Synthesis of 3-Chloro-4-fluoro-7,8-dihydro-6 H -isoquinolin-5-one and Its Derivatives

Article abstract of DOI:10.1055/s-0029-1219818

Synthesis of novel 3-chloro-4-fluoro-7,8-dihydro-6H-isoquinolin-5-one and its derivatives using sequential ortho-formylation/ortho-allylation reactions of 2-chloro-3-fluoropyridine and ring-closing metathesis is described.

Full text of DOI:10.1055/s-0029-1219818

LETTER
1397
Synthesis of 3-Chloro-4-fluoro-7,8-dihydro-6H-isoquinolin-5-one and Its
Derivatives
3
-Chloro-4
u
-
fluoro-7,8-
r
dihydro-
a
6
H
-
isoquin
j
olin-5-one an
V
d
Its Derivatives elcicky,* Daniel Pflieger
Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland
Fax +41(61)3248847; E-mail: juraj.velcicky@novartis.com
Received 23 January 2010
closing metathesis (RCM)10 of such diallyl intermediates,
followed by reduction/oxidation of RCM-product 6 was
expected to lead to the target compound 5.
Abstract: Synthesis of novel 3-chloro-4-fluoro-7,8-dihydro-6H-
isoquinolin-5-one and its derivatives using sequential ortho-formy-
lation/ortho-allylation reactions of 2-chloro-3-fluoropyridine and
ring-closing metathesis is described.
F
Key words: ortho-lithiation, ring-closing metathesis, fluoro pyri-
O
dine, isoquinolinone, fused-ring system
F
O
HN
Cl
HN
N
O
O
N
H
In the past decades, fluorine has become increasingly pop-
ular in the field of medicinal chemistry.1 This trend has
been fueled by the interesting properties of the fluorine atom,
such as: (1) its ability to undergo weak hydrogen bonding
(C–F···H–X)1e or electrostatic interactions (C–F···C=O)2
with protein structures, thereby increasing their binding
affinity to such proteins; (2) Its high electronegativity can
be used to influence the pKa of the proximal acidic or ba-
sic groups;3 (3) Its small size, which is comparable to that
of the hydrogen atom in terms of van der Waals radius, to-
gether with the high C–F bond energy, makes fluorine an
excellent substitute for metabolically labile hydrogens.1,4
The latter approach has been used, for example, in the de-
velopment of EGFR tyrosine kinase inhibitor Gefitinib
(1).5 Other examples of successful applications of fluorine
in drug discovery include the anticancer agent Fluorou-
racil (2), the cholesterol-lowering drug Fluvastatin (3) and
the antibacterial agent Ciprofloxacin (4) (Figure 1).
O
Gefitinib (1)
Fluorouracil (2)
O
HO
HO
OH
O
N
O
F
F
OH
N
N
HN
Fluvastatin (3)
Ciprofloxacin (4)
Figure 1 Examples of fluorine-containing drugs on the market
N
N
Cl
Cl
Recently, we became interested in the preparation of flu-
orinated isoquinolinones such as 5. However, although
simple 7,8-dihydro-6H-isoquinolin-5-one can be prepared
by oxidation of commercially available 5,6,7,8-
tetrahydroisoquinoline6,7a and is a useful starting point for
the synthesis of biologically active agents,7 to best of our
knowledge, no fluorine-containing analog of 5 is known
in the literature; this prompted us to develop a synthetic
route to such compounds and our results are described in
this paper.
