α-Hydroxy-Tetrazoles as Latent Ethynyl Moieties: A Mechanistic Investigation

Article abstract of DOI:10.1002/ejoc.201800143

This article focuses on the dehydration of α-hydroxy-tetrazoles, leading to tetraazafulvenes and then to vinylic carbenes that rearrange into ethynyl moieties through the Fritsch-Buttenberg-Wiechell rearrangement. Each step of this sequence was scrutinized, either by examination of the substrate and/or dehydrating agent scope, or through AM1 calculations, in order to understand the limiting step of this process. This underrated transformation appears to be a viable alternative to existing methods used for transforming aldehydes into alkynes.

Full text of DOI:10.1002/ejoc.201800143

A Journal of
Accepted Article
Title: Alpha hydroxy tetrazoles as latent ethynyl moieties: a
mechanistic investigation
Authors: Pierre Quinodoz, Karen Wright, Bruno Drouillat, Mikhail
Kletskii, Oleg Burov, Anton Lisovin, and François Couty
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800143
Link to VoR: http://dx.doi.org/10.1002/ejoc.201800143
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10.1002/ejoc.201800143
European Journal of Organic Chemistry
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Alpha hydroxy tetrazoles as latent ethynyl moieties: a
mechanistic investigation
Pierre Quinodoz, [a] Karen Wright, [a] Bruno Drouillat, [a] Mikhail E. Kletskii, [b] Oleg N. Burov,[b] Anton. V.
Lisovin, [b] and François Couty* [a]
Abstract: This article focuses on the dehydration of alpha hydroxy
Supporting information for this article is given via a link at the end of the
tetrazoles, leading to tetraazafulvenes and then to vinylic carbenes,
that rearrange into ethynyl moieties through the Fritsch–Buttenberg–
Wiechell (FBW) rearrangement. Each step of this sequence was
scrutinized, either through examination of the substrate and/or
dehydrating agent scope, or through AM1 calculations, in order to
understand the limiting step of this process. This underrated
transformation appears to be a viable alternative to the existing
methods used to transform an aldehyde into an alkyne.
document.
These studies suggested an alternative pathway to transform an
aldehyde into an alkyne which involves: (i) transformation of the
aldehyde into an AHT, and (ii) its dehydration; this generates a
tetraazafulvene which then expulses two molecules of N2 to
generate the vinyl carbine, and finally evolves to the alkyne
Introduction
Following the seminal work of Colvin1 and Corey-Fuchs2 who
reported in the early 70’s the two-step sequence to transform a
carbonyl compound into an alkyne, this very useful synthetic
transformation has been thoroughly studied and recently
reviewed.3 Most of these methods rely on the generation of an
intermediate vinyl carbene, which rearranges through the
Fritsch–Buttenberg–Wiechell (FBW) rearrangement. In this field,
Seyferth-Gilbert,4 or Ohira-Bestmann5 reagents and their
variants6 have become popular for this transformation. Though
the scope of all these existing tools cover the vast majority of
substrates, some drawbacks still remain such as the need for a
base in the process, the cost of the reagents, and the hazards
associated with diazo compounds. Thus, new procedures for
this transformation are still highly desirable.
Alpha hydroxy tetrazoles (AHTs) were reported as early as
19667 to dehydrate upon heating, or under the action of DCC,
generating vinyl carbenes after expulsion of dinitrogen.
Alternatively, alpha cyano mesylates were reported to generate
vinyl carbenes via decomposition of derived intermediate
tetrazoles.8 However such reactions have been scarcely used
as synthetic tools, until Wardrop9 reported its use for the
generation of vinyl carbenes, evolving either through FBW
rearrangement or insertion reactions. We have recently shown
that alpha-hydroxy-beta azido tetrazoles (AHBAT) can be used
as one carbon atom staples for orthogonal double CuAAC
ligations, this procedure involving in a key-step the mild
generation of an alkyne from an AHT through EDC or DIC
treatment.10
through FBW rearrangement (Scheme 1).
Scheme 1. General scheme for the transformation of AHTs into alkynes.
This two step sequence is particularly appealing for several
reasons. First, many routes are available to produce AHTs from
aldehydes. Also, the second step appears to be ideal in terms of
waste by-products, since only water and dinitrogen are produced.
Finally, this dehydration does not imply the use of a base,
contrary to the aforementioned methods. This article aims to
study the feasibility of this transformation, focusing on the
dehydration step, and answer the inherent questions about its
scope and detailed mechanism.
Results
In order to study the scope of this transformation, we first had to
select an array of representative AHTs. Synthesis of such
compounds is well documented and involves different
disconnections starting from either alpha-keto tetrazoles,11
carbonyl compounds,12 cyanoepoxides,13 or cyanohydrins.14
Since direct synthesis from carbonyl compounds leads to N-
protected tetrazoles, thus implying an additional deprotection
step, we selected the as yet unexplored route involving
formation of an intermediate OTMS cyanohydrin, formed upon
reaction of the aldehyde with TMSCN and Et3N (cat.).
Subsequent cycloaddition with TMSN3 catalyzed by Bu2SnO
gave the tetrazoles. This reaction was conducted in one pot,
[
a]
Institut Lavoisier de Versailles, UMR 8180
Université de Versailles St-Quentin-en-Yvelines, Université Paris
Saclay. 45 av. des Etats-Unis, 78035 Versailles Cedex, France
E-mail: couty@chimie.uvsq.fr; http://www.ilv.uvsq.fr
Fax: +33 (0)1 39 25 44 52
[
b]
Department of Chemistry, Southern Federal University, 7, Zorge St.,
344090, Rostov-on-Don, Russian Federation
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10.1002/ejoc.201800143
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yielding after mild desilylation in acidic medium the AHTs 1-16 in
good overall yields. It is noteworthy that the potential
cycloaddition on the aromatic nitrile in 2 is very slow under these
reaction conditions, so that the tetrazole was formed selectively
on the cyanohydrin. Only one limitation was found with an alpha
disubstituted aldehyde, which failed to give tetrazole 7, probably
for steric reasons (Figure 1). The series 5-16 was designed in
order to detect possible participation of a moiety present in the
side-chain (amine or carbamate), in the crucial elimination step
(vide infra). Additionally, AHTs 17-19 were prepared from
AHBATs,13 and 20 was prepared in excellent yield (91%) by
addition of phenyllithium on the corresponding benzoyl tetrazole.
cyanophosphonates from carbonyl compounds, demonstrates
that tetrazoles fitted with an alpha leaving group are indeed
latent alkynes, and nicely complements the available tools
mentioned in the introduction. For our part, we explored briefly
this possibility starting from either cyanocarbonates or
cyanomesylates,8 but without much success, since yields of
alkynes culminated around 20%. A single set of experiments
should however be mentioned here, which illustrates that this
reaction can be highly substrate-dependent. While alkyne 22
was produced from benzylic cyanocarbonate 21, albeit in low
yield, aliphatic cyanocarbonate 23 gave only the corresponding
tetrazole 24 without
a trace of alkyne under the same
cycloaddition conditions (Scheme 2).
TMSN3 (1.5 equ.)
Bu2SnO (0.5 equ.),
toluene, 60°C, 5days
OCO2Et
Cl
Cl
CN
22%
21
Cbz
22
TMSN3 (1.5 equ.)
Bu2SnO (0.5 equ.),
toluene, 60°C, 15h
Cbz
Bn
N
OCO2Et
CN
Bn
N
OCO2Et
88%%
24
23
N
HN
N
N
Scheme 2. Different behaviour of aliphatic and benzylic cyanocarbonates in
cycloaddition conditions.
