Straightforward synthesis of (R,R/S,S)-2-[2-(2-aryl)-1-phenyl-ethyl]-morpholines: a new class of inhibitors of the norepinephrine transporter

Article abstract of DOI:10.1016/j.tetlet.2007.02.013

Diastereoselective synthesis of (R,R/S,S)-2-[2-(2-aryl)-1-phenyl-ethyl]-morpholines 6 has been achieved through the preparation of key E-enol-triflate 4 and its further coupling with benzylzinc reagents and final hydrogenation.

Full text of DOI:10.1016/j.tetlet.2007.02.013

Tetrahedron Letters 48 (2007) 2603–2605
Straightforward synthesis of (R,R/S,S)-2-[2-(2-aryl)-1-
phenyl-ethyl]-morpholines: a new class of inhibitors
of the norepinephrine transporter
Javier Agejas* and Carlos Lamas*
Lilly SA, Avda de la Industria, 30, 28108, Alcobendas, Madrid, Spain
Received 9 November 2006; revised 31 January 2007; accepted 2 February 2007
Available online 7 February 2007
Abstract—Diastereoselective synthesis of (R,R/S,S)-2-[2-(2-aryl)-1-phenyl-ethyl]-morpholines 6 has been achieved through the
preparation of key E-enol-triflate 4 and its further coupling with benzylzinc reagents and final hydrogenation.
Ó 2007 Elsevier Ltd. All rights reserved.
Norepinephrine (NE) plays a very important role in the
central nervous system.1 Selective inhibitors of norepi-
nephrine transporter (NET) like Atomoxetine (1) (Strat-
teraTM) and Reboxetine (2) (EdronaxTM) are marketed for
the treatment of affective disorders (Fig. 1).2
the triflate group, which allows a palladium cross-cou-
pling with benzylzinc halides and (b) the right E stereo-
chemistry, which yields, after single final hydrogenation,
the desired 2,20-anti analogs 6. Finally, 4 would be pre-
pared from ketone 3, which was available on a large
scale in our laboratory4 (Fig. 2).
In our continued exploration of new inhibitors,3,4 we
targeted the family of compounds 6. This series features
the same 2,20-anti stereochemistry as Reboxetine, which
is critical for the inhibitory activity. In this context, the
main synthetic challenge we faced was the stereoselective
preparation of these analogs. For this purpose, we envis-
aged that morpholine 4 could serve as key intermediate.
This compound features two valuable characteristics: (a)
The preparation of the desired E-enol-triflate 4 required
considerable experimental optimization. Firstly, depro-
tonation of ketone 3 with bases such as LiHMDS or
KHMDS in THF at ꢀ78 °C gave predominantly the
undesired Z-enol-triflate 7.5 This may be due to the for-
mation of highly stabilized metal chelate I by coordina-
tion of the metal cation with the oxygen of the
morpholine ring (Fig. 3).
Taking these findings into account, we turned our atten-
tion to the search of conditions in which the formation
of this highly stabilized internal chelate could be
avoided. Addition of 18-crown-6 could trap the metal
from the reaction (especially potassium6) and, thus, pre-
t
vent formation of the internal chelate. Using BuOK
(1.1 equiv), 18-crown-6 (1.1 equiv), PhN(SO2CF3)2
(1.2 equiv) in THF, the desired E-enol-triflate 4 was ob-
tained in 70% yield and 10:1 ratio of E- to Z-enol-triflate
(1–7 mmol scale). To our surprise, the isolated yields
and the observed stereoselectivity were much lower
Figure 1.
t
when we used a new batch of BuOK rather than the
bottle which had been in our laboratory for some time.
With a freshly opened bottle of the base, 4 was isolated
only in 40–45% yield and poor 1.1:1 ratio of E- to Z-
enol-triflate. As BuOK is known to be hygroscopic,
we hypothesized that the older bottle might contain
Keywords: Stereoselective synthesis; Enol-triflate; Palladium coupling;
Norepinephrine inhibitors.
*
Corresponding authors. Tel.: +34 916633454 (J.A.); tel.: +34
916633405; fax: +34 916233501 (C.L.); e-mail addresses: agejas_
francisco_javier@lilly.com; lamas_carlos@lilly.com
t
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.02.013

