Synthesis and practical use of 1H-1,2,3-benzotriazole-5-carboxaldehyde for reductive amination

Article abstract of DOI:10.1080/00397910500214151

A reliable synthetic procedure to obtain multigram quantities of 1H-1,2,3-benzotriazole-5-carboxaldehyde has been developed. This material can be used in reductive amination reactions with primary and secondary amines to provide good to excellent yields o

Full text of DOI:10.1080/00397910500214151

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Synthesis and Practical Use of
1H‐1,2,3‐Benzotriazole‐5‐carboxal
for Reductive Amination
Mikhail Krasavin a , Dmitry G. Pershin a , Denis
Larkin a & Dmitry Kravchenko a
a Chemical Diversity Research Institute , Khimki,
Moscow, Russia
Published online: 18 Aug 2006.
To cite this article: Mikhail Krasavin , Dmitry G. Pershin , Denis
Larkin & Dmitry Kravchenko (2005) Synthesis and Practical Use of
1H‐1,2,3‐Benzotriazole‐5‐carboxaldehyde for Reductive Amination, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 35:19, 2587-2595
To link to this article: http://dx.doi.org/10.1080/00397910500214151
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Synthetic Communicationsw, 35: 2587–2595, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500214151
Synthesis and Practical Use of 1H-1,2,3-
Benzotriazole-5-carboxaldehyde for
Reductive Amination
Mikhail Krasavin, Dmitry G. Pershin, Denis Larkin,
and Dmitry Kravchenko
Chemical Diversity Research Institute, Khimki, Moscow, Russia
Abstract: A reliable synthetic procedure to obtain multigram quantities of 1H-1,2,3-
benzotriazole-5-carboxaldehyde has been developed. This material can be used in
reductive amination reactions with primary and secondary amines to provide good to
excellent yields of the desired products without protection of the starting material.
Keywords: 1H-1,2,3-benzotriazole, building blocks, compound libraries, reductive
amination
1H-1,2,3-Benzotriazole moiety has a documented prominence in a number of
antitumor aromatase inhibitors[1] and is present, for instance, in the marketed
antiemetic dopamine D2 antagonist Alizapride.[2] Additionally, there are
reports on benzotriazole derivatives having an auxin-like effect on plant
growth.[3] This prompted us to consider benzotriazole as an attractive struc-
tural feature to be utilized in the development of combinatorial compound
libraries of medicinal and agricultural relevance. In particular, we required
multigram quantities of 1H-1,2,3-benzotriazole-5-carboxaldehyde (1a) (or any
N-protected form thereof, such as 1b) to be used as a 1H-1,2,3-benzotriazole-
containing building block in reductive amination by primary and secondary
amines.
Received in Poland May 10, 2005
Address correspondence to Mikhail Krasavin, Chemical Diversity Research
Institute, 2a Rabochaya St., Khimki, Moscow Reg., 114401 Russia. Tel.:
þ7(095)995-4942; Fax: þ7(095)926-9780; E-mail: myk@chemdiv.com
2587

