Some practical methods for the application of 5-metallo-1-benzyl-1H- tetrazoles in synthesis

Article abstract of DOI:10.1055/s-0032-1316737

Nucleophilic reagents such as 5-lithiotetrazoles are synthetically powerful tools for the installation of tetrazole functional groups, but they are of limited utility due to the instability of tetrazole-derived carbanions. Herein, we report practical methods for the generation and use of new 5-metallo-1-benzyl-1H-tetrazoles (M=K, MgX, ZnX) derived from either 1-benzyl-1H-tetrazole or 1-benzyl-5-bromo-1H-tetrazole. By varying the metal counterion, the tetrazole carbanion stability was improved. Potassium- and magnesium-derived reagents underwent additions to carbonyl compounds at -30 and -20°C, respectively. The isolated yields (41-85%) from these and other reactions were comparable to those reported for 5-lithiotetrazoles at much lower temperatures (-78 to -98 °C). Georg Thieme Verlag Stuttgart ? New York.

Full text of DOI:10.1055/s-0032-1316737

LETTER
▌2231
lSetoterme Practical Methods for the Application of 5-Metallo-1-benzyl-1H-
tetrazoles in Synthesis
5-Metallo-1-benzyl-1H-tetrazoles in Synthesis
Sean H. Wiedemann,*a Matthew M. Bio,*b Liane M. Brown,a Karl B. Hansen,a Neil F. Langillea
a
Amgen, Inc., Chemical Process R&D, 360 Binney Street, Cambridge, MA 02142, USA
b
Amgen, Inc., Chemical Process R&D, One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA
Fax +1(617)4443916; E-mail: sean.wiedemann@amgen.com
Received: 26.03.2012; Accepted after revision: 01.07.2012
of allowing the tetrazole moiety to be installed at a late
stage in a complex setting while avoiding the use of azide
reagents7.
Abstract: Nucleophilic reagents such as 5-lithiotetrazoles are syn-
thetically powerful tools for the installation of tetrazole functional
groups, but they are of limited utility due to the instability of tetra-
zole-derived carbanions. Herein, we report practical methods for
the generation and use of new 5-metallo-1-benzyl-1H-tetrazoles
(M = K, MgX, ZnX) derived from either 1-benzyl-1H-tetrazole or
1-benzyl-5-bromo-1H-tetrazole. By varying the metal counterion,
the tetrazole carbanion stability was improved. Potassium- and
magnesium-derived reagents underwent additions to carbonyl
compounds at –30 and –20 °C, respectively. The isolated yields
(41–85%) from these and other reactions were comparable to those
reported for 5-lithiotetrazoles at much lower temperatures (–78 to
–98 °C).
PG
N
N
N
N
HN
HN
O
N
N
N
N
N
H
HO
R1
+
R1
R1
R2
N
R2
1
R2
3
4
5
Scheme 2 Retrosynthetic analysis of drug candidate 1
A number of tetrazole synthetic equivalents (Figure 1) are
capable of participating in C–C bond-forming reactions.8
These reagents operate through reactive 5-metallo-
tetrazole intermediates that are formed either by metal
insertion into the C5–X bond or by selective deproton-
ation at the C5 position.
Key words: nucleophilic addition, Grignard reaction, metalation,
tetrazoles, counterion effects
The tetrazole functional group, by virtue of its ability to
act as a carboxylic acid isostere, has been incorporated
into a number of drug-candidate structures.1 Our research
group recently became interested in methods for the for-
mation of tetrazoles2 with the generic structure 1, where
R1 and R2 are generally aryl groups. Initial routes to 1
called for reacting an elaborated nitrile 2 with an azide
species via [3+2] cycloaddition (Scheme 1).3 Due to safe-
ty concerns and problems of efficiency on larger reaction
scales, we sought alternatives to this strategy.4
PG
Bn
SEM
BOM
N
N
N
N
N
N
N
N
N
N
N
N
N
H
SnBu3
H
Br
N
N
N
6
7
8 PG = PMB (a),
BOM (b), Bn (c)
9
alkylation
Stille
Suzuki
coupling
coupling
addition
Figure 1 Tetrazole synthetic equivalents with developed methodol-
ogy
NaN3, Et3N
Et3N⋅HCl
N
HN
3
N
N
2
H
1
The greatest limitation to the application of 5-metallo-
tetrazoles in synthesis to date has been their susceptibility
to spontaneous decomposition (Scheme 3).9 The tetrazole
ring can undergo [3+2] cycloreversion with loss of N2.
