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Synlett 2016; 27(11): 1693-1698
DOI: 10.1055/s-0035-1561602
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© Georg Thieme Verlag Stuttgart · New York

Indium(III) Chloride Promoted Highly Efficient Tandem Rearrangement–α-Addition Strategy towards the Synthesis of α-Hydroxyamides

Kadari Lingaswamy
D-207, Discovery Laboratory, Organic and Biomolecular Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India   Email: ylprapurna.iict@gov.in
,
Dumpala Mohan
D-207, Discovery Laboratory, Organic and Biomolecular Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India   Email: ylprapurna.iict@gov.in
,
Palakodety Radha Krishna
D-207, Discovery Laboratory, Organic and Biomolecular Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India   Email: ylprapurna.iict@gov.in
,
Y. Lakshmi Prapurna*
D-207, Discovery Laboratory, Organic and Biomolecular Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India   Email: ylprapurna.iict@gov.in
› Author Affiliations
Further Information

Publication History

Received: 20 October 2015

Accepted after revision: 10 March 2016

Publication Date:
07 April 2016 (online)

 
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Abstract

A new tandem process is reported that provides access to α-hydroxyamides from epoxides for the first time. Herein, we explore ­InCl3-mediated tandem rearrangement of epoxides to aldehydes and α-addition of TosMIC to in situ derived aldehydes. An unprecedented C–C bond-forming reaction is disclosed that features mild conditions, high yields, and shorter reaction times.


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Key words

C–C bond formation - indium(III) chloride - epoxides - TosMIC - tandem rearrangement - α-addition

The α-hydroxyamides are useful building blocks for the synthesis of biologically active natural products,[1] especially depsipeptide compounds.[2] They have been identified as inhibitors of methionine aminopeptidase-2 and HIV protease, potent antitumor activity, and play an important role in medicinal chemistry.[3] Due to the significance of this core, the convenient formation of this moiety has attracted much attention in recent years. Classically, α-hydroxyamides have been synthesized by condensation of lactic acid with an amine and the most direct method is the Passerini-type reaction.[4] [5] [6] Since the early studies by Passerini,[7] Ugi, and co-workers[8] the power of α-addition reaction in constructing polyfunctional molecules has been well appreciated. The Passerini-type reaction, that is, reaction of aldehydes with isocyanides under acid-free conditions attracts chemists for wider applications. Although the Lewis acid mediated α-addition of isocyanides to aldehydes has been well studied,[9] most of these methods suffer from formation of undesired products and moreover, catalyst turnover for conventional Lewis acid catalysis requires the cleavage of the Lewis acid from the product.[10] Later on, dramatic improvement has been reported in the enantioselective α-addition of isocyanides to aldehydes.[11]

Bearing a formally divalent carbon, isocyanides are capable of engaging in carbon–carbon bond-forming reactions known as α-additions. p-Toluenesulfonylmethyl isocyanide (TosMIC), a unique isocyanide is widely used in the synthesis of heterocycles.[12] It is a densely functionalized building block with three functional groups that can engage in a multitude of reactions. In the course of our research aimed at expanding the TosMIC chemistry,[13] [14] we attempted InCl3-mediated nucleophilic ring-opening of epoxides with TosMIC. However, our results revealed the addition of TosMIC to epoxide does not form the expected product 3a but affords instead the α-hydroxyamides 2a–k through unprecedented tandem rearrangement of epoxides to aldehydes and subsequent α-addition of TosMIC to aldehydes (Scheme [1]). To the best of our knowledge, this is the first example of synthesis of α-hydroxyamides directly from epoxides. Moreover, a full investigation on the literature reveals that TosMIC has not been used as an isonitrile component in most of the α-additions of isocyanides to aldehydes reported thus far. A few reported formation of byproducts along with the desired product when TosMIC was employed as a nucleophile in this reaction.[11b]

