A convenient approach towards the 1-aminomethyl-1-fluorocycloalkane scaffold

Article abstract of DOI:10.1016/j.tetlet.2013.08.127

A three-step synthesis towards 1-aminomethyl-1-fluorocycloalkanes was developed starting from methylenecycloalkanes. Methylenecyclobutane, methylenecyclopentane and methylenecyclohexane were first bromofluorinated to provide the corresponding Markovnikov

Full text of DOI:10.1016/j.tetlet.2013.08.127

Tetrahedron Letters 54 (2013) 6110–6113
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A convenient approach towards the 1-aminomethyl-
1-fluorocycloalkane scaffold
⇑
⇑
Matthias Moens, Matthias D’hooghe , Norbert De Kimpe
Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 July 2013
Revised 23 August 2013
Accepted 30 August 2013
Available online 7 September 2013
A three-step synthesis towards 1-aminomethyl-1-fluorocycloalkanes was developed starting from meth-
ylenecycloalkanes. Methylenecyclobutane, methylenecyclopentane and methylenecyclohexane were first
bromofluorinated to provide the corresponding Markovnikov products, 1-bromomethyl-1-fluor-
ocycloalkanes, which were then converted towards the title compound via azide substitution and hydro-
genation. The bromofluorination of methylenecyclopropane, however, led to both the Markovnikov and
the anti-Markovnikov product.
Keywords:
Ó 2013 Elsevier Ltd. All rights reserved.
Fluorinated building blocks
Bromofluorination
Bicyclobutonium ion
Methylenecycloalkane
The introduction of fluorine into organic compounds has al-
ready proven its relevance with regard to the modulation of the
biological properties (lipophilicity, acidity, basicity, . . .) of these
compounds.1 Furthermore, the constant need for innovation in
the pharmaceutical and the agrochemical sector stimulates the
search for new and active fluorinated building blocks.2 Such a
building block should be easily accessible, stable and potentially
multifunctional to use in several syntheses. Over the years a broad
diversity of methods has been developed to prepare fluorine-con-
taining compounds. In particular, the introduction of fluorine and
the simultaneous creation of a reactive electrophilic centre in the
b-position with respect to fluorine is of high interest. This can be
achieved by a non-symmetrical bromofluorination addition reac-
tion across a wide range of olefinic moieties, including terminal,
endocyclic, electron-deficient and electron-rich alkenes.3 The high
functional group tolerance and regioselectivity of the bromofluori-
nation reaction applied to olefins make this approach a very useful,
efficient and versatile method to synthesize monofluorinated
building blocks starting from diverse alkenes.4
the construction of libraries in medicinal chemistry research. Fluo-
rinated cycloalkanes in general are widely encountered in active
substances for the treatment of asthma, diabetes, multiple sclero-
sis, psychiatric diseases and cancer,5 as well as in insecticides6
and herbicides.7
The synthesis of 1-aminomethyl-1-fluorocycloalkanes was ini-
tiated from commercially available methylenecycloalkanes 1a–c.
Only methylenecyclopropane 1d had to be synthesized starting
from 3-chloro-2-methylpropene and potassium bis(trimethyl-
silyl)amide (KHMDS) under vigorous reflux in toluene, according
to a literature method.8
Fluorine was introduced in the first step of the synthesis of 1-
aminomethyl-1-fluorocycloalkanes by a bromofluorination addi-
tion across the exocyclic double bond of methylenecycloalkanes
by triethylamine trihydrofluoride (Et3NÁ3HF) and N-bromosuccini-
mide (NBS) in dichloromethane. The bromofluorination reaction is
generally recognized as a very mild and useful method to introduce
fluorine.4
The regioselectivity of this addition is influenced by the nature
of the alkene, although usually the addition of fluoride takes places
at the most substituted carbon atom, leading to a Markovnikov
addition product.3,4,9,10 For the four- to six-membered meth-
ylenecycloalkanes 1a–c, the bromofluorination with 1.5 equiv of
triethylamine trihydrofluoride (Et3NÁ3HF) and 1.1 equiv of N-bro-
mosuccinimide (NBS) in dichloromethane led exclusively to 1-bro-
momethyl-1-fluorocycloalkane Markovnikov adducts 2a–c in good
yields (69–80%) after 5 h (Scheme 1).12 For methylenecyclopro-
pane 1d, however, the regioselectivity was found to be different.
