Diastereoselective synthesis of fused [1,3]oxazines from ethyl pyruvate, activated acetylenes and N-heterocycles

Abstract

The 1:1 zwitterionic intermediates obtained from the reaction between isoquinoline, quinoline, pyridine, or N-methylimidazole with activated acetylenes are trapped by ethyl pyruvate to produce highly functionalized fused [1,3]oxazines in good yields. [PUBLICATION ABSTRACT]

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Mol Divers (2010) 14:343347 DOI 10.1007/s11030-009-9174-4

FULL-LENGTH PAPER

Diastereoselective synthesis of fused [1,3]oxazines from ethyl pyruvate, activated acetylenes and N-heterocycles

Issa Yavari Anvar Mirzaei Zinatosadat Hossaini

Sanaz Souri

Received: 2 March 2009 / Accepted: 29 May 2009 / Published online: 4 July 2009 Springer Science+Business Media B.V. 2009

Abstract The 1:1 zwitterionic intermediates obtained from the reaction between isoquinoline, quinoline, pyridine, or N-methylimidazole with activated acetylenes are trapped by ethyl pyruvate to produce highly functionalized fused [1,3]oxazines in good yields.

Keywords Ethyl pyruvate Activated acetylenes

Quinoline Isoquinoline [1,3]Oxazine

Introduction

The development of simple synthetic routes to widely used organic compounds from readily available reagents is one of the major tasks in organic synthesis [1]. Consequently, domino reactions including multicomponent reactions (MCRs) have been used as a powerful tool to achieve this goal [28]. At the forefront of these chemical methodologies, these domino processes have created molecular complexity and diversity from readily accessible starting materials in one single operation [915]. The reactants of the one-pot MCRs have been involved in the classical Mannich reaction, which is one of the most important CC bond forming reactions for production of nitrogenous molecules [1618]. Bridgehead nitrogen heterocycles are of interest because they constitute an important class of natural and nonnatural products, many of which exhibit useful biological activity [19].

As part of our current studies on the development of new routes in heterocyclic synthesis [2023], we report an efcient synthetic route to [1,3]oxazine derivatives. Thus, the reaction of ethyl pyruvate (1), electron-decient acetylenic

I. Yavari (B) A. Mirzaei Z. Hossaini S. Souri

Chemistry Department, Tarbiat Modares University, 14115-175 Tehran, Irane-mail: [email protected]

compounds 2 with isoquinoline (3) led to trialkyl 2-methyl-2H-11b H-[1,3]oxazino[2,3-a]isoquinoline-2,3,4-tricarboxylates (4) in good yields (Scheme 1). Similar reactions involving isoquinoline and other N-heterocycles with activated acetyls or isocyanates have been reported [24].

Result and discussion

The structures of compounds 4a4d were conrmed from their 1H- and 13C-NMR spectroscopic data, as well as IR spectra. The 1H NMR spectrum of 4a in CDCl3 exhibited signals for the methyl ( 1.76ppm), methoxy ( 3.68 and3.88ppm), methylene ( 4.25ppm), and methine ( 6.19ppm) H-atoms, along with multiplets at 5.687.92ppm for the isoquinoline moiety. The 13C NMR spectrum of 4a exhibited 20 signals in agreement with the proposed structure. Partial assignments of these resonances are given in the Experimental section. The stereochemistry of compounds 4a and 4c are conrmed by nuclear Overhauser effect (NOE) measurements. Thus, when the methine signal was irradiated, the CH2O protons were enhanced by about 10%, while the CH3 group showed no significant enhancement. Thus, the stereo-chemistry was deduced from the NOE measurements, and the same conguration was assumed for the other derivatives of 4, as well as for compounds 79, on account of their NMR spectroscopic similarities.

Although the mechanistic details of the reaction are not known, a plausible rationalization may be advanced to explain the product formation. Presumably, the reaction involves the initial formation of a 1:1 zwitterionic intermediate [25] 5 between isoquinoline and the activated acetylene, which reacts with 1 to produce 6. Intermediate 6 can cyclize under the reaction conditions employed to produce 4 (Scheme 2).

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344 Mol Divers (2010) 14:343347

Scheme 1 Synthesis of fused [1,3]oxazine derivatives from isoquinoline

H3C

CO2R' CH3

CH2Cl2

CO2Et

r.t.

