Facile synthesis of 1-Alkoxy-1H-benzo- and 7-azabenzotriazoles from peptide coupling agents, mechanistic studies, and synthetic applications

Article abstract of DOI:10.3762/bjoc.10.200

(1H-Benzo[d][1,2,3]triazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), 1H-benzo[d][1,2,3]triazol-1-yl 4- methylbenzenesulfonate (Bt-OTs), and 3H-[1,2,3]triazolo[4,5-b]pyridine-3-yl 4-methylbenzenesulfonate (At-OTs) are classically utilized in peptide synthesis for amide-bond formation. However, a previously undescribed reaction of these compounds with alcohols in the presence of a base, leads to 1-alkoxy-1H-benzo- (Bt-OR) and 7-azabenzotriazoles (At-OR). Although BOP undergoes reactions with alcohols to furnish 1-alkoxy-1H-benzotriazoles, Bt-OTs proved to be superior. Both, primary and secondary alcohols undergo reaction under generally mild reaction conditions. Correspondingly, 1-alkoxy-1H-7-azabenzotriazoles were synthesized from At-OTs. Mechanistically, there are three pathways by which these peptide-coupling agents can react with alcohols. From 31P{_1H}, [_18O]-labeling, and other chemical experiments, phosphonium and tosylate derivatives of alcohols seem to be intermediates. These then react with BtO_- and AtO- produced in situ. In order to demonstrate broader utility, this novel reaction has been used to prepare a series of acyclic nucleoside-like compounds. Because BtO_- is a nucleofuge, several Bt-OCH₂Ar substrates have been evaluated in nucleophilic substitution reactions. Finally, the possible formation of Pd πallyl complexes by departure of BtO_- has been queried. Thus, alpha-allylation of three cyclic ketones was evaluated with 1-(cinnamyloxy)-1H-benzo[d][1,2,3]triazole, via in situ formation of pyrrolidine enamines and Pd catalysis.

Full text of DOI:10.3762/bjoc.10.200

Facile synthesis of 1-alkoxy-1H-benzo- and
7-azabenzotriazoles from peptide coupling agents,
mechanistic studies, and synthetic applications
Mahesh K. Lakshman*, Manish K. Singh, Mukesh Kumar, Raghu Ram Chamala,
Vijayender R. Yedulla, Domenick Wagner, Evan Leung, Lijia Yang, Asha Matin
and Sadia Ahmad
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2014, 10, 1919–1932.
Department of Chemistry, The City College and The City University of
New York, 160 Convent Avenue, New York, NY 10031, USA
doi:10.3762/bjoc.10.200
Received: 17 April 2014
Accepted: 10 July 2014
Published: 19 August 2014
Email:
Mahesh K. Lakshman* - lakshman@sci.ccny.cuny.edu
* Corresponding author
Associate Editor: B. Stoltz
Keywords:
© 2014 Lakshman et al; licensee Beilstein-Institut.
License and terms: see end of document.
alkoxy; azabenzotriazole; benzotriazole; peptide-coupling;
phosphonium
Abstract
(1H-Benzo[d][1,2,3]triazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), 1H-benzo[d][1,2,3]triazol-1-yl
4-methylbenzenesulfonate (Bt-OTs), and 3H-[1,2,3]triazolo[4,5-b]pyridine-3-yl 4-methylbenzenesulfonate (At-OTs) are classically
utilized in peptide synthesis for amide-bond formation. However, a previously undescribed reaction of these compounds with alco-
hols in the presence of a base, leads to 1-alkoxy-1H-benzo- (Bt-OR) and 7-azabenzotriazoles (At-OR). Although BOP undergoes
reactions with alcohols to furnish 1-alkoxy-1H-benzotriazoles, Bt-OTs proved to be superior. Both, primary and secondary alco-
hols undergo reaction under generally mild reaction conditions. Correspondingly, 1-alkoxy-1H-7-azabenzotriazoles were synthe-
sized from At-OTs. Mechanistically, there are three pathways by which these peptide-coupling agents can react with alcohols. From
31P{1H}, [18O]-labeling, and other chemical experiments, phosphonium and tosylate derivatives of alcohols seem to be intermedi-
ates. These then react with BtO− and AtO− produced in situ. In order to demonstrate broader utility, this novel reaction has been
used to prepare a series of acyclic nucleoside-like compounds. Because BtO− is a nucleofuge, several Bt-OCH2Ar substrates have
been evaluated in nucleophilic substitution reactions. Finally, the possible formation of Pd π–allyl complexes by departure of BtO−
has been queried. Thus, alpha-allylation of three cyclic ketones was evaluated with 1-(cinnamyloxy)-1H-benzo[d][1,2,3]triazole,
via in situ formation of pyrrolidine enamines and Pd catalysis.