Let us now focus on the dehydration step of AHTs, leading to
the corresponding ethynyl moiety. For the preliminary screening
of the dehydrating agent, we first selected an array of four AHTs:
3, 6 and 17/18, fitted either with a benzylic or aliphatic group at
the hydroxyl position. Compounds 17/18 were reported by us to
produce efficiently an alkyne upon treatment with DIC.10
Numerous dehydrating or activating reagents were tested with
these substrates, including carbodiimides, peptide coupling
reagents (such as HATU, BOP, or EEDQ), fluorination reagents
(DAST, X-talFluor), Burgess’s reagent, Martin’s sulfurane, SOCl2,
Appel’s reagent, with contrasting results. This large screening
led us to focus on two standardized reactions, selected for their
ability to produce the expected alkynes and their easy
implementation. They include treatment with DIC (1.2 eq., DCM,
rt, 24h), and with DAST, diethylaminosulfur trifluoride, (1.5 eq.,
DIPEA, 1 eq., DCM, 0°C, 1h). The following Table 1 records the
yields (%) of, unless otherwise stated, isolated alkynes 1a-6a
and 12a-20a .
Figure 1. Structures of AHTs 1-16 prepared via OTMS cyanohydrins, and of
AHTs 17-20, prepared by other procedures.
It should be pointed out here that in order to promote the
dehydration step of an AHT and ultimately produce the alkyne,
two routes are possible: activation of the hydroxyl moiety in the
cyanohydrin before the cycloaddition step leading to the
tetrazole, or, as will be discussed here, activation of the hydroxyl
in the AHT after cycloaddition. A very successful example of the
first route has been recently disclosed by Harusawa et al15 and
involves activation of the hydroxyl as a phosphonate. The
efficiency of this process, based on the facile preparation of
AHT
DIC
30a
47a
0
DAST
26a
Alkyne
1a
2a
3a
4a
1
2
3
4
5
32a
12a
trace
57a
8
42a
5a
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6
8
9
52
59
29
nt
60
nt
nt
70
57
43
44
61
6a
8a
9a
line with the report of Wardrop,9 and contrasts with the poor
yields obtained in the first series 1-4. These results led us to
focus on the mechanism of the elimination step, which might be
the limiting one in the overall process, since the efficiency of the
reaction seems to be higher in the case of moieties able to
participate via an SNi mechanism, and promote elimination. First,
to gain insight into the detailed mechanism of the reaction with
DIC, the elimination step (C ‰ D + E) in model substrate A
leading to tetraazafulvene D and urea E was computed through
PCM quantum chemical calculations (PBE0/6-31++G(d,p) level
of theory, see SI). This process requires an activation energy of
23.9 kcal.mol-1, and can therefore readily occur at rt. Produced
tetraazafulvene D and urea E lie at higher energy (21.1 kcal.mol-
1) than the initial system, reflecting the loss of aromaticity of the
heterocycle (Figure 2). It should be noted that the acidity of the
tetrazole is a very important parameter for the success of the
reaction, allowing acidic catalysis for the initial nucleophilic
addition of the hydroxyl on the carbodiimide.16
10
11
12
13
14
15
16
17
18
19
20
10a
11a
12a
13a
14a
15a
16a
17a
18a
19a
20a
nt
trace
trace
20
trace
nt
39
73
64
65
80
64
78b
nt
60
70
a
Yield determined by NMR, with an internal standard
b
(trimethoxybenzene or mesitylene).
DIPEA. nt: not tested.
Pyridine was used instead of
Thionyl chloride was also used as activating agent, but this
reagent did not produce any alkyne. In place, 5-tetrazoyl
oxazolidinone 25 or oxazinanone 26 were produced in good
yields from 11 and 12 respectively (Scheme 3).
Scheme 3. Thionyl chloride activation of 11 or 12 produces 25 or 26.
Discussion
It appears that DIC and DAST are both suitable activating
agents, able to produce the alkyne from AHT, but yields are
greatly dependent on the type of substrate used. Three types of
substrates can be classified: first, with benzylic substrates 1-4,
yields are consistently low, always below 50%, though
increasing when electron-withdrawing groups are present on the
aromatic ring; with aliphatic compounds 5,9,10,16, either devoid
of a moiety able to participate in the elimination process in the
side-chain, or remote from the carbon bearing the hydroxyl,
yields are modest (around 50%) and DAST appears to be
slightly more efficient than DIC. Finally, with compounds 6,8,11
and 17-19, all fitted with a nucleophilic moiety (N-carbamate or
triazole), alpha to the hydroxylated carbon, yields are much
higher, near or above 60%, and our previously reported AHBAT
17-18 substrates appear to be privileged compounds for this
transformation.10 The presence of a tertiary amine, such as in
14-15 was however not compatible with these conditions. The
case of AHT 20, fitted with a quaternary benzylic position, and
leading to diphenyl acetylene 20a in excellent yield is perfectly in
Figure 2. Relative Gibbs free energies (∆G) along the course of model
elimination step in C. Process stoichiometry was taken into account.
Calculated geometries of the main stationary points (interatomic distances in
Å). PCM/PBE0/6-311++G(d,p), calculations in dichloromethane.
Decomposition of model tetraazafulvene
D
into the
corresponding vinyl carbene G was also computed at the same
level of theory in simulated DCM. Calculations show that this is a
stepwise process going through the intermediate diazoalkene F.
The overall process is highly exothermic and requires 9.7
kcal.mol-1 for the first activation step, and 11.4 kcal.mol-1 for the
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10.1002/ejoc.201800143
European Journal of Organic Chemistry
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second one, which is significantly lower than the dehydration
step (Figure 3). Though we were not able to isolate or
characterize by NMR any tetraazafulvene or diazoalkene, such
intermediates can be detected by high resolution mass
spectroscopy analysis (ESI) of AHTs such as 1 and 3,
suggesting a non-negligible lifetime.
nucleophile (an internal carbamate in this case), thereby
restoring the aromaticity of the tetrazolate (Scheme 4). This
process explains the formation of 25 and 26 (Scheme 3) upon
activation with thionyl chloride. In these cases, the chloride
anion attacks the O-benzyl group in 30, producing the
oxazolidinone, or the homologous oxazinanone. This propensity
of intermediate tetraazafulvenes to act as Michael acceptors
might also explain the low yields obtained in the case of benzylic
AHTs 1-4. With these substrates, conjugation in the produced
tetraazafulvenes might stabilize these intermediates and extend
their lifetime, thus allowing competitive Michael addition with
nucleophiles present in the reaction medium. Although we could
not isolate such adducts, LCMS analysis of the crude reaction
mixture resulting from reaction of 3 with EDC in DCM showed
that the major detected product was an adduct between EDC
and 3, which might result from Michael addition of the produced
urea on the tetraazafulvene. Furthermore, by running the
reaction in MeOH instead of DCM, compound 31, probably
resulting from Michael addition of methanol on the intermediate
tetraazafulvene, was isolated in fair yield (Scheme 5).
N
N
N
NH
N
+
O
N
N
N
O
N
N
BnO
Bn
29
BnO
Bn
28
Me
20.3 Kcal.mol-1
DMCD
N
O
11
O
Me
Me
Me
N
N
H
N
H
H
Spontaneous
N
BnO
O
N
N
N
N
N
N
OH
N
N
NH
Bn
27
N
30
N
Figure 3. Relative Gibbs free energies (∆G) along the course of the model
elimination step of N2 in D. Process stoichiometry was taken into account.
Calculated geometries of the main stationary points: interatomic distances in
Å, valence angles in degrees. PCM/PBE0/6-31++G(d,p) calculations in
dichloromethane.
Scheme 4. Computed elimination from AHT 11 leads to an intermediate
tetraazafulvene that spontaneously reacts through intramolecular Michael
addition with a nearby carbamate.