After bromofluorination, both regioisomers 2d and 3d were iso-
lated from a complex mixture in a 1:3 ratio, in a much lower yield
The goal of this research is to develop a synthetic pathway to-
wards novel 1-aminomethyl-1-fluorocycloalkanes starting from
the corresponding methylenecycloalkanes, as the synthesis of
these fluorinated (aminomethyl)cycloalkane building blocks has
not been discussed in the literature so far. Furthermore, it is be-
lieved that these fluorinated compounds are suitable for use in
⇑
Corresponding authors. Tel.: +32 9 264 9394; fax: +32 9 264 6221 (M.D.); tel.:
+32 9 264 5951; fax: +32 9 264 6221 (N.D.K.).
E-mail addresses: matthias.dhooghe@UGent.be (M. D’hooghe), norbert.dekimpe
@UGent.be (N. De Kimpe).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.08.127

M. Moens et al. / Tetrahedron Letters 54 (2013) 6110–6113
6111
1.5 equiv Et3N·3HF
1.1 equiv NBS
1.2 equiv NaN3
1.2 equiv NaI
Br
F
N3
F
CH2Cl2, 0°C-> rt, 5h
DMSO, 100°C, 16h
n
n
n
1a n = 1
1b
2a (80%)
2b
4a (70%)
4b
n = 2
1c n = 3
(69%)
2c (72%)
(68%)
4c (53%)
1) 20% Pd/C 2) HCl (g)
EtOAc, 10 min
5 bar H2
EtOAc, rt, 16h
O
Ph
HCl·H2N
F
F
HN
2.1 equiv Et3N
1.2 equiv BzCl
n
CHCl3, 0°C-> rt, 1h
n = 2
5a
(47%)
5b (58%)
5c
6b
(55%)
(38%)
Scheme 1. Synthesis of 1-aminomethyl-1-fluorocycloakanes 5a–c.
(19–25%) as compared to the other cycloalkanes (Scheme 2). In the
literature, the bromofluorination of isobutene has been shown to
lead exclusively towards the Markovnikov product, that is 1-bro-
mo-2-fluoro-2-methylpropane,9 which excludes sterical hindrance
as a determining factor for the regioselectivity in the bromofluori-
nation of methylenecyclopropane.11 As the bromofluorination is
generally considered to follow an ionic mechanism,10b the stability
of the cyclopropyl carbenium ions, that is 1-(bromomethyl)cyclo-
propyl cation A and 1-bromocycloprop-1-ylmethylcarbenium ion
B, will probably play a crucial role in the regioselectivity of this
reaction (Scheme 2).
Numerous experimental and computational studies have been
reported on the structure and energetics of the cyclopropylcarbinyl
cation,13 however its structure has not yet been fully estab-
lished.13,14 Despite the fact that the cyclopropylcarbinyl carbenium
ion is a primary cation, it is assumed that this ion is a quiet stable
ion, in which the three-membered ring stabilizes the positively
charged centre.15 This stability can probably be explained by an
+
+
+
+
C
D
Scheme 3.
r-Delocalized bicylobutonium structures.
In addition, 1-substituted cyclopropyl cations are only consid-
ered to be stabilized when the substituent is a strong -donor
p
(i.e., NR2, OR). For other substituents the barrier to ring opening
is so small that it is unlikely that these cations will exist.17 The for-
mation of this cation A, which is attacked by a nucleophilic fluorine
atom yielding the Markovnikov product, is reported here, but the
low yield and the low regioselectivity point out the unstability of
this cation. In the literature, only a few non-symmetrical addition
reactions have been performed on methylenecyclopropane 1d. For
example, the reaction of methylenecyclopropane 1d with HOBr18c
(NBS in H2O) or PhSeBr18e yielded, in agreement with our results,
(mainly) the anti-Markovnikov products.18
equilibrium which involves a set of
r-delocalized bicyclobutonium
structures. (Scheme 3).13–16
Most of the computational studies report a close proximity in
energy of the cyclopropylcarbinyl cation C and these bicyclobuto-
nium structures D, which results in an equilibrium between these
two types of cations.13,16 This explains the stability of the 1-bro-
mocyclopropylmethylcarbenium ion and, as a consequence, the
formation of the anti-Markovnikov product, 1-bromo-1-fluorom-
ethylcyclopropane 3d.
