Synlett 2021; 32(05): 525-531
DOI: 10.1055/s-0040-1707902
cluster
The Power of Transition Metals: An Unending Well-Spring of New Reactivity
© Georg Thieme Verlag Stuttgart · New York

Iron-Catalyzed Diastereoselective Synthesis of Disubstituted Morpholines via C–O or C–N Bond Formation

,
Alexandre Dupas
,
Tian Zeng
,
Further Information

Publication History

Received: 28 April 2020

Accepted after revision: 23 June 2020

Publication Date:
23 July 2020 (online)

 


In expression of our deepest gratitude to Prof. Barry M. Trost.

Abstract

The diastereoselective synthesis of 2,6- and 3,5-disubstituted morpholines was achieved from 1,2-amino ethers and 1,2-hydroxy amines substituted by an allylic alcohol using an iron(III) catalyst. The morpholines were obtained either by C–O or C–N bond formation. A plausible mechanism is suggested, involving a thermodynamic equilibrium to explain the formation of the cis diastereoisomer as the major product.


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Nitrogen- and oxygen-containing heterocycles are present in a great diversity of compounds. Morpholine, which contains these two heteroatoms, has a high industrial importance and a wide range of applications from rubber additives to optical brighteners.[1] Moreover, the morpholine scaffold is frequently encountered in biologically active compounds.[2] Therefore, a variety of methods has been developed to access this heterocycle,[3] such as the use of vinyl sulfonium salts along with amino alcohols,[4] the ring-opening of epoxides or aziridines,[5] or the electrochemical activation of C=C double bonds.[6] In the field of metal-catalyzed synthesis of morpholines,[3f] several strategies have been developed depending on which bond is constructed (i.e. C–N, C–O, or C–C bond). In particular, the formation of the C–O bond by activation of allylic alcohols have attracted our interest. For example, Saikia et al. have described the diastereoselective synthesis of cis-2,6-disubstituted morpholines B via the activation of (Z)-allylic alcohols A using a Pd(II) catalyst, followed by the intramolecular addition of an alcohol.[7] Bandini et al. reported a similar transformation, with the help of a cationic gold catalyst, starting from C.[8]

In the context of our studies concerning the use of iron salts for the diastereoselective synthesis of disubstituted heterocycles by activation of allylic alcohols,[9] we have envisioned that iron salts like iron trichloride could also induce the formation of disubstituted morpholines F and H from the corresponding substituted amino alcohols E and G (Scheme [1])

Zoom Image
Scheme 1 Metal-catalyzed activation of allylic alcohols to access disubstituted morpholines

The synthesis of the amino allylic alcohols 6ai, precursors of 2,6-disubtituted morpholines F, was achieved from the commercially available amino acetaldehyde dimethyl acetal 1 according to the sequence depicted in Scheme [2]. After protection of the amine with a tosyl group, the sulfonamide 2 was transformed into the propargyl amine 3 in 95% yield (propargyl bromide, K2CO3, acetone, reflux), which was then used as a platform to access a diversity of amino allylic alcohols 6. Deprotonation of the acetylenic moiety (n-BuLi, THF) and addition of an aldehyde (R1 = Ph, Me, H) led to the corresponding propargylic alcohols 4ac. Cleavage of the acetal moiety under acidic conditions (PTSA, 100 °C) led to an aldehyde intermediate, which was transformed by addition of a nucleophile into different secondary alcohols 5ai. Finally, the partial reduction of the acetylenic bond (LiAlH4, THF, 0 °C to rt) gave the desired allylic alcohols 6ai. (Scheme [2])

Zoom Image
Scheme 2 Synthesis of the 2,6-disubstituted morpholines precursors

A second strategy was employed for the synthesis of amino allylic alcohols 10ad precursors of 3,5-disubstituted morpholines H. Propargyl ethers 8ad were obtained by the regioselective opening of monosubstituted aziridines 7ad by the propargylic alcohol in DMSO under basic conditions (t-BuOK, DMSO).[10] The terminal triple bond was then functionalized by addition of the lithium acetylide on the benzaldehyde. The resultant propargyl alcohols 9ad were partially reduced, as previously, by LiAlH4 to the corresponding allylic alcohols 10ad (Scheme [3]).

Zoom Image
Scheme 3 Synthesis of the 3,5-disubstituted morpholines precursors

In order to test the heterocyclization, 6a was treated with FeCl3·6H2O (5 mol%) in CH2Cl2 at room temperature. After only 15 minutes, full conversion of 6a was observed, and the monosubstituted morpholine 11a was isolated in good yield (77%) (Scheme [4]).

