A one-pot synthesis of tetrazolones from acid chlorides: Understanding functional group compatibility, and application to the late-stage functionalization of marketed drugs

Article abstract of DOI:10.1039/c6ob01644h

A one-pot and scalable synthesis of tetrazolones (tetrazol-5-ones) from acid chlorides using azidotrimethylsilane is presented. The reaction tolerates many functional groups and can furnish aryl-, heteroaryl-, alkenyl-, or alkyl-substituted tetrazolone products in moderate to excellent yield (14-94%). No reduction in yield was observed when the reaction was undertaken on a larger-scale (20-36 g). The method could be used for the late-stage functionalization of pharmaceuticals, to provide tetrazolone congeners of the marketed drugs aspirin, indomethacin, probenecid, telmisartan, bexarotene, niacin (vitamin B3), and the active metabolite of the recently-launched immuno-modulatory agent, BG-12 (Tecfidera). The ability of a tetrazolone group to serve as a bioisostere of a carboxylic acid, and to improve drug pharmacokinetic profiles is also highlighted.

Full text of DOI:10.1039/c6ob01644h

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A one-pot synthesis of tetrazolones from acid
chlorides: understanding functional group
compatibility, and application to the late-stage
functionalization of marketed drugs†‡
Cite this: DOI: 10.1039/c6ob01644h
Matthew A. J. Duncton* and Rajinder Singh
A one-pot and scalable synthesis of tetrazolones (tetrazol-5-ones) from acid chlorides using azidotri-
methylsilane is presented. The reaction tolerates many functional groups and can furnish aryl-, hetero-
aryl-, alkenyl-, or alkyl-substituted tetrazolone products in moderate to excellent yield (14–94%).
No reduction in yield was observed when the reaction was undertaken on a larger-scale (20–36 g). The
method could be used for the late-stage functionalization of pharmaceuticals, to provide tetrazolone
congeners of the marketed drugs aspirin, indomethacin, probenecid, telmisartan, bexarotene, niacin
(vitamin B3), and the active metabolite of the recently-launched immuno-modulatory agent, BG-12
(Tecfidera®). The ability of a tetrazolone group to serve as a bioisostere of a carboxylic acid, and to
improve drug pharmacokinetic profiles is also highlighted.
Received 1st August 2016,
Accepted 31st August 2016
DOI: 10.1039/c6ob01644h
www.rsc.org/obc
The tetrazole group is a well-known substructure within medic-
inal chemistry and is present in a wide-selection of marketed
drugs.1 In many instances, a tetrazole may act as a non-classi-
cal bioisostere of a carboxylic acid,2 but its contribution may
also extend beyond isosteric replacement.3 Relative to their
tetrazole counterparts, a tetrazol-5-one group (henceforth,
referred to as a tetrazolone), in which oxygen has been added
to the 5-position of the tetrazole ring, has been utilized much
less frequently by medicinal chemists. For example, a search
of approved drugs indicate that only one marketed compound,
the analgesic alfentanil 1, contains a tetrazolone moiety
(Fig. 1).1,4,5 A low occurrence of tetrazolones within medicinal
chemistry is unfortunate, as the tetrazolone group has many
attractive features. For example, when the nitrogen at the
4-position is unsubstituted, the tetrazolone has a similar pKa
when compared with a tetrazole congener,6 and can lower the
calculated octanol–water partition coefficient (clog P).
Therefore, it may be possible that a tetrazolone could also
function as a non-classical bioisostere of a carboxylic acid.7
Additionally, when anionic species are considered, the pres-
ence of an oxygen stabilizes the localization of electron-density
at the nitrogen 4-position.8 Thus, the 4-position of a tetra-
Fig. 1 Alfentanil 1, L-770,644 2, and some characteristics of the tetra-
zole and tetrazolone groups.1,2,5–7,11
zolone is easy to alkylate,9 or arylate,10 to provide 1,4-di-
substituted analogues. Studies with such compounds have
shown that improvements to drug metabolism and pharamco-
kinetic properties (DMPK) can be observed. For example,
within a series of β3-adrenergic receptor agonists, the tetra-
zolone L-770,644 2, showed improved DMPK in dog, when com-
pared to imidazolidinone, or imidazolone relatives (Fig. 1).11
Therefore, an expedient synthesis of compounds containing a
tetrazolone group would be beneficial for both organic and
medicinal chemists, especially if the methodology could be
Rigel Pharmaceuticals, 1180 Veterans Boulevard, South San Francisco, CA 94080,
USA. E-mail: mattduncton@yahoo.com, mduncton@rigel.com
†A separate paper describing the ability of a tetrazolone to act as a bioisostere of
a carboxylic acid has been submitted.
‡Electronic supplementary information (ESI) available. See DOI: 10.1039/
c6ob01644h
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Table 1 Reaction
azidotrimethylsilane
of
2-bromo-3-fluorobenzoyl
chloride
with
applied to the late-stage functionalization of fully-decorated
compounds with pharmacological activity.
