Novel synthesis of benzotriazolyl alkyl esters: an unprecedented CH2insertion

Article abstract of DOI:10.1039/d0ra10413b

We have developed a novel method for the synthesis of benzotriazolyl alkyl esters (BAEs) fromN-acylbenzotriazoles and dichloromethane (DCM) under mild conditions. This reaction is one of few examples to show the use of DCM as a C-1 surrogate in carbon-heteroatom bond formation and to highlight the versatility of using DCM as a methylene building block.

Full text of DOI:10.1039/d0ra10413b

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Novel synthesis of benzotriazolyl alkyl esters: an
unprecedented CH2 insertion†
Cite this: RSC Adv., 2021, 11, 7564
abd
Mohamed Elagawany,abc Lingaiah Maramab and Bahaa Elgendy
*
Received 10th December 2020
Accepted 8th February 2021
We have developed a novel method for the synthesis of benzotriazolyl alkyl esters (BAEs) from N-
acylbenzotriazoles and dichloromethane (DCM) under mild conditions. This reaction is one of few
examples to show the use of DCM as a C-1 surrogate in carbon–heteroatom bond formation and to
highlight the versatility of using DCM as a methylene building block.
DOI: 10.1039/d0ra10413b
rsc.li/rsc-advances
strong affinity to the surface and can be detected by SERRS at very
low levels and consequently allow for an enzyme assay with ultra-
sensitivity for enzyme turnover monitoring.4–6
The most common synthetic approaches to synthesize BAEs
are condensation of the hydroxymethylbenzotriazole and
carboxylic acids,3 and the reaction of the appropriate sodium
benzotriazolate with chloromethyl esters.4
Dichloromethane (DCM) is reported to react with strong
nucleophiles,7–9 and bases.10 For example, DCM is reported to
degrade at low temperature in bispidine and give 1,3-
Introduction
Benzotriazolyl alkyl esters (BAEs) are bifunctional building
blocks that can be used for the construction of a myriad of
multifunctional chemical compounds. The benzotriazolyl (Bt)
and acyloxy groups are good leaving groups and can be selec-
tively eliminated to provide useful scaffolds for the synthesis of
important chemical compounds. For example, upon treatment
of benzotriazolyl alkyl esters with organozinc reagents, one can
substitute the benzotriazolyl moiety with several groups (e.g. alkyl,
aryl, alkenyl,.etc) to synthesize esters.1 Alternatively, chemo-
selective reduction of benzotriazolyl alkyl esters with SmI2 leads to
the cleavage of the acyloxy group and formation of a Bt bearing
radical that undergoes cross-coupling with carbonyl compounds
to form a variety of b-(benzotriazole-1-yl)alcohols.2
Multifunctional ligands based on the BAE moiety (i.e. I and
II, Fig. 1) were developed as nitrogen-donor ligands, and were
shown to have the ability to coordinate to transition metals such
as Rh(I), Ir(I), and Co(II). These ligands stabilized their metal
ions in multiple oxidation states and geometries, and improved
their activity in the carbonylation of methanol. These ligands
were synthesized by condensation of the hydroxymethyl-
benzotriazole and carboxylic acids in DCM in the presence of
DCC, DMAP, and 4-pyrrolidinopyridine.3
Aryl azo benzotriazolyl alkyl esters (III, Fig. 1) are used as masked
enzyme substrates that can be detected by surface-enhanced reso-
nance Raman scattering (SERRS) only aer hydrolysis by the enzyme
of interest. This enzymatic hydrolysis generates the dye that has
aDepartment of Pharmaceutical and Administrative Sciences, University of Health
Sciences and Pharmacy, St. Louis, MO 63110, USA. E-mail: belgendy@wustl.edu
bCenter for Clinical Pharmacology, Washington University School of Medicine, St.
Louis College of Pharmacy, St. Louis, MO 63110, USA
cDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, Damanhour
University, Damanhour, Egypt
dChemistry Department, Faculty of Science, Benha University, Benha 13518, Egypt
† Electronic supplementary information (ESI) available. CCDC 1998062. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/d0ra10413b
Fig. 1 (A) Examples of multifunctional ligands based on BAE moiety (I
and II) and aryl azo BAE enzyme substrates (III). (B) Compounds IV–IX
synthesized using DCM as a C-1 surrogate.