This process is irreversible, and the metallocyanamide by-
product 12 that it generates can interfere with desired re-
activity. Very low reaction temperatures (≤–78 °C) do
effectively suppress metallotetrazole decomposition, but
such conditions can be impractical on large scales. In an
effort to extend the range and practicality of trans-
formations available for direct tetrazole installation, we
explored the properties of some available tetrazole syn-
thetic equivalents and their metalated derivatives.
H
C
R1
4
N
R1
5
PhMe/H2O, 85 °C
R2
R2
2
1
Scheme 1 Typical tetrazole synthesis via [3+2] cycloaddition
Other common approaches to the synthesis of 5-substitut-
ed tetrazoles include multicomponent coupling reactions
and the transformation of carboxylic acid derivatives into
tetrazoles via imidoyl azides.5 Ultimately, we were at-
tracted to the idea of preparing 1 from an advanced tetra-
zolylcarbinol intermediate 3, which could be further
traced back to a tetrazole carbanion synthon 4 and a ke-
tone 5 (Scheme 2).6 This approach offered the advantage
SYNLETT 2012, 23, 2231–2236
Advanced online publication: 17.08.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1316737; Art ID: ST-2012-S0278-L
© Georg Thieme Verlag Stuttgart · New York

2232
S. H. Wiedemann et al.
LETTER
quire forcing conditions. A small amount of a Grignard re-
agent was generated by the deprotonation of tetrazole 8c
with isopropylmagnesium chloride at –20 °C; however, it
formed at a rate that was competitive with the rate of its
decomposition under these conditions.
PG
PG
N–
N
PG
C
N
Δ
– N2
N
N
N
N
N
M
M+
M
N
N
10
transition state 11
12
Scheme 3 Thermal decomposition of 5-metallotetrazoles
Ultimately, THF solutions of (1-benzyl-1H-tetrazol-5-yl)-
magnesium bromide (10c) were conveniently prepared in
ca. 30 minutes at –40 °C using the halogen–metal
exchange reaction between bromotetrazole 9 and 2-
methoxyphenylmagnesium bromide (Scheme 4). The
quantitative formation of 10c may be attributed to a sig-
nificant difference in basicity between the two Grignard
reagents.
The 1-benzyl-tetrazolyl structure was selected for further
study because it met three critical design criteria. 1) An
ideal tetrazole precursor should be preparable as a single
isomer; 2) the metalation of such a precursor should pro-
ceed under conditions practical for large-scale manufac-
turing, and 3) an ideal metalated precursor should possess
a proper balance of stability and reactivity (see Supporting
Information for further discussion). Thus, we established
practical syntheses of two precursors, 1-benzyl-1H-tetra-
zole (8c) and 5-bromo-1-benzyl-1H-tetrazole (9), capable
of providing entry into the 5-metallo-1-benzyl-1H-tetra-
zoles 10 (PG = Bn).
To progress from merely forming 10c to exploiting it in a
robust synthetic process, we had to measure its lifetime.
Several solutions of 10c were prepared at –40 °C, aged at
various temperatures and quenched with acetic acid (Fig-
ure 2). The resulting mixtures of tetrazole 8c and N-benz-
ylcyanamide 13 were assayed by HPLC to determine
extents of decomposition.10
Pioneering work on the use of 5-lithio-1-benzyl-1H-tetra-
zole (10a) in synthesis was carried out by Satoh and Mar-
copulos. They described the formation of 10a by
treatment of 8c with n-butyllithium at –98 °C in
TMEDA–THF.8d This reaction and the subsequent reac-
tion of 10a with electrophiles were reported to be depen-
dent on careful control of reagent addition rate and
efficient cooling. These characteristics rendered lithium-
based methods unusable to us. To date, there have been no
reports of metallotetrazole synthetic methodology based
on the use of other metal counterions.
We began to develop new synthetic methods by studying
various practical means of forming metallotetrazoles 10.
The potassium salt 10b was prepared by deprotonation of
8c with potassium tert-butoxide at –40 °C (Scheme 4).
The salt underwent extensive (>50%) and inconsistent de-
composition during formation, indicating that it is tran-
sient under the given conditions. Nevertheless, by
successfully accessing 10b at moderately low tempera-
tures, we demonstrated that metallotetrazole stability
could be modulated through the choice of counterion.
Figure 2 First-order decomposition of a tetrazole Grignard reagent
Bn
Bn
The results of our decomposition-rate studies are depicted
in Figure 2. The data fit well to first-order functions, as
would be expected for a spontaneous unimolecular de-
composition reaction. There is good agreement between
the rate data and our qualitative observations that 10c is
N
N
KOt-Bu
N
N
N
N
H
K
t-BuOH
+
+
DMAc–THF, –40 °C
<15 min
N
8c
N
10b
Bn
Bn
relatively stable at –40 °C (t = 20 h), somewhat labile at
½
N
ArMgBr
N
N
N
N
N
–20 °C (t = 3 h), and transient at 0 °C (t = 0.5 h). This
Br
MgBr
ArBr
½
½
THF, –40 °C
30 min
N
9
N
stability profile constitutes a remarkable improvement
over the characteristics of lithium species 10a. We attri-
bute it to the relatively covalent character of the Mg–C
bond.
