N-Morpholinomethyl-5-lithiotetrazole: A Reagent for the One-Pot Synthesis of 5-(1-Hydroxyalkyl)tetrazoles

Article abstract of DOI:10.1021/acs.joc.9b01885

An efficient, one-pot method for the preparation of 5-(1-hydroxyalkyl)tetrazoles is reported. N-Morpholinomethyl-5-lithiotetrazole, generated by the deprotonation of 4-(N-tetrazolylmethyl)morpholine with LiHMDS, undergoes addition to ketones and aldehydes (both aromatic and aliphatic) to form 5-(1-hydroxyalkyl)tetrazoles in a high yield, after acidic workup. The reported protocol displays a broad substrate scope and functional group tolerance, avoids the use of cyanide- or azide-based reagents, and provides access to sterically congested and unsaturated tetrazoles, which are difficult to access by other means.

Full text of DOI:10.1021/acs.joc.9b01885

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Article
N-Morpholinomethyl-5-lithiotetrazole: A Reagent for
the One-Pot Synthesis of 5-(1-Hydroxyalkyl)tetrazoles
Panagiotis D. Alexakos, and Duncan John Wardrop
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01885 • Publication Date (Web): 04 Sep 2019
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The Journal of Organic Chemistry
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N-Morpholinomethyl-5-lithiotetrazole: A Reagent for the One-Pot
Synthesis of 5-(1-Hydroxyalkyl)tetrazoles.
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Panagiotis D. Alexakos and Duncan J. Wardrop*
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, Illinois 60607-7061
Supporting Information Placeholder
ABSTRACT: An efficient, one-pot method for the preparation of 5-(1-hydroxyalkyl)tetrazoles is reported. N-Morpholinome-
thyl-5-lithiotetrazole, generated by the deprotonation of 4-(N-tetrazolylmethyl)morpholine with LiHMDS, undergoes addi-
tion to ketones and aldehydes (both aromatic and aliphatic) to form 5-(1-hydroxyalkyl)tetrazoles in high yield, after acidic
workup. The reported protocol displays broad substrate scope and functional group tolerance, avoids the use of cyanide or
azide-based reagents, and provides access to sterically-congested and unsaturated tetrazoles, which are difficult to access by
other means.
of 1-allyl-5-lithio-1H-tetrazole (3) to ketones and aldehydes
INTRODUCTION
Since Bladin’s preparation of tetrazole in 1892, this ni-
trogen-rich heterocycle and its derivatives have found ap-
plication in an array of disciplines. In medicinal chemistry,
tetrazoles are deployed as metabolically-stable cis-con-
4
and catalytic de-N-allylation of 5 (Scheme 2, A). Despite
1
its high efficiency, this approach requires low reaction tem-
peratures, to prevent decomposition of 3, and a discrete N-
deprotection step. Wishing to avoid these drawbacks and
thereby increase the practicality of our alkylidenecarbene
methodology, we sought to develop a one-pot process for
the preparation of 5-(1-hydroxyalkyl)tetrazoles 1, employ-
ing a tractable, N-protected 5-metallotetrazole which could
be unmasked during reaction workup following carbonyl
addition. Herein, we report on our studies to this end and
the successful development of morpholinomethyl-5-lithio-
2
strained peptide bonds and carboxylic acid isosteres, and
are among the ten most common heterocycles in FDA-
3
approved drugs. Tetrazoles have also found use as organo-
4
5
catalysts, potent anion binders, capping ligands for nano-
6
materials, N-donors in functionalized metal-organic mate-
7
8
rials and metal-coordinating peptides, as well as high-en-
9
14
ergy materials. That the synthesis of tetrazoles remains a
tetrazole as a versatile tetrazole synthetic equivalent.
topic of intense interest after more than 125 years, reflects
the enduring relevance of this ring system.
Although N-substituted 5-metallotetrazoles have proven
valuable for the introduction of the tetrazole ring system,
their practicality is tempered by limited protecting group
options and a susceptibility to undergo irreversible frag-
mentation to form lithium cyanamides 8 and dinitrogen
1
0
Scheme 1. 5-(1-Hydroxyalkyl)tetrazoles as Latent Al-
kylidenecarbenes.
(Scheme 2, B). While Raap established the competency of 1-
methyl-5-lithio-1H-tetrazole as a nucleophile capable of C-
1
5
C bond formation, Satoh developed the first 5-metal-
lotetrazole reagent which offered access to free 1H-te-
1
6-17
trazoles.
Lithiation of 1-benzyl-1H-tetrazole (6), in this
Our interest in tetrazoles arises from the potential of 5-
1-hydroxyalkyl)tetrazoles 1 as latent alkylidenecarbenes
Scheme 1). Previously, we demonstrated that treatment of
case, generated anion 7 which, although unstable above -98
°C, underwent reaction with carbonyl compounds to form 1,
after de-N-benzylation under forcing conditions. More re-
cently, Wiedemann has demonstrated that the magnesium
and zinc derivatives of 7 display improved thermal stability
which was attributed to increased carbon-metal bond cova-
(
(
1 with carbodiimides triggers a sequence of dehydration
and fragmentation to generate alkylidenecarbene 2, and the
products of their reactions under mild, non-basic conditions
1
1-13
18
(Scheme 1).
In this previous study, a two-step proce-
lency. The instability of N1-substituted tetrazole carbani-
dure was developed to access substrates 1, namely addition
ons is thought to arise, in part, from allylic strain between
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the metal center and adjoining N-alkyl group (C, Scheme 2).
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N2-substituted anions, which lack this interaction, are more
stable, as noted by Boosker, who found that while 12 spon-
taneously decomposes at -100 °C, its N2-isomer 11 has an
1
9
appreciable lifetime at -78 °C. Unfortunately, the prepara-
tion of 10 is inefficient and its use as a tetrazole equivalent
entails cleavage of the extant N-benzyloxymethyl acetal
As illustrated in Scheme 2 (D), we envisioned that car-
bonyl addition of 14, the anion(s) generated from 13, and
acidic hydrolysis of the resulting adduct would offer direct
(
BOM) group under strong acidic conditions or through hy-
1
6b
drogenolysis.
2
3
access to 5-(1-hydroxyalkyl)tetrazoles 1. Wary that
deprotonation of 13 with alkyl lithium reagents might be
Scheme 2. 5-Metallotetrazoles: Generation, Reactivity
and Preparation of 5-(1-Hydroxyalkyl)tetrazoles.
