A Fresh Look at the Staudinger Reaction on Azido Esters: Formation of 2H-1,2,3-Triazol-4-ols from α-Azido Esters Using Trialkyl Phosphines

Article abstract of DOI:10.1021/acs.orglett.6b02204

Phenyl esters of α-azido acids react with trialkylphosphines in THF/H₂O to give 5-substituted 2H-1,2,3-triazol-4-ols in good to excellent yields. In contrast, their reaction with PPh₃ in THF/H₂O give the amino esters as the major product and no triazoles. Reaction between an α-azido phenyl ester and P(OEt)₃ provided the corresponding phosphoramidate in excellent yield, but no triazole was formed.

Full text of DOI:10.1021/acs.orglett.6b02204

Letter
pubs.acs.org/OrgLett
A Fresh Look at the Staudinger Reaction on Azido Esters: Formation
of 2H‑1,2,3-Triazol-4-ols from α‑Azido Esters Using Trialkyl
Phosphines
Scott D. Taylor* and Chuda Raj Lohani
Department of Chemistry, University of Waterloo, 200 University Avenue West, Waterloo, Ontario Canada, N2L 3G1
S
* Supporting Information
ABSTRACT: Phenyl esters of α-azido acids react with
trialkylphosphines in THF/H2O to give 5-substituted 2H-1,2,3-
triazol-4-ols in good to excellent yields. In contrast, their reaction
with PPh3 in THF/H2O give the amino esters as the major
product and no triazoles. Reaction between an α-azido phenyl ester and P(OEt)3 provided the corresponding phosphoramidate
in excellent yield, but no triazole was formed.
ince its discovery almost 100 years ago,1 the Staudinger
reaction has proven to be one of the most versatile
Here we report a previously unnoticed variant of the
Staudinger reaction on α-azido esters in which phosphazides,
generated from the reaction of trialkyl phosphines with phenyl
esters of α-azido acids in THF/H2O, undergo an intramolecular
cyclization to provide 2H-1,2,3-triazol-4-ols in good to excellent
yields. Interestingly, when the reactions were conducted using
PPh3, triazoles were not obtained. Instead, the dominant
products were the reduced amines resulting from the classic
Staudinger pathway. Similarly, when the reaction was
conducted using P(OEt)3, a phosphoramidate was formed in
high yield but no triazole was formed.
Our interest in the Staudinger reaction stems from our use of
α-azido acids as building blocks for solid phase peptide
synthesis.7−9 As part of these studies, we wished to determine
the rate by which PMe3 reduces the azido group in resin-bound
peptides containing an N-terminal α-azido residue to give the
corresponding peptides with the desired amino terminus,
compared to the analogous reaction in solution. We began
these studies by studying the rate by which the simple model
amino ester, compound 3 (Scheme 2), undergoes reaction with
PMe3 in solution. Hence, compound 3 was subjected to 1.2
equiv of PMe3 and the reaction was followed by HPLC and 1H
NMR (Scheme 2). Surprisingly, the NMR spectrum revealed
that, in addition to the expected α-amino ester 4, an almost
equimolar amount of ethanol was formed within 30 min along
with another unidentified compound. Subjecting compound 3
S
reactions in organic chemistry. Its importance in organic
synthesis cannot be underestimated, as its many variants allows
for the preparation of a wide variety of compounds.2 It is also a
key reaction in chemical biology due to its application in highly
chemoselective ligations for the preparation of bioconjugates.3
In its original form, as reported by Staudinger and Meyer, the
Staudinger reaction involves the reaction of a phosphine with
an azide to form an iminophosphorane (2 in Scheme 1).1 The
Scheme 1. Mechanism of the Staudinger Reaction
mechanism has been studied in detail, and it has been shown to