The crude mixture of cyclopropanes 2d and 3d was first filtered
over a silica plug and eluted with pentane. After evaporation of the
solvent the mixture was distilled at atmospheric pressure, yielding
several fractions with different regioisomeric ratios (2d:3d), rang-
ing from 1:6 to 2:1. Subsequently a mixture of these bromofluori-
nated cyclopropanes 2d:3d (1:3) was treated with NaN3 and NaI
analogously to the other cycloalkanes 2a–c. The only difference
2.5 equiv Et3N·3HF
1.2 equiv NaI
N3
F
F
Br
Br
F
1.5 equiv NBS
F
Br
1.2 equiv NaN3
+
+
CH2Cl2, 0°C, 5h
DMSO, 100°C, 16h
1d
2d:3d
4d
3d
1:3 (19-25%)
1) 20% Pd/C
5 bar H2
2) HCl (g)
EtOAc, 10 min
Br
EtOAc, rt, 16h
Br
Br
HCl·H2N
F
Br
+
5d
(6%, yield over 2 steps)
A
B
Scheme 2. Bromofluorination of methylenecyclopropane 1d.

6112
M. Moens et al. / Tetrahedron Letters 54 (2013) 6110–6113
De Smaele, D.; Duvey, G.; De Kimpe, N. J. Org. Chem. 2006, 71, 7100–7102; (f)
Verniest, G.; Piron, K.; Van Hende, E.; Thuring, J. W.; Macdonald, G.; Deroose, F.;
De Kimpe, N. Org. Biomol. Chem. 2010, 8, 2509–2512.
was that, after the workup, the solvent was distilled off at atmo-
spheric pressure to prevent loss of the very volatile azide 4d. With-
out further purification, the mixture of 1-azidomethyl-1-
fluorocyclopropane 4d and 1-fluoromethyl-1-bromocyclopropane
3d was reduced under H2-pressure (5 bar) in ethyl acetate.
The pure 1-bromomethyl-1-fluorocycloalkanes 2a–c, obtained
after a vacuum distillation, were treated with 1.2 equiv of NaN3
and 1.2 equiv of NaI in DMSO at 100 °C to give bromide by azide
displacement, yielding the fluorinated (azidomethyl)cycloalkanes
4a–c.19 The reduction of these fluorinated azido compounds 4a–c
was achieved applying H2-pressure (5 bar) in the presence of Pd/
4. Lübke, M.; Skupin, R.; Haufe, G. J. Fluorine Chem. 2000, 102, 125–135.
5. (a) Grabowska, U.; Joensson, D.; Klasson, B.; Wiktelius, D. PCT Int. Appl. WO
2012172473 A1, 2012; Chem. Abstr, 2012, 158, 105131.; (b) Mercurio, F.; Chan,
K. W. H. PCT Int. Appl WO 2011153197, 2011; Chem. Abstr.2011, 156, 53174.;
(c) Inoue, S.; Tsuboi, Y.; Ikeda, Y.; Nakajima, T.; Fujimoto, N.; Iwasaki, S.;
Fukano, Y. PCT Int. Appl. WO 2011148922, 2011; Chem. Abstr. 2011, 156,
35095.; (d) Michaelides, M.; Judd, A.; Fix-Stenzel, S. PCT Int. Appl. WO
2011143459, 2011; Chem. Abstr. 2011, 155, 683762.; (e) Am E., Christopher W.;
Fish, B., A.; Johnson, D., S.; Lira, R.; O’Donnell, C., J.; Pettersson, M., Y.; Stiff, C. M.
PCT Int. Appl. WO 2011092611, 2011; Chem. Abstr. 2011, 155, 240742.; (f)
Jubault, P.; Quirion, J.-C.; Lion, C.; Lemonnier, G. Eur. Pat. Appl. EP 2279997,
2011; Chem. Abstr. 2011, 154, 235001.
6. O’Sullivan, A. C.; Hughes, D.; Jeanguenat, A.; Muehlebach, M.; Loiseleur, O. PCT
Int. Appl. WO 2006040113, 2006; Chem. Abstr. 2006, 144, 364548.
7. Michrowska-Pianowska, A. A.; Major, J.; Hutzler, J.; Newton, T. W.; Evans, R. R.;
Kreuz, K.; Grossmann, K.; Song, D.; S., A.; Witschel, M. PCT Int. Appl. WO
2012010633, 2012; Chem. Abstr. 2012, 156, 203256.
8. Binger, P.; Brinkmann, A.; Wedemann, P. Synthesis 2002, 10, 1344–1346.
9. (a) Alvernhe, G.; Laurent, A.; Haufe, G. Synthesis 1987, 6, 562–564; (b) Haufe, G.;
Alvernhe, G.; Laurent, A.; Ernet, T.; Goj, O.; Kröger, S.; Sattler, A. Org. Synth., Coll.