Zoom Image
Scheme 4 Iron-catalyzed heterocyclization – formation of the C–O bond

To evaluate the diastereoselectivity, the hexyl-substituted N-tethered amino alcohol 6b was first chosen for the optimization of the reaction conditions. When 6b was treated with 5 mol% of FeCl3·6H2O (CH2Cl2, 24 h) morpholine 11b was obtained as a mixture of two diastereoisomers (cis/trans = 54:46; Table [1], entry 1). The same ratio was obtained with an increased catalyst loading (10 mol%) and an extended reaction time (48 h), while morpholine 11b was isolated in good yield (81%; entry 2). The temperature of the reaction was found to be a critical parameter. Indeed, heating the reaction mixture up to 50 °C led to a great improvement of the diastereoisomeric outcome. After 15 min at 50 °C, the cis/trans ratio was 60:40 and, after 2 h, the cis diastereoisomer was obtained as the major product (cis/trans = 94:6; entries 3 and 4). Under the same conditions, other Lewis or Brønsted acids led to either low diastereoselectivity or the degradation of the products. For example, bismuth(III) triflate and indium(III) chloride efficiently catalyze the cyclization, but, in each case, the morpholine was formed as a mixture of two diastereoisomers (cis/trans = 64:36 and 54:46, respectively; entries 5 and 6). Palladium(II) acetate was, for its part, found to be totally inefficient in this transformation (entry 7). Brønsted acids were also tested. While the use of HCl in Et2O led to the formation of the 2,6-disubstitued morpholines albeit with no diastereoselectivity (entry 8), the use of triflic acid (TfOH) led to the complete degradation of the starting material (entry 9).

Table 1 Optimization of the Reaction Conditions to Access 2,6-Disubstuted Morpholinesa

Entry

Lewis acid

x (mol%)

Time (h)

Temp ( °C)

Yield (%)

cis/trans b

1

FeCl3·6H2O

 5

24

rt

n.d.c

54:46

2

10

48

rt

81

54:46

3

10

 0.25

50

n.d.

60:40

4

10

 2

82

94:6

5

Bi(OTf)3

10

 2

50

69

64:36

6

InCl3

10

 2

50

73

54:46

7

Pd(OAc)2

10

 2

d

8

HCle

10

 2

79

51:49

9

TfOH

10

 2

f

a Compound 6b was dissolved in CH2Cl2 in a tube. The Lewis acid was added to the solution, the tube was sealed, and the mixture stirred at rt or 50 °C during the specified time.

b The dr was measured by 1H NMR spectroscopy of the crude reaction mixture after a short filtration through a plug of silica to remove the iron salts, and eluted with CH2Cl2.

c Not determined.

d No conversion.

e HCl in Et2O.

f Degradation of the starting material.

Zoom Image
Scheme 5 FeCl3·6H2O-catalyzed synthesis of cis-2,6-disubstituted morpholines

The optimized conditions were then applied to the previously synthesized amino alcohols 6 in order to access a diversity of 2,6-disubstituted morpholines. The isopropyl-substituted substrate 6c led to the corresponding morpholine 11c with a good yield of 77% and a high dr in favor of the cis diastereoisomer (cis/trans = 94:6). Similarly, the trifluoromethylated morpholine 11d was isolated with a yield of 75% and a slightly lower dr than for 11c (cis/trans = 90:10). The presence of a vinyl moiety has no influence on the reaction, as 11e was obtained in 80% yield with a cis/trans ratio of 92:8, while the phenyl-substituted substrate 6f led to 11f with a high yield of 89% (cis/trans = 95:5). Interestingly, a furyl-substituted morpholine 11g can also be obtained. As the furyl group tends to polymerize under the reaction conditions, the reaction was stopped after only 30 min, which may explain the low dr of 11g (cis/trans = 60:40) (Scheme [5]).

The enantioenriched amino alcohol (R)-6f [11] was also involved in the heterocyclization. After 2 h at 50 °C, the enantioenriched morpholine (2S,6R)-11f was obtained with an excellent yield of 89%, a high diastereoselectivity (cis/trans = 95:5) and a high ee of 95% (cis diastereoisomer).[12] This result shows that the stereocenter of 6f is recovered in 11f and that the configuration of the C2 stereocenter is induced by the configuration of the C6 center (Scheme [6]).

