Acyl transfer catalysis with 1,2,4-Triazole anion

Article abstract of DOI:10.1021/ol900098q

1,2,4-Triazole anion has been identified as an active acyl transfer catalyst suitable for the aminolysis and transesterification of esters.

Full text of DOI:10.1021/ol900098q

ORGANIC
LETTERS
2009
Vol. 11, No. 7
1499-1502
Acyl Transfer Catalysis with
1,2,4-Triazole Anion
Xing Yang and Vladimir B. Birman*
Department of Chemistry, Washington UniVersity, Campus Box 1134, One Brookings
DriVe, St. Louis, Missouri 63130
birman@wustl.edu
Received January 16, 2009
ABSTRACT
1,2,4-Triazole anion has been identified as an active acyl transfer catalyst suitable for the aminolysis and transesterification of esters.
Neutral nucleophiles (Figure 1), such as 4-dialkylaminopy-
(7),6 have proved to be effective acyl transfer catalysts. As
such, they have found a variety of applications in organic
synthesis.7 Their chiral derivatives have demonstrated con-
siderable utility in catalyzing enantioselective transforma-
tions.8 By contrast, the potential of anionic nucleophiles in
acyl transfer catalysis remains much less explored.
ridines (1),1 N-alkylimidazoles (2),2 phosphines (3),3 imi-
In the course of our studies on enantioselective acyl
transfer catalysis, we became interested in achieving catalytic
acylation of amines using easily accessible achiral acyl
donors.9 Carboxylic esters would be especially attractive in
this regard, since their uncatalyzed reaction with amines is
typically very slow at ambient temperature. However, the
Figure 1. Achiral acyl transfer catalysts.
(6) DBN 6 and THTP 7: Birman, V. B.; Li, X.; Han, Z. Org. Lett. 2007,
9, 37.
(7) For a recent review, see: Denmark, S. E.; Beutner, G. L. Angew.
Chem., Int. Ed. 2008, 47, 1560.
dazolylidene carbenes (4),4 1,2-diamines (5),5 and the
recently introduced bicyclic amidines (6) and isothioureas
(8) Chiral DMAP derivatives: (a) Wurz, R. P. Chem. ReV. 2007, 107,
5570. Chiral NMI derivatives: (b) Miller, S. J. Acc. Chem. Res. 2004, 37,
601. Ishihara, K.; Kosugi, Y.; Akakura, M. J. Am. Chem. Soc. 2004, 126,
12212. Chiral phosphines: (c) Vedejs, E.; Daugulis, O. J. Am. Chem. Soc.
2003, 125, 4166. Chiral N-heterocyclic carbenes: (d) Enders, D.; Niemeier,
O.; Henseler, A. Chem. ReV. 2007, 107, 5606. Marion, N.; D´ıez-Gonza´lez,
S.; Nolan, S. P. Angew. Chem., Int. Ed. 2007, 46, 2988. Chiral vic-diamines:
(e) Oriyama, T.; Imai, K.; Sano, T.; Hosoya, T. Tetrahedron Lett. 1998,
39, 3529. Chiral bicyclic amidines: (f) Birman, V. B.; Uffman, E. W.; Jiang,
H.; Li, X.; Kilbane, C. J. J. Am. Chem. Soc. 2004, 126, 12226. Chiral
bicyclic isothioureas: (g) Birman, V. B.; Li, X. Org. Lett. 2006, 8, 1351.
Birman, V. B.; Li, X. Org. Lett. 2008, 10, 1115.
(1) DMAP 1: Ho¨fle, G.; Steglich, W.; Vorbrüggen, H. Angew. Chem.,
Int. Ed. Engl. 1978, 17, 569.
(2) NMI 2: Connors, K. A.; Pandit, N. K. Anal. Chem. 1978, 50, 1542.
(3) PBu3 3: Vedejs, E.; Diver, S. T. J. Am. Chem. Soc. 1993, 115, 3358.
(4) Imidazolylidene carbenes 4: Grasa, G. A.; Kissling, R. M.; Nolan,
S. P. Org. Lett. 2002, 4, 3583. Nyce, G. W.; Lamboy, J. A.; Connor, E. F.;
Waymouth, R. M.; Hedrick, J. L. Org. Lett. 2002, 4, 3587.
(5) TMEDA 5: Sano, T.; Ohashi, K.; Oriyama, T. Synthesis 1999, 1141.
10.1021/ol900098q CCC: $40.75
Published on Web 03/12/2009
2009 American Chemical Society