10c
Scheme 4 Preparation of potassio- and magnesiotetrazoles 10b and
10c
With the described formation methods and stability data
for 10b and 10c as a starting point, we evaluated the addi-
tion of new metallotetrazoles to carbonyl compounds
(Scheme 5, Table 1). This well-studied reaction was first
described by Satoh and Marcopulos for lithium salts
Next, we endeavored to prepare a tetrazole Grignard re-
agent. The direct reaction of bromotetrazole 9 with mag-
nesium metal was not attempted because direct metalation
of such an electron-poor bromide would be expected to re-
Synlett 2012, 23, 2231–2236
© Georg Thieme Verlag Stuttgart · New York

LETTER
5-Metallo-1-benzyl-1H-tetrazoles in Synthesis
2233
derived from PMB-, BOM-, and Bn-protected tetrazoles
8a–c.8c,d They obtained good yields (70–78% isolated) of
(1-benzyl-1H-tetrazol-5-yl)carbinol products 14 from re-
actions in THF at –98 °C (method termed ‘lit. Li’).11
Bn
KOt-Bu, –30 °C – in situ K
N
DMAc–THF (9:1)
N
N
H
O
N
N
Bn
NBn
8c (2.0 equiv)
R1
R2
N
N
5
OH
R2
N
N
or
M
Table 1 Results of Metallotetrazole 10 Additions to Aldehydes and
Ketones According to Scheme 5
R1
Bn
N
N
THF, <6 h
then AcOH
N
N
10
14
Br
Entry
Product
14
Methoda
Isolated
N
2-MesMgBr, –20 °C – in situ Mg
or
N
yield (%)b
9 (1.1 equiv)
i-PrMgCl, –20 °C – preform Mg
N
N
Bn
N
Scheme 5 The addition of 5-metallo-1-benzyl-1H-tetrazoles 10 to al-
OH
dehydes and ketones
N
1
14a
in situ K
73 (67)
We discovered that 10b and 10c participate in carbonyl
addition as well. Moreover, they do so at temperatures
above their proven range of thermal stability if they are
charged in excess or if they are generated in situ in the
presence of a compatible electrophile. Three new proto-
cols for the application of metallotetrazoles in synthesis at
moderately low reaction temperatures (–25 ± 5 °C) are
presented, each with different advantages.
N
Bn
N
N
OH
N
in situ K
in situ Mg
92 (85)
93
2
14b
N
Bn
N
N
in situ K
in situ Mg
(64)
73 (70)
The first method, termed ‘in situ K’, calls for the slow ad-
dition of potassium tert-butoxide to a solution of tetrazole
8c (2.0 equiv) and an electrophile at –30 °C. This protocol
is simple and uses relatively safe, inexpensive reagents.
Its substrate scope with respect to the nucleophile compo-
nent was tested for a small set of protected tetrazoles with
mixed results (Scheme 6).
3
4
OH
Ph
14c
14d
N
Ph
N
Bn
N
N
in situ Mg
lit. Lic
69 (63)
(70)
OH
Ph
Bn
N
H
N
N
N
OH
N
in situ K
preform Mg 79 (72)
78
in situ K
5
14e
Me2NOC
Me2NOC
N
N
N
i)
H (2.0 equiv)
N
N
N
N
PG
N
Bn
PG
N
N
N
ii) KOt-Bu (2.0 equiv)
O
OH
N
in situ K
in situ Mg
<20
84 (70)
OH
6
7
8
9
14f
14g
14h
14i
DMAc–THF (9:1)
–30 °C, 3 h
iii) AcOH
MeO
Me2NOC
Bn
Me2NOC
N
Bn
N
N
15
16
in situ K
preform Mg 60 (56)
59
BOM
N
Bn
OH
Ph
N
N
N
N
N
Me
N
N
N
N
N
N
N
N
N
Bn
N
N
N
N
N
product not
detected
product not
detected
product 16a
85% isolated
product 16b
66% isolated
OH
N
in situ Mg
preform Mg 52
54 (41)
Scheme 6 Tetrazole substrate scope of the ‘in situ K’ method
N
Bn
The second metallotetrazole addition method, termed ‘in
situ Mg’, calls for the slow addition of a hindered
electron-rich aryl Grignard reagent to a solution of bromo-
tetrazole 9 and an electrophile at –20 °C. When these spe-
cies are combined, Grignard reagent 10c forms in situ.
