A versatile method for the preparation of 2,2-disubstituted morpholine analogues

Article abstract of DOI:10.1016/S0040-4039(00)00016-2

We describe a versatile synthetic method for the preparation of 2,2- disubstituted morpholine analogues. Iodo-etherification of 1,1-disubstituted olefin with N-Boc-aminoethanol using NIS proceeded smoothly in a regioselective manner and the following cyclization was accomplished in good yield. We successfully applied this method for the preparation of the key intermediate 2 of tachykinin receptor antagonist. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00016-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 1785–1788
A versatile method for the preparation of 2,2-disubstituted
morpholine analogues
Toshiyasu Takemoto, Yukiko Iio and Takahide Nishi ∗
Medicinal Chemistry Research Laboratories, Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
Received 19 November 1999; revised 16 December 1999; accepted 17 December 1999
Abstract
We describe a versatile synthetic method for the preparation of 2,2-disubstituted morpholine analogues. Iodo-
etherification of 1,1-disubstituted olefin with N-Boc-aminoethanol using NIS proceeded smoothly in a regioselec-
tive manner and the following cyclization was accomplished in good yield. We successfully applied this method
for the preparation of the key intermediate 2 of tachykinin receptor antagonist. © 2000 Elsevier Science Ltd. All
rights reserved.
In the course of our studies on tachykinin receptor antagonist, we have already reported that morpho-
line derivative 1 exhibited high binding affinities for tachykinin receptors.1 For the synthesis of these
morpholine derivatives, 2-[(2R)-(3,4-dichlorophenyl)morpholin-2-yl]ethanol (2) is recognized as a key
intermediate. We previously reported an asymmetric synthetic method for the preparation of 2 using
the Sharpless asymmetric dihydroxylation and the Mitsunobu reaction.2 Although this method is useful
for the preparation of an optically active form, it is not suitable for large-scale synthesis because of the
difficulties in handling osmium and multi steps. Therefore we focused our attention on an alternative
synthetic strategy.
To the best of our knowledge, the general synthetic method for the construction of the 2,2-disubstituted
morpholine ring from olefin can be classified into the two main routes depicted in Scheme 1. In route
A, epoxide 4 is opened by aminoethanol, and the following cyclization under dehydration conditions
yields morpholine 6.3 Route B proceeds via 3-oxomorpholine 9 and involves α-bromoacetylation of the
aminoalcohol 7 derived from epoxide 4.4
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00016-2
tetl 16296

1786
Scheme 1. General method for the synthesis of morpholine ring
As a part of our ongoing research concerned with the construction of morpholine ring, we focused
our attention on the use of haloetherification, a process which has been extensively used for the
functionalization on olefin.5 Here we report a versatile short-step method for the synthesis of 2,2-
disubstituted morpholine via iodoetherification. Our proposed strategy is illustrated in Scheme 2. Initial
formation of an iodonium ion intermediate 10 is generated using N-iodosuccinimide (NIS), and then the
resulting iodonium ion reacts with N-Boc-aminoethanol in a regioselective manner to afford the iodoether
11. Cyclization of 11 by base treatment leads to the desired 2,2-disubstituted morpholine analogue 12.
We conjecture that this methodology could be a useful general procedure for the synthesis of a variety of
2,2-disubstituted morpholines from a 1,1-disubstituted olefin.
Scheme 2. Regioselective iodoetherification and cyclization to form morpholine ring
Table 1 shows a number of examples of this chemistry.6 A variety of 2,2-disubstituted morpholine
analogues could be prepared readily in this procedure. Iodoetherification employed with NIS and N-Boc-
aminoethanol in CH3CN at 25°C.7 A screening of appropriate solvents for iodoetherification showed
a dramatic solvent effect, and the best solvent was CH3CN. Other solvents such as THF, 1,4-dioxane,
and CH2Cl2 gave poor results (5–10% yield). Attempts at haloetherification via bromonium ion using
N-bromosuccinimide were unsatisfactory due to diminished yield. As can be seen in entries 1–3, α-
methylstyrene substrate gave good results (89–96% yield). We also investigated the substrate in this
reaction, which had aliphatic substituents. In this case, both acyclic and cyclic substrate reacted to
afford the product in 54–72% yield (entries 4–7). All these 1,1-disubstituted olefins yielded the product
regioselectively.
In the ensuing step of the morpholine ring formation, we examined various combinations of base and
solvent. Treatment of a DMF solution of iodide 14a–g with NaH resulted in good yield of the morpholine
15a–g, as shown in Table 2.6
With the technology in hand to synthesize 2,2-disubstituted morpholine analogues, we directed our
efforts to the completion of the synthesis of 2, a key intermediate of the tachykinin receptor antagonist.
The synthetic route to optically active (2R)-2 is outlined in Scheme 3. Styrene derivative 16 was treated
with N-Boc-aminoethanol (10 equiv.) and NIS (4 equiv.) in CH3CN at 70°C to obtain iodide 17 in
72% yield. Treatment of 17 with NaH in DMF at 70°C cleanly provided morpholine 18 in 77% yield.
Deprotection of both the triphenylmethyl (Tr) group and Boc group of 18 by 4N HCl proceeded smoothly
in 79% yield after recrystallization. Next, the resulting racemic (RS)-2 was resolved with D-(−)-tartaric

