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Synlett 2018; 29(09): 1171-1175
DOI: 10.1055/s-0036-1591775
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© Georg Thieme Verlag Stuttgart · New York

Copper-Catalyzed Tandem Multi-Component Approach to 1,3-Oxazines at Room Temperature by Cross-Dehydrogenative Coupling Using Methanol as C1 Feedstock

Paran J. Borpatra
Department of Applied Sciences, GUIST, Gauhati University, Guwahati 781014, Assam, India   Email: mohitdd.deb@gmail.com   Email: baruah.pranjal@gmail.com
,
Mohit L. Deb*
Department of Applied Sciences, GUIST, Gauhati University, Guwahati 781014, Assam, India   Email: mohitdd.deb@gmail.com   Email: baruah.pranjal@gmail.com
,
Pranjal K. Baruah*
Department of Applied Sciences, GUIST, Gauhati University, Guwahati 781014, Assam, India   Email: mohitdd.deb@gmail.com   Email: baruah.pranjal@gmail.com
› Author Affiliations

M.L.D. is thankful to Science and Engineering Research Board (SERB), India (Grant No. SB/FT/CS-073/2014) for financial support under Fast Track Scheme. P.K.B. is thankful to DST, India, (Grant No. SB/FT/CS-100/2012) for financial support. P.J.B. thanks AICTE for a research fellowship.
Further Information

Publication History

Received: 25 January 2018

Accepted after revision: 13 February 2018

Publication Date:
20 March 2018 (online)

 
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Abstract

A copper(II)-catalyzed multi-component one-pot approach for the synthesis of 1,3-oxazines at room temperature is reported here. Methanol is used as the solvent as well as the carbon source. The methylene carbon of the oxazine product comes from methanol via formaldehyde. tert-Butyl hydroperoxide is used as the oxidant. The reaction uses an environmentally benign metal catalyst and oxidant. No inert atmosphere or precaution is required for the reaction. Most importantly, the reaction avoids the use of carcinogenic formaldehyde.


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Key words

methanol - 1,3-oxazine - copper(II) catalyst - multi-component reaction - C–H functionalization

The development of sustainable processes for organic synthesis which exploit inexpensive and easily available feedstocks and reagents has recently become a centre of attraction in chemical research.[1] For this purpose, methanol has appeared as a renewable resource with high potential which is used to produce plentiful daily-life commodities and industrial chemicals.[2] It is a very simple aliphatic, cheap and biodegradable alcohol, which is used as an alternative fuel for internal combustion.[3] Usually, methylation of organic molecules is achieved by using toxic methyl compounds such as methyl iodide, dimethyl sulfate and diazomethane,[4] or by using carcinogenic formaldehyde.[5] However, methanol can be used as a C1 source through the in situ generation of formaldehyde by dehydrogenative activation of methanol. The formaldehyde thus generated can be transformed to methyl, methylene and hydroxylmethyl functional groups.[6] Researchers have even used methanol as a carbonyl source to synthesize urea derivatives.[7] Usually Ru, Ir and Rh complexes are employed to catalyze these reactions.[6] [7] [8] However, rarely a Cu catalyst is used.[9]

1,3-Oxazine derivatives have shown anti-HIV, antitumor, antibacterial, antituberculosis, fungicidal and many other activities.[10] In addition, specifically 1,3-naphthoxazine derivatives are highly useful for the treatment of ­Parkinson’s disease and as potent nonsteroidal progesterone receptor agonists.[11] Many synthetic routes have been developed for their preparation;[12] however, because the cross-dehydrogenative coupling (CDC) technique offers many advantages such as atom-economical, directive and environmentally benign properties and non-requirement of prefunctionalized substrates,[13] synthetic chemists also synthesized these compounds by using this strategy.[14]

Moreover, multi-component reactions are one of the most powerful techniques in synthetic organic chemistry for the synthesis of highly functionalized organic molecules.[15] They have gained much attention because of their advantages such as atom and step economy, simpler procedures and as an energy-saving synthetic tactic to generate new bonds in a single step.[16] By using these techniques, we herein disclose a tandem three-component route to 1,3-oxazines in methanol as the solvent as well as C1 source by CDC (Scheme [1]). To the best of our knowledge, this is the first report of synthesizing 1,3-oxazines with use of methanol as the C1 source.