This powerful, but seldom-used strategy relies on the met-
al–halogen exchange of 9 occurring faster than the rate at
which undesired addition of the hindered Grignard re-
agent to the electrophile occurs.12 When 2-mesityl-
N
N
preform Mg 78 (74)
OH
N
H
lit. Lic
(71)
Ph
a Methods: ‘in situ K’ – slow addition of KOt-Bu to 8c and 5 at –30 °C;
‘in situ Mg’ – slow addition of 2-MesMgBr to 9 and 5 at –20 °C; ‘pre-
form Mg’ – addition of i-PrMgCl to 9 at –20 °C, followed by addition
of 5; for details, see the experimental section.
b Assay yields determined by HPLC.
c Addition of 5 to 10a at –98 °C; ref. 8d.
© Georg Thieme Verlag Stuttgart · New York
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2234
S. H. Wiedemann et al.
LETTER
magnesium bromide was used as a magnesium source, no
products of mesityl addition to carbonyls 5 were detected.
H2 (1 atm)
Pd/C (5 wt%)
MeOH, 50 °C
N
N
NBn
NH
N
N
OH
R2
OH
R2
N
N
The ‘in situ Mg’ method is indicated when greater re-
action temperatures and functional-group tolerance are
desired. Grignard reagent 10c is considered to be milder
and less basic than potassium reagent 10b, but it is also
less convenient to use. One additional chemical step is
necessary to prepare 10c from common starting material
8c versus the preparation of 10b. This drawback is bal-
anced by the fact that the ‘in situ Mg’ method calls for a
more modest molar excess of the tetrazole component (9,
1.1 equiv) than the ‘in situ K’ method does (8c, 2.0 equiv).
R1
R1
14
R1, R2
3
=
H,
Ph
3e (92%)
3i (91%)
Scheme 7 Deprotection of representative 5-hydroxyalkyl-1-benzyl-
1H-tetrazoles 14 by hydrogenolysis
lithiotetrazoles.15 Weinreb amides are competent acylat-
ing agents in this context, providing access to acyl tetra-
zoles, which behave as α-keto acid mimics in molecular
biology.16 Pleasingly, Grignard reagent 10c also reacted
with N-methoxy-N-methylbenzamide (17) to provide
benzoyl tetrazole 18 in good yield (69% isolated,
Scheme 8). As in the classical Grignard reactions, the
Grignard acylation reaction may be performed at a sig-
nificantly higher temperature (–20 °C) than that reported
previously for analogous 5-lithiotetrazole additions (–78
to –98 °C).8c,d,16
The third method, termed ‘preform Mg’, calls for in-
dependent preparation of a chloromagnesium Grignard
reagent 10d at –20 °C and subsequent reaction of it with
an electrophile at the same temperature. Among the three
protocols described, the ‘preform Mg’ method requires
the greatest number of process operations. On the other
hand, it affords the lowest risk of base-mediated side reac-
tions, and it permits inexpensive i-PrMgCl to be used as
the magnesium source.
The results of metallotetrazole additions to nonenolizable
aldehydes and ketones are summarized in Table 1 (entries
1–4). The ‘in situ K’ protocol provided good yields (64–
85% isolated) for this substrate class. The combination of
preparing the reactive anion 10b in situ and using it in
moderate excess (2.0 equiv) was essential to overcoming
its intrinsic instability at ≥40 °C. The ‘in situ Mg’ proto-
col also provided good yields (64–85% isolated) for addi-
tions to nonenolizable carbonyl compounds.
Bn
Bn
O
O
N
N
in situ Mg
N
N
N
N
Me
MgBr
+
Ph
N
THF, –20 °C
1 h, 69%
N
N
Ph
OMe
10c
17
18
Scheme 8 Acylation of Grignard reagent 10c
The results of metallotetrazole additions to enolizable al-
dehydes and ketones are summarized in Table 1 (entries
5–9).13 For this substrate class, the presence of a strong
Brønsted base would be expected to interfere with the de-
sired reactivity. Indeed, the ‘in situ K’ protocol provided
mixed results. Improved yields were obtained using either
the ‘in situ Mg’ protocol or the ‘preform Mg’ protocol
(e.g., Table 1, entry 6). In general, isolated yields for eno-
lizable substrates tended to be lower than those observed
for nonenolizable substrates (35–72%).
