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Synthesis 2015; 47(05): 712-720
DOI: 10.1055/s-0034-1379641
paper
© Georg Thieme Verlag Stuttgart · New York

A Concise and Efficient Synthesis of Substituted Morpholines

Sundeep Dugar
a   Sphaera Pharma Pte. Ltd., 8 Temasek Boulevard, #22-03 Suntec Tower, 038988, Singapore
,
Amit Sharma
b   Sphaera Pharma Pvt. Ltd., Plot No 32, Sector 5, IMT Manesar 122051, India   Email: dinesh.m@sphaerapharma.com
,
Bilash Kuila
b   Sphaera Pharma Pvt. Ltd., Plot No 32, Sector 5, IMT Manesar 122051, India   Email: dinesh.m@sphaerapharma.com
,
Dinesh Mahajan*
b   Sphaera Pharma Pvt. Ltd., Plot No 32, Sector 5, IMT Manesar 122051, India   Email: dinesh.m@sphaerapharma.com
,
Sandeep Dwivedi
b   Sphaera Pharma Pvt. Ltd., Plot No 32, Sector 5, IMT Manesar 122051, India   Email: dinesh.m@sphaerapharma.com
,
Vinayak Tripathi
b   Sphaera Pharma Pvt. Ltd., Plot No 32, Sector 5, IMT Manesar 122051, India   Email: dinesh.m@sphaerapharma.com
› Author Affiliations
Further Information

Publication History

Received: 19 September 2014

Accepted after revision: 17 November 2014

Publication Date:
23 December 2014 (online)

 
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Abstract

A simple and efficient method has been developed for the synthesis of substituted morpholines by a sequence of coupling, cyclization, and reduction reactions of easily available amino alcohols and α-halo acid chlorides. Various mono-, di-, and trisubstituted morpholines, spiro morpholines, and ring-fused morpholines, as well as morpholine homologues, were synthesized in good to excellent yields by a single methodology under similar reaction conditions. The method was also used in a multigram synthesis of (3S)-3-methylmorpholine.


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Key words

morpholines - amides - cyclizations - coupling - reductions

Morpholines are an important class of heterocyclic compounds that are found in many natural or synthetic organic molecules of biological and pharmacological interest.[1] The morpholine moiety is a weaker base than piperidine and this imparts unique and desirable physiochemical properties to the morpholine scaffold.[2] Additionally, C-substituted morpholines can possess additional unique conformational, steric, and electronic properties, imparting unique biological properties and therapeutic applications to the molecules to which they are attached. The World Drug Index lists several drugs containing unsubstituted, substituted, or fused morpholine scaffolds[3] that show a wide range of therapeutic actions. These include antitumor, antiinflammatory, and antidepressant activities, tachykinin receptor activity, NK-1 antagonist activity, serotonin agonist activity, antifungal and antibacterial activities.[1] For example, the morpholine scaffold is present in the antidepressant reboxitine, the antiemetic aprepitant, and the agrochemical fungicides fenpropimorph and tridemorph (Figure [1]).[4] Substituted chiral morpholine derivatives have also been used as chiral organocatalysts[5] and chiral auxiliaries[6] in enantioselective synthesis, and as chiral templates in the synthesis of α-hydroxy acids and oxacycles.[7] Morpholines also have various important industrial applications, for example, as polymerization catalysts,[8] as adsorbents in the purification of liquids and gases,[9] as fuels,[10] and as ink additives.[11] Despite this wide range of applications in the pharmaceutical, agrochemical, and materials industries and in organic catalysis, very limited attention has been paid to the development of robust and versatile methods for the synthesis of chiral and achiral substituted morpholines.

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Figure 1

The few synthetic approaches that are mentioned in the literature involve transformations of amino acids,[12] amino alcohols,[13] epoxides,[14] olefins,[15] imines,[16] or vinyl sulfonium salts[17] into various substituted morpholine derivatives. Additionally, several methods for morpholine synthesis exploit metal-catalyzed cyclizations[18] or involve aziridines[19] or aziridinium ions as intermediates.[1c] However, these reported approaches lack versatility in application, and therefore no single approach provides access to multiple analogues, even when these are structurally related. Hence, a general synthetic approach that would lead to chiral or achiral monosubstituted morpholines (e.g., 2 or 3-substituted morpholines), disubstituted morpholine (2,3-, 2,5-, 2,6-, or 3,5-disubstituted morpholines), bicyclic fused morpholines, or spiro morpholines, as well as morpholine homologues, would be highly desirable. Further, most reported synthetic approaches are not amenable to application in scalable commercial syntheses of active pharmaceutical ingredients because they involve long synthetic sequences or the use of protecting groups or expensive reagents.

