Synthesis of α,β-unsaturated α′-haloketones through the chemoselective addition of halomethyllithiums to Weinreb amides

Article abstract of DOI:10.1021/jo401236t

A straightforward synthesis of variously functionalized α,β-unsaturated α′-haloketones has been achieved through the chemoselective addition of halomethyllithium carbenoids to Weinreb amides at -78 C. A comparative study employing the corresponding esters under the same reaction conditions pointed out that the instability of the tetrahedral intermediate formed from the latter is responsible for the observed formation of carbinols instead of the desired haloketones.

Full text of DOI:10.1021/jo401236t

Note
pubs.acs.org/joc
Synthesis of α,β-Unsaturated α′-Haloketones through the
Chemoselective Addition of Halomethyllithiums to Weinreb Amides
Vittorio Pace,* Laura Castoldi, and Wolfgang Holzer
Department of Drug and Natural Product Synthesis, University of Vienna, Althanstrasse 14, Vienna, A-1090, Austria
S
* Supporting Information
ABSTRACT: A straightforward synthesis of variously functionalized α,β-
unsaturated α′-haloketones has been achieved through the chemo-
selective addition of halomethyllithium carbenoids to Weinreb amides at
−78 °C. A comparative study employing the corresponding esters under
the same reaction conditions pointed out that the instability of the
tetrahedral intermediate formed from the latter is responsible for the
observed formation of carbinols instead of the desired haloketones.
α-Haloketones are invaluable versatile intermediates in organic
synthesis as a consequence of the high reactivity displayed
toward nucleophiles by both the electrophilic methylene and
the carbonyl carbon atom.1 The conjugation of the carbonyl
group with a vinyl fragment introduces a third electrophilic site
within this short carbon array; thus, the complex α,β-
unsaturated α′-haloketone additionally becomes a Michael
acceptor.2 Indeed, in organic synthesis this motif has been
employed in a plethora of transformations ranging from the
synthesis of (bioactive) heterocycles2,3 and natural products
analogues (e.g., coruscanones)4 to the preparation of silyloxy-
1,3-dien-7-ynes.5 Some known synthetic routes to α,β-
unsaturated α′-haloketones are displayed in Scheme 1. A
common route is the halogenation protocol (via a), where an
α,β-unsaturated-α′-methylketone is transformed into a kineti-
cally unstable (silyl)enol ether, which is subsequently trapped
with a halonium source.2a,3b Alternatively, Wittig-type con-
densation between an aldehyde and a phosphorane derived
from 1,3-dichloroacetone has been used (via b).3a,6 Moreover,
an approach employing a Cu(I)-mediated 1,2-H shift of copper
chlorocarbenoids, generated from noneasily accessible trichlor-
omethyl carbinols (via c) has been employed.7 Unfortunately,
these strategies suffer from a series of drawbacks ranging from
chemo- and regioselective issues (i.e., overhalogenations,
sensitivity of the conjugated C−C double bond to electrophilic
haloniums) to low efficiency and lack of generality, for instance,
in the case of Wittig-type reactions with EDG-substituted
aldehydes or with Cu(I)-mediated processes.
bromomethylation reaction with LiCHBr2 and n-BuLi at −90
°C (Scheme 1, bottom, via e).9 Thus, we considered the use of
simpler monohalomethyllithium carbenoids (LiCH2X)10 ap-
propriate for the direct functionalization of a carboxylic
surrogate.
Therefore, herein we present a chemoselective protocol to
achieve α,β-unsaturated α′-haloketones via the lithium
carbenoids homologation of suitable Weinreb amides (Scheme
1, bottom central). We also highlight why esters are not optimal
substrates for such transformations at −78 °C because of
double addition of the carbenoids, thus giving carbinols instead
of the desired haloketones. To this end, we initially investigated
the reaction of commercially available ethyl cinnamate (1a)
with in situ formed chloromethyllithium (Table 1). By
performing the reaction at −78 °C with an excess of LiCH2Cl,
only carbinol 2 resulting from double addition of the carbenoid
to the ester could be isolated in 79% yield (entry 1).
Analogously, also in the case of stoichiometric addition,
carbinol 2 was the only reaction product (entry 2). On the
other hand, when the reaction mixture was kept at −115 °C
(Villieras conditions11) the desired chloroketone 3a was the
major reaction product (51%) along with 15% of the carbinol 2
(entry 3). An analogous outcome was observed when other
cinnamate esters 1b−d (methyl, benzyl, isopropyl) were used
instead of 1a (entries 4−9). These preliminary results indicated
that esters are prone to undergo a double addition of the
carbenoid at −78 °C, because of the instability of the
tetrahedral intermediate at that temperature (vide infra).
Thus, we turned our attention to the corresponding Weinreb
amide 1e because of the well-known stability of the tetrahedral
intermediate formed upon addition of organometallic species to
this carboxylic derivative.12 Pleasingly, the addition of LiCH2Cl
to such a substrate (1e) provided exclusively the desired
chloroketone 3a in excellent yield (88%, entry 10) without any
trace of the corresponding carbinol. By lowering temperature to
Alternatively, the homologation of an α,β-unsaturated
aldehyde to the corresponding halohydrin through the addition
of a carbenoid followed by an oxidation step (Scheme 1,
bottom, via d) has proven to be a moderately efficient two-pot
procedure to access the target compounds.8 In this sense, we
argued that a homologation protocol of an adequate carboxylic
acid derivative would satisfy the demand of an economic and
direct access to the desired haloketones. To the best of our
knowledge, the only example for the transformation of an α,β-
unsaturated ester into an α,β-unsaturated α′-haloketone has
been reported by Kowalski through a complex sequential
Received: June 17, 2013
© XXXX American Chemical Society
A
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The Journal of Organic Chemistry
Note
Scheme 1. Context of Presented Work
Table 1. Halomethylation of Esters and Weinreb Amides
use of a more stable but less nucleophilic magnesium
carbenoid13did not provide any reaction product (entry 14).
Analogously, the established reaction conditions allowed the
efficient preparation of the corresponding α-bromo and α-
iodoketones 3b and 3c, respectively, starting from CH2Br2 and
CH2I2 as the carbenoid precursors (entries 15 and 16).
