
Brzozowski, Z.; Saczewski, F.; Gdaniec, M. Eur. J . Med. Chem. 2000,
characterized by their physical and spectral properties that are
consistent with known compounds (see Supporting Information).
3
5, 1053. (c) J ensen, N. P.; Ager, A. L.; Bliss, R. A.; Canfield, C. J .;
Kotecka, B. M.; Rieckmann, K. H.; Terpinski, J .; J acobus, D. P. J . Med.
Chem. 2001, 44, 3925.
Ack n ow led gm en t. We thank the National Science
Council for financial support.
(13) (a) Beijer, F. H.; Sijbesma, R. P.; Vekemans, J . A. J . M.; Meijer,
E. W.; Kooijman, H.; Spek, A. L. J . Org. Chem. 1996, 61, 6371. (b)
Deans, R.; Rotello, V. M. J . Org. Chem. 1997, 62, 4528. (c) Balogh, D.
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Oliveira, O. N., J r.; Meijer, E. W.; J anssen, R. A. J . Langmuir 2001,
Su p p or tin g In for m a tion Ava ila ble: Physical and spec-
tral data and pertinent references for amides 3, tetrazoles 4,
and triazines 5. These materials are available free of charge
via the Internet at http://pubs.acs.org.
1
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14) (a) Smolin, E. M.; Rapoport, I. In The Chemistry of Heterocyclic
(
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(
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