An efficient Passerini tetrazole reaction (PT-3CR)

Article abstract of DOI:10.1039/c6gc00910g

A sonication accelerated, catalyst free, simple, high yielding and efficient method for the Passerini-type three-component reaction (PT-3CR) has been developed. It comprises the reaction of an aldehyde/ketone, an isocyanide and a TMS-azide in methanol:wat

Full text of DOI:10.1039/c6gc00910g

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An Efficient Passerini Tetrazole Reaction (PT-3CR)
Ajay L. Chandgude, Alexander Dömling*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
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A sonication accelerated, catalyst free, simple, high yielding and
In 1921, three component reaction between carboxylic
efficient method for the Passerini-type three component reaction acids, oxo components and isocyanides for the synthesis of α-
(PT-3CR) has been developed. It comprises reaction of an acyloxy amide was discovered by Passerini (P-3CR).5,7c In 1961,
aldehyde/ketone,
a
isocyanide and
a
TMS-azide in Ugi reported the first time the synthesis of tetrazoles via
methanol:water (1:1) as the solvent system. Use of sonication not Passerini-type 3CR (PT-3CR) using HN3 and Al(N3)3.6 Even
only accelerated the rate of the reaction but also provided up to though the use of HN3 or NaN3 in Passerini reaction for the
quantitative yields. This reaction is applicable to a broad scope of synthesis of tetrazoles PT-3CR was reported, the highly toxic
aldehyde/ketone and isocyanides.
and explosive nature of HN3 and NaN3 limit its application.7
Use of TMSN3 as a safe substitute for HN3 was then introduced
by Hulme.8 However TMSN3 use as azide source in the PT-3CR
resulted into very low yield and the TMS-ether was found as a
major product instead. Similarly protected amino aldehydes in
DCM also resulted in generally low yield9 and the described
reaction times were up to 96 hours.9a Reported PT-3CR are not
well suitable for the aromatic aldehydes.7 The use of different
Lewis acids as catalyst like AlCl3 to activate aldehydes forms
inseparable mixture of desired product with α-hydroxy-amide
Introduction
with a maximum of 30% yield.10 Zhu and co-workers used
TMSN3 as test reaction component in the asymmetric PT-3CR,
Tetrazoles scaffolds are extensively used in medicinal
chemistry and in industry like agriculture, explosives and
photography.1 1,5-disubstituted tetrazoles are important ring
system having applications as, bio-active agents or drugs like
cilostazol, pentylenetetrazole, latamoxef, BMS-317180 and cis-
amide bond isosteres in peptides (fig 1). This propel the need
for efficient synthetic methods for tetrazoles.2 Different
reactions have been developed for the direct access to diverse
1,5-disubstituted tetrazoles, but three and four-component
reactions (MCR) are mostly preferred due to its convergent,
atom-efficient and flexible nature.3 Multicomponent reactions
are considered an ideal synthesis and that’s why its use in
synthetic chemistry is tremendously increasing.4
nevertheless they could not avoid the formation of
amide.7b
α-hydroxy-
Department of Drug Design, University of Groningen,
Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands
E-mail: a.s.s.domling@rug.nl
Homepage: http://www.drugdesign.nl/
Fig 1. Some bio-active agents/drugs containing the tetrazole
moiety.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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To the best of our knowledge, no efficient, diverse and high Use of Iodine, to trap TMS as TMSI also fails to improve the
yielding PT-3CR reaction has yet been reported. We report reaction yield. 17% product formed when reaction was carried
herein a sonication-promoted catalyst free, TMSN3-modified out in water without any additive. TBAF in methanol:water
PT-3CR using methanol:water (1:1) as solvent with diverse (1:1) enhanced the yield up to 63%; however comparable yield
scope and affording good to excellent yields.
were received when the reaction was carried out without TBAF
in the same solvent system. Thus we concluded that the use of
TBAF is not fruitful, where as the solvent system has a major
impact.
Results and discussion
We started our investigation by using tert-butyl isocyanide,
We foresaw that the accelerating effect of sonication could
phenylacetaldehyde and TMSN3 as starting materials (Table 1). potentially speed up the reaction and increases yields.