We carried out a brief search for new reactions of metallo-
tetrazoles that might be uniquely enabled by the present
methodology. From this screen, we discovered that tetra-
zole Grignard reagent 10c reacts with phenyldisulfide
(19) to give 1-benzyl-5-(phenylthio)-1H-tetrazole (20) in
good yield (64% isolated, Scheme 9). This result is of par-
ticular interest because sulfonyltetrazoles, which are read-
ily prepared by oxidation of tetrazolyl thioethers, are
versatile electrophilic tetrazole-transfer reagents.17
In the cases where direct comparisons were available be-
tween our methods and the lithiotetrazole-based method,
differences in reaction yield were insignificant (Table 1,
entries 4 and 9). The present methods are more robust and
scalable than existing methods, and the reagents that they
employ are more convenient to handle than n-butyllithi-
um.
Bn
Bn
N
N
in situ Mg
N
N
N
N
PhS-SPh
MgBr
S
+
THF, –20 °C
3.5 h, 64%
N
10c
N
20
19
Ph
Scheme 9 Reaction of Grignard reagent 10c with phenyldisulfide
The Grignard reagent 10c was used to prepare a corre-
sponding (1-benzyl-1H-tetrazol-5-yl)zinc halide reagent
10e via transmetalation with ZnCl2 at –20 °C (Scheme
10). The stability of 10e was not measured quantitatively.
Qualitatively, it exhibited the greatest stability of the
5-metallotetrazoles studied, persisting in THF solution at
room temperature over a period of days.18
The deprotection of 5-(1-hydroxyalkyl)-1-benzyl-1H-
tetrazoles 14 under standard hydrogenolysis conditions
has been described elsewhere.14 Representative reactions
involving adducts derived from a ketone and an aldehyde,
14e and 14i, respectively, proceeded in high yield (91–
92%), providing the free NH-tetrazoles 3e and 3i as ex-
pected (Scheme 7).
Organozinc halide reagent 10e seemed to offer the great-
est potential for accessing new reaction manifolds un-
In addition to aldehydes and ketones, a small number of
other electrophiles have been reported to react with 5-
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© Georg Thieme Verlag Stuttgart · New York

LETTER
5-Metallo-1-benzyl-1H-tetrazoles in Synthesis
2235
available to 5-lithiotetrazoles. To date, the study of In summary, several useful reactions of metallotetrazoles
transition-metal-mediated cross-coupling reactions of may now be carried out under practical conditions by
5-metallotetrazoles has been limited to the Stille coupling varying the counterion and manner of reagent addition.
of 5-(tributylstannyl)tetrazole 7 (Figure 1).8b In consider- This technology was successfully applied to the medium-
ing a Negishi-type coupling of 10e, we were encouraged scale synthesis of 16a, which was further transformed into
by reports of successful copper- and palladium-catalyzed a drug candidate with general structure 1. A detailed
cross-coupling reactions involving zincated N-hetero- description of this work will be disclosed separately.
cycles.19 Nevertheless, tetrazole is a highly σ-electron-de-
ficient heterocycle. Its reactivity toward cross-coupling
was expected to be modest at best.
General Procedure for the Use of (1-Benzyl-1H-tetrazol-5-
yl)potassium (10b) in Synthesis – ‘in situ K’
In the event, the Pd-catalyzed cross-coupling of tetrazole
zinc reagent 10e with 2-bromopyridine (21) furnished
pyridyl tetrazole 22 in moderate yield (31% isolated) after
a prolonged reaction time under standard conditions
(Scheme 10). This albeit unoptimized example illustrates
the potential for a general synthetic route to 5-aryltetra-
zoles that would be complementary to the Suzuki cou-
pling of bromotetrazole 9.8e,20
To a three-neck flask equipped with an overhead stirrer was charged
the electrophile (5.44 mmol), 1-benzyl-1H-tetrazole (8c, 1.74 g,
10.9 mmol, 2.00 equiv), N,N-dimethylacetamide (17.5 mL, 2.8 M),
and THF (1.9 mL, 0.31 M). The flask was purged with nitrogen and
cooled to –30 °C. KOt-Bu (1.0 M in THF, 10.9 mL, 10.9 mmol,
2.00 equiv) was added to the reaction dropwise over 45 min, main-
taining the internal temperature between –33 to –28 °C. The reac-
tion was stirred at –30 °C for 2 h. The reaction was quenched with
AcOH (0.78 mL, 2.50 equiv). The product was isolated by a combi-
nation of extraction, followed by chromatography and/or crystalli-
zation.