As part of our ongoing interest in developing molecules with antitumor activities, we were interested in developing a simple, short, and versatile approach to the synthesis of substituted morpholines.[20] Our retrosynthetic analysis (Scheme [1]) illustrates what we surmised might be a straightforward approach to these molecules that would also permit versatility, as substituents R1, R2, R3, and R4 on the morpholine ring might be incorporated independently.

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Scheme 1 Retrosynthetic analysis

Substituted amino alcohols and α-halo acid chlorides, the two key starting materials for our proposed synthesis of substituted morpholines (Scheme [1]), are either commercially available or can be synthesized easily on a large scale in chiral or achiral forms. The proposed method involves synthesis of an amide 3 (Scheme [2]), followed by an intramolecular cyclization and reduction to give the corresponding morpholine analogue 5. This strategy has previously been reported, but with a limited scope, focusing exclusively on syntheses of specific molecules of interests.[13] Here, we report an improved and expanded scope of this approach in the synthesis of various C-substituted morpholines and morpholine homologues.

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Scheme 2 General synthetic scheme for morpholine synthesis

A reaction of (2S)-2-aminopropan-1-ol with chloroacetyl chloride in equimolar ratios in a solvent mixture of tetrahydrofuran and water at –10 °C for one hour gave the corresponding chiral acyclic amide 3a in 90% yield. Without purification, the crude product 3a was subjected to intramolecular cyclization with potassium tert-butoxide (4 equiv) in isopropyl alcohol–dichloromethane at 0 °C for two hours to give the desired morpholinone 4a. Reduction of morpholinone 4a with lithium aluminum hydride (3 equiv) gave (3S)-3-methylmorpholine (5a) in 70% yield (Table [1], entry 1).

Similarly, the reactions of acyclic amides 3b–l, derived from alcohols 1, with acid chlorides 2 gave the corresponding morpholines 5b–l in good to excellent yields without loss of chirality (Table [1], entries 2–12). By using this approach, we therefore successfully synthesized morpholines with various substituents, such as methyl or ethyl groups, at the 2- or 3-positions (5a–f, 5h, and 5i), the C-2 spiro-substituted morpholine 5g, and the C-2 substituted morpholine homologues 5j and 5k.

Attempts to synthesize disubstituted morpholines gave some interesting results. The synthesis of (2R,3S)-2,3-dimethylmorpholine (5l) proceeded uneventfully. Acylation of the disubstituted amino alcohol 1l with chloroacetyl chloride followed by intramolecular cyclization and subsequent reduction gave the corresponding disubstituted morpholinone 5l in 83% yield (Table [1], entry 12). However, attempts to synthesize 2,6-dimethylmorpholines gave a mixture of diastereomers in a 60:40 ratio (entries 13–15). The chiral nature of the products was independent of that of the 2-chloropropanoyl chloride. When the synthesis of the 2,5-dimethyl analogue was attempted, the conversion was clean with the formation of a single syn-diastereomer, once again irrespective of the chirality or chiral purity of the 2-chloropropanoyl chloride (entries 16–18). However, this dia­stereoselectivity was found to be influenced by the reaction temperature, as a loss of diastereoselectivity through epimerization occurred when the same reaction was attempted at 60 °C and a mixture of syn- and anti-diastereoisomers was obtained as observed in a previous study.[13j] Furthermore, it appeared that the final chirality is controlled by the chirality of the amino alcohol (entries 18 and 19). Finally, it appears that the chirality of the product is predominantly controlled by the chirality of the substituent in the 2-position of the amino alcohol (entry 20). Whereas we observed no diastereoselectivity for substituents at the 2- and 6-positions of the corresponding morpholinones, the presence of a substituent in the 3-position directed the chiral outcome, and a single diastereomer was obtained.