2004, 10, 128–133.
10. (a) Maeda, M.; Abe, M.; Kojima, M. J. Fluorine Chem. 1987, 34, 337–346; (b)
Sasson, R.; Rozen, S. J. Fluorine Chem. 2006, 127, 962–965; (c) Eddarir, S.;
Mestdagh, H.; Rolando, C. Tetrahedron Lett. 1991, 32, 69–72.
C
(20 wt%) in ethyl acetate. Finally, 1-aminomethyl-1-fluor-
ocycloalkanes 5a–d were precipitated as hydrochloric acid salts
by bubbling dry HCl gas through the crude mixture, delivering
the salts 5a–c in acceptable yields (38–58%) (Scheme 1) and the
hydrochloric salt 5d in 6% yield over two steps (Scheme 2).20 1-
Aminomethyl-1-fluorocyclopentane 5b was treated with triethyl-
amine in chloroform (to liberate the free amine) and immediately
reacted with benzoyl chloride, yielding N-[(1-fluorocyclopen-
tyl)methyl]benzamide (55%) 6b.21 Structural analyses of the frag-
mentation patterns (MS, EI) of the fluorinated bromomethyl- 2a–
c and (azidomethyl)cycloalkanes 4a–c further established their
structures (Supporting information).
In conclusion, a convenient synthetic pathway towards new
fluorinated building blocks was developed via an easy three-step
procedure, starting from methylenecycloalkanes. The introduction
of fluorine was achieved by regioselective bromofluorination of
these olefins, except for methylenecyclopropane, which gave rise
to a mixture of regioisomers. Substitution of bromide by azide
led to the corresponding fluorinated (azidomethyl)cycloalkanes
in good yields. Subsequent hydrogenation of the latter azides fur-
nished 1-aminomethyl-1-fluorocycloalkanes, which were isolated
as their stable hydrochloride salts. The latter fluorinated (amino-
methyl)cycloalkanes can be considered as new building blocks in
synthetic medicinal chemistry.
11. Volta, L.; Stirling, C. J. M. Phosphorus, Sulfur, and Silicon and the Related Elements
2009, 184, 1508–1522.
12. The general procedure is exemplified for the synthesis of 1-bromomethyl-1-
fluorocyclopentane 2b. An ice cooled solution of methylenecyclopentane (2.0 g,
24.2 mmol) and triethylamine trihydrofluoride (6 mL, 36.4 mmol) in dry
dichloromethane (50 mL) was treated with N-bromosuccinimide (4.8 g,
26.6 mmol). After the removal of the ice bath the reaction was continued for
5 h at room temperature. The reaction mixture was poured into ice water
(50 mL), made slightly basic with aqueous 28% ammonia and extracted with
dichloromethane (3 Â 30 mL). The combined extracts were washed with 0.1 M
hydrochloric acid (3 Â 20 mL) and saturated sodium bicarbonate solution
(3 Â 20 mL). After drying over magnesium sulfate and evaporation of the
solvent, the crude mixture was purified by distillation under reduced pressure,
yielding 1-bromomethyl-1-fluorocyclopentane 2b (3.0 g, 69%) as pure
compound. Colourless oil. 1H NMR (300 MHz, CDCl3): d 1.63–2.14 (8H, m),
3.59 (2H, d, J = 18.7 Hz). 13C NMR (J = 75 MHz, CDCl3):
d 24.5, 37.0 (d,
J = 24.2 Hz), 37.7 (d, J = 28.8 Hz), 104.2 (d, J = 180.0 Hz). 19F NMR (282 MHz,
CDCl3):d À142.1 to À141.6 (1F, m). IR
mmax 2964, 1433, 1340, 1256, 1213, 985,
839, 656. GC–MS (EI) m/z (%): 180/182 (M+, 0.02), 101 (M+-Br, 15), 87 (100), 81
(43), 67 (56), 59 (10), 41 (19).
13. (a) Olah, G. A.; Prakash, S. G. K.; Reddy, P. V. Chem. Rev. 1992, 92, 69–95; (b)
Olah, G. A.; Prakash, S. G. K.; Rasul, G. J. Am. Chem. Soc. 2008, 130, 9168–9172.
