Stereoselective synthesis of cis- and trans-3-fluoro-1-phenylcyclobutyl amine

Article abstract of DOI:10.1016/j.tetlet.2008.04.018

A stereoselective approach to the synthesis of cis- and trans-3-fluoro-1-phenylcyclobutylamine has been developed. Excellent stereoselectivity was obtained by the reduction of the appropriately substituted cyclobutanone to give either cis- or trans-isomers of 3-hydroxyl-1-phenylcyclobutylamine, which was stereoselectively converted to the 3-fluoro derivative.

Full text of DOI:10.1016/j.tetlet.2008.04.018

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3554–3557
Stereoselective synthesis of cis- and trans-3-fluoro-1-
phenylcyclobutyl amine
Pengcheng P. Shao *, Feng Ye
Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA
Received 25 February 2008; revised 1 April 2008; accepted 2 April 2008
Available online 6 April 2008
Abstract
A stereoselective approach to the synthesis of cis- and trans-3-fluoro-1-phenylcyclobutylamine has been developed. Excellent stereo-
selectivity was obtained by the reduction of the appropriately substituted cyclobutanone to give either cis- or trans-isomers of 3-hydro-
xyl-1-phenylcyclobutylamine, which was stereoselectively converted to the 3-fluoro derivative.
Ó 2008 Elsevier Ltd. All rights reserved.
Introducing fluorine to organic molecules is a common
practice in medicinal chemistry due to the unique steric
and electronic properties of this substituent.1 Fluorine is
a close steric replacement for hydrogen. As the most elec-
tronegative element, fluorine produces significant electronic
changes in a molecule without creating substantial steric
perturbation. Additionally, fluorine forms strong covalent
bonds with carbon (116 kcal/mol for C–F bond versus
100 kcal/mol for C–H bond),2 which makes fluorine substi-
tution a preferred method to block C–H activated meta-
bolic transformations.
1-Phenylcyclobutylamine is a common structural motif
in biologically active molecules, and it is widely used in
drug discovery and agriculture chemical projects.3 In order
to decrease the possible metabolic liability of the cyclobutyl
ring, we were interested in the synthesis of fluorinated
1-phenylcyclobutylamines such as 1a and 1b for use in
a recent drug discovery project.
Our retrosynthetic analysis of 1a and 1b is outlined in
Scheme 1. We envisioned that 1a and 1b could be conve-
niently synthesized from the corresponding carboxylic acid
precursors via a Curtius rearrangement. Since the polarity
difference between cis- and trans-fluoro compounds is
expected to be small, we anticipated that purification of
cis- and trans-isomers should be carried out at the hydroxy
ester stage (3a,3b), and that a stereospecific conversion of
the hydroxy group to fluorine would be required. The syn-
thesis of 3-hydroxy-1-phenylcyclobutanecarbonitrile was
previously reported, but the stereoselectivity had not been
determined.4 Cyclization of 4-chloro-phenylacetonitrile
and epibromohydrin was reported to give modest selectiv-
ity in favor of the cis-isomer (cis:trans = 3.3:1).5,6 It was
our interest to develop a synthesis in which both isomers
could be selectively synthesized from a common precursor.
We hoped to access both isomers selectively by screening of
different ketone reduction conditions. However, the stere-
oselectivity of cyclobutanone (4,5) reduction is hard to pre-
dict due to the small energy difference between planar and
the puckered conformation of cyclobutane.7 Finally, 4 and
5 may be prepared from commercially available 1,3-
dibromo-2,2-dimethoxypropane and phenylacetonitrile.8
Our synthesis that involved the treatment of phenylace-
tonitrile and 1,3-dibromo-2,2-dimethoxypropane with 2.2
equiv of NaH in dry DMSO at 60 °C for 6 h afforded ketal
6 in 73% yield following the silica gel chromatography
F
F
NH2
1a
NH2
1b
*
Corresponding author. Tel.: +1 732 594 2955; fax: +1 732 594 5350.
E-mail address: pengcheng_shao@merck.com (P. P. Shao).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.04.018