Zoom Image
Scheme 1 Synthetic route to 1,3-oxazines

We chose the combination of 2-naphthol (1a) and tetrahydroisoquinoline (2a) in MeOH using different catalysts/oxidants to synthesize 1,3-oxazine 3a. By using Fe(III), Ru(III) and I2 catalysts in the presence of TBHP as the oxidant no reaction was observed. Copper(II) acetate monohydrate (10 mol%) in the presence of TBHP (2 equiv) gave 3a in 56% yield (Table [1], entry 4). However, increasing the amount of solvent from 2 to 5 mL increased the yield and we isolated product 3a in 68% yield; this were the optimal conditions for this reaction (Table [1], entry 11). The reason may be that in higher dilution the unidentified little impurities which otherwise formed were not observed. However, further dilution lowered the product yield (Table [1], entry 12). Additional changes of the oxidant to H2O2 or oxone gave lower yield or no yield (Table [1], entries 5–6). Other copper catalysts such as CuBr, CuSO4 . 5H2O and copper triflate offered lower yields (Table [1], entries 8–10). An increase of the reaction time did not improve the yield (Table [1], compare entry 11 and entry 13). At higher temperature the reaction was unsuccessful to form the product (Table [1], entry 7). Increase of catalyst/oxidant loading did not affect the yield (Table [1], entries 16 and 14), but reduction of their amount reduced the yield to a little extent (Table [1], entries 17 and 15).

Table 1 Optimization of the Reaction Conditionsa

Entry

Catalyst (mol%)

Oxidant (equiv)

MeOH (mL)

Time (h)

Yield (%)

 1

FeCl3 . 6H2O (10)

TBHP (2)

2

15

–

 2

RuCl3 . 3H2O (10)

TBHP (2)

2

15

–

 3

I2 (10)

TBHP (2)

2

15

–

 4

Cu(OAc)2 . H2O (10)

TBHP (2)

2

15

56

 5

Cu(OAc)2 . H2O (10)

H2O2 (2)

2

15

34

 6

Cu(OAc)2 . H2O (10)

Oxone (2)

2

15

–

 7

Cu(OAc)2 . H2O (10)

TBHP (2)

2

 5b

–

 8

CuBr (10)

TBHP (2)

2

15

38

 9

CuSO4 . 5H2O (10)

TBHP (2)

2

15

35

10

Cu(OTf)2 (10)

TBHP (2)

2

15

14

11

Cu(OAc)2 . H2O (10)

TBHP (2)

5

15

68

12

Cu(OAc)2 . H2O (10)

TBHP (2)

7

15

62

13

Cu(OAc)2 . H2O (10)

TBHP (2)

5

20

67

14

Cu(OAc)2 . H2O (10)

TBHP (2.5)

5

15

68

15

Cu(OAc)2 . H2O (10)

TBHP (1.5)

5

15

55

16

Cu(OAc)2 . H2O (15)

TBHP (2)

5

15

66

17

Cu(OAc)2 . H2O (5)

TBHP (2)

5

15

58

a Unless otherwise mentioned, all reactions were performed by using 1a (1 mmol, 144 mg) and 2a (1 mmol, 133 mg) in MeOH at room temperature. Products were purified by column chromatography and yields are given for the isolated products.

b Reaction was carried out under reflux.

Zoom Image
Figure 1 Single-crystal X-ray structure of 3a

After establishing the optimal conditions, we subsequently investigated the substrate scope for the synthesis of 3, and the products were characterized by NMR and mass spectroscopy as well as single-crystal X-ray crystallography (see Figure [1] and Figure [2]).[17] [18] We screened different amines such as pyrrolidine, piperidine and obtained moderate yields. Open-chain amines did not respond to this reaction. We also screened different naphthols and obtained optimistic results. Moreover, we used phenolic substrates for this reaction; however, they gave relatively low yields. Other alcohols such as ethyl, propyl or benzyl alcohol did not give positive results.