F
O
F
OH
5
6
N
N
Cl
Cl
F
F
OH
8
7
Since introduction of a fluorine atom into organic
molecules8 can still represent a quite challenging exercise,
our strategy (Scheme 1) was based on the formation of the
cyclohexyl ring of 5 starting from commercially available
2-chloro-3-fluoropyridine (8). A double allylation of this
compound by means of a sequential ortho-lithiation9 reac-
tion was envisioned to provide the intermediate 7. Ring-
Scheme 1 Synthetic strategy towards tetrahydroisoquinolinone (5)
The synthesis began with the preparation of the substrate
for RCM, 7 (Scheme 2). Lithiation of 2-chloro-3-fluoro-
pyridine (8) occurred, as expected, at the 4-position
(ortho- to fluorine atom)11 as evidenced by the formation
of products 9a–c, which were isolated in good yields after
quenching the lithium species 8-Li with acrolein, N,N-
dimethylformamide (DMF) or N-methoxy-N-methylacet-
amide.12
SYNLETT 2010, No. 9, pp 1397–1401
x
x.
x
x.
2
0
1
0
Advanced online publication: 13.04.2010
DOI: 10.1055/s-0029-1219818; Art ID: G01710ST
© Georg Thieme Verlag Stuttgart · New York

1398
J. Velcicky, D. Pflieger
LETTER
Next, we planned to use a second ortho-lithiation/allyla-
tion sequence with hydroxyallyl intermediate 9a
(Scheme 3). In order to achieve this task, we believed that
it would be advantageous to attach an ortho-directing
group,13 such as methoxymethyl (MOM),14 to the alcohol
functionality of 9a. Unexpectedly, all attempts to intro-
duce the MOM-group under standard conditions failed;
while weak bases such as Hünig’s base afforded no prod-
uct even at 50 °C, use of sodium hydride at 10 °C led to
the isomerized enol ether 10 instead of desired MOM-
protected alcohol 11.
N
N
a) NaH, MOM-Cl
(43%)
Cl
Cl
F
O
F
OH
MOM
9a
10
b) MOM-Cl quenching
(36%) (see text)
N
Cl
F
O
MOM
N
12 (0%)
c) LDA
Cl
+
Br
N
N
F
O
N
LDA
MOM
Cl
Cl
Li
Cl
11
F
F
F
O
8
8-Li
MOM
13 (54%)
O
O
Scheme 3 Reagents and conditions: (a) NaH (1.5 equiv), 10 °C,
10 min, MOM-Cl (1.3 equiv), THF, 10 °C to r.t., 2 h; (b) MOM-Cl
(1.1 equiv cf. LDA) added 2 h after acrolein addition to 8-Li; (c) LDA
(1.5 equiv), THF, –78 °C, 30 min, then electrophile (1.5 equiv),
–78 °C to r.t., 2 h.
O
H
N
DMF
(71%)
(87%)
(61%)
N
N
N
idyl lithium 14 was extremely messy, while varying the
temperature or using CuCN instead of CuBr also proved
to be ineffective. It is worth mentioning that no ortho-
lithiation of 4-pyridinyl carboxaldehyde of any kind has
been reported in the literature. In addition, allylation of a
close analog (3-pyridinyl carboxaldehyde), as reported by
Zhai,16a also proved to be difficult (44% yield), as did its
iodination, as reported by Gronowitz (18% yield).16b
H
Cl
Cl
Cl
F
F
OH
O
F
O
9a
9b
9c
Scheme 2 Reagents and conditions: LDA (1.7 equiv), THF, –78 °C,
30 min, then electrophile (2 equiv), –78 °C to r.t., 2 h.
Interestingly, while no reaction was observed with NaH at
–78 °C, the enol ether 10 was formed again simply by al- Finally, Comins’ modified method15b,c was tried for the
lowing the reaction temperature to reach 23 °C. We fur- preparation of intermediate 15 directly from pyridine 8.
ther observed that the formation of compound 10 already Thus, 8-Li (formed using t-BuLi in this case) was added
occurred at –20 °C, demonstrating the ease of such to N-formyl-N,N¢,N¢-trimethylethylene-1,2-diamine lead-
ing directly to the intermediate 14 upon a second depro-
tonation with n-BuLi. Subsequent transmetallation with
CuBr and quenching of the cuprate with allyl bromide
provided compound 15 in moderate yield (41%) directly
from pyridine 8.17 The advantage of this approach over the
isomerization. The required intermediate 11 could finally
be obtained by direct MOM-Cl quenching of the 9a-alco-
holate formed by addition of 4-pyridyl anion (8-Li) to ac-
rolein (Scheme 3). Nevertheless, the expected second
ortho-lithiation of 11 failed because LDA deprotonated
this material at the benzylic position, leading to the forma- aldehyde route is not only the higher yields of 15 obtained
tion of compound 13 by quenching with allyl bromide, in- this way, but also that it avoids the need to isolate the in-
stead of forming the anticipated product 12.
termediate aldehyde 9b.