Zoom Image
Scheme 6 Formation of an enantioenriched morpholine

Table 2 Influence of the Allylic Substitution

Entry

R1

Solvent

Temp ( °C)

Yield (%)

cis/trans

1

Me

CH2Cl2

 50

80

50:50

2

C2H4Cl2

100

97

92:8

3

H

CH2Cl2

 50

 0a

4

C2H4Cl2

100

50

50:50

a No conversion of 6i.

To evaluate the importance of the substituent of the allylic alcohol, 6h (R1 = Me) and 6i (R1 = H) were also treated with FeCl3·6H2O. In dichloromethane at 50 °C for 2 h, 6h was transformed to the corresponding morpholine 11h with a good yield of 80%, however, without any diastereoselectivity (cis/trans = 50:50; Table [2], entry 1). The reaction medium had to be heated up to 100 °C in dichloroethane (DCE), in a sealed tube, to obtain an excellent yield in 11h (97%) and a cis/trans ratio of 92:8 in favor of the cis diastereoisomer (entry 2). Compound 6i, incorporating a primary allylic alcohol, was subjected to similar conditions. At 50 °C in CH2Cl2, no cyclization occurred. At 100 °C in DCE the vinyl-substituted morpholine 11i was isolated with a modest yield of 50% but without any diastereoselectivity (entries 3 and 4). These results show that a stabilizing electron-donating group favors the heterocyclization and is mandatory to induce a good diastereoselectivity (vide infra).

Having demonstrated the efficiency of FeCl3 as a catalyst for the formation of 2,6-disubstituted morpholines, we hypothesized that similar conditions could be applied to adequate substrates to lead to 3,5-disubstituted morpholines. In the same manner as before, the unsubstituted amino ether 10a was treated with a catalytic amount of FeCl3·6H2O (5 mol%) in CH2Cl2, at room temperature. After 15 min, the monosubstituted morpholine 12a was isolated with a good yield of 81% (Scheme [7]).

Zoom Image
Scheme 7 Iron-catalyzed heterocyclization: formation of the C–N bond

Compound 10b was chosen for the optimization of the reaction conditions. The amino ether was first treated with 5 mol% of FeCl3·H2O in CH2Cl2 (rt, 2 h). Although the expected morpholine was isolated in 75% yield, analysis of the crude reaction mixture by 1H NMR spectroscopy showed an unexpected cis/trans ratio of 36:64 (Table [3], entry 1). When the reaction was run for 168 h, the dr slowly evolved to reach a 1 to 1 ratio of diastereoisomers (cis/trans = 52:48; entry 2). Increasing the catalyst loading to 10 mol% resulted in an improvement of the dr, as morpholine 12b was isolated as an 83:17 mixture of cis and trans diastereoisomers after 168 h (entry 3). Once again, the temperature was found to be of importance for the outcome of the cyclization. When 10b was treated with 10 mol% of FeCl3·6H2O, in CH2Cl2 at 30 °C for 30 h, a similar yield in morpholine was observed (75%) and the dr went up to 90:10 in favor of the cis compound (entry 4). At 40 °C, it took only 1 h to reach the full conversion of 10b, and the 3,5-disubstituted morpholine 12b was formed with a good yield of 77% and with a good dr (cis/trans = 90:10; entry 5). It is worth noting that by further increasing of the temperature, a degradation of the morpholine was observed, without any change in the dr (entries 6 and 7).[13] Other Lewis or Brønsted acids were also examined for this heterocyclization, but none of them gave as good results as iron trichloride (entries 8–11).

Table 3 Optimization of the Reaction Conditions for the Synthesis of 3,5-Disubstituted Morpholinesa

Entry

Lewis acid

x (mol%)

Time (h)

Temp ( °C)

Yield (%)

cis/trans b

 1

FeCl3·6H2O

 5

  2

rt

75

36:64

 2

 5

168

rt

75

52:48

 3

10

168

rt

76

83:17

 4

10

 30

30

75

90:10

 5

10

  1

40

77

90:10

 6

10

  2.5

40

n.d.c

90:10

 7

10

  1

50

n.d.c

90:10

 8

Bi(OTf)3

10

  2

40

70

90:10

 9

InCl3

10

  2

40

35

36:64

10

PdCl2

10

  2

40

d

11

HCle

10

  2

40

16f

36:64

a Compound 10b was dissolved in CH2Cl2 in a tube. The Lewis acid was added to the solution, the tube was sealed, and the mixture stirred at rt or 50 °C during the specified time.

b The dr was measured by 1H NMR spectroscopy of the crude reaction mixture after a short filtration through a plug of silica plug to remove the iron salts and eluted with CH2Cl2.

c Not determined.

d No conversion.

e HCl in Et2O.

f Partial degradation of the starting material or of the product.