2604
J. Agejas, C. Lamas / Tetrahedron Letters 48 (2007) 2603–2605
Figure 2.
Table 1.
Entry
R
5, Yielda (%)
6, Yielda (%)
a
b
c
d
e
f
OEt
OMe
Ph
80
85
88
88
87
76
84
85
80
81
80
82
85
72
iPr
OPh
OTBDMS
Br
Figure 3.
b
g
h
—
b
Cl
—
more water and that the presence of water might cause a
change of the reaction mechanism favoring the forma-
tion of the desired E-enol-triflate. To test this hypothe-
sis, we screened the effect of varying equivalents of
water on the reaction mechanism. From this study, we
found the optimal conditions for the formation of 4 to
a Isolated yield.
b The reaction was not done.
In summary, we report herein a highly efficient route to
(R,R/S,S)-2-[2-(2-aryl)-1-phenyl-ethyl]-morpholines 6.
The biological activity of the target compounds will be
communicated in due course.
t
be 1 equiv of 3, 1.3 equiv of BuOK, 1.3 equiv of 18-
crown-6, 1.4 equiv of PhN(SO2CF3)2 and just 0.5 equiv
of water. Under these conditions, yields of 65–70%
and stereoselectivity ratios of 8–10:1 were consistently
achieved.
t
Preparation of 4: To a solution of BuOK (95% from
Aldrich, 110 mg, 0.93 mmol) and water (0.5 equiv) in
anhydrous THF (4.2 ml/mmol) were added, at 0 °C
under nitrogen atmosphere, 18-crown-6 (246 mg,
0.93 mmol) and 3 (200 mg, 0.71 mmol, a single portion
as solid) and the mixture was stirred at this temperature
for 15 min and, then, at room temperature for 45 min.
Next, N-phenyltrifluoromethanesulfonimide was added
(357 mg, 1 mmol, a single portion as solid) and the final
mixture was stirred overnight at room temperature. The
solvent was removed and Et2O was added to the residue.
The mixture was filtered off and the solid was washed
twice with Et2O. The combined filtrated was evaporated
and the crude was purified by column chromatography
on silica gel eluting with hexane–dichloromethane 1:1
to afford 210 mg of 4 as a pale yellow oil (71% yield).
1H NMR (CDCl3, 300 MHz): 7.57 (dd, J = 1.3 and
8.2 Hz, 2H), 7.43–7.26 (m, 8H), 4.02 (t, J = 4.8 Hz,
2H), 3.67 (s, 2H), 3.45 (s, 2H), 2.68 (t, J = 4.8 Hz,
2H). LC–MS (m/z): 414 (M++1).
The next step was the palladium catalyzed coupling of 4
with ortho-substituted benzylzinc derivatives.7,8 Thus,
when commercially available 2-ethoxybenzylzinc chlo-
ride (1.2 equiv), 4 (1 equiv), and Pd(PPh3)4 (5 mol %)
were refluxed for 1 h in anhydrous THF, we obtained
the desired compound 5a in an excellent 80% yield
(Scheme 1; Table 1, entry a). Similarly, very good yields
were achieved under these conditions for other analogs
listed in Table 1, including sterically hindered ones (en-
tries c, d, f). Furthermore, these conditions were com-
patible with the presence of halogens (entries g,9 h),
which allows further functionalization at that position.
Finally, standard palladium-catalyzed hydrogenation of
compounds 5 in methanol afforded the desired analogs 6
in good yields and with the required 2,20-anti stereo-
chemistry (Scheme 1; Table 1).
Scheme 1.

