Superacidic activation of α,β-unsaturated amides and their electrophilic reactions

Article abstract of DOI:10.1002/ejoc.200400313

The electrophilic reactivity of α,β-unsaturated amides towards weak nucleophiles such as arenes and cyclohexane, initiated either with triflic acid (CF₃SO₃H) or with excess AlCl₃, has been studied. The amides generally condense readily with aromatics in the presence of AlCl₃ to give 3-arylpropionamides and related compounds in excellent yields, while some amides also undergo selective ionic hydrogenation with cyclohexane to give saturated amides. The proposed mechanism of these reactions involves dicationic intermediates (superelectrophiles). The direct observation of a dicationic species (by low-temperature NMR) is reported. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200400313

FULL PAPER
Superacidic Activation of α,β-Unsaturated Amides and Their Electrophilic
Reactions[‡]
[a]
[a]
[a]
´
Konstantin Yu. Koltunov,* Stephane Walspurger, and Jean Sommer
Keywords: Electrophilic reactions / Superacids / Superelectrophilic activation
The electrophilic reactivity of α,β-unsaturated amides to-
wards weak nucleophiles such as arenes and cyclohexane,
initiated either with triflic acid (CF3SO3H) or with excess
AlCl3, has been studied. The amides generally condense
readily with aromatics in the presence of AlCl3 to give 3-
arylpropionamides and related compounds in excellent
drogenation with cyclohexane to give saturated amides. The
proposed mechanism of these reactions involves dicationic
intermediates (superelectrophiles). The direct observation of
a dicationic species (by low-temperature NMR) is reported.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
yields, while some amides also undergo selective ionic hy- Germany, 2004)
Introduction
theoretical calculations[7,10] and, in some cases, low-tem-
perature NMR observations.[7,14]
The analogous reactivity of α,β-unsaturated amides has
not thus far been investigated. However, superacidic acti-
vation of the amides could involve their O-protonation[16,17]
or O-complexation[18] with Lewis acid, with subsequent
additional protonation of CϭC (or CϵC) bonds. Thus, it
was recently shown that cinnamanilide 5 cleanly undergoes
intramolecular cyclization in triflic acid to give quinolinone
6 in good yield.[19] It was postulated that superelectrophilic
activation involved O,C-diprotonation of 5 to produce di-
cations 7 (X ϭ H; Scheme 2). Similar reaction also occurred
under classical FriedelϪCrafts conditions at elevated tem-
perature to give 6, albeit in lower yields due to its sub-
sequent reversible conversion into carbostyril 8.[19Ϫ21] The
latter reaction is predominant, for example, upon treatment
of 5 with excess AlCl3 in chlorobenzene.[22] Remarkably,
similar treatment of 5 in benzene mostly gives product 9,
due to competing intermolecular reaction (Scheme 2).[22]
Given the reactivities of unsaturated carbonyl com-
pounds 1 and amide 5, it seemed likely that a variety of α,β-
unsaturated amides might also generally exhibit analogous
reactivity. In this paper we wish to present our study on
superacid-induced reactivity of α,β-unsaturated amides
towards aromatic compounds and cyclohexane.