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M. Krasavin et al.
In selecting the starting point for synthesis of this hitherto unreported
aldehyde, we considered two options: 1) generation of 5-1H-1,2,3-benzotria-
zolyl anion via lithium–halogen exchange on the Boc-protected version of the
known 5-bromo-1H-1,2,3-benzotriazole[4] (2b) with subsequent trapping with
an electrophilic formylating agent; or 2) reductive manipulation on the ester
group of the unprotected (3a) or protected methyl 1H-1,2,3-benzotriazole-5-
carboxylate[5] (3b) (Scheme 1).
Initial attempts to perform lithium–halogen exchange on the unprotected
bromide 2a (2.5 equiv of t-BuLi, ether, 2788C, then DMF, 2788C ! rt)
resulted in destruction of the 1H-1,2,3-triazole nucleus. Boc-protection of
2a (Boc2O, DMF, rt[6]) and repeated attempts to introduce a formyl group
using the same set of reagents at different temperatures (2788C to 2408C)
and with various workup techniques provided the desired aldehyde 1b,
1
albeit in ,20% yield. (The yield was estimated based on examination of H
NMR spectrum of the crude reaction mixture. When acidic workup conditions
were used, the unprotected aldehyde 1a was detected, in similar low yield.)
Seeking to increase the yield of the desired aldehyde 1, we turned to the
reduction of the ester 3. Boc-protection was viewed as inappropriate because it
would be incompatible with the harsh reduction conditions. (The Boc group in
2b was found to be extremely labile even upon attempted chromatographic
isolation of that material on silica gel.) Before exploring alternative protecting
groups, we attempted reduction of the ester 3a with DIBAL-H (THF, 2788C)
and found it difficult to avoid overreduction of the aldehyde. Several attempts
to suppress the formation of the unwanted alcohol (formed in 10–25% yield)
were unsuccessful. However, no disruption of the “uncapped” 1H-1,2,3-
triazole moiety was observed. We therefore relied on the literature
precedence[7] and reduced the ester 3a completely to the alcohol 4 at room
temperature. Reoxidation of 4 to the corresponding aldehyde (1a) was
found to be most efficient with pyridinium dichromate (PDC) using either
THF or acetone, and not the traditional dichloromethane. (Other oxidation
conditions tried included MnO2/acetone and Swern oxidation [DMSO-
oxalyl chloride or DMSO-trifluoroacetic anhydride].) Because both these
solvents are prone to forming potentially explosive peroxides, the reactions
were carried out in an inert argon atmosphere (the reaction medium was
tested for the presence of peroxides using potassium iodide–starch strip.
The solution gave negative peroxide test results throughout the process.)
Scheme 1.

1H-1,2,3-Benzotriazole-5-carboxaldehyde
2589
Scheme 2.
The overall yield of the target aldehyde 1a was satisfactory: 72% (Scheme 2).
The yield was found to be reproducible on a multigram scale (see the Exper-
imental Section).
Having prepared the target aldehyde 1a, we proceeded to explore its
utility as a reagent in the reductive amination by primary and secondary
amines. Because we encountered no reports in the literature about the
reductive amination in presence of the unprotected 1H-1,2,3-triazole
moiety, we first tried to protect the aldehyde 1a as its Boc-derivative (1b).
The resulting 4 : 1 mixture of N1- and N3-substituted products was again
found unstable, even after prolonged storage. (Upon prolonged storage at
room temperature, the solutions of 1b tend to accumulate N-tert-butylated
6-formyl-1H-benzotriazole via extrusion of CO2, as evidenced by LC MS
analysis.) Thus, our goal was to establish that the aldehyde 1a itself could
be used without protection.
As illustrated in Scheme 3, reductive amination of 1a with a set of various
primary and secondary amines (aliphatic as well as aromatic) yielded the
desired 5-aminomethyl 1H-1,2,3-benzotriazole derivatives 6a–j in good to
excellent yields (Table 1). Primary amines were first reacted with 1a in
benzene to form Schiff bases 5. The latter were isolated and, without
further purification, reduced with sodium borohydride in methanol.
Scheme 3.