A general trend can thus be outlined from these experimental
and theoretical results: the first step of this transformation
(dehydration or AHT decomposition into urea and
tetraazafulvalene) appears to be the rate-limiting one. In order to
best fit with our tested substrates, further calculations were
conducted with AHTs 27, mimicking a simplified 17/18 (Scheme
4), 11 and 20. For these compounds, the activation energies for
the steps leading to the corresponding tetraazafulvene when
reacting with dimethylcarbodiimide were determined. Model
compound 27, which is the structural analogue of derivatives 17
and 18, required 23.6 kcal.mol-1 to eliminate the urea, which is
close to the value for compound 11 (20.3 kcal.mol-1). These
values are in line with simplified model A, which requires 23.9
kcal.mol-1 (Figure 2). Remarkably, 20 required only 6.8 kcal.mol-1,
thus highlighting the positive effect of an additional phenyl group
to promote dehydration. It should be noted that calculation
showed that tetraazafulvene 29, resulting from 11, collapses
spontaneously to zwitterionic compound 30, thus demonstrating
that such a tetraazafulvene can act as a Michael acceptor with a
Scheme 5. Formation of alpha-OMe tetrazole 31 is observed when
dehydration of 3 is conducted in MeOH.
Activation with DAST appeared also to be an efficient means to
promote this reaction. We found that addition of 1 equiv. of a
base, DIPEA, was necessary to attain good yields: this is best
illustrated with substrate 11 reacting with DAST, with or without
this added base: with DIPEA, the expected alkyne 11b was
produced in 61% yield, along with 15% of 32, while an
unseparable mixture of tetrazole regioisomers 32 (43:57) was
exclusively produced without DIPEA (Scheme 6).
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Experimental Section
General information: 1H and 13C NMR spectra were recorded at 200 or
300 and 75 MHz, respectively; chemical shifts (δ) are reported in ppm
and coupling constants (J) reported in Hertz and rounded up to 0.1 Hz.
Splitting patterns are abbreviated as follows: singlet (s), doublet (d),
triplet (t), quartet (q), septuplet (sep), multiplet (m), broad (br), or a
combination of these. Solvents were used as internal standard when
assigning NMR spectra (δ H: CDCl3 7.26 ppm ; δ C: CDCl3 77.0 ppm).
Assignments for signals from 1H and 13C in the NMR spectra were
validated by two-dimensional correlated spectroscopy (2D COSY) and
Heteronuclear Multiple Bond Correlation (HMBC). IR data were collected
with an ATR-FT-IR spectrometer. All reactions were carried out under
argon. DCM was distilled from CaH2. Column chromatography was
performed on silica gel (230–400 mesh) with use of various mixtures of
CH2Cl2, EtOAc, petroleum ether (35-60°C fraction) (PE) and methanol.
TLC was performed on Merck Kieselgel 60 F254 plates. Melting points
are uncorrected. Isomeric ratios were determined by NMR analysis of
crude reaction mixtures before purification.
Scheme 6. The addition of a base (DIPEA) is important to attain good yields of
alkyne upon treatment with DAST.
Regioisomers 32 are produced by nucleophilic substitution
involving two molecules of zwitterion 30, or its protonated form
30+H+ (Scheme 7). Thus, if the medium remains acidic (reaction
of the hydroxyl with DAST produces one equivalent of HF),
substantial amounts of 30+H+ are obtained, precluding back
formation to tetraazafulvene 29 and its further decomposition to
11b. The aforementioned bimolecular reaction can therefore
occur at a reasonable rate to give 32. Thus, this result questions
the reversibility of 30 leading to 29.
All reactions were performed on 1 mmol scale.
General procedure for the synthesis of AHT
N
Cyanohydrin formation
N
N
N
N
N
N
N
N
N
HF
N
In a dried round-bottomed flask, the aldehyde (1 eq.) was dissolved in
DCM (2 mL/mmol). TMSCN (1.2 eq.) and triethylamine (0.2 eq.) were
then added and the mixture was stirred for 30 minutes at room
temperature. The solvent was then removed and the crude used directly
for the cycloaddition step. For 21 and 23, ethylcyanoformate was used
instead of TMSCN and the crude product purified by flash
chromatography over silica gel using a PE/EtOAc mixture as eluent. For
14 and 15, the silylated cyanohydrin was purified by flash
chromatography over silica gel using a PE/EtOAc mixture as eluent and
the non-substituted cyanhohydrin was obtained.
O
O
N
- N2
O
N
N
H
11b
OBn
OBn
N
OBn
Bn
29
Bn
Bn
30 + H+
30
N
N
N
N
N
N
O
N
N
O
N
N
32
H
O
OBn
Bn
Bn
30 + H+
Bn
30
Cycloaddtion
In a dried round-bottomed flask, the cyanohydrin was dissolved in
toluene (5 mL/mmol). After the addition of Bu2SnO (0.5 eq.) and TMSN3
(1.5 eq.), the mixture was stirred at 60°C until complete conversion
(usually 24h) and the residue was purified by flash chromatography over
silica gel using a DCM/MeOH/AcOH mixture as eluent.
Scheme 7. A plausible mechanism for the formation of 32.
Conclusions
(4-Chlorophenyl)(1H-tetrazol-5-yl)methanol 1
In conclusion, we have studied in detail the dehydration of AHTs,
leading ultimately to alkynes. Carbodiimides and DAST/DIPEA
were identified as suitable activation reagents to promote this
process. The two-step transformation of aldehydes into AHTs,
followed by dehydration and evolution to the alkyne appears to
be a viable process with a reasonable scope of aldehydes,
especially those fitted with an alpha carbamate or triazole.
Computational studies of the involved mechanism demonstrated
that the limiting step is the initial dehydration (or AHT
decomposition into urea and tetraazafulvalene) leading to an
intermediate tetraazafulvene. The latter evolves through a
stepwise mechanism to the carbene via sequential expulsion of
two molecules of dinitrogen, and might, in some cases, react as
a Michael acceptor in a competing way. This procedure
complements the existing tools for the transformation of
aldehydes into ethynyl moieties and can be performed under
very mild conditions.
White solid (97%); Mp: 187-189°C (dec.) Rf= 0.15 (DCM/MeOH/AcOH
97/3/2); 1H NMR (300 MHz, CDCl3): δ = 7.35 (d, J = 8.5 Hz, 2H, Ar), 7.28
(d, J = 8.6 Hz, 2H, Ar), 6.05 (s, 1H, CHOH) ppm. 13C NMR (75 MHz,
CDCl3): δ = 160.73 (Cq), 140.56 (Cq), 135.28 (Cq), 129.83 (CAr), 129.14
(CAr), 67.85 (CHOH) ppm. IR: νmax = 3344, 1568, 1489, 1250, 1052, 786,
614 cm-1. HRMS (TOF MSES positive mode) m/z calcd. for C8H8ClN4O
[MH]+ : 211.0395; found : 211.0395.
(4-Cyano)(1H-tetrazol-5-yl)methanol 2
White solid (70%); Mp: 139-141°C (dec.); Rf= 0.15 (DCM/MeOH/AcOH
97/3/2); 1H NMR (300 MHz, MeOD): δ = 7.77 (d, J = 8.3 Hz, 2H, Ar), 7.70
(d, J = 8.3 Hz, 2H, Ar), 6.28 (s, 1H, CHOH) ppm. 13C NMR (75 MHz,
MeOD): δ = 160.33 (Cq), 147.05 (Cq), 133.66 (CAr), 128.44 (CAr), 119.45
(Cq), 113.25 (Cq), 67.75 (CHOH) ppm. IR: νmax = 3278, 2231, 1564,
1405, 1247, 1056, 796, 569 cm-1. HRMS (TOF MSES positive mode) m/z
calcd. for C9H8N5O [MH]+ : 202.0729; found : 202.0727.