Despite their broad utility in organic chemistry, little
work has been done to investigate the reactivity of amides
towards weak nucleophiles such as nonactivated arenes and
alkanes. Their reactions in FriedelϪCrafts-type chemistry
are unusual and are mostly known for BischlerϪ
Napieralski and related methods of preparation of hetero-
cyclic compounds.[2,3] The use of amides has serious limi-
tations because of competing hydrolysis and other acid-cat-
alysed reactions. In contrast, FriedelϪCrafts reactions in-
volving other carbonyl compounds are well known and are
widely used in organic synthesis; α,β-unsaturated aldehydes,
ketones and carboxylic acids (common structure 1), for ex-
ample, offer a route to a variety of corresponding β-aryl-
ated derivatives 2 (Scheme 1).[4] In liquid superacids, com-
pounds 1 generally give indanones and indenes as second-
ary products.[5Ϫ7] Ketones 1 (Y ϭ Alk, Ar) also undergo
selective ionic hydrogenation with cyclohexane in super-
acidic media.[8Ϫ10] The key reactive intermediates in this
range of reactions (provided R ϭ Alk or Ar) were recog-
nised to be superelectrophilic[11Ϫ13] dicationic species
3.[7Ϫ10,14] The concentrations of these species, the result of
a second protonation of the less reactive monocationic form
4, are generally too low for direct observation by NMR as
long-living dications. The intermediacy of a dicationic spec-
ies is, however, strongly supported by kinetic studies,[5,15]
Results and Discussion
[‡]
For preliminary publication, see ref.[1]
[a]
Benzene was used as the first aromatic substrate, in reac-
tions with amides 10aϪh in the presence of AlCl3. As ex-
pected, β-addition products 11aϪh were mostly produced
(Table 1). The reaction takes place under mild conditions,
Laboratoire de physico-chimie des hydrocarbures, UMR 7513,
´
Universite L. Pasteur,
4 rue B. Pascal, 67000 Strasbourg, France
Fax: (internat.) ϩ 33-390241487
E-mail: kkoltunov@chimie.u-strasbg.fr
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DOI: 10.1002/ejoc.200400313
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K. Y. Koltunov, S. Walspuger, J. Sommer
FULL PAPER
Scheme 1. Reactions of compounds 1 with aromatics and cyclohexane
Scheme 2. Electrophilic reactions of cinnamanilide 5
at room temperature, and appears to be fast (reaction time to the ability of excess quantities of aluminium halides to
0.5 to 5 h) in the presence of a 2.5-fold molar excess of produce low concentrations of highly acidic protonic super-
AlCl3. This procedure is very clean and gives the products acids, such as HAlHal4 and HAl(OH)Hal3 (Hal ϭ Cl, Br),
in good or quantitative yields. In the case of methacrylam- through reaction with water (usually present in ‘‘dry’’ com-
ide (10b) both β- and α-phenylated derivatives 11b and 14 mercially available materials).[9,27] For purposes of compari-
were obtained, with the former dominating, in reaction be- son, the HBr/AlBr3 system (Ho Ϫ17.5[9]) has been claimed
haviour similar to that of the analogous methacrylic acid.[2] to be a 103 times stronger acid than triflic acid (Ho ϭ
The reactivities of acetylenic amides 10h and 10i appeared Ϫ14.1[9]).
to be similar to those of their ethylenic analogues 10d and
When amides 10aϪe, 10g and 10h were involved in reac-
5. Remarkably, the cyclization of 10i into 4-phenylcarbos- tion with o-dichlorobenzene, a poor nucleophile normally
tyril (15) was previously known to occur in large excesses inert towards electrophilic alkylation,[28] notable differences
of polyphosphoric acid, requiring 120 °C in order to pro- in their reactivities were demonstrated. Precursors 10cϪe,
ceed.[23]
10g and 10h, unlike 10aϪb, reacted readily with this arene
It was also demonstrated, with the examples of amides to give mostly the corresponding addition products 12
10a, 10e and 10i, that the same reactions were initiated, but (Table 1). Similar differences in reactivity were also found
not as efficiently, by triflic acid (Table 1). This result is in for reaction with cyclohexane: compound 10g smoothly
agreement with earlier observations: the efficiency of elec- underwent selective ionic hydrogenation to give the satu-
trophilic activation through the action of excesses of alu- rated derivative 13g. Amide 10d also reacted with cyclohex-
minium halides is similar to that achieved by strong super- ane under mild conditions, but to give a complex reaction
acids such as CF3SO3HϪSbF5 (Ho Ϫ16 to Ϫ18.5[9]) and mixture, probably due to secondary reactions similar to
even HFϪSbF5 (Ho Ͻ Ϫ20 [9]).[19,24Ϫ26] This may be related those previously described for analogous ionic hydrogen-
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Superacidic Activation of α,β-Unsaturated Amides
FULL PAPER
ation of ketones 1 (R ϭ Ph).[10] Compound 10c did not reactivity in triflic acid, which is acidic enough for exhaus-
react at room temperature, but at elevated temperature it tive O-protonation of the amides,[16] (ii) the higher reactivit-
gave 13c in good yield (93%). In contrast, amides 10a and ies of 10e and 10f than of 10aϪb toward benzene, whereas
10b reacted slowly with cyclohexane at elevated temperature the latter should produce significantly stronger monoc-
to give 13a and 13b in low yields (Table 1).