Remarkably, under the reaction conditions applied the C−C
double bond was not affected (i.e., cyclopropanation which is
known to be accomplished by using Li carbenoids14), as
reported for analogous substrates under Corey−Chaykovsky
conditions.15
Once the optimal conditions had been established, we next
examined the scope of the reaction. Various substituted
cinnamoyl-type Weinreb amides afforded the corresponding
α-haloketones of type 5 in high yields (Table 2). Some points
merit mention: (a) a strong electron-releasing group (i.e.,
OMe) in activating position on the aromatic ring determines a
considerable increase of the reaction time; however efficiency
was not altered (to ensure non-degradation of the carbenoids,
ICH2Cl, and MeLi−LiBr were added portionwise); (b)
substituents susceptible to reduction, such as halogens (5e,
5f, 5h) or even a nitro group (5g) are well tolerated; (c) an
extended cinnamoyl system (5k), substituents across the
olefinic double bond (5o−p), and also switching to the
accordant alkyne system (5i), do not affect the reaction.
Importantly, α-chloro-α′-fluoro ketone 5n could be obtained in
higher efficiency compared to previous procedures involving
sulfur ylides.16 Interestingly, the protocol is also applicable to
naphtalenic (5j) and heteroaromatic substrates (5l, m): in the
latter cases, no concomitant lithiations at the ortho positions to
the heteroatoms are observed at all.
b
b
temp (°
C)
yield of 2
yield of 3
entry substrate MCH2X (equiv)
(%)
(%)
1
1a
1a
1a
1b
1c
1d
1d
1e
1a
1e
1e
1e
1e
1e
LiCH2Cl (1.8)
LiCH2Cl (1.0)
LiCH2Cl (1.8)
LiCH2Cl (1.8)
LiCH2Cl (1.8)
LiCH2Cl (1.8)
LiCH2Cl (1.8)
LiCH2Cl (1.8)
LiCH2Cl (1.8)
LiCH2Cl (1.8)
LiCH2Cl (1.8)
LiCH2Cl (3.0)
LiCH2Cl (3.0)
−78
−78
−115
−78
−78
−78
−115
−115
−115
−78
−90
−78
79
48
15
80
73
52
11
18
21
2
3
51
4
5
6
7
33
47
56
88
96
94
63
8
9
10
11
12
13
14
c
c
−60
−78
Mg(CH Cl)2
c2
(3.0)
c
d
15
16
1e
1e
LiCH2Br (3.0)
−78
−78
89
c
e
LiCH2I (3.0)
92
a
Unless otherwise indicated, MCH2X were generated from ICH2Cl
b
c
and MeLi-LiBr in equimolar amounts. Isolated yields. Generated
from 4.0 equiv of dihalomethane and 3.0 equiv of MeLi−LiBr or i-
d
e
PrMgCl−LiCl (entry 14). 3b. 3c.
Remarkably, the procedure could also be applied to the
synthesis of α,β-unsaturated ketones presenting cycloalkyl type
substituents on the β-carbon such as a cyclohexyl (5q) or a
cyclopropyl group (5r). However, in this latter case an
inseparable mixture of E/Z isomers was obtained.
To rationalize the observed chemoselectivity, we considered
the exceptional stability at −78 °C of the intermediate II
furnished by the N-methoxy group of the Weinreb amide I,
which evidently does not allow a second addition of LiCH2X
(Scheme 2, path a). As a consequence of this high stability of
II, the desired α-haloketone III is formed only after acidic
−90 °C, a further increase in the yield of 3a was noticed (96%,
entry 11), thus confirming the influence of this parameter on
the stability of the carbenoid. A further improvement was the
use of an excess of iodochloromethane (4.0 equiv) and MeLi−
LiBr (3.0 equiv) which overcame this deleterious effect of
temperature, and by running the reaction at −78 °C,
chloroketone 3a was obtained in an excellent 94% yield
without needing to perform any chromatographic purification
(entry 12). Attempts to increase the temperature up to −60 °C
significantly decreased the yield (entry 13) and, remarkably, the
B
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Note
a
Table 2. Chloromethylation of Variously Functionalized α,β-Unsaturated Weinreb Amides
a
Yields are referred to isolated products; otherwise indicated E/Z > 99:1 (1H NMR).
hydrolysis of the tetrahedral intermediate II. By contrast, the
addition of the carbenoid to an ester IV results in the formation
of a tetrahedral intermediate V (not stable at −78 °C), which is
in equilibrium with the transient α-haloketone III, the latter
more susceptible to a second attack of the carbenoid
(compared to the starting ester), and thus furnishing the
carbinol VI (Scheme 2, path b). This explanation is in
agreement with the finding that by running the halomethylation
of esters at −115 °C the major product is the α-haloketone.
Thus, it is conceivable that the tetrahedral intermediate V
formed through monoaddition to an ester, is only stable (thus,
hindering the second addition) at that very low temperature but
not at −78 °C.
To conclude, we have disclosed a direct and straightforward
access to synthetically useful α,β-unsaturated α′-haloketones
through the addition of halomethyllithium carbenoids to
Weinreb amides. Remarkably, the use of these starting materials
allows the chemoselective addition of only one equivalent of
the carbenoids without any trace of side products such as
carbinol or 1,4-addition products neither cyclopropanes
generated through Simmons−Smith-type processes. Interest-
ingly, the observed experimental results fit with the theoretical
explanation based on the temperature-dependent stability of
the tetrahedral intermediate formed upon addition of the
carbenoids to esters, which at −78 °C undergo double addition
to provide carbinols instead of the desired α-haloketones.