CO2R'

EtO2C

2,4 R' Yield/ % of 4

CO2Me CO2Et

Me Et

84 85 80 82

Scheme 2 Proposed mechanism for the one-pot synthesis of fused [1,3]oxazines

N R

+ 1

2 +

CO2R'

H3C CO2Et

Under similar conditions, the reaction between quinoline, pyridine, or N-methylimidazole with dialkyl acetylenedicarboxylates in the presence of 1 led to fused [1,3]oxazines 79 in good yields (Scheme 3). The stereochemistry of these compounds is conrmed by nuclear Overhauser effect measurements.

In conclusion, we report a novel transformation involving activated acetylenes and isoquinoline, quinoline, pyri-dine, or N-methylimidazole in the presence of ethyl pyruvate, which affords bridgehead nitrogen-containing heterocycles. The present procedure has the advantage that, not only is the reaction performed under neutral conditions, but also the reactants can be mixed without any prior activation or modication.

Material and methods

Ethyl pyruvate, isoquinoline, quinoline, pyridine, N-methylimidazole, and acetylenic compounds were obtained from Fluka and were used without further purication. IR spectra:

Shimadzu IR-460 spectrometry. 1H and 13C NMR spectra were recorded on a Bruker DRX-500 Avance instrument using CDCl3 as the deuterated solvent containing tetramethylsilane as internal standard, at 500.1 and 125.7MHz, respectively; in parts per million, J in hertz. EIMS (70eV): Finnigan-MAT-8430 mass spectrometry, in m/z. Elemental analyses (C, H, N) were performed with a Heraeus CHN-O-Rapid analyzer.

General procedure

To a stirred solution of the acetylenic ester 2 (2mmol) and ethyl pyruvate (0.23g, 2mmol) in 15mL of CH2Cl2 was added the N-heterocycle (2mmol) at room temperature. After completion of the reaction (23h) as indicated by TLC (EtOAc/n-hexane, 4:1), the solvent was removed under reduced pressure, and the residue was puried by column chromatography over silica gel (Merck 230240mesh) using a 4:1 n-hexane-EtOAc mixture as eluent to afford pure product.

Scheme 3 Synthesis of fused[1,3]oxazines from quinoline,pyridine, andN-methylimidazole N O CO2Et

CH3

N O CO2Et

CH3

O CO2Et

CH3

RO2C

MeO2C

CO2Me

7 Yield/ %

b Et

CO2R

8 (76%) 9 (82%)

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Mol Divers (2010) 14:343347 345

2-Ethyl 3,4-dimethyl 2-methyl-2H-11bH-[1,3]oxazino [2,3-a]isoquinoline-2,3,4-tricarboxylate (4a)

White powder, mp 150152 C, yield: 0.65g (84%). IR (KBr) (max/cm1): 1754, 1765, 1715, 1510, 1324 and 1100 cm1.

1H NMR (500.1MHz, CDCl3): = 1.28 (t, 3 H, 3 J =

7.2 Hz, Me), 1.76 (s, 3 H, Me), 3.68 (s, 3 H, MeO), 3.88 (s, 3 H, MeO), 4.244.26 (m, 2 H, CH2O), 5.68 (d, 1 H,

3 J = 7.8 Hz, CH), 6.19 (s, 1 H, CH), 6.25 (d, 1 H, 3 J =

7.8 Hz, CH), 7.16 (t, 1 H, 3 J = 7.4 Hz, CH), 7.55 (d, 1 H,

3 J = 7.4 Hz, CH), 7.76 (d, 1 H, 3 J = 8.2 Hz, CH), 7.92 (d, 1

H, 3 J = 8.2 Hz, CH) ppm. 13C NMR (125.7MHz, CDCl3):

= 13.9 (Me), 23.6 (Me), 51.4 (MeO), 52.9 (MeO), 61.3

(CH2O), 77.5 (CH), 80.0 (C), 103.6 (CH), 112.6 (C), 123.8 (CH), 124.8 (CH), 126.2 (C), 126.7 (CH), 127.6 (CH), 129.2 (CH), 135.8 (C), 141.6 (C), 163.3 (CO2), 164.7 (CO2), 170.7 (CO2) ppm. MS: m/z (%) = 387 (M+, 10), 356 (54), 328(70), 258 (68), 129 (100), 59 (50), 31 (47). Anal. Calc. for C20H21NO7(387.39): C, 62.01; H, 5.46; N, 3.62%. Found:

C, 62.00; H, 5.44; N, 3.65%.