ationic electrophiles 17, (iii) and, moreover, the remarkably
There are two possible mechanistic pathways for the elec- high reactivities of amides 10dϪg towards such weak
trophilic reactions of amides 10aϪg. At least in case of pre- nucleophiles as o-dichlorobenzene and cyclohexane. For
cursors 10cϪg, the proposed reaction mechanism suggests this reason we suggest that the reactive intermediate is the
the formation of superelectrophilic dicationic intermediates dicationic species 16, probably in equilibrium with the cor-
such as α-C-protonated complexes 16 (X ϭ AlnCl3nϪ) or responding monocations 17. In the cases of amides 10a and
analogous O,C-diprotonated dications 16 (X ϭ H) in low 10b, however, the key intermediates are most probably
concentrations (Scheme 3).
monocationic species 17. These species seem to be electro-
Similarly, dicationic species 7 may be regarded as key philic enough to react with benzene under mild conditions,
alkylating intermediates in the reaction 5 Ǟ 9 (Scheme 2). but not sufficiently reactive towards cyclohexane and o-di-
In our opinion, to view these reactions as ‘‘traditional’’ chlorobenzene.
FriedelϪCrafts alkylations (ionic hydrogenations) involving
In view of the close basicity of CϭC and CϵC bonds,[29]
the intermediacy only of monocationic species 17 cannot we also suggest the reactivity of acetylenic amides 10h and
explain all the experimental results, such as: (i) the lower 10i be considered as involving the intermediacy of dicat-
Table 1. Electrophilic reactions of amides 10aϪi
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K. Y. Koltunov, S. Walspuger, J. Sommer
FULL PAPER
Table 1 (continued)
[a] The yields are of isolated, pure products. [b] Recovery of 10a is 80%. [c] The overall yield of isomeric 3-(2,3- and 3,4-dichlorophenyl)pro-
pionamides. [d] The overall yield of mixture 11b and 14 in 2:1 ratio. [e] Predominant formation of 3,3-diaryl-2-propenamides was detected
by NMR monitoring.
Scheme 3. Proposed mechanism for the electrophilic reactions of amides 10cϪg
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Superacidic Activation of α,β-Unsaturated Amides
FULL PAPER
Scheme 4. Proposed mechanism for the electrophilic reactions of amides 10h and 10i
ionic species 18 (Scheme 4). A similar mechanism, invoking group signal around δ ϭ 4.6 ppm in the proton NMR and
O,C-diprotonated species, was suggested and supported by δ ϭ 36 ppm in the carbon NMR. The proton spectrum also
theoretical calculations for the ‘‘parent’’ reaction between shows the signal of the hydrogen bound to the carbonyl
phenylacetylenecarboxylic acid and benzene in the presence oxygen at δ ϭ 10.6 ppm and the signal of the amino hydro-
of triflic acid.[7]
gens at δ ϭ 8.7 ppm (HSO3F, Ϫ80 °C), similarly to chemi-
Our attempts to observe cationic or dicationic intermedi- cal shifts of O-protonated amides.[16] The chemical shifts of
ates as long-lived species by NMR under superacid con- signals assigned to the benzylic site of the dication are in
ditions gave the following results:
agreement with those reported for analogous benzylic dicat-
1. In HSO3FϪSbF5(ϪSO2) and CF3SO3HϪSbF5, com- ionic systems.[30] Furthermore, we also succeeded in ob-
pounds 10dϪg and 5 essentially gave side products, most serving a similar O,C-diprotonated dication 19 by pro-
probably due to oxidation by SbF5.
tonation of 4-methoxycinnamic acid (20) in fluorosulfuric
2. In the weaker superacids, HSO3F (Ho ϭ Ϫ15.1[9]) or acid. Dications 16g and 19 are believed to be close ana-
CF3SO3H, only O-monoprotonated cations were observed logues of dications 3aϪe previously generated upon pro-
when 10dϪf and 5 were dissolved.
tonation of β-phenylcinnamic acid,[7] α,β-unsaturated ke-
3. The 1H and 13C NMR spectra obtained when 10g was tones,[14] 2-naphthols[31,32] and 4-hydroxy-1-methyl-
dissolved in HSO3F or CF3SO3H at Ϫ80 °C (Ϫ30 °C, 2(1H)quinolinone,[19] respectively, in the stronger superac-
respectively) showed total conversion of the compound into ids HSO3F(HF)ϪSbF5ϪSO2ClF or CF3SO3HϪSbF5
O,C-diprotonated dication 16g (Scheme 5). This, due to (Scheme 5).