Table 1 Synthesis of Substituted Morpholines 5 a

Entry

Substrate 1

Substrate 2

Intermediate 4

Product 5

Yieldb (%)

1

4a

5a

71

2

4b

5b

75

3

4c

5c

78

4

4d

5d

74

5

4e

5e

72

6

4f

5f

80

7

4g

5g

90

8

4h

5h

70

9

4i

5i

75

10

4j

5j

80

11

4k

5k

72

12

4l

5l

83

13

4m

5m

80c

14

4n

5n

80c

15

4o

5o

84c

16

4p

5p

80

17

4q

5q

80

18

4r

5r

81

19

4s

5s

80

20

4t

5t

72

21

4u

5u

72

22

4v

5v

82

23

4w

5w

84

24

4x

5x

74

a Reaction conditions: (i) K2CO3, THF–H2O, –10 °C, 1 h; (ii) t-BuOK (4 equiv), i-PrOH–CH2Cl2, r.t., 1 h; (iii) LAH (3 equiv), THF, r.t., 16 h.

b Isolated yield.

c dr 60:40 (1H NMR).

The stereochemistry of the products was assigned by means of NOESY experiment.[21] For example, morpholinone 4r showed H-2/Ha-6/H-5 spatial proximity, with a strong NOESY cross-peak, indicating a cis-orientation of the methyl groups in the 2- and 5-positions (Figure [2]).

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Figure 2 NOESY signal assignment for morpholinone 4r.

1H, COSY, and NOESY NMR[21] spectroscopy confirmed the structure and stereochemistry of the trisubstituted morpholinone 4t, as shown in Figure [3].

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Figure 3 NOESY signal assignment for morpholinone 4t

Interestingly, the final intramolecular cyclization requires reorientation of the acyclic amide from the more stable transoid orientation to a higher energy cisoid orientation, probably via the imino hemiacetal, as shown in Scheme [3]. At this time, the overall mechanism for the final cyclization is unclear; however, stereocontrol by the substituent in the 2-position of the amino alcohol is clear and demonstrable. However, the reason for this control cannot yet be explained.

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Scheme 3

We also successfully applied our synthetic approach to the synthesis of several fused morpholines. Saturated and unsaturated fused morpholines 5u–x (Table [1], entries 21–24) were synthesized in good to moderate yields from the corresponding amino alcohols and chloroacetyl chloride.

In summary, our approach provides a concise, simple, and robust method for the synthesis of various substituted morpholines, including 2-substituted, 2,3-, 2,5-, and 2,6-disubstituted, 2,3,6 trisubstituted, bicyclic fused, and spirocyclic morpholines, as well as 7- and 8-atom morpholine homologues, in good to excellent yields. The concise and simple reactions, inexpensive reagents, and readily available starting materials suggest the method might be suitable for commercial use. The approach was also shown to be applicable to a multigram synthesis of (3S)-3-methylmorpholine.[21]

Unless otherwise mentioned, commercial available materials were used without further purification. Air-sensitive reactions were carried out under N2. Anhyd solvents and all key starting materials were obtained from Sigma-Aldrich Corp. NMR spectra were recorded on a Bruker 300 MHz spectrometer with CDCl3 or DMSO-d 6 as solvent. Chemical shifts (δ) are quoted in ppm relative to the internal solvent as a reference. Mass spectra were recorded in ESI mode on an Agilent 6120 Quadrupole LC/MS instrument.


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Chloro Amides 3; General Procedure

An aqueous solution of K2CO3 (3 equiv) in H2O (50 mL) was added to a solution of amino alcohol 1 (1 equiv) in THF (50 mL) at –10 °C. Chloroacyl chloride 2 (1.1 equiv) was added from a syringe at –10 °C syringe­ with vigorous stirring, and the mixture was then stirred at –10 °C for 1 h. The mixture was poured into H2O (50 mL) and extracted with CH2Cl2 (2 × 100 mL). The organic layer was finally dried (Na2SO4), filtered, and concentrated.