0
1
2
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4
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7
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9
0
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2
4
competitive with aminal lithiation, we opted to evaluate a
weaker base, specifically lithium hexamethyldisilazide
(
LiHMDS), using benzophenone (15a) as an electrophilic
trap. The results of our optimization study are summarized
in Table 1.
Table 1. Optimization Studiesa,b
1
3
yield
(%)
t (h)b
T (°C)c
entry
base
d
(
equiv)
1
2
3
4
1.1
1.5
1.5
1.5
LiHMDS
LiHMDS
LiHMDS
LiHMDS
0.50
0.50
0.25
1.00
-78
-78
-78
-78
73
92
85
26
5
2
2
LiHMDS
LiHMDS
0.25
0.50
-78
-78
95
97
6e
7
2
2
2
LiHMDS
LiHMDS
KHMDS
0.50
-
0
< 2
98
15
8f
-78
-78
9
0.50
aUnless otherwise noted, reactions were conducted in the
following manner: i) 13 (1.1-2.0 mmol), LiHMDS (1.1 equiv),
THF, -78 °C; ii) 15a (1 mmol), -78 °C, 2 h→rt, 16 h; iii) 1 M HCl,
b
c
rt 1 h. Anion maturation time. Deprotonation temperature.
RESULTS AND DISCUSSION
d
Isolated yield of 16a, after purification by flash chromatog-
Our search for an N-protected tetrazole anion precursor,
which could be unmasked under mild hydrolytic conditions,
led us to the work of Katritzky, who successfully utilized the
N-pyrrolidinomethyl (aminal) group to facilitate C5-lithita-
e
raphy on silica gel. Method A: lithiation of 13; addition of 15.
f
Method B: lithiation of 13 in the presence of 15.
Treatment of a THF solution of 13 with LiHMDS (1.1
equiv) at -78 °C for 30 min, addition of benzophenone
(15a), and in-situ hydrolysis of the aminal group with aque-
ous HCl (1 M) for 1 h, provided tertiary alcohol 16a in 73%
yield (entry 1). Since the mass balance of 15a was recov-
ered in this case, the number of molar equivalents of 13 was
increased to 1.5 (entry 2) and then 2.0 (entry 6, Method A),
leading to significant improvements in yield. In comparison
to 5-lithiotetrazoles 3, 7 and 12, the anion generated from
13 displays improved thermal stability at -78 °C but, as an-
ticipated, undergoes decomposition at higher temperatures
2
0
tion of 1,2,4-triazoles. In light of its ready availability,
through the reaction of morpholine with tetrazole and for-
21
maldehyde, and favorable physical properties, 4-(N-te-
trazolylmethyl)morpholine (13) was selected as a candi-
date for evaluation and prepared in multi-gram quantities
(
eq 1). In common with other N-(α-aminoalkyl)heterocy-
cles, 13 displays fluxional behavior in solution, existing in
-THF as a 56:44 equilibrium mixture of N2 (13a) and N1
(13b) tautomers that interconvert rapidly at room temper-
d
8
2
2
ature.
(entry 7) and after extended time periods (entry 4). That
decreasing anion maturation time had little impact on over-
all efficiency, suggests that tetrazole metalation is rapid (en-
tries 3 and 5). Considering this observation, we evaluated
the viability of in-situ carbanion generation and were most
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The Journal of Organic Chemistry
encouraged to find that deprotonation of 13 (2.0 equiv) in
1
2
3
4
5
6
7
8
9
the presence of 15a, termed Method B, provided 16a in
near quantitative yield (entry 8). Although Wiedemann and
Bio have demonstrated that 2-benzyl-5-potassio-1H-te-
trazole can be generated in situ from 6 and behaves as a
proficient nucleophile when used in molar excess, our ef-
forts to generate the potassium congener of 14 using
KHMDS were largely unsuccessful (entry 9). Given the op-
erational convenience and efficiency offered by in-situ
metallotetrazole generation, we proceeded to explore the
scope of Method B with a range of ketones and aldehydes; a
summary of these studies is outlined in Scheme 3.
18
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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0
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0
1
2
3
4
5
6
7
8
9
0
In common with benzophenone (15a), cyclic diaryl ke-
tones underwent addition to provide tertiary alcohols 16b-
d in excellent yield (83-92%). Importantly, Method B is
amendable to scale up, with 16a being prepared in quanti-
tative yield on a 5.5 mmol scale, without need for purifica-
tion following isolation. That the by-products of aminal hy-
drolysis and tetrazole anion fragmentation are water solu-
ble is a useful feature of the reported chemistry as removal
of N-alkyl cyanamide byproducts has proved problematic
1
8
with tetrazole equivalents 3 and 9. Upon extending the
protocol to cyclic ketones, we were delighted to find that de-
spite their potential to undergo enolization, these sub-
strates underwent efficient addition to yield the desired
products 16e-h (78-99%). In this regard, the near quantita-
tive formation of 16e from cyclopentanone is particularly
notable since the previously reported yield of this product
1
6b
was only 34%, over two steps. Addition to 1-tetralone
was less efficient than other substrates which, in addition to
enolate formation, may be attributable to the acid sensitiv-
ity of tertiary alcohol 16i, which has previously been noted
16b
by Satoh. (R)-(-)-carvone underwent exclusive 1,2-addi-
tion with high diastereoselectivity to yield allylic alcohol
16j; our assignment of stereochemistry in this case was
based on literature precedent.25
Scheme 3. Substrate Scope of Method B (In-Situ Genera-
a,b
tion of 2-Morpholinomethyl-5-lithiotetrazole)
a
Isolated yields, after purification by flash chromatography
b
on silica gel. Method B: addition of LiHMDS (2.1 mmol) to 15
1 mmol) and 14 (2 mmol) at -78 °C. For experimental details,
see Supporting Information. Product isolated as a single dia-
stereomer.
(
c
The successful formation of piperidine 16k and nortro-
pinone derivative 16l, which was isolated as a single dia-
2
6
stereomer arising from exo-face addition, indicate a toler-
ance for carbamate functionality. Extension of Method B to
aromatic aldehydes, to provide benzylic alcohols 16m-p
and the α,β−unsaturated aldehyde citral, to yield 16q also
proved high-yielding. Our method’s tolerance for aryl bro-
mides, alkynes, and alkenes is notable as these functional
groups are largely incompatible with the N-deprotection
methods employed with existing 5-metallotetrazole rea-
gents.
In conclusion, we have developed N-morpholinomethyl-
5-lithiotetrazole as a readily accessible reagent for the one-
pot preparation of 5-(1-hydroxyalkyl)tetrazoles 1 from
both enolizable and non-enolizable ketones and aldehydes.