EXPERIMENTAL SECTION
■
1
General Experimental Methods. All H NMR and 13C NMR
spectra were recorded on spectrometers operating at 200, 300, 400, or
500 MHz and at 50, 75, 100, or 125 MHz. The 15N and 19F NMR
experiments were conducted on a 400 MHz spectrometer (40 and 377
MHz, respectively). The 15N NMR spectra were referenced against
external nitromethane; for the 19F NMR spectra absolute referencing
via the Ξ ratio was used. All melting points are uncorrected. Column
chromatography purifications were conducted on silica gel 60 (40−63
μm). TLC was carried out on aluminum sheets precoated with silica
gel 60F254; the spots were visualized under UV light (λ = 254 nm)
and/or KMnO4 (aq) was used as revealing system. All nonaqueous
reactions were run under an inert atmosphere (argon) with flame-
dried glassware using standard techniques. THF was distilled over Na
using benzophenone as an indicator. Cynamic esters, chloroiodo-
C
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Note
Scheme 2. Temperature-Based Mechanistic Explanation of the Different Behavior toward Halomethylithium Reagents of
Weinreb Amides (Path a) and Esters (Path b)
methane, dibromomethane, diiodomethane, and MeLi−LiBr complex
(1.5 M in diethyl ether) are commercially available. Weinreb amides
1e,17 4a,17 4b,18 4c,19 4d,20 4e,21 4f,18 4g,17 4h,22 4i,23 4j,24 4k,17 4l,21
4m,25 4n,26 4o,27 4p,27 and 4r28 are known compounds prepared as
previously reported. However, copies of 1H and 13C NMR spectra are
provided in the Supporting Information.
(3E)-1-Chloro-4-phenyl-3-buten-2-one (3a).7 Following the
general procedure, starting from (2E)-N-methoxy-N-methyl-3-phenyl-
acrylamide (1e) (0.27 g, 1.43 mmol), ICH2Cl (1.0 g, 0.41 mL, 5.7
mmol), and MeLi−LiBr (2.85 mL, 4.28 mmol) in THF, α-
chloroketone 3a was obtained in 95% yield (0.23 g) as a pale yellow
1
solid. H NMR (400 MHz, CDCl3) δ: 7.71 (d, J = 16.1 Hz, 1H,
PhCH), 7.59 (m, 2H, Ph H-2, H-6), 7.43 (m, 1H, Ph H-4), 7.42 (m,
2H, Ph H), 6.98 (d, 1H, J = 16.1 Hz), 4.30 (s, 2H, CH2Cl). 13C NMR
(100 MHz, CDCl3) δ: 191.1 (CO), 145.2 (Ph-CH), 133.9 (Ph C-
1), 131.1 (Ph C-4), 129.0 (Ph C-3), 129.0 (Ph C-5), 128.6 (Ph C-2),
Preparation of (2E)-3-Cyclohexyl-N-methoxy-N-methylacry-
lamide (4q). To a dry THF (9 mL) solution of (E)-methyl 3-
cyclohexylacrylate29 (575 mg, 3.42 mmol, 1 equiv) cooled at −10 °C
was added N,O-dimethylhydroxylamine hydrochloride (500 mg, 5,13
mmol, 1.5 equiv), and after 2 min, i-PrMgCl (2 M THF solution)
(1.06 g, 5.13 mL, 10.26 mmol, 3.0 equiv) was added dropwise during 5
min. The solution was allowed to reach rt during 3 h and then was
quenched with satd NH4Cl. The organic phase was extracted with
Et2O (3 × 15 mL), dried, and filtered. After removal of the solvent in
vacuo, Weinreb amide 4q was obtained in 94% yield (634 mg) as a
light yellow oil. 1H NMR (300 MHz CDCl3,) δ: 6.93 (dd, J = 15.6, J =
7.0 Hz, 1H), 6.34 (dd, J = 15.6, J = 1.4 Hz, 1H), 3.70 (s, 3H), 3.23 (s,
3H), 2.22−2.09 (m, 1H), 1.79−1.65 (m, 5H), 1.29−1.14 (m, 5H). 13C
NMR (75 MHz, CDCl3) δ: 167.1, 152.6, 115.9, 61.3, 40.4, 32.1, 31.7,
31.3, 25.6, 25.4, 25.4. IR (NaCl, νmax, cm−1): 2964, 1685, 1620, 1419,
1390, 1297, 1171, 1012, 706. Anal. Calcd for C11H19NO2: C, 66.97; H,
9.71; N, 7.10. Found: C, 67.09; H, 9.59; N, 7.23.
General Procedure for the Halomethylation of Weinreb
Amides with Li Carbenoids. To a solution of Weinreb amide (1.0
equiv) in THF cooled at −78 °C was added the dihalomethane (4.0
equiv), and subsequently, MeLi−LiBr complex (1.5 M solution in
diethyl ether, 3.0 equiv) was added dropwise during 5 min. The
resulting solution was stirred at that temperature for 1−2 h (see text),
and then NH4Cl saturated aqueous solution was added at −78 °C.
After removal of the cooling bath, the mixture was allowed to reach rt
and washed with Et2O and brine. The two resulting phases were
separated, and the organic phase was dried over anhydrous MgSO4,
filtered, and removed in vacuo to give the desired haloketones in a
pure form without needing to perform further purifications.
128.6 (Ph C-6), 121.6 (CHCO), 47.4 (CH2Cl). IR (NaCl, νmax
,
cm−1): 3080, 1682, 1594, 1511, 1255, 904. Mp: 56 °C (lit.7 mp 55
°C). Anal. Calcd for C10H9ClO: C, 66.49; H, 5.02. Found: C, 66.35;
H, 4.89.
(3E)-1-Bromo-4-phenyl-3-buten-2-one (3b).30 Following the
general procedure, starting from (2E)-N-methoxy-N-methyl-3-phenyl-
acrylamide (1e) (0.27 g, 1.43 mmol), CH2Br2 (990 mg, 0.40 mL, 5.7
mmol), and MeLi-LiBr (2.85 mL, 4.28 mmol) in THF, α-
bromoketone 3b was obtained in 89% yield (0.29 g) as a pale yellow
1
solid. H NMR (400 MHz, CDCl3) δ: 7.70 (d, J = 16.1 Hz, 1H,
ArCH), 7.59 (m, 2H Ph H-2, 6), 7.42 (m, 1H; Ph H-4), 7.41 (m,
2H, Ph H-3, Ph), 6.95 (d, J = 16.1 Hz, CHCO), 4.09 (s, 2H,
CH2Cl). 13C NMR (100 MHz, CDCl3) δ: 191.0 (CO), 145.4
(ArCH), 133.9 (Ph C-1), 131.1 (Ph C-4), 129.0 (Ph C-3), 129.0
(Ph C-5), 128.6 (Ph C-4), 128.6 (Ph C-6), 122.2 (CHCO), 33.1
(CH2Cl). IR (NaCl, νmax, cm−1): 1693, 1611, 1498, 1450, 1390, 1069,
990, 890, 749. Mp: 45 °C (lit.30 mp 44−45 °C). Anal. Calcd for
C10H9BrO: C, 53.36; H, 4.03. Found: C, 53.48; H, 4.17.