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Morpholin-2-ones 4; General Procedure

A solution of t-BuOK (4 equiv) in i-PrOH (100 mL) was added dropwise to a solution of chloro amide 3 (1 equiv) in CH2Cl2 (100 mL) at 0 °C. The resulting mixture was stirred at r.t. for 1 h then neutralized to pH 7 with 2 M aq HCl. The solvent was removed under reduced pressure to give a white product, which was taken up in EtOAc (100 mL). The solution was washed with H2O (2 ×100 mL), and the organic layer was separated, dried (Na2SO4), filtered, and concentrated.


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Morpholines 5; General Procedure

A solution of LAH (2 equiv) in THF (100 mL) under N2 was cooled 0 °C in an ice bath. A solution of morpholinone 4 (1 equiv) in THF (20 mL) was added dropwise, and the resulting mixture was stirred at r.t. for 16 h. The mixture was cooled to 0 °C and the reaction was carefully quenched by sequential addition of H2O (2 mL), 2 M aq NaOH (2 mL), and H2O (8 mL). The resulting slurry was stirred at r.t. for 1 h then filtered through Celite. The filter cake was washed with EtOAc (3 × 100 mL) then discarded. The filtrate was dried (Na2SO4), separated, and concentrated to give a colorless oil.


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2-Chloro-N-[(1S)-2-hydroxy-1-methylethyl]acetamide (3a); Typical Procedure

A solution of K2CO3 (5.52 g, 39.99 mmol) in H2O (50 mL) was added to a solution of (2S)-2-aminopropan-1-ol (1.0 g, 13.33 mmol) in THF (50 mL) at –10 °C. ClCH2COCl (1.16 mL, 14.66 mmol) was added from a syringe with vigorous stirring, and the mixture was stirred at –10 °C for 1 h. The mixture was then poured in H2O (50 mL) and extracted with CH2Cl2 (2 × 100 mL). The organic layer was separated, dried (Na2SO4­), filtered, and concentrated to give a colorless oil; yield: 1.71 g (85%, 11.2 mmol).

1H NMR (300 MHz, CDCl3): δ = 6.73 (br s, 1 H), 4.1 (m, 1 H), 4.05 (s, 2 H), 3.70 (m, 1 H), 3.57 (m, 1 H), 2.57 (br s, 1 H), 1.22 (d, J = 6.0 Hz, 3 H).

MS: m/z = 152 [M + 1].


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(5S)-5-Methylmorpholin-3-one (4a); Typical Procedure

A soln of t-BuOK (4.45 g, 39.72 mmol) in i-PrOH (100 mL) was added dropwise to a solution of chloro amide 3a (1.50 g, 9.93 mmol) in CH2Cl2­ (100 mL) at 0 °C. The solution was stirred at r.t. for 1 h then neutralized by slow addition of 2 M aq HCl. The solvent was removed under reduced pressure to give a white solid. The solid was taken up in EtOAc (100 mL) and the solution was washed with H2O (2 × 100 mL). The organic layer was separated, dried (Na2SO4), filtered, and concentrated to give a colorless oil; yield: 0.92 g (80%, 8.0 mmol).

1H NMR (300 MHz, CDCl3): δ = 6.75 (br s, 1 H), 4.21–4.06 (m, 2 H), 3.91–3.86 (m, 1 H), 3.71 (m, 1 H), 3.35 (m, 1 H), 1.19 (d, J = 6.0 Hz, 3 H).

MS: m/z = 116 [M + 1].


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(3S)-3-Methylmorpholine (5a);[22] Typical Procedure

LAH (0.892 g, 23.47 mmol) in THF (100 mL) was cooled to 0 °C under N2 in an ice bath. A solution of morpholinone 4a (0.90 g, 7.82 mmol) in THF (20 mL) was added dropwise, and the solution was stirred at r.t. for 16 h. The mixture was cooled to 0 °C and the reaction was carefully quenched by successive addition of H2O (2 mL), 2 M aq NaOH (4 mL), and H2O (6 mL). The resulting slurry was stirred at r.t. for 1 h then filtered through Celite. The filter cake was washed with EtOAc (3 × 100 mL) then discarded. The filtrate was dried (Na2SO4), separated, and concentrated to give a colorless oil; yield: 0.56 g (71%, 5.5 mmol).