2590
M. Krasavin et al.

1H-1,2,3-Benzotriazole-5-carboxaldehyde
2591
Secondary amines reacted directly in the presence of sodium triacetoxy boro-
hydride to give the respective tertiary amine products. All of the products thus
obtained were found to be stable compounds of at least 95% purity as
confirmed by LC MS and 1H NMR spectroscopy (see Experimental Section).
In summary, we have developed a reliable synthetic procedure that
provides access to multigram quantities of hitherto unknown 1H-1,2,3-benzo-
triazole-5-carboxaldehyde 1a and demonstrated its utility as a carbonyl
partner in reductive amination reactions with a structurally diverse set of
amines requiring no protection of the 1H-1,2,3-triazole fragment.
EXPERIMENTAL
All reactions were run in oven-dried glassware in an atmosphere of nitrogen.
Melting points were measured with a Buchi B-520 melting-point apparatus
and are not corrected. Analytical thin-layer chromatography was carried out
on EM Separations Technology F254 silica-gel plates. Compounds were visu-
alized with short-wavelength UV light. 1H NMR and 13C NMR spectra were
recorded on Bruker DPX-300 spectrometers in DMSO-d6 using TMS as an
internal standard. Mass-spectral analyses were obtained on a PE SCIEX
API 150EX mass spectrometer. All solvents and reagents were obtained
from commercial sources and used without purification.
5-Hydroxymethyl-1H-1,2,3-benzotriazole (4)
Dry methyl 1H-1,2,3-benzotriazole-5-carboxylate (3a) (88.5 g, 0.50 mol) in
four portions at room temperature was added to a stirred suspension of
lithium aluminum hydride (21.8 g, 0.57 mol) in anhydrous THF (1.2 L).
Slight exothermic reaction was observed. The mixture was stirred at room
temperature for 4 h and then treated with ethyl acetate (50 mL). After
additional stirring for 30 min, the reaction mixture was poured into ice
water (1.5 L). The resulting slurry was acidified to pH 3–4 with 10%
sulfuric acid, the aqueous layer was saturated with NaCl, and the organic
layer was separated. The aqueous layer was extracted with THF
(2 ꢀ 500 mL); the combined organic extracts were dried over anhydrous
Na2SO4, filtered, and concentrated in vacuo to yield a grey solid that was
dried in high vacuum (approx. 1 mm of Hg). This material contained a
1
small amount of the unreacted ester 3a (as indicated by H NMR analysis).
The latter was removed by boiling the crude product in diethyl ether
(100 mL), cooling the mixture to room temperature, and filtering the solids
off. The product was air dried to provide 4 (68.0 g, 80%) as grey solid:
mp ¼ 148–1508C. The spectral data of this material were consistent with
those reported previously:[7] 1H NMR (300 MHz, d6-DMSO) d 15.64 (br s,
1H, N1-H), 7.84 (unresolved d, 1H), 7.80 (s, 1H), 7.36 (d, J ¼ 8.1 Hz, 1H),