Zoom Image
Scheme 1 InCl3-mediated synthesis of α-hydroxyamides from epoxides

First, we examined the reaction of the styrene oxide (1a) with TosMIC using various Lewis acids (Table [1]). Neither BF3·OEt2 nor CuI gave the product (Table [1], entries 1 and 6). But the other Lewis acids like Zn(OTf)2, FeCl3, Cu(OTf)2, and RuCl3 gave lower yields (Table [1], entries 2, 4, 5, and 7). InCl3 was found to be effective to furnish the product 2a in less reaction time and high yield. It was also found that THF–H2O (9:1) was the optimal solvent for this reaction. To determine the optimal catalyst loading the reaction using styrene oxide with TosMIC was conducted with varying amounts of InCl3 (Table [2]). A maximum yield of 90% was obtained with 50 mol% of catalyst (Table [2], entry 4). Increase in catalyst loading to 100 mol% did not have any significant effect on the yield of the product (Table [2], entry 5). Particularly noteworthy was the dependence of reaction outcome on addition of water which facilitates easy hydrolysis. The reaction provided the α-substituted alcohol product 2a instead of the expected β-substituted alcohol product 3a, that is, the nucleophilic oxirane ring opening with isonitrile functionality of TosMIC. Although the nucleophilic ring opening of the epoxide is well established, the α-substituted alcohol synthesis remains typically limited.[15]

Table 1 Optimization of Reaction Conditionsa

Entry

Catalyst

Solvent

Time (min)

Yield (%)b

 1

BF3·OEt2

THF

60

 0

 2

Zn(OTf)2

THF

30

56

 3

InCl3

THF

30

80

 4

FeCl3

THF

60

50

 5

Cu(OTf)2

THF

20

55

 6

CuI

THF

60

 0

 7

RuCl3

THF

25

55

 8

InCl3

MeCN

30

75

 9

InCl3

THF–H2O

30

90c

10

InCl3

CH2Cl2

30

75

a Reaction conditions: epoxide (1.0 equiv), TosMIC (1.0 equiv), Lewis acid (0.5 equiv), and solvent.

b The yields refer to isolated products purified by column chromatography.

c The best yield was obtained in THF–H2O (9:1).

Table 2 Optimization of Catalyst Loading for the Synthesis of α-Hydroxyamides

Entry

InCl3

Time (min)

Yield (%)a

1

  0

60

–

2

 10

60

71

3

 30

60

82

4

 50

30

90

5

100

30

90

a Yields refer to pure isolated products.

The spectral analysis revealed 2a as the predominant product. Thus, the 1H NMR spectrum of product 2a shows characteristic N–H as a broad singlet at δ = 7.55 ppm, methylene protons at δ = 4.65 ppm as a doublet (J = 6.97 Hz), CH–OH at δ = 4.21 ppm, two C–H protons as doublet of doublets at δ = 3.04 and 2.62 ppm, and all other protons resonated at their appropriate values. The possible formation of 3a was discounted in view of the 1H NMR analysis of 2a wherein CH–OH proton appeared at δ = 4.21 ppm. The same proton which otherwise would have appeared down-field shifted in 3a than reported herein. Further, the formation of 2a was unambiguously demonstrated by 13C NMR analysis, and the IR spectrum revealed characteristic stretching frequencies at 3319 and 1675 cm–1 due to N–H and C=O functional groups. Observation of α-substituted alcohols in these reactions can be explained by tandem rearrangement of epoxide to aldehyde[16] followed by α-addition of TosMIC to aldehyde. While the rearrangement and α-additions are known separately, a simple method capable of effecting both elementary steps has not been identified. Indeed, the significance of this novel protocol is that it performs both operations in a single pot to afford α-hydroxyamides from easily accessed epoxides and TosMIC. To our delight, the test reaction between benzaldehyde 4 and TosMIC furnished the corresponding α-hydroxyamide 4a in high yield, which itself has the ability to open a new era of InCl3-mediated Passerini-type reaction under mild conditions. In Scheme [2, a] plausible mechanism for InCl3-mediated facile synthesis of α-hydroxyamides is outlined. Even though, the Lewis acid mediated rearrangement of epoxide to aldehyde is already known in the literature, in order to find the aldehyde formation, two parallel reactions of styrene oxide with and without addition of TosMIC were performed under standard conditions.[17a] Identification of aldehyde was done by comparing both the reaction sets, the reaction mixture without TosMIC showed the corresponding aldehyde,[17b] which was also seen in the reaction mixture wherein TosMIC was present which was further consumed (analysis by TLC) to give the α-hydroxyamide product. Moreover, the 1H NMR analysis of the crude reaction mixture showed a triplet at δ = 9.73 ppm (J = 2.32 Hz) indicating the aldehyde formation as an intermediate (see Supporting Information).