1H NMR (300 MHz, CDCl3): δ = 3.75 (m, 2 H), 3.45 (m, 1 H), 3.07 (m, 1 H), 3.01–2.81 (m, 3 H), 0.95 (d, J = 6.3 Hz, 3 H).

MS: m/z = 102 [M + 1].

Compounds 5b–x were synthesized by the general procedure. All the products except 5g and 5k have been reported in the literature.[1c] [12d] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] The 1H NMR spectra of the two new molecules 5g and 5k are presented in the Supporting Information. All the morpholine products have been used to synthesize new chemical entities of medicinal interest; this information is documented elsewhere.[20]


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(3R)-3-Methylmorpholine (5b)[22]

Colorless liquid; yield: 0.33 g (75%, 3.3 mmol).

1H NMR (300 MHz, CDCl3): δ = 0.95 (d, J = 6.6 Hz, 3 H), 2.82–3.02 (m, 3 H), 3.08 (t, J = 10.8 Hz, 1 H), 3.47 (m, 1 H), 3.71–3.81 (m, 2 H).

MS: m/z = 102 [M + 1].


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(3S)-3-Ethylmorpholine (5d)[23]

Colorless liquid; yield: 0.32 g (74%, 2.86 mmol).

1H NMR (300 MHz, DMSO-d6 ): δ = 0.80–0.87 (m, 3 H), 1.11–1.23 (m, 2 H), 2.66–2.72 (m, 2 H), 2.89–2.96 (m, 1 H), 3.21–3.31 (m, 2 H), 3.57–3.65 (m, 2 H), 9.64 (br s, 1 H).

MS: m/z = 116 [M + 1].


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(3R)-3-Ethylmorpholine (5e)[23]

Colorless liquid; yield: 0.32 g (72%, 2.78 mmol).

1H NMR (300 MHz, DMSO-d6 ): δ = 0.88–0.97 (m, 3 H), 1.46–1.72 (m, 2 H), 2.91–3.18 (m, 3 H), 3.46 (dd, J = 12.3, 10.2 Hz, 1 H), 3.71 (td, J = 11.8, 2.7 Hz, 1 H), 3.82–3.97 (m, 2 H), 9.68 (br s, 1 H).

MS: m/z = 116 [M + 1].


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3,3-Dimethylmorpholine (5f)[24]

Colorless liquid; yield: 0.35 g (80%, 3.09 mmol).

1H NMR (300 MHz, CDCl3): δ = 1.18 (s, 6 H), 2.88–2.91 (m, 2 H), 3.27–3.30 (m, 1 H), 3.33 (s, 2 H), 3.55–3.63 (m, 2 H).

MS: m/z = 116 [M + 1].


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9-Oxa-6-azaspiro[4.5]decane (5g)

Colorless viscous gel; yield: 0.49 g (90%, 2.90 mmol).

1H NMR (300 MHz, CDCl3): 1.43–1.75 (m, 8 H), 2.88 (t, J = 5.1 Hz, 3 H), 3.63 (t, J = 5.1 Hz, 3 H).

MS: m/z = 142 [M + 1].


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(2S)-2-Methylmorpholine (5h)[1c]

Viscous gel; yield: 0.31 g (70%, 3.04 mmol).

1H NMR (300 MHz, DMSO-d 6): δ = 1.10 (d, J = 6.3 Hz, 3 H), 2.66 (m, 1 H), 2.93 (m, 1 H), 3.18 (m, 2 H), 3.61–3.75 (m, 2 H), 3.89–3.94 (m, 1 H), 8.81 (br s, 1 H).

MS: m/z = 102 [M + 1].


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(3S)-3-Methyl-1,4-oxazepane (5j)[25]

Light-yellow gel; yield: 0.37 g (80%, 3.13 mmol).

1H NMR (300 MHz, DMSO-d6 ): δ = 1.05 (d, J = 6 Hz, 3 H), 1.55–1.65 (m, 2 H), 2.40–2.56 (m, 2 H), 2.90–2.96 (m, 1 H), 3.30–3.70 (m, 4 H), 8.80 (br s, 1 H).

MS: m/z = 116 [M + 1].


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(3S)-3-Methyl-1,4-oxazocane (5k)

Light-yellow liquid; yield: 0.33 g (72%, 2.51 mmol).