Importantly, introduction of the 1H-tetrazole system can be
made without recourse to azide salts and the attendant dan-
27
gers of hydrazoic acid, which has been detected during the
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Page 4 of 8
preparation of 1-benzyl-1H-tetrazole (6).18 In the cases
where comparisons can be made, the current approach to
-(1-hydroxyalkyl)tetrazole is more efficient than existing
5-metallotetrazole reagents, which require two discrete
steps to access 1H-tetrazoles.
pressure to provide a residue which was recrystallized from a
1:2 mixture of hexanes and CH Cl to give 13 (4.75 g, 28.1
mmol, 99%) as a mixture of N-tautomers: white, crystalline
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
2
5
2
2
solid; mp 81-82 °C [lit. 81-82 °C]; FTIR νmax 3116, 2969, 2954,
2
1
1
6
8
923, 2904, 2869, 2846, 1478, 1456, 1435, 1422, 1398, 1386,
366, 1327, 1319, 1295, 1264, 1240, 1217, 1167, 1147, 1110,
101, 1071, 1035, 1008, 963, 897, 859, 853, 775, 753, 717, 672,
EXPERIMENTAL SECTION
-
1 1
52, 623 cm ; H NMR (400 MHz, CDCl
.52 (s, 0.8 H, 13a), 5.49 (s, 1.6 H, 13a), 5.29 (s, 0.4 H, 13b),
3
) δ 8.70 (s, 0.2 H, 13b),
General Comments. All non-aqueous reactions were car-
ried out in oven- or flame-dried glassware under an atmos-
phere of dry nitrogen, unless otherwise noted. Except as other-
wise indicated, all reactions were magnetically stirred and
monitored by analytical thin-layer chromatography using
Merck pre-coated silica gel plates with F254 indicator. Visuali-
zation was accomplished by UV light (254 nm), potassium per-
manganate solution, or phosphomolybdic acid solution. Flash
column chromatography was performed according to the
method of Still using silica gel 60 (mesh 230-400) supplied by
3.67 (t, J = 4.4 Hz, 4.0 H, 13a/b), 2.62 (t, J = 4.8 Hz, 3.2 H, 13a),
1
3
1
2.58 (t, J = 4.4 Hz, 0.8 H, 13b); C{ H} NMR (100 MHz, CDCl
3
) δ
53.0 (13a), 143.2 (13b), 74.4 (13b), 70.2 (13a), 67.0 (13b),
1
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
6.8 (13a), 50.2 (13a) 50.1 (13b); H NMR (500 MHz, d -THF)
8
δ 9.01 (s, 0.44H, 13b), 8.63 (s, 0.56H, 13a), 5.53 (s, 1.14H, 13a),
.35 (s, 0.86 H, 13b), 3.58 (2, 4.0 H, 13a/b + d -THF), 2.56-2.53
m, 4.0 H, 13a/b); C{ H} NMR (100 MHz, d -THF) δ 150.6
13a), 141.5 (13b), 71.7 (13a), 67.1 (13b), 64.5 (13a), 64.5
5
8
1
3
1
(
(
(
8
+
13b), 50.2 (13b) 47.9 (13a); HRMS (EI-TOF) m/z: [M] Calcd
O: 169.0964; Found 169.0965.
Method A, Preformation of Tetrazole Anion.
2
8
E. Merck. Yields refer to chromatographically and spectro-
graphically pure compounds, unless otherwise noted. Anhy-
drous tetrahydrofuran (THF) was passed through a solvent dis-
pensing system under a dry argon atmosphere. Compound 13
was prepared using a modification of the method reported by
for C
6
H
11
N
5
1
1
Diphenyl(1H-tetrazol-5-yl)methanol (16a) To a stirred so-
lution of 4-((N-tetrazolyl)methyl)morpholine (13) (326 mg, 2
mmol, 2 equiv) in THF (4.0 mL), under nitrogen at -78 °C (ace-
2
2
Katritsky. All other reagents and starting materials, unless
otherwise noted, were purchased from commercial vendors
and used without further purification. While all procedures in-
volving tetrazoles were conducted without incident, it is advis-
able to take appropriate safety precautions, such as the use of
shields in a fume hood and personal protection equipment,
when undertaking work with these potentially energetic heter-
ocycles.
tone/CO
2
), was added a freshly prepared solution of LHMDS
(
351 mg, 2.1 mmol, 2.1 equiv) in THF (2.0 mL), dropwise via
syringe. After stirring for 30 min at -78 °C, a solution of benzo-
phenone (15a) (182 mg, 1 mmol, 1.0 equiv) in THF (2.0 mL)
was added dropwise. The reaction was stirred for 2 h at -78 °C,
allowed to warm to room temperature over 14 h, and then con-
centrated under reduced pressure. The remaining residue was
treated with aqueous HCl (1 M, 25 mL), stirred at room temper-
ature for 1 h, and the solution extracted with EtOAc (3 x 50 mL).
Analytical Methods. All melting points were determined in
unsealed Pyrex capillaries with a Thomas Hoover Unimelt
melting point apparatus and are uncorrected. Infrared spectra
The combined extracts were dried over Na
centrated under reduced pressure and the residue was purified
by flash column chromatography on silica gel (MeOH/CH Cl
4:96), to provide 16a (244 mg, 97%): white, crystalline solid;
2
SO
4
, filtered, con-
1
were recorded using a Nicolet iS5 FTIR spectrophotometer. H
2
2
,
1
3
1
NMR and C{ H} NMR spectra were recorded on a Bruker
1
13
Avance 400 (400 MHz, H, 100 MHz, C) or a Bruker Avance
5
1
1
mp 178-180 °C [lit. 173-175 °C]; FTIR νmax 3303, 2852, 2739,
1
13
00 (500 MHz, H, 125 MHz, C) spectrometer. Chemical shift
2
1
CD
678, 2597, 2298, 1558, 1491, 1448, 1382, 1271, 1172, 1130,
values (δ) are reported in ppm relative to residual chloroform
-
1
1
064, 1052, 896, 768, 749, 716 cm ; H NMR (400 MHz,
1
13
(
δ 7.26 ppm for H; δ 78.0 ppm for C), methanol (δ 3.31 ppm
1
3
1
3
OD) δ 7.43-7.40 (m, 4 H); 7.38-7.32 (m, 6 H); C{ H} NMR
OD) δ 162.6, 144.1, 128.31, 128.26, 127.3, 77.0.