hindered rotation about the CϪC6H4ϪOCH3 bonds, shows
4. Our attempts to generate dicationic species 16 by treat-
two ‘‘frozen’’ conformers (cis/trans isomers) of the dication ment with aluminium halides were unsuccessful. Dissolving
in 1:2 ratio (HSO3F, Ϫ80 °C). The spectra show the CH2 amide 10g in an AlBr3/CH2Br2 system gave, as expected,
Scheme 5. Generation of long-living dications 16g and 19 and related structures 3aϪe
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K. Y. Koltunov, S. Walspuger, J. Sommer
FULL PAPER
the corresponding complex 17 (X ϭ AlnBr3nϪ), but sub-
sequent saturation of the obtained solution with gaseous
HBr resulted in side reactions.
From the synthetic point of view, the studied reactions
may represent a convenient alternative to known prep-
arations of 3-arylpropionamides, important intermediates
in organic synthesis.[33Ϫ36] It is also worth noting that the
utility of AlCl3 as a plausible alternative to strong protic
(super)acids to initiate reactions involving superelectro-
philic species has probably been underestimated. Whereas
the presence of small amounts of base (water) drastically
minium chloride, benzene and compounds 10a, 10b, 10d and 20
were purchased and used as received. Amides 10c and 10eϪi were
prepared from the corresponding commercially available carboxylic
acids by treatment with excess SOCl2, followed by quenching with
aqueous ammonia or an amine. Antimony pentafluoride was dis-
tilled twice under argon. Elevated temperature reactions were car-
ried out in 15 mL pressure tubes.
Dications 16g and 19 were generated by carefully dissolving
samples of 10g and 20 (10 mg), respectively, in NMR tubes filled
with 0.5 mL of fluorosulfuric (triflic) acid at Ϫ78 °C (Ϫ30 °C).
Dication 16g, Major Isomer: (HSO3F, Ϫ80 °C) 1H NMR: δ ϭ 4.52
decreases the acidity of superacid,[37] traces of humidity are (s, 3 H), 4.57 (s, 2 H), 7.36 (d, J ϭ 7 Hz, 1 H), 7.53 (d, J ϭ 7 Hz,
1 H), 8.31 (s, 1 H), 8.32 (d, J ϭ 7 Hz, 1 H), 8.4 (d, J ϭ 7 Hz, 1
H), 8.66 (br. s, 2 H), 10.6 (br. s, 1 H) ppm. 13C NMR: δ ϭ 35.7,
62.2, 118.7, 127, 136.3, 143.2, 158.1, 171.4, 177.2, 188.7 ppm.
rather beneficial to the reactivity of aluminium halides,
which may be used without special dryness of starting mate-
rials or solvent and do not require inert gas atmospheres.
Recently, we have also found that many reactions proceed-
ing through dicationic, superelectrophilic intermediates can
be successfully mediated by H-form zeolites and other avail-
able solid acids.[38] Among other reactions, the transform-
ations 5 Ǟ 6, 10i Ǟ 15 and 10e Ǟ 11e, 12e have been per-
formed.[38]
During the preparation of this paper we have learned of
new data in press concerning the possibility of superelectro-
philic activation of amides with triflic acid, which provided
an increase in the reactivities both of a protonated amide
group and of closely situated protonated functional groups,
resulting in acylation or alkylation of aromatics.[39] This is
in agreement with our results.
1
Minor Isomer: H NMR: δ ϭ 4.52 (s, 3 H), 4.57 (s, 2 H), 7.32 (d,
J ϭ 7 Hz, 1 H), 7.59 (d, J ϭ 7 Hz, 1 H), 8.17 (d, J ϭ 7 Hz, 1 H),
8.31 (s, 1 H), 8.57 (d, J ϭ 7 Hz, 1 H), 8.66 (br. s, 2 H), 10.6 (br. s,
1 H) ppm. 13C NMR: δ ϭ 35.7, 62.2, 120, 125.5, 136.3, 147.8,
153.2, 171.4, 177.2, 188.6 ppm.