Triethyl 2-methyl-2H-11bH-[1,3]oxazino [2,3-a]isoquinoline-2,3,4-tricarboxylate (4b)

Pale yellow powder, mp 158160 C; yield: 0.70g (85%).

IR (KBr) (max/cm1): 1747, 1735, 1720, 1462, 1387 and 1290 cm1. 1H NMR (500.1MHz, CDCl3): = 1.29 (t,

3 H, 3 J = 7.4 Hz, Me), 1.37 (t, 3 H, 3 J = 7.5 Hz, Me),

1.41 (t, 3 H, 3 JHH = 7.4 Hz, Me), 1.84 (s, 3 H, Me), 4.22

4.24 (m, 2 H, CH2O), 4.304.32 (m, 2 H, CH2O), 4.424.44 (m, 2 H, CH2O), 5.76 (d, 1 H, 3 J = 7.7 Hz, CH), 6.30 (s,

1 H, CH), 6.35 (d, 1 H, 3 J = 7.7 Hz, CH), 7.11 (d, 1 H,

3 J = 7.7 Hz, CH), 7.25 (t, 1 H, 3 J = 6.3 Hz, CH), 7.30 (t,

1 H, 3 J = 6.3 Hz, CH), 7.40 (d, 1 H, 3 J = 7.7 Hz, CH)

ppm. 13C NMR (125.7MHz, CDCl3): = 13.8 (Me), 13.9

(Me), 14.2 (Me), 23.9 (Me), 60.7 (CH2O), 61.5 (CH2O), 62.4 (CH2O), 77.8 (CH), 80.2 (C), 103.7 (CH), 112.9 (C), 124.1 (CH), 126.0 (CH), 126.2 (C), 126.9 (CH), 127.9 (CH), 129.4 (CH), 129.8 (C), 142.1 (C), 163.1 (CO2), 164.4(CO2), 171.0 (CO2) ppm. MS: m/z (%) = 415 (M+, 15), 370 (64), 342(68), 286 (62), 129 (100), 73 (84), 45 (67). Anal. Calc. for C22H25NO7 (415.44): C, 63.61; H, 6.07; N, 3.37%. Found:

C, 63.60; H, 6.07; N, 3.37%.

2-Ethyl 3-methyl 2-methyl-2H-11bH-[1,3]oxazino [2,3-a]isoquinoline-2,3-dicarboxylate (4c)

White powder, mp 165167 C, yield: 0.53g (80%). IR (KBr) (max/cm1): 1764, 1752, 1724, 1410, 1384 and 1298 cm1.

1H NMR (500.1MHz, CDCl3): = 1.26 (t, 3 H, 3 J = 7.5 Hz,

Me), 1.74 (s, 3 H, Me), 3.74 (s, 3 H, MeO), 4.284.30 (m, 2 H, CH2O), 5.64 (d, 1 H, 3 J = 7.8 Hz, CH), 6.25 (s, 1 H, CH),

6.34 (d, 1 H, 3 J = 7.8 Hz, CH), 7.16 (t, 1 H, 3 J = 7.4 Hz,

CH), 7.55 (d, 1 H, 3 J = 7.4 Hz, CH), 7.76 (d, 1 H, 3 J = 8.2 Hz,

CH), 7.84 (s, 1 H, CH), 7.92 (d, 1 H, 3 J = 8.2 Hz, CH) ppm.

13C NMR (125.7MHz, CDCl3): = 13.7 (Me), 22.8 (Me),

50.5 (MeO), 61.1 (CH2O), 77.4 (CH), 79.6 (C), 102.7 (CH), 107.3 (C), 124.4 (CH), 126.2 (C), 126.3 (CH), 126.4 (CH), 126.5 (CH), 128.7 (CH), 129.9 (C), 139.6 (CH), 164.9 (CO2), 171.1(CO2) ppm. Anal. Calc. for C18H19NO6(329.35): C,65.64; H, 5.81; N, 4.25%. Found: C, 65.50; H, 5.85; N,4.28%.

Diethyl 2-methyl-2H-11bH-[1,3]oxazino [2,3-a]isoquinoline-2,3-dicarboxylate (4d)

White powder, mp 174176 C, yield: 0.56g (82%). IR (KBr) (max/cm1): 1751, 1748, 1724, 1356, 1289 and 1145 cm1.

