Synthesis of 1,2,4-triazolines: Base-catalyzed hydrazination/cyclization cascade of α-isocyano esters and amides

Article abstract of DOI:10.1021/ol102812c

A convenient, efficient synthesis of 1,2,4-triazolines from α-isocyano esters/amides and azodicarboxylates is presented. The developed reaction cascade is based on a base-catalyzed hydrazination-type reaction followed by a subsequent cyclization providing

Full text of DOI:10.1021/ol102812c

ORGANIC
LETTERS
2011
Vol. 13, No. 2
328-331
Synthesis of 1,2,4-Triazolines:
Base-Catalyzed Hydrazination/
Cyclization Cascade of r-Isocyano
Esters and Amides
David Monge, Kim L. Jensen, Irene Mar´ın, and Karl Anker Jørgensen*
Center for Catalysis, Aarhus UniVersity, 8000 Aarhus C, Denmark
kaj@chem.au.dk
Received November 19, 2010
ABSTRACT
A convenient, efficient synthesis of 1,2,4-triazolines from r-isocyano esters/amides and azodicarboxylates is presented. The developed reaction
cascade is based on a base-catalyzed hydrazination-type reaction followed by a subsequent cyclization providing the triazolines in good to
excellent yields (75-99%). Phosphine-catalyzed and preliminary asymmetric phase-transfer catalysis approaches have also been investigated.
Nitrogen-containing heterocycles are of great importance in
the pharmaceutical industry since they often exhibit interest-
ing biological activities. The 1,2,4-triazole moiety constitutes
the key structure of a wide range of compounds that have
antiviral, anticancer, anti-inflammatory, and anticonvulsant
properties.1 Surprisingly, the saturated 1,2,4-triazolines be-
long to an underutilized class of heterocycles, whose potential
biological properties remain largely unexplored. Recently,
a convenient method for the synthesis of 1,2,4-triazolines
using oxazolones and azodicarboxylates was described by
Tepe et al.2 The products accessed by this approach feature
a quaternary C3 carbon atom containing a carboxylic acid
functional group and an aryl/alkyl substituted C5 carbon atom
(Figure 1, left). Other syntheses of related 1,2,4-triazole
derivatives utilize oxazoles,3 imidazopyridines,4 or N-[(tri-
methylsilyl)methyl] iminium triflates.5 Herein, we present
an alternative synthesis from readily available R-isocyano
Figure 1. Analysis of 1,2,4-triazoline structures accessed by
different nucleophiles.
esters/amides 1 and azodicarboxylates 2 leading to 1,2,4-
triazolines 3 bearing a quaternary C3 carbon atom containing
(1) (a) Todoulou, O. G.; Papadaki-Valiraki, A. E.; Ikeda, S.; De Clercq,
E. Eur. J. Med. Chem. 1994, 29, 611. (b) Bekircan, O.; Kahveci, B.; Kucuk,
M. Turk. J. Chem. 2006, 30, 29. (c) Tandon, M.; Barthwal, J. P.; Bahalla,
T. N.; Bhargava, K. P. Indian J. Chem. 1981, 20B, 1017. (d) Gulerman,
N.; Rollas, S.; Kiraz, M.; Ekinci, A. C.; Vidin, A. Farmaco 1997, 52, 691.
(2) Saleem, R. S. Z.; Tepe, J. J. J. Org. Chem. 2010, 75, 4330.
(3) (a) Ibata, T.; Isogami, Y.; Tamura, H. Chem. Lett. 1988, 1551. (b)
Hassner, A.; Fischer, B. Tetrahedron 1989, 45, 3535. (c) Shi, X.; Ibata, T.;
Suga, H.; Matsumoto, K. Bull. Chem. Soc. Jpn. 1992, 65, 3315. (d) Ibata,
T.; Suga, H.; Isogami, Y.; Tamura, H.; Shi, X. Bull. Chem. Soc. Jpn. 1992,
65, 2998.
(4) Anderson, D. J.; Watt, W. J. Heterocycl. Chem. 1995, 32, 1525.
10.1021/ol102812c  2011 American Chemical Society
Published on Web 12/17/2010

an ester or amide functional group and a hydrogen substituent
at C5 (Figure 1, right).