The highly functionalized pyridine 15 could easily be con-
Due to the observed high acidity of the benzylic position
in 11, we changed our initial strategy and, instead, tried to verted further into the required RCM precursor 7a by ad-
reach the desired intermediate 7a starting from aldehyde dition of vinyl Grignard reagent18 (Scheme 4). As
9b (Scheme 4). This task could be achieved using expected, the planned RCM of diallyl compound 7a with
Comins’ method for the in situ protection/ortho-lithiation Grubbs’ II catalyst18 proceeded smoothly, providing the
of aromatic aldehydes.15a The requisite allylaldehyde 15 desired cyclized product 6a in excellent isolated yield
was obtained in 30% yield (on a 120 mmol scale) after (97%). Grubbs’ I catalyst18 worked as well, but the prod-
transmetallation of 5-pyridyl lithium species 14 with uct 6a was obtained in lower yield (71%).
CuBr and subsequent nucleophilic substitution with allyl
bromide. Despite further optimization of this reaction, no
increase in the yield of intermediate 15 could be achieved.
For example, direct reaction of allyl bromide with 5-pyr-
Further transformation of the alcohol 6a into ketone 5a
was planned to be achieved by an isomerization of allylic
alcohol to the corresponding ketone19 (Scheme 5). In con-
trast to the conversion of 9a into the enol ether 10, which
Synlett 2010, No. 9, 1397–1401 © Thieme Stuttgart · New York

LETTER
3-Chloro-4-fluoro-7,8-dihydro-6H-isoquinolin-5-one and Its Derivatives
1399
N
N
N
N
a) PtO2, H2 (1 atm)
(73%)
H
Cl
Cl
Cl
Cl
F
F
OH
OH
F
F
O
bases,
6a
16a
9b
8
Wilkinson cat.
or xylol, Δ
a) Me2NCH2CH2NMeLi
then n-BuLi
b) t-BuLi then
b) Swern oxidation
(89%)
X
Me2NCH2CH2NMeCHO
then n-BuLi
(30%)
(41%)
N
N
N
Li
N
c) CuBr
then
Cl
H
N
Cl
F
O
Br
Cl
F
O
5a
OLi
F
14
15
Scheme 5 Reagents and conditions: (a) PtO2 (10 wt-%), H2 (1 atm),
MeOH, r.t., 1 h; (b) (ClCO)2 (1.1 equiv), DMSO (2.2 equiv), Et3N (5
equiv), CH2Cl2, –60 °C to r.t., 4 h.
d)
MgBr
(76%)
N
N
a) Grubbs' II cat.
R
N
N
n
Cl
Cl
n
e) Grubbs' II cat.
(97%)
F
OH
7a–d
F
R
HO
Cl
Cl
F
F
OH
OH
6a–d
6a
7a
b) PtO2, H2
Scheme 4 Reagents and conditions: (a) N,N,N¢-trimethylethylene-
1,2-diamine (1.4 equiv), n-BuLi (1.5 equiv), THF, –40 °C, 30 min
then –10 °C, 30 min; 9b (1 equiv), THF, –40 °C, 30 min; n-BuLi
(1.5 equiv), –40 °C to –30 °C, 2 h; (b) t-BuLi (1.05 equiv), –78 °C,
1 h; N-formyl-N,N¢,N¢-trimethylethylene-1,2-diamine (1.05 equiv),
n-BuLi (1.5 equiv), THF, –40 °C to –30 °C, 3 h; (c) CuBr (1.3 equiv),
–30 °C to 0 °C, 1 h; allyl bromide (1.6 equiv), –30 °C to –10 °C, 1 h;
(d) vinylmagnesium bromide (1.5 equiv), THF, 0 °C, 1 h; (e) Grubbs’
II cat. (5 mol%), CH2Cl2, r.t., 1 h.