(4'-Chloro-[1,1'-biphenyl]-4-yl)(1H-tetrazol-5-yl)methanol 3
White solid (87%); Mp: 215-217°C (dec.); Rf= 0.10 (DCM/MeOH/AcOH
96/2/2); 1H NMR (300 MHz, MeOD): δ = 7.56-7.40 (m, 6H, Ar), 7.36-7.28
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10.1002/ejoc.201800143
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(m, 2H, Ar), 6.09 (s, 1H, CHOH) ppm. 13C NMR (75 MHz, MeOD): δ =
162.14 (Cq), 141.75 (Cq), 141.07 (Cq), 140.59 (Cq), 134.57 (CAr), 129.96
(CAr), 129.50 (CAr), 128.23 (CAr), 128.11 (CAr), 68.72 (CHOH) ppm. IR:
νmax = 3354, 1574, 1485, 1098, 1054, 791 cm-1. HRMS (TOF MSES
positive mode) m/z calcd. for C14H12ClN4O [MH]+ : 287.0700; found :
287.0696.
Ethyl benzyl(5-hydroxy-5-(1H-tetrazol-5-yl)pentyl)carbamate 10
White solid (86%); Mp: 95-97°C; Rf= 0.3 (DCM/MeOH/AcOH 97/3/2); 1H
NMR (300 MHz, MeOD): δ = 7.37-7.19 (m, 5H, Ph), 5.03 (dd, J = 7.2, 5.6
Hz, 1H, CHOH), 4.49 (s, 2H, NCH2Ph), 4.16 (q, J = 6.8 Hz, 2H, CH2CH3),
3.33-3.16 (m, 2H, NCH2CH2), 2.98-1.76 (m, 2H, CH2), 1.65-1.47 (m, 2H,
CH2), 1.45-1.17 (m, 5H, CH2 and CH2CH3) ppm. 13C NMR (75 MHz,
MeOD): δ = 161.27 (Cq), 158.73 (Cq), 139.36 (Cq), 129.62 (CAr), 128.70
(CAr), 128.41 (CAr), 65.93 (CHOH), 62.79 (CH2CH3), 51.26 (NCH2Ph),
47.90 and 47.31 (NCH2CH2), 37.22 (CH2), 28.79 and 28.39 (CH2), 23.10
(CH2), 15.00 (CH2CH3) ppm. IR: νmax = 3341, 2925, 1664, 1431, 1249,
1095, 695 cm-1. HRMS (TOF MSES positive mode) m/z calcd. for
C16H24N5O3 [MH]+ : 334.1875; found : 334.1879.
(1H-Tetrazol-5-yl)(p-tolyl)methanol 4
White solid (98%); Mp: 163-165°C (dec.); Rf= 0.5 (DCM/MeOH/AcOH
96/4/2); 1H NMR (300 MHz, MeOD): δ = 7.21 (d, J = 8.1 Hz, 2H, Ar), 7.08
(d, J = 8.0 Hz, 2H, Ar), 6.00 (s, 1H, CHOH), 2.21 (s, 3H, Me) ppm. 13C
NMR (75 MHz, MeOD): δ = 161.00 (Cq), 139.53 (Cq), 138.72 (Cq), 130.36
(CAr), 127.50 (CAr), 68.48 (CHOH), 21.18 (Me) ppm. IR: νmax = 3405,
1571, 1513, 1438, 1115, 1066, 939, 784, 771, 574, 519 cm-1. HRMS
(TOF MSES positive mode) m/z calcd. for C9H11N4O [MH]+ : 191.0933;
found : 191.0934.
Benzyl benzyl(2-hydroxy-2-(1H-tetrazol-5-yl)ethyl)carbamate 11
White solid (85%); Mp: 157-159°C; Rf= 0.35 (DCM/MeOH/AcOH 95/3/2);
1H NMR (300 MHz, MeOD): δ = 7.29-7.02 (m, 10H, Ph), 5.33-5.12 (m,
1H, CHOH), 4.96 and 5.00 (two s, 2H, Cbz), 4.65-4.36 (m, 2H, NCH2Ph),
3.65 (td, J = 14.5, 5.0 Hz, 1H, NCHHCHOH), 3.55-3.33 (m, 1H,
NCHHCHOH) ppm. 13C NMR (75 MHz, MeOD): δ = 159.46 (Cq), 158.29
(Cq), 138.90 and 138.63 (Cq), 137.78 (Cq), 129.71 (CAr), 129.54 (CAr),
129.17 (CAr), 129.00 (CAr), 128.74 and 128.55 (CAr), 128.48 and 128.33
(CAr), 68.72 and 68.65 (Cbz), 65.22 and 64.86 (CHOH), 53.19 and 52.85
(NCH2Ph), 52.67 and 52.06 (NCH2CHOH) ppm. IR: νmax = 3401, 3059,
3027, 2518, 1678, 1426, 1237, 728, 700 cm-1. HRMS (TOF MSES
positive mode) m/z calcd. for C18H20N5O3 [MH]+ : 354.1566; found :
354.1566.
1-(1H-Tetrazol-5-yl)octan-1-ol 5
White solid (70%); Mp: 116-118°C; Rf= 0.2 (DCM/MeOH/AcOH 97/3/2);
1H NMR (300 MHz, MeOD): δ = 5.05 (dd, J = 7.3, 5.6 Hz, 1H, CHOH),
4.92 (s, 1H, OH), 2.00-1.78 (m, 2H, CH2CHOH), 1.50-1.23 (m, 10H, CH2),
0.91 (t, J = 6.6 Hz, 3H, Me) ppm. 13C NMR (75 MHz, MeOD): δ = 161.34
(Cq), 66.06 (CHOH), 37.64 (CH2), 32.92 (CH2), 30.32 (CH2), 30.28 (CH2),
25.90 (CH2), 23.68 (CH2), 14.41 (CH3) ppm. IR: νmax = 3400, 2921,
2848, 1567, 1467, 1436, 1317, 1253, 1076, 1058, 952, 601, 534 cm-1.
HRMS (TOF MSES positive mode) m/z calcd. for C9H19N4O [MH]+ :
199.1559; found : 199.1559.
Benzyl benzyl(3-hydroxy-3-(1H-tetrazol-5-yl)propyl)carbamate 12
Ethyl benzyl(2-hydroxy-2-(1H-tetrazol-5-yl)ethyl)carbamate 6
White solid (81%); Mp: 134-136°C; Rf= 0.5 (DCM/MeOH/AcOH 97/3/2);
1H NMR (300 MHz, MeOD): δ = 7.45-7.10 (m, 10H, Ph), 5.16 (s, 2H,
OCH2Ph), 5.10-5.00 (m, 1H, CHOH), 4.52 (s, 2H, NCH2Ph), 3.63-3.35 (m,
2H, NCH2CH2), 2.30-1.98 (m, 2H, NCH2CH2) ppm. 13C NMR (75 MHz,
MeOD): δ = 161.05 (Cq), 158.19 (Cq), 139.02 (Cq), 137.98 (Cq), 129.69
(CAr), 129.57 (CAr), 129.15 (CAr), 128.96 (CAr), 128.75 (CAr), 128.51 (CAr),
68.57 (OCH2Ph), 64.08 (CHOH), 51.63 (NCH2Ph), 44.64 and 43.85
(NCH2CH2), 36.07 and 35.48 (NCH2CH2) ppm. IR: νmax = 3381, 1668,
1434, 1231, 1022, 735, 695 cm-1. HRMS (TOF MSES positive mode) m/z
calcd. for C19H22N5O3 [MH]+ : 368.1723; found : 368.1729.