1
Dication 19, Major Isomer: (HSO3F, Ϫ80 °C) H NMR: δ ϭ 4.54
(s, 3 H), 4.83 (s, 2 H), 7.37 (d, J ϭ 7 Hz, 1 H), 7.55 (d, J ϭ 7 Hz,
1 H), 8.3 (s, 1 H), 8.29 (d, J ϭ 7 Hz, 1 H), 8.4 (d, J ϭ 7 Hz, 1 H)
ppm. 13C NMR: δ ϭ 36.3, 62.3, 119, 127.1, 136.2, 143.3, 158.2,
1
168.2, 189, 189.3 ppm. Minor Isomer: H NMR: δ ϭ 4.54 (s, 3 H),
4.83 (s, 2 H), 7.33 (d, J ϭ 7 Hz, 1 H), 7.61 (d, J ϭ 7 Hz, 1 H), 8.2
(d, J ϭ 7 Hz, 1 H), 8.3 (s, 1 H), 8.55 (d, J ϭ 7 Hz, 1 H) ppm. 13C
NMR: δ ϭ 36.3, 62.4, 120.2, 125.7, 136.1, 147.9, 153.2, 168, 188.9,
189.3 ppm.
Quenching of these acidic solutions with ice provided the starting
materials once more, whereas their preliminary warming to Ϫ30Ϫ0
°C caused irreversible changes.
Conclusion
Reactions with Benzene
A direct, one-step synthesis of β-arylpropionamides and
related compounds through superacid-induced reactions
between α,β-unsaturated amides and aromatic species has
been developed. α,β-Unsaturated amides also undergo
selective ionic hydrogenation with cyclohexane to give their
saturated derivatives. We suggest that dicationic electro-
philes, such as those directly observable by low-temperature
NMR when α,β-unsaturated amides are dissolved in liquid
superacids, offer a convenient explanation consistent with
the reaction mechanism. In general, the ability of α,β-un-
saturated amides to undergo activation in the presence of
strongly acidic agents through the formation of dicationic
intermediates makes it possible for the latter to act as a
novel synthons and extends the applicability of
FriedelϪCrafts-type reactions in the field of amides.
3-Phenylpropionamide (11a): Compound 10a (0.2 g, 2.8 mmol) was
added to a stirred mixture of AlCl3 (0.95 g, 7.1 mmol) and benzene
(3 mL). The resulting mixture was stirred at 25 °C for 2 h, and was
then poured over several grams of ice and extracted with CH2Cl2.
The organic phase was separated, dried with anhydrous Na2SO4
and concentrated in vacuo to give white crystalline 11a (0.419 g,
99%): M.p. 103Ϫ104 °C, ref.[40a] m.p. 104Ϫ105 °C. H NMR: δ ϭ
2.52 (t, J ϭ 7.8 Hz, 2 H), 2.96 (t, J ϭ 7.8 Hz, 2 H), 5.49 (br. s, 1
H), 5.86 (br. s, 1 H), 7.1Ϫ7.3 (m, 5 H) ppm.[40b] 13C NMR: δ ϭ
31.4, 37.5, 126.3, 128.3, 128.6, 140.7, 174.8 ppm.[40b]
1
2-Methyl-3-phenylpropionamide (11b) and 2-Methyl-2-phenylpro-
pionamide (14): A mixture of AlCl3 (0.95 g, 7.1 mmol) and 10b
(0.2 g) in benzene (3 mL) was stirred at 25 °C for 3 h followed by
workup as described above to give a solid mixture of 11b and 14
(0.41 g, 97%) in 2:1 ratio. C10H13NO (163.2): calcd. C 73.6, H 8,
1
N 8.6; found C 73.4, H 7.9, N 8.2. Compound 11b: H NMR: δ ϭ
1.17 (d, J ϭ 6.8 Hz, 3 H), 2.53 (m, 1 H), 2.66 (dd, J ϭ 13.0 Hz7,
7.2 Hz, 1 H), 2.99 (dd, J ϭ 13.0 Hz7, 7.3 Hz, 1 H), 5.3 (br. s, 1 H),
5.6 (br. s, 1 H), 7.1Ϫ7.4 (m, 5 H) ppm. 13C NMR: δ ϭ 17.6, 40.2,
42.8, 126.3, 128.4, 129, 139.7, 178.7 ppm. Compound 14: 1H NMR:
δ ϭ 1.58 (s, 6 H), 5.2 (br. s, 1 H), 5.7 (br. s, 1 H), 7.1Ϫ7.4 (m, 5 H)
ppm. 13C NMR: δ ϭ 26.9, 46.8, 127, 128.4, 128.7, 145, 180.4 ppm.