2592
M. Krasavin et al.
5.41 (br s, 1H, OH), 4.68 (s, 2H, CH2); 13C NMR (75 MHz, d6-DMSO) d
141.9, 136.8, 136.7, 126.0, 114.2, 62.9; LCMS m/z 150 (M þ Hþ).
1H-1,2,3-Benzotriazole-5-carboxaldehyde (1a)
5-Hydroxymethyl-1H-1,2,3-benzotriazole (4) (35.0 g, 0.23 mol) was dissolved
in anhydrous acetone (500 mL) and treated with pyridinium dichromate (99 g,
1.1 equiv, added in small portions over 30 min). The reaction vessel was
thoroughly degassed and filled with argon. The dark reaction mixture was
stirred at room temperature for 4 h. At that point TLC analysis (5% MeOH-
CH2Cl2) indicated full conversion of the starting material. The solution was
decanted off the solid catalyst and the latter was washed with several
portions of acetone (3 ꢀ 200 mL) until full disappearance of the product in
the washings (checked by TLC). The solvent was removed in vacuo and the
resultant oily mixture was loaded on a silica-gel column and eluted with
50 ! 100% ethyl acetate in hexanes. The fractions containing the product
were pooled and concentrated to give 1a (30.4 g, 90%) as a fine colorless
crystalline solid: mp ¼ 178–1798C. 1H NMR (300 MHz, d6-DMSO) d 16.08
(br s, 1H), 10.12 (s, 1H), 8.59 (s, 1H), 7.98 (d, J ¼ 8.5 Hz, 1H), 7.91 (dd,
J ¼ 8.5, 1.1 Hz, 1H); 13C NMR (75 MHz, d6-DMSO) d 192.4, 140.8 (br),
139.3 (br), 133.3, 124.4, 122.0, 114.3; LCMS m/z 148 (M þ Hþ); Anal.
calcd. for C7H5N3O: C, 57.14; H, 3.43; N, 28.56. Found: C, 57.15; H, 3.45;
N, 28.57.
General Procedure 1: Preparation of Secondary Amines 6a–f
A primary amine (1 equiv.) was added to a suspension of the aldehyde 1a
(200 mg, 1.36 mmol) in benzene (5 mL) and the resulting mixture was
heated at reflux for 3–5 h. (The suspension cleared up shortly after reaching
the reflux temperature, if the solution remained cloudy, a small amount
[0.2–0.3 mL] of anhydrous ethanol was added.) Then the solution was evap-
orated to dryness. The resulting solid or oil-like imines 5a–f were used in the
next step without purification (except 5a—see Table 1).If necessary, the oily
products may be triturated with petroleum ether to initiate crystallization.
The imines 5a–f were dissolved in anhydrous methanol (5 mL), treated
with NaBH4 (0.5 equiv), and stirred at room temperature until full consump-
tion of the starting imine was evidenced by TLC analysis (typically 24 h).
The solvent was removed in vacuo. The oily residue was purified by one of
the three techniques (see Table 1): 1) dissolved in a small amount of
methanol (2 mL). Large excess of ethereal HCl was added, the precipitated
hydrochloride was filtered off, and it was dried in vacuo, 2) The product
was crystallized from an appropriate solvent system, 3) The crude product
was purified by column chromatography.