14. Koch, W.; Liu, B.; DeFrees, D. J. J. Am. Chem. Soc. 1988, 110, 7325–7328.
15. Olah, G. A.; Spear, R. J.; Hiberty, P. C.; Hehre, W. J. J. Am. Chem. Soc. 1976, 98,
7470–7471. and literature cited herein..
16. (a) Kollmar, H. Tetrahedron Lett. 1970, 36, 3133–3136; (b) Levi, B. A.; Blurock, E.
S.; Hehre, W. J. J. Am. Chem. Soc. 1979, 101, 5537–5539; (c) Wiberg, K. B.; Shobe,
D.; Nelson, G. L. J. Am. Chem. Soc. 1993, 115, 10645–10652.
Acknowledgments
The authors are indebted to Ghent University (GOA) and Jans-
sen Research and Development, a division of Janssen Pharmaceuti-
cal NV, for financial support.
17. (a) Lien, M. H.; Hopkinson, A. C. J. Mol. Struct. 1985, 121, 1–12; (b) Khalil, S. M. Z.
Naturforsch. 1988, 43a, 801–805.
Supplementary data
18. (a) Anderson, B. J. Org. Chem. 1962, 27, 2720–2724; (b) Salaün, J.; Garnier, B.;
Conia, J. M. Tetrahedron 1974, 30, 1413–1421; (c) Köster, R.; Arora, S.; Binger, P.
Liebigs Ann. Chem. 1973, 1619–1627; (d) Kirschning, A.; Monenschein, H.;
Schmeck, C. Angew. Chem., Int. Ed. 1999, 38, 2594–2596; (e) Zhou, S.; Zemlicka,
J. Tetrahedron 2005, 61, 7112–7116.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
08.127.
19. The general procedure is exemplified for the synthesis of 1-azidomethyl-1-
fluorocyclopentane 4b. Sodium azide (0.43 g, 6.6 mmol) was added to
a
References and notes
stirred solution of 1-bromomethyl-1-fluorocycloalkane (1.0 g, 5.5 mmol) and
sodium iodide (0.99 g, 6.6 mmol) in anhydrous DMSO (10 mL). The mixture
was allowed to react for 16 h at 100 °C. After cooling down, H2O (15 mL) was
added and the mixture was extracted with pentane (3 Â 10 mL). The combined
organic phases were washed with H2O (3 Â 10 mL) and brine (2 Â 10 mL).
Drying over magnesium sulfate and evaporation under reduced pressure
yielded 1-azidomethyl-1-fluorocyclopentane 4b (0.54 g, 68). Colourless oil. 1H
NMR (300 MHz, CDCl3): d 1.60–2.07 (8H, m), 3.42 (2H, d, J = 20.9 Hz). 13C NMR
(75 MHz, CDCl3): d 24.1, 35.9 (d, J = 24.2 Hz), 57.1 (d, J = 25.4 Hz), 106.1 (d,
177.7 Hz). 19F NMR (282 MHz, CDCl3): d À145.7 to À145.1 (1F, m). IR (ATR,
1. (a) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37,
320–330; (b) Hagmann, W. K. J. Med. Chem. 2008, 51, 4359–4369; (c) Dolbier,
W. R. J. Fluorine Chem. 2005, 126, 157–163; (d) Kirk, K. L. Org. Process Res. Dev.
2008, 12, 305–321; (e) Kirk, K. L. J. Fluorine Chem. 2006, 127, 1013–1029; (f)
Smart, B. E. J. Fluorine Chem. 2006, 109, 3–11.
2. (a) Fustero, S.; Sanz-Cervera, J. F.; Aceña, J. L.; Sanchez-Rosello, M. Synlett 2009,
525–549; (b) Percy, J. M.; Prime, M. E. J. Fluorine Chem. 1999, 100, 147–156; (c)
Arnone, A.; Bravo, P.; Frigerio, M.; Salani, G.; Viani, F. Tetrahedron 1994, 50,
13485–13492; (d) Verniest, G.; Surmont, R.; Van Hende, E.; Deroose, F.;
Thuring, J. W.; De Kimpe, N. J. Org Chem. 2009, 73, 5458–5461; (e) Surmont, R.;
Verniest, G.; Colpaert, F.; Macdonald, G.; Thuring, J. W.; Deroose, F.; De Kimpe,
N. J. Org. Chem. 2008, 74, 1377–1380; (f) Surmont, R.; Verniest, G.; Thuring, J.
W.; Macdonald, G.; Deroose, F.; De Kimpe, N. J. Org. Chem. 2010, 75, 929–932;
(g) Surmont, R.; Verniest, G.; De Kimpe, N. Org. Lett. 2010, 12, 4648–4651.