Bn
Bn
i) i-PrMgCl, 30 min
II) ZnCl2, 20 min
N
N
N
N
N
N
General Procedure for the Use of (1-Benzyl-1H-tetrazol-5-
yl)magnesium Bromide (10c) in Synthesis – ‘in situ Mg’
To a three-neck flask equipped with an overhead stirrer was charged
1-benzyl-5-bromo-1H-tetrazole (9) (550 mg, 2.30 mmol,
1.10 equiv) and THF (7.50 mL, 0.28 M). The flask was purged with
nitrogen, and the electrophile (2.09 mmol) was added. The resulting
mixture was cooled to –20 °C. Mesitylmagnesium bromide (1.0 M
in THF, 2.30 mL, 2.30 mmol, 1.10 equiv) was added to the reaction
dropwise over 30 min, maintaining the internal temperature be-
tween –24 to –20 °C. The reaction solution was then stirred at –20 °C
until electrophile consumption was judged to be complete by
HPLC. The reaction was quenched with AcOH (0.13 mL,
1.10 equiv), and the resulting crude mixture was partitioned be-
tween H2O and MTBE. The product was isolated from the organic
phase by chromatography and/or crystallization.
Br
ZnX
THF, –20 °C
N
N
9
10e X = Cl, Br
Bn
N
Pd(PPh3)4 (5 mol%)
N
N
+
10e
THF, 20 °C
3 d, 31%
Br
N
21
N
N
(1.5 equiv)
22
Scheme 10 Preparation and Negishi coupling of a tetrazole zinc ha-
lide reagent
Until now, applications of 5-metallotetrazoles in synthesis
were limited to the use of lithium reagents, which require
very low reaction temperatures (–78 to –98 °C), or tin re-
agents, which require high reaction temperatures
(>100 °C). These two examples can now be seen as lower
and upper bounds, respectively, on the working tempera-
ture range of 5-metallotetrazoles. The potassium, magne-
sium, and zinc salts of 1-benzyl-1H-tetrazoles 10b–e
collectively fill a missing intermediate temperature range
from –40 to 20 °C. Each of these salts may now be conve-
niently prepared from tetrazole 8c or bromotetrazole 9 by
deprotonation, metal–halogen exchange, and/or trans-
metalation.
General Procedure for the Use of (1-Benzyl-1H-tetrazol-5-
yl)magnesium Chloride (10d) in Synthesis – ‘preform Mg’.
To a three-neck flask equipped with an overhead stirrer was charged
1-benzyl-5-bromo-1H-tetrazole (9) (550 mg, 2.30 mmol,
1.10 equiv) and THF (4.0 mL). The flask was purged with nitrogen,
and the resulting mixture was cooled to –20 °C. A THF solution of
a suitable magnesium reagent, typically i-PrMgCl (2.30 mmol,
1.10 equiv), was added to the reaction mixture dropwise over 15
min, maintaining the internal temperature below –20 °C. The reac-
tion was stirred at –20 °C for 5 min. A solution of electrophile
(2.09 mmol) in THF (3.50 mL) was added dropwise over 20 min,
maintaining the internal temperature below –20 °C. The reaction
solution was stirred at –20 °C until electrophile consumption was
judged to be complete by HPLC. The reaction was quenched with
AcOH (0.13 mL, 1.10 equiv), and the resulting crude mixture was
partitioned between H2O and MTBE. The product was isolated
from the organic phase by chromatography and/or crystallization.
Not surprisingly, the reactivities and stabilities of metallo-
tetrazoles in the series from lithium to zinc vary inversely
with respect to one another. Grignard reagents 10c and
10d may offer the best mix of properties. Within their
range of thermal stability (–20 ± 20 °C) they react
smoothly with a variety of electrophiles, and only a small
excess charge of the tetrazole component is required
(1.1 equiv). Other metallotetrazoles offer advantages in
specific situations; for example, a zinc salt may be em-
ployed when elevated reaction temperatures are neces-
sary, or a potassium salt may be employed when the
handling of pyrophoric reagents is undesirable.
5-Hydroxy-5-[1-(benzyl)-1H-tetrazol-5-yl]-10,11-dihydro-
N2,N2,N8,N8-tetramethyl-5H-dibenzo[α,δ]cycloheptene-2,8-
dicarboxamide (16a)
The reaction was carried out according to the ‘in situ K’ method. To
a 5 L jacketed reactor was charged 10,11-dihydro-N2,N2,N8,N8-
tetramethyl-5H-dibenzo[α,δ]cyclohepten-5-one-2,8-dicarboxamide
(15, 200.9 g, 98.5%, 0.565 mol), 1-benzyl-1H-tetrazole (8c,
182.3 g, 99.5% 1.13 mol, 2.00 equiv), N,N-dimethylacetamide
(1800 mL), and THF (200 mL). The flask was purged with nitrogen
for 25 min. The jacket temperature was set to –35 °C. Addition of
KOt-Bu (1.0 M solution in THF; 1027 g, 1.14 mol, 2.00 equiv) was
carried out over 90 min at a rate such that the reaction temperature
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2231–2236

