Synthesis of fluorinated 1-(3-Morpholin-4-yl-phenyl)-ethylamines

Article abstract of DOI:10.1016/S0960-894X(03)00240-3

The synthesis of four (±)-fluorinated 1-(3-morpholin-4-yl-phenyl)-ethylamines and an enantioselective approach to these amines through reductive amination are described.

Full text of DOI:10.1016/S0960-894X(03)00240-3

Bioorganic & Medicinal Chemistry Letters 13 (2003) 1725–1728
Synthesis of Fluorinated 1-(3-Morpholin-4-yl-phenyl)-Ethylamines
Yong-Jin Wu,a,* Huan He,a Li-Qiang Sun,a Dedong Wu,b Qi Gaob and Hui-Yin Lic
aDepartment of Neuroscience Chemistry, The Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway,
Wallingford, CT 06492, USA
bDepartment of Analytical Sciences, The Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway,
Wallingford, CT 06492, USA
cChemical Process Research and Development, The Bristol-Myers Squibb Pharmaceutical Research Institute, Deepwater, NJ 08023, USA
Received 3 February 2003; accepted 1 March 2003
Abstract—The synthesis of four (Æ)-fluorinated 1-(3-morpholin-4-yl-phenyl)-ethylamines and an enantioselective approach to these
amines through reductive amination are described.
# 2003 Elsevier Science Ltd. All rights reserved.
Substituted 1-phenylethylamines are ubiquitous build-
ing blocks for amide formation and reductive alkylation
in medicinal chemistry programs. These amines have
been incorporated into numerous drug candidates such
as CP-544372 (Fig. 1)1 a macrolide antibiotic with
activity against both macrolide-susceptible and MLSB-
resistant organisms, and H 409/22 (Fig. 1),2 a NPY
antagonist in phase II clinical trial for the treatment of
cardiovascular disorders. In a recent medicinal chem-
istry program, we introduced a morpholine moiety into
the meta position of 1-phenylethylamine, and the
resulting 1-(3-morpholin-4-yl-phenyl)ethylamine (1) was
used in an amide library synthesis. It was found that the
incorporation of the morpholine moiety resulted in both
improved solubility and pharmacokinetic properties. As
introduction of fluorine into biologically active com-
pounds can profoundly alter their chemical, physical,
and biological properties,3 we were interested in the
Figure 1.
fluorinated analogues of 1. Simultaneous introduction
of both morpholine and fluorine into the phenyl ring of
Linezolid (Fig. 1), a new antibacterial agent, has been
shown to provide improved safety profiles over pre-
viously identified oxazolinone antibacterials.4 This
report describes the synthesis of four (Æ)-fluorinated
1-(3-morpholin-4-yl-phenyl)ethylamines, 2, 3, 4, and 5
as well as an enantioselective approach to these amines
(Fig. 2).
*Corresponding author. Tel.: +1-203-677-7485; fax: +1-203-677-
7702; e-mail: yong-jin.wu@bms.com
Figure 2.
0960-894X/03/$ - see front matter # 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0960-894X(03)00240-3

