Ajay L.
Chandgude
and
Alexander
Dömling
*
Department of Drug Design, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands. E-mail: a.s.s.domling@rug.nl; Web: http://www.drugdesign.nl/
First published on 19th May 2016
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:
water (1
:
1) as the solvent system. The use of sonication not only accelerated the rate of the reaction but also provided good to excellent quantitative yields. This reaction is applicable to a broad scope of aldehydes/ketones and isocyanides.
In 1921, a three-component reaction between carboxylic acids, oxo components and isocyanides for the synthesis of α-acyloxy amide was discovered by Passerini (P-3CR).5,7c In 1961, Ugi reported the synthesis of tetrazoles via a Passerini-type 3CR (PT-3CR) for the first time using HN3 and Al(N3)3.6 Even though the use of HN3 or NaN3 in Passerini reactions for the synthesis of tetrazoles was reported, the highly toxic and explosive nature of HN3 and NaN3 limit its application.7 The use of TMSN3 as a safe substitute for HN3 was then introduced by Hulme.8 However the use of TMSN3 as an azide source in the PT-3CR resulted in a 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 yields9 and the described reaction times were up to 96 hours.9a Reported PT-3CRs are not very suitable for aromatic aldehydes.7 The use of different Lewis acids as catalysts, like AlCl3, to activate aldehydes forms inseparable mixtures of the desired product with α-hydroxy-amide, with a maximum yield of 30%.10 Zhu and co-workers used TMSN3 as a test reaction component in the asymmetric PT-3CR; nevertheless, they could not avoid the formation of α-hydroxy-amide.7b
To the best of our knowledge, no efficient, diverse and high yielding PT-3CR reaction has yet been reported. We report herein a sonication-promoted catalyst free, TMSN3-modified PT-3CR using methanol:
water (1
:
1) as solvent with diverse scope and affording good to excellent yields.
Entry | Catalyst | Solvent | Time (h) | Product yieldb (%) |
---|---|---|---|---|
a The reaction was carried out with phenylacetaldehyde (1 mmol), tert-butyl isocyanide (1 mmol), and TMSN3 (1 mmol) at room temperature. b Yield of isolated product. c 1 equivalent TBAF·3H2O. d 1 equivalent TBAF in 1 M THF. e 1 equivalent KF. f 1 equivalent CsF. g Reaction carried out at 70 °C. nd = not determined. | ||||
1 | TBAFc | — | 12 | Trace |
2 | TBAFd | DCM | 12 | Trace |
3 | TBAFc | H2O | 12 | Trace |
4 | TBAFc | MeOH | 12 | 25 |
5 | KFe | DCM | 12 | nd |
6 | CsFf | DCM | 12 | nd |
7 | CsFf | MeOH | 12 | nd |
8 | CsFf | H2O | 12 | nd |
9 | I2![]() |
DCM | 12 | nd |
10 | I2![]() |
H2O | 12 | nd |
11 | H2O | 12 | 17 | |
12 | TBAFc | MeOH![]() ![]() ![]() ![]() |
12 | 63 |
13 | MeOH![]() ![]() ![]() ![]() |
12 | 64 | |
14 | Sonication |
MeOH![]() ![]() ![]() ![]() |
2 | 97 |
15 | Sonicationg | — | 3 | 31 |
16 | Sonication | DCM | 2 | 34 |
17 | Sonication | H2O | 2 | 71 |
The use of iodine, to trap TMS as TMSI, also failed to improve the reaction yield. 17% product formed when the reaction was carried out in water without any additive. TBAF in methanol:
water (1
:
1) enhanced the yield up to 63%; however comparable yields were obtained when the reaction was carried out without TBAF in the same solvent system. Thus we concluded that the use of TBAF is not fruitful, whereas the solvent system has a major impact.
We foresaw that the accelerating effect of sonication could potentially speed up the reaction and increase yields. Ultrasound in general12 and also in the context of MCR12d is often used in organic synthesis due to its advantages such as increasing the reaction efficacy while decreasing waste byproducts, short reaction times, cleaner reactions, easier experimental procedures and having low energy requirements. Recently, the popularity of sonication-assisted synthesis as a green synthetic approach has significantly increased and has resulted in a plethora of ‘better’ reactions.13 Ultrasound in chemical reactions works via a physical phenomenon called acoustic cavitation, which forms, expands and collapses gaseous and vaporous cavities in an ultrasound irradiated liquid. The mechanical effect of cavitation destroys 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, the use of sonication not only accelerated the reaction from 12 to two hours, but provided excellent quantitative yields using methanol:
water (1
:
1) as the solvent system, noteworthily without the necessity of any previously used additive (Table 1, entry 14). We used a simple ultrasonic cleaning bath which is the most widely available and cheapest source of ultrasonic irradiation. A recent study has shown that both ultrasonic cleaning baths and ultrasonic probe systems are efficient in Passerini reactions.14 The ultrasonic cleaning bath offers further advantages; for example, the reaction vessel can be put directly into the bath without any adaptation. This is in contrast to the ultrasonic probe system, which is more expensive and also requires special vessels, making it inconvenient to use.