N
N
c) Swern oxidation
R
R
Cl
Cl
n
n
F
F
O
HO
5a–d
16a–d
Scheme 6 Reagents and conditions: (a) Grubbs’ II cat. (5 mol%),
CH2Cl2, r.t., 2 h (18 h for 7b and 7d); (b) PtO2 (10 wt.%), H2 (1 atm.),
MeOH, r.t., 1 h; (c) (ClCO)2 (1.1 equiv), DMSO (2.2 equiv), Et3N
(5 equiv), CH2Cl2, –60 °C to r.t., 4 h; for yields, see Table 1.
was easily performed, the basic isomerization of cyclic
compound 6a failed due to prevailing aromatization of the
cyclohexene ring, leading to 3-chloro-4-fluoro-isoquino-
line (e.g., NaH, MeI, THF, 10→23 °C, 2 h, 61%). Since
thermal isomerization (heating in xylene)19b and isomer-
ization catalyzed by rhodium catalyst (Wilkinson)19c also
failed, we decided to explore a two-step process (oxida-
tion/reduction).
(Table 1). The RCM worked well for all derivatives and
afforded the cyclized products 6b–d in good yields
(Scheme 6, Table 1), although the cyclization of substitut-
ed derivatives 7b and 7d were slower and thus required
longer reaction times (18 h). The last two steps also
worked smoothly for the unsubstituted derivative 6c, pro-
viding ketone 5c20 in good yield. Hydrogenation of substi-
tuted intermediates 6b and 6d afforded the corresponding
saturated alcohols in somewhat lower yields as a separa-
ble mixture of syn/anti diastereomers (2.6:1 for 16b and
1:2 for 16d). Interestingly, the hydrogenation took place
from two different sides, depending on the ring size.
While the six-membered alcohol 6b was predominantly
hydrogenated from the side opposite to the hydroxyl
group, the seven-membered ring in 6d was hydrogenated
from the same side as the hydroxyl group. Both outcomes
can, however, be explained by conformational analysis of
six- versus seven-membered rings, assuming that the hy-
droxyl group adopts a pseudo-equatorial position and that
the hydrogenation occurs from convex side of the ring
In order to avoid possible aromatization of 6a by oxida-
tion, we started with reduction of the allylic double bond.
Interestingly, Pd/C catalyzed hydrogenation (1 atm. of
H2) of allylic alcohol 6a led predominantly to aromatiza-
tion rather than reduction. Using Raney-Ni as a catalyst,
the reaction was not only very slow but became also
messy with time. Finally, PtO2 was found to be the cata-
lyst of choice, affording the saturated alcohol 16a in good
yield (73%) under 1 atm. of H2 (Scheme 5). Oxidation of
benzylic alcohol 16a to ketone 5a20 was successfully
achieved by Swern oxidation (89%) while, quite surpris-
ingly, the initially applied MnO2 was found to be too weak
to oxidize this benzylic alcohol.
To apply the developed synthesis for the preparation of
other derivatives, dienols 7b–d were prepared by addition
of appropriate Grignard reagents18 to the aldehyde 15
Synlett 2010, No. 9, 1397–1401 © Thieme Stuttgart · New York

1400
J. Velcicky, D. Pflieger
LETTER
H.; Bendels, S.; Zimmerli, D.; Schneider, J.; Diederich, F.;
Kansy, M.; Müller, K. ChemMedChem 2007, 2, 1100.
(b) Schlosser, M. Angew. Chem. Int. Ed. 1998, 37, 1496.