proceed via initial formation of a phosphazide (1 in Scheme 1)
which, upon loss of N2, produces the iminophosphorane.2,4 The
iminophosphorane can by hydrolyzed to give an amine and a
phosphine oxide. Later, Staudinger reported that the nitrogen
atom of the iminophosphorane is highly nucleophilic and can
react with electrophiles, such as aldehydes and ketones, to give
imines (aza-Wittig reaction).5 Since this report, it has been
shown that the iminophosphorane can react with a wide variety
of electrophiles, including esters and amides, especially if the
reaction is intramolecular, to give a wide variety of products.2,3
Although there are numerous examples in the literature
demonstrating the reaction of an iminophosphorane with an
electrophile, there are only a few reports describing the reaction
of phosphazides with electrophiles even though, under
appropriate conditions, and with the appropriate phosphines
and azides, stable phosphazides can be isolated and
characterized.4,6
Scheme 2. Products Formed upon Treatment of Esters 3 and
6 with PMe3/THF/H2O
Received: July 26, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02204
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Organic Letters
Letter
to just THF/H2O for 24 h did not result in any reaction of any
kind indicating that the formation of ethanol was not due to
hydrolysis of the ester bond. HPLC analysis of the reaction
mixture after 30 min revealed two major peaks one of which
was due to the expected product 4. Isolation of the other
product followed by 1H, 13C NMR and HRMS analysis
revealed it to be the 2H-1,2,3-triazol-4-ol 5,10 which was
obtained in a 47% yield. This structural assignment was
confirmed by X-ray crystallography (see the Supporting
Information). Subjecting phenyl ester 6 to the same conditions
gave triazole 5 as the sole product as determined by HPLC.
The formation of compound 5 is most likely due to
cyclization of phosphazide 7, to give intermediate 8 (triazole
pathway, Scheme 3), before 7 can lose nitrogen and give the
smoothly, usually within 1−2 h,11 to give the corresponding
triazoles in good to excellent isolated yields. HPLC analysis of
the crude reaction mixtures revealed that the triazoles were
essentially the sole product. Ester 19 gave triazole 29, as
determined by HPLC and MS; however, for unknown reasons,
this compound was unstable and we were unable to isolate it.
Triazalones 30 and 31 were obtained when using α,α-
disubstituted azido esters 20 and 21. These triazolones proved
to be very thermosensitive and could not be subjected to
temperatures greater than 50 °C with rapid loss of N2 and
polymerization.12
Subjecting ester 32 (Scheme 4), which could potentially
form either a five-membered ring triazole (compound 33) or
Scheme 4. Formation of Triazole 33 from Ester 32
Scheme 3. Proposed Mechanism for Formation of Triazole 5
the six-membered ring triazolone (compound 34), to PMe3/
THF/H2O gave the five-membered ring triazole 33 exclusively,
indicating that formation of five-membered triazole is favored
over the formation of six-membered ring triazolone.
When ester 35 was subjected to PMe3 in THF/H2O, in
addition to amine 36, 3-phenyl-1H-pyrazol-5-ol (37) was
obtained in a 56% yield (Scheme 5). To account for the
Scheme 5. Proposed Mechanism for the Formation of 37
from 35
iminophosphorane 11 (Staudinger pathway). Hydrolysis of 8
gives compound 9 which upon protonation gives triazolone 10.
Tautomerization of 10 yields the aromatic triazole 5. The fact
that phenyl ester 6 gave only compound 5 indicates that loss of
the leaving group is rate-determining.