Table 1. Scope of the Synthesis of 1,2,4-Triazolines 3 from
The unique properties of the isocyano group, which may
function as both electrophile and nucleophile, have turned
these compounds into indispensable reagents for organic
synthesis.6 Beyond the classical multicomponent Ugi and
Passerini reactions,7 the most important applications of
isocyanides are in the synthesis of various heterocycles.8 In
particular, isocyano esters/amides have been employed as
key building blocks for the syntheses of 1,3-azoles, azolines,
pyrroles, pyrrolines, 1,2,4-triazoles, 2-imidazolidinones, 5,6-
dihydro-4H-1,3-oxazines, and thiazines.9 To the best of our
knowledge, the reaction of R-isocyano ester derivatives with
azodicarboxylates giving access to 1,2,4-triazolines has not
been described to date.
Initially, we examined the base-catalyzed reaction employ-
ing isocyano esters (1a, R1 ) Ph; 1b, R1 ) Bn), prepared
from amino acids by formylation/dehydration protocols,10
and commercially available di-tert-butyl azodicarboxylate
(DTBAD) (see Supporting Information). Preliminary results
showed organic bases such as Et3N11 for 1a or 1,8-
diazabicycloundec-7-ene (DBU)11 for 1b as the most prom-
ising catalysts providing the 1,2,4-triazolines 3 in excellent
yields in CH3CN at room temperature. The generality of this
novel transformation was studied for a series of isocyano
esters 1 and azodicarboxylates 2 [diethyl azodicarboxylate
(DEAD, 2a), diisopropyl azodicarboxylate (DIAD, 2b),
DTBAD 2c, and dibenzyl azodicarboxylate (DBAD, 2d)]
using 10 mol % of base in CH3CN (0.2 M) at room
temperature (Table 1). Employing aryl/alkyl (R1 ) Ph, Bn,
CH2CH2Ph, i-Pr, i-Bu) substituted isocyano esters (R2 )
OMe, OBn, Ot-Bu) showed that the outcome of the reaction
is relatively independent of substituents and the 1,2,4-
triazolines 3a-n were obtained in excellent yields
(87-99%).
Isocyano Estersa
entry
R1
R2
1
R3
base
yield (%)b
1
2
3
4
5
6
7
8
Ph
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
OMe
OMe
OMe
OBn
OBn
1a
1b
1b
1c
1c
t-Bu Et3N
3a: 99
3b: 98
3c: 99
3d: 93
3e: 99
3f: 95
3g: 94
3h: 92
3i: 87
3j: 93
3k: 99
3l: 95
3m: 93
3n: 92
Et DBU
t-Bu DBU
Et DBU
t-Bu DBU
Ot-Bu 1d Et
Ot-Bu 1d i-Pr
Ot-Bu 1d t-Bu DBU
DBU
DBU
9
Ot-Bu 1d Bn
DBU
t-Bu DBU
t-Bu DBU
t-Bu DBU
10
11
12
13
14
CH2CH2Ph Ot-Bu 1e
i-Pr
i-Bu
i-Bu
i-Bu
Ot-Bu 1f
OBn 1g
Ot-Bu 1h i-Pr
DBU
Ot-Bu 1h t-Bu DBU
a Reactions performed at 0.25 mmol scale of 1 in CH3CN (0.2 M).
Reation time typically 18 h (see Supporting Information). b Isolated by flash
chromatography.
The importance of amide bonds in biologically active
molecules14 and the interest for improved understanding
of bioactive conformations have stimulated the synthesis
of new constrained peptidomimetics based on heterocyclic
motives.15 Therefore, the protocol was expanded to include
isocyano amides, prepared by aminolysis/alkylation pro-
tocols.16
The acidity of isocyano amides differ considerably from
their ester analogues, and their reactivity profile (isocyano
group vs R-carbanion) is often governed by steric con-
strains, reaction conditions, and the combination of sub-
strates.17
To further demonstrate the efficiency of the developed
methodology, reactions were performed on a 2 mmol scale,
as exemplified by the synthesis of 3e (99%), 3f (99%), and
3g (96%) in excellent yields.