The optimized conditions were next applied to the previously synthesized amino ethers 10ce. When 10c, substituted by an isopropyl group was subjected to the heterocyclization, the corresponding 3,5-disubstituted morpholine 12c was isolated with a good yield (78%) and a good dr (cis/trans = 93:7). The amino ether 10d, incorporating a phenyl group led, for its part, to the corresponding morpholine 12d in 70% yield (cis/trans = 83:17). Finally, the α,α-dimethyl amino ether 10e led to the 3,5,5-trisubstituted morpholine 12e with a modest yield of 60%, probably because of the steric hindrance next to the nitrogen (Scheme [8]).

Zoom Image
Scheme 8 FeCl3·6H2O-catalyzed synthesis of cis-3,5-disubstituted morpholines

During the optimization process, it has been highlighted that the dr evolves with time, suggesting an equilibration process (Table [1], entries 3 and 4; Table [3] entries 1 and 2). The results obtained with substrates 6h and 6i, bearing different substituents at the allylic position, suggest that the presence of an electron-donating group is required to produce morpholines in good yields and diastereoselectivity (Table [2]). Thus, it may be hypothesized that the cyclization process proceeds through a carbocation. From our previous results in iron-catalyzed heterocycle synthesis,[9] the following mechanism could be proposed for both the 2,6- and the 3,5-disubstitued morpholines. The activation of the allylic alcohols E and G by FeCl3 could promote the loss of water and the formation of a delocalized carbocation (J and L), stabilized by the substituent of the allylic alcohol. The intramolecular attack of the oxygen or the nitrogen would lead to the morpholines F and H, respectively, as a mixture of cis and trans diastereoisomers. At this point, an iron-induced thermodynamic equilibrium could take place, by a ring-opening/ring-closing process, toward the formation of the more stable cis diastereoisomer. This equilibrium would be even easier if the carbocation is stabilized by an electron-donating group, explaining why a better diastereoselectivity is observed when starting from benzylic allylic alcohols rather than methyl- or unsubstituted allylic alcohols (Scheme [9]).

Zoom Image
Scheme 9 Plausible mechanisms for the iron-catalyzed heterocyclization

To explain why the cis diastereoisomer is always predominant after the thermodynamic equilibrium, the relative stability of each of the two diastereoisomers has to be compared, regarding the spatial orientation of their substituents. In the case of the 2,6-disubstituted morpholines F, the cis diastereoisomer, whose two substituents stand in an equatorial position, is more stable than the trans diastereoisomer. Indeed, in the trans diastereoisomer, one of the two substituents has to be axial, thus generating unfavorable 1,3-diaxial interactions with the hydrogen at C6 (Scheme [10]).

Zoom Image
Scheme 10 Relative stability of cis and trans diastereoisomers in 2,6-disubstituted morpholines

Regarding the 3,5-disubtituted morpholine H, a similar reasoning can be applied. However, the presence of the N-tosyl group has to be considered (Scheme [11]). Indeed, it has been described that the N–S bond in sulfonamides has a partial double bond character.[14a] Crystallographic data previously obtained for 2,6-disubstituted N-tosyl piperidines also suggest that the SO2 moiety is in an equatorial position.[14b] Therefore, substituents α to the nitrogen may promote 1,3-allylic interactions with the N-tolyl group if they stand in an equatorial position.[15] For this reason, a cis diaxial diastereoisomer would be more stable than a trans one, in spite of diaxial interactions between the R3 group at C5 and the styrenyl group at C3. Actually, this steric interaction may be the cause of the lower dr observed for 3,5- compared to 2,6-disubstituted morpholines as the difference in energy between the two diastereoisomers may be smaller.