A variety of other α-azido phenyl esters were subject to
PMe3/THF/H2O (Table 1). In all cases, the esters reacted
Table 1. Formation of Triazole 5 and 22−31 from Azido
Esters 6 and 12−21
substrate
R1
R2
product (% yield)
6
CH2Ph
Ph
H
H
H
H
H
H
H
H
H
Ph
5 (89)
22 (83)
23 (87)
24 (95)
25 (89)
26 (84)
27 (85)
28 (88)
29 (0)
12
13
14
15
16
17
18
19
20
21
formation of 37 we propose that phosphazide 38 undergoes an
intramolecular proton transfer to give betaine 39 which then
undergoes elimination of trimethylphosphinimine to provide
the diazo compound 40. This reacts with PMe3 to give
phosphinazine 41 which cyclizes to produce compound 42
which loses PMe3 to give compund 37. The fact that the
reaction required about 1.6 equiv of PMe3 before all of 35 was
consumed is consistent with this mechanism; however, further
studies will be required before this mechanism can be
validated.13
CH2-indole(Boc)
CH2Ph-pOtBu
CH2CH2COOtBu
(CH2)4NHBoc
CH3
CH2CH(CH3)2
CH2OBn
Ph
30 (85)
31 (80)
−(CH2)4−
B
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There are numerous reports in the literature describing the
reduction of azido groups in α-azido esters to give α-amino
esters using phosphines. The majority of these reports utilized
PPh3, though there are several instances where alkyl phosphines
were used including PMe3.14−17 The formation of triazoles was
not mentioned in any of these reports. Therefore, the reaction
of ester 6 with other phosphines, as well with P(OEt)3, was
examined (Scheme 6). HPLC and MS analysis of the crude
As mentioned earlier, there have been reports in the
literature describing the reduction of azido groups in α-azido
14−16
17
alkyl esters using PMe3
and PBu3 in THF/H2O though
none of these reports mentioned triazole formation as a
competing reaction. In all of these cases, the amine product was
not isolated but instead the crude or in situ generated amine
was reacted with an electrophile, such as an activated ester to
form an amide bond14,16,17 or with BOC-ON.15 It is worth
noting that the yield of the amide or Boc-protected product was
very poor to low (11−47%). It is possible that competing
triazole formation may have contributed to these low yields.
Loke et al. reported the reduction of an α-azido benzyl ester to
the corresponding amino ester in apparently quantitative yield
(the amine was not purified) by reacting the azido ester with
1.1 equiv of PMe3 in THF in the absence of water for 3 h
followed by the addition of water.20 Reaction of ester 3 with 1.1
equiv of PMe3 in the absence of water gave iminophosphorane
11 in almost quantitative yield after 30 min, as determined by
31P NMR of the crude reaction mixture (δ for 11 = 11.2 ppm),
indicating the presence of water is required for cyclization to
the triazole and loss of EtOH, possibly by acting as a general
acid (Scheme 8). Addition of water and stirring for 2 h gave
Scheme 6. Reaction of Compound 6 with Various
Phosphines and P(OEt)3
Scheme 8. Stepwise Approach to the Synthesis of Amine 4
from Azido Ester 3 Using PMe3
reaction mixtures from the reaction of PBu3 and POct3 with
ester 6 in THF/H2O indicated that these phosphines also gave
compound 5 as the major product with only trace amounts of
amine 43. However, triazole 5 was not formed when ester 6
was subjected to PPh3 in THF/H2O for 16 h. Instead, amine 43
was the major product.18 HPLC and MS analysis of the crude
reaction mixtures from the reaction of the azido esters listed in
Table 1 with PPh3/THF/H2O for 16 h revealed that these
esters also gave only products resulting from the Staudinger
pathway. Moreoever, we did not detect compound 37 (by
HPLC) when ester 35 was treated with PPh3: only products
resulting for the classical Staudinger pathway were detected.
The reason for the difference in product distribution between
PPh3 and the other phosphines examined here is not entirely
clear. However, it is possible that the more bulkyl phenyl
groups in PPh3 prevent the cyclization of the intermediate
phosphazide, though electronic effects that may favor or
disfavor the loss of nitrogen from the phosphazide probably
also play a role. That electronic effects can also play a role in
determining which pathway is favored is supported by the
observation that P(OEt)3 gave only phosphoramidate 44 in
excellent yield. This compound was formed as a result of loss of
nitrogen from the phosphazide (Staudinger pathway) to give
the corresponding iminophosphorane followed by N-proto-
nation and loss of EtOH (Scheme 6).19
ester 4 as almost the sole product as determined by HPLC.