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diazaadamantane hydrochloride (IV) as the major product
(Fig. 1).11 Methylene bridged cyclic amines such as dipyrrolidyl-
methane (V), dipiperidylmethane (VIa), and dimorpholinyl-
methane (VIb) are useful chelating ligands (Fig. 1). These ligands
can be synthesized easily at room temperature by stirring the
corresponding bases with DCM in absence of light.12 Similarly,
methylenebispyridinium dichloride (VII) was formed when pyri-
dine was dissolved in DCM and le for long time.13 DCM was used
as a C-1 surrogate in several synthetic reactions. For example,
Zhang et al. used DCM as a C-1 building block in the synthesis of
propargylamines VIII via CuCl catalysis.14 Another example was the
synthesis of substituted benzofurane IX via a three component
reaction involving DCM as a source of methylene in a C]C bond
formation.15
Fig. 2 (A) 1H NMR of 3a. (B) 1H NMR of 3b. (C) Overlay of 1H NMR of 3a
(green) and 3b (red).
In continuation of our work developing new synthetic
approaches for the preparation of biologically active
compounds,16–26 we discovered and developed a new method-
ology for the synthesis of BAEs via CH2 insertion using DCM.
The new method is general, convenient and has a broad scope
of applicability to various substrates.
(DCM) as a co-solvent to enhance the solubility of the starting
materials. The reaction mixture became homogeneous, but no
reaction took place. We repeated the reaction using one equiva-
lent of DMAP, but no change was observed at room temperature.
Heating the reaction mixture at 60 ꢀC for 12 h led to consumption
of the acyl benzotriazole and formation of a new product 3a,
which was isolated and puried (Scheme 1). Aminotropone 1a was
isolated as a side product. The molecular weight of the expected
product 4 is 444, but LC/MS of 3a showed a molecular weight of
397 (M + H) (i.e. 48 mass unit difference from 4 and 31 mass unit
difference from 2a). Comparing 1H NMR spectrum of 3a to
spectrum of 2a showed two additional protons at 6.50 and
7.70 ppm. The two protons appeared as douplets with the same
coupling constant (i.e. J ¼ 11.3 Hz). The 13C NMR spectrum
showed an extra aliphatic carbon at 68.2 ppm. We ran a series of
2D NMR to identify the product and we found that the two
unexpected protons at 6.50 and 7.70 ppm are attached to the same
aliphatic carbon at 68.2 ppm and the new product has the Boc-L-
Phe moiety.
When we tried the coupling of aminotropone 1a with either acyl
benzotriazole (2b) and/or benzoyl benzotriazole (2c) (Scheme 1)
under the same reaction conditions (ACN/DCM, DMAP/60 ꢀC), we
obtained products that has the same mass differences from
substrates and expected products that was observed in the case of
Boc-L-Phe–Bt (i.e. 31 and 48). Coupling of other aminotropones (i.e.
1b and 1c), and tropone 1d led to the formation of similar unex-
pected products with 48 mass unit difference than the expected
products. In both cases aminotropones (1b and 1c) and tropone
Results and discussion
One of our ongoing research programs is to develop tropolones
as antibacterial agents.27,28 While developing aminoacid conju-
gates of aminotropones 1a, we used acyl benzotriazole as an
acylating reagent. Aminotropones were reported to couple with
similar acylating reagents such as acid chlorides under
conventional reaction conditions.29,30 When we reacted amino-
tropone 1a with acyl benzotriazole 2a in acetonitrile (ACN) in
presence of Hunig's base (Scheme 1) according to standard
protocol of coupling using N-acyl benzotriazole as an acylating
reagent,16,22 we observed no progress aer one hour of stirring at
room temperature, and the starting materials were largely
insoluble. Therefore, we added few drops of dichloromethane
Scheme 1 Reaction of aminotropones (1a–c) and tropone (1d) with Fig. 3 An ORTEP representation of the X-ray crystallography structure
acyl benzotriazoles 2a–c.
of BAE 3c with the ellipsoid shown at 50% contour % probability level.
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Table 1 Optimization of conditionsa
Entry
Solvent
Base
Yield (%)
1
2
3
4
5
6
7
8
Acetonitrile
DCM
DMF
THF
1,4-Dioxane
Toluene
DMAP (1 equiv.)
DMAP (1 equiv.)
DMAP (1 equiv.)
DMAP (1 equiv.)
DMAP (1 equiv.)
DMAP (1 equiv.)
DMAP (1 equiv.)
DMAP (1 equiv.)
DIPEA (1–3 equiv.)
TEA (1–3 equiv.)
DBU (1 equiv.)
KOH (1 equiv.)
t-BuOK (1 equiv.)
DMAP (1 equiv.)
DMAP (1 equiv.)
DMAP (1 equiv.)
DMAP (1 equiv.)
DMAP (1 equiv.)