(3E)-1-Iodo-4-phenyl-3-buten-2-one (3c):31 Following the
general procedure, starting from (2E)-N-methoxy-N-methyl-3-phenyl-
acrylamide (1e) (0.27 g, 1.43 mmol), CH2I2 (1.53 g, 0.46 mL, 5.7
mmol), and MeLi-LiBr (2.85 mL, 4.28 mmol) in THF, α-iodoketone
3c was obtained in 92% yield (0.36 g) as a pale yellow solid. 1H NMR
(400 MHz, CDCl3) δ: 7.69 (d, J = 16.4 Hz, 1H), 7.59−7.57 (m, 2H),
7.43−7.41 (m, 3H), 6.89 (d, J = 16.4 Hz, 1H), 4.02 (s, 2H). 13C NMR
(100 MHz, CDCl3) δ: 192.1, 144.8, 133.8, 130.9, 128.9, 128.4, 122.2,
D
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Note
5.0. IR (NaCl, νmax, cm−1): 1640, 1573, 1438, 1270, 1072, 990, 874,
803, 764, 704. Mp: 57 °C (lit.31 mp 56.5−58.5 °C). Anal. Calcd for
C10H9IO: C, 44.14; H, 3.33. Found: C, 44.32; H, 3.50.
1601, 801, 782. Mp: 100 °C (lit.6b mp 99−101 °C). Anal. Calcd for
C11H11ClO: C, 67.87; H, 5.70. Found: C, 67.74; H, 5.84.
(3E)-1-Chloro-4-(2-chlorophenyl)-3-buten-2-one (5e). Follow-
ing the general procedure, starting from (2E)-3-(2-chlorophenyl-N-
methoxy-N-methylacrylamide (4e) (0.32 g, 1.43 mmol), ICH2Cl (1.0
g, 0.41 mL, 5.7 mmol), and MeLi−LiBr (2.85 mL, 4.28 mmol) in
THF, α-chloroketone 5e was obtained in 84% yield (0.26 g) as an
orange, thick oil. 1H NMR (400 MHz, CDCl3) δ: 8.11 (d, J = 16.1 Hz,
1H, ArCH), 7.68 (1H, dd, J = 7.6 Hz, 1.9 Hz, Ph H-6), 7.44 (m, 1H,
Ph H-3), 7.35 (m, 1H, Ph H-4), 7.30 (m, 1H, Ph H-5), 6.95 (d, J =
16.1 Hz, CHCO), 4.33 (s, 2H, CH2Cl). 13C NMR (100 MHz,
CDCl3) δ: 191.1 (CO), 140.9 (ArCH), 135.7 (Ph C-2), 132.2
(Ph C-1), 131.8 (Ph C-4), 130.4 (Ph C-3), 127.7 (Ph C-6), 127.2 (Ph
C-5), 124.2 (CHCO), 47.2 (1J(CH2) = 148.5 Hz, 3J(CH2, CH) =
1.2 Hz, CH2Cl). IR (NaCl, νmax, cm−1): 1684, 1605, 1594, 1362, 805.
Anal. Calcd for C10H8Cl2O: C, 55.84; H, 3.75. Found: C, 55.91; H,
3.61.
(3E)-1-Chloro-2-(chloromethyl)-4-phenyl-3-buten-2-ol (2).32
To a solution of ethyl cinnamate (176 mg, 1.0 mmol) in THF (3 mL)
cooled at −78 °C was added chloroiodomethane (317 mg, 1.8 mmol,
0.13 mL) and, after 2 min, MeLi−LiBr ethereal solution (1.5 M, 1.8
mmol, 1.20 mL). The resulting solution was stirred at that temperature
for 1 h, and then NH4Cl saturated aqueous solution was added at −78
°C. After removal of the cooling bath the mixture was allowed to reach
rt and washed with Et2O and brine. The two resulting phases were
separated, and the organic phase was dried over anhydrous MgSO4,
filtered, and removed in vacuo to give 2 after flash chromatography on
silica gel (hexanes−AcOEt, 9:1) as a light yellow oil (182 mg, 79%
yield). 1H NMR (500 MHz, CDCl3) δ: 7.35−7.17 (m, 5H), 6.83 (d, J
= 15.9 Hz, 1H), 6.24 (d, J = 15.9 Hz, 1H), 3.71 (d, J = 9.9 Hz, 1H),
3.24 (d, J = 9.9 Hz, 1H), 2.59 (s, 1H). 13C NMR (125 MHz, CDCl3)
δ: 135.8, 132.5, 128.6, 128.2, 127.1, 126.7, 74.2, 49.3 (×2). IR (NaCl,
νmax, cm−1): 3502, 2993, 712, 961, 903. Anal. Calcd for C11H12Cl2O:
C, 57.16; H, 5.23. Found: C, 57.33; H, 5.38.
(3E)-1-Chloro-4-(3-fluorophenyl)-3-buten-2-one (5f). Follow-
ing the general procedure, starting from (2E)-3-(3-fluorophenyl)-N-
methoxy-N-methylmethylacrylamide (4f) (0.30 g, 1.43 mmol),
ICH2Cl (1.0 g, 0.41 mL, 5.7 mmol), and MeLi-LiBr (2.85 mL, 4.28
mmol) in THF, α-chloroketone 5f was obtained in 92% yield (0.26 g)
as a yellow thick oil. 1H NMR (400 MHz, CDCl3) δ: 7.66 (d, J = 16.1
Hz, 1H, Ph−CH), 7.38 (m, 1H, Ph H-5), 7.36 (m, 1H, Ph H-6),
7.28 (m, 1H, Ph H-2), 7.13 (m, 1H, Ph H-4), 6.97 (d, J = 16.1 Hz, 1H,
CHCO), 4.29 (s, 2H, CH2Cl). 13C NMR (100 MHz, CDCl3) δ:
(3E)-1-Chloro-4-(4-methoxyphenyl)-3-buten-2-one3a (5a).