Sticky oil crystallizing on standing (83%); Mp: 103-105°C; Rf= 0.15
(DCM/MeOH/AcOH 95/3/2); 1H NMR (300 MHz, MeOD): δ = .27-7.08 (m,
5H, Ph), 5.21 (d, J = 5.8 Hz, 1H, CHOH), 4.63-4.35 (m, 2H, CH2Ph),
4.10-3.82 (m, 2H, CH2CH3), 3.70-3.51 (m, 1H, NCHHCHOH), 3.51-3.32
(m, 1H, NCHHCHOH), 1.07 (dd, J = 12.4, 5.9 Hz, 3H, CH2CH3). ppm. 13
C
NMR (75 MHz, MeOD): δ = 159.53 (Cq), 158.54 and 158.37 (Cq), 138.98
and 138.80 (Cq), 129.70 (CAr), 128.76 and 128.52 (CAr), 128.36 (CAr),
65.17 and 64.87 (CHOH), 63.07 (CH2CH3), 52.88, 52.6 and 52.49
(NCH2Ph), 51.92 (NCH2CHOH), 14.74 (CH2CH3) ppm. IR: νmax = 3420,
1665, 1420, 1235, 1112, 1030, 695 cm-1. HRMS (TOF MSES positive
mode) m/z calcd. for C13H18N5O3 [MH]+ : 292.1410; found : 292.1412.
Ethyl (2-hydroxy-2-(1H-tetrazol-5-yl)ethyl)carbamate 13
White foam (56%); Rf= 0.2 (DCM/MeOH/AcOH 96/4/2); 1H NMR (300
MHz, MeOD): δ = 5.03 (t, J = 5.7 Hz, 1H, CHOH), 3.94 (q, J = 7.1 Hz, 2H,
CH2CH3), 3.48 (dd, J = 14.1, 5.2 Hz, 1H, NHCHH), 3.38 (dd, J = 14.1, 6.8
Hz, 1H, NHCHH), 1.10 (t, J = 7.1 Hz, 3H, CH2CH3) ppm. 13C NMR (75
MHz, MeOD): δ = 160.30 (Cq), 159.29 (Cq), 65.91 (CHOH), 61.97
(CH2CH3), 46.97 (NHCH2), 14.93 (CH2CH3) ppm. IR: νmax = 3354, 2929,
1667, 1454, 1250, 1093, 1030, 774, 695 cm-1. HRMS (TOF MSES
positive mode) m/z calcd. for C6H12N5O3 [MH]+ : 202.0940; found :
202.0941.
[1-Benzyl-2-hydroxy-2-(2H-tetrazol-5-yl)-ethyl]-carbamic acid benzyl
ester 8
White solid (44%); Mp: 158°C, Rf = 0.1 (DCM/MeOH/AcOH : 95/5/1) ; 1H
NMR (300 MHz, CD3OD): δ = 7.30-7.12 (m, 5H, Ar), 5.14 (d, J = 3.0 Hz,
1H, CHOH), 4.20- 4.14 (m, 1H, NCH), 3.90 (q, J = 6.9 Hz, 2H,OCH2),
3.08 (dd, J = 13.5, 6.6 Hz, 1H, PhCHH), 2.81-2.74 (m, 1H, PhCHH), 1.11
(t, J = 6.9 Hz, 3H, Me) ppm. 13C NMR (75 MHz, CD3OD): δ = 159.6 (Cq),
158.4 (Cq), 139.4 (CAr), 130.3 (CAr), 129.5 (CAr), 127.5 (CAr), 67.2
(CHOH), 61.8 (OCH2), 58.3 (CHN), 38.0 (PhCH2), 14.8 (Me) ppm. IR :
νmax = 3303, 2983, 1665, 1547, 1527, 1443, 1247, 1049, 775, 751, 699
cm-1. HRMS (TOF MSES positive mode) m/z calcd. For C13H18N5O3
[MH]+ : 292.1410; found : 292.1414.
2-(Dibenzylamino)-1-(1H-tetrazol-5-yl)ethanol 14
Sticky oil (87%); Rf= 0.1 (DCM/MeOH/AcOH 95/3/2); 1H NMR (300 MHz,
MeOD): δ = 7.26-7.13 (m, 10H, Ph), 5.14 (t, J = 6.4 Hz, 1H, CHOH), 3.80
(s, 4H, NCH2Ph), 3.07-2.92 (m, 2H, NCH2CH) ppm. 13C NMR (75 MHz,
MeOD): δ = 161.35 (Cq), 137.50 (Cq), 130.69 (CAr), 129.64 (CAr), 129.02
(CAr), 64.16 (CHOH), 59.66 (NCH2Ph), 59.02 (NCH2CH) ppm. IR: νmax =
3110, 1457, 735, 696 cm-1. HRMS (TOF MSES positive mode) m/z calcd.
for C17H20N5O [MH]+ : 310.1668; found : 310.1664.
Ethyl benzyl(3-hydroxy-3-(1H-tetrazol-5-yl)propyl)carbamate 9
Sticky oil (82%); Rf= 0.3 (DCM/MeOH/AcOH 96/4/2); 1H NMR (300 MHz,
MeOD): δ = 7.37-7.17 (m, 5H, Ph), 5.07 (dd, J = 7.7, 4.8 Hz, 1H, CHOH),
4.50 (s, 2H, NCH2Ph), 4.16 (q, J = 7.1 Hz, 2H, CH2CH3), 3.60-3.27 (m,
2H, NCH2CH2), 2.30-1.97 (m, 2H, NCH2CH2), 1.25 (t, J = 6.7 Hz, 3H,
CH2CH3) ppm. 13C NMR (75 MHz, MeOD): δ = 161.02 (Cq), 158.50 (Cq),
139.13 (Cq), 129.69 (CAr), 128.75 (CAr), 128.51 (CAr), 64.09 (CHOH),
62.97 (CH2CH3), 51.49 (NCH2Ph), 44.31 and 43.74 (NCH2CH2), 35.94
and 35.47 (NCH2CH2), 14.99 (CH2CH3) ppm. IR: νmax = 3344, 2983,
1654, 1424, 1240, 1092, 698 cm-1. HRMS (TOF MSES positive mode)
m/z calcd. for C16H24N5O3 [MH]+ : 306.1566; found : 306.1565.
3-(Dibenzylamino)-1-(1H-tetrazol-5-yl)propan-1-ol 15
Sticky oil (81%); Rf= 0.25 (DCM/MeOH/AcOH 90/10/2); 1H NMR (300
MHz, MeOD): δ = 7.32-7.15 (m, 10H, Ph), 4.92 (t, J = 5.8 Hz, 1H, CHOH),
3.95 and 3.79 (two d, J = 13.4 Hz, 4H), 3.08-2.93 (m, 1H, NCHHCH2),
2.90-2.75 (m, 1H, NCHHCH2), 2.30-2.03 (m, 2H, NCH2CH2) ppm. 13C
NMR (75 MHz, MeOD): δ = 164.43 (Cq), 135.38 (Cq), 131.17 (CAr),
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10.1002/ejoc.201800143
European Journal of Organic Chemistry
FULL PAPER
129.94 (CAr), 129.67 (CAr), 66.20 (CHOH), 58.71 (NCH2Ph), 51.13
(NCH2CH2), 32.57 (NCH2CH2) ppm. IR: νmax = 3097, 1454, 1068, 1026,
732, 695 cm-1. HRMS (TOF MSES positive mode) m/z calcd. for
C18H22N5O [MH]+ : 324.1824; found : 324.1825.
(NCH2Ph), 35.36 (NCH2CCH), 14.67 (CH2CH3) ppm. IR: νmax = 3287,
3246, 2986, 1692, 1415, 1231, 1114, 1017, 697 cm-1. HRMS (TOF
MSES positive mode) m/z calcd. for C13H16NO [MH]+ : 218.1181; found :
218.1174.