Introduction
Benzotriazole derivatives are of importance in diverse contexts. [1], halogenated benzotriazoles have been shown to inhibit heli-
As examples, in medicinal chemistry substituted benzotriazoles case activity of hepatitis C [2], N-alkylbenzotriazoles were
have been evaluated as inhibitors of respiratory syncytial virus shown to be active and selective towards HCV NTPase/heli-
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Beilstein J. Org. Chem. 2014, 10, 1919–1932.
case [3]. Benzotriazoles also possess anti-amoebic properties, N-substituted benzotriazolyl derivatives, as compared to
particularly against the human pathogen Acanthamoeba that can N-alkyl and N-acyl compounds, those with a C–O–N bond are
infect a variety of organs such as brain, eyes, skin, and lungs less common. Typically the latter are synthesized by the alkyl-
[4]. Triazole and benzotriazole derivatives have been evaluated ation of BtOH with alkyl halides [17,18], quaternary alkyl am-
as antitumor agents, with several showing high activities [5], monium salts [19], or via a Mitsunobu reaction (Scheme 1)
and a benzotriazole derivative was shown to inhibit prolifera- [20].
tion of hepatocarcinoma [6]. Several N-alkylbenzotriazoles
show potent antimicrobial action [7] and others have been eval- Herein, we report a facile approach to 1-alkoxy-1H-benzo- (Bt-
uated as aromatase inhibitors [8]. Benzotriazole derivatives OR) and 7-azabenzotriazoles (At-OR) by a previously
have also been reported to be inhibitors of MAP kinases [9]. unstudied reaction of benzotriazole-based peptide-coupling
Although esters of BtOH are generally intermediates in amide reagents with alcohols [21]. We also describe studies on the
synthesis, stable ones have recently been evaluated against the underlying mechanism and a preliminary disclosure of the
new coronavirus responsible for SARS, and several compounds potential synthetic applications of these products. Figure 1
were shown to be irreversible inhibitors of the viral proteinase shows examples of commercially available phosphonium (e.g.,
3CLpro (also called Mpro) [10]. Benzotriazoles with ether link- BOP, PyBOP, PyAOP, and PyClock) and iminium reagents
ages on the phenyl ring have been reported to be promising (e.g., HBTU, TBTU, HATU, HCTU, and TCTU – uronium
entities in the treatment of glutamate mGluR2 receptor dysfunc- forms are shown) that are commonly used for amide-bond for-
tion-related diseases, such as neurological and psychological mation.
disorders [11].
Results and Discussion
Synthesis of 1-alkoxy-1H-benzo- and
7-azabenzotriazoles (Bt-OR and At-OR)
Benzotriazole-derived compounds also have applications in ma-
terials chemistry. For example, 5-alkyl- and 5-alkanoylamino-
benzotriazoles have been developed to prevent corrosion at
metal surfaces, as metal deactivators, and to prevent degrad-
ation of lubricants and coatings [12,13]. Esters of benzotriazole
and alkylbenzotriazoles have been reported as components in
organic lubricating compositions and in turbine lubricants
[14,15]. Of relevance to this work a single ether of hydroxyben-
zotriazole has been evaluated in lubricant compositions [16].
We have previously described the use of (benzotriazol-1-
yloxy)tris(dimethylamino)phosphonium hexafluorophosphate
(BOP) for the dehydration of aldoximes to cyanides [22]. In that
work, analysis of the reaction course by 31P{1H} NMR did not
show the formation of a new phosphorus signal other than that
for HMPA, which is a reaction byproduct. However, prior
investigations by others [23,24] and by us [25-27] have demon-
strated the formation of phosphonium ions by the reaction of
BOP with the oxygen atoms in amide linkages of purines and
related heterocycles. In fact, related to these observations we
New approaches to benzotriazole derivatives are therefore
expected to have a broad-ranging impact. Among the various
Scheme 1: Examples of methods for the synthesis of 1-alkoxy-1H-benzo[d][1,2,3]triazoles.
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Beilstein J. Org. Chem. 2014, 10, 1919–1932.
Scheme 2: Three possible mechanisms for the reaction of BOP with
oxygen nucleophiles.
yields of Bt-OMe (1a, 48% and 50%, respectively). Use of
MeOH as reaction solvent itself resulted in a 47% yield of 1a.
These results seem to imply that maximal conversion of BOP to
the N-alkoxybenzotriazoles is around 50%, possibly due to a
competing reaction between BOP and DBU (see below). Never-
theless, 1° and 2° alcohols appear to react with BOP in the pres-
Figure 1: Examples of commercially available reagents for amidation
reactions.
have demonstrated the isolation and synthetic utility of a ence of a base, leading to the direct formation of N-alkoxyben-
nucleoside phosphonium salt [28]. Thus, to us the reaction of zotriazoles.
oximes with BOP was an intriguing result, leading us to query
whether a benzotriazolyl intermediate, rather than a phospho- Because reactions with BOP produce HMPA, a suspected nasal
nium ion, was formed en route to the cyanide. This line of carcinogen, and the modest yields of the N-alkoxybenzotria-
reasoning would then suggest that 1-alkoxy-1H-benzotriazoles zoles obtained, we decided to investigate other reactive BtOH
may indeed be obtainable from the reactions of alcohols with derivatives for this reaction. A variety of phosphorus and
BOP, and that different reaction pathways may be operative sulfonate derivatives of BtOH has been synthesized and studied
depending upon the nature of the nucleophile (Scheme 2). as peptide-coupling agents [30]. Amongst these we selected the
However, the formation of 1-alkoxy-1H-benzotriazoles by such easily synthesized tosylates of BtOH (Bt-OTs) and its 7-aza
an approach appeared implausible on the basis of prior observa- analogue AtOH (At-OTs). Furthermore, we have used Bt-OTs
tions, where no reaction of BOP with the free hydroxy groups for conversion of aldoximes to nitriles and this reagent was gen-
of nucleosides was observed [23,25].
erally comparable to BOP in those reactions. This factor addi-
tionally favored the selection of these two tosylate derivatives.