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Y.-J. Wu et al. / Bioorg. Med. Chem. Lett. 13 (2003) 1725–1728
Fluoro amine 2 was prepared from 2-fluoro-3-chloro-
acetophenone (6)5 in three steps using the palladium-
catalyzed amination conditions that we recently devel-
oped for 4-fluoro-3-bromo-acetophenone (Scheme 1).6
Reaction of 6 with morpholine was sluggish using
Pd(OAc)2 and ligand 9 in the presence of Cs2CO3 in
benzene under reflux, while the same reaction using
NaOtBu as a base afforded a 20:1 mixture of the fluor-
ide 7 and the chloride 8 as shown by LC–MS analysis of
the crude product. Under the latter conditions, no pro-
ducts resulting from the palladium-catalyzed a-arylation
variety of basic conditions, and the failure of this cycli-
zation presumably results from the reduced basicity of
the amine in 12 due to the presence of two electron-
withdrawing groups: acetyl group and fluorine at meta
and ortho positions, respectively. With this in mind, we
then reduced ketone 12 to alcohol 13 using sodium
borohydride. As we had hoped, compound 13, upon
treatment with bromoethyl ether in the presence of dii-
sopropylethylamine, underwent smooth cyclization to
give N-aryl morpholine 14. This compound was con-
verted to azide 15 using diphenylphosphoryl azide,10
and reduction of the azide generated fluoro amine 3.
7
of the acetyl groupwere observed. Compound 7 was
obtained in 73% yield after purification of the crude
product through silica gel flash chromatography. Oxime
formation followed by reduction afforded fluoro amine 2.
We subsequently developed a shorter route to fluoro
amine 3 using the palladium-catalyzed amination that
we recently reported (Scheme 3).6 Bromide 16, upon
treatment with morpholine in the presence of Pd(OAc)2
and ligand 9 using Cs2CO3 as a base in benzene under
reflux, furnished fluoride 17 in 80% yield. The trans-
formation from acetophenone 17 to fluoro amine 3 was
carried out through reduction of the oxime.
The synthesis of fluoro amine 3 is outlined in Scheme 2.
The commercially available 4-fluoro-acetophenone (10)
was nitrated with concentrated sulfuric acid and fuming
nitric acid to give compound 11,8 which was reduced
selectively to amine 12 through hydrogenation using
sulfided platinum on carbon [Pt(S)/C] as catalyst.9 Our
attempts to convert the amine in 12 into the morpholine
ring using bromoethyl ether were unsuccessful under a
Scheme 4 depicts the synthesis of fluoro amine 4.
Exposure of 3,5-difluoro-acetophenone (18) to mor-
pholine in the presence of potassium carbonate brought
about the facile nucleophilic substitution of the fluor-
ine,11 and the resulting N-aryl morpholine 19 was con-
verted to fluoro amine 4.
The synthesis of fluoro amine 5 was carried out in a five-
stepsequence ( Scheme 5). Regioselective nitration of
2-fluoroacetophenone (20) and reduction of the result-
ing nitro compound 21 furnished amine 22. In contrast
with its 4-fluoro counterpart 12 (Scheme 2), the 6-fluoro
amine 22 underwent clean cyclization with bromoethyl
ether in the presence of diisopropylethylamine to afford
N-aryl morpholine 23. Conversion of 23 to fluoro-amine
5 was carried out in a straightforward fashion.
Next, we explored the asymmetric synthesis of (S)-3 from
acetophenone 17 (Scheme 3) through reductive amina-
tion with (S)-1-phenylethylamine.12 Imine 24 was formed
cleanly using TiCl4 as a Lewis acid and a dehydration
Scheme 1. (a) Morpholine (1.ꢀ5 equiv), Pd(OAc)2 (15 mol% Pd), 9 (30
.
EtOH, 25 h; (c) H2, Ra–Ni, 30% NH3 H2O in MeOH, 100% over two
steps.
.
mol%), NaOtBu, toluene, 80 C, 0.5 h, 73%; (b) NH2OH HCl, Et3N,
Scheme 3. (a) Morpholine (4ꢀequiv), Pd(OAc)2 (10 mol% Pd), 9 (10
.
mol%), Cs2CO3, benzene, 80 C, 17 h, 79%; (b) NH2OH HCl, Et3N,
EtOH, 72 h; (c) H2, Ra–Ni, 30% NH3H2O in MeOH, 75% over two
steps.
Scheme 2. (a) Concd H2SO4, fuming HNO3, À15 ꢀC, 79%; (b) H2 (50
psi), Pt(S)/C, EtOH, 80%; (c) NaBH4, MeOH, CH2Cl2, 99%; (d)
bromoethyl ether, i-Pr2NEt, toluene, 110 ꢀC, 87%; (e) Ph2P(O)N3,
DBU, 0 ꢀC, 90%; (f) LiAlH4, THF, À40 ꢀC, 99%.
Scheme 4. (a) Morpholine, K2CO3, 150 ꢀC, 72 h, 48%; (b)
NH2OH HCl, Et3N, EtOH, 72 h; (c) H2, Ra–Ni, 30% NH3 H2O in
MeOH, 74% over two steps.
.
.