93
93
55
63
N.R.
N.R.
N.R.
N.R.
N.R.
N.R.
65
N.R.
N.R.
N.R.
20
Fig. 4 1H and 13C Chemical shift assignments of 3a and 3b; and
chemical structure of 3c.
Water
Ethanol
9
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
10
11
12
13
14b
15b,c
16b,d
17b,e
18b,f
(1d) were isolated as side products. We repeated the reaction under
same conditions but avoided using DCM as a co-solvent and we
obtained the expected amide and benzotriazole as a side product.
We hypothesized that the extra CH2 was generated from
DCM and to test this hypothesis, we ran the reaction in
deuterated DCM. We obtained product 3b and by analyzing and
comparing the 1H NMR spectra of 3a and 3b, we found that the
two spectra were superimposed with the extra two protons
disappeared in case of deuterated DCM, which suggests that
these protons are generated from DCM (Fig. 2). The molecular
formula of 3a (C21H24N4O4Na+) was determined by HRESIMS
data (m/z 419.1687 [M + Na]+, calcd 419.1690). Similarly, the
molecular formula of 3b (C21H22D2N4O4Na+) was determined by
HRESIMS data (m/z 421.1812 [M + Na]+, calcd 421.1815).
50
95
95
a
Conditions: 2c (0.3 mmol), base (0.3 mmol), in solvent (4 mL) and
b
DCM (1 mL) at 60 ꢀC for 5 h. Anhydrous solvents and inert argon
c
d
e
conditions. H2O (2.0 equiv.). H2O (5.0 equiv.). H2O (10.0 equiv.).
f
H2O (20.0 equiv.).
(Table 1). Screening numerous solvents revealed that ACN and
Finally, we were able to determine the structure of the DCM were the best solvents and gave the desired product 5a in
product to be benzotriazolyl alkyl ester using X-ray crystallog- 93% yield (Table 1, entries 1 and 2). Although using DCM only as
raphy. Deprotection of the Boc group of 3a using TFA in DCM a solvent and reagent afforded the product in high yield (93%),
led to the formation of 3c that was suitable to obtain a single ACN is preferred to minimize the hazardous of using larger
crystal X-ray structure (Fig. 3). The molecular formula of 3c quantity of DCM and to design a reaction that is green in nature.
(C16H16N4O2Na+) was determined by HRESIMS data (m/z Replacing ACN with DMF or THF led to the formation of the
319.1165 [M + Na]+, calcd 319.1165).
product in lower yields (i.e. 55 and 63%, respectively) (Table 1,
The structures of 3a and 3b were further conrmed following entries 3–4). No product was observed when ACN was replaced by
a thorough analysis of 2D NMR data. All the protons and 1,4-dioxane, toluene, water, or ethanol (Table 1, entries 5–8).
carbons were assigned based on COSY, HSQC, and HMBC
correlations (Fig. 4).
To identify the optimum base for the reaction, we screened
several other bases in addition to DMAP in the best identied
To determine if aminotropone derivatives contribute to the solvent (i.e. ACN) (Table 1, entries 9–13). DMAP was found to
observed transformation, we carried out the reaction in absence give the best result (Table 1, entry 1). No reaction was observed
of aminotropone and obtained the same product in the same when DIPEA or TEA were used, and the starting material
reaction time and with the same yield, which indicates that remained intact. When DBU was used, the product 5a was ob-
aminotropone did not play a role in this transformation.
tained in 65% (entry 11). The use of KOH or potassium-tert-
We hypothesize that the mechanism of this reaction takes butoxide led to hydrolysis of the starting N-acyl benzotriazole 2c
place via: (i) base-catalysed hydrolysis of N-acyl benzotriazole.31 (entries 12 and 13).
(ii). In situ formation of chloromethyl benzotriazole through
To further conrm the proposed mechanism and verify that
reaction of benzotriazole with DCM in presence of base (ben- water is the source of oxygen in the formed product, we have
zotriazole was reported to react with DCM in DMF in presence conducted a series of controlled experiments with anhydrous
of sodium hydride at reux conditions).32 (iii) The base facili- solvents under inert conditions and using water as a reagent to
tates the formation of acyloxy anion that reacted with chlor- test if water is the source of oxygen and if this is the case to
omethyl benzotriazole to form the desired BAE.33
determine how many equivalents of water are needed to ensure
To explore the scope of this reaction, we started rst by sufficient reactivity (Table 1, entries 14–18). Compound 5a was not
optimizing the reaction conditions using synthesis of (1H-benzo formed using anhydrous ACN and DCM in absence of water under
[d][1,2,3]triazol-1-yl)methyl benzoate (5a) as a template reaction argon and starting materials remained intact (entry 14). When we
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added H2O to the reaction, compound 5a was formed and the best
yield was achieved using 10.0 equivalents of H2O. Increasing H2O
to 20 equivalents did not improve the yield further and no
hydrolysis of starting materials was observed. Therefore, H2O is
the source of oxygen and 10 equiv. is the optimum ratio to obtain
the desired product in the model reaction.