To gain insights in the mechanism for this reaction, we performed control experiments. A representative reaction was carried out in complete absence of air/O2 (in N2 atmosphere), which did not affect the yield. This ensures that molecular O2 is not the oxidant in this reaction. We also performed the reaction in the presence of radical scavengers such as BHT and TEMPO (using 1.5 equiv of each), under the optimized conditions, which provided very low yield of 3a (12% of 3a was obtained by using BHT and 8% of 3a by using TEMPO). These experiments indicate that the reaction proceeds through a free-radical route. Moreover, when we replaced MeOH with CD3OD, 49% of deuterated product 3a' was formed, which was confirmed through NMR and mass spectroscopy analysis. This suggests that the methylene carbon of the product absolutely comes from MeOH (Scheme [2]).

To check the possibility of a [4+2] cycloaddition mechanism for this reaction, we performed a cross reaction between 2c' and 2e' (synthesized by a reported procedure[14a]) under the optimized conditions. However, we did not notice any cross product from the reaction and obtained only two normal CDC products, namely 3c and 3e (Scheme [3]). Therefore, we believe that this method for the synthesis of 1,3-oxazines does not proceed through [4+2] cycloaddition of imine and o-quinone methide unlike the mechanism reported by Maycock et al.[14a]

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Figure 2 Substrate scope for the synthesis of compound 3. Reaction conditions: 1 (1.0 mmol), 2 (1.0 mmol), Cu(OAc)2 . H2O (10 mol%, 20 mg), TBHP (70% in H2O, 2 equiv, 257 mg) in MeOH (5 mL) at room temperature. Products were purified by column chromatography using silica gel (100–200 mesh) and yields are given for the isolated products.
Zoom Image
Scheme 2 Deuterium labeling for mechanistic investigation. This particular reaction was carried out by using TBHP in decane, because otherwise, in the presence of water, partial deuterium exchange occurred.
Zoom Image
Scheme 3 Cross experiment for mechanistic proof
Zoom Image
Scheme 4 Tentative mechanism for the reaction

Based on the above experiments, a tentative mechanism is proposed for the reaction (Scheme [4]). First, TBHP in the presence of Cu(II) gives tert-butyl peroxy radical (X) and Cu(II) is converted into Cu(I). Radical X then reacts with one molecule of MeOH generating hydroxymethyl radical (Y). Subsequently, TBHP in the presence of Cu(I) gives tert-butoxy radical (Z), which in the presence of a hydroxymethyl radical gives formaldehyde. Next, the 3-component Mannich reaction of naphthol, amine and formaldehyde gives α-alkyl amino naphthol 2', which is then converted into the corresponding iminium ion 2'' in the presence of Cu(II) and finally cyclized to the desired product 3.

In conclusion, we have successfully developed a 3-component route for the synthesis of 1,3-oxazines using methanol as C1 feedstock. The methylene carbon of the product originates from methanol. The reaction is carried out at room temperature and utilizes an environmentally benign metal catalyst. On the basis of our control experiments, a tentative free-radical mechanism is also proposed.


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Acknowledgment

The authors acknowledge Dr. Ranjit Thakuria, Dept. of Chemistry, Gauhati University for X-ray structure analysis and Dr. S. Karmakar, Gauhati University for collecting single-crystal X-ray data.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/s-0036-1591775.
  • Supporting Information


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Zoom Image
Scheme 1 Synthetic route to 1,3-oxazines
Zoom Image
Figure 1 Single-crystal X-ray structure of 3a
Zoom Image
Figure 2 Substrate scope for the synthesis of compound 3. Reaction conditions: 1 (1.0 mmol), 2 (1.0 mmol), Cu(OAc)2 . H2O (10 mol%, 20 mg), TBHP (70% in H2O, 2 equiv, 257 mg) in MeOH (5 mL) at room temperature. Products were purified by column chromatography using silica gel (100–200 mesh) and yields are given for the isolated products.
Zoom Image
Scheme 2 Deuterium labeling for mechanistic investigation. This particular reaction was carried out by using TBHP in decane, because otherwise, in the presence of water, partial deuterium exchange occurred.
Zoom Image
Scheme 3 Cross experiment for mechanistic proof
Zoom Image
Scheme 4 Tentative mechanism for the reaction