1787
Table 1
Iodoetherification of exo-olefin with N-Boc-aminoethanol using NIS
Table 2
Cyclization of iodoether compound using NaH
acid in EtOH to give (R)-2 with high enantiomeric purity. Treatment of an EtOH solution of racemic
(RS)-2 with 0.5 equiv. of D-(−)-tartaric acid resulted in 86% yield, from tartaric acid, of (R)-2/ D-(−)-
tartaric acid salt with 91% ee. Recrystallization with EtOH–H2O gave white crystals, and a subsequent
base treatment gave (R)-2 of >99% ee in 95% yield.6
In conclusion, a potentially useful and versatile method for the preparation of 2,2-disubstituted

1788
Scheme 3. Synthesis of key intermediate for tachykinin receptor antagonist
morpholine analogues has been achieved. The enantiomerically pure (R)-2 prepared by the above method
has been successfully incorporated into a number of tachykinin receptor antagonists.
References
1. Nishi, T.; Fukazawa, T.; Kurata, H.; Ishibashi, K.; Nakajima, K.; Yamaguchi, T.; Itoh, K. Sankyo Co., Ltd, 1996; EP-776893-
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2. Nishi, T.; Ishibashi, K.; Nakajima, K.; Iio, Y.; Fukazawa, T. Tetrahedron: Asymmetry 1998, 9, 3251.
3. Kato, S.; Morie, T.; Harada, H.; Yoshida, N.; Matsumoto, J. Chem. Pharm. Bull. 1992, 40, 652. Moussa, G. E. M.; Basyouni,
M. N.; Shaban, M. E. Indian J. Chem., Sect. B 1980 19, 798. Loftus, F. Synth. Commun. 1980, 10, 59. Buriks, R. S.; Lovett,
E. G. J. Org. Chem. 1987, 52, 23. Bettoni, G.; Franchini, C.; Perrone, R.; Tortorella, V. Tetrahedron 1980, 36, 409. Firestone,
R. A.; Pisano, J. M.; Falck, J. R.; McPhaul, M. M.; Krieger, M. J. Med. Chem. 1984, 27, 1037. Jinbo, Y.; Kondo, H.; Taguchi,
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4. Berg, S.; Larsson, L.-G.; Renyi, L.; Ross, S. B.; Thorberg, S.-O.; Thorell-Svantesson, G. J. Med. Chem. 1998, 41, 1934.
Morie, T.; Kato, S.; Harada, H.; Matsumoto, J. Heterocycles 1994, 38, 1033. Melloni, P.; Della T. A.; Lazzari, E.; Mazzini,
G.; Meroni, M. Tetrahedron 1985, 41, 1393. Kashima, C.; Harada, K. J. Chem. Soc., Perkin Trans. 1 1988, 1521. Balsamo,
A.; Ceccarelli, G.; Crotti, P.; Macchia, B.; Macchia, F.; Tognetti, P. Eur. J. Med. Chem. Chim. Ther. 1982, 17, 471. Clark, R.
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6. All new compounds are fully characterized by their spectroscopic and analytical data.
7. Typical procedure: Preparation of 14c (Table 1, entry 3): A round-bottomed flask was charged with α-methylstyrene (71 mg,
0.60 mmol), N-Boc-aminoethanol (145 mg, 0.72 mmol), and CH3CN (4.0 mL). NIS (162 mg, 0.72 mmol) was successively
added. The reaction mixture was vigorously stirred at room temperature for 2 h. The solution was poured into brine and
extracted with EtOAc. The combined EtOAc layer was washed with water and dried over MgSO4. The solvent was removed
in vacuo, and the residue was purified by preparative TLC (n-hexane:EtOAc 5:1) and yielded as a colorless oil (234 mg,
96% yield): FT-IR (neat) νmax 3430, 3363, 2978, 2933, 1714, 1506, 1448, 1392, 1366, 1273, 1251, 1170, 1093, 1079, 764,
1
401 cm−1; H NMR (400 MHz, CDCl3) δ 7.41–7.24 (m, 5H), 5.03 (bs, 1H), 3.53 (d, J=10.4 Hz, 1H), 3.45 (d, J=10.4 Hz,
1H), 3.38–3.17 (m, 4H), 1.71 (s, 3H), 1.45 (s, 9H); HRMS (FAB) calcd for C16H25O3NI (M+H+) 406.0879, found 406.0872.
Preparation of 15c (Table 2, entry 3): A round-bottomed flask was charged with 14c (234 mg, 0.56 mmol) and DMF (4.0
mL). NaH (30 mg, ca. 60% mineral oil suspension, 0.75 mmol) was successively added. The reaction mixture was vigorously
stirred at room temperature for 3 h. The solution was poured into brine and extracted with EtOAc. The combined EtOAc
layer was washed with water and dried over MgSO4. After evaporation of the solvent, the desired product was purified by
preparative TLC (n-hexane:AcOEt 4:1) and yielded as a colorless oil (145 mg, 91% yield): FT-IR (neat) νmax 2976, 2929,
2869, 1699, 1449, 1425, 1366, 1281, 1242, 1172, 1137, 1095, 868, 764, 701 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.53–7.21
(m, 5H), 4.40–4.27 (m, 1H), 3.73–3.44 (m, 3H), 3.28–3.10 (m, 2H), 1.51 (bs, 3H), 1.41 (bs, 9H); HRMS (EI) calcd for
C16H23O3N (M+) 277.1674, found 277.1679.