2236
S. H. Wiedemann et al.
LETTER
hazardous materials (e.g., hydrazoic acid, see ref. 3) are
was maintained between –26 to –30 °C. The purple reaction suspen-
sion was aged for 45 min at –30 °C, and then AcOH (113.3 mL, 1.97
mol, 3.50 equiv) was added over 60 min. A color change from pur-
ple to yellow was observed concurrently with acidification of the re-
action mixture. The reaction suspension was warmed to 15 °C and
H2O (200 mL) was added. The resulting biphasic mixture was con-
centrated by distillation (50 °C, 250–50 mbar) until GC analysis of
the residue indicated 3.4 v/v (%) THF. HPLC analysis of the homo-
geneous concentrate indicated 94.3% assay yield. After being
cooled and aged at r.t. overnight, the product solution was reheated
to 50 °C. H2O (200 mL) was added over 30 min, followed by crystal
seed (16a, 5.15 g, 2.5% by mass). The seeded suspension was aged
for 45 min, and then H2O (800 mL) was added over 3 h. The result-
ing slurry was cooled from 50 to 20 °C over 3 h. After 15 h of fur-
ther aging at this temperature, the slurry was filtered through a
fritted glass funnel. The wet cake was displacement washed with
N,N-dimethylacetamide–H2O (60:40, 400 mL). A mother liquor
loss of 7.4% of 16a was measured for the combined filtrate. The wet
cake was dried under a stream of nitrogen to give the title compound
as a white granular solid (259 g, 98.8% 16a by mass, 85.2%); mp
148–156 °C. 1H NMR (400 MHz, CDCl3): δ = 2.70 (m, 4 H), 2.83
(br s, 6 H), 2.88 (br s, 6 H), 5.34 (s, 2 H), 6.74 (br s, 1 H), 6.90 (d,
J = 1.7 Hz, 2 H), 6.99 (m, 2 H), 7.09 (dd, J = 8.2, 1.8 Hz, 2 H), 7.20
(m, 3 H), 7.81 (d, J = 8.1 Hz, 2 H). 13C NMR (100 MHz, CDCl3): δ
= 31.1, 35.0, 39.4, 51.4, 72.1, 124.5, 124.8, 128.0, 128.1, 128.4,
128.9, 133.4, 135.6, 136.9, 141.9, 157.2, 171.2. IR: 917, 1048,
directed to appropriate commercial suppliers.
(8) (a) 2-Trimethylsilylethoxymethyl-1H-tetrazole (6) in an
alkylation reaction: Bookser, B. C.; Kasibhatla, S. R.;
Appleman, J. R.; Erion, M. D. J. Med. Chem. 2000, 43, 1495.
(b) 2-Benzyloxymethyl-5-(tributylstannyl)tetrazole (7) in
Stille couplings: Bookser, B. C. Tetrahedron Lett. 2000, 41,
2805. (c) 1-(Benzyloxymethyl)-1H-tetrazole (8b) in
addition reactions: Satoh, Y.; Moliterni, J. Synlett 1998, 528.
(d) 1-p-Methoxybenzyl-1H-tetrazole (8a) and 1-benzyl-1H-
tetrazole (8c) in addition reactions: Satoh, Y.; Marcopulos,
N. Tetrahedron Lett. 1995, 36, 1759. (e) 1-Benzyl-5-bromo-
1H-tetrazole (9) in Suzuki couplings: Yi, K. Y.; Yoo, S.-e.
Tetrahedron Lett. 1995, 36, 1679.
(9) The decomposition of metallotetrazoles to cyanamides was
reported by early investigators, see ref. 6. Because of the
instability of metallocyanamides themselves, their formation
has often been inferred from trapping reactions, see ref. 8b,
6. We used several analytical methods to confirm their
existence in our hands, see Supporting Information.
(10) When the reactions described herein were carried out at r.t.
(simulating an unexpected loss of reaction cooling),
complete, base addition-controlled decomposition of the
tetrazole component was observed, accompanied by
moderate evolution of N2.
(11) For a recent synthesis of 5-hydroxyalkyl-1H-tetrazoles via
an enantioselective Passerini-type reaction, see: Tao, Y.;
Mei-Xiang, W.; De-Xian, W.; Jieping, Z. Angew. Chem. Int.
Ed. 2008, 47, 9454.
+
1385, 1416, 1624 cm–1. HRMS: m/z calcd for C29H31N6O3
[M + H]+: 511.24522; found: 511.24661.
(12) Poirier, M.; Chen, F.; Bernard, C.; Wong, Y.-S.; Wu, G. G.
Org. Lett. 2001, 3, 3795.
(13) While dibenzosuberone (5e) is not capable of forming an
enolate in the classical sense, it can form an extended O-
stabilized anion upon deprotonation at one of the ethylene
bridge positions.
