Lithiation Substitution of Unprotected Benzyltetrazoles

Article abstract of DOI:10.1021/acs.orglett.9b02633

1H-Tetrazoles occupy an important role in modern medicinal chemistry, but few methods for their modification exist. Many extant protocols require the use of a difficult to remove N-alkyl-protecting group, precluding the products from use as carboxylate bioisosteres, the major role of tetrazoles in pharmaceuticals. We herein report a convenient, protecting-group-free lithiation-substitution protocol for benzylic tetrazoles. Metalation with n-BuLi at 0 °C followed by electrophilic trapping gave a range of α-functionalized benzyltetrazoles in up to 91% yield.

Full text of DOI:10.1021/acs.orglett.9b02633

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Lithiation Substitution of Unprotected Benzyltetrazoles
Jeff Y. F. Wong, Agnieszka Lewandowska, Benjamin R. Trowse, and Graeme Barker*
Institute of Chemical Sciences, Heriot-Watt University, Edinburgh EH14 4AS, U.K.
S
* Supporting Information
ABSTRACT: 1H-Tetrazoles occupy an important role in
modern medicinal chemistry, but few methods for their
modification exist. Many extant protocols require the use of a
difficult to remove N-alkyl-protecting group, precluding the
products from use as carboxylate bioisosteres, the major role of
tetrazoles in pharmaceuticals. We herein report a convenient, protecting-group-free lithiation-substitution protocol for benzylic
tetrazoles. Metalation with n-BuLi at 0 °C followed by electrophilic trapping gave a range of α-functionalized benzyltetrazoles in
up to 91% yield.
etrazoles occupy a privileged position in pharmaceutical
chemistry and appear in multiple blockbuster drugs,1
most famously the angiotensin II receptor antagonist family
typified by the first example, losartan.2 Other bioactive
examples include amide-mimetic tetrazoles such as BMS-
317180 (Figure 1).3 A recent survey of 1175 drug structures
Scheme 1
T
Figure 1.
zole; however, subsequent deprotection was inconvenient,
accomplished by passing gaseous HCl through a solution of
the product in CH2Cl2.12 Transition-metal-catalyzed tetrazole
functionalizations also rely on protecting group strategies.13,14
In this context, we report a ready lithiation-substitution
procedure for unprotected 5-benzyltetrazoles, allowing ready
access to functionalized N-H tetrazolyl products.
We were motivated by the observation that many naturally
occurring carboxylate protein ligands are derived from α-amino
acids and feature adjacent stereocenters, making α-stereogenic
tetrazoles an important target (e.g., Figure 1).3,15−19 To begin,
we decided to investigate conditions for the lithiation
substitution of the parent 5-benzyltetrazole 1, followed by
electrophilic trapping with Me2SO4 (Table 1). We proposed
that trapping would occur preferentially at the more
nucleophilic carbanion vs N1 or N2. To our surprise, after
listed in the FDA Orange Book showed tetrazole as the sixth
most common heteroaryl ring system.4 Most frequently, they
are employed as bioisosteres of carboxylates,5 displaying a
similar size, shape, electronic distribution, and pKa.6 N-H
tetrazoles do not occur in nature, and bioactive tetrazoles
display considerable metabolic stability compared with the
analogous carboxylate.7
Despite this ubiquity in medicinal chemistry, the metalation
substitution of tetrazoles remains relatively unexplored. In
1991, Flippin reported that an unprotected 5-phenyltetrazole
underwent ready ortho-metalation in the presence of s-BuLi,
and subsequent electrophilic trapping afforded the o-function-
alized products in good yields (Scheme 1).8 Other protocols
rely on preliminary tetrazole N-alkylation before metalation of
the 5-substituent.9−11 A major limitation of these methods is
difficulty of deprotecting N-alkyltetrazole products, rendering
them unsuitable for use as carboxylate bioisosteres. Huff and
co-workers reported the metalation of 2-trityl-5-methyltetra-
Received: July 26, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02633
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1
entry
x
y
temp/°C
time/h
yield of 2
yield of 3
yield of 4
1
2
3
4
5
2.2
2.2
2.2
3.0
3.0
1.0
3.0
3.0
4.0
4.0
0
0
−35
0
1
1
1
1
3
19%
6%
4%
27%
25%
24%
20%
37%
43%
51%
0%
0%
0%
0%
0%
0
metalation using n-BuLi in THF at 0 °C (a temperature
convenient for use on an industrial process chemistry scale) for
1 h and then trapping with 1.0 equiv of Me2SO4, dimethylated
benzyltetrazoles 2 and 3 were isolated in 19% and 24% yield,
respectively (43% in total yield), with no evidence of
monomethylated product 4 observed (entry 1). Neither
increasing the amount of electrophile nor reducing the
reaction temperature gave an increase in product yields
(entries 2 and 3). It was found that yields could be increased
by increasing the amount of electrophile further and metalating
using 3.0 equiv of base (entry 4), and slightly increasing the
reaction time gave us our optimal conditions (entry 5).
With optimized conditions in hand, we explored the
electrophile scope (Scheme 2) and proposed that electrophiles
other than Me2SO4 would be less likely to facilitate N-
alkylation. To our delight, this proved to be the case, and the
monosubstituted desired products were obtained in good yield
after trapping with MeI to give 4 in 85% yield, allyl bromide to
give 5 (81% yield), and BnBr (7, 91%). Silylation was
accomplished using TBMDSCl to give 6 in 80% yield. Other
electrophiles included benzophenone (8, 84%), acetone (9,
74%), pivaldehyde (10, 82%), an isocyanate (11, 72%), and a
Weinreb amide (12, 65%). A more modest yield was obtained
after trapping with DMF to give 13 in 32% yield. Finally, we
