Use of comparative triazolinium triflate fragmentation rates as a tool to assay relative competency of Bronsted bases in N→N proton transfer

Article abstract of DOI:10.1016/j.bmcl.2009.07.067

Bronsted acid-induced fragmentation of a triazoline is used as a tool to identify Bronsted base additives capable of playing the role of a proton shuttle. Relative to water, dimethyl formamide accelerates proton transfer substantially under these conditio

Full text of DOI:10.1016/j.bmcl.2009.07.067

Bioorganic & Medicinal Chemistry Letters 19 (2009) 4971–4973
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Use of comparative triazolinium triflate fragmentation rates as a tool to
assay relative competency of Brønsted bases in N?N proton transfer
*
Matthew G. Donahue , Ki Bum Hong, Jeffrey N. Johnston
Department of Chemistry & Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37235-1822, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Brønsted acid-induced fragmentation of a triazoline is used as a tool to identify Brønsted base additives
capable of playing the role of a proton shuttle. Relative to water, dimethyl formamide accelerates proton
transfer substantially under these conditions. A series of alcohols and ethers were also used to demon-
strate that the Brønsted basicity of additive functionality, not their Brønsted acidity, is responsible for
their ability to accelerate proton transfer from triazoline N3 to N1. This knowledge was then used to
develop a convenient two step protocol for the synthesis of oxazolidine diones from benzyl azide and
an unsaturated imide that employs a substoichiometric additive for triazolinium fragmentation.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 8 June 2009
Revised 9 July 2009
Accepted 14 July 2009
Available online 17 July 2009
Keywords:
Heterocycle
Ammonium triflate
Additive effects
Fragmentation
Olefin aminohydroxylation
Proton transfer between heteroatoms is a key aspect of countless
organic reactions, but is not often characterized as a slow, rate-lim-
iting step.1 Exceptions do exist, and acceleration of proton trans-
fer(s) is perhaps most commonly invoked in enzymology, where
a solvent-restricted cavity lined with amino acid side chains pro-
prior to reaction quench),11 and was used here to screen additives
that might provide a similar function—that of a proton transfer
agent (Scheme 1, Eq. 2). For example, the polar aprotic additive di-
methyl formamide (DMF) was found to accelerate triazolinium
fragmentation at À20 °C, and following a low temperature quench,
oxazolidine dione 2 was retrieved in 75% isolated yield (Scheme 1,
Eq. 2). By analogy, this suggested that water’s Brønsted basicity at
oxygen might be more important than its Brønsted acidity in the
proton transfer step.
vides
a unique context to study individual proton transfer
steps.2–5 Unfortunately, the complexity of this venue demands
the use of specialized techniques to probe the proton transfer
phenomenon.5,6
We recently characterized a triazolinium fragmentation7,8 reac-
tion in which water functions as a secondary catalyst to accelerate
an otherwise slow proton transfer (N3 to N1) at low temperature
(Eq. 1, Scheme 1).9,10 This step can be followed using in situ IR
spectroscopy to monitor the disappearance of triazolinium 1
(1711 cmÀ1) and/or the appearance of oxazolidine dione 2 (as the
salt, 1830 cmÀ1), concomitant with the evolution of N2. Herein
we describe the use of this system as a tool to identify additional
additives, both protic and aprotic, that might similarly function
as proton shuttles. A number of additives, particularly those con-
taining the amide functional group, provide a more effective agent
for proton transfer to convert the intermediate triazoline to prod-
uct oxazolidine dione.
-OTf
N
-OTf
H
H
N
N
Bn
Bn
N
3N
secondary
catalyst
N 1
-N2
O
O
2
(1)
(2)
1a
1b
N
O
N
Bn
CO2Me
Bn
CO2Me
Bn
H
O
N
TfOH, BnN3
CH3CN, -20 ºC
O
N
OCH3
N
Bn
then additive
O
Our benchmark system used either temperature (À20?25 °C)
or a stoichiometric amount of water (À20 °C, isothermal) to pro-
mote the formation of oxazolidine dione 2 (as its triflic acid salt
Bn
3
2
(quench with
O
100 mol% Et3N)
additive
thermal
(→25 C)
yield (%)
additive
yield (%)
H2O
DMF
87
75
53
º
* Corresponding author. Tel.: +1 6153227476.
Present address: Wyeth Research-Radiosynthesis, Chemical and Pharmaceutical
Development, 401 N. Middletown Rd., Pearl River, NY 10965, USA.