Zoom Image
Scheme 11 Relative stability of cis and trans diastereoisomers in 3,5-disubstituted morpholines

Postfunctionalization of the synthesized 2,6-disubstituted morpholines 11 was then envisaged. The amino moiety in 11b can be deprotected with magnesium powder under ultrasonic activation[16] leading to morpholine 13 in good yield (88%). It is worth noting that the dr remains intact during this process. The styrenic double bond can also be transformed to introduce a new substituent on the morpholine ring. Oxidative cleavage under classical conditions (OsO4, NMO then NaIO4) followed by the reduction of the subsequent aldehyde (NaBH4, EtOH) led to the primary alcohol 14 with an excellent yield (82% from 11b; Scheme [12]).[17]

Zoom Image
Scheme 12 Synthetic transformations of the 2,6-disubstituted morpholine 11b

Similarly, 3,5-disubstituted morpholines can be postfunctionalized. The amino group in 12b can be deprotected using the same conditions as before (Mg, MeOH, ultrasound) to produce the secondary amine 15 in 66% yield (cis/trans = 91:9).[18] The styrenyl moiety can also be cleaved under oxidative conditions (OsO4, NMO then NaIO4) and the primary alcohol 16 was obtained after reduction of the resulting aldehyde (NaBH4, EtOH) with a yield of 67% (from 12b) and with an unchanged cis/trans ratio of 90:10 (Scheme [13]).

Zoom Image
Scheme 13 Synthetic transformations of the 3,5-disubstituted morpholine 12b

Iron trichloride has been successfully used for the synthesis of both 2,6- and 3,5-disubtituted morpholines by promoting the formation of either a C–O or a C–N bond. This catalyst constitutes a cheap and environmentally benign alternative to palladium and gold catalysts. In each case, the substituted morpholines were isolated mostly as cis diastereoisomers, as the result of a thermodynamic equilibrium occurring by a ring-opening/ring-closing process.[19] Post-transformations of the obtained morpholines were also achieved, showing that they can be used as a platform to access libraries of complex molecules.


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Supporting Information

  • References and Notes

  • 1 Mjos K. In Kirk-Othmer Encyclopaedia of Chemical Technology, 3rd ed., Vol. 2. Wiley Interscience; New York: 1978: 295-308
  • 2 Vitaku E, Smith DT, Njardarson JT. J. Med. Chem. 2014; 57: 10257

    • For reviews on the synthesis of morpholines and derivatives, see:
    • 3a Pal’chikov VA. Russ. J. Org. Chem. 2013; 49: 787
    • 3b Wijtmans R, Vink M.K. S, Schoemaker HE, van Delft FL, Blaauw RH, Rutjes FP. J. T. Synthesis 2004; 641
    • 3c Trstenjak U, Ilaš J, Kikelj D. Synthesis 2012; 44: 3551
    • 3d Varela J, Saá C. Synthesis 2016; 48: 3470
    • 3e Palchykov VA, Chebanov VA. Chem. Heterocycl. Compd. 2019; 55: 324
    • 3f Aubineau T, Cossy J. Chem. Eur. J. 2019; 46: 7513
    • 3g Tzara A, Xanthopoulos D, Kourounakis AP. ChemMedChem 2020; 15: 392
  • 4 Yar M, Fritz SP, Gates PJ, McGarrigle EM, Aggarwal VK. Eur. J. Org. Chem. 2012; 160
    • 5a Jiao P.-F, Zhao B.-X, Wang W.-W, He Q.-X, Wan M.-S, Shin D.-S, Miao J.-Y. Bioorg. Med. Chem. Lett. 2006; 16: 2862
    • 5b Wang L, Liu Q.-B, Wang D.-S, Li X, Han X.-W, Xiao W.-J, Zhou Y.-G. Org. Lett. 2009; 11: 1119
  • 6 Claraz A, Courant T, Masson G. Org. Lett. 2020; 22: 1580
  • 7 Borah M, Borthakur U, Saikia AK. J. Org. Chem. 2017; 82: 1330
  • 8 Bandini M, Monari M, Romanello A, Tragni M. Chem. Eur. J. 2010; 16: 14272
  • 9 Cornil J, Gonnard L, Bensoussan C, Serra-Muns A, Gnamm C, Commandeur C, Commandeur M, Reymond S, Guérinot A, Cossy J. Acc. Chem. Res. 2015; 48: 761
  • 10 Nyasse B, Grehn L, Ragnarsson U.  Chem. Commun. 1997; 11: 1017
  • 11 See the Supporting Information for the synthesis of substrate (R)-6f.
  • 12 The ee has been measured by chiral SFC of the 2-hydroxymethylenic morpholine obtained after oxidative cleavage of the styrenic moiety.
  • 13 Attempts to favor the formation of the trans diastereoisomer at temperature lower than rt were unsuccessful.
    • 14a Modaressi-Alam AR, Amirazizi HA, Bagheri H, Bijanzadeh H.-R, Kleinpeter E. J. Org. Chem. 2009; 74: 4740
    • 14b Guérinot A, Serra-Muns A, Gnamm C, Bensoussan C, Reymond S, Cossy J. Org. Lett. 2010; 12: 1808 ; the possibility to have the SO2 group in an axial position cannot be totally ruled out