confirmed that 3.0 equiv of base is required when trapping
with electrophiles other than Me2SO4after metalation of 1
using 2.2 equiv of n-BuLi under our standard conditions
followed by trapping with Ph2CO, only a 71% yield of 8 was
obtained, compared with 84% when using 3.0 equiv of base.
We note that this requirement for 3.0 equiv of base has also
been observed by Flippin during ortho-metalation of 5-
phenyltetrazole (Scheme 1).8
Having demonstrated the electrophile scope and overcome
the potential problem of N-substitution, we wondered whether
less nucleophilic bases than n-BuLi might also effect the
desired metalation. Thus, under our optimized conditions,
metalation of 1 with LDA followed by trapping with
benzophenone gave 8 in 90% yield, while a similar procedure
using LiHMDS gave 8 in only 20% yield (Scheme 3). While
Scheme 2
Scheme 3
a
b
1
Isolated yield. Conversion determined by H NMR spectroscopy.
using LDA may be more compatible with substrates bearing
electrophilic motifs, we note that LDA is both more expensive
(£49.90 for 100 mL of a 2.0 M solution in THF/hexanes/
ethylbenzene vs £43.60 for 100 mL of a 2.0 M solution of n-
BuLi in hexanes, Sigma-Aldrich 2019) and usually obtained
from reaction of n-BuLi and diisopropylamine; we thus
propose that our optimized n-BuLi conditions are more
convenient in most cases.
Next, we turned our attention to exploring the benzylte-
trazole substrate scope (Scheme 4). Haloaryl substrates were
well tolerated with chlorinated product 14 being obtained in
66% yield after trapping with allyl bromide. Electron-poor
fluorinated products 15 and 16 were isolated in 84% and 80%
yield, respectively, while electron-rich 17 was afforded in 69%
yield. We also explored sterically hindered substrates: 1-
a
b
Using 1.1 equiv of MeI. 71% after metalation with 2.2 equiv of n-
c
1
BuLi. As determined by H NMR spectroscopy in the presence of
Me2SO2.
B
DOI: 10.1021/acs.orglett.9b02633
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4
Scheme 5
and electrophilic trapping were carried out as per our standard
conditions, followed by evaporation and deprotection using
HCl(aq) in MeOH at 70 °C for 2 h.22 After workup and
purification, we were furnished with phenolic tetrazole 28 in
70% yield (Scheme 5). Finally, we investigated the possibility
of developing an enantioselective lithiation-substitution proto-
col. After investigating the use of multiple chiral diamine
alkyllithium ligands, we were unable to obtain enantioenrich-
ments better than 60:40 er (see SI for full details)
optimization of stereoselective proceedures as well as α-
functionalization of unprotected 5-alkyltetrazoles remains a
focus of research in our group.
To conclude, we have developed a convenient, general, and
high-yielding protocol for the α-lithiation substitution of
unprotected 5-benzyltetrazoles using a readily obtained base,
n-BuLi, at an industrially convenient temperature. Function-
alized tetrazoles were obtained in up to 91% yield. Expansion
of this methodology to generalized 5-alkyltetrazoles as well as
enantioselective examples remains a focus of our ongoing
research.
a
After lithiation for 4 h.
naphthyl product 19 (82% yield) was readily obtained, as was
ortho-methyl 18 (91%) after lengthening the lithiation reaction
time from 3 to 4 h. After attempted lithiation trapping of
trifluoromethyl substrate 20, expected product 21 was not
ASSOCIATED CONTENT
* Supporting Information
■
S
1
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02633.
obtained; inspection of the H NMR spectrum of the crude
reaction mixture suggested a mixture of polymeric products,
presumably arising from the elimination of fluoride to give
cyclohexadienyl species observed by Schlosser during the
metalation of para-trifluoromethyltoluene, followed by poly-
merization as reported by Aitken.20,21 Attempted substitution
of an alkyltetrazole substrate was similarly unsuccessful, with
no product 23 (or its 2-methyl isomer) obtained from 5-n-
propyltetrazole 22. Further attempts to metalate 23 using s-
BuLi and longer reaction times yielded only modest amounts
of α-substituted products (see SI for details).
Experimental procedures and characterization data
(PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: graeme.barker@hw.ac.uk.
ORCID
We next wished to explore heterocyclic examples. Attempted
lithiation substitution of thiophenyl example 24 gave an 11%
yield of the expected product 25 and 32% yield of the
disubstituted product 26 (Scheme 5), indicating that
heterocyclic ring metalation was competitive with the desired
reaction.
Instead, we turned our attention to attempting to lithiate a
protected phenol-bearing tetrazole. Thus, 27 was subjected to
our standard reaction conditions, and inspection of the crude
reaction mixture suggested that substitution had taken place;
however, that partial MOM deprotection had also occurred.
To remedy this, a deliberate one-pot MOM deprotection step
was included in our standard reaction protocol. Thus, lithiation
Graeme Barker: 0000-0002-2351-1802
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
All authors are affiliated with Heriot-Watt University. We
gratefully acknowledge the EPSRC and Heriot-Watt University
for a DTP PhD Scholarship (JYFW). Mass spectrometry data
were acquired at the EPSRC National Mass Spectrometry
Facility at Swansea University. We thank Dr. David Ellis for
NMR support and Dr. Arno Kraft for pointing out previous
fluorine-elimination results by Schlosser.
C
DOI: 10.1021/acs.orglett.9b02633
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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