Lastly, reactions under sonication in DCM or in neat conditions provided smaller yields, of 34% and 31% respectively, and the formation of TMS-ether as a side product was observed. The use of pure water as the solvent under sonication conditions provided the product in 71% yield. The use of 1 equivalent of TMSN3 avoids the danger of forming hydrazide from excess azide. This catalyst free reaction doesn't require any work-up.
With these optimized conditions in hand, we next examined the generality of this PT-3CR by reacting different aldehydes with different isocyanides (Table 2). Good to excellent yields 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 yields. Paraformaldehyde also reacts when pure water was used as the solvent. Reaction with one or six equivalents of paraformaldehyde in a methanol:
water system only forms mono-substituted tetrazole. The reaction of benzyl isocyanide with aliphatic aldehydes gave excellent yields.
Entry | 1 | R3![]() |
Yieldc (%) |
---|---|---|---|
a The reaction was carried out with 1 mmol 1, 1 mmol 2, 1 mmol TMSN3. b cy = cyclohexyl, octyl = 2-isocyano-2,4,4-trimethylpentane. c Yield of isolated product. d 6 equivalents of paraformaldehyde in water as solvent and at 60 °C. iPr = isopropyl. | |||
Aldehydes | |||
1 | C6H5–CH2–CHO | C6H5–CH2 | 96 (3a) |
2 | iPr-CHO | (CH3)3–C | 98 (3b) |
3 | CH3–(CH2)2–CHO | C6H5–CH2 | 80 (3c) |
4 | C6H5–CH2–CHO | t Octyl | 77 (3d) |
5 | iPr-CHO | CN–CH2–CH2 | 72 (3e) |
6 | C6H5–(CH2)2–CHO |
![]() |
53 (3f) |
7 | C6H5–(CH2)2–CHO | Cy | 76 (3g) |
8 | C6H5–CH2–CHO | 2-BrC6H4–CH2 | 77 (3h) |
9 | H–CHOd | 2-BrC6H4–CH2 | 42 (3i) |
10 | iPr-CHO | 2-BrC6H4–CH2 | 80 (3j) |
11 | C6H5–(CH2)2–CHO | (CH3)3–C | 88 (3k) |
12 | CH3–CH2–CHO | C6H5–CH2 | 91 (3l) |
13 | (CH3)2–CH–CH2–CHO | C6H5–CH2 | 92 (3m) |
14 | C6H5–CH2–CHO | (CH3)3–C | 97 (3n) |
15 | C6H5–CHO | (CH3)3–C | 41 (3o) |
16 | 2,6-(Cl)2C6H3–CHO | C6H5–CH2 | 71 (3p) |
20 | 2,3-(Cl)2C6H3–CHO | Cy | 73 (3q) |
17 | 2-MeO-5-BrC6H3–CHO | C6H5–CH2–CH2 | 46 (3r) |
18 | 2-BrC6H4–CHO | Cy | 60 (3s) |
19 | 2-Cl-3,4-(OCH3)2C6H2–CHO | Cy | 42 (3t) |
21 |
![]() |
Cy | 39 (3u) |
22 | 2,5-(OCH3)2C6H3–CHO | Cy | 48 (3v) |
Ketones | |||
23 | Cyclohexanone | C6H5–CH2 | 84 (3w) |
24 | 1-Benzylpiperidin-4-one | C6H5–CH2 | 46 (3x) |
Isocyanides, easy to deprotect in acidic and basic conditions, are compatible with the developed methodology (Table 2, entries 2, 4 and 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, the compatibility of 1,1-diethoxy-2-isocyanoethane as the isocyanide component could be used in further reactions as aldehyde or halogen functional groups for coupling reactions.
We also explored the scope of ketones in the developed method (Table 2, entries 23 and 24). Cyclohexanone gives a good yield of 84%. The important building block piperidone is also compatible with the reaction.
Fused tetrazoles are important scaffolds as they possess a wide spectrum of activity and vast industrial applications. As functional groups bearing isocyanides are compatible in our developed method, we foresaw a quick and easy access to fused tetrazoles. 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, formed 5,11-dihydrobenzo[f]tetrazolo[5,1-c][1,4]oxazepine in 89% yield (Scheme 1).
Footnote |
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6gc00910g |
This journal is © The Royal Society of Chemistry 2016 |