P. P. Shao, F. Ye / Tetrahedron Letters 49 (2008) 3554–3557
3555
F
OH
O
F
Br
Br
Curtis
stereospecific
fluorination
stereoselective
reduction
rearrangement
cyclization
CO2R
MeO OMe
+
NH2
CO2Me
CO2Me
CN
R = H,
4
3a -cis
3b -trans
1a -cis
1b -trans
2a -cis
2b -trans
R = Me, 5
Scheme 1. Retrosynthetic analysis.
(Scheme 2). The deprotection of dimethylketal gave keto-
nitrile 7 in quantitative yield. The hydrolysis of the steri-
cally hindered nitrile from the ketal intermediate 6
afforded low yield under acidic conditions. However, the
nitrile was cleanly hydrolyzed under basic conditions after
refluxing in a mixture of 1-BuOH and 50% KOH aqueous
solution for 12 h.9 The subsequent deprotection of this
dimethylketal intermediate gave ketoacid product 4 as a
colorless solid. Ketoacid 4 was then converted to ketoester
5 conveniently by treatment with TMSCHN2.
We next investigated the stereoselective ketone reduc-
tion, and the results are summarized in Table 1. The reduc-
tion of ketonitrile 7 with NaBH4 gave low selectivity for the
trans-isomer, while selectivity was reversed with L-Select-
ride favoring the cis-isomer. 10 However, the selectivity
using either reagent was modest (cis:trans 6 4:1), and the
apparent effect of temperature on selectivity was quite
small. We then turned our attention to ketoester 5. The
trans-isomer 3b was the favored product with both NaBH4
and L-Selectride reduction of 5; however, selectivity was
much higher with NaBH4. A more significant effect of tem-
perature onstereoselectivity was also observed with NaBH4
reduction of 5, as lower temperatures gave higher trans-
selectivity. The ester substituent afforded a moderate influ-
ence on stereoselectivity in NaBH4 reductions as demon-
strated by slightly better selectivity with benzylester 8
than methylester 5. The NaBH4 mediated reduction of
ketoacid 4 was completely non-selective over a wide range
of temperatures. However, to our surprise, excellent cis-
selectivity was observed with L-Selectride reduction of 4.
Higher temperatures afforded higher selectivity, and selec-
tivity was severely eroded when the reduction was carried
out at ꢀ78 °C. Thus, with proper starting materials and
reduction conditions, excellent selectivity can be achieved
for both cis- and trans-isomers.
The factors influencing stereoselectivity in these cases
are not apparent. However, it is likely that the conforma-
tion of cyclobutanone, the steric bulkiness and electronic
nature of the substituents, the size and reactivity of the
reducing agent all contribute to the stereoselectivity out-
come. The conformation difference of cyclobutanone of
nitrile 7 and ester 5 is likely one of the main contributors
causing drastic difference in stereoselectivity between these
two compounds. NOE data indicated that nitrile 7 prefers
puckered conformation IV positioning the larger phenyl
group at equatorial position with smaller NOE effect
between H1 and H2 (Fig. 1), while ester 5 adopts the con-
formation closer to planar V.11 In the case of ketoacid
reduction, carboxylic acid may react with the reducing
agent (VI and VII) before the ketone gets reduced, likely
affecting the selectivity.
Once a selective synthesis for both isomers 3a and 3b
was established, we turned to investigate the stereospecific
conversion of the hydroxy group to fluorine (Scheme 3).
The conversion of the hydroxyl to fluorine with (diethyl-
amino)sulfur trifluoride (DAST) afforded scrambling of
the carbinol stereocenter.12 We were pleased to find a
two step, one-pot procedure by first converting alcohol to
triflate following the displacement of triflate with tetrabut-
ylammonium fluoride (TBAF), which gave excellent yield
O
OH
HO
MeO OMe
f,d
a
b, c
MeO OMe
Br
CN
+
CO2H
Br
CO2Me
CO2Me
CN
73%
85%
76%
3a
3b
1
4
6
:
15
quant
d
quant
c
OH
O
O
HO
e
CO2Me
CO2Me
CN
CO2Me
95%
3b
16
3a
1
7
5
:
Scheme 2. Reagents and conditions: (a) NaH, DMSO, 60 °C, 6 h; (b) nBuOH, KOH 50%, 125 °C, 12 h; (c) 50% H2SO4 (cat), acetone, 75 °C, 2 h; (d)
TMSCHN2, MeOH, CH2Cl2, 21 °C; (e) NaBH4, MeOH, ꢀ78 °C, 15 min; (f) L-Selectride, THF, 50 °C, 15 min.