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Barlow, J. J.; Healy, M. P.; Woodburn, J. R.; Ashton, S. E.;
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Med. Chem. Lett. 2001, 11, 1911.
(which is different in these two ring systems). Mixtures of
both diastereomers were easily oxidized to provide the fi-
nal products20 5b and 5d in good yields.
Table 1 Yields of Compounds 5 (see Scheme 6)a
Compound
a
b
c
d
n
0
0
1
1
(6) (a) Lardenois, P.; Frost, J.; Dargazanli, G.; George, P. Synth.
Commun. 1996, 26, 2305. (b) Nicolaou, K. C.; Baran, P. S.;
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(b) Singh, R. P.; Shreeve, J. M. Acc. Chem. Res. 2004, 37,
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García-Fortanet, J.; Kinzel, T.; Buchwald, S. L. Science
2009, 325, 1661.
(9) (a) Schlosser, M. Synlett 2007, 3076. (b) Gros, P.; Fort, Y.
Eur. J. Org. Chem. 2002, 3375. (c) Mongin, F.; Quéguiner,
G. Tetrahedron 2001, 57, 4059. (d) Marsais, F.; Queguiner,
G. Tetrahedron 1983, 39, 2009.
(10) (a) Deiters, A.; Martin, S. F. Chem. Rev. 2004, 104, 2199.
(b) Schuster, M.; Blechert, S. Angew. Chem. Int. Ed. Engl.
1997, 36, 2036. (c) Brown, R. C. D.; Satcharoen, V.
Heterocycles 2006, 70, 705.
(11) Recent examples on ortho-fluoro lithiation, see:
(a) Humphries, A. C.; Gancia, E.; Gilligan, M. T.; Goodacre,
S.; Hallett, D.; Merchant, K. J.; Thomas, S. R. Bioorg. Med.
Chem. Lett. 2006, 16, 1518. (b) Bobbio, C.; Schlosser, M.
J. Org. Chem. 2005, 70, 3039. (c) Marzi, E.; Bobbio, C.;
Cottet, F.; Schlosser, M. Eur. J. Org. Chem. 2005, 10, 2116.
(d) Ondi, L.; Volle, J.-N.; Schlosser, M. Tetrahedron 2005,
61, 717.
(12) Balasubramaniam, S.; Aidhen, I. S. Synthesis 2008, 3707.
(13) (a) Snieckus, V. Chem. Rev. 1990, 90, 879. (b) Epsztajn, J.;
Jóźwiak, A.; Szcześniak, A. K. Curr. Org. Chem. 2006, 10,
817. (c) Azzouz, R.; Bischoff, L.; Fruit, C.; Marsais, F.
Synlett 2006, 1908.
R
H
Me
H
Me
7
6
76
97
73
89
51
59
71
80
75
58
74
75
16
50 (2.6:1)b
73
63 (1:2)b
86
5
a Isolated yield (%).
b Diastereomeric ratio (syn/anti).
In summary, we have developed a short synthesis of novel
fluorinated 5-isoquinolinones such as 5a and its seven-
membered or substituted derivatives. The key diallyl pre-
cursor 7 was prepared in one step starting from commer-
cially available 2-chloro-3-fluoropyridine by Comins’
sequentional ortho-formylation/substitution protocol.
Ring-closing metathesis of diallyl derivative 7a worked
well, and the product 5a was reached from the RCM inter-
mediate 6a by a reduction/oxidation sequence. Keto- and
chloro-substituents contained in these molecules are use-
ful functional groups that can serve for further derivatiza-
tion of such compounds leading to more complex
molecules containing the 3-fluoro-pyridine motif for use
as pharmaceuticals or agrochemicals. In addition, the de-
scribed methodology could also potentially be applied for
the introduction of a cyclohexenone ring (or of other ring
sizes) into different aromatic compounds allowing for
(ortho)lithiation.
(14) (a) Townsend, C. A.; Bloom, L. M. Tetrahedron Lett. 1981,
22, 3923. (b) Stagliano, K. W.; Malinakova, H. C.