We hypothesized that, the use of fluoride ion sources like Ultrasound in general12 and also in the context of MCR12d is
TBAF, CsF and KF could trigger both TMSN3 activation.11 often used in organic synthesis due to its advantages such as,
However when the reaction was carried out with TBAF with increase reaction efficacy while decreasing waste byproducts,
different solvents like DCM, water or neat, the product was short reaction times, cleaner reactions, easier experimental
formed only in trace amount (Table 1, entries 1–3). procedure and having low energy requirements. Recently
Surprisingly methanol as a solvent increased the isolated yield popularity of sonication-assisted synthesis as a green synthetic
to 25%. Carrying out the reaction with alternative F- sources, approach is extremely increasing and resulted in a plethora of
KF in DCM or CsF in DCM, methanol and water resulted only in ‘better’ reactions.13 Ultrasound in chemical reactions works via
small amounts of product formation.
a physical phenomenon called, “acoustic cavitation”; which
forms, expands and collapses gaseous and vaporous cavities in
an ultrasound irradiated liquid.
A mechanical effect of
Table 1. Optimization of reaction conditionsa
cavitation destroy the attractive forces of molecules in the
liquid phase and so accelerates reaction rates by facilitating
mass transfer in the microenvironment.13 To our delight, use
of sonication not only accelerated the reaction from 12 to two
hours, but provided quantitative yield in methanol:water (1:1)
as the solvent system and noteworthy without the necessity of
any previously used additive (Table 1, entry 14). We used
simple ultrasonic cleaning bath which is most widely available
and cheapest source of ultrasonic irradiation. Recent study
shows that, both ultrasonic cleaning bath and ultrasonic probe
system are efficient in Passerini reaction.14 The ultrasonic
cleaning bath offers further advantage like, reaction vessel can
be put directly into the bath without any adaptation. In
contritely to the ultrasonic probe system, which is more
expensive and also require special vessels and so inconvenient
to use.
Entry
Catalyst
Solvent
Time (h)
Product
Yield%b
1
TBAFc
TBAFd
TBAFc
TBAFc
KFe
CsFf
CsFf
CsFf
-
12
12
trace
2
DCM
trace
3
4
5
6
7
8
9
H2O
12
12
12
12
12
12
12
trace
25
MeOH
DCM
DCM
MeOH
H2O
nd
nd
nd
nd
Lastly, reactions under sonication in DCM or at neat
conditions provided less yields, 34% and 31% respectively, and
the formation of TMS-ether as side product was observed.
Pure water as the solvent under sonication conditions
provided the product in 71% yield. Use of 1 equivalents of
TMSN3 avoids the danger of forming hydrazide from excess
azide. This catalyst free reaction doesn’t require any work-up.
With this optimized condition in hand, we next examined
the generality of this PT-3CR by reacting different aldehydes
with different isocyanides (Table 2). Good to excellent yield
were obtained with linear and branched aliphatic aldehydes.
Aromatic aldehydes are also compatible substrates for this
process (Table 2, entries 15-22). Electron donating (methoxy)
and withdrawing groups (Cl, Br, NO2) at different positions like
ortho, meta and para are valid providing moderate to good
yield. Paraformaldehyde also reacts when pure water was
used as the solvent. Reaction with one or six equivalent
paraformaldehyde in methanol:water system only forms
mono-substituted tetrazole. Benzyl Isocyanide with aliphatic
aldehydes gave excellent yield.
f
I2
DCM
nd
f
I2
10
H2O
12
nd
11
12
H2O
12
12
17
63
TBAFc
MeOH:H2O
(1:1)
13
14
MeOH:H2O
(1:1)
12
2
64
97
Sonication
MeOH:H2O
(1:1)
15
16
17
Sonicationg
Sonication
Sonication
-
3
2
2
31
34
71
DCM
H2O
a
The reaction was carried out with phenylacetaldehyde (1 mmol), tert-butyl
b
isocyanide (1 mmol), and TMSN3 (1 mmol) at room temperature. Yield of
isolated product. C 1 equivalent TBAF. 3H2O. d 1 equivalent TBAF in 1M THF. e
1
f
g
equivalent KF. 1 equivalent CsF. reaction carried out at 70 °C. nd- not
determined
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Isocyanides easy to deprotect in acidic and basic conditions are
compatible in the developed methodology (Table 2, entries 2,
4, 5). The functional group tolerance of the isocyanide (Table
2, entries 5-6 and 8–10), in this protocol provides multiple
opportunities for various further chemical manipulations. For
example compatibility of 1,1-diethoxy-2-isocyanoethane as
isocyanide component could be used in further reactions as
aldehyde or halogens for coupling reactions.
Table 2. Substrate Scope for the PT-3CRa
R3b
Yield
(%)c
We also explore the scope of ketones in the developed
method (Table 2, entries 23 and 24). Cyclohexanone gives
good yield 84%. The important building block piperidone is
also compatible with the reaction.