To investigate if this kind of CH2 insertion could take place
with other N-acyl derivatives, we used N-phenylbenzamide and
N,N-diphenylbenzamide as substrates (Scheme 2A). No reaction
was observed in both cases under the optimized reaction
conditions. Finally, we ran a competition experiment in the
presence of piperidine as a strong nucleophile. The amide
product was obtained exclusively with no insertion taking place
at all (Scheme 2B). This observation illustrates that in presence
of strong nucleophile, the coupling is the preferred pathway,
which is usually the case in coupling reactions involving N-acyl
benzotriazoles. Insertion of CH2 was the favored pathway in
case of aminotropones (Scheme 1) due to their weak
nucleophilicity.
To further explore the generality of this reaction, we screened
various aromatic acyl benzotriazoles (2d–s) bearing electron
donating groups, electron withdrawing groups, and substituted
at o-, m-, and p- positions of the phenyl ring. We have also used
1H-benzotriazol-1-yl-2-pyrazinyl methanone as a representative
of heterocyclic acyl benzotriazoles. The desired BAEs (5a–n)
were obtained in all cases in moderate to excellent yields (63–
93%) (Fig. 5). It is worth mentioning that compounds 5b,e,h,k
were obtained in low yields (i.e. <10%) using our standard
reaction conditions. Yields were improved signicantly when we
used DBU as a base under the same reaction conditions (i.e. 64–
71%). Compounds 5b,e,h,k possess ortho-substituents at the phenyl
ring and we hypothesize that these compounds have better steric
complementarity with DBU over DMAP. Compound 5p was the only
exception because it was obtained in good yield (75%) using DMAP.
Although 5p is analogous to 5h (both 5p and 5h possess the same
ortho-methoxy substituent), the meta-chloro substituent in 5p most
likely contributed to the observed difference in reactivity.
Fig. 5 Benzotriazolyl alkyl esters (BAEs) 5a–n.
methodology to synthesize amino acid derivatives of benzo-
triazolyl alkyl ester. Boc-L-Phe- benzotriazolyl alkyl ester (3a,
Fig. 4) was synthesized in 94% yield. This compound was
deprotected in TFA/DCM (1 : 1) and gave the free aminoacid
derivative 3c in quantitative yield (Fig. 4). Using deuterated
DCM afforded compound 3b in 91% yield (Fig. 4). This clearly
showed that our method was compatible with Boc protecting
group. The method was also compatible with Cbz protecting
group and we synthesized both Cbz-L-Phe- and Cbz-L-Val-
Aliphatic BAEs (6a–d) were synthesized from their corre-
sponding N-acylbenzotriazoles (Fig. 6). Acetate, propionate, and
phenylacetate derivatives were synthesized in 88–93% yield. The
adamantane-1-carboxylate benzotriazolyl alkyl ester (6d) was
synthesized in 91% yield. Moreover, we extended our new
Scheme
2 (A) Reaction of N-phenylbenzamide and N,N-diphe-
nylbenzamide with DCM. (B) Competition experiment using piperidine
as a nucleophile.
Fig. 6 Benzotriazolyl alkyl esters (BAEs) 6a–f.
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benzotriazolyl alkyl ester (6e and 6f) in 88 and 91% yield,
respectively.
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Conclusions
In summary, we have developed a simple and practical method
for the synthesis of benzotriazolyl alkyl esters (BAEs), which are
bi-functional building blocks useful for the synthesis of
numerous multifunctional compounds. The structure of BAE 3c
was conrmed using X-ray crystallography. We used DCM as
a C-1 surrogate in a carbon–heteroatom bond formation under
metal-free conditions that highlights the versatility of using
DCM as a building block. The new method is convenient and
requires simple operation, applicable to broad scope of
substrates, and products are obtained in high yields.
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Conflicts of interest
12 S. J. Kyran, S. G. Sanchez, C. J. Arp and D. J. Darensbourg,
Syntheses and Structures of [CH2(NCnH2n)2]Mo(CO)4 (n ¼
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There are no conicts to declare.
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of Pharmacy, St. Louis, MO 63110, USA.
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