      This has been observed on piperidines substrates. See for example:
    • 15a Cariou CA. M, Snaith JS. Org. Biomol. Chem. 2006; 4: 51
    • 15b Toumieux S, Compain P, Martin OR, Selkti M. Org. Lett. 2006; 8: 4493
    • 15c Kishore Vandavasi J, Hu W.-P, Chandru Senadi G, Chen H.-T, Chen H.-Y, Hsieh K.-C, Wang J.-J. Adv. Synth. Catal. 2015; 357: 2788
  • 16 Nyasse B, Grehn L, Ragnarsson U. Chem. Commun. 1997; 11: 1017
  • 17 The cis/trans ratio could not be measured because of overlapping signals in the 1H NMR spectrum.
  • 18 Measured by GC/MS analysis of the crude mixture.
  • 19 Experimental Procedure for the Synthesis of 2,6- or 3,5-Disubstituted Morpholines In a tube was added the amino alcohol in CH2Cl2. FeCl3·6H20 was then added to the solution, the tube was sealed, and the mixture was heated at the specified temperature for 1–2 h. After cooling, the suspension was filtered through a short plug of silica gel, and elution was achieved with CH2Cl2 to remove the iron salts. The filtrate was concentrated under vacuum to afford the morpholine which was in most cases recovered as a pure product. Purification by flash chromatography on silica gel was performed if needed. cis-(E)-2-Isopropyl-6-styryl-4-tosylmorpholine (10c) 1H NMR (400 MHz, CDCl3): δ = 7.64 (d, J = 8.1 Hz, 2 H), 7.40–7.18 (m, 7 H), 6.73–6.59 (m, 1 H), 6.06 (dd, J = 16.1, 5.6 Hz, 1 H), 4.29–4.19 (m, 1 H), 3.68 (dapp, J = 11.3 Hz, 2 H), 3.41–3.29 (m, 1 H), 2.43 (s, 3 H), 2.05 (ddapp, J = 21.7, 10.8 Hz, 2 H), 1.77–1.65 (m, 1 H), 0.98 (d, J = 6.8 Hz, 3 H), 0.93 (d, J = 6.8 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 143.9, 136.3, 132.3, 132.1, 129.8 (2 C), 128.6 (2 C), 128.0, 127.8 (2 C), 126.6 (2 C), 126.1, 80.1, 75.6, 50.0, 47.7, 31.6, 21.6, 18.6, 18.4. MS (EI, 70 eV): m/z (abundance) = 385 (3, M+•), 281 (14), 230 (29), 130 (16), 129 (12), 115 (10), 98 (100), 91 (30), 69 (16), 56 (16). HRMS: m/z calcd for C22H28NO3S [M + H]+: 386.1784; found: 386.1789. cis-(E)-3-Isopropyl-5-styryl-4-tosylmorpholine (12c) 1H NMR (400 MHz, CDCl3): δ = 7.76 (d, J = 8.2 Hz, 2 H), 7.38–7.19 (m, 7 H), 6.67 (dd, J = 16.2, 1 H), 6.56–6.41 (m, 1 H), 4.45–4.35 (m, 1 H), 3.92 (d, J = 11.8 Hz, 1 H), 3.87 (d, J = 12.0 Hz, 1 H), 3.38 (dd, J = 10.9, 3.4 Hz, 1 H), 3.20 (dd, J = 11.9, 4.0 Hz, 1 H), 3.11 (dd, J = 12.0, 3.6 Hz, 1 H), 2.43 (s, 3 H), 2.32–2.23 (m, 1 H), 1.05 (d, J = 6.7 Hz, 3 H), 0.94 (d, J = 6.7 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 143.4, 138.7, 136.6, 132.8, 130.0 (2 C), 128.7 (2 C), 127.9, 127.7, 127.0 (2 C), 126.5 (2 C), 69.1, 66.6, 59.6, 52.9, 28.4, 21.6, 20.6, 20.2. MS (EI, 70 eV): m/z (abundance) = 342 (23), 268 (19), 187 (11), 171 (16), 156 (12), 155 (37), 130 (16), 129 (26), 128 (11), 117 (33), 115 (27), 91 (100), 69 (14), 65 (15). HRMS: m/z calcd for C22H27NNaO3S [M + Na]+: 408.1604; found: 408.1606.