J. Agejas, C. Lamas / Tetrahedron Letters 48 (2007) 2603–2605
2605
General method for the synthesis of 5: Compound 4
(1 equiv) and Pd(PPh3)4 (5 mol %) were added to a solu-
tion of benzylzinc reagent (1.2 equiv) in anhydrous THF
(7.5 ml/mmol) under nitrogen atmosphere and the
mixture was stirred at 95 °C for 1 h. The reaction was
allowed to reach room temperature and quenched with
water. Then, it was filtered through Celite, dried over
anhydrous sodium sulfate, filtered again, and the solvent
removed. The residue was purified by column chroma-
tography on silica gel eluting with dichloromethane–
methanol 98:2 yielding the title compounds 5. Example
made by Dr. Magnus Walter in order to write this
manuscript.
References and notes
1. Southwick, S. M.; Bremner, J. D.; Rasmusson, A.; Morgan,
C. A.; Arnsten, A.; Charney, D. S. Biol. Psychiatry 1999,
46, 1192–1204.
2. Bymaster, F. P.; Katner, J. S.; Nelson, D. L.; Hemrick-
Luecke, S. K.; Threlkeld, P. G.; Heiligenstein, J. H.; Morin,
S. M.; Gehler, D. R.; Perrry, K. W. Neuropsychopharma-
cology 2002, 27, 699–711; Scates, A. C.; Doraiswamy, P. M.
Ann. Pharmacotherapy 2000, 34, 1302–1312.
3. Boot, J.; Cases, J.; Clark, B. P.; Findlay, J.; Gallagher, P.;
Hayhurst, L.; Mann, T.; Montalbetti, C.; Rathmell, R. E.;
Rudyk, H.; Walter, M.; Whatton, M.; Wood, V. Bioorg.
Med. Chem. Lett. 2005, 15, 699–703.
1
5a: H NMR (CDCl3, 200 MHz): 7.31–7.09 (m, 11H),
6.90–6.75 (m, 3H), 4.00–3.81 (m, 4H), 3.63 (s, 2H),
3.54 (s, 2H), 3.24 (s, 2H), 2.58–2.54 (m, 2H), 1.35 (t,
J = 7 Hz, 3H). LC–MS (m/z): 400 (M++1).
General method for the synthesis of 6: To a 1:1 weighting
ratio of 5 and Pd/C (10%) in methanol (10 ml/mmol)
was bubbled hydrogen with a balloon. Then, the mix-
ture was stirred under this atmosphere, keeping the bal-
loon, at room temperature for 4 h. The reaction was
filtered through Celite and washed twice with methanol.
The solvent was removed and the residue was purified
by chromatography on silica gel eluting with dichloro-
methane–methanol 9:1 affording the title compounds
6. Example 6a: 1H NMR (CDCl3, 200 MHz): 7.22–
6.99 (m, 6H), 6.88 (dd, J = 1.9 and 7.8 Hz, 1H), 6.74–
6.67 (m, 2H), 3.96–3.60 (m, 5H), 3.42 (dd, J = 3.5 and
12.5 Hz, 1H), 3.12 (bs, 1H), 3.03–2.80 (m, 4H), 2.68–
2.43 (m, 2H), 1.34 (t, J = 6.9 Hz, 3H). LC–MS (m/z):
312 (M++1).
4. Cases, J.; Masters, J.; Walter, M.; Campbell, G.; Haughton,
L.; Gallagher, P.; Dobson, D.; Mancuso, V.; Bonnier, B.;
Giard, T.; Defrance, T.; Vanmarsenille, M.; Ledgard, A.;
White, C.; Ouwerkerk, S.; Brunelle, F.; Dezutter, N.;
Herbots, C.; Lienard, J.; Findlay, J.; Hayhurst, L.; Boot, J.;
Thompson, L.; Hemrick, S. Bioorg. Med. Chem. Lett. 2006,
16, 2022–2025.
1
5. Compound 7: H NMR (CDCl3, 300 MHz): 7.35–7.25 (m,
10H), 4.13 (t, J = 4.9 Hz, 2H), 3.51 (s, 2H), 3.17 (s, 2H),
2.65 (t, J = 4.9 Hz, 2H). LC–MS (m/z): 414 (M++1).
6. Izatt, R. M.; Nelson, D. P.; Rytting, J. H.; Haymore, B. L.;
Christensen, J. J. J. Am. Chem. Soc. 1971, 93, 1619–1623;
Mazor, M. H.; McCammon, J. A.; Lybrand, T. P. J. Am.
Chem. Soc. 1989, 111, 55–56.
7. The preparation of the non commercial benzylzinc reagents
was conducted applying the conditions developed by Rieke
from benzylic bromides and chlorides: Zhu, L.; Wehmeyer,
R. M.; Rieke, R. D. J. Org. Chem. 1991, 56, 1445–1453.
8. The cross coupling was conducted using standard condi-
tions related to aryl halides: Minato, A.; Tamao, K.;
Hayashi, T.; Suzuki, K.; Kumada, M. Tetrahedron Lett.
1980, 21, 845–848; Shiota, T.; Yamamori, T. J. Org. Chem.
1999, 64, 453–457.
Acknowledgments
We thank Dr. Juan Felix Espinosa, Nuria Esturau, and
Paloma Vidal for their support in conducting NMR
studies and assignment of enol-triflates 4 and 7 and ana-
logs 5. We also greatly appreciate all the suggestions
9. With this substituent, the reaction time was only 20 min in
order to avoid formation of side overcoupling material.