1-(1H-Tetrazol-5-yl)-4-(trityloxy)butan-1-ol 16
(1-Benzyl-prop-2-ynyl)-carbamic acid ethyl ester 8a
White solid (75%); Mp: 152-154°C; Rf= 0.4 (DCM/MeOH/AcOH
99.5/0.5/2); 1H NMR (300 MHz, MeOD): δ = 7.49 – 7.36 (m, 6H, Ar), 7.36
– 7.06 (m, 9H, Ar), 5.04 (dd, J = 7.6, 5.2 Hz, 1H, CHOH), 3.14 (t, J = 6.3
Hz, 2H, CH2OTr), 2.17 – 1.85 (m, 2H, CH2), 1.80 – 1.62 (m, 2H, CH2)
ppm. 13C NMR (75 MHz, MeOD): δ = 161.23 (Cq), 145.69 (Cq), 129.80
(CAr), 128.76 (CAr), 128.03 (CAr), 87.82 (Cq), 65.92 (CHOH), 64.13 (CH2),
34.66 (CH2), 26.52 (CH2) ppm. IR: νmax = 3401, 1590, 1488, 1446, 1257,
1072, 752, 701, 636 cm-1. HRMS (TOF MSES negative mode) m/z calcd.
for C24H22N4O2 [M-H+] : 399.1811; found : 399.1811.
Colorless oil (59%); Rf : 0.7 (DCM/MeOH/AcOH : 89/10/1) ; 1H NMR (300
MHz, CDCl3): δ = 7.27-7.16 (m, 5H, Ar), 4.76 (bs, 1H, NHCO), 4.66 (bs,
1H, NCH), 4.00 (q, J = 7.2 Hz, 2H,OCH2), 2.98-2.84 (m, 2H, PhCH2),
2.22 (d, J = 2.4 Hz, 1H, C≡CH), 1.15 (t, J = 7.2 Hz, 3H, Me) ppm. 13C
NMR (75 MHz, CDCl3): δ = 155.4 (Cq), 136.1 (Cq), 129.8 (CAr), 128.3
(CAr), 127.0 (CAr), 82.5 (C≡CH), 72.4 (C≡CH), 61.2 (OCH2), 44.2 (CHN),
41.6 (PhCH2), 14.6 (Me) ppm. IR : νmax = 3294, 3030, 2980, 2942,
1691, 1521, 1495, 1332, 1239, 1038, 749, 698, 644 cm-1. HRMS (TOF
MSES positive mode) m/z calcd. for C13H16NO2 [MH]+ : 218.1181; found
: 218.1173.=
Benzyllbenzyl(2-((ethoxycarbonyl)oxy)-2-(1H-tetrazol-5-
yl)ethyl)carbamate 24
Ethyl benzyl(but-3-yn-1-yl)carbamate 9a
Colorless oil (43%); Rf= 0.45 (PE/EtOAc: 90/10); 1H NMR (300 MHz,
CDCl3): δ = 7.48-7.12 (m, 5H, Ph), 4.61 (s, 2H, NCH2Ph), 4.32-4.15 (m,
2H, CH2CH3), 3.55-3.33 (m, 2H, NCH2CH2), 2.55-2.32 (m, 2H, NCH2CH2),
2.01 (t, J = 2.6 Hz, 1H, CCH), 1.43-1.22 (m, 3H, CH2CH3) ppm. 13C NMR
(75 MHz, CDCl3): δ = 156.6 and 156.30 (Cq), 137.84 (Cq), 128.62 (CAr),
127.90 (CAr), 127.43 (CAr), 81.89 and 81.55 (CCH), 69.75 (CCH), 61.60
(CH2CH3), 51.01 (NCH2Ph), 45.96 and 45.13 (NCH2CH2), 18.31 and
17.94 (NCH2CH2), 14.70 (CH2CH3) ppm. IR: νmax = 3294, 2976, 1690,
1418, 1236, 1212, 1116, 698, 635 cm-1. HRMS (TOF MSES positive
mode) m/z calcd. for C13H16NO [MH]+ : 232.1338; found : 232.1335.
Sticky oil (88%); Rf= 0.3 (DCM/MeOH/AcOH 96/2/2); 1H NMR (300 MHz,
MeOD): δ = 7.32-6.98 (m, 10H, Ph), 6.22-6.04 (m, 1H, NCH2CHTet),
4.99 (s, 2H, Cbz), 4.55-4.33 (m, 2H, NCH2Ph), 4.05 (q, J = 7.1 Hz, 2H,
OCH2CH3), 3.85-3.69 (s, 2H, NCH2CHTet), 1.14 (t, J = 7.1 Hz, 3H,
OCH2CH3) ppm. 13C NMR (75 MHz, MeOD): δ = 158.04 (Cq), 156.79 and
156.55 (Cq), 155.44 (Cq), 138.64 and 138.39 (Cq), 137.66 (Cq), 129.77
(CAr), 128.69 (CAr), 128.60 (CAr), 129.57 (CAr), 129.22 (CAr), 129.02 (CAr),
128.77 (CAr), 128.35 (CAr), 69.86 and 69.58 (CHOCO2Et), 69.00 and
68.79 (Cbz), 66.11 (OCH2Me), 52.80 and 52.56 (NCH2Ph), 50.77 and
49.76 (NCH2CHTet), 14.50 (Me) ppm. IR: νmax = 2960, 1750, 1670,
1247, 1125, 1021, 733, 696 cm-1. HRMS (TOF MSES positive mode) m/z
calcd. for C21H24N5O5 [MH]+ : 426.1781; found : 426.1791.
Ethyl benzyl(hex-5-yn-1-yl)carbamate 10a
Colorless oil (44%); Rf= 0.55 (PE/EtOAc: 90/10); 1H NMR (300 MHz,
CDCl3): δ = 7.48-7.12 (m, 5H, Ph), 4.52 (s, 2H, NCH2Ph), 4.22 (q, J = 7.0
Hz, 2H, CH2CH3), 3.37-3.15 (m, 2H NCH2CH2), 2.22 (td, J = 6.8, 2.4 Hz,
2H, CH2CCH), 1.98 (t, J = 2.6 Hz, 1H, CCH), 1.75-1.60 (m, 2H, CH2),
1.60-1.43 (m, 2H, CH2), 1.40-1.20 (m, 3H, CH2CH3) ppm. 13C NMR (75
MHz, CDCl3): δ = 156.97 and 156.58 (Cq), 138.05 (Cq), 128.54 (CAr),
127.86 (CAr), 127.29 (CAr), 84.08 (CCH), 68.58 (CCH), 61.40 (CH2CH3),
50.18 and 49.99 (NCH2Ph), 46.15 and 45.44 (NCH2CH2), 27.00 and
26.82 (CH2), 25.58 (CH2), 18.13 (CH2), 14.72 (CH2CH3) ppm. IR: νmax =
3297, 3252, 2926, 1689, 1421, 1229, 1117, 698, 630 cm-1. HRMS (TOF
MSES positive mode) m/z calcd. for C16H22NO2 [MH]+ : 260.1651;
found : 260.1646.
General procedure for the activation of AHT
DIC and EDC
In a dried round-bottomed flask under argon atmosphere was added DIC
or EDC (1.2 eq.) to a suspension of AHT in distilled DCM at room
temperature. The reaction mixture was allowed to stir at room temparture
for 24 hours. The solvent was then removed and the residue was purified
by flash chromatography on silica gel with a mixture of PE/EtOAc.
DAST
In a dried round-bottomed flask under argon atmosphere, DIPEA (1.0
eq.) was added to a suspension of AHT in distilled DCM at 0°C. After
complete dissolution, DAST (1.5 eq.) was added at 0°C. The reaction
mixture was allowed to stir at room temparture for 20 minutes and
methanol was then added (1 mL/mmol). The solvent was then removed
and the residue was purified by flash chromatography on silica gel with a
mixture of PE/EtOAc.