3. (a) Shellhamer, D. F.; Horney, M. J.; Pettus, B. J.; Pettus, T. L.; Stringer, J. M.;
Heasley, V. L.; Syvret, R. G.; Dobrolsky, J. M., Jr. J. Org. Chem. 1999, 64, 1094–
1098; (b) Haufe, G.; Wesel, U.; Schulze, K.; Alvernhe, G. J. Fluorine Chem. 1995,
74, 283–291; (c) Gregorcic, A.; Zupan, M. J. Org. Chem. 1984, 49, 333–336; (d)
Van Hende, E.; Verniest, G.; Deroose, F.; Thuring, J. W.; Macdonald, G.; De
Kimpe, N. J. Org. Chem. 2009, 74, 2250–2253; (e) Van Brabant, W.; Verniest, G.;
cmÀ1): max 1340, 1279, 1034, 923, 891. GC–MS (EI) m/z (%): 143 (M+,
mN3 2095; m
0.9), 87 (58), 67 (100), 59 (24), 41 (43).
20. The general procedure is exemplified for the synthesis of 1-aminomethyl-1-
fluorcyclopentane hydrochloride 5b.
A
solution of 1-azidomethyl-1-
fluorocyclopentane (130 mg, 0.91 mmol) in EtOAc (3 mL), and 20 wt% of Pd/C
was stirred under H2 pressure (5 bar) for 16 h at room temperature. The
mixture was then filtered over CeliteÒ and the solids were washed with ethyl
acetate (10 mL). After introduction of dry HCl (g) the obtained crystals were
filtered and washed with diethyl ether to obtain the pure compound 5b
(82 mg, 58%). White crystals. 1H NMR (300 MHz, CDCl3): d 1.61–2.18 (8H, m),
3.29 (1H, d, J = 19.3 Hz), 8.65 (3H, br s). 13C NMR (75 MHz, CDCl3) d 24.0, 36.2
(d, J = 23.1 Hz), 46.0 (d, J = 24.2 Hz), 103.5 (d, J = 176.5 Hz).19F NMR (282 MHz,

M. Moens et al. / Tetrahedron Letters 54 (2013) 6110–6113
NH 2959; max 2871, 1598,
6113
CDCl3): d À148.2 to À147.6 (1F, m). IR (ATR, cmÀ1):
m
m
chromatography on silicagel (petroleum ether/EtOAc 7:1), yielding N-[(1-
fluorocyclopentyl)methyl]benzamide 6b (65 mg, 55%) as white crystals. 1H
NMR (300 MHz, CDCl3): d 1.60–2.06 (8H, m), 3.76 (2H, dd, J = 22.6, 5.5 Hz), 6.64
(1H, br s), 7.38–7.54 (3H, m), 7.79 (2H, d, J = 7.7 Hz) . 13C NMR (75 MHz, CDCl3)
d 24.1 , 35.9 (d, J = 23.1 Hz), 46.3 (d, J = 23.1 Hz), 107.0 (d, J = 174.2 Hz), 127.1,
128.7, 131.7, 134.5, 167.8. 19F NMR (282 MHz, CDCl3): d À146.4 to À145.9 (1F,
m). IR (ATR, cmÀ1): mNH 3296; mC@O 1638; mmax 2963, 2935, 1548, 1317, 1159,
1002, 803, 696, 664. HRMS (ES) calcd for C13H16FNO: 222.1289 [M+H]+; Found:
222.1287.
1512, 1456, 1351, 1101, 978, 849.
21. Synthesis of N-[(1-fluorocyclopentyl)methyl]benzamide 6b. To a stirred solution
of 1-aminomethyl-1-fluorcyclopentane hydrochloride (82 mg, 0.53 mmol) in
dry chloroform (2 mL) was added triethylamine (112 mg, 1.13 mmol). After
10 min the mixture was cooled to 0 °C and benzoyl chloride (82 mg,
0.58 mmol) was added. The reaction was stopped after 1 h by adding H2O
(1 mL). The aqueous phase was extracted with chloroform (3 Â 1 mL) and the
combined organic phases were washed with 0.1 M HCl (2 Â 1 mL) and
saturated NaHCO3 (2 Â 1 mL). After drying over magnesium sulfate and
evaporation of the solvent, the crude mixture was purified via column