aforementioned neutral Lewis base catalysts,7 which suc-
cessfully promote acylations with carboxylic anhydrides
(1-3, 6, and 7) or acyl chlorides (5), can attack only highly
activated esters. Imidazolylidene carbenes 4, which have
gained popularity as transesterification catalysts,4 have also
proved to be ineffective in promoting ester aminolysis.10
Recently, Mioskowski et al. reported that a variety of
unactivated esters undergo efficient aminolysis under solvent-
free conditions in the presence of TBD 8 (Figure 2), which
Table 1. Catalytic Activity Test
entry
additive
t1/2
1
none
ND (6%/3 days)
ND (7%/3 days)
ND (38%/3 days)
66 h
ND (13%/3 days)
5.7 h
2
3
DMAP 1
TBD 8
4
5
2-hydroxypyridine 9
HOBt 10
6
Catechol 11
7
Bu4NCN (12)
2.2 h
8
9
Thiazolidine-2-thione 13
Benzaldoxime 14
N-Hydroxysuccinimide 15
Imidazole 16
24 h
57 h
3 days
9 h
2.2 h
8 min
40 min
4.3 h
10
11
12
13
14
15
16
Pyrazole 17
1,2,4-Triazole 18
1,2,3-Triazole 19
Benzotriazole 20
Tetrazole 21
ND (11%/3 days)
anions effected significant rate acceleration (entries 6 and
7). The most remarkable results were obtained in the azole
series (entries 11-16). 1,2,4-Triazole 18 displayed by far
the greatest activity among all the nucleophiles tested.
Diminished activity was also found in the case of its close
structural analogues with higher or lower pKa values, 1,2,3-
triazole 19 and pyrazole 17.13
Although 1,2,4-triazole and pyrazole were shown to
catalyze aminolysis of nitrophenyl, thiocresyl and cyanom-
ethyl esters decades ago,14 they were believed to act as
bifunctional catalysts and accordingly were used in the
absence of base. To differentiate between the anionic and
the bifunctional modes of catalysis in our case, we examined
the effect of substituting DBU with a weaker base, triethy-
lamine, or not adding any base at all (Figure 3). Very little
Figure 2. Protic nucleophiles.
was proposed to act as a bifunctional Lewis base catalyst.11
Its catalytic activity, however, is only moderate, requiring a
high catalyst loading (30 mol%).
We considered the possibility of catalyzing ester aminoly-
sis with anionic nucleophiles, which might be expected a
priori to be more nucleophilic than their neutral counterparts,
and therefore better able to attack the ester group. Although
the anions of protic nucleophiles 9-12 have been reported
in the literature to promote this reaction, their catalytic
activities were usually rather modest.12
In an effort to identify more active anionic acyl transfer
catalysts potentially suitable for asymmetric catalyst design,
we tested the aforementioned 9-12 and several other
commercially available protic nucleophiles (8, 13-21) for
their ability to promote the reaction of phenyl acetate with
isopropylamine in the presence of stoichiometric amounts
of DBU (Table 1). For comparison, we also included DMAP
1, a powerful aprotic Lewis base acylation catalyst. Most
compounds tested showed only negligible effect. Among the
previously reported catalysts, only catechol and cyanide
Figure 3. Anionic vs bifunctional mode of catalysis.
(9) Previously, catalytic kinetic resolution of amines has only been
achieved using substituted 5-acyloxyoxazoles as stoichiometric acyl donors:
(a) Arai, S.; Bellemin-Laponnaz, S.; Fu, G. C. Angew. Chem., Int. Ed. 2001,
40, 234. (b) Arp, F. O.; Fu, G. C. J. Am. Chem. Soc. 2006, 128, 14264.
(10) (a) Movassaghi, M.; Schmidt, M. A. Org. Lett. 2005, 7, 2453. (b)
Vora, H. U.; Rovis, T. J. Am. Chem. Soc. 2007, 129, 13796. (c) Bode,
J. W.; Sohn, S. S. J. Am. Chem. Soc. 2007, 129, 13798.
reaction was observed in the absence of DBU, which supports
the anionic mode of catalysis. Salts of azoles 17-20 have
been recently described in the patent literature as catalysts
for isocyanate oligomerization and polyisourethane produc-
(11) Sabot, C.; Kumar, K. A.; Meunier, S.; Mioskowski, C. Tetrahedron
Lett. 2007, 48, 3863.
(12) 2-Pyridinolate anion: (a) Nakamizo, N. Bull. Chem. Soc. Jpn. 1971,
2006. Cyanide anion: (b) Hoegberg, T.; Stroem, P.; Ebner, M.; Raemsby,
S. J. Org. Chem. 1987, 52, 2033. Kabouche, Z.; Bruneau, C.; Dixneuf,
P. H. Tetrahedron Lett. 1991, 32, 5359. HOBt anion: (c) Horiki, K.;
Murakami, A. Heterocycles 1989, 28, 615. Catechol monoanion: (d)
Ivanova, G.; Bratovanova, E.; Petkov, D. J. Peptide Sci. 2002, 8, 8.
(13) Calculated values pKa (17) ) 14.0, pKa (18) ) 10.2, pKa (19) )
8.7 were obtained through SciFinder.
(14) (a) Beyerman, H. C.; Maasen van den Brink, W. Proc. Chem. Soc.
(London) 1963, 266. (b) Wieland, T.; Kahle, W. Chem. Ber. 1966, 691,
212.
1500
Org. Lett., Vol. 11, No. 7, 2009