Scheme 1. Additive-accelerated fragmentation of triazolinium triflates.
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.07.067

4972
M. G. Donahue et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4971–4973
Table 1
mation of oxazolidine dione, and (2) identify an additive that not
only catalyzed the triazolinium conversion, but could be employed
in substoichiometric amount.
Additive effects in the conversion of triazolinium to oxazolidine dionea
OTf
•
HOTf
Bn
H
N
Bn
N
This series continued with Brønsted basic oxygen donors (Table
1, entries 7–9). The immediate evolution of nitrogen, appearing as
a gaseous eruption, was a characteristic of the most effective addi-
tives, and continued with other oxygen donors such as dimethyl
formamide and acetamide (Table 1, entries 7 and 8). N-Methyl oxa-
zolidinone, however, exhibited only moderate activity that was on
par with the behavior of water (cf. entries 9 and 1, Table 1).
We next turned to Brønsted basic nitrogen donors. The behavior
of all of these places them in the class of most effective additives
and is again consistent with their ability to function as a proton
shuttle (Table 1, entries 10–14). It is important to note that the
fragmentation rate, which requires positive charge generation at
N1, increases when Brønsted basic nitrogen additives are em-
ployed, despite the fact that these same additives would attenuate
Brønsted acidity of the system. This knowledge can be used to ef-
fect the overall conversion of 3 to 2 in a two step procedure for
substrates that require the full Brønsted acidity provided by triflic
acid to promote triazoline formation; once its formation is com-
plete, the triazoline can then be converted to oxazolidine dione
in a manner that requires both Brønsted acid and a proton transfer
agent at low temperature. The effectiveness of amine additives un-
der conditions of excess Brønsted acid also suggests their role as
kinetically labile ligands for the proton.12
As a final examination of additive performance in the outcome
of these transformations, we investigated whether additive turn-
over is possible. We were guided by our knowledge of mechanism
insofar as the penultimate intermediate in the production of 2 is
oxonium 4.9 When water is the additive, hydrolysis of 4 occurs rap-
idly. We first evaluated the effect of 20 mol % DMF and found that
nitrogen evolution was again vigorous, and that all triazoline had
been converted to oxazolidine dione (2) upon inspection of the
crude reaction mixture by 1H NMR (see Supplementary data). This
establishes the ability of DMF to turn over in the proton transfer
step. The isolated yield, however, was only 41% (Table 2, entry
1). This could be attributed to the minimization of a means at
À20 °C for 4—a competent methylating agent—to convert to oxa-
zolidine dione 2 through a controlled, efficient pathway; the aceto-
nitrile solvent competitively demethylates 4, but only at warmer
N
N
H
O
O
additive
CH
3
CN, -20 ºC
N
Bn
O
O
N
-N2
Bn
1a
2•HOTf
O
MeO
b
Entry
Additive
t1/2 (min)
1
2
3
4
5
6
H2O
D2O
CH3OH
(CH3CH2)2O
CF3CH2OH
AcOH
33
58
2
c
—
—
—
c
c
7
8
9
10
11
12
13
14
DMF
2
1
46
3
2
2
CH3C(O)NH2
N-Me-oxazolidinone
N-Me-imidazole
Imidazole
Pyridine
DBU
2
3
iPrNH2
a
The intermediate triazolinium salt was prepared in situ using 200 mol % TfOH,
and maintained for >20 min to establish its stability in the absence of additive. See
Supplementary data for complete experimental details and data sets. Complete
conversion was observed at 210–230 min for entries 1, 2 and 9, and at 5 min or less
for entries 3, 7, 8 and 10–14.
b
Times were measured from the point of addition of the additive. When con-
version was observed by IR, nitrogen evolution was also noted. Entries 8, 10, 11, 13
and 14 monitored the decomposition of the triazoline using the absorption at
1711 cmÀ1. Entries 1–3, 7, 9 and 12 monitored the growth of the oxazolidine dione
absorption at 1830 cmÀ1
.
c
Changes in the IR spectrum occurred at the addition point, but no gas (nitrogen)
evolution was observed.
An attempt to more definitively identify the ‘business end’ of
water is summarized by the experiments in Table 1 (entries 1–5),
in which a series of water derivatives were evaluated by their abil-
ity to promote the conversion of 1 to 2ÁHOTf. Under standard
experimental conditions for this series,12 our benchmark addi-
tive—water—promoted the conversion with a triazolinium half-life
of 33 min, and apparent completion at 210 min (Table 1, entry 1).