Competition experiments12 revealed that DBAD is the
most reactive azodicarboxylate counterpart in the present
reaction conditions, which is in accordance with recent
investigations by Mayr on the electrophilicities of azodicar-
boxylates (Bn > Et > i-Pr > t-Bu).13
To our delight, preliminary studies using 1i (R1 ) Ph, R2
) morpholinyl) and 1j (R1 ) Bn, R2 ) morpholinyl) with
DTBAD employing the optimized conditions for isocyano
esters (10 mol % of DBU in CH3CN) afforded the 1,2,4-
triazolines (3o, 3r) in excellent yields, 99% and 98%,
respectively, at room temperature (see Supporting Informa-
tion). Interestingly, when Et3N was used in combination with
1i, an inseparable mixture of products was obtained. The
scope of the reaction was then evaluated for a series of
isocyano amides 1 and azodicarboxylates 2 (Table 2). By
(5) Tsuge, O.; Hatta, T.; Tashiro, H.; Maeda, H. Heterocycles 2001,
55, 243.
(6) For a general review, see: (a) Suginome, M.; Ito, Y. In Science of
Synthesis, Vol. 19; Murahashi, S.-I., Ed.; Thieme: Stuttgart, 2004; p 445.
(7) For general reviews on multicomponent reactions, see: (a) Do¨mling,
A. Chem. ReV. 2006, 106, 17. (b) Do¨mling, A.; Ugi, I. Angew. Chem., Int.
Ed. 2000, 39, 3168.
(8) For a recent review, see: Lygin, A. V.; Meiere, A. D. Angew. Chem.,
Int. Ed. 2010, 49, 9094.
(14) For example, see: MacMillan, K. S.; Boger, D. L. J. Med. Chem.
2009, 52, 5771.
(9) For a general review, see: Gulevich, A. V.; Zhdanko, A. G.; Orru,
R. V. A.; Nenajdenko, V. G. Chem. ReV. 2010, 110, 5235.
(10) Hong, R. S.; Bouma, M. J.; Schmitz, R. F.; Kanter, F.; Lutz, M.;
Spek, A. L.; Orru, R. Org. Lett. 2003, 5, 3759.
(15) For example, see: Petit, S.; Fruit, C.; Bischoff, L. Org. Lett. 2010,
12, 4928.
(16) Housseman, C.; Zhu, J. Synlett 2006, 11, 1777.
(17) For examples on multicomponent reactions giving access to different
heterocycles, see: (a) Elders, N.; Ruijter, E.; Kanter, F. J. J. D.; Groen,
M. B.; Orru, R. V. A. Chem.sEur. J. 2009, 15, 6096. (b) Elders, N.; Ruijter,
E.; Kanter, F. J. J. D.; Janssen, E.; Lutz, M.; Spek, A. L.; Orru, R. V. A.
Chem.sEur. J. 2009, 15, 6096. (c) Mossetti, R.; Pirali, T.; Tron, G. C.;
Zhu, J. Org. Lett. 2010, 12, 820.
(11) Rodima, T.; Kaljurand, I.; Pihl, A.; Ma¨emets, V.; Leito, I.; Koppel,
I. A. J. Org. Chem. 2002, 67, 1873. pKBH+ in CH3CN: Et3N (18.8), DBU
(24.2), TBD (26.0).
(12) 1d (R1 ) Bn, R2 ) Ot-Bu) + DBAD (1.2 equiv) + DTBAD (1.2
equiv) f 3i (major, > 90%).
(13) Kanzian, T.; Mayr, H. Chem.sEur. J. 2010, 16, 11670.
Org. Lett., Vol. 13, No. 2, 2011
329

Table 2. Scope of the Synthesis of 1,2,4-Triazolines 3 from
Scheme 1. Proposed Mechanism
Isocyano Amidesa
entry
R1
R2
1
R3
base yield (%)b
1
2
3
4
5
6
7
8
9
Ph
Bn
Bn
Bn
Bn
i-Bu
H
Bn
morpholinyl 1i
morpholinyl 1j
morpholinyl 1j
morpholinyl 1j
morpholinyl 1j
t-Bu DBU
Et DBU
3o: 99
3p: 89
3q: 94
3r: 98
nr
3s: 75
3t: 79
3u: 90
3v: 93
nr
by this study, we decided to explore an alternative PPh3-
promoted reaction.20 To our delight, using stoichiometric or
substoichiometric amounts of PPh3 (30-100 mol %), the
model reaction between isocyano esters 1 and azodicarboxy-
lates 2 proceed very rapidly affording 60-80% conversions
after a few minutes.21 Finally, performing the reaction with
20 mol % of PPh3 at 80 °C afforded full conversions in 3-18
h. As outlined in Table 3, the isolated yields were lower
i-Pr DBU
t-Bu DBU
Bn
TBDc
morpholinyl 1k t-Bu DBUd
pyrrolidinyl 1l t-Bu DBU
pyrrolidinyl 1m t-Bu TBDc
p-BrC6H4 pyrrolidinyl 1n t-Bu TBDc
i-Bu
10
pyrrolidinyl 1o t-Bu TBDc
a Reactions performed at 0.25 mmol scale of 1 in CH3CN (0.2 M).