tion.15 To the best of our knowledge, they have not been
utilized in other types of acyl transfer reactions.
Optimization of reaction conditions was undertaken next.
Solvent effects were examined using 2 mol % loading of
1,2,4-triazole and R˜-phenethylamine as a test substrate
(Figure 4). The reaction rates diminished significantly at high
was clearly advantageous. At this point, we wished to
ascertain whether the conjugate acid of DBU was essential
for the aminolysis reaction. In fact, both tetrabutylam-
monium and sodium triazolides were even more active
than the DBU salt.16 These results suggest that, although
the cation may play an important role in the reaction, the
presence of a hydrogen bond donor is not required.
Overall, these observations are consistent with the mech-
anism outlined in Figure 6.
Figure 6. Catalytic cycle with 1,2,4-triazole anion.
Figure 4. Solvent effect on aminolysis of phenyl acetate.
Several representative substrates were acetylated on a
preparative scale using slight excess of isopropenyl acetate
and 5 mol % of each DBU and triazole (Figure 7). In addition
conversions, suggesting that accumulation of the phenolate
anion and/or depletion of available base led to less effective
catalysis. Although the highest initial rates were observed
in polar solvents, such as MeCN and DMSO, benzene was
deemed to be more practical, as it displayed less of a rate
drop-off. Replacing phenyl acetate with isopropenyl acetate,
however, proved to be even more convenient. Even though
the latter displayed lower reactivity, which necessitated a
higher loading of triazole, it generated only acetone as
byproduct, thus obviating the need for stoichiometric amounts
of DBU (Figure 5). In this case, the use of polar solvents
Figure 7. Preparative scale acetylation of substrates.
to amines, the new procedure proved effective for the
transesterification of alcohols and acylation of oxazolidino-
nes. Under the reaction conditions, the stereochemical
integrity of methyl L-phenylalaninate was fully preserved
under the reaction conditions, whereas the more base-
(15) (a) Koecher, J.; Richter, F.; Laas, H.-J.; Wintermantel, M. PCT
Int. Appl., WO 2002092658 A1, 2002. (b) Kometani, H.; Tamano, Y. PCT
Int. Appl., WO 2008018601 A1, 2008.
(16) t1/2 ) 4 h (Bu4N+) and 5.5 h (DBU-H+) in CDCl3 at 10 mol %
catalyst loading; t1/2 ) 12 min (Na+) and 45 min (DBU-H+), in DMSO at
5 mol % catalyst loading under conditions similar to those in Figure 5.
Despite its lower activity, DBU triazolide, which is easily prepared in situ
and soluble in common organic solvents, was used for the remainder of
this study.
Figure 5. Solvent effect on aminolysis of isopropenyl acetate.
Org. Lett., Vol. 11, No. 7, 2009
1501