3556
P. P. Shao, F. Ye / Tetrahedron Letters 49 (2008) 3554–3557
Table 1
Cis- and trans-selectivity from cyclobutanone reduction
Reducing agent
Temperature (°C)
OH
H
H
O
OH *
*
R
R
R
Ketones
cis- isomer*
trans- isomer*
NaBH4
21
0
3
2
1
4
7
4
3
2
1
2
O
ꢀ78
L-Selectride
21
N
ꢀ78
7
O
NaBH4
0
1
1
1
1
1
8
O
ꢀ35
ꢀ78
21
ꢀ78
11
16
1
OMe
L-Selectride
5
2
O
NaBH4
21
1
1
1
2
8
20
1
O
ꢀ78
L-Selectride
21
O
Ph
ꢀ78
3
8
O
NaBH4
21
1
1
15
11
2
1
1
1
1
1
O
ꢀ78
OH
L-Selectride
50
21
ꢀ78
4
H3
H3
R
R
R
H3
O
O
O
1 H2
H1
H
H2
H1
H2
III
II
I
NOE between H1 and H2 I < II < III
H
B
Bui
O
iBu
iBu
N
OMe
H
O
O
B
intramolecular
O
H
O
O
O
O
O
H1
H2
H1
H2
intermolecular
IV
intermolecular
VII
V
VI
5.7 %
2.8 %
NOE between
H1 and H2
Fig. 1.