Our recent work on a two-step one-pot etherification of purine
nucleosides, quinazoline, and pyrimidines, had led some As can be seen from Table 2, Bt-OTs is superior to BOP, and a
interesting preliminary observations [29]. Although BOP did wide range of 1° and 2° alcohols underwent reaction with
not react with MeOH in the absence of a base, in the presence Bt-OTs giving good to excellent yields of 1-alkoxy-1H-benzo-
of Cs2CO3 rapid formation of HMPA was observed and triazoles. Some notable results are as follows. Despite the
1-methoxy-1H-benzotriazole (1-methoxy-1H-benzo[d][1,2,3]- leaving group ability of BtO−, elimination to styrene does not
triazole) was isolated [29]. This evidence clearly showed that appear to be a significant problem in the reactions with the
alcohols are capable of reaction with BOP in the presence of a isomeric phenylethanols (Table 2, entries 5 and 6). Not unex-
base. Thus, we first evaluated whether the reaction of BOP with pectedly, reaction with 1,3-butanediol occurred predominantly
alcohols was general and we elected to use DBU as base for at the 1° hydroxy group (Table 2, entry 12). The reaction with
cost considerations. Table 1 shows the results of this analysis. propargyl alcohol proceeded uneventfully (Table 2, entry 14).
The reaction of 4-nitrobenzyl alcohol (Table 2, entry 15) was
Reaction of BOP with either 1.4 or 2.7 molar equiv of MeOH, complicated by the formation of 4-nitrobenzaldehyde. This can
in the presence of 1.4 molar equiv of DBU, gave comparable potentially occur by benzylic deprotonation, due to the
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Table 1: Reactions of alcohols with BOP and DBU.a
Entry
Alcohol
Product
Time (h at rt)
Compound: yieldb
1a: 48%
1a: 50%c
1a: 47%d
24
24
1
2
3
4
24
48
48
1b: 52%
1c: 52%
1d: 39%
5
6
72
48
1e: 43%
1f: 39%
aReactions were conducted with 1.1 mmol of BOP (ca. 0.2 M in THF), 1.2 molar equiv of alcohols, and DBU, at room temperature. bYields are of
isolated and purified products. cYield obtained with 2.7 molar equiv of MeOH. dYield obtained with MeOH as reaction solvent.
Table 2: Reactions of various alcohols with Bt-OTs.
Entry
Alcohol
Product
Time, temp
3 h, rt
Compound: yielda
1
1a: 66%
2
3
4
3 h, rt
1b: 85%
1c: 73%
1d: 91%
3 h, rt
1.5 h, rt
5
24 h, rt
1e: 77%
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Table 2: Reactions of various alcohols with Bt-OTs. (continued)
6
8 h, rt
3 h, rt
1f: 90%
1g: 83%
7
8
2.5 h, rt
4 h, rt
1h: 74%
1i:72%
1j: 51%
9
10
24 h, rt
11
12
2.5 h, rt
4 h, rt
1k: 87%
1l: 48%
13
14
15
24 h, 60 °C
3.5 h, rt
6 h, rt
1m: 53%
1n: 79%
1o: 68%
16
3 h, rt
1p: 84%
aYields are of isolated and purified products.
enhanced acidity of these protons in 1o or a reactive intermedi- mation of the desired product 1o in good yield (see Supporting
ate. Such a problem was not encountered in the reactions of Information File 1 for details). Reaction of phenol with Bt-OTs
other benzylic alcohols. Use of K2CO3 in place of DBU did not resulted in the formation of the phenyl tosylate (Table 2, entry
ameliorate this problem encountered with 4-nitrobenzyl alcohol. 16), indicating the potential use of this reagent as a tosylating
However, use of slightly modified conditions resulted in the for- agent for phenols. The outcome in the phenol reaction may be
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Beilstein J. Org. Chem. 2014, 10, 1919–1932.
linked to the potential reaction pathway, an aspect that is the exact nature of the interaction of these bases with BOP, it is
described below. However, because phenoxide is a softer clear that a reaction occurs, and this may be responsible for the
nucleophile as compared to alkoxide, we had to consider lower yields in the reactions of alcohols with BOP. These data
whether this was a factor in the reaction mechanism.
additionally supported the use of Bt-OTs as an alternative.
In reactions of alcohols with BOP or Bt-OTs, the product struc- Although no new phosphonium resonance from a new reactive
ture is independent of the mechanism since all possible mecha- species was observed in the NMR experiments, this did not ne-
nisms result in the same product. However, for reactions with cessarily exclude pathway a. Thus, we decided to pursue a
unsymmetrical peptide-coupling agents, an understanding of the second line of investigation via [18O]-labeling. For this experi-
mechanistic details would be required. Thus, the next stage in ment, we prepared PhCH2[18O]H via a known procedure [31].
these investigations focused on this aspect.