Therefore, triazole formation can be avoided by performing the
reaction in THF/H2O with PPh3 or stepwise with PMe3 and
probably other alkylphosphines.21
Very few reports have appeared in the literature describing
the synthesis of triazoles of the type described here. Kees et al.
reported the synthesis of triazole 49 in 31% yield by
diazotization of β-ketoamide 48 with methane sulfonyl azide
followed by cyclization of the resulting α-diazoamide in
NaOMe/MeOH (Scheme 9A).22 Hohenlohe-Oehringen re-
ported the synthesis of compound 30 in 70% yield via
hydrogenolysis of α-azido ester 50 (Scheme 9B).23 However,
Ikeda et al. later reported a yield of only 18%.12 Finally, Benati
et al. claimed to have prepared compounds 22 and 30 in 48%
Scheme 9. Literature Routes to 2H-1,2,3-Triazol-4-ols
Although we are unaware of any reports describing the
synthesis of triazoles using the route described here, it is worth
noting that Molina and co-workers reported the synthesis of
compound 46 in 78% yield by treating 45 with PBu3 in ether
(Scheme 7). Treating 45 with PPh3 yielded iminophosphorane
47 in 90% yield.6h
Scheme 7. Molina’s Synthesis of Compounds 46 and 47
C
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́ ́
Lopez-Leonardo, C.; Llamas-Botía, J.; Foces-Foces, C.; Fernandez-
and 23% yield respectively by subjecting α-azido esters 51 and
52 to Bu3SnH (Scheme 9C).24 However, no characterization
data of any kind for these compounds were provided. They
suggested that the reaction proceeds via a free radical
mechanism. The route to 2H-1,2,3-triazol-4-ols reported here
represents a significant improvement on these literature
procedures and now makes this class of compounds readily
accessible.
In summary, we have reported a variant of the Staudinger
reaction that appears to have escaped notice, in spite of the vast
body of work that has been done on the Staudinger reaction
over the past century. This Staudinger variant provides 2H-
1,2,3-triazol-4-ols simply by reacting readily prepared α-azido
phenyl esters with triakyl phosphines. The reaction proceeds
under very mild conditions and is complete usually within 1−2
h at rt. Thus, these types of triazoles, which were once
challenging to produce in good yield, are now readily accessible.
Further studies on the mechanism of this reaction and its
implications on the synthesis of depsipeptides are in progress
and will be reported in due course.
Castano, C. Tetrahedron 1996, 52, 9629−9642. (f) Fresneda, P. M.;
Castaneda, M.; Sanz, M. A.; Molina, P. Tetrahedron Lett. 2004, 45,
1655−1657. (g) Fresneda, P. M.; Castaneda, M.; Sanz, M. A.; Bautista,
D.; Molina, P. Tetrahedron 2007, 63, 1849−1856. (h) Velasco, M. D.;
Molina, P.; Fresneda, P. M.; Sanz, M. A. Tetrahedron 2000, 56, 4079−
4084. (i) Myers, E. L.; Raines, R. T. Angew. Chem., Int. Ed. 2009, 48,
2359−2363.
(7) Lohani, C. R.; Taylor, R.; Palmer, M.; Taylor, S. D. Org. Lett.
2015, 17, 748−751.
(8) Lohani, C. R.; Taylor, R.; Palmer, M.; Taylor, S. D. Bioorg. Med.
Chem. Lett. 2015, 25, 5490−5494.
(9) Lohani, C. R.; Rasera, B.; Scott, B.; Palmer, M.; Taylor, S. D. J.
Org. Chem. 2016, 81, 2624−2628.
(10) Tautomers other than the one shown are possible.
(11) Azido esters 20 and 21 required 10 h.
(12) Ikeda et al. reported that triazole 30 undergoes thermal
polymerizations yielding poly(α,α-diphenylglycine) at 50 °C higher.