1H NMR (300 MHz, CDCl3): δ = 1.30 (d, J = 5.8 Hz, 3 H), 1.89–1.96 (m, 2 H), 3.13–3.21 (m, 2 H), 3.48–3.51 (m, 2 H), 3.62–3.67 (m, 2 H), 3.73–3.81 (m, 3 H), 8.86 (br s, 1 H).

MS: m/z = 131 [M + 1].


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(2R,3S)-2,3-Dimethylmorpholine (5l)[26]

Colorless liquid; yield: 0.37 g (83%, 3.21 mmol).

1H NMR (300 MHz, CDCl3): δ = 1.09 (d, J = 1.8 Hz, 3 H), 1.11 (d, J = 1.5 Hz, 3 H), 2.62–2.69 (m, 1 H), 2.90–2.93 (m, 1 H), 3.00–3.08 (m, 1 H), 3.52–3.60 (m, 1 H), 3.72–3.84 (m, 2 H).

MS: m/z = 116 [M + 1]


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2,6-Dimethylmorpholine (5n)[27]

Colorless liquid; yield: 0.35 g (80%, 3.09 mmol).

1H NMR (300 MHz, CDCl3): δ (major) = 1.13 (d, J = 6.3 Hz, 3 H, CH3), 1.21 (d, J = 6.3 Hz, 3 H, CH3), 2.51–2.57 (ABX, 2 H, CH), 2.91–2.96 (ABX, 2 H, CH), 3.88–3.97 (m, 2 H); δ (minor) = 1.21 (d, J = 6.3 Hz, 6 H, 2 × CH3), 2.38–2.46 (ABX, 2 H, CH), 2.80–2.85 (ABX, 2 H, CH), 3.52–3.63 (m, 2 H).

MS: m/z = 116 [M + 1].


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(2R,5S)-2,5-Dimethylmorpholine (5q)[28]

Colorless liquid; yield: 0.35 g (80%, 3.09 mmol).

1H NMR (300 MHz, CDCl3): δ = 0.95 (d, J = 6.3 Hz, 3 H), 1.12 (d, J = 6.3 Hz, 3 H), 2.58 (dd, J = 10.2, 2.1 Hz, 1 H), 2.77 (d, J = 3.9 Hz, 1 H), 2.77–2.98 (m, 2.5 H), 3.53–3.72 (m, 1.5 H), 8.89 (br s, 1 H).

MS: m/z = 116 [M + 1]


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(2R,3S,6S)-2,3,6-Trimethylmorpholine (5t)[29]

Colorless liquid; yield: 0.33 g (72%, 2.51 mmol).

1H NMR (300 MHz, CDCl3): 0.85 (d, J = 6.3 Hz, 3 H), 0.97 (d, J = 6.0 Hz, 3 H), 0.98 (d, J = 6.0 Hz, 3 H), 2.41–2.42 (m, 1 H), 2.57–2.64 (m, 4 H), 3.38–3.46 (m, 1 H).

MS: m/z = 130 [M + 1]


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3,4-Dihydro-2H-1,4-benzoxazine (5u)[30]

Brown liquid; yield: 0.32 g (72%, 2.41 mmol).

1H NMR (300 MHz, CDCl3): δ = 3.41–3.44 (m, 2 H), 3.74 (br s, 1 H), 4.24–4.27 (m, 2 H), 6.54–6.68 (m, 2 H), 6.73–6.79 (m, 2 H).

MS: m/z = 136 [M + 1].


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(±)-(4aR*,8aR*)-Octahydro-2H-1,4-benzoxazine (5v)[12d]

Light-yellow liquid; yield: 0.37 g (82%, 2.64 mmol).

1H NMR (300 MHz, CDCl3): δ = 1.22–1.46 (m, 4 H), 1.66–1.68 (m, 2 H), 1.82–1.90 (m, 2 H), 2.72–2.85 (m, 1 H), 2.98–3.20 (m, 2 H), 3.40–3.46 (m, 1 H), 3.73–3.82 (m, 1 H), 3.88–3.93 (m, 1 H), 9.55 (br s, 1 H).

MS: m/z = 142 [M + 1].