1
13
1
for H; δ 49.2 ppm for C), acetone (δ 2.05 ppm for H; δ 29.9
ppm for C), and dimethyl sulfoxide (δ 2.50 ppm for H; δ 39.5
ppm for C). Multiplicities are indicated by s (singlet), d (dou-
blet), t (triplet), q (quartet), p (pentet), h (heptet), m (multi-
plet) and br (broad) app (apparent). The identification of H
and C signals was achieved using a combination of H, C,
DEPT, COSY, HMBC, HMQC and NOESY experiments. High-res-
olution electrospray ionization (HRMS (ESI-TOF and EI-TOF))
mass spectra were obtained on a Waters Micromass Q-Tof Ul-
tima instrument at the University of Illinois Mass Spectrometry
Laboratory. High-resolution electron ionization (HRMS-ESI)
mass spectra were obtained on a Waters Micromass 70-VSE in-
strument at the University of Illinois Mass Spectrometry Labor-
atory. Optical rotations were measured with a Rudolph Re-
(
100 MHz, CD
3
1
3
1
+
HRMS (ESI-TOF) m/z: [M+H] Calcd for C14
Found 253.1087.
H
13
N O: 253.1089;
4
13
Method B, In-Situ Tetrazole Anion Generation.
1
1
1
Diphenyl(1H-tetrazol-5-yl)methanol (16a). To a stirred so-
lution of 4-((N-tetrazolyl)methyl)morpholine (13) (338 mg, 2
mmol, 2 equiv) and benzophenone (15a) (182 mg, 1 mmol, 1
1
3
1
13
equiv) in THF (5.0 mL), under nitrogen at -78 °C (acetone/CO ),
2
was added a freshly prepared solution of LHMDS (351 mg, 2.1
mmol, 2.1 equiv) in THF (2.0 mL) dropwise via syringe over 5
min. The reaction was stirred for 2 h at -78 °C, allowed to warm
to room temperature over 14 h, and then concentrated under
reduced pressure. The remaining residue was treated with
aqueous HCl (1 M, 25 mL), stirred at room temperature for 1 h,
and the solution extracted with EtOAc (3 x 50 mL). The com-
search Analytical Autopol IV polarimeter equipped with a Na
temperature
wavelength
lamp (589 nM, D) and reported as follows: [α]
(c, sol-
bined extracts were dried over Na
under reduced pressure and the residue was purified by flash
2
SO
4
, filtered, concentrated
25
-
1
-2 -1
vent); [α]D is reported in 10 deg cm g ; concentration (c) is
reported g in per 100 mL.
column chromatography on silica gel (MeOH/CH
2
2
Cl , 4:96) to
4
-((N-Tetrazolyl)methyl)morpholine (13).22 To a cold (0 °C),
provide 16a (248 mg, 98%) as a white solid.
stirred solution of tetrazole (2.00 g, 28.5 mmol) in methanol
(20 mL) was added morpholine (2.74 mL, 31.4 mmol, 1.1
equiv) and the mixture stirred for 15 min. An aqueous solution
of formaldehyde (2.8 mL, 37%, 34 mmol, 1.2 equiv) was added
dropwise and the mixture stirred for 12 h at room temperature.
The reaction mixture was then concentrated under reduced
9-(1H-Tetrazol-5-yl)-9H-fluoren-9-ol (16b).29 Following
Method B, a solution of 13 (340 mg, 2 mmol, 2 equiv) and 9-
fluorenone (15b) (180 mg, 1 mmol, 1 equiv) in THF (5.0 mL),
under nitrogen at -78 °C (acetone/CO ), was added a freshly
2
prepared solution of LHMDS (351 mg, 2.1 mmol, 2.1 equiv) in
THF (2.0 mL) dropwise via syringe over 5 min, to provide, after
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The Journal of Organic Chemistry
work up and purification by column chromatography on silica
gel (MeOH/CH Cl , 4:96), 16b (242 mg, 97%): yellow solid; mp
102-115 °C dec; FTIR νmax 3314, 3064, 2852, 2736, 1651, 1606,
1266, 1258, 1190, 1146, 1123, 1105, 1077, 997, 933, 901, 849,
-
1 1
1
2
3
4
5
6
7
8
9
2
2
761, 662 cm ; H NMR (400 MHz, CD
1.84 (m, 2 H), 1.79 (ddd, J = 15.6, 8.9, 3.3 Hz, 2 H), 1.63 (m, 3 H),
3
OD) δ 2.01 (m, 2 H), 1.92-
1
3
1
1
6
7
587, 1539, 1450, 1286, 1198, 1103, 1033, 916, 770, 748, 729,
1.48-1.38 (m, 1 H); C{ H} NMR (100 MHz, CD
3
OD) δ 163.8,
-
1
1
+
84 cm ; H NMR (400 MHz, CD
.48-7.41 (m, 4 H), 7.33-7.29 (m, 2 H); C{ H} NMR (101 MHz,
3
OD) δ 7.77 (d, J = 7.5 Hz, 2 H),
69.0, 37.2, 25.2, 21.4. HRMS (ESI-TOF) m/z: [M+H] Calcd for
1
3
1
C
7
H
13
N
4
O: 169.1089; Found 169.1086.
CD
3
OD) δ 161.3, 147.2, 140.2, 130.0, 128.5, 124.8, 120.5, 78.5.
1-(1H-Tetrazol-5-yl)cycloheptan-1-ol (16g).16a Following
-
HRMS (ESI-TOF) m/z: [M-H] Calcd for C14
Found 249.0766.