(14) (a) Wuts, P. G. M.; Greene, T. W. Greene’s Protective
Groups in Organic Synthesis; John Wiley and Sons:
Hoboken, 2007. (b) For examples, see ref. 8d, 15e, and
references cited therein.
(15) (a) For 5-lithiotetrazole additions to halonium donors, see
ref. 8c–e. (b) For 5-lithiotetrazole additions to
Acknowledgment
The authors acknowledge Jason Tedrow and Eric Fang for helpful
discussions and support.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
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References and Notes
(1) Herr, R. J. Bioorg. Med. Chem. 2002, 10, 3379.
(2) (a) Koldobskii, G. Russ. J. Org. Chem. 2006, 42, 469.
(b) Katritzky, A. R.; Cai, C.; Meher, N. K. Synthesis 2007,
1204; and references cited therein.
(3) For a description of the hazards associated with hydrazoic
acid, see: Wiss, J.; Fleury, C.; Heuberger, C.; Onken, U.;
Glor, M. Org. Process Res. Dev. 2007, 11, 1096.
(4) Microreactors are an increasingly promising alternative
technology for safe tetrazole synthesis using HN3: Gutmann,
B.; Roduit, J.-P.; Roberge, D.; Kappe, C. O. Angew. Chem.
Int. Ed. 2010, 49, 7101.
(5) For a general review of the chemistry of tetrazoles, see:
(a) Butler, R. N. In Comprehensive Heterocyclic Chemistry
II, Vol. 4; Storr, R. C., Ed.; Elsevier: Oxford, 1996, 905.
(b) Bhatt, U. In Modern Heterocyclic Chemistry; Alvarez-
Builla, J.; Vaquero, J. J.; Barluenga, J., Eds.; Wiley-VCH:
Weinheim, 2011, 1401.
(6) For a seminal report on the lithiation and elaboration of 1-
methyl-1H-tetrazole, see: Raap, R. Can. J. Chem. 1971, 49,
2139.
diethylchlorophosphate, see ref. 8d. (c) For 5-lithiotetrazole
additions to chlorotributylstannane, see ref. 8b. (d) For 5-
lithiotetrazole additions to an ester, see: Kumar, S.; Pearson,
A. L.; Pratt, R. F. Bioorg. Med. Chem. 2001, 9, 2035. (e) For
5-lithiotetrazole additions to nitroalkenes, see: Schwarz, J.
B.; Colbry, N. L.; Zhu, Z.; Nichelson, B.; Barta, N. S.; Lin,
K.; Hudack, R. A.; Gibbons, S. E.; Galatsis, P.; DeOrazio, R.
J.; Manning, D. D.; Vartanian, M. G.; Kinsora, J. J.;
Lotarski, S. M.; Li, Z.; Dickerson, M. R.; El-Kattan, A.;
Thorpe, A. J.; Donevan, S. D.; Taylor, C. P.; Wustrow, D. J.
Bioorg. Med. Chem. Lett. 2006, 16, 3559.
(16) Colarusso, S.; Gerlach, B.; Koch, U.; Muraglia, E.; Conte, I.;
Stansfield, I.; Matassa, V. G.; Narjes, F. Bioorg. Med. Chem.
Lett. 2002, 12, 705.
(17) (a) Gol’tsberg, M. A.; Koldobskii, G. I. Russ. J. Org. Chem.
1995, 31, 1552. (b) Gol’tsberg, M. A.; Koldobsky, G. I.
Chem. Heterocycl. Compd. 1996, 32, 1300. (c) Gol’tsberg,
M. A.; Koldobskii, G. Russ. J. Org. Chem. 1996, 32, 1194.
(18) Our efforts to prepare a tetrazole-boronate reagent were as
fruitless as those reported by others, see: Primas, N.;
Bouillon, A.; Rault, S. Tetrahedron 2010, 66, 8121.
(19) Bhanu Prasad, A. S.; Stevenson, T. M.; Citineni, J. R.;
Nyzam, V.; Knochel, P. Tetrahedron 1997, 53, 7237.
(20) For direct C–H arylation of 1-substituted tetrazoles, see:
Špulák, M.; Lubojacký, R.; Šenel, P.; Kuneš, J.; Pour, M.
J. Org. Chem. 2009, 75, 241.
(7) When using a tetrazole synthetic equivalent, preparation of
the energetic heterocycle is necessarily deferred to an earlier
synthetic stage. While we do describe synthetic methods for
the tetrazole building blocks used in the present work (see
Supporting Information), investigators wishing to minimize
their exposure to risks associated with the handling of
Synlett 2012, 23, 2231–2236
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