As shown in Scheme 3, we reasoned that exclusive reaction via
pathway a should produce an unlabeled product, reaction via
pathway b and/or c should result in the [18O]-labeled product,
Mechanistic studies
Our investigations began with the reactions of BOP. We and competing pathways should result in a mixture of labeled
reasoned that among the three pathways shown in Scheme 2, and unlabeled products.
31P{1H} NMR may allow for distinguishing pathway a from b
and c. Thus, we conducted experiments with 2-phenylethanol as With this mechanistic rationale two reactions of BOP were
a representative 1° alcohol. BOP and 2-phenylethanol were conducted in parallel with PhCH2OH as well as PhCH2[18O]H
mixed in a 1:1 molar ratio at −78 °C in THF. The mixture was and DBU. The product yields from both reactions were nearly
then transferred to the NMR probe maintained at −30 °C, and a identical (ca 39%). High-resolution mass spectrometric analysis
spectrum was acquired. The only resonances observed were indicated that the ratio of the peak areas [M + 2]+/[M]+ was
those of BOP (δ = 42.7 and −145.5 ppm). DBU (1 molar equiv) 0.015 for products from both reactions. Pathway a alone can
was added and the reaction was monitored every five minutes at account for this result and it appears that no leakage occurs via
−30 °C. The only observable resonance that began to emerge pathways b and c. A comparable [18O]-labeling experiment was
was that of HMPA (δ = 22.9 ppm). Reacquisition of data after conducted with Bt-OTs, where again no incorporation of the
leaving the mixture at room temperature overnight only showed label was observed in the product, and the ratio of the peak
an increase in the HMPA resonance (Figure 2).
areas [M + 2]+/[M]+ was 0.014. These results showed that both
reagents, BOP and Bt-OTs, appear to react via similar path-
We also conducted 31P{1H} experiments where BOP was inde- ways, not involving direct reactions at either the N1 or N3 atom
pendently exposed to DBU and Cs2CO3. In both cases, rapid in the benzotriazole ring. In support of this inference, a reaction
disappearance of BOP was observed with concomitant forma- of Bt-OTs with allyl alcohol was conducted at −78 °C.
tion of HMPA. Although at the present time we do not know Quenching this reaction after 30 min, followed by preparative
Figure 2: Evaluation of the reaction between 2-phenylethanol and BOP by 31P{1H} NMR.
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Scheme 3: Possible products in the [18O]-labeling experiments.
TLC of a portion of the mixture, led to the isolation of the allyl those reported [35] for 1-methoxy-1H-4-azabenzotriazole
alcohol tosylate [32,33]. However, even at this low temperature, (1-methoxy-1H-[1,2,3]triazolo[4,5-b]pyridine) and 1-methoxy-
formation of 1-(allyloxy)-1H-benzotriazole (1c) was clearly 1H-7-azabenzotriazole (3-methoxy-3H-[1,2,3]triazolo[4,5-
evident, indicating the ease of this transformation. In the light of b]pyridine) did not allow for ready identification. A NOE
these results, the reaction of phenol with Bt-OTs is consistent experiment did not result in observable interactions of the OMe
with the proposed pathway a, and it appears that both alkoxides resonance with the aromatic system. Because neither experi-
and phenoxides react in a similar manner. The mechanistic basis ment allowed for unambiguous discrimination between the two
in reactions of alcohols with BOP and Bt-OTs described above structures, 1-methoxy-1H-7-azabenzotriazole was prepared via
appears to parallel that reported for the activation of carboxylic a known procedure [35]. The chemical shifts for the aromatic
acids by BOP. In the carboxylic acid activation studies, only protons in the authentic 1-methoxy-1H-7-azabenzotriazole
two mechanisms were proposed, namely reaction of the prepared, the product obtained from the reaction of At-OTs and
carboxylate at the phosphorus center (equivalent to pathway a MeOH, as well as the literature data are shown in Table 3. From
in Scheme 3) or a SN2’ reaction at the N3 atom (equivalent to the Δδ values in this table, it becomes clear that the product
pathway b in Scheme 3) [34]. Experiments with [18O]-labeled obtained in Scheme 4 is in fact 1-methoxy-1H-7-azabenzotria-
benzoate indicated that conversion of carboxylic acids to the zole. Additionally, the melting point of this product was
acyl HOBt derivatives occurs by a two-step process, via an 94.5–95.5 °C, which is consistent with that reported for
intermediate acyloxyphosphonium ion [34].
1-methoxy-1H-7-azabenzotriazole (93–94 °C [35]) and the
authentic material synthesized herein (94–95 °C). By contrast,
One final set of experiments was conducted to evaluate the the reported melting point of 1-methoxy-1H-4-azabenzotriazole
mechanism in the context of a desymmetrized benzotriazole. is significantly higher (140–144 °C) [35].