1H NMR (500.1MHz, CDCl3): = 1.23 (t, 3 H, 3 J =

7.3 Hz, Me), 1.28 (t, 3 H, 3 J = 7.4 Hz, Me), 1.65 (s, 3 H,

Me), 4.324.34 (m, 2 H, CH2O), 4.384.40 (m, 2 H, CH2O),5.72 (d, 1 H, 3 J = 7.9 Hz, CH), 6.47 (s, 1 H, CH), 6.52 (d,

1 H, 3 J = 7.8 Hz, CH), 7.35 (t, 1 H, 3 J = 7.4 Hz, CH),

7.48 (d, 1 H, 3 J = 7.4 Hz, CH), 7.72 (d, 1 H, 3 J = 8.2 Hz,

CH), 7.87 (s, 1 H, CH), 7.90 (d, 1 H, 3 J = 8.2 Hz, CH) ppm.

13C NMR (125.7MHz, CDCl3): = 13.7 (Me), 22.8 (Me),

50.5 (CH2O), 61.1 (CH2O), 77.4 (CH), 79.6 (C), 102.7 (CH), 107.3 (C), 124.4 (CH), 126.2 (C), 126.3 (CH), 126.4 (CH), 126.5 (CH), 128.7 (CH), 129.9 (C), 139.6 (CH), 164.9 (CO2), 171.1(CO2) ppm. Anal. Calc. for C19H21NO5(343.37): C,66.46; H, 6.16; N, 4.08%. Found: C, 66.42; H, 6.20; N,4.10%.

3-Ethyl 1,2-dimethyl 3-methyl-3H,4aH-[1,3]oxazino [3,2-a]quinoline-1,2,3-tricarboxylate (7a)

Yellow powder, mp 142144 C, yield: 0.58g (75%). IR (KBr) (max/cm1): 1780, 1768, 1754, 1541, 1487 and 1290 cm1. 1H NMR (500.1MHz, CDCl3): = 1.34 (t, 3 H,

3 J = 6.5 Hz, Me), 1.81 (s, 3 H, Hz, Me), 3.83 (3 H, s,

MeO), 3.90 (s, 3 H, MeO), 4.284.30 (m, 2 H, CH2O), 5.55 (d, 1 H, 3 J = 4.3 Hz, CH), 6.01 (dd, 1 H, 3 J = 9.8 Hz,

4 J = 4.3 Hz, CH), 6.76 (d, 1 H, 3 J = 8.5 Hz, CH), 6.86

(d, 1 H, 3 J = 9.8 Hz, CH), 7.03 (t, 1 H, 3 J = 7.4 Hz,

CH), 7.247.26 (m, 2 H, 2 CH) ppm. 13C NMR (125.7MHz, CDCl3): = 13.9 (Me), 24.7 (Me), 52.1 (MeO), 53.0 (MeO),

61.7 (CH2O), 78.4 (C), 79.1 (CH), 114.0 (CH), 118.1 (CH), 121.0 (C), 121.8 (CH), 121.0 (C), 128.3 (CH), 129.0 (CH), 129.4 (CH), 135.9 (C), 139.4 (C), 164.1 (CO2), 165.2 (CO2), 170.2 (CO2) ppm. MS: m/z (%) = 387 (M+, 5), 280 (48), 328(70), 258 (86), 129 (100), 45 (56), 31 (44). Anal. Calc. for C20H21NO7(387.38): C, 62.01; H, 5.46; N, 3.62%. Found:

C, 62.00; H, 5.45; N, 3.65%.

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346 Mol Divers (2010) 14:343347

Triethyl 3-methyl-3H-4aH-[1,3]oxazino[3,2-a]quinoline-1,2,3-tricarboxylate (7b)

Yellow powder, mp 154156 C, yield: 0.58g (72%). IR (KBr) (max/cm1): 1747, 1738, 1720, 1654, 1547, 1325 and 1245 cm1. 1H NMR (500.1MHz, CDCl3): = 1.27