1H-1,2,3-Benzotriazole-5-carboxaldehyde
2593
N-(1H-1,2,3-benzotriazol-5-ylmethyl)-N-phenylamine (6a): mp ¼ 165–
1
1688C. H NMR (300 MHz, d6-DMSO) d 7.61 (s, 1H), 7.58 (s, 1H), 6.97–
7.05 (m, 3H), 6.62 (dd, J ¼ 0.9, 8.7 Hz, 2H), 6.48 (tt, J ¼ 0.9, 7.4 Hz, 1H),
6.14 (br s, 1H), 4.31 (s, 2H); 13C NMR (75 MHz, d6-DMSO) d 148.9, 144.4
(br), 143.9 (br), 131.5, 128.6, 120.2, 115.4, 115.3, 113.7, 112.2, 47.2; MS
MHþ ¼ 225; HRMS (EI) m/z calcd. for C13H13N4 (MHþ): 225.2674.
Found: 225.2670.
N-(1H-1,2,3-benzotriazol-5-ylmethyl)-N-benzylamine dihydrochloride (6b):
mp ¼ 1758C (decomp.). 1H NMR (300 MHz, d6-DMSO) d 10.01 (br s, 1H), 8.18
(s, 1H), 7.94 (d, J ¼ 8.5 Hz, 1H), 7.65 (dd, J ¼ 1.3, 8.5Hz, 1H), 7.56–7.60
(m, 2H), 7.37–7.45 (m, 3H), 4.32 (t, J ¼ 5.7 Hz, 2H), 4.15 (t, 5.7 Hz, 2H);
13C NMR (75 MHz, d6-DMSO) d 140.0 (br), 138.6 (br), 131.9, 130.0, 129.1,
128.7, 128.5, 127.4, 117.0, 114.9, 49.6 (two signals); MS MHþ ¼ 239; HRMS
(EI) m/z calcd. for C14H15N4 (MHþ): 239.2945. Found: 239.2944.
N-(1H-1,2,3-benzotriazol-5-ylmethyl)-N-(3-methoxypropyl)amine dihydro-
chloride (6c): mp ¼ 137–1388C. 1H NMR (300MHz, d6-DMSO) d 9.67 (br s,
bound HCl and two N-H, 4H), 8.19 (s, 1H), 7.94 (d, J ¼ 8.5 Hz, 1H), 7.67 (dd,
J ¼ 1.5, 8.5 Hz, 1H), 4.29 (t, J ¼ 5.6 Hz, 2H), 3.37 (t, J ¼ 6.0 Hz, 2H), 3.20
(s, 3H), 2.90 (m, 2H), 1.94 (m, 2H); 13C NMR (75 MHz, d6-DMSO) d 138.6
(two signals), 129.3, 127.3, 116.9, 115.0, 68.8, 57.8, 49.7, 44.0, 25.5; MS
MHþ ¼ 221; HRMS (EI) m/z calcd. for C11H17N4O (MHþ): 221.2764.
Found: 221.2767.
4-f2-[(1H-1,2,3-benzotriazol-5-ylmethyl)amino]ethylgbenzenesulfonamide
(6d): mp ¼ 173–1758C. 1H NMR (300 MHz, d6-DMSO) d 8.34 (s, 1H), 7.90
(s, 1H), 7.64 (d, J ¼ 8.5 Hz, 1H), 7.60 (AXA0X0, J ¼ 8.3 Hz, 4H), 7.52 (dd,
J ¼ 1.3, 8.5 Hz, 1H), 3.81 (t, J ¼ 7.0 Hz, 2H), 3.01 (t, J ¼ 7.0 Hz, 2H); 13C
NMR (75 MHz, d6-DMSO) d 145.4, 144.4, 144.1, 141.8, 129.2, 128.8,
125.5, 119.0, 118.2, 115.6, 61.4, 52.8, 49.8; MS MHþ ¼ 332; HRMS (EI)
m/z calcd. for C15H18N5O2S (MHþ): 332.3990. Found: 332.3993.
N-(1H-1,2,3-benzotriazol-5-ylmethyl)-N-(3,4-dimethoxyphenyl)amine
(6e): 1H NMR (300 MHz, d6-DMSO) d 15.6 (br s, 1H), 7.86 (d, J ¼ 8.7 Hz,
1H), 7.81 (s, 1H), 7.44 (d, J ¼ 8.7 Hz, 1H), 6.65 (d, J ¼ 8.7 Hz, 1H), 6.36
(d, J ¼ 2.5 Hz, 1H), 6.04 (dd, J ¼ 2.5, 8.7 Hz, 1H), 7.44 (d, J ¼ 8.7 Hz,
1H), 4.39 (d, J ¼ 5.6 Hz, 2H), 3.65 (s, 3H), 3.58 (s, 3H); 13C NMR
(75 MHz, d6-DMSO) d 150.8, 145.0, 144.5, 141.2, 139.6 (br), 126.1 (br),
125.7, 116.0, 115.4, 112.9, 103.9, 99.8; MS MHþ ¼ 285; HRMS (EI) m/z
calcd. for C15H17N4O2 (MHþ): 285.3204. Found: 285.3207.
N-(1H-1,2,3-benzotriazol-5-ylmethyl)-5-chloropyridin-2-amine trihydro-
1
chloride (6f): mp ¼ 110–1128C. H NMR (300 MHz, d6-DMSO) d 9.00–
11.00 (br, bound HCl, 3H), 8.05 (d, J ¼ 2.3 Hz, 1H), 7.95 (s, 1H), 7.90