For this we considered the reaction of At-OTs [30] with MeOH,
where we believed location of the OMe moiety could be ascer- Having ascertained the overall mechanism by which alcohols
tained relative to the aromatic protons via NOE experiments react with Bt-OTs as well as At-OTs, and that this mechanism is
(Scheme 4).
not altered by the presence of the additional nitrogen atom in
At-OTs, the reactions of At-OTs with alcohols were then evalu-
ated (Table 4). Reactions with At-OTs appear to be more
temperature sensitive than those with Bt-OTs, and reaction
mixtures can turn to dark colors at elevated temperatures.
After demonstrating the one-step preparation of 1-alkoxy-1H-
benzo- and 7-azabenzotriazoles, our next focus was the poten-
tial applications of this chemistry. Since the heterocyclic moiety
resembles a nucleobase, we first considered synthesis of nucleo-
side-like entities (Scheme 5). In this context, N-alkylbenzotria-
zolyl derivatives and ribonucleoside analogues containing a
Scheme 4: Two possible products from the reaction of At-OTs with
MeOH.
Reaction of At-OTs with MeOH yielded a 1-methoxyazabenzo- benzotriazole as a nucleobase surrogate have shown interesting
triazole (At-OMe), and the 1H NMR spectrum of the crude activities towards NTPase/helicase of Flaviviridae viruses [1,2].
reaction mixture indicated the presence of only one product. Compounds 3a,b and 5a,b shown in Scheme 5 are both
Comparison of the 1H NMR data of the purified material to N-substituted benzotriazoles and, upon appropriate folding of
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Table 3: Comparison of chemical shifts for the aromatic protons in the isomeric 1-methoxyazabenzotriazoles.a
Compound
Ar–H chemical shift (δ ppm)
Δδ (ppm)
8.73
8.37
7.41
8.73 − 8.37 = 0.36
8.37 − 7.41 = 0.96
8.73 − 7.41 = 1.32
1-Methoxy-1H-azabenzotriazole obtained by reaction of At-OTs
8.67
8.31
7.36
8.67 − 8.31 = 0.36
8.31 − 7.36 = 0.95
8.67 − 7.36 = 1.31
+ MeOH
8.75
8.40
7.43
8.75 − 8.40 = 0.35
8.40 − 7.43 = 0.97
8.75 − 7.43 = 1.32
b
8.80
8.04
7.52
8.80 − 8.04 = 0.36
8.04 − 7.52 = 0.52
8.80 − 7.52 = 1.28
b
aSpectra were obtained in CDCl3. bReference [35].
Table 4: Reactions of various alcohols with At-OTs.
Entry
Alcohol
Product
Time, temp
Compound: yielda
1
24 h, rt
24 h, rt
24 h, rt
2a: 74%
2
3
2b: 69%
2c: 80%
4
24 h, 60 °C
2d: 64%
5
6
24 h, rt
24 h, rt
2e: 68%
2f: 67%
7
24 h, rt
2g: 68%
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Table 4: Reactions of various alcohols with At-OTs. (continued)
8
24 h, 60 °C
2h: 59%
2i: 34%
2j: 73%
9
24 h, 60 °C
10
2 h, rt
aYields are of isolated and purified products.
Scheme 5: Synthesis of acyclic nucleoside-like compounds.
the aliphatic chain, they resemble acyclic nucleosides (3a,b) Reaction of compound 1f with NaN3 in DMSO at 100 °C for
and ribonucleosides (5a,b).
28 h led to the formation of (2-azidoethyl)benzene, as assessed
by 1H NMR. However, this reaction was incomplete and about
12% of 1f remained unreacted. Nevertheless, these results indi-
cate the leaving group ability of BtO− from benzylic sp3 carbon
centers and are interesting in the context of the previously
unknown reactivity of this class of compounds. Whether the
At-OR derivatives are more reactive in such reactions will be
interesting to evaluate in the future.
Reaction of Bt-OTs and At-OTs with 1,3-propanediol gave
products 3a and 3b, arising from reaction at one hydroxy group,
in good yields. In these reactions minor amounts of products
arising by reaction at both hydroxy groups were observed. Simi-
larly, reactions of 3-butenol gave products 4a and 4b in good to
high yields, which were converted to the acyclic ribonucleo-
side-like diols (±)-5a and (±)-5b, respectively.
On the basis of the leaving group ability of BtO− in the substitu-
We next assessed the leaving group ability of the benzotri- tion reactions shown above, our final question was about the re-
azolyloxy group. Although carboxylic acid esters of benzotri- activity of an allylic benzotriazolyl derivative under palladium-
azole react efficiently with nucleophiles, this is mechanistically catalyzed conditions. The benzoyl ester of BtOH has been eval-
distinct from direct displacement. Thus, four of the 1-alkoxy- uated in a decarboxylative Pd-mediated Heck reaction, leading
1H-benzotriazoles (three 1° and one 2°) were utilized in substi- to a modest product yield [36]. However, this appears to be the
tution reactions with cyanide, azide, phenoxide, and benzotri- only example of a BtOH derivative in Pd-mediated reactions. In
azole. These reactions were conducted in DMSO at 100 °C and principle, formation of π–allyl complexes from allylic benzotri-
the results are shown in Figure 3. In the presence of Cs2CO3, azolyloxy products described herein should be feasible. In this
reactions with benzotriazole as nucleophile yielded the N1- and context, N-allylbenzotriazole derivatives undergo reaction with
N2-alkyl products in variable ratios, but in good overall yields preformed enamines, in the presence of Pd(OAc)2 and PPh3
(>75%). Whereas the 1-alkoxy-1H-benzotriazoles used in these [37]. Super-stoichiometric ZnBr2 was necessary for these reac-
reactions were benzylic, and therefore more reactive, we also tions, in the absence of which no reaction was observed [37].