  • References and Notes

  • 1 Mjos K. In Kirk-Othmer Encyclopaedia of Chemical Technology, 3rd ed., Vol. 2. Wiley Interscience; New York: 1978: 295-308
  • 2 Vitaku E, Smith DT, Njardarson JT. J. Med. Chem. 2014; 57: 10257

    • For reviews on the synthesis of morpholines and derivatives, see:
    • 3a Pal’chikov VA. Russ. J. Org. Chem. 2013; 49: 787
    • 3b Wijtmans R, Vink M.K. S, Schoemaker HE, van Delft FL, Blaauw RH, Rutjes FP. J. T. Synthesis 2004; 641
    • 3c Trstenjak U, Ilaš J, Kikelj D. Synthesis 2012; 44: 3551
    • 3d Varela J, Saá C. Synthesis 2016; 48: 3470
    • 3e Palchykov VA, Chebanov VA. Chem. Heterocycl. Compd. 2019; 55: 324
    • 3f Aubineau T, Cossy J. Chem. Eur. J. 2019; 46: 7513
    • 3g Tzara A, Xanthopoulos D, Kourounakis AP. ChemMedChem 2020; 15: 392
  • 4 Yar M, Fritz SP, Gates PJ, McGarrigle EM, Aggarwal VK. Eur. J. Org. Chem. 2012; 160
    • 5a Jiao P.-F, Zhao B.-X, Wang W.-W, He Q.-X, Wan M.-S, Shin D.-S, Miao J.-Y. Bioorg. Med. Chem. Lett. 2006; 16: 2862
    • 5b Wang L, Liu Q.-B, Wang D.-S, Li X, Han X.-W, Xiao W.-J, Zhou Y.-G. Org. Lett. 2009; 11: 1119
  • 6 Claraz A, Courant T, Masson G. Org. Lett. 2020; 22: 1580
  • 7 Borah M, Borthakur U, Saikia AK. J. Org. Chem. 2017; 82: 1330
  • 8 Bandini M, Monari M, Romanello A, Tragni M. Chem. Eur. J. 2010; 16: 14272
  • 9 Cornil J, Gonnard L, Bensoussan C, Serra-Muns A, Gnamm C, Commandeur C, Commandeur M, Reymond S, Guérinot A, Cossy J. Acc. Chem. Res. 2015; 48: 761
  • 10 Nyasse B, Grehn L, Ragnarsson U.  Chem. Commun. 1997; 11: 1017
  • 11 See the Supporting Information for the synthesis of substrate (R)-6f.
  • 12 The ee has been measured by chiral SFC of the 2-hydroxymethylenic morpholine obtained after oxidative cleavage of the styrenic moiety.
  • 13 Attempts to favor the formation of the trans diastereoisomer at temperature lower than rt were unsuccessful.
    • 14a Modaressi-Alam AR, Amirazizi HA, Bagheri H, Bijanzadeh H.-R, Kleinpeter E. J. Org. Chem. 2009; 74: 4740
    • 14b Guérinot A, Serra-Muns A, Gnamm C, Bensoussan C, Reymond S, Cossy J. Org. Lett. 2010; 12: 1808 ; the possibility to have the SO2 group in an axial position cannot be totally ruled out