N,N-Dibenzylbut-3-yn-1-amine 15a
Colorless oil (20%); Rf= 0.7 (PE/EtOAc: 95/5); 1H NMR (300 MHz,
CDCl3): δ = 7.35-7.12 (m, 10H, Ph), 3.56 (s, 4H, NCH2Ph), 2.63 (t, J =
7.4 Hz, 2H, NCH2CH2), 2.30 (td, J = 7.4, 2.4 Hz, 2H, NCH2CH2), 1.86 (t, J
= 2.6 Hz, 1H, CCH) ppm. 13C NMR (75 MHz, CDCl3): δ = 139.32 (Cq),
128.79 (CAr), 128.29 (CAr), 127.03 (CAr), 83.00 (CCH), 69.09 (CCH),
58.10 (NCH2Ph), 52.06 (NCH2CH2), 17.06 (NCH2CH2) ppm. IR: νmax =
3126, 1609, 731, 696, 638 cm-1. HRMS (TOF MSES positive mode) m/z
calcd. for C18H20N [MH]+ : 250.1596; found : 250.1592.
Thionyl chloride
In a dried round-bottomed flask under argon atmosphere DIPEA (1.0 eq.)
was added to a suspension of AHT in distilled DCM. After complete
dissolution, SOCl2 (2 eq.) was added at room temperature. The reaction
mixture was allowed to stir at room temparture for 24 hours, then
quenched with satured aqueous NaHCO3 and extracted with DCM. The
combined organic layers were dried over MgSO4, evaporated and the
residue purified by flash chromatography on silica gel with a mixture of a
DCM/MeOH/AcOH mixture.
((Pent-4-yn-1-yloxy)methanetriyl)tribenzene 16a
White solid (64%); Rf= 0.55 (PE/EtOAc: 95/5); 1H NMR (300 MHz,
CDCl3): δ = 7.37 (dd, J = 5.2, 3.4 Hz, 6H, Ar), 7.28 – 7.07 (m, 9H, Ar),
3.09 (t, J = 6.1 Hz, 2H, CH2), 2.27 (td, J = 7.3, 2.6 Hz, 2H, CH2), 1.81 (t, J
= 2.6 Hz, 1H, CCH), 1.74 (q, J = 6.7 Hz, 2H, CH2) ppm. 13C NMR (75
MHz, CDCl3): δ = 144.31 (Cq), 128.73 (CAr), 127.77 (CAr), 126.93 (CAr),
86.43 (Cq), 84.21 (Cq), 68.43 (CCH), 61.98 (CH2), 29.21 (CH2), 15.62
(CH2) ppm. IR: νmax = 3296, 1488, 1448, 1070, 1014, 744, 705, 635 cm-
1. HRMS (TOF MSES positive mode) m/z calcd. for C24H23O [MH]+ :
327.1749; found : 327.1747.
Ethyl benzyl(prop-2-yn-1-yl)carbamate 6a
Colorless oil (70%); Rf= 0.4 (PE/EtOAc: 90/10); 1H NMR (300 MHz,
CDCl3): δ = 7.30-7.14 (m, 5H, Ph), 4.53 (s, 2H, NCH2Ph), 4.15 (q, J = 7.1
Hz, 2H, CH2CH3), 4.05-3.80 (m, 2H, NCH2CCH), 2.15 (t, J = 2.4 Hz, 1H,
CCH), 1.21 (t, J = 7.1 Hz, 3H, CH2CH3) ppm. 13C NMR (75 MHz, CDCl3):
δ = 156.04 (Cq), 136.99 (Cq), 128.62 (CAr), 128.2 and 127.81 (CAr),
127.58 (CAr), 78.99 (CCH), 72.00 (CCH), 61.99 (CH2CH3), 49.14
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10.1002/ejoc.201800143
European Journal of Organic Chemistry
FULL PAPER
3-Benzyl-5-(1H-tetrazol-5-yl)oxazolidin-2-one 25
[1]
E. W. Colvin, B. J. Hamill, J. Chem. Soc. Chem. Commun. 1973, 151-
152.
[2]
[3]
E. J. Corey, P. L. Fuchs, Tetrahedron Lett. 1972, 13, 3769-3772.
D. Habrant, V. Rauhala, A. M. P. Köskinen, Chem. Soc. Rev. 2010, 39,
2007-2017.
(Thionyl chloride procedure)
White solid (88%); Mp: 129-131°C; Rf= 0.1 (DCM/MeOH/AcOH 96/2/2);
1H NMR (300 MHz, MeOD): δ = 7.34-7.14 (m, 5H, Ph), 5.78 (dd, J = 9.1,
5.9 Hz, 1H, CHTet), 4.48 and 4.30 (two d, J = 14.9 Hz, 2H, NCH2Ph),
3.89 (t, J = 9.2 Hz, 1H, NCHHCHTet), 3.77 (dd, J = 9.2, 5.9 Hz, 1H,
NCHHCHTet) ppm. 13C NMR (75 MHz, MeOD): δ = 157.09 (Cq), 155.97
(Cq), 134.47 (Cq), 129.08 (CAr), 128.45 (CAr), 128.17 (CAr), 66.31 (CHTet),
48.60 (NCH2CHTet), 48.44 (NCH2Ph) ppm. IR: νmax = 1746, 1436, 1261,
1053, 1029, 694 cm-1. HRMS (TOF MSES positive mode) m/z calcd. for
C11H12N5O2 [MH]+ : 246.0994; found : 246.0991.
[4]
[5]
U. Weerasooriya, J. C. Gilbert, J. Org. Chem. 1979, 44, 4997-4999.
G. J. Roth, B. Liepold, S. G. Müller, H. J. Bestmann, Synthesis, 2004,
59–62.
[6]
[7]
[8]
D. F. Taber, S. Bai, P. F. Guo, Tetrahedron Lett. 2008, 49, 6904-6906.
H. Behringer, M. Martner, Tetrahedron Lett. 1966, 7, 1663-1669.
For examples of generation of vinyl carbenes from alpha cyano
mesylates in a carbohydrate series, see: a) M. J. Pérez-Pérez, M. J.
Camarasa, Tetrahedron, 1994, 50, 7269-7282. b) A. Nguyen Van
Nhien, R. Leon, D. Postel, M. Carmo-Carreiras, A. G. Garcia, J. Marco-
Contelles, J. Carbohydr. Chem. 2005, 24, 369-377. c) R. Cordonnier, A.
Nguyen Van Nhien, E. Soriano, J. Marco-Contelles, Tetrahedron, 2010,
66, 736-742. d) A. N. Van Nhien, R. Cordonnier, M. D. Le Bas, S.
Delacroix, E. Soriano, J. Marco-Contelles, D. Postel, Tetrahedron 2009,
65, 9378-9394. e) A. N. Van Nhien, E. Soriano, J. Marco-Contelles, D.
Postel, Carbohydrate Research. 2009, 344, 1605-1611.
D. J. Wardrop, J. P. Komenda, Org. Lett. 2012, 14, 1548-1551. For an
3-Benzyl-6-(1H-tetrazol-5-yl)-1,3-oxazinan-2-one 26
(Thionyl chloride procedure)
White foam (70%); Mp: 134-136°C; Rf= 0.4 (DCM/MeOH/AcOH 96/4/2);
1H NMR (300 MHz, MeOD): δ = 7.32-7.13 (m, 5H, Ph), 5.83-5.69 (m, 1H,
CHTet), 4.54 (s, 2H, NCH2Ph), 3.46-3.20 (m, 2H, NCH2CH2), 2.60-2.29
(m, 2H, NCH2CH2) ppm. 13C NMR (75 MHz, MeOD): δ = 154.64 (Cq),
153.68 (Cq), 135.30 (Cq), 129.01 (CAr), 128.23 (CAr), 128.00 (CAr), 70.71
(CHTet), 53.04 (NCH2Ph), 42.81 (NCH2CH2), 26.01 (NCH2CH2) ppm. IR:
νmax = 3034, 2932, 1668, 1445, 1266, 1238, 1135, 725, 694 cm-1.