Following the general procedure, starting from (E)-N-methoxy-3-(4-
methoxyphenyl)-N-methylacrylamide (4a) (0.32 g, 1.43 mmol),
ICH2Cl (1.0 g, 0.41 mL, 5.7 mmol), and MeLi-LiBr (2.85 mL, 4.28
mmol) in THF, α-chloroketone 5a was obtained in 83% yield (0.25 g)
1
as a colorless solid. H NMR (300 MHz, CDCl3) δ: 7.68 (d, J = 15.9
1
Hz, 1H), 7.54 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 6.86 (d, J
= 16.0 Hz, 1H), 4.28 (s, 2H), 3.85 (s, 3H). 13C NMR (75 MHz,
CDCl3) δ: 191.4, 162.3, 145.2, 130.7, 130.7, 126.8, 119.4, 114.7, 144.7,
55.6, 47.6. IR (NaCl, νmax, cm−1): 1681, 1594, 1571, 1511, 1302, 1255,
1172, 905, 727. Mp: 98 °C (lit.3a mp 98 °C). Anal. Calcd for
C11H11ClO2: C, 62.72; H, 5.26. Found: C, 62.61; H, 5.15.
191.1 (CO), 163.0 (d, J(C,F) = 247.4 Hz, Ph C-3), 143.7 (d,
3
4J(C,F) = 2.8 Hz, Ph-CH), 136.2 (d, J(C,F) = 7.7 Hz, Ph C-1),
130.6 (d, 3J(C,F) = 8.3 Hz, Ph C-5), 124.7 (d, 4J(C,F) = 2.9 Hz, Ph C-
2
6), 122.7 (CHCO), 118.0 (d, 2J = 21.5 Hz, Ph C-4), 114.7 (d, J =
22.0 Hz, Ph C-2), 47.4 (CH2Cl). 19F NMR (377 MHz, CDCl3) δ:
−112.1. IR (NaCl, νmax, cm−1): 1681, 1602, 1591, 1362, 1297, 1078,
905, 727. Anal. Calcd for C10H8ClFO: C, 60.47; H, 4.06. Found: C,
60.34; H, 4.19.
(3E)-1-Chloro-4-(3-methoxyphenyl)-3-buten-2-one (5b). Fol-
lowing the general procedure, starting from (E)-N-methoxy-3-(3-
methoxyphenyl)-N-methylacrylamide (4b) (0.32 g, 1.43 mmol),
ICH2Cl (1.0 g, 0.41 mL, 5.7 mmol), and MeLi-LiBr (2.85 mL, 4.28
mmol) in THF, α-chloroketone 5b was obtained in 95% yield (0.29 g)
(3E)-1-Chloro-4-(2-nitrophenyl)-3-buten-2-one (5g). Follow-
ing the general procedure, starting from (E)-N-methoxy-N-methyl-3-
(2-nitrophenyl)acrylamide (4g) (0.34 g, 1.43 mmol), ICH2Cl (1.0 g,
0.41 mL, 5.7 mmol), and MeLi−LiBr (2.85 mL, 4.28 mmol) in THF,
α-chloroketone 5g was obtained in 76% yield (0.24 g) as a yellow thick
oil. 1H NMR (500 MHz, CDCl3) δ: 8.14 (d, J = 16.0 Hz, 1H), 7.72−
7.58 (m, 4H), 6.87 (d, J = 16.0 Hz, 1H), 4.38 (s, 2H). 13C NMR (126
MHz, CDCl3) δ: 190.8, 148.5, 133.7, 131.9, 130.9, 130.4, 129.2, 126.6,
125.2, 46.9. IR (NaCl, νmax, cm−1): 1684, 1605, 1592, 1360, 1273,
1128, 904, 807. Anal. Calcd for C10H8ClNO3: C, 53.23; H, 3.57; N,
6.21. Found: C, 53.35; H, 3.44; N, 6.08.
1
as a thick oil. H NMR (500 MHz, CDCl3) δ: 7.67 (d, J = 16.0 Hz,
1H), 7.33 (m, 1H), 7.18 (m, 1H), 7.08 (m, 1H), 6.95 (d, J = 16.0 Hz,
1H), 4.36 (s, 2H), 3.85 (s, 3H). 13C NMR (125 MHz, CDCl3) δ:
191.2, 158.8, 145.1, 135.2, 130.0, 121.9, 121.3, 116.9, 113.4, 55.3, 47.4.
IR (NaCl, νmax, cm−1): 1684, 1608, 1579, 1246, 905, 727. Anal. Calcd
for C11H11ClO2: C, 62.72; H, 5.26. Found: C, 62.85; H, 4.99.
(3E)-1-Chloro-4-(2-methoxyphenyl)-3-buten-2-one (5c). Fol-
lowing the general procedure, starting from (E)-N-methoxy-3-(2-
methoxyphenyl)-N-methylacrylamide (4c) (0.32 g, 1.43 mmol),
ICH2Cl (1.0 g, 0.41 mL, 5.7 mmol), and MeLi-LiBr (2.85 mL, 4.28
mmol) in THF, α-chloroketone 5c was obtained in 87% yield (0.26 g)
as a light yellow thick oil. 1H NMR (400 MHz, CDCl3) δ: 8.02 (d, J =
16.3 Hz, 1H, ArCH), 7.56 (m, 1H, Ph H-6), 7.39 (m, 1H, Ph H-4),
7.02 (d, J = 16.3 Hz, CHCO), 6.98 (m, 1H, Ph H-5), 6.93 (m, 1H,
Ph H-3), 4.33 (s, 2H, CH2Cl), 3.90 (s, 3H, ArOCH3). 13C NMR (100
MHz, CDCl3) δ: 191.6 (CO), 158.8 (Ph C-2), 140.4 (ArCH),
132.4 (Ph C-4), 129.1 (Ph C-6), 122.8 (Ph C-6), 122.4 (CHCO),
120.8 (Ph C-5), 111.2 (Ph C-3), 55.5 (ArOCH3), 47.3 (CH2Cl). IR
(NaCl, νmax, cm−1): 3075, 1682, 1613, 1583, 1242, 902, 708. Anal.