      This has been observed on piperidines substrates. See for example:
    • 15a Cariou CA. M, Snaith JS. Org. Biomol. Chem. 2006; 4: 51
    • 15b Toumieux S, Compain P, Martin OR, Selkti M. Org. Lett. 2006; 8: 4493
    • 15c Kishore Vandavasi J, Hu W.-P, Chandru Senadi G, Chen H.-T, Chen H.-Y, Hsieh K.-C, Wang J.-J. Adv. Synth. Catal. 2015; 357: 2788
  • 16 Nyasse B, Grehn L, Ragnarsson U. Chem. Commun. 1997; 11: 1017
  • 17 The cis/trans ratio could not be measured because of overlapping signals in the 1H NMR spectrum.
  • 18 Measured by GC/MS analysis of the crude mixture.
  • 19 Experimental Procedure for the Synthesis of 2,6- or 3,5-Disubstituted Morpholines In a tube was added the amino alcohol in CH2Cl2. FeCl3·6H20 was then added to the solution, the tube was sealed, and the mixture was heated at the specified temperature for 1–2 h. After cooling, the suspension was filtered through a short plug of silica gel, and elution was achieved with CH2Cl2 to remove the iron salts. The filtrate was concentrated under vacuum to afford the morpholine which was in most cases recovered as a pure product. Purification by flash chromatography on silica gel was performed if needed. cis-(E)-2-Isopropyl-6-styryl-4-tosylmorpholine (10c) 1H NMR (400 MHz, CDCl3): δ = 7.64 (d, J = 8.1 Hz, 2 H), 7.40–7.18 (m, 7 H), 6.73–6.59 (m, 1 H), 6.06 (dd, J = 16.1, 5.6 Hz, 1 H), 4.29–4.19 (m, 1 H), 3.68 (dapp, J = 11.3 Hz, 2 H), 3.41–3.29 (m, 1 H), 2.43 (s, 3 H), 2.05 (ddapp, J = 21.7, 10.8 Hz, 2 H), 1.77–1.65 (m, 1 H), 0.98 (d, J = 6.8 Hz, 3 H), 0.93 (d, J = 6.8 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 143.9, 136.3, 132.3, 132.1, 129.8 (2 C), 128.6 (2 C), 128.0, 127.8 (2 C), 126.6 (2 C), 126.1, 80.1, 75.6, 50.0, 47.7, 31.6, 21.6, 18.6, 18.4. MS (EI, 70 eV): m/z (abundance) = 385 (3, M+•), 281 (14), 230 (29), 130 (16), 129 (12), 115 (10), 98 (100), 91 (30), 69 (16), 56 (16). HRMS: m/z calcd for C22H28NO3S [M + H]+: 386.1784; found: 386.1789. cis-(E)-3-Isopropyl-5-styryl-4-tosylmorpholine (12c) 1H NMR (400 MHz, CDCl3): δ = 7.76 (d, J = 8.2 Hz, 2 H), 7.38–7.19 (m, 7 H), 6.67 (dd, J = 16.2, 1 H), 6.56–6.41 (m, 1 H), 4.45–4.35 (m, 1 H), 3.92 (d, J = 11.8 Hz, 1 H), 3.87 (d, J = 12.0 Hz, 1 H), 3.38 (dd, J = 10.9, 3.4 Hz, 1 H), 3.20 (dd, J = 11.9, 4.0 Hz, 1 H), 3.11 (dd, J = 12.0, 3.6 Hz, 1 H), 2.43 (s, 3 H), 2.32–2.23 (m, 1 H), 1.05 (d, J = 6.7 Hz, 3 H), 0.94 (d, J = 6.7 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 143.4, 138.7, 136.6, 132.8, 130.0 (2 C), 128.7 (2 C), 127.9, 127.7, 127.0 (2 C), 126.5 (2 C), 69.1, 66.6, 59.6, 52.9, 28.4, 21.6, 20.6, 20.2. MS (EI, 70 eV): m/z (abundance) = 342 (23), 268 (19), 187 (11), 171 (16), 156 (12), 155 (37), 130 (16), 129 (26), 128 (11), 117 (33), 115 (27), 91 (100), 69 (14), 65 (15). HRMS: m/z calcd for C22H27NNaO3S [M + Na]+: 408.1604; found: 408.1606.

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Scheme 1 Metal-catalyzed activation of allylic alcohols to access disubstituted morpholines
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Scheme 2 Synthesis of the 2,6-disubstituted morpholines precursors
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Scheme 3 Synthesis of the 3,5-disubstituted morpholines precursors
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Scheme 4 Iron-catalyzed heterocyclization – formation of the C–O bond
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Scheme 5 FeCl3·6H2O-catalyzed synthesis of cis-2,6-disubstituted morpholines
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Scheme 6 Formation of an enantioenriched morpholine
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Scheme 7 Iron-catalyzed heterocyclization: formation of the C–N bond
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Scheme 8 FeCl3·6H2O-catalyzed synthesis of cis-3,5-disubstituted morpholines
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Scheme 9 Plausible mechanisms for the iron-catalyzed heterocyclization
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Scheme 10 Relative stability of cis and trans diastereoisomers in 2,6-disubstituted morpholines
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Scheme 11 Relative stability of cis and trans diastereoisomers in 3,5-disubstituted morpholines
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Scheme 12 Synthetic transformations of the 2,6-disubstituted morpholine 11b
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Scheme 13 Synthetic transformations of the 3,5-disubstituted morpholine 12b