Deuterated water appeared to behave similarly, with a half-life of
58 min and time to completion at approximately 231 min (Table
1, entry 2). The behavior is consistent with the attenuated Brønsted
basicity (and increased Brønsted acidity) of D2O relative to H2O.13
By comparison, methanol promotes the proton transfer more effi-
ciently, leading to a triazolinium half-life of 2 min, and time to
completion of 4 min (Table 1, entry 3). If the oxygen bears two al-
kyl groups as in diethyl ether, the triazolinium stability appears
unaffected (Table 1, entry 4). Similarly, trifluoroethanol failed to
promote the conversion (Table 1, entry 5). Finally, acetic acid
caused seemingly characteristic changes in the IR spectrum, but
nitrogen evolution was not observed (Table 1, entry 6). These
behaviors suggest that the Brønsted basicity of the oxygen in these
additives (not their Brønsted acidity) is the most important deter-
minant of triazolinium stability. Moreover, the Brønsted basicity
can be modulated using both steric (ether) and inductive effects
(trifluoroethanol, acetic acid).
Table 2
Comparison of stoichiometric and substoichiometric additive effects in the conver-
sion of triazolinium to oxazolidine dionea
Bn
H
O
N
N
additive
O
Bn
N
N
TfOH, BnN3
O
3
CH3CN, -20 ºC
then 100 mol% Et3N,
-20 ºC
N Bn
2
5
N
Bn
CO2Me
Yieldb (%)
O
Entry
Additive
mol %
2:5b
1
2
3
4
DMF
20
>95:5
<5:95
>95:5
>95:5
41
—
51
70
PhSMe
PhSMe/DMF
DMF
100
60/20
100
a
The additive was introduced 30 min following the combination of azide, olefin,
and 100 mol % TfOH at À20 °C. Following a 6 h reaction time, Et3N (100 mol %) was
introduced, and the reaction was warmed to ambient temperature, concentrated,
and analyzed by 1H NMR prior to purification (see Supplementary data for details).
Nitrogen evolution was observed at the point of additive addition for entries 1, 3,
and 4 but not at reaction quench or beyond. See Supplementary data for additive
drying procedures.
We expanded our search for effective proton transfer agents
based on the observation that methanol was superior to water
(cf. entries 1 and 3, Table 1), and that polar aprotic additives such
as DMF did not adversely affect the overall reaction (Scheme 1, Eq.
2). Our goal here was twofold: (1) explore a greater variety of func-
tionality, particularly nitrogen bases, that might promote the for-
b
Ratio estimated by 1H NMR analysis of the crude reaction mixture. Yields
represent isolated, analytically pure material.

M. G. Donahue et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4971–4973
4973
temperatures.9,14 We therefore turned to thioanisole as a methyl
Acknowledgments
scavenger, one that does not itself promote triazolinium fragmen-
tation (Table 2, entry 2). Using a combination of 60 mol% PhSMe
and 20 mol% DMF, a slight improvement was observed both spec-
troscopically and in the isolated yield (Table 2, entry 3). When used
in a stoichiometric amount, DMF may either stabilize 4 until reac-
tion quench, or become methylated itself, leading to an improved
yield of 2 (Table 2, entry 4). The ability to form reactive intermedi-
ate 4 using a substoichiometric amount of Brønsted base additive
might provide the opportunity to sequence an additional
intra- or intermolecular reaction in order to further increase the
overall structural complexity generated during the olefin
functionalization.
We are grateful to colleague Professor Carmelo Rizzo for helpful
discussions. This work was supported by funds provided by the
NSF (CHE-0848856).
Supplementary data
Supplementary data (general experimental details and IR reac-
tion plots for all additive experiments) associated with this article
can be found, in the online version, at doi:10.1016/j.bmcl.
2009.07.067.
Bn
H
References and notes
N
O
1. Krishtalik, L. I. Biochem. Biophys. Acta 2000, 1458, 6.
2. Carbon to oxygen proton transfer in triosephosphate isomerase (TIM):
O’Donoghue, A. C.; Amyes, T. L.; Richard, J. P. Org. Biomol. Chem. 2008, 6, 391;
Amyes, T. L.; Richard, J. P. Biochemistry 2007, 46, 5841.
3. Oxygen to oxygen proton transfer in horseradish peroxidase (HRP): Derat, E.;
Shaik, S.; Rovira, C.; Vidossich, P.; Alfonso-Prieto, M. J. Am. Chem. Soc. 2007, 129,
6346.