Tetrahedron Lett. 1998, 39, 4941.
(15) (a) Comins, D. L. Synlett 1992, 615. (b) Comins, D. L.;
Baevsky, M. F.; Hong, H. J. Am. Chem. Soc. 1992, 114,
10971. (c) Josien, H.; Ko, S.-B.; Bom, D.; Curran, D. P.
Chem. Eur. J. 1998, 4, 67.
Acknowledgment
We would like to thank Roland Steiner for the preparation of com-
pound 9c. We are also grateful to Susanne Osswald from the analy-
tical department for NMR determination of the cis/anti
stereochemistry of compounds 16b and 16d.
(16) (a) Luo, S.; Fang, F.; Zhao, M.; Zhai, H. Tetrahedron 2004,
60, 5353. (b) Bjoerk, P.; Aakermann, T.; Hoernfeldt, A.-B.;
Gronowitz, S. J. Heterocycl. Chem. 1995, 32, 751.
(17) Preparation of compound 15: t-BuLi (1.7 M in heptane, 14.1
mL, 24 mmol) was added within 15 min to a solution of 2-
chloro-3-fluoropyridine (3 g, 22.8 mmol) in anhydrous THF
(70 mL) at –78 °C. After stirring for 1 h at –78 °C, N-
formyl-l-N,N¢,N¢-trimethylethylene-1,2-diamine (3.21 g,
24 mmol) was added slowly and the reaction mixture was
left to warm to –40 °C, followed by addition of n-BuLi
(1.6 M in hexane, 21.4 mL, 34.2 mmol). The red-brown
solution was stirred for 3 h at –30 °C before CuBr (4.25 g,
29.6 mmol) was added. The reaction mixture was then
allowed to reach 0 °C and was stirred at this temperature for
1 h. After cooling back to –30 °C, a solution of allylbromide
(3.1 mL, 36.5 mmol) in anhydrous THF (50 mL) was added.
References and Notes
(1) (a) Hagmann, W. K. J. Med. Chem. 2008, 51, 4359.
(b) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V.
Chem. Soc. Rev. 2008, 37, 320. (c) Kirk, K. L. J. Fluorine
Chem. 2006, 127, 1013. (d) Isanbor, C.; O’Hagan, D.
J. Fluorine Chem. 2006, 127, 303. (e) Böhm, H.-J.; Banner,
D.; Bendels, S.; Kansy, M.; Kuhn, B.; Müller, K.; Obst-
Sander, U.; Stahl, M. ChemBioChem 2004, 5, 637.
(2) Olsen, J. A.; Banner, D. W.; Seiler, P.; Obst-Sander, U.;
D’Arcy, A.; Stihle, M.; Müller, K.; Diederich, F. Angew.
Chem. Int. Ed. 2003, 42, 2507.
(3) (a) Morgenthaler, M.; Schweizer, E.; Hoffmann-Röder, A.;
Benini, F.; Martin, R. E.; Jaeschke, G.; Wagner, B.; Fischer,
Synlett 2010, No. 9, 1397–1401 © Thieme Stuttgart · New York

LETTER
3-Chloro-4-fluoro-7,8-dihydro-6H-isoquinolin-5-one and Its Derivatives
1401
After stirring for 1 h at –10 °C, the mixture was quenched by
2.66 (t, J = 6.3 Hz, 2 H), 2.06 (m, 2 H); 13C NMR (100 MHz,
DMSO-d6): d = 193.6, 150.5 (d, JC,F = 273 Hz), 145.1 (d,
JC,F = 8 Hz), 139.5, 135.8 (d, JC,F = 20 Hz), 126.9, 39.3,
25.0, 21.5; ESI-HRMS: m/z [M + H]+ calcd for C9H8ClFNO:
200.0278; found: 200.0274; 5b: 1H NMR (500 MHz,
DMSO-d6): d = 8.38 (s, 1 H), 3.03 (m, 2 H), 2.77 (m, 1 H),
addition of sat. aq NH4Cl, filtered over Hyflo® and rinsed
with diethyl ether. The organic layer was then washed with
sat. aq NH4Cl and brine. After drying over Na2SO4 and
filtration, the mixture was concentrated under vacuum. The
crude mixture was further purified by gradient MPLC (ethyl
acetate–cyclohexane, 5→15%), followed by a second
MPLC (diethyl ether–cyclohexane, 10→15%) to provide the
product 15 (1.85 g, 41%) as a yellow oil. Spectral data for
compound 15: 1H NMR (500 MHz, DMSO-d6): d = 10.31 (s,
1 H), 8.32 (s, 1 H), 5.97 (m, 1 H), 5.07 (dd, J = 10.2, 1.5 Hz,
1 H), 5.00 (dd, J = 17.2, 1.6 Hz, 1 H), 3.72 (d, J = 6.3 Hz,
2 H); 13C NMR (100 MHz, DMSO-d6): d = 187.6, 153.0 (d,
JC,F = 268 Hz), 146.3 (d, JC,F = 7 Hz), 136.4 (d, JC,F = 20
Hz), 135.2, 128.8 (d, JC,F = 6 Hz), 116.6, 32.2; ESI-HRMS:
m/z [M + H]+ calcd for C9H8ClFNO: 200.0278; found:
200.0274.
2.14 (m, 1 H), 1.84 (m, 2 H), 1.12 (d, J = 6.6 Hz, 3 H); 13
C
NMR (125 MHz, DMSO-d6): d = 197.1, 151.2 (d, JC,F = 274
Hz), 145.9 (d, JC,F = 8 Hz), 140.0, 136.4 (d, JC,F = 20 Hz),
127.5, 42.9, 29.8, 24.7, 14.8; ESI-HRMS: m/z [M + H]+
calcd for C10H9ClFNO: 214.0430; found: 214.0431;
5c: 1H NMR (500 MHz, DMSO-d6): d = 8.26 (s, 1 H), 2.86
(m, 2 H), 2.75 (m, 2 H), 1.79 (m, 4 H); 13C NMR (125 MHz,
DMSO-d6): d = 201.6, 149.4 (d, JC,F = 264 Hz), 145.1, 136.3
(d, JC,F = 20 Hz), 135.9 (d, JC,F = 11 Hz), 135.1, 41.5, 28.3,
24.7, 22.3; ESI-HRMS: m/z [M + H]+ calcd for
C10H10ClFNO: 214.0430; found: 214.0430; 5d: 1H NMR
(500 MHz, DMSO-d6): d = 8.26 (s, 1 H), 2.91 (m, 1 H), 2.83
(m, 1 H), 2.71 (m, 1 H), 2.65 (m, 1 H), 2.02 (m, 1 H), 1.90
(m, 1 H), 1.48 (m, 1 H), 0.98 (d, J = 6.7 Hz, 3 H); 13C NMR
(100 MHz, DMSO-d6): d = 198.9, 148.5 (d, JC,F = 263 Hz),
144.5 (d, JC,F = 6 Hz), 135.6, 135.5, 135.1, 49.2, 33.1, 30.1,
27.5, 21.3; ESI-HRMS: m/z [M + H]+ calcd for
(18) Grubbs’ catalysts I and II and Grignard reagents were
purchased from Aldrich Co. and used as obtained
(19) (a) Uma, R.; Crévisy, C.; and Grée, R. Chem. Rev. 2003,
103, 27. (b) Xu, M.; Vasella, A. Helv. Chim. Acta 2006, 89,
1140. (c) Wang, P. X.; White, C. R. WO 2005/047291 A1.
(20) Characterization of final compounds. 5a: 1H NMR (500
MHz, DMSO-d6): d = 8.40 (s, 1 H), 2.97 (t, J = 6.1 Hz, 2 H),
C11H12ClFNO: 228.0586; found: 228.0586
Synlett 2010, No. 9, 1397–1401 © Thieme Stuttgart · New York

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