Entry
1
Aldehydes
1
2
3
4
5
6
C6H5 -CH2-CHO
iPr-CHO
C6H5-CH2
96 (3a)
98 (3b)
80 (3c)
77 (3d)
72 (3e)
53 (3f)
Fused tetrazoles are important scaffold as it poses a wide
spectrum activity and vast industrial applications. As functional
group bearing isocyanides are compatible in our developed
method, we foresaw a quick and easy access to fused
tetrazole. According to our synthetic plan, the use of
functionalized PT-3CR product for post modification would
allow an anticipated cyclization process. (1-(2-bromobenzyl)-
1H-tetrazol-5-yl)methanol (3i) when refluxed with Copper(II)
triflate, in the presence of base it formed 5,11-
dihydrobenzo[f]tetrazolo[5,1-c][1,4]oxazepine with 89% yield
(Scheme 1).
(CH3)3-C
C6H5-CH2
tOctyl
CH3-(CH2)2-CHO
C6H5-CH2-CHO
iPr-CHO
CN-CH2-CH2
C6H5-(CH2)2-CHO
7
C6H5-(CH2)2-CHO
C6H5-CH2-CHO
H-CHOd
Cy
76 (3g)
77 (3h)
42 (3i)
80 (3j)
88 (3k)
91 (3l)
92 (3m)
97 (3n)
41 (3o)
71 (3p)
73 (3q)
46 (3r)
60 (3s)
42 (3t)
39 (3u)
8
2-BrC6H4-CH2
2-BrC6H4-CH2
2-BrC6H4-CH2
(CH3)3-C
C6H5-CH2
C6H5-CH2
(CH3)3-C
(CH3)3-C
C6H5-CH2
Cy
9
10
11
12
13
14
15
16
20
17
18
19
21
iPr-CHO
C6H5-(CH2)2-CHO
CH3-CH2-CHO
(CH3)2-CH-CH2-CHO
C6H5-CH2-CHO
C6H5-CHO
2,6-(Cl)2C6H3-CHO
2,3-(Cl)2C6H3-CHO
2-MeO-5-BrC6H3-CHO
2-BrC6H4-CHO
Scheme 1. Synthesis of fused tetrazole.
C6H5-CH2-CH2
Cy
Conclusions
2-Cl-3,4-(OCH3)2C6H2-CHO
Cy
In conclusion, we have developed a novel, efficient, safe and
general sonication assisted Passerini tetrazole reaction (PT-
3CR) to access 5-(1-hydroxyalkyl)tetrazoles in good to excellent
yield. The herein described Passerini tetrazole procedure
provides multiple advantages over previous described
procedures. The reaction does not use highly toxic and
explosive staring materials like HN3, Al(N3)3 or NaN3. This
catalyst free reaction avoids the use of any dangerous or
adverse catalysts such as Al-salen chiral complex, AlCl3.
Sonifiactions was found as a superior reaction condition
resulting in high conversion and giving high yields of Passerini
products and no TMS-ether side product as often observed
previously. Sonification is also well known to be compatible
with upscaling procedures. The scope of the reaction could be
dramatically extended including aliphatic, aromatic aldehydes
and also ketones. Due to the extended functional group
compatibility of the reaction many new scaffold amenable by
post-condensation reactions can be foreseen as we have
illustrated by the synthesis of a Cu-mediated fused tetrazole.
CHO
O
Cy
O
NO2
22
2,5-(OCH3)2C6H3-CHO
Cy
48 (3v)
Ketones
23
24
cyclohexanone
C6H5-CH2
C6H5-CH2
84 (3w)
46 (3x)
1-benzylpiperidin-4-one
a The reaction was carried out with 1 mmol 1, 1 mmol 2, 1 mmol TMSN3. b cy =
cyclohexyl, toctyl
c
=
2-isocyano-2,4,4-trimethylpentane. Yield of isolated
d
product. 6 equivalent of paraformaldehyde in water as solvent and at 60°C.
iPr = isopropyl
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Altogether we believe that our procedure is superior to all
previously reported Passerini tetrazole reactions and will be
the method of choice for the future.
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Acknowledgements
We thank the University of Groningen. The Erasmus Mundus
Scholarship “Svaagata” is acknowledged for a fellowship to A.
Chandgude. The work was financially supported by the NIH
(1R01GM097082-01) and by Innovative Medicines Initiative
(grant agreement n° 115489).
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