Zoom Image
Scheme 2 A plausible reaction pathway

Encouraged by these results, we next turned our attention to investigate the scope of the reaction. Generally, various epoxides (Table [3], entries 1a–k) containing different substituents underwent the reaction under the standard conditions to give the corresponding α-hydroxyamides (2a–k) as the sole products. It indicates InCl3-mediated isomerization of epoxides proceeded with complete regio­selectivity. InCl3 is a mild Lewis acid for complete regioselective transformation and has a great functional-group tolerance.

1-Aryl-, 1,1-diaryl-, 1,1-dialkyl-, and aryl-substituted epoxides underwent rearrangement to the corresponding aryl-substituted acetaldehydes by exclusive hydride shift (Table [3], entries 1 and 4–12). On the other hand, as observed in the rearrangement of stilbene oxide, that is, 1,2-diaryl epoxide, phenyl migration predominates the hydrogen shift (Table [3], entry 3). The formation of 2f (Table [3], entry 7) can be explained by the rearrangement of α-pinene oxide to the expected aldehyde.[18] However, the reaction with 1l, which is a nonaromatic epoxide has proven unsuccessful (Table [3], entry 13). Presumably, the incipient carbocation formed by the initial cleavage of epoxide is much less stabilized in alkyl-substituted epoxide compared to the aryl-substituted one. But in case of 2f and 2k the product formation can be explained by better stabilization of carbocation on the tertiary center. These reactions are usually fast and high-yielding. The spectral data of products 2b–k further established the conclusive formation of the α-substituted alcohol product. However, the present protocol did not furnish the desired product when tert-butyl isonitrile and cyclohexyl isonitrile were used as isonitrile components. The reason for this may be attributed to the higher nucleophilicity of these compounds compared to TosMIC.[19]

Table 3 InCl3-Promoted Synthesis of α-Hydroxyamides from Epoxidesa

Entry

Substrate

Productb

Time (min)

Yield (%)c

1

1a

2a

30

90

2

4

4a

30

90

3

1b

2b

40

92

4

1c

2b

30

94

5

1d

2d d

30

92

 6

1e

2e

 30

90

 7

1f

2f d

 60

85

 8

1g

2g

 45

89

 9

1h

2h

 40

90

10

1i

2i d

 30

88

11

1j

2j

 20

92

12

1k

2k

 90

80

13

1l

n.d.f

180

 0e

14

5

5a

 90

85

a Reaction conditions: epoxide (1.0 equiv), TosMIC (1.0 equiv), InCl3 (0.5 equiv), and THF–H2O (9:1).

b All the products were characterized from spectral data.

c Isolated yields after purification by column chromatography.

d The products 2d,f,i were obtained as diastereomeric mixtures.

e Formation of unisolable products is observed.

f Not detected.

In general ketones are less reactive than aldehydes towards nucleophilic attack. A simple method for the α-addition of isocyanides to carbonyl compounds is still lacking. For instance, the susceptibility of the reaction with ketone, that is, cyclohexanone (Table [2], entry 14) under the same reaction conditions was next examined. It is noteworthy to mention that the reaction of TosMIC with 5 under the present conditions proceeded smoothly to afford 5a in good yield. As far as we know, this is the first example of α-addition of TosMIC to ketone.

In conclusion, we have described for the first time a tandem protocol that provides efficient synthesis of α-hydroxyamides directly from epoxides.[20] A mechanistically novel reaction pathway for the construction of C–C bond formation was disclosed. Considering the mild reaction conditions, tolerance of various functional groups, easy availability of substrates, high regioselectivity, and shorter reaction times, the methodology described here undoubtedly will find new applications in future synthetic endeavors. The products obtained by the present protocol are densely functionalized and can act as unique building blocks.


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Acknowledgment

We are grateful to DST (GAP 0485), New Delhi for generous financial support. The authors K.L. and D.M. thank UGC, New Delhi for financial support in the form of a fellowship.

Supporting Information

    Supporting information for this article is available online at http://dx.doi.org.accesdistant.sorbonne-universite.fr/10.1055/s-0035-1561602.
  • Supporting Information


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Zoom Image
Scheme 1 InCl3-mediated synthesis of α-hydroxyamides from epoxides
Zoom Image
Scheme 2 A plausible reaction pathway