Calcd for C11H11ClO2: C, 62.72; H, 5.26. Found: C, 62.64; H, 5.13.
(3E)-1-Chloro-4-(4-methylphenyl)-3-buten-2-one6b (5d). Fol-
lowing the general procedure, starting from (2E)-N-methoxy-N-
methyl-3-(4-methylphenyl)acrylamide (4d) (0.29 g, 1.43 mmol),
ICH2Cl (1.0 g, 0.41 mL, 5.7 mmol), and MeLi−LiBr (2.85 mL, 4.28
mmol) in THF, α-chloroketone 5d was obtained in 92% yield (0.26 g)
as a yellowish solid. 1H NMR (400 MHz, CDCl3) δ: 7.69 (d, J = 16.1
Hz, 1H, ArCH), 7.48 (m, 2H, Ph H-2,6), 7.22 (m, 2H, Ph H-3,5),
6.93 (d, J = 16.1 Hz, 1H, CHCO), 4.29 (s, 2H, CH2Cl), 2.39 (s, 3H,
ArCH3). 13C NMR (100 MHz, CDCl3) δ: 191.3 (CO), 145.3
(ArCH), 141.8 (Ph C-4), 131.2 (Ph C-1), 129.8 (Ph C-3), 129.8
(Ph C-5), 128.7 (Ph C-2), 128.7 (Ph C-6), 120.6 (CHCO), 47.4
(CH2Cl), 21.6 (ArCH3). IR (NaCl, νmax, cm−1): 1690, 1662, 1618,
(3E)-1-Chloro-4-[4-(trifluoromethyl)phenyl]-3-buten-2-one
(5h). Following the general procedure, starting from (E)-N-methoxy-
N-methyl-3-(4-(trifluoromethyl)phenyl)acrylamide (4h) (0.37 g, 1.43
mmol), ICH2Cl (1.0 g, 0.41 mL, 5.7 mmol), and MeLi−LiBr (2.85
mL, 4.28 mmol) in THF, α-chloroketone 5h was obtained in 87%
1
yield (0.31 g) as a yellow thick oil. H NMR (500 MHz, CDCl3) δ:
7.72 (d, J = 16.0 Hz, 1H, COCHCH), 7.65−7.70 (m, 4H, Ph-H),
7.06 (d, J = 16.0 Hz, 1H, COCH), 4.31 (s, 2H, CH2). 13C NMR (126
MHz, CDCl3) δ: 191.0 (CO), 143.2 (COCHCH), 137.3 (Ph C-
1), 132.4 (q, J = 32.8 Hz, Ph C-4), 128.7 (Ph C-2,6), 126.0 (q, J = 3.9
Hz, Ph C-3,5), 123.7 (q, J = 272.5 Hz, CF3), 123.6 (COCH), 47.5
(CH2). 19F NMR (471 MHz, CDCl3) δ: −62.93. IR (NaCl, νmax
,
cm−1): 1684, 1604, 1593, 1362, 1173, 1077, 905, 728. Anal. Calcd for
C11H8ClF3O: C, 53.14; H, 3.24. Found: C, 53.00; H, 3.36.
1-Chloro-4-phenyl-3-butyn-2-one33 (5i). Following the general
procedure, starting from N-methoxy-N-methyl-3-phenylpropiolamide
(4i) (0.27 g, 1.43 mmol), ICH2Cl (1.0 g, 0.41 mL, 5.7 mmol), and
MeLi−LiBr (2.85 mL, 4.28 mmol) in THF, α-chloroketone 5i was
1
obtained in 90% yield (0.23 g) as a yellow thick oil. H NMR (300
MHz, CDCl3) δ: 7.64−7.54 (m, 2H), 7.51−7.37 (m, 3H), 4.33 (s,
2H). 13C NMR (126 MHz, CDCl3) δ: 179.0, 133.5, 131.6, 128.9,
128.9, 119.3, 95.5, 85.7, 49.6. IR (NaCl, νmax, cm−1): 2201, 1671, 758,
689. Anal. Calcd for C10H7ClO: C, 67.24; H, 3.95. Found: C, 67.09; H,
4.06.
E
dx.doi.org/10.1021/jo401236t | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(3E)-1-Chloro-4-(2-naphthyl)-3-buten-2-one (5j). Following
the general procedure, starting from (E)-N-methoxy-N-methyl-3-
(naphthalen-2-yl)acrylamide (4j) (0.35 g, 1.43 mmol), ICH2Cl (1.0
g, 0.41 mL, 5.7 mmol), and MeLi−LiBr (2.85 mL, 4.28 mmol) in
THF, α-chloroketone 5j was obtained in 83% yield (0.27 g) as a pale
37.2 Hz, t, J = 2.2 Hz). IR (NaCl, νmax, cm−1): 1685, 1605, 1594, 1362,
1174, 907, 724. Anal. Calcd for C10H8ClFO: C, 60.47; H, 4.06. Found:
C, 60.34; H, 3.93.
(3E)-1-Chloro-3-methyl-4-phenyl-3-buten-2-one (5o). Fol-
lowing the general procedure, starting from (E)-N-methoxy-N-2-
dimethyl-3-phenylacrylamide (4o) (0.29 g, 1.43 mmol), ICH2Cl (1.0
g, 0.41 mL, 5.7 mmol), and MeLi−LiBr (2.85 mL, 4.28 mmol) in
THF, α-chloroketone 5o was obtained in 88% yield (0.24 g) as a
1
yellow thick oil. H NMR (500 MHz CDCl3) δ 8.02−7.97 (m, 1H),
7.87 (ddd, J = 14.9, 10.2, 4.7 Hz, 4H), 7.71 (dt, J = 8.7, 2.1 Hz, 1H),
7.60−7.50 (m, 2H), 7.04 (dd, J = 47.7, 15.9 Hz, 1H), 4.34 (s, 2H). 13C
NMR (126 MHz, CDCl3) δ: 191.6, 145.7, 135.0, 133.6, 131.8, 131.7,
129.3, 129.1, 128.2, 128.1, 127.3, 123.8, 122.6, 122.0, 47.9. IR (NaCl,
νmax, cm−1): 3083, 1683, 1591, 901. Anal. Calcd for C14H11ClO: C,
72.89; H, 4.81. Found: C, 73.01; H, 4.71.