HRMS (TOF MSES positive mode) m/z calcd. for C12H14N5O2 [MH]+ :
260.1147; found : 260.1145.
[9]
isolated example reporting the trapping of
a vinylidene carbene
generated from an AHT, see: Y. Wang, M. E. Muratore, Z. Rong, A. M.
Echavarren, Angew. Chem. Int. Ed. 2014, 53, 14022-14026.
5-((4'-Chloro-[1,1'-biphenyl]-4-yl)(methoxy)methyl)-1H-tetrazole 31
[10] K. Wright, P. Quinodoz, B. Drouillat, F. Couty, Chem. Commun. 2017,
53, 321-323.
(EDC procedure with methanol used as solvent instead of DCM)
White solid (60%); Mp: 189-191°C (dec.); Rf= 0.25 (DCM/MeOH/AcOH
96/2/2); 1H NMR (300 MHz, MeOD): δ = 7.54 (d, J = 8.3 Hz, 2H, Ar), 7.50
(d, J = 8.6 Hz, 2H, Ar), 7.40 (d, J = 8.3 Hz, 2H, Ar), 7.32 (d, J = 8.6 Hz,
2H, Ar), 5.72 (s, 1H, CHOMe), 3.35 (s, 3H, CHOMe) ppm. 13C NMR (75
MHz, MeOD): δ = 159.27 (Cq), 141.83 (Cq), 140.36 (Cq), 138.19 (Cq),
134.77 (Cq), 130.01 (CAr), 129.55 (CAr), 128.88 (CAr), 128.40 (CAr), 77.66
(CHOMe), 57.68 (Me) ppm. IR: νmax = 1485, 1437, 1075, 805, 654 cm-1.
HRMS (TOF MSES positive mode) m/z calcd. for C15H14ClN4O [MH]+ :
301.0860; found : 301.0856.
[11] a) B. E. Fischer, A. J. Thomson, J. P. Horwitz, J. Org. Chem. 1959, 24,
1640-1654. b) C. David Jones, M. A. Winter, K. S. Hirsch, N. Stamm, H.
M. Taylor, H. E. Holden, J. D. Davenport, E. IV. Krumkalns, R. G. Surh,
J. Med. Chem. 1990, 33, 416-429. c) B. C. H. Mat, A. D. Abell,
Tetrahedron Lett. 2001, 42, 5641-5644.
[12] By nucleophilic addition of lithiated tetrazoles, see: a) Y. Satoh, J.
Moliterny, Synlett, 1998, 528-530. See also ref 8. By Ugi reactions, see:
a) T. Yue, M. –X. Wang, D. –X. Wang, J. Zhu, Angew. Chem. Int. Ed.
2008, 47, 9454-9457. b) A. Chandgude, A. Dömling, Green Chem.
2016, 18, 3718-3721. c) Z. –L Ren, J. –C Liu, M. –W. Ding, Synthesis,
2017, 49, 745-754.
3-Benzyl-5-(1-benzyl-1H-tetrazol-5-yl)oxazolidin-2-one and 3-benzyl-
5-(2-benzyl-2H-tetrazol-5-yl)oxazolidin-2-one 32
[13] P. Quinodoz, C. Lo, M. Kletskii, O. Burov, J. Marrot, F.Couty Organic
Chemistry Frontiers, 2015, 2, 492-496.
Colorless oil (60%); Rf= 0.2 (min.), 0.3 (maj.) (PE/EtOAc: 70/30); 1H
NMR (300 MHz, CDCl3): δ = 7.34-7.14 (m, 5H, Ph), 5.78 (dd, J = 9.1, 5.9
Hz, 1H, CHTet), 4.48 and 4.30 (two d, J = 14.9 Hz, 2H, NCH2Ph), 3.89 (t,
[14] a) I. Cristiano, F. Gomez-Zavaglia, J. Phys. Chem. A, 2010, 114,
13076-13085. b) A. Vasudevan, Z. Ji, R.R. Frey, C. K. Wada, D.
Steinman, H. R. Heyman, Y. Guo, M. L. Curtin, J. Guo, J. Li, L. Pease,
K. B. Glaser, P. A. Marcotte, J. J. Bouska, S. K. Davidsen, M. R.
Michaelides, Bioorg. Med. Chem. Lett. 2003, 13, 3909-3913. c) A.
Johansson, A. Poliakov, E. Åkerblom, K. Wiklund, G. Lindeberg, S.
Winiwarter, U.H. Danielson, B. Samuelsson, A. Hallberg, Bioorg. Med.
Chem. 2003, 11, 2551-2568.
J
=
9.2 Hz, 1H, NCHHCHTet), 3.77 (dd,
J = 9.2, 5.9 Hz, 1H,
NCHHCHTet) ppm. 13C NMR (75 MHz, CDCl3): δ = 163.91 (CqM), 156.87
M
m
(Cq (CO)), 155.75 (Cq (CO)), 151.37 (Cqm), 135.26 (Cq), 134.64 (Cq),
132.63 (Cq), 132.59 (Cq), 129.38 (CAr), 129.32 (CAr), 129.27 (CAr), 129.15
(CAr), 129.06 (CAr), 128.92 (CAr), 128.60 (CAr), 128.40 (CAr), 128.26 (CAr),
128.20 (CAr), 128.15 (CAr), 128.12 (CAr), 66.03 (CMHTet), 64.57 (CmHTet),
57.22 (TetCMH2Ph), 51.97 (TetCmH2Ph), 48.54 (CH2NCmH2Ph), 48.47
(CH2NCMH2Ph), 48.00 (CMH2NCH2Ph), 46.90 (CmH2NCH2Ph) ppm. IR:
νmax = 1745, 1436, 1261, 1053, 1030, 694 cm-1. HRMS (TOF MSES
positive mode) m/z calcd. for C18H18N5O2 [MH]+ : 336.1460; found :
336.1460.
[15] H. Yoneyama, M. Numata, K. Uemura, Y. Usami, S. Harusawa, J. Org.
Chem. 2017, 82, 5538-5556.
[16] Addition of a base (DIPEA) able to neutralize the tetrazole upon
reaction with DIC inhibits production of the alkyne.
Acknowledgements
The University of Versailles St-Quentin-en-Yvelines, University
Paris-Saclay and the CNRS are acknowledged for funding. PQ
acknowledges l’École polytechnique for a PhD grant.
Keywords: ethynylation • tetrazoles • vinyl carbenes.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800143
European Journal of Organic Chemistry
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Alpha hydroxy tetrazoles as latent
ethynyl moieties: a mechanistic
investigation
Pierre Quinodoz, Karen Wright, Bruno
Drouillat, Mikhail E. Kletskii, Oleg N.
Burov, Anton V. Lisovin, and François
Couty *
This article focuses on the dehydration of alpha hydroxy tetrazoles (AHTs),
leading to ethynyl moieties via a vinyl carbene. The mechanism is scrutinized,
through either examination of the substrate and/or dehydrating agent scope, or
through PCM/PBE0/6-31++G(d,p) quantum chemical calculations in
dichloromethane. This underrated transformation appears to be a viable
alternative to the existing methods to transform an aldehyde into an alkyne.
Page No. – Page No.
This article is protected by copyright. All rights reserved.