assessed the reactivity of 1-phenethoxy-1H-benzotriazole (1f). With these data in mind, we decided to evaluate a few reactions
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Beilstein J. Org. Chem. 2014, 10, 1919–1932.
Figure 3: Products from the nucleophilic substitution reactions.
of cinnamyloxy benzotriazolyl derivative 1g. However, instead results appear to indicate that the easily synthesized allylic
of using preformed enamines, we chose to utilize a combina- benzotriazolyl derivatives described herein may be promising
tion of metal- and organocatalysis, wherein the enamine is reagents for the α-allylation of carbonyl compounds.
formed in situ [38]. Exposure of 1.5 molar equiv each of cyclo-
hexanone, N-benzylpiperidone, and 4-tert-butylcyclohexanone As a final note, while this work was in progress, synthesis of
to compound 1g, Pd(PPh3)4 (5 mol %), and pyrrolidine pyridopyrazine-1,6-diones was reported, beginning from
(30 mol %) in DMSO at room temperature, led to the corres- 6-hydroxypicolinic acids and amino ethanols [39]. Here, HATU
ponding γ,δ-unsaturated cycloalkanones (Figure 4).
(Figure 1) not only functioned in the conventional role of
carboxylic acid activating agent for amide formation, but it was
Good yields of products 18 and 19 were obtained (literature serendipitously discovered that HATU also caused an unusual
yields are superior, ca. 90% [37,38]) and the yield of com- activation of the alcohol moiety, leading to N-alkylation. In the
pound 20 was excellent. Although the present conditions are not presence of iPr2NEt, reaction of HATU with benzyl-, n-butyl-,
optimized, these results appear to indicate that the yields may and p-nitrobenzyl alcohol led to the formation of the corres-
be dependent upon the nature of the cycloalkanone and not ponding 1-alkoxy-1H-7-azabenzotriazoles [39]. The regiochem-
solely upon the reactivity of the allylic benzotriazolyl deriva- istry in these reactions was identical to that reported here. What
tive. However, there are some notable factors. ZnBr2 is essen- is notable about reagents such as HBTU and HATU is that they
tial to the formation of π–allyl complexes from N-allylbenzotri- are commonly encountered in the guanidinium (N form) rather
azole derivatives, by assisting in the departure of the benzotria- than the uronium (O form). Although the uronium form can be
zolyl anion [37]. In the current cases, no additive is necessary synthesized and is a more reactive species, it undergoes rapid
for the departure of BtO−. Furthermore, the enamine was isomerization to the guanidinium form in the presence of bases
formed in situ in this study, with catalytic pyrrolidine. These [40]. Thus, it can be reasonably anticipated that formation of
Figure 4: γ,δ-Unsaturated cycloalkanones obtained from 1g.
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Beilstein J. Org. Chem. 2014, 10, 1919–1932.
Bt-OR and At-OR from the reactions of alcohols with HBTU combination of 31P{1H}, [18O]-labeling, and other chemical
and HATU would proceed via the intermediacy of a uronium experiments. The reaction of phenol with Bt-OTs yielded only
salt of the alcohol, leading to a regiochemical outcome with the phenyl tosylate, which is consistent with this mechanism.
unsymmetrical reagents as shown in Scheme 6.
This reaction also shows that Bt-OTs (and At-OTs) could serve
as tosylating agents for phenols as well. Further, the utilities of
this reaction, as well as some of the products have been
explored. In this vein, acyclic nucleoside-like compounds
containing benzo- and azabenzotriazole as a nucleobase surro-
gate have been synthesized. Because benzotriazole derivatives
have potentially important pharmacological applications, we
anticipate expansion of this chemistry in the future to a broader
range of nucleoside-like entities for biological assays. The
ability of BtO− to function as a nucleofuge, led us to explore its
displacement. In this context, several 1-alkoxy-1H-benzotria-
zoles obtained from benzylic alcohols underwent substitution
reaction with a range of nucleophiles, and a simple alkyl deriva-
tive also underwent reaction although the reaction was slightly
incomplete. Finally, we have evaluated the departure of BtO−
from an allylic position leading to a putative Pd π–allyl com-
plex. In unoptimized preliminary results, Pd-catalyzed α-allyla-
tion of three cyclic ketones was accomplished with a cinnamyl-
Scheme 6: Formation of Bt-OR and At-OR from HBTU and HATU type
of compounds.