1
brown thick oil. H NMR (500 MHz, CDCl3) δ 7.52 (d, J = 1.5 Hz,
1H), 7.46−7.37 (m, 5H), 4.59 (s, 2H), 2.13 (d, J = 1.4 Hz, 3H). 13C
NMR (126 MHz, CDCl3) δ: 193.3, 140.8, 135.3, 135.1, 130.0, 130.0,
129.3, 128.7, 128.7, 45.4, 13.6. IR (NaCl, νmax, cm−1): 1677, 1598,
1574, 1378, 1093, 904, 728. Anal. Calcd for C11H11ClO: C, 67.87; H,
5.70. Found: C, 67.72; H, 5.83.
(3E,5E)-1-Chloro-6-phenyl-3,5-hexadien-2-one (5k). Follow-
ing the general procedure, starting from (E)-N-methoxy-N-methyl-3-
(naphthalen-2-yl)acrylamide (4k) (0.31 g, 1.43 mmol), ICH2Cl (1.0 g,
0.41 mL, 5.7 mmol), and MeLi−LiBr (2.85 mL, 4.28 mmol) in THF,
α-chloroketone 5k was obtained in 93% yield (0.27 g) as a brown thick
oil. 1H NMR (400 MHz, CDCl3) δ: 7.48 (m, J = 15.3 Hz, 10.7 Hz, 1H,
CHCHCO), 7.48 (m, 2H, Ph H-2, H-6), 7.38 (m, 2H, Ph H-3, H-
5), 7.35 (m, 1H, Ph H-4), 7.02 (d, J = 15.5 Hz, 1H, ArCH), 6.92
(dd, J = 15.5 Hz, 10.7 Hz, 0.6 Hz, 1H, ArCHCH), 6.52 (d, J = 15.3
Hz, 1H, CHCHCO), 4.23 (s, 2H, CH2Cl). 13C NMR (100 MHz,
CDCl3) δ: 191.1 (CO), 145.2 (CHCHCO), 143.2 (ArCH),
135.7 (Ph C-1), 129.6 (Ph C-6), 128.9 (Ph C-3), 128.9 (Ph C-5),
127.4 (Ph C-2), 127.4 (Ph C-6), 126.2 (ArCHCH), 124.8 (CH
CHCO), 47.2 (CH2Cl). IR (NaCl, νmax, cm−1): 3081, 1685, 1590,
1275, 905, 788. Anal. Calcd for C12H11ClO: C, 69.74; H, 5.36. Found:
C, 69.91; H, 5.21.
(3E)-1-Chloro-4-phenyl-3-penten-2-one34 (5p). Following the
general procedure, starting from (E)-N-methoxy-N-methyl-3-phenyl-
but-2-enamide (4p) (0.29 g, 1.43 mmol), ICH2Cl (1.0 g, 0.41 mL, 5.7
mmol), and MeLi−LiBr (2.85 mL, 4.28 mmol) in THF, α-
chloroketone 5p was obtained in 89% yield (0.25 g) as a pale yellow
1
solid. H NMR (300 MHz, CDCl3) δ 7.56−7.52 (m, 2H), 7.44−7.42
(m, 3H), 6.71 (d, J = 1.2 Hz, 1H), 4.20 (s, 2H), 2.61 (d, J = 1.3 Hz,
3H). 13C NMR (75 MHz, CDCl3) δ: 191.9, 158.5, 142.1, 129.8, 128.8,
128.8, 126.7, 126.7, 120.1, 49.6, 19.0. IR (NaCl, νmax, cm−1): 1677,
1597, 1446, 1378, 1093, 905. Mp: 71 °C (lit.34 mp 71−71.5 °C). Anal.
Calcd for C11H11ClO: C, 67.87; H, 5.70. Found: C, 67.99; H, 5.59.
(3E)-1-Chloro-4-cyclohexyl-3-buten-2-one (5q). Following the
general procedure, starting from (E)-3-cyclohexyl-N-methoxy-N-
methylacrylamide (4q) (0.28 g, 1.43 mmol), ICH2Cl (1.0 g, 0.41
mL, 5.7 mmol), and MeLi−LiBr (2.85 mL, 4.28 mmol) in THF, α-
chloroketone 5q was obtained in 87% yield (0.23 g) as a pale yellow
(3E)-1-Chloro-4-(2-thienyl)-3-buten-2-one (5l). Following the
general procedure, starting from (2E)-N-methoxy-N-methyl-3-(2-
thienyl)acrylamide(4l) (0.28 g, 1.43 mmol), ICH2Cl (1.0 g, 0.41
mL, 5.7 mmol), and MeLi−LiBr (2.85 mL, 4.28 mmol) in THF, α-
chloroketone 5l was obtained in 82% yield (0.22 g) as a brown thick
1
oil. H NMR (300 MHz, CDCl3) δ 6.92 (dd, J = 16.0, 6.8 Hz, 1H),
6.24 (dd, J = 16.0, 1.4 Hz, 1H), 4.21 (s, 2H), 2.22−2.11 (m, 1H),
1.80−1.71 (m, 5H), 1.32−1.09 (m, 5H). 13C NMR (75 MHz, CDCl3)
δ 191.6, 155.5, 123.8, 47.2, 40.9, 32.1, 31.7, 25.9, 25.9, 25.7. IR (NaCl,
νmax, cm−1): 1684, 1615, 1380, 1280, 1051, 901. Anal. Calcd for
C10H15ClO: C, 64.34; H, 8.10. Found: C, 64.47; H, 8.22.