2594
M. Krasavin et al.
(d, J ¼ 8.5 Hz, 1H), 7.85 (dd, J ¼ 2.3, 9.4 Hz, 1H), 7.47 (d, J ¼ 8.5 Hz, 1H),
7.11 (d, J ¼ 9.4 Hz, 1H), 4.82 (s, 2H); 13C NMR (75 MHz, d6-DMSO) d 153.0,
141.5, 138.7 (br), 138.4 (br), 136.6, 135.0, 125.5, 117.8, 115.4, 113.7, 113.0,
56.0; MS MHþ ¼ 260; HRMS (EI) m/z calcd. for C12H11ClN5 (MHþ):
260.7000. Found: 260.6998.
General Procedure 2: Preparation of Tertiary Amines 6g–j
An amine (1.1 equiv) and NaBH(OAc)3 (2.2 equiv) were added to a solution of
the aldehyde 1a (200 mg, 1.36 mmol) in anhydrous dichloromethane (10 mL).
The resulting mixture was stirred at room temperature until full consumption
of the starting imine was evidenced by TLC analysis (typically 24 h). The
solvent was removed in vacuo and water (5 mL) and ethyl acetate (15 mL)
were added to the residue. The biphasic mixture was stirred vigorously for
15 min; then, the aqueous phase was made basic with 1M aqueous KOH,
and the organic layer was separated. The aqueous solution was extracted
with ethyl acetate (3 ꢀ 10 mL). The combined organic solutions were dried
over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue
was either dissolved in small amount of ether (3–5 mL) and the product
6 was isolated as hydrochloride upon addition of excess ethereal HCl, or it
was purified by column chromatography.
5-f[4-(2,5-dimethylphenyl)piperazin-1-yl]methylg-1H-1,2,3-benzotriazole
(6 g): mp ¼ 58–608C. 1H NMR (300 MHz, d6-DMSO) d 7.87 (d, J ¼ 8.5 Hz,
1H), 7.80 (s, 1H), 7.43 (dd, J ¼ 1.3, 8.5 Hz, 1H), 6.99 (d, J ¼ 7.5 Hz, 1H),
6.81 (s, 1H), 6.73 (d, J ¼ 7.5 Hz, 1H), 3.70 (s, 2H), 2.82 (t, J ¼ 4.3 Hz,
4H), 2.55 (br s, 4H), 2.22 (s, 3H), 2.16 (s, 3H); 13C NMR (75 MHz, d6-
DMSO) d 137.0 (br), 136.2 (br), 133.3, 132.5, 131.4, 129.3, 127.6, 126.4,
124.2, 120.3, 119.6, 119.5, 62.8, 54.0, 52.2, 21.7, 18.0; MS MHþ ¼ 322;
HRMS (EI) m/z calcd. for C19H24N5 (MHþ): 322.4287. Found: 322.4290.
5-(piperidin-1-ylmethyl)-1H-1,2,3-benzotriazole dihydrochloride (6h):
mp ¼ 111–1138C. 1H NMR (300 MHz, d6-DMSO) d 8.26 (s, 1H), 7.94
(d, J ¼ 8.7 Hz, 1H), 7.75 (dd, J ¼ 1.3, 8.7 Hz, 1H), 4.43 (d, J ¼ 5.3 Hz,
2H), 3.25 (m, 2H), 2.87 (m, 2H), 1.61–1.87 (m, 6H); 13C NMR (75 MHz,
d6-DMSO) d 138.7 (br), 138.6 (br), 128.4, 127.0, 118.6, 114.8, 58.5, 51.4,
22.0, 21.6; MS MHþ ¼ 217; HRMS (EI) m/z calcd. for C13H17N4 (MHþ):
217.2881. Found: 217.2885.
N-(1H-1,2,3-benzotriazol-5-ylmethyl)-N-benzyl-N-methylamine (6i): 1H
NMR (300 MHz, d6-DMSO) d 7.87 (d, J ¼ 8.5 Hz, 1H), 7.80 (s, 1H), 7.44
(dd, J ¼ 1.1, 8.5 Hz, 1H), 7.29–7.37 (m, 4H), 7.20–7.26 (m, 1H), 3.63
(s, 2H), 3.51 (s, 2H), 2.09 (s, 3H); 13C NMR (75 MHz, d6-DMSO) d 171.9,
170.2, 139.0, 137.0, 128.5, 128.1, 126.8, 126.0, 115.0 (br), 113.5 (br), 61.0,

1H-1,2,3-Benzotriazole-5-carboxaldehyde
2595
59.7, 41.6; MS MHþ ¼ 253; HRMS (EI) m/z calcd. for C15H17N4 (MHþ):
253.3216. Found: 253.3212.
5-(pyrrolidin-1-ylmethyl)-1H-1,2,3-benzotriazole dihydrochloride (6j):
1
mp .1808C (decomp.). H NMR (300 MHz, d6-DMSO) d 11.65 (br s, 1H),
8.25 (s, 1H), 8.01 (br s, bound HCl, 2H), 7.93 (d, J ¼ 8.5 Hz, 1H), 7.75 (dd,
J ¼ 1.1, 8.5 Hz, 1H), 4.52 (d, J ¼ 6.0 Hz, 2H), 3.29 (m, 2H), 3.08 (m, 2H),
1.97 (m, 2H), 1.88 (m, 2H); 13C NMR (75 MHz, d6-DMSO) d 138.9 (br),
138.5 (br), 128.8, 127.7, 117.7, 115.0, 56.3, 52.4, 22.6; MS MHþ ¼ 203;
HRMS (EI) m/z calcd. for C11H15N4 (MHþ): 203.2610. Found: 203.2612.
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