Y.-J. Wu et al. / Bioorg. Med. Chem. Lett. 13 (2003) 1725–1728
1727
Scheme 5. (a) Concd H2SO4, fuming HNO3, À15 ꢀC, 55%; (b) H2 (50
psi), Pt(S)/C, EtOH, 57%; (c) bromoethyl ether, i-Pr2NEt, toluene,
ꢀ
.
110 C, 73%; (d) NH2OH HCl, Et3N, EtOH, 72 h; (d) H2, Ra–Ni,
.
30% NH3 H2O in MeOH, 84% over two steps.
Scheme 6. (a) (S)-1-Phenylethylamine, TiCl4, Et3N, toluene, 12 h;
(b) H2 (30 psi), MeOH, Ra–Ni, 2 h, 92% de, 99%; (c) HCOONH4, Pd/
C, MeOH, 92% ee, 93%; (d) HCl in ether, >99% ee, 71% after
recrystallization.
agent, and hydrogenation of the crude imine 24 with
Raney nickel provided the secondary amine (S,S)-25 in
92% de as shown by HPLC analysis. The same dia-
stereoselectivity was obtained when the reduction was
carried out with sodium borohydride in methanol at
À78 ꢀC. At room temperature, however, the same
reduction gave only 72% de.
The methodology developed for the synthesis of (S)-3
should be applicable to the preparation of (R)-3 and the
individual enantiomers of 2, 4, and 5 starting from
appropriate chiral 1-phenylethylamines and fluorinated
acetophenones.
Subsequent hydrogenolytic cleavage of the crude bis-
phenylethylamine 25 (92% de) with ammonium formate
and Pd/C13 occurred adjacent to the less substituted
phenyl ring, and (S)-3 was obtained exclusively in 92%
ee. The optical purity was determined after derivatiza-
tion with benzyl chloroformate and chiral HPLC ana-
lysis of the carbamtes. The crude hydrogenation
product was treated with hydrogen chloride in ether,
and the resulting dihydrochloride salt was recrystallized
from acetone/H2O/hexanes (20:4:1). The racemate was
obtained as crystals, and the mother liquid was con-
centrated to give (S)-3 dihydrochloride in 71% yield and
>99% ee. The absolute configuration of (S)-3 was
confirmed by X-ray diffraction analysis of its dihydro-
chloride hydrate (Fig. 3, Scheme 6).
In summary, we have synthesized four (Æ)-fluorinated
1-(3-morpholin-4-yl-phenyl)ethylamines and developed
an enantioselective approach to these amines through
reductive amination.14 We anticipate these fluorinated
amines to be versatile intermediates for medicinal
chemistry programs.
Acknowledgements
We thank Drs. John Starrett and David Smith for sup-
port of this project and Dr. William Schmitz for proof-
reading this report.
References and Notes
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14. All new compounds have spectral and analytical data in
agreement with the indicated structures. Compound 2: 1H
NMR (400 MHz, CD3OD) d 1.63 (3H, d, J=6.8 Hz), 3.29
(4H, m), 3.90 (4H, m), 4.75 (1H, q, J=6.8 Hz), 4.88 (2H, s),
7.26–7.35 (3H, m); 13C NMR (100 MHz, CD3OD) d 19.75,
46.14 (d, J=6 Hz), 53.17 (2C), 67.35 (2C), 122.06, 123.58,
126.83 (d, J=4 Hz), 127.86 (d, J=12 Hz), 139.17 (d, J=11
Hz), 154.43 (d, J=247 Hz). Compound 3: 1H NMR
(400 MHz, CD3OD) d 1.33 (3H, d, J=6.8 Hz), 3.05 (4H, m),
3.81 (4H, m), 3.98 (1H, q, J=6.8 Hz), 4.83 (2H, s), 6.92–7.03
(3H, m); 13C NMR (100 MHz, CD3OD) d 25.43, 52.04, 52.27
(2C), 68.10 (2C), 116.88 (d, J=21 Hz), 117.76 (d, J=3 Hz),
121.18 (d, J=8 Hz), 141.18 (d, J=9 Hz), 144.87, 156.02 (d,
J=242 Hz). Compound 4: 1H NMR (400 MHz, CD3OD) d
1.36 (3H, d, J=6.4 Hz), 3.06 (4H, m), 3.79 (4H, m), 4.26 (1H,
q, J=6.4 Hz), 4.83 (2H, s), 6.81 (1H, m), 6.91 (1H, dd, J=9.2,
8.8 Hz), 7.03 (1H, dd, J=3.2, 6.4 Hz); 13C NMR (100 MHz,
CD3OD) d 24.2, 46.4 (d, J=10 Hz), 51.6 (2C), 68.1 (2C),
115.9, 116.6 (d, J=20 Hz), 117.1 (d, J=10 Hz), 135.0 (d,
J=10 Hz), 149.8, 156.05 (d, J=230 Hz). Compound 5: 1H
NMR (400 MHz, CD3OD) d 1.37 (3H, d, J=6.8 Hz), 3.07
(4H, m), 3.80 (4H, m), 4.27 (1H, q, J=6.8 Hz), 4.84 (2H, s),
6.81 (1H, m), 6.92 (1H, t, J=9.2 Hz), 7.03 (1H, dd, J=2.8,
6.4 Hz); 13C NMR (100 MHz, CD3OD) d 24.11, 46.45 (d,
J=3 Hz), 51.60 (2C), 68.07 (2C), 115.92 (d, J=4 Hz), 116.62
(d, J=23 Hz), 117.18 (d, J=9 Hz), 134.74 (d, J=14 Hz),
149.83, 156.05 (d, J=235 Hz). Compound 7: 1H NMR
(400 MHz, CDCl3) d 2.63 (3H, d, J=5.2 Hz), 3.09 (2H, m),
3.88 (2H, m), 7.12 (2H, m), 7.43 (1H, m); 13C NMR
(100 MHz, CDCl3) d 31.6, 51.2 (2C), 67.0 (2C), 123.2, 124.3
(d, J=10 Hz), 126.9, 127.0, 140.8 (d, J=10 Hz), 155.6 (d,
J=260 Hz), 196.6.