H
9
N
4
O: 249.0776;
Method B, a solution of 13 (338 mg, 2 mmol, 2 equiv) and cy-
cloheptanone (15g) (112 mg, 118 µL, 1 mmol, 1 equiv) in THF
5-(1H-Tetrazol-5-yl)-10,11-dihydro-5H-dibenzo[a,d][7]annu-
(5.0 mL), under nitrogen at -78 °C (acetone/CO ), was added a
2
1
8
len-5-ol (16c). Following Method B, a solution of 13 (338 mg,
freshly prepared solution of LHMDS (351 mg, 2.1 mmol, 2.1
equiv) in THF (2.0 mL) dropwise via syringe over 5 min, to pro-
vide, after work up and purification by column chromatog-
raphy on silica gel (acetone/hexanes, 1:4), 16g (164 mg, 90%):
white solid; mp 120-124 °C dec; FTIR νmax 3097, 2952, 2861,
2365, 2255, 2197, 2117, 1538, 1448, 1357, 1275, 1247, 1199,
2
1
mmol, 2 equiv) and dibenzosuberone (15c) (208 mg, 1 mmol,
equiv) in THF (5.0 mL) was treated with a solution of LHMDS
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
351 mg, 2.1 mmol, 2.1 equiv) in THF (2.0 mL) to provide, after
work up and purification by column chromatography on silica
gel (MeOH/CH Cl , 4:96), 16c (230 mg, 83%): white solid; mp
10-113 °C; FTIR νmax 3306, 3177, 3062, 2946, 2192, 1651,
1644, 1563, 1482, 1292, 1161, 1106, 917, 869, 783, 660, 636,
2
2
-1
1
1
1088, 1038, 1012, 998, 914, 870, 914, 745, 648 cm ; H NMR
(400 MHz, CD OD) δ 2.18 (ddd, J = 14.6, 9.2, 1.3 Hz, 2 H), 2.03
(ddd, J = 14.6, 9.2, 1.3 Hz, 2 H), 1.83-1.58 (m, 8 H); C{ H} NMR
(100 MHz, CD OD) δ 164.6, 72.9, 41.2, 29.5, 21.8. HRMS (ESI-
3
-
1
1
13
1
596 cm ; H NMR (400 MHz, CD
7
3
OD) δ 8.04-8.01 (m, 2 H), 7.31-
.24 (m, 4 H), 7.15 (dd, J = 7.1, 1.8 Hz, 2 H), 2.83 (s, 4 H); 13C{ H}
1
3
NMR (100 MHz, CD
3
OD) δ 162.5, 141.5, 138.3, 130.6, 128.4,
TOF) m/z: [M+H]
183.1244.
+
Calcd for C
8
H
15
4
N O: 183.1246; Found
+
1
26.2, 125.6, 72.2, 32.5. HRMS (ESI-TOF) m/z: [M+Na] Calcd
for C16
H
14
N
4
ONa: 301.1065; Found 301.1064.
1-(1H-Tetrazol-5-yl)cyclooctan-1-ol (16h). Following Method
B, a solution of 13 (338 mg, 2 mmol, 2 equiv) and cyclooctanone
(15h) (126 mg, 1 mmol, 1 equiv) in THF (5.0 mL), under nitro-
5
-(1H-Tetrazol-5-yl)-5H-dibenzo[a,d][7]annulen-5-ol (16d).
Following Method B, a solution of 13 (338 mg, 2 mmol, 2 equiv)
and dibenzosuberenone (15d) (206 mg, 1 mmol, 1 equiv) in
gen at -78 °C (acetone/CO ), was added a freshly prepared so-
2
THF (5.0 mL), under nitrogen at -78 °C (acetone/CO
2
), was
lution of LHMDS (351 mg, 2.1 mmol, 2.1 equiv) in THF (2.0 mL)
dropwise via syringe over 5 min, to provide, after work up and
purification by column chromatography on silica gel (ace-
tone/hexanes, 1:4), 16h (154 mg, 79%): white solid; mp 121-
127 °C dec; FTIR νmax 3093, 3000, 2958, 2854, 2806, 2780,
2752, 2626, 2194, 1644, 1538, 1474, 1446, 1376, 1365, 1294,
added a freshly prepared solution of LHMDS (351 mg, 2.1
mmol, 2.1 equiv) in THF (2.0 mL) dropwise via syringe over 5
min, to provide, after work up and purification by column chro-
matography on silica gel (MeOH/CH
2
Cl
2%): yellow solid; mp 143-145 °C dec; FTIR νmax 3310, 3063,
021, 2358, 1668, 1621, 1599, 1484, 1436, 1322, 1302, 1282,
2
, 4:96), 16d (253 mg,
9
3
1
-
1 1
1270, 1247, 1139, 1050, 1008, 903, 851, 736 cm ; H NMR
(400 MHz, (CD CO) δ 2.23-2.09 (m, 4 H), 1.78-1.51 (m, 10 H);
H} NMR (100 MHz, (CD
-1
1
221, 1158, 1032, 913, 798, 770, 744, 663 cm ; H NMR (400
)
3 2
MHz, CD
2 H), 7.38-7.37 (m, 4 H), 6.78 (s, 2 H); C{ H} NMR (100 MHz,
3
OD) δ 8.14-8.12 (m, 2 H), 7.53 (ddd, J = 8.0, 5.3, 3.4 Hz,
13C{
1
3
)
2
CO) δ 163.3, 73.1, 36.4, 28.2,
1
3
1
+
24.8, 21.6. HRMS (ESI-TOF) m/z: [M+H] Calcd for C
9
H
17
4
N O:
CD OD) δ 160.8, 140.2, 133.3, 131.1, 128.8, 128.5, 127.4, 123.6,
3
197.1402; Found 197.1399.
7
2
1.4. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C16
77.1089; Found 277.1078.
1
H
13
N
4
O:
(±)-1-(1H-Tetrazol-5-yl)-1,2,3,4-tetrahydronaphthalen-1-ol
1
6b
(16i). Following Method B, a solution of 13 (338 mg, 2 mmol,
-(1H-Tetrazol-5-yl)cyclopentan-1-ol (16e).16b Following
2 equiv) and α-tetralone (15i) (146 mg, 133 µL, 1 mmol, 1
Method B, a solution of 13 (338 mg, 2 mmol, 2 equiv) and cy-
clopentanone (15e) (112 mg, 118 µL, 1 mmol, 1 equiv) in THF
equiv) in THF (5.0 mL), under nitrogen at -78 °C (acetone/CO ),
2
was added a freshly prepared solution of LHMDS (351 mg, 2.1
mmol, 2.1 equiv) in THF (2.0 mL) dropwise via syringe over 5
min, to provide, after work up and purification by column chro-
matography on silica gel (acetone/hexanes, 1:4), 16i (146 mg,
68%): yellow oil; FTIR νmax 3062, 3021, 2943, 2873, 2840,
2464, 2219, 2069, 1491, 1336, 1280, 1194, 1166, 1117, 971,
(5.0 mL), under nitrogen at -78 °C (acetone/CO ), was added a
2
freshly prepared solution of LHMDS (351 mg, 2.1 mmol, 2.1
equiv) in THF (2.0 mL) dropwise via syringe over 5 min, to pro-
vide, after work up and purification by column chromatog-
raphy on silica gel (acetone/hexanes, 1:4), 16e (154 mg,
1
6b
-1 1
>
99%): white solid; mp 112-115 °C [lit. 112-114 °C]; FTIR
818, 746, 728 cm ; H NMR (400 MHz, CD OD) δ 7.24-7.18 (m,
3
νmax 3373, 3298, 2966, 2871, 2703, 2605, 1866, 1662, 1598,
2 H), 7.13 (td, J = 7.3, 1.9 Hz, 1 H), 7.04 (dd, J = 7.8, 0.7 Hz, 1 H),
2.93 (t, J = 6.4 Hz, 2 H), 2.39 (ddd, J = 13.4, 8.7, 3.2 Hz, 1 H), 2.23
1
1
564, 1444, 1398, 1323, 1252, 1212, 1144, 1070, 1040, 1012,
-1
1
13
1
002, 902, 883, 757, 719, 661 cm ; H NMR (400 MHz, CD
3
OD)
(ddd, J = 13.4, 8.7, 3.2 Hz, 1 H), 2.14-1.96 (m, 2 H); C{ H} NMR
δ 2.18-2.14 (m, 2 H), 2.12-2.08 (m, 2 H), 2.00 (m, 2 H), 1.92-1.89
(100 MHz, CD
3
OD) δ 163.9, 138.2, 137.4, 129.3, 128.36, 128.29,
1
3
1
+
(m, 2 H); C{ H} NMR (100 MHz, CD
2
1
3
OD) δ 162.7, 77.4, 41.1,
3.9. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C
O:
55.0933; Found 155.0931.