sensitive methyl D-phenylglycinate underwent complete
racemization.
Aminolysis of unactivated esters catalyzed by the 1,2,4-
triazole anion was investigated next (Table 2). In most
cases, the reactions in the presence of DBU alone were
extremely sluggish even at elevated temperatures under
solvent-free conditions. Addition of 1,2,4-triazole uni-
formly resulted in a dramatic rate acceleration. It is
particularly noteworthy that methyl L-phenylalaninate
underwent smooth cyclocondensation to produce the
corresponding diketopiperazine as a 95:5 mixture of cis-
and trans-diastereomers. The uncatalyzed version of this
reaction is well-known, but usually requires prolonged
heating well above 100 °C and gives only moderate
yields.17 The present protocol may find utility in the
synthesis of structurally complex diketopiperazines.18
Table 2. Aminolysis of Unactivated Esters
entry
1
ester
MeCO2Me
amine
temp °C % yielda
PhCH2NH2
23
45
23
70
23
70
23
70
23c
23
23
70
23c
23
95
23
95
23
95
90
83 (3)
94 (4)
26b (2)
92 (3)
43b (1)
94 (2)
23b (nd)
62 (2)
52b (8)
84 (50)
58b (1)
91 (7)
84 (5)
2b (nd)
77 (2)
1b (nd)
71 (5)
3b (nd)
84 (2)
79 (7)
In summary, we have demonstrated that the 1,2,4-triazole
anion serves as an effective acyl transfer catalyst in both
aminolysis and transesterification reactions. Further inves-
tigation of the synthetic utility of azole anions and their
potential in asymmetric catalysis are under active investiga-
tion in our laboratory.
2
3
4
5
6
PhCO2Me
PhCH2NH2
PhCH2NH2
PhCH2NH2
Me(CH2)6CO2Me
i-PrCO2Me
MeCH(OH)CO2Me PhCH2NH2
Acknowledgment. Financial support of this study by
NIGMS (R01 GM072682) is gratefully acknowledged.
MeCO2Et
PhCH2NH2
7
8
γ-butyrolactone
Me(CH2)6CO2Me
PhCH2NH2
piperidine
Supporting Information Available: Experimental pro-
1
9
Me(CH2)6CO2Me
Me(CH2)6CO2Me
PhCH(Me)NH2
c-C6H11NH2
cedures and H NMR spectra of compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
10
11
OL900098Q
L-Phe-OMe
a Isolated yield is given, unless specified otherwise. % Conversion by
1H NMR in the absence of 18 is given in parentheses. b Yield estimated by
1H NMR. c Carried out in CDCl3 at 1.0 M of amine.
(17) Scho¨llkopf, U.; Busse, U.; Kilger, R.; Lehr, P. Synthesis 1984, 271.
(18) Schkeryantz, J. M.; Woo, J. C. G.; Siliphaivanh, P.; Depew, K. M.;
Danishefsky, S. J. J. Am. Chem. Soc. 1999, 121, 11964.
1502
Org. Lett., Vol. 11, No. 7, 2009