Reation time typically 18 h (see Supporting Information). b Isolated by flash
chromatography. c Reaction perfomed with 20 mol % of TBD. d Reaction
perfomed with 20 mol % of DBU.
Table 3. Phosphine-Catalyzed Examplesa
employing DEAD, DIAD, and DTBAD, the corresponding
1,2,4-triazolines 3o-r were obtained in excellent yields
(89-99%, entries 1-4). However, the more electrophilic
DBAD remained unreactive toward the nucleophilic addition
of 1j, even when employing 20 mol % of 1,5,7-
triazabicyclo(4.4.0)dec-5-ene (TBD)11 (entry 5), suggesting
that the initial quatenary CsN bond formation may be
strongly hindered by steric bulk around the isocyano aceta-
mide and azodicarboxylate NdN bond. When the benzyl
group was exchanged for a branched isobutyl chain, 20 mol
% of DBU were required and product 3s was obtained in
75% yield (entry 6). Pyrrolidinyl amides were also investi-
gated, and product 3t with a hydrogen substituent was
obtained in 79% yield (entry 7). When employing R-sub-
stituted pyrrolidinyl amides slightly modified reaction condi-
tions [TBD (20 mol %), azodicarboxylate (2 equiv) in
CH3CN (0.3 M)] were required. Benzyl substituted pyrro-
lidine derivatives 1m,n afforded the 1,2,4-triazolines 3u,v
in 90 and 93% yield, respectively (entries 8,9). Attempts to
incorporate a branched isobutyl chain (1o) were unsuccessful
(entry 10).
The reaction is believed to involve a base-catalyzed
hydrazination via nucleophilic attack of deprotonated iso-
cyanide 1 to the azodicarboxylate 2, followed by a 5-endo-
dig ring closure of intermediate A to give the 1,2,4-triazoline
3 as outlined in Scheme 1. However, a concerted [2 +
3]-cycloaddition of base-activated 1 with the azodicarboxy-
late 2, followed by protonation of the resulting anion at C5,
cannot be excluded.
Kolasa and Miller have reported the synthesis of few
triazolines from N-acyl glycine esters utilizing Mitsunobu
reaction conditions PPh3/DIAD.18 The mechanism may
involve the Huisgen zwitterion19 acting as a base for the
initial abstraction of the relatively acidic R-proton. Inspired
entry
R1
R2
Ot-Bu
Ot-Bu
OMe
morpholinyl
morpholinyl
1
R3
Et
Bn
Bn
t-Bu
Bn
yield (%)b
1
Bn
Bn
Bn
Bn
Bn
1d
1d
1b
1j
3f: 73
3i: 80
3w: 91
3r: 70d
nr
2
3c
4
5
1j
a Reactions performed at 0.25 mmol scale of 1 in CH3CN (0.2 M).
Reation time typically 18 h (see Supporting Information). b Isolated by flash
chromatography. c Reaction performed with 10 mol % of PPh3. d Isolated
as a mixture with isocyano amide 1j.
than those obtained using base-catalyzed conditions (73-91%,
entries 1-3). As in the base-catalyzed system, the reactivity
profile of 1 seems to correlate with the R-acidity.22 Moreover,
the addition of isocyano amide 1j to DTBAD was slower
and did not reach full conversion (entry 4, Table 2 vs Table
3).
It is believed that the PPh3-catalyzed reaction may involve
Huisgen zwitterions as catalytic species,23 as observed by
(18) Kolasa, T.; Miller, M. J. Tetrahedron Lett. 1988, 29, 4661.