-(1H-Tetrazol-5-yl)cyclohexan-1-ol (16f). Following Method
126.4, 70.6, 38.5, 29.3, 18.9. HRMS (ESI-TOF) m/z: [M+H]
Calcd for C11 O: 217.1089; Found 217.1080.
6
H
11
N
4
H
13
N
4
(1R,5R)-2-Methyl-5-(prop-1-en-2-yl)-1-(1H-tetrazol-5-yl)cy-
clohex-2-en-1-ol (16j). Following Method B, a solution of 13
(338 mg, 2 mmol, 2 equiv) and (R)-carvone (16j) (150 mg, 156
µL mmol, 1 equiv) in THF (5.0 mL), under nitrogen at -78 °C
1
B, a solution of 13 (338 mg, 2 mmol, 2 equiv) and cyclohexa-
none (15f) (98 mg, 104 µL, 1 mmol, 1 equiv) in THF (5.0 mL),
under nitrogen at -78 °C (acetone/CO
2
), was added a freshly
(acetone/CO ), was added a freshly prepared solution of
2
prepared solution of LHMDS (351 mg, 2.1 mmol, 2.1 equiv) in
THF (2.0 mL) dropwise via syringe over 5 min, to provide, after
work up and purification by column chromatography on silica
gel (acetone/hexanes, 1:4), 16f (132 mg, 78%): white solid; mp
LHMDS (351 mg, 2.1 mmol, 2.1 equiv) in THF (2.0 mL) drop-
wise via syringe over 5 min, to provide, after work up and pu-
rification by column chromatography on silica gel (ace-
tone/hexanes, 1:4), 16j (214 mg, 97%) as a single diastere-
25
1
20-127 °C dec; FTIR νmax 3157, 3099, 2984, 2941, 2847, 2750,
omer: yellow solid; mp 107-115 °C dec; [α]D = -105.1 (c 0.85,
CHCl ); FTIR ν 3410, 3091, 2971, 2944, 2852, 2707, 2592,
2
649, 1547, 1520, 1446, 1435, 1424, 1411, 1370, 1355, 1273,
3
max
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The Journal of Organic Chemistry
Page 6 of 8
2
509, 2450, 1799, 1647, 1557, 1539, 1527, 1449, 1435, 1374,
chromatography on silica gel (acetone/hexanes, 1:4), 16n (233
mg, 91%): white solid; mp 178-180 °C dec; FTIR νmax 3343,
2851, 2683, 2503, 2065, 2015, 1907, 1677, 1587, 1572, 1488,
1442, 1430, 1403, 1395, 1370, 1316, 1297, 1280, 1255, 1180,
1117, 1051, 1010, 937, 850, 834, 823, 793, 783, 759, 730, 712,
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1320, 1273, 1264, 1222, 1190, 1123, 1107, 1067, 1045, 1003,
-1 1
981, 959, 895, 865, 822, 798, 771, 645 cm ; H NMR (400 MHz,
CD CO) δ 5.71 (m, 1 H), 4.71 (m, 2 H), 2.92-2.85 (m, 1 H),
.28-2.21 (m, 2 H), 1.99 (m, 2 H), 1.70 (s, 3 H), 1.61 (s, 3 H);
(
)
3 2
2
1
3
1
-1 1
C{ H} NMR (100 MHz, (CD
3
)
2
CO) δ 161.4, 148.8, 135.1, 126.7,
690, 647 cm ; H NMR (400 MHz, CD
2 H), 7.41 (d, J = 8.3 Hz, 2 H), 6.16 (s, 1 H); C{ H} NMR (100
MHz, CD OD) δ 159.6, 140.0, 131.8, 128.4, 122.3, 66.9. HRMS
3
OD) δ 7.54 (d, J = 8.5 Hz,
1
3
1
1
09.0, 72.3, 43.4, 38.6, 31.2, 20.3, 17.1. HRMS (ESI-TOF) m/z:
+
[M+H] Calcd for C11
H
17
N
4
O: 221.1402; Found 221.1401.
3
+
Benzyl 4-hydroxy-4-(1H-tetrazol-5-yl)piperidine-1-carbox-
(ESI-TOF) m/z: [M+H] Calcd for C
254.9882.