Because the guanidinum forms of HBTU and HATU have oxy benzotriazolyl derivative, through in situ formed pyrroli-
lower reactivity than the uronium forms [40] slightly more dine enamines. Overall, the potential scope of this new chem-
forcing conditions may be needed to obtain satisfactory reactiv- istry appears promising, ranging from the development of novel
ity. Consistent with this, compound 2c was obtained in 83% molecules with new applications, to synthetic methodology. We
yield from a reaction of benzyl alcohol, HATU, and iPr2NEt, in anticipate reporting additional developments in this area in the
refluxing CH2Cl2 for 16–20 h [39]. By contrast, compound 2c future.
was obtained in a comparable 80% yield in a 24 h reaction with
Experimental
At-OTs and DBU at room temperature. In our hands however,
reaction of HATU with some other alcohols of interest have not General experimental considerations
been successful so far.
Thin-layer chromatography was performed on 200 μm
aluminum-foil-backed silica gel plates. Column chromato-
graphic purifications were performed on 200–300 mesh silica
Conclusion
In this study we have investigated a one-step alkylation gel. THF was distilled from LAH and then redistilled from Na
1-hydroxy-1H-benzotriazole (BtOH) and its 7-aza analogue prior to use. Ethyl acetate (EtOAc) and hexanes were distilled
(AtOH), via a previously unknown reaction of alcohols with from CaSO4, commercial CH2Cl2 was redistilled. Other
benzotriazole-based peptide-coupling agents. Although reac- commercially available compounds were used without further
tions of alcohols proceeded with (benzotriazol-1-yloxy)tris(di- purification. 1H NMR spectra were recorded at 500 MHz and
methylamino)phosphonium hexafluorophosphate (BOP) and are referenced to the residual protonated solvent resonance.
DBU, Bt-OTs was a more effective reagent. Correspondingly, 13C NMR spectra were recorded at 125 MHz and are refer-
the 7-aza derivatives were synthesized from At-OTs. Method- enced to the solvent resonance. Chemical shifts (δ) are reported
ologically, this one-step process allows for the direct conver- in parts per million (ppm) and coupling constants (J) are in
sion of alcohols to N-alkoxy benzo- and azabenzotriazoles, hertz (Hz). Standard abbreviations are used to designate reso-
eliminating the necessity for alkyl halides or more cumbersome nance multiplicities.
methods. Mechanistic studies indicate that reactions of alcohols
with these peptide-coupling reagents, in the presence of a base, General procedure for the reactions of alcohols with
appear to proceed by formation of alcohol phosphonium deriva- BOP
tives (with BOP), or alcohol tosylates (with Bt-OTs), and not In a dry vial equipped with a stirring bar was placed BOP
through direct displacement of the leaving group by attack at (0.486 mg, 1.1 mmol) in anhydrous THF (5 mL). The alcohol
the N1 or by a SN2’-type of process by reaction at the N3 of the (1.36 mmol) was added, followed by the dropwise addition of
triazolyl moiety. The mechanistic analyses were conducted by a DBU (1.36 mmol). The reaction mixture was stirred at room
1929

Beilstein J. Org. Chem. 2014, 10, 1919–1932.
temperature for the duration indicated in Table 1. The mixture by sequential elution with 50% and 60% EtOAc in hexanes.
was diluted with EtOAc, washed with brine, and then with Compound 2j was obtained as colorless solid (63.5 mg, 73%
water. The organic layer was separated, dried over anhydrous yield). Rf 0.24 (SiO2/30% EtOAc in hexanes); 1H NMR
Na2SO4, and evaporated under reduced pressure. Products were (500 MHz, CDCl3) δ 8.72 (dd, J = 1.5, 4.4 Hz, 1H, Ar-H), 7.37
purified by chromatography on a silica gel column using a (dd, J = 1.4, 8.4 Hz, 1H, Ar-H), 7.41 (dd, J = 4.4, 8.4 Hz, 1H,
gradient of EtOAc in hexanes. The products from these reac- Ar-H), 5.27 (d, J = 2.6 Hz, 2H, OCH2), 2.60 (t, J = 2.4 Hz, 1H,
tions were identical to those produced from the reactions of ≡C-H); 13C NMR (125 MHz, CDCl3) δ 151.6, 140.2, 135.1,
Bt-OTs for which full characterization is provided.
129.5, 121.0, 79.9, 75.4, 67.9; HRMS–ESI TOF (m/z): [M +
H]+ calcd for C8H7N4O, 175.0614; found, 175.0621.