1
oil. H NMR (400 MHz, CDCl3) δ: 7.83 (d, J = 15.6, 1H ArCH),
3
3
7.45 (dd, J = 5.1, 1H, Th H-5), 7.36 (d, J = 3.6 Hz, 1H, Th H-3),
7.09 (dd, 3J = 5.1 Hz, 3J = 3.6 Hz, 1H, Th H-4), 6.76 (d, J = 15.6 Hz,
1H; CHCO), 4.24 (s, 2H, CH2Cl). 13C NMR (100 MHz, CDCl3)
δ: 190.9 (CO), 139.4 (Th C-2), 137.5 (1J = 158.1 Hz, ArCH),
132.8 (1J (ThC3,H3) = 167.5 Hz, Th C-3), 129.8 (1J (ThC5,H5) =
186.8 Hz, 2J (ThC5,H4) = 7.3 Hz, 3J (ThC5,H3) = 10.9 Hz, Th C-5),
128.5 (1J (ThC4,H4) = 169.5 Hz, 2J (ThC4,H3) = 5.2 Hz, 3J
(ThC4,H5) = 4.0 Hz, Th C-4), 120.1 (1J = 159.3 Hz, 3J = 2.8 Hz, 
CHCO), 47.4 (1J(CH2) = 149.4 Hz, 3J(CH2, CH) = 2.8 Hz,
CH2Cl). IR (NaCl, νmax, cm−1): 3078, 1681, 1587, 1279. Anal. Calcd
for C8H7ClOS: C, 51.48; H, 3.78; S, 17.18. Found: C, 51.48; H, 3.63;
S, 17.32.
(3E/Z)-1-Chloro-4-cyclopropyl-3-buten-2-one (5r). Following
the general procedure, starting from (E)-3-cyclopropyl-N-methoxy-N-
methylacrylamide (4r) (0.22 g, 1.43 mmol), ICH2Cl (1.0 g, 0.41 mL,
5.7 mmol), and MeLi−LiBr (2.85 mL, 4.28 mmol) in THF, α-
chloroketone 5r was obtained in 91% yield (0.19 g) as a pale yellow
1
oil. H NMR (300 MHz, CDCl3) δ: 6.48−6.38 (m, 3.4H, major +
minor), 4.16 (s, 2H, major), 3.86 (s, 1.1H, minor), 1.65−1.59 (m, 2H,
major + minor), 1.05−1.02 (m, 3.5H major + minor), 0.75−0.69 (m,
3.5H, major + minor). 13C NMR (75 MHz, CDCl3) δ: 191,4, 190.3,
156.0, 155.8, 123.0, 122.7, 47.0, 15.2, 15.0, 9.5, 9.4, 4.6. IR (NaCl, νmax
,
(3E)-1-Chloro-4-(2-furyl)-3-buten-2-one6a (5m). Following the
general procedure, starting from (E)-3-(furan-2-yl)-N-methoxy-N-
methylacrylamide (4m) (0.26 g, 1.43 mmol), ICH2Cl (1.0 g, 0.41
mL, 5.7 mmol), and MeLi−LiBr (2.85 mL, 4.28 mmol) in THF, α-
chloroketone 5m was obtained in 77% yield (0.19 g) as a colorless
cm−1): 1686, 1681, 1597, 1381, 903. Anal. Calcd for C7H9ClO: C,
58.14; H, 6.27. Found: C, 58.28; H, 6.42.
ASSOCIATED CONTENT
■
1
thick oil. H NMR (300 MHz, CDCl3) δ: 7.53 (d, J = 1.8 Hz, 1H),
S
* Supporting Information
Copies of 1H NMR and 13C NMR for all compounds (Weinreb
amides and α-haloketones). This material is available free of
charge via the Internet at http://pubs.acs.org.
7.47 (d, J = 15.6 Hz, 1H), 6.86 (d, J = 15.6 Hz, 1H), 6.74 (d, J = 3.5
Hz, 1H), 6.51 (dd, J = 3.5, 1.8 Hz, 1H), 4.24 (s, 2H). 13C NMR (75
MHz, CDCl3) δ: 191.6, 151.3, 146.2, 131.5, 119.3, 117.9, 113.4, 48.2.
IR (NaCl, νmax, cm−1): 3087, 1691, 1606, 1590, 1232, 908, 809. Anal.
Calcd for C8H7ClO2: C, 56.32; H, 4.14. Found: C, 56.44; H, 4.26.
(3Z)-1-Chloro-3-fluoro-4-phenyl-3-buten-2-one16 (5n). Fol-
lowing the general procedure, starting from (2Z)-2-fluoro-N-
methoxy-N-methyl-3-phenylacrylamide (4n) (0.29 g, 1.43 mmol),
ICH2Cl (1.0 g, 0.41 mL, 5.7 mmol), and MeLi−LiBr (2.85 mL, 4.28
mmol) in THF, α-chloroketone 5n was obtained in 91% yield (0.26 g)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: vpace@farm.ucm.es.
Notes
1
as a light yellow thick oil. H NMR (400 MHz, CDCl3) δ: 7.68 (m,
The authors declare no competing financial interest.
2H; Ph H-2,6), 7.43 (m, 3H, Ph H-3,4,5), 6.95 (d, J = 37.2 Hz, 1H
ArCH), 4.51 (d, J = 2.3 Hz, CH2Cl). 13C NMR (100 MHz, CDCl3)
δ: 185.8 (d, 2J = 34.6 Hz, CO), 152.4 (d, 1J = 270.4, 1J (CF, CH)
=6.0 Hz, CF), 131.0 (d, 4J = 8.2, Ph C-2), 131.0 (d, 4J = 8.2, Ph C-
ACKNOWLEDGMENTS
■
6
The University of Vienna and the Federal Austrian Ministry of
Education for a postgraduate Ernst Mach fellowship (to L.C.)
are gratefully acknowledged for support.
6) 130.5 (d, J = 2.8 Hz, Ph C-4), 130.4 (Ph C-1), 129.0 (Ph C-3),
2
129.0 (Ph C-5), 117.3 (d, J = 4.2 Hz, ArCH), 45.6 (1J (CH2) =
150.0 Hz, CH2Cl). 19F NMR (377 MHz, CDCl3) δ: −127.6 (d, J =
F
dx.doi.org/10.1021/jo401236t | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(19) Chen, G.; Cho, S. J.; Huang, X.-P.; Jensen, N. H.; Svennebring,
A.; Sassano, M. F.; Roth, B. L.; Kozikowski, A. P. ACS Med. Chem. Lett.
2011, 2, 929−932.
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