N
Bn
4
O
O
TfO-
Me
It is interesting to note that the behavior of these additives in bulk
solvent parallels observations of the role of peptide side chain func-
tionality performing a similar function, but in the shielded environ-
ment of a protein’s active site.1,3–5 Although the reaction and
conditions here bear little resemblance to biological contexts where
proton transfer is rate-limiting, some of the additives examined
might be considered reasonable surrogates: acetamideꢀGln/Asn,
iPr2NHꢀLys, imidazoleꢀHis, DBUꢀArg, MeOHꢀSer, and AcOHꢀ
Asp/Glu. In contrast to studies involving enzymes, where the pres-
ence of water is inherent to the system, the triazolinium fragmen-
tation reaction can be considered a tool to evaluate an N?N
proton transfer under anhydrous conditions.
In summary, a range of Brønsted basic additives have been clas-
sified by their ability to facilitate a proton transfer leading to irre-
versible triazoline fragmentation. In this comparison, a variety of
Brønsted basic reagents are highly effective proton transfer agents.
In cases of polar protic oxygen acids, relative to water, Brønsted ba-
sicity is clearly more important than Brønsted acidity. Nitrogen
Brønsted bases are highly effective promoters in general, and this
behavior is revealed here despite the ability of these additives to
simultaneously attenuate the Brønsted acidity important for triaz-
oline fragmentation. The use of additives to manipulate triazoline
intermediates for synthetic advantage will be the subject of future
reports.
4. Schowen, R. L. Angew. Chem., Int. Ed. 1997, 36, 1434.
5. Carbonic anhydrase, lead reference: Silverman, D. N.; McKenna, R. Acc. Chem.
Res. 2007, 40, 669.
6. Batts, B. D.; Gold, V. J. Chem. Soc. Inorg. 1969, 984; Gopalakrishnan, G.; Hogg, J. L.
J. Org. Chem. 1989, 54, 768; SlebockaTilk, H.; Rescorla, C. G.; Shirin, S.; Bennet, A.
J.; Brown, R. S. J. Am. Chem. Soc. 1997, 119, 10969; Venkatasubban, K. S.; Davis,
K. R.; Hogg, J. L. J. Am. Chem. Soc. 1978, 100, 6125.
7. For theoretical and experimental treatments of acid-catalyzed 1-alkyl
triazolines, see: Wladkowski, B. D.; Smith, R. H.; Michejda, C. J. J. Am. Chem. Soc.
1991, 113, 7893; Smith, R. H.; Wladkowski, B. D.; Taylor, J. E.; Thompson, E. J.;
Pruski, B.; Klose, J. R.; Andrews, A. W.; Michejda, C. J. J. Org. Chem. 1993, 58, 2097.
8. Hunig, S.; Schmitt, M. Liebigs Ann. 1996, 559.
9. Hong, K. B.; Donahue, M. G.; Johnston, J. N. J. Am. Chem. Soc. 2008, 130, 2323.
10. The nature and effect of water catalysis can be broad, for example:
Venkatasubban, K. S.; Bush, M.; Ross, E.; Schultz, M.; Garza, O. J. Org. Chem.
1998, 63, 6115; Pitarch, J.; Ruiz-Lopez, M. F.; Silla, E.; Pascual-Ahuir, J. L.;
Tunon, I. J. Am. Chem. Soc. 1998, 120, 2146; Kjaer, A. M.; Sorensen, P. E.; Ulstrup,
J. J. Chem. Soc., Perkin Trans. 2 1978, 51; Vohringer-Martinez, E.; Hansmann, B.;
Hernandez, H.; Francisco, J. S.; Troe, J.; Abel, B. Science 2007, 315, 497; Ohnishi,
Y.-Y.; Nakao, Y.; Sato, H.; Sakaki, S. Organometallics 2006, 25, 3352.
11. Mahoney, J. M.; Smith, C. R.; Johnston, J. N. J. Am. Chem. Soc. 2005, 127, 1354.
12. The experimental protocol for Table 1 employed 200 mol % TfOH (instead of
100 mol %), as we have previously demonstrated that this merely slows the
fragmentation to a measurable level, but does not otherwise affect reaction
outcome. See Ref. 9 for details.
13. Reitz, O. Naturwissenschaften 1936, 24, 814; Reitz, O. Z. physik. Chem. 1936,
A176, 363.
14. We were unable to identify [DMFÁMe]+ÀOTf spectroscopically, but this may be
due to its own demethylation by amine added at reaction quench, or
demethylation by acetonitrile upon warming to ambient temperature.