8
H
8
4
N OBr: 254.9881; Found
ylate (16k). Following Method B, a solution of 13 (338 mg, 2
mmol, 2 equiv) and N-Cbz piperidone (15k) (233 mg, 1 mmol,
(±)-Anthracen-9-yl(1H-tetrazol-5-yl)methanol (16o). Fol-
lowing Method B, a solution of 13 (338 mg, 2 mmol, 2 equiv)
and 9-anthraldehyde (15o) (206 mg, 1 mmol, 1 equiv) in THF
1
equiv) in THF (5.0 mL), under nitrogen at -78 °C (ace-
tone/CO ), was added a freshly prepared solution of LHMDS
351 mg, 2.1 mmol, 2.1 equiv) in THF (2.0 mL) dropwise via sy-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
(
(5.0 mL), under nitrogen at -78 °C (acetone/CO ), was added a
2
ringe over 5 min, to provide, after work up and purification by
column chromatography on silica gel (acetone/hexanes, 1:4),
1
2956, 2874, 1667, 1548, 1497, 1478, 1434, 1365, 1279, 1243,
1154, 1086, 1027, 1002, 978, 904, 860, 754, 736, 697, 660, 594
cm ; H NMR (400 MHz, CD
freshly prepared solution of LHMDS (351 mg, 2.1 mmol, 2.1
equiv) in THF (2.0 mL) dropwise via syringe over 5 min, to pro-
vide, after work up and purification by column chromatog-
raphy on silica gel (acetone/hexanes, 1:4), 16o (207 mg, 75%):
brown solid; mp 208-214 °C dec; FTIR νmax 3327, 3139, 2858,
2473, 1698, 1674, 1651, 1634, 1590, 1580, 1447, 1417, 1367,
1318, 1303, 1283, 1248, 1170, 1070, 934, 892, 870, 817, 808,
6k (253 mg, 83%): colorless oil; FTIR νmax 3307, 3138, 3032,
-
1 1
3
OD) δ 7.37-7.30 (m, 5 H), 5.15 (s,
2
H), 5.07 (s, 2 H), 3.96 (d, J = 13.5 Hz, 2 H), 2.11 (m, 2 H), 1.94
1
3
1
-1 1
(
1
m, 2 H); C{ H} NMR (100 MHz, CD
28.6, 128.1, 127.9, 67.4, 67.2, 39.7, 36.4. HRMS (ESI-TOF) m/z:
3
OD) δ 163.1, 155.9, 137.1,
782, 758, 733, 693 cm ; H NMR (400 MHz, (CD
(s, 1 H), 8.54 (dd, J = 6.5, 3.4 Hz, 2 H), 8.10 (dd, J = 6.5, 3.4 Hz, 2
3
)
2
CO) δ 8.63
+
13
1
[M+H] Calcd for C14
H
18
N
5
O
3
: 304.1410; Found 304.1410.
H), 7.83 (s, 1 H), 7.49 (dd, J = 6.5, 3.4 Hz, 4 H); C{ H} NMR (100
MHz, (CD CO) δ 159.6, 130.7, 129.2, 128.7, 127.92, 127.80,
124.8, 123.4, 122.8, 61.8. HRMS (ESI-TOF) m/z: [M+H] Calcd
O: 277.1089; Found 277.1078.
Benzyl-(1R,3r,5S)-3-hydroxy-3-(1H-tetrazol-5-yl)-8-azabicy-
)
3 2
+
clo[3.2.1]octane-8-carboxylate (16l). Following Method B, a so-
lution of 13 (338 mg, 2 mmol, 2 equiv) and N-Cbz nortropinone
(15l) (259 mg, 1 mmol, 1 equiv) in THF (5.0 mL), under nitro-
for C16
H
13
N
4
(±)-(4-(Phenylethynyl)phenyl)(1H-tetrazol-5-yl)methanol
(16p). Following Method B, a solution of 13 (338 mg, 2 mmol,
2 equiv) and 4-(phenylethynyl)benzaldehyde (15p) (206 mg, 1
mmol, 1 equiv) in THF (5.0 mL), under nitrogen at -78 °C (ace-
gen at -78 °C (acetone/CO ), was added a freshly prepared so-
2
lution of LHMDS (351 mg, 2.1 mmol, 2.1 equiv) in THF (2.0 mL)
dropwise via syringe over 5 min, to provide, after work up and
purification by column chromatography on silica gel (ace-
tone/hexanes, 1:4), 16l (259 mg, 79%) as a single diastere-
omer: white solid; mp 94-100 °C dec; FTIR νmax 3322, 3031,
2953, 1661, 1497, 1417, 1356, 1325, 1223, 1175, 1092, 1041,
tone/CO ), was added a freshly prepared solution of LHMDS
2
(351 mg, 2.1 mmol, 2.1 equiv) in THF (2.0 mL) dropwise via sy-
ringe over 5 min, to provide, after work up and purification by
column chromatography on silica gel (acetone/hexanes, 1:4),
16p (228 mg, 83%): yellow solid; mp 165-170 °C dec; FTIR νmax
3401, 3155, 2924, 2850, 2585, 2190, 1660, 1597, 1563, 1510,
1486, 1436, 1408, 1367, 1298, 1250, 1177, 1111, 1042, 955,
-
1 1
979, 928, 912, 882, 862, 836, 737, 696, 596 cm ; H NMR (400
MHz, CD OD) δ 9.16 (s, 1 H), 7.39-7.29 (m, 5 H), 5.17 (s, 2 H),
.07 (s, 2 H), 4.40 (s, 2 H), 2.42-2.35 (m, 4 H), 2.09-1.99 (m, 4
3
5
1
3
1
-1 1
H); C{ H} NMR (100 MHz, CD
28.6, 128.1, 127.8, 68.7, 67.1, 53.4, 42.2, 41.5, 29.7, 28.1, 27.3.
3
OD) δ 164.4, 154.3, 137.2,
858, 846, 822, 801, 757, 726, 692, 595 cm ; H NMR (400 MHz,
(CD CO) δ 9.24 (s, 1 H), 7.58-7.55 (m, 6 H), 7.42 (m, 3 H), 6.39
(s, 1 H); C{ H} NMR (100 MHz, (CD ) CO) δ 159.3, 143.3,
1
)
3 2
+
13
1
HRMS (ESI-TOF) m/z: [M+H] Calcd for C16
Found 330.1560.
H
20
N
5
O
3
: 330.1566;
3
2
141.4, 131.98, 131.89, 131.83, 129.0, 127.1, 123.4, 89.9, 89.2,
±)-Phenyl(1H-tetrazol-5-yl)methanol (16m).16a,14c Follow-
67.3. HRMS (ESI-TOF) m/z: [M-H] Calcd for C16
-
H
11
(
4
N O:
ing Method B, a solution of 13 (338 mg, 2 mmol, 2 equiv) and
benzaldehyde (15m) (106 mg, 102 µL, 1 mmol, 1 equiv) in THF
275.0933; Found 275.0935.