P. P. Shao, F. Ye / Tetrahedron Letters 49 (2008) 3554–3557
3557
OH
F
F
F
F
g
c,d,e
a,b
f
CO2Me
CO2Me
86%
CON3
NHCBz
92%
NH2
3a -trans
3b -cis
2a -cis
2b -trans
9a -cis
9b -trans
10a -cis
10b -trans
1a -cis
1b -trans
Scheme 3. Reagents and conditions: (a) Tf2O, pyridine, CH2Cl2, ꢀ78 °C to 21 °C over 15 min; (b) TBAF 2 equiv, 21 °C, 15 min; (c) LiOH, MeOH, H2O,
50 °C, 2 h; (d) DIEA, Ethylchloroformate, acetone, 0 °C, 30 min; (e) NaN3, 21 °C, 30 min; (f) BnOH, toluene, 110 °C, 16 h; (g) Pd/C, H2 50 psi, EtOH,
4 h.
4. Corbel, B.; Durst, T. J. Org. Chem. 1976, 41, 2348.
5. Jeffery, J. E.; Kerrigan, F.; Miller, T. K.; Smith, G.; Tometzki, G. B.
of the fluorinated product with complete inversion of
stereochemistry.
J. Chem. Soc., Perkin Trans. 1 1996, 2583.
With pure 2a and 2b in hand, the final conversion of the
6. Complete
cis-selective cyclization with phenylacetic acid and
ester to the corresponding amine was accomplished. The
hydrolysis of esters 2a and 2b, and the subsequent addition
of sodium azide to the activated carboxylates afforded the
corresponding acyl azides 9a and 9b. These were converted
to the benzyl carbamate-protected amines 10a and 10b by
Curtius rearrangement of the acyl azides followed by trap-
ping of the isocyanate intermediates with benzyl alcohol
(40% yield over 4 steps). Finally, removal of the CBz group
by hydrogenolysis was straightforward, affording 1a and 1b
in 24% and 19% overall yield, respectively, from common
starting materials.13
In summary, we report the first stereoselective synthesis
of cis- and trans-3-fluoro-1-phenylcyclobutyl amines 1a
and 1b. Excellent selectivity for both cis- and trans-isomers
has been achieved from the reduction of ketoacid 4 with L-
Selectride or from ketoester 5 with NaBH4, respectively.
epibromohydrin has been achieved. Personal communication with
Dr. Jinjun Yin.
7. (a) Manatt, S. L.; Vogel, M.; Knutson, D.; Roberts, J. D. J. Am.
Chem. Soc. 1964, 86, 2645; (b) Langley, C. H.; Lii, J.-H.; Allinger, N.
L. J. Comput. Chem. 2001, 22, 1451.
8. Pigou, P. E.; Schiesser, C. H. J. Org. Chem. 1988, 53, 3841.
9. Korb, G.; Flemming, H.; Lehnert, R.; Rybczynski, W. WO200018715.
10. Cis- and trans-isomers were assigned based on NOE effects, and the
ratio was determined by 1H NMR integration of H1 and H2 of the cis-
and trans-isomers.
3.8%
CN
H3
CN
OH
H3
H4
H4
OH
H2
H1
H2
H1
2.9%
3.1%
3%
.
11. The preferred conformations of 3-Ph-3-R-substituted cyclobutanones
(4, 7, 5, and 8) were calculated using two molecular mechanics
methods, MMFFs and OPLS-2005, in simulated high-dielectric
solvent. However, the two methods yielded conflicting results.
MMFFs calculation showed conformation I is the preferred confor-
mation (pucker angle h for 4, 7, 5, and 8: 29.2°, 22.6°, 29°, and 29.4°)
while OPLS calculation indicated conformation III being preferred
(pucker angle h for 4, 7, 5, and 8:23°, 21.4°, 23.2°, and 22.8°). Density
Acknowledgments
We thank Professor Robert Boeckman for useful discus-
sions on the mechanism of stereoselectivity in cyclobuta-
none reduction, Dr. Jinjun Yin for sharing unpublished
results, and Dr. Daniel McMasters for performing the
molecular mechanics and ab initio calculations. We also
thank Ms. Deborah Pan and Dr. Joseph L. Duffy for
proof-reading the manuscript.
*
functional theory (DFT) calculations (B3LYP/6-31G ) indicated that
the cyclobutanone is nearly planar (conformation II with pucker
angle h for 4, 7, 5, and 8: 8.4°, 8.8°, 8.6°, and 9.4°).
12. (a) Middleton, W. J. J. Org. Chem. 1975, 40, 574; (b) Avent, A. G.;
Bowler, A. N.; Doyle, P. M.; Marchand, C. M.; Young, D. W.
Tetrahedron Lett. 1992, 33, 1509; (c) Demange, L.; Menez, A.;
Dugave, C. Tetrahedron Lett. 1998, 39, 1169.
References and notes
13. Compound 1a: 1H NMR (500 MHz, CDCl3): d (ppm) 7.46 (d,
3
3
0
0
JH–H = 7.4 Hz, 2H), 7.40 (t,
JH–H = 7.6 Hz, 2H), 7.30 (t,
1. (a) Filler, R. Organofluorine Compounds in Medicinal Chemistry and
Biomedical Applications. In Studies in Organic Chemistry 48; Filler,
R., Ed.; Elsevier: New York, 1993; pp 1–386; (b) Fluorine in
Bioorganic chemistry; Welch, J. T., Eswarakrishnan, S., Eds.; Wiley:
New York, 1991; pp 1–261; (c) Lin, P.; Jing, J. Tetrahedron 2000, 56,
3635.
2. McAtee, J. J.; Schinazi, R. F.; Liotta, D. C. J. Org. Chem. 1998, 63,
2161 and references cited therein.
3. (a) Silverman, R. B.; Zieske, P. A. Biochemistry 1996, 25, 341; (b) Cui,
Yi; Tinker, A.; Clapp, L. H. Br. J. Pharmcol. 2003, 139, 122; (c)
Ohnari, M.; Nishio, K.; Sakurai, K. WO2001068671.
3
2
0
JH–H = 7.4 Hz, 1H), 4.88 (dm, JH–F = 62.7 Hz, 1H), 3.1 (m, 2H),
2.5 (m, 2H); 13C NMR (CDCl3): d (ppm) 146.5, 128.9, 127.3, 125.8,
1
3
82.3 (d, JC–F = 205.4 Hz), 52.1 (d, JC–F = 17.3 Hz), 46.8 (d,
2JC–F = 19.2 Hz); 19F NMR (CDCl3): d (ppm) ꢀ65.8. Compound
1b: 1H NMR (500 MHz, CDCl3): d (ppm) 7.40 (t, JH–H = 7.6 Hz,
3
0
2H), 7.32 (d, 3JH–H = 7.6 Hz, 2H), 7.28 (t, JH–H = 7.4 Hz, 1H), 5.43
3
0
0
(dm, 2JH–F = 56.3 Hz, 1H), 2.7 (m, 4H); 13C NMR (CDCl3): d (ppm)
1
150.1, 129.0, 126.9, 124.3, 85.0 (d, JC–F = 208.3 Hz), 51.7 (d,
3JC–F = 19.2 Hz), 44.1 (d, JC–F = 20.2 Hz); 19F NMR (CDCl3): d
2
(ppm) ꢀ65.8.