(3 H, t, 3 J = 7.1 Hz, Me), 1.30 (t, 3 H, 3 J = 7.1 Hz, Me),

1.34 (t, 3 H, 3 J = 7.1 Hz, Me), 1.64 (s, 3 H, Me), 4.204.40

(m, 6 H, 3 CH2O), 5.52 (d, 1 H, 3 J = 4.4 Hz, CH), 5.93

5.95 (m, 1 H, CH), 6.756.80 (m, 2 H, CH), 6.96 (t, 1 H,

3 J = 7.4 Hz, CH), 7.167.18 (m, 2 H, CH) ppm. 13C NMR

(125.7MHz, CDCl3): = 13.6 (Me), 13.7 (Me), 13.9 (Me),

24.8 (CH3), 61.2 (CH2O), 61.7 (CH2O), 62.0 (CH2O), 78.7 (CH), 79.1 (C), 114.2 (C), 118.2 (CH), 121.7 (CH), 128.0(C), 128.2 (CH), 129.0 (CH), 129.1 (CH), 129.2 (CH), 135.9(C), 139.8 (C), 163.6 (CO2), 164.7(CO2), 170.2 (CO2) ppm.

Anal. Calc. for C22H25NO7(415.44): C, 63.61; H, 6.07; N,3.37%. Found: C, 63.61; H, 6.05; N, 3.32%.

2-Ethyl 3,4-dimethyl 2-methyl-2H-9aH-pyrido[2, 1-b][1,3]oxazine-2,3,4-tricarboxylate (8)

Pale yellow powder, mp 165167 C, yield: 0.51g (76%).

IR (KBr) (max/cm1): 1780, 1774, 1725, 1657, 1430 and 1154 cm1. 1H NMR (500.1MHz, CDCl3): = 1.17 (t, 3 H,

3 J = 7.2 Hz, Me), 1.78 (s, 3 H, Me), 3.62 (s, 3 H, MeO), 3.82

(s, 3 H, MeO), 4.124.14 (m, 2 H, CH2O), 5.055.07 (m, 1 H, CH), 5.26 (d, 1 H, 3 J = 7.2 Hz, CH), 5.635.65 (m, 1 H,

CH), 6.156.17 (m, 1 H, CH), 7.86 (d, 1 H, 3 J = 7.4 Hz, CH)

ppm. 13C NMR (125.7MHz, CDCl3): = 13.8 (Me), 20.9

(Me), 52.9 (MeO), 53.3 (MeO), 61.5 (CH2O), 78.5 (CH),79.3 (C), 104.3 (CH), 111.4 (CH), 124.7 (CH), 124.8 (CH), 134.3 (CH), 163.3 (CO2), 164.6 (CO2), 170.4 (CO2) ppm.

Anal. Calc. for C16H19NO7(337.32): C, 56.97; H, 5.68; N,4.15%. Found: C, 56.90; H, 5.65; N, 4.13%.

2-Ethyl 3,4-dimethyl 2-methyl-2H-9aH-imidazo[2, 1-b][1,3]oxazine-2,3,4-tricarboxylate (9)

Yellow powder, mp 160162 C, yield: 0.56g (82%). IR (KBr) (max/cm1): 1775, 1767, 1747, 1652, 1425 and 1129 cm1. 1H NMR (500.1MHz, CDCl3): = 1.25 (t, 3 H,

3 J = 7.2 Hz, Me), 1.65 (s, 3 H, Me), 2.47 (s, 3 H, MeN),

3.58 (s, 3 H, MeO), 3.74 (s, 3 H, MeO), 4.224.25 (m, 2 H, CH2O), 6.54 (s, 1 H, CH), 7.04 (d, 1 H, 3 J = 5.4 Hz, CH),

7.42 (d, 1 H, 3 J = 5.4 Hz, CH) ppm. 13C NMR (125.7MHz,

CDCl3): = 14.3 (Me), 21.4 (Me), 36.5 (MeN), 51.5 (MeO),

52.8 (MeO), 62.4 (CH2O), 75.4 (C), 100.3 (CH), 105.8 (CH), 112.4 (C), 132.4 (CH), 140.1 (C), 163.4 (CO2), 165.8 (CO2), 172.4 (CO2) ppm. Anal. Calc. for C15H20N2O7 (340.33): C, 52.94; H, 5.92; N, 8.23%. Found: C, 52.90; H, 5.85; N,8.24%.

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Springer Science+Business Media B.V. 2010

Diastereoselective synthesis of fused [1,3]oxazines from ethyl pyruvate, activated acetylenes and N-heterocycles

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