They also reported that it decomposes violently at temperatures above
75 °C; see: Ikeda, K.; Smets, G.; L’Abbe, G. J. Polym. Sci., Polym. Chem.
Ed. 1973, 11, 1167−1176.
(13) To account for one of the products that was formed during their
studies on the reaction of PPh3 with α-azidoacetonitriles, Molina and
co-workers suggested a mechansim by which a phosphazide undergoes
elimination of triphenylphosphinimine to provide a diazo compound
which reacts with PPh3 to give a phosphinazine. See ref 6e. See also ref
6i for examples of phosphine-mediated conversion of azides into diazo
compounds.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02204.
(14) Nicolaou, K. C.; Lizos, D. E.; Kim, D. W.; Schlawe, D.; de
Noronha, R. G.; Longbottom, D. A.; Rodriquez, M.; Bucci, M.; Cirino,
G. J. Am. Chem. Soc. 2006, 128, 4460−4470.
Experimental procedures, characterization data and
NMR spectra for esters 6, 12−21, 32, and 35, triazoles
5, 22−29, and 33, triazolones 30 and 31, pyrazole 37,
and phosphoramidate 44 (PDF)
(15) Feldman, K. S.; Vidulova, D. B.; Karatjas, A. G. J. Org. Chem.
2005, 70, 6429−6440.
(16) Ghosh, S. K.; Somanadhan, B.; Tan, K. S.; Butler, M. S.; Lear,
M. J. Org. Lett. 2012, 14, 1560−1563.
X-ray crystallographic data for compound 5 (CIF)
(17) Coste, A.; Bayle, A.; Marrot, J.; Evano, G. Org. Lett. 2014, 16,
1306−1309.
AUTHOR INFORMATION
Corresponding Author
■
(18) HPLC analysis of the reaction mixture showed that, in addition
to the major peak corresponding to amine 43, several much smaller
peaks were present, none of which corresponded to triazole 5. One of
these peaks was phenol. MS analysis of some of these peaks revealed
that they were compounds resulting from self-reaction (which results
in loss of phenol) of the iminophosphorane.
*E-mail: s5taylor@uwaterloo.ca.
Notes
The authors declare no competing financial interest.
(19) For recent examples of phosphoramidate syntheses from azides
and phosphites, see: (a) Serwa, R.; Wilkening, I.; Del, S. G.;
Muehlberg, M.; Claussnitzer, I.; Weise, C.; Gerrits, M.; Hackenberger,
C. P. R. Angew. Chem., Int. Ed. 2009, 48, 8234−8239. (b) Serwa, R.;
Majkut, P.; Horstmann, B.; Swiecicki, J.-M.; Gerrits, M.; Krause, E.;
Hackenberger, C. P. R. Chem. Sci. 2010, 1, 596−602.
(20) Loke, I.; Park, N.; Kempf, K.; Jagusch, C.; Schobert, R.; Laschat,
S. Tetrahedron 2012, 68, 697−704.
(21) Reacting ester 6 with PMe3 in THF for 30 min followed by the
addition of water and stirring for 2 h also resulted in the formation of
compound 4 as the major product, and no triazole 5 was formed as
determined by HPLC and MS. However, phenol was also formed and
a variety of smaller peaks were evident in the HPLC chromatogram of
the crude reaction mixture which were most likely due to compounds
resulting from self-reaction of the initially formed iminophosphorane.
(22) Kees, K. L.; Caggiano, T. J.; Steiner, K. E.; Fitzgerald, J. J.; Kates,
M. J.; Christos, T. E.; Kulishoff, J. M.; Moore, R. D.; McCaleb, M. L. J.
Med. Chem. 1995, 38, 617−628.
ACKNOWLEDGMENTS
■
This research was supported by a Discovery Grant from the
Natural Sciences and Engineering Research Council (NSERC)
of Canada to SDT.
REFERENCES
■
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