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(±)-(4aS*,7aS*)-Octahydrocyclopenta[b][1,4]oxazine (5w)[31]

Light-brown oil; yield: 0.38 g (84%, 2.97 mmol).

1H NMR (300 MHz, DMSO-d6 ): δ = 1.38–1.72 (m, 4 H), 1.86 (m, 2 H), 2.82–3.05 (m, 2 H), 3.21 (m, 1 H), 3.64 (m, 1 H), 3.76 (m, 1 H), 4.01 (m, 1 H), 9.8 (br s, 1 H).

MS: m/z = 128 [M + 1]


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(2S)-2-Aminopropan-1-ol; Multigram Synthesis

Anhyd THF (1.5 L) was placed in a three-necked, 5-L, round-bottom flask, and cooled to 0 °C. LAH (59 g, 1.5 mol) was carefully added, maintaining a temperature of 0 °C. l-Alanine (70 g, 0.78 mol) was then added portionwise at 0 °C over 45 min. The mixture was slowly allowed to warm to r.t. and then refluxed for 24 h. When the reaction was complete, the mixture was cooled to 0 °C, the reaction was quenched with sat. aq K2CO3 (100 mL), and the mixture was stirred for 1 h. A 5% soln of MeOH in CH2Cl2 (2 L) was added, and the mixture was stirred for an additional 1 h. The mixture was then filtered through a Celite pad, and the filtrate was dried (Na2SO4) and concentrated to give a colorless oil; yield: 55 g (85%).


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2-Chloro-N-[(1S)-2-hydroxy-1-methylethyl]acetamide (3a); Multigram Synthesis

A solution of K2CO3 (303.5 g, 2.19 mol) in H2O (600 mL) was added to a solution of (2S)-2-aminopropan-1-ol (55 g, 0.73 mol) in THF (1 L) at –10 °C. ClCH2COCl (65 mL, 0.80 mol) was added slowly from a dropping funnel at –10 °C with a vigorous stirring, and the mixture was stirred at –10 °C for 1 h. The mixture was poured into H2O (50 mL) and extracted with CH2Cl2 (3 × 500 mL). The organic layer was dried (Na2SO4), filtered, and concentrated to give a colorless oil; yield: 95 g (85%).


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(5S)-5-Methylmorpholin-3-one (4a); Multigram Synthesis

t-BuOK (307 g, 2.51 mol) in i-PrOH (1 L) was added dropwise to a solution of acetamide 3a (95 g, 0.62 mol) in CH2Cl2 (1 L) at 0 °C, and the solution was stirred at r.t. for 1 h. The mixture was neutralized to pH 7 with 2 M aq HCl. The solvent was removed under reduced pressure to give white solid. The solid was taken up in EtOAc (3 × 500 mL) and the solution washed with H2O (3 × 250 mL). The organic layer was separated, dried (Na2SO4), filtered, and concentrated to give a colorless oil; yield: 60 g (83%).


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(3S)-3-Methylmorpholine (5a);[22] Multigram Synthesis

LAH (59.32 g, 1.51 mol) in THF (1 L) was cooled to 0 °C in an ice bath. A solution of morpholinone 4a (60 g, 0.52 mol) in THF (500 mL) was added dropwise, and the solution was stirred at r.t. for 16 h. The mixture was then cooled to 0 °C and the reaction was carefully quenched by successive addition of H2O (2 mL), 2 M aq NaOH (35 mL), and H2O (70 mL). The resulting slurry was stirred at r.t. for 1 h then filtered through Celite. The filter cake was washed with EtOAc (4 × 250 mL) and discarded. The filtrate was dried (Na2SO4), separated, and concentrated to give a colorless oil; yield: 45 g (86%).


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Supporting Information

    Supporting information for this article is available online at http://dx.doi.org.accesdistant.sorbonne-universite.fr/10.1055/s-0034-1379641. Detailed experimental procedures and spectroscopic information are provided.
  • Supporting Information


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Figure 1
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Scheme 1 Retrosynthetic analysis
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Scheme 2 General synthetic scheme for morpholine synthesis
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Figure 2 NOESY signal assignment for morpholinone 4r.
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Figure 3 NOESY signal assignment for morpholinone 4t
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Scheme 3