(19) Reviews on zwitterions in C-C and C-N bond-forming reactions:
(a) Nair, V.; Menon, R. S.; Sreekanth, A. R.; Abhilash, N.; Biju, A. T.
Acc. Chem. Res. 2006, 39, 520. (b) Nair, V.; Biju, A. T.; Mathew, S. C.;
Babu, B. P. Chem.sAsian J. 2008, 3, 810.
(20) Review on nucleophile phosphine organocatalysis: Methot, J. L.;
Roush, W. R. AdV. Synth. Catal. 2004, 346, 1035.
(21) The reactions do not reach full conversions.
(22) Isocyano esters are more reactive than isocyano amides. For
examples, see: (a) Janvier, P.; Sun, X.; Bienayme´, H.; Zhu, J. J. Am. Chem.
Soc. 2002, 124, 2560. (b) Bonne, D.; Dekhane, M.; Zhu, J. Angew. Chem.,
Int. Ed. 2007, 46, 2485.
330
Org. Lett., Vol. 13, No. 2, 2011

1H NMR and 31P NMR spectroscopy (see Supporting
Information), although the exact role of these species in the
present system is not known.24
To highlight the synthetic potential of the 1,2,4-triazolines
3, their mono-deprotection into 4 is presented in Scheme 2.
triazolines 3. By employing phase-transfer conditions (K3PO4-
toluene) and a catalyst derived from cinchonine, triazolines
3c,e,h were obtained in excellent yields (>95%) and moderate
enantioselectivities (up to 60% ee for 3h) as shown in
Scheme 3.
Scheme 2. Mono-deprotection of 1,2,4-Triazolines 3
Scheme 3. Synthesis of Optically Enriched 1,2,4-Triazolines 3
Using Asymmetric Phase-Transfer Catalysis
In conclusion, we have developed a new base-catalyzed
hydrazination/cyclization cascade reaction of readily avail-
able isocyano esters/amides and azodicarboxylates for the
synthesis of novel 1,2,4-triazolines bearing a quaternary C3
stereogenic center containing an ester or amide functional
group. The synthetic procedure proved to be general,
operationally simple, and high-yielding. We have also
demonstrated an alternative PPh3-catalyzed approach, which
may expand the perspectives for developing new reactions
using the combination of phosphines-azodicarboxylates.
Finally, preliminary studies of the asymmetric synthesis of
3 using phase-transfer catalysis were described.
a Yield based on recovered starting material. b For X-ray crystal structure
of compound 5a (C gray, H white, O red, N blue, S yellow).
Performing the reaction with NaOEt (3 equiv) in a EtOH/
CHCl3 (2:1) mixture25 at 50 °C afforded the mono-depro-
tected heterocycles 4a and 4b in 70 and 60% yield,
respectively.
The product 4a resulting from the attack of the ethoxide
to the more accessible (N1) was transformed into 5a using
standard tosylation conditions. The structure of 5a was
verified by X-ray crystallography as depicted in Scheme 2.26
Next, we investigated the asymmetric version of this new
reaction for the synthesis of enantiomerically enriched 1,2,4-
Acknowledgment. This research was made possible by
the Carlsberg Foundation and OChem Graduate School. D.M.
and I.M. thank the Ministerio de Ciencia e Innovacion of
Spain for postdoctoral and predoctoral fellowships. Thanks
are expressed to Helle Svendsen for performing X-ray
analysis.
(23) Hong, D.; Zhu, Y.; Lin, X.; Wang, Y. Tetrahedron 2010, doi:
10.1016/j.tet.2010.11.043.
(24) For example, formation of radicals in the Mitsunobu reaction has
been observed: Camp, D.; Hanson, G. R.; Jenkins, I. D. J. Org. Chem.
1995, 60, 2977.
(25) (a) Reactions performed in neat alcohol resulted in decomposition
of starting material. (b) Using NaOMe (4 equiv, 0.5 M solution) in MeOH/
CHCl3 (2:1) at 50 °C afforded 4a in 48% yield.
Supporting Information Available: Detailed experimen-
tal procedures and compound characterizations. This material
is available free of charge via the Internet at http://pubs.acs.org.
(26) CCDC-801217 contains the supplementary crystallographic data.
These data can be obtained free of charge from The Cambridge Crystal-
lographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
OL102812C
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