Most methods for preparing tetrazolones rely on a reaction
of an isocyanate with an azide (Fig. 2). For example, reaction of
phenylisocyanate with NaN3/AlCl3 gives N-phenyltetrazolone in
a 76% yield.12 The same reaction can proceed in quantitative
yield if azidotrimethylsilane is used as the source of azide.13
The isocyanate can also be prepared in situ, via a Curtius
rearrangement, and this has led to syntheses starting from
acid chlorides, progressing through an acyl azide to isocyanate
to tetrazolone in one pot. For example, NaN3/AlCl3,12 or NaN3/
SiCl4 have been used for this transformation.14 One paper has
described the use of azidotrimethylsilane in carbon tetra-
chloride for the synthesis of thienyltetrazolones from thenoyl
Entry
TMS-N3 (equiv.)
Yield of 4 (%)
1
2
3
4
6.0
4.5
3.0
82
76
37
80–94
4.0–6.0 (20–36 g scale)
chlorides.15,16 However, only three examples were described, high purity (>96%). The reaction could also be scaled-up
and an acylated tetrazolone by-product could also be formed, without any loss in yield. For instance, undertaking reactions
if the stoichiometry of azidotrimethylsilane was low. Our own with 20–36 g of acid chloride 3 and 4.0–6.0 equivalents of
research group has an interest in compounds containing a TMS-N3 resulted in a 80–94% isolated yields of tetrazolone 4
tetrazolone, and we have previously disclosed uses within a (entry 4). These yields were similar to that obtained when
series of kinase inhibitors.17 As part of our efforts to broaden commercially-available
2-bromo-4-fluoro-isocyanatobenzene
the use of tetrazolones within medicinal chemistry,18 we was reacted with TMS-N3 under similar conditions, indicating
wished to examine their preparation in further detail. In this that acylazide formation and subsequent Curtius rearrange-
paper we report an expedient synthesis of tetrazolones from ment progressed uneventfully.4
acid chlorides using azidotrimethylsilane, which is used as
Next, we examined the application of the optimal reaction
both a co-reactant and solvent. Such a protocol can minimize conditions identified above (at least 6.0 equivalents of neat
the formation of by-products, and provide tetrazolone products TMS-N3) with a diverse range of acid chloride substrate. In
in moderate to excellent yield. The facile nature of the process order to demonstrate that tetrazolone formation could be
was demonstrated by conducting reactions up to 36 g in scale, undertaken in a parallel manner, we performed some reac-
and by utilizing the methodology for the late-stage function- tions in sealed vials employing a pressure-release cap, usually
alization of marketed drugs.19
undertaking multiple reactions in a single heating block. After
Our synthesis of tetrazolones began by examining the reac- completion of the reaction, the mixture was worked-up by eva-
tion of 2-bromo-4-fluorobenzoyl chloride 3 with azidotri- porating the excess TMS-N3, extracting using a base/acid proto-
methylsilane (TMS-N3) at 100 °C (Table 1). Reacting 3 (1.5 g) col, and purifying further with silica gel chromatography if
with 6.0 equiv. of TMS-N3 afforded the desired tetrazolone 4 in required. The results of our experiments are shown in Table 2.
82% isolated yield (entry 1). Reducing the stoichiometry of As can be seen, the reaction tolerates a diverse-range of
TMS-N3 led to significant formation of a symmetrical urea functionality on the acid chloride. For example, alkyl, trifluoro-
by-product, and a lower isolated yield of desired tetrazolone 4. methyl, aryl, heteroaryl, alkenyl, nitro, fluoro, chloro, bromo,
For example, the use of 4.5 equivalents of TMS-N3 gave a 76% iodo, ketone, nitrile, pentafluorosulfanyl, ether, thioether,
yield of tetrazolone 4 (entry 2), while the use of 3.0 equivalents ester, amide and sulfonamide groups all remain intact under
of TMS-N3 gave a 37% yield of tetrazolone 4 (entry 3), together the reaction conditions (entries 1–21). Additionally, reactions
with large quantities of a symmetrical urea, 1,3-bis-(2-bromo-4- of acid chlorides directly attached to heteroaryl, alkenyl, or
fluorophenyl)urea.4 Significantly, it was found that the desired alkyl-moieties were also successful (entries 22–26). A number
tetrazolone 4 was easily obtained from all the above reaction of reactions in Table 2 deserve further comment. For instance,
mixtures by cooling, evaporation of the excess TMS-N3 and use reactions of acid chlorides containing trifluoromethyl- or
of a base/acidification extraction process to give product of fluoro-groups were notable, as fluorine is a valuable substitu-
ent within medicinal chemistry (entries 4, 6 and 7).20 It was
also significant to observe that groups prone to nucleophilic
aromatic displacement, such as activated halides, remain
intact under the reaction conditions (entries 6, 7, 9 and 10).