(±)-(E)-3,7-Dimethyl-1-(1H-tetrazol-5-yl)octa-2,6-dien-1-ol
(16q). Following Method B, a solution of 13 (338 mg, 2 mmol,
2 equiv) and geranial (15q) (152 mg, 170 µL, 1 mmol, 1 equiv)
(
5.0 mL), under nitrogen at -78 °C (acetone/CO
2
), was added a
freshly prepared solution of LHMDS (351 mg, 2.1 mmol, 2.1
equiv) in THF (2.0 mL) dropwise via syringe over 5 min, to pro-
vide, after work up and purification by column chromatog-
raphy on silica gel (acetone/hexanes, 1:4), 16m (125 mg,
in THF (5.0 mL), under nitrogen at -78 °C (acetone/CO ), was
2
added a freshly prepared solution of LHMDS (351 mg, 2.1
mmol, 2.1 equiv) in THF (2.0 mL) dropwise via syringe over 5
min, to provide, after work up and purification by column chro-
matography on silica gel (acetone/hexanes, 1:5), 16q (222 mg,
99%): yellow oil; FTIR νmax 3339, 3138, 2965, 2917, 2855,
1667, 1621, 1563, 1489, 1447, 1376, 1282, 1245, 1160, 1096,
16a
7
1%): white solid; mp 129-132 °C dec [lit. 178-179 °C]; FTIR
max 3390, 3157, 3065, 2948, 2838, 2691, 2574, 2458, 1883,
1667, 1563, 1495, 1455, 1434, 1370, 1285, 1249, 1144, 1101,
ν
-
1 1
9
58, 836, 823, 750, 695 cm ; H NMR (400 MHz, CD
3
OD) δ 9.20
-
1 1
(
(
s, ), 7.47 (m, 2 H), 7.40-7.36 (m, 2 H), 7.34-7.30 (m, 1 H), 6.19
s, 1 H); C{ H} NMR (100 MHz, (CD
1019, 975, 872, 821, 746, 654 cm ; H NMR (400 MHz, CDCl
δ 5.37 (m, 1H), 5.09 (m, 1 H), 4.80 (d, J = 8.4 Hz, 1 H), 1.82 (d, J
3
)
1
3
1
3
)
2
CO) δ 159.4, 140.7,
+
13
1
1
for C
28.5, 128.2, 126.4, 67.3. HRMS (ESI-TOF) m/z: [M+H] Calcd
= 1.4 Hz, 3 H), 1.69 (s, 3 H), 1.62 (s, 3 H); C{ H} NMR (100
MHz, CDCl ) δ 146.1, 132.4, 123.8, 119.9, 104.2, 79.8, 40.1, 26.5,
26.1, 18.14, 18.08. HRMS (ESI-TOF) m/z: [M+H] Calcd for
O: 223.1559; Found 223.1555.
8
H
9
N
4
O: 177.0776; Found 177.0770.
3
+
(
±)-(4-Bromophenyl)(1H-tetrazol-5-yl)methanol (16n). Fol-
lowing Method B, a solution of 13 (338 mg, 2 mmol, 2 equiv)
and p-bromobenzaldehyde (15n) (185 mg, 1 mmol, 1 equiv) in
THF (5.0 mL), under nitrogen at -78 °C (acetone/CO
added a freshly prepared solution of LHMDS (351 mg, 2.1
mmol, 2.1 equiv) in THF (2.0 mL) dropwise via syringe over 5
min, to provide, after work up and purification by column
C
11
H
19
N
4
2
), was
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The Journal of Organic Chemistry
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015, 5, 60938-60955; (f) Ostrovskii, V. A.; Popova, E. A.; Trifonov,
1H NMR and 13C{1H} NMR spectra (PDF)
R. E. Developments in Tetrazole Chemistry (2009–16). Adv. Heter-
ocycl. Chem. 2017, 123, 1-62. (g) Moderhack, D. Tetrazolecarbalde-
hydes and their Derivatives. Heterocycles 2017, 94, 195-235; (h)
Wentrup, C. Flash Vacuum Pyrolysis of Azides, Triazoles, and Te-
trazoles. Chem. Rev. 2017, 117, 4562. (i) Neochoritis, C. G.; Zhao, T.;
Dömling, A. Tetrazoles via Multicomponent Reactions. Chem. Rev.
2019, 119, 1970-2042.
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AUTHOR INFORMATION
Corresponding Author
*
Email: wardropd@uic.edu
ORCID
(11) Wardrop, D. J.; Komenda, J. P. Dehydrative Fragmentation
of 5-Hydroxyalkyl-1H-tetrazoles: A Mild Route to Alkylidenecar-
benes. Org. Lett. 2012, 14, 1548-1551.
(12) For recent applications of this methodology, see: (a)
Wright, K.; Quinodoz, P.; Drouillat, B.; Couty, F. One Carbon Staple
for Orthogonal Copper-Catalyzed Azide-Alkyne Cycloadditions.
Chem. Commun. 2017, 53, 321-323. (b) Quinodoz, P.; Wright, K.;
Drouillat, B.; Kletskii, M. E.; Burov, O. N.; Lisovin, A. V.; Couty, F. α-
Hydroxy-tetrazoles as Latent Ethynyl Moieties: A Mechanistic In-
vestigation. Eur. J. Org. Chem. 2019, 2019, 342-350.
(13) For related transformations, see: (a) Czernecki, S.; Valéry,
J.-M. Unusual Formation of Acetylenic Sugar from the Cyanohy-
drins of 1,2-3,4-Di-ortho-isopropylidene-α-D-galacto-hexodialdo-
1,5-pyranose. J. Carbohydr. Chem. 1986, 5, 235-240; (b) Pérez-Pé-
rez, M.-J.; Camarasa, M.-J. Alkylidene Carbenes as Intermediates in
the Synthesis of Highly Functionalized Branched-Chain Sugars and
Nucleosides. Tetrahedron 1994, 50, 7269-7282; (c) Bertha, F.; Fet-
ter, J.; Lempert, K.; Kajtar-Peredy, M.; Czira, G.; Koltai, E. Migratory
Aptitudes of Hydrogen, Benzoyl, 4-Methoxyphenyl and 4-Nitro-
phenyl Groups in Some Unsaturated Carbenes (Vinylidenes). Tet-
rahedron 2001, 57, 8889-8895; (d) Cordonnier, R.; Van Nhien, A.
N.; Soriano, E.; Marco-Contelles, J.; Postel, D. Experimental and
Computational Investigation of the Unexpected Formation of β-
Substituted Polyoxygenated Furans from Conveniently Functional-
ized Carbohydrates. Tetrahedron 2010, 66, 736-742; (f) Yoneyama,
H.; Numata, M.; Uemera, K.; Usami, Y.; Harusawa, S. Transformation
of Carbonyl Compounds into Homologous Alkynes under Neutral
Conditions: Fragmentation of Tetrazoles Derived from Cyanophos-
phates. J. Org. Chem. 2017, 82, 5538-5556.
Duncan J. Wardrop: 0000-0002-1234-5626
Author Contributions
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The manuscript was written through contributions of all au-
thors. All authors have given approval to the final version of
the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We thank the University of Illinois at Chicago, College of Liberal
Arts and Sciences (LAS) for financial support.
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(
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