General procedure for the reactions of alcohols with
Bt-OTs
1-Benzyl-3-cinnamylpiperidin-4-one (19)
In a dry vial equipped with a stirring bar was placed Bt-OTs in To a solution of cinnamyloxybenzotriazole (1g, 125.6 mg,
anhydrous THF. The alcohol was added, followed by the drop- 0.50 mmol) in DMSO (2 mL), Pd(PPh3)4 (28.8 mg, 25 μmol,
wise addition of DBU. The reaction mixture was stirred either 5 mol %) was added, and the mixture was stirred at room
at room temperature or at 60 °C for the duration indicated in temperature for 5 min. Then N-benzylpiperidone (278 µL,
Table 2 and then worked up. The stoichiometry of reactants was 1.50 mmol) and pyrrolidine (12 µL, 0.15 mmol, 30 mol %)
dependent upon the volatility of the alcohol. Generally, with were added. The reaction vial was flushed with nitrogen gas and
lower boiling alcohols, Bt-OTs was the limiting reagent, the mixture was stirred at room temperature for 2 h. The mix-
whereas Bt-OTs was used in excess with higher boiling ones. ture was then diluted with EtOAc and was washed with water
Also, if initial experiments gave poorer results with a lower followed by brine. The organic layer was dried over anhydrous
amount of an alcohol, then reactions were conducted with Na2SO4 and evaporated. The crude material was chro-
higher excesses of the alcohol. Specific experimental and work- matographed on a silica gel column using 18% EtOAc in
up details are provided under the individual compound head- hexanes as eluting solvent. Compound 19 was obtained as a
ings.
pale yellow solid (100.9 mg, 66% yield). Rf 0.26 (SiO2/30%
EtOAc in hexanes); 1H NMR (500 MHz, CDCl3) δ 7.34–7.27
(m, 9H, Ar-H), 7.22–7.18 (m, 1H, Ar-H), 6.37 (d, J = 15.8 Hz,
1H, =CH), 6.14 (dt, J = 7.5, 15.4 Hz, 1H, =CH), 3.70 and 3.53
Representative examples
1-(1-Phenylethoxy)-1H-benzo[d][1,2,3]triazole (1e)
The compound was synthesized from Bt-OTs (1.16 g, (two d, JA,B = 12.7 Hz, 2H, CH2), 3.09 and 3.00 (two AB m,
4.0 mmol), 1-phenylethanol (580 μL, 4.8 mmol), and DBU 2H, CH2), 2.69–2.22 (m, 7H, CH2, CH2, CH2, CH); 13C NMR
(720 μL, 4.8 mmol) in anhydrous THF (20 mL) over 24 h at (125 MHz, CDCl3) δ 210.4, 138.4, 137.5, 132.1, 129.1, 128.7,
room temperature. The volatiles were evaporated and the crude 127.7, 127.3, 126.3, 62.0, 58.6, 53.5, 49.9, 41.1, 31.2;
material was purified on a silica gel column using 6% EtOAc in HRMS–ESI TOF (m/z): [M + H]+ calcd for C21H24NO,
hexanes as eluting solvent. Compound 1e was obtained as a 306.1852; found, 306.1833.
white solid (0.282 g, 77% yield). Rf 0.38 (SiO2/30% EtOAc in
hexanes); 1H NMR (500 MHz, CDCl3) δ 7.91 (d, J = 8.3 Hz,
Supporting Information
1H, Ar-H), 7.36 (m, 2H, Ar-H), 7.29–7.27 (m, 5H, Ar-H), 7.13
(d, J = 8.3 Hz, 1H, Ar-H), 5.76 (q, J = 6.6 Hz, 1H, OCH), 1.86
Supporting Information File 1
(d, J = 6.3 Hz, 3H, CH3); 13C NMR (125 MHz, CDCl3) δ
143.1, 138.1, 129.4, 128.7, 128.2, 127.6, 127.4, 124.2, 119.8,
108.9, 88.9, 19.9; HRMS–ESI TOF (m/z): [M + H]+ calcd for
C14H14N3O, 240.1131; found, 240.1121.
Experimental.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-10-200-S1.pdf]
Supporting Information File 2
NMR spectra.
3-(Prop-2-yn-1yloxy)-3H-[1,2,3]triazolo[4,5,b]pyri-
dine (2j)
The compound was synthesized from At-OTs (0.159 g,
0.55 mmol), propargyl alcohol (60 μL, 0.5 mmol), and DBU
(89 μL, 0.6 mmol) in anhydrous THF (2.5 mL) over 2 h at room
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-10-200-S2.pdf]
temperature. The reaction mixture was partitioned between Acknowledgements
EtOAc and water. The organic layer was separated, dried over This work was supported by National Institutes of Health Grant
anhydrous Na2SO4, and evaporated under reduced pressure. R21AI094545 from the National Institute of Allergy and Infec-
The crude product was chromatographed on a silica gel column tious Diseases. Infrastructural support at CCNY was provided
1930

Beilstein J. Org. Chem. 2014, 10, 1919–1932.
16.Braid, M. Lubricant compositions and ether or ester of
by National Institutes of Health Grant G12MD007603 from the
National Institute on Minority Health and Health Disparities.
We thank the following individuals for their assistance: Prof.
(Emeritus) Louis Carpino (University of Massachusetts,
Amherst) for providing 1H NMR spectra of synthetic samples
of 1-methoxy-1H-4-azabenzotriazole and 1-methoxy-1H-7-
azabenzotriazole, Ms. Nonka Sevova and Dr. Bill Boggess
(University of Notre Dame Mass Spectrometry and Proteomics
Facility) for some of the HRMS analyses (supported by NSF
Grant CHE-0741793), and Dr. Padmanva Pradhan (NMR lab
manager at CCNY) for assistance with some NMR experiments.
1-hydroxybenzotriazole as antioxidant in the compositions. U.S. Patent
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N
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