Additionally, the efficiency of the reaction seemed to be
unaffected by the presence of large ortho-substituents (entries
9–11). In this respect, the formation of a tetrazolone analog of
the commercial herbicide 2,4-D was particularly rewarding
(entry 11). The reaction of an acid chloride containing a
ketone group is also noteworthy, as no evidence for con-
comitant Schmidt reaction was observed (entry 12). Similarly,
Fig. 2 Representative synthesis of tetrazolones.11–16
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Table 2 Tetrazolone formation with acid chlorides and azidotrimethylsilane
Entry
1
Starting material
Product
Yield (%)
76
Entry
14
Starting material
Product
Yield (%)
65a
2
3
66
61
15
16
73a
20
4
5
56
90
17
18
56
82a
6
70
19
68a
7
8
86
60
20
21
33a
89a
9
76
66
22
23
65
30
10
11
43a
24
86
12
13
59a
90
25
26
62a
14
a Acid chloride prepared from acid prior to reaction with azidotrimethylsilane – reported yield is from acid to tetrazolone (see ESI).
azidotrimethylsilane did not react with a substrate containing within medicinal chemistry (entry 14).21 The successful
a nitrile group (entry 13). The successful reaction of an acid outcome of this reaction also provides another illustration as
chloride containing a pentafluorosulfanyl substituent was also to the robust nature of this substituent. Of particular signi-
gratifying, since there has been intense interest in the penta- ficance, were reactions that provided tetrazolone congeners of
fluorosulfanyl group as a “super trifluoromethyl” equivalent marketed drugs. Our aim with this work was to demonstrate
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an ability to form a tetrazolone in a final-step, from fully-func-
tionalized substrates commonly encountered by medicinal
chemists, and to evaluate the ability of a tetrazolone group to
serve as a carboxylic acid bioisostere (see accompanying
paper). Toward this end, a small set of readily-available
marketed drugs were chosen for reaction. We started, by
preparing a tetrazolone congener of aspirin. The reaction
proceeded uneventfully, and gave a 56% isolated yield of tetra-
zolone product (entry 17). We then proceeded to prepare tetra-
zolone analogs of the marketed drugs indomethacin,
probenecid, telmisartan and bexarotene, which are approved
for inflammation, gout, blood-pressure modulation and
cancer, respectively (entries 18–21).22 Isolated yields were good
(33–89%). In particular, the preparation of a tetrazolone of
telmisartan (6t; entry 20) was pleasing, as related marketed
‘sartans’ (e.g. candesartan, irbesartan, losartan, olmesartan,
valsartan), contain a tetrazole group. Thus, it will be possible
to compare the biological activity of tetrazolone 6t to both a
marketed acid congener (Telmisartan), and a tetrazole relative
(see accompanying paper). Also of significance, was the
reaction with hetroaroyl chlorides. Both electron-deficient six-
membered heterocycles (entry 22), and electron-rich five-
membered heterocycles (entries 23 and 24) formed tetrazolone
Notes and references
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a 62% yield of tetrazolone 6y (entry 25). This is an interesting
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In summary, this paper describes a facile synthesis of
tetrazolones from acid chlorides, using azidotrimethylsilane as 16 In an attempt to prepare an isocyanate, one other paper has
a co-reactant and solvent. The reaction tolerates functional
groups commonly encountered within medicinal chemistry,
and has shown a particular aptitude for preparing tetrazolone
noted the formation of a tetrazolone by-product from reaction
of an acid chloride with azidotrimethylsilane. See: K. Burger,
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this paper will be of interest to medicinal chemists, where the
late-stage functionalization of agents with pharmacological
activity, and use of novel bioisosteres of carboxylic acids, is
highly soughtafter.23,24
R. Kolluri, J. Ramphal and S. Holland, US Patent, 0130415,
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Acknowledgements
We thank Mark Irving, Van Ybarra and Duayne Tokushige of
Rigel, Inc. analytical chemistry for high-resolution mass
spectrometry.
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as
a
carboxylic
acid
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presented at 252nd ACS National Meeting and Exposition,
Philadelphia, PA, United States, August 21–25, 2016,
MEDI-238.
19 M. A. J. Duncton, M. A. Estiarte, R. J. Johnson, M. Cox, 23 The suitability of this reaction for continuous synthesis
D. J. R. O’Mahony, W. T. Edwards and M. G. Kelly, J. Org.
Chem., 2009, 74, 6354–6357.
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using flow chemistry is under evaluation.
24 For an accompanying paper describing the use of a
tetrazolone group as a bioisostere of a carboxylic acid see,
M. A. J. Duncton, R. B. Murray, G. Park and R. Singh,
Org. Biomol. Chem., DOI: 10.1039/c6ob01646d.
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