Experimental Section
General Remarks: The 1H and 13C NMR spectra were recorded
with a Bruker ADVANCE 300 spectrometer at 300.17 and
75.48 MHz, respectively. The chemical shifts were measured relative
to the solvent signals (CDCl3, δ ϭ 7.26 ppm and δC ϭ 77.0 ppm).
The chemical shifts of dications 16g and 19 in fluorosulfuric acid
were measured relative to internal dichloromethane (δ ϭ 5.32 ppm
and δC ϭ 54.0 ppm) with a Bruker AM 400 spectrometer at 400
and 100 MHz, respectively. Triflic and fluorosulfuric acids, alu-
3-Phenylbutyramide (11c): A mixture of AlCl3 (0.37 g, 2.8 mmol)
and 10c (0.1 g, 1.2 mmol) in benzene (3 mL) was stirred at 25 °C
for 3 h and after usual workup gave 11c (0.178 g, 93%) as a white
crystalline solid: M.p. 104Ϫ105 °C, ref.[41a] m.p. 104Ϫ105 °C. 1H
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Superacidic Activation of α,β-Unsaturated Amides
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NMR: δ ϭ 1.31 (d, J ϭ 7 Hz, 3 H), 2.41 (dd, J ϭ 14.3, 7.8 Hz, 1
H), 2.5 (dd, J ϭ 14.3, 7.8 Hz, 1 H), 3.26 (m, 1 H), 5.45 (br. s, 1
49.6, H 4.2, N 6.4; found C 49.4, H 4.3, N 6.3. Compound 12a-1:
1H NMR: δ ϭ 2.51 (t, J ϭ 7.4 Hz, 2 H), 2.93 (t, J ϭ 7.4 Hz, 2 H),
H), 5.87 (br. s, 1 H), 7.15Ϫ7.3 (m, 5 H) ppm.[41b] 13C NMR: δ ϭ 5.5 (br. s, 1 H), 5.8 (br. s, 1 H), 7.05 (dd, J ϭ 8.2, 2.1 Hz, 2 Hz, 1
17.8, 36.8, 44.8, 126.5, 126.8, 128.6, 145.8, 174.5 ppm.
H), 7.31 (d, J ϭ 2.1 Hz, 2 Hz, 1 H), 7.35 (d, J ϭ 8.2 Hz, 1 H) ppm.
Compound 12a-2: H NMR: δ ϭ 2.55 (t, J ϭ 7.4 Hz, 2 H), 3.13 (t,
J ϭ 7.4 Hz, 2 H), 5.6 (br. s, 1 H), 5.7 (br. s, 1 H), 7.07 (t, J ϭ 7.6
Hz, 1 H), 7.13 (dd, J ϭ 7.6 Hz, 2 Hz, 1 H), 7.26 (d, J ϭ 7.6 Hz, 1
H) ppm.
1
3,3-Diphenylpropionamide (11d): mixture of AlCl3 (0.5 g,
A
3.7 mmol) and 10d (0.2 g, 1.4 mmol) in benzene (3 mL) was stirred
at 25 °C for 4 h and after usual workup gave 11d (0.298 g, 97%) as
a white crystalline solid: M.p. 127Ϫ128 °C, ref.[42a] m.p. 125Ϫ126
1
°C. H NMR: δ ϭ 2.94 (d, J ϭ 7.8 Hz, 2 H), 4.55 (t, J ϭ 7.8 Hz,
3-(3,4-Dichlorophenyl)butyramide (12c-1) and 3-(2,3-Dichlorophe-
nyl)butyramide (12c-2): Ratio 2.5:1. C10H11Cl2NO (232.1): calcd. C
51.8, H 4.8, N 6; found C 51.7, H 4.9, N 6.1. Compound 12c-1: 1H
NMR: δ ϭ 1.31 (d, J ϭ 6.9 Hz, 3 H), 2.3Ϫ2.6 (m, 2 H), 3.25 (m,
1 H), 5.7 (br. s, 1 H), 5.9 (br. s, 1 H), 7.15Ϫ7.3 (m, 3 H) ppm.
Compound 12c-2: 1H NMR: δ ϭ 1.28 (d, J ϭ 6.9 Hz, 3 H), 2.3Ϫ2.6
(m, 2 H), 3.8 (m, 1 H), 5.7 (br. s, 1 H), 6.1 (br. s, 1 H), 7.15Ϫ7.3
(m, 3 H) ppm.
1 H), 5.29 (br. s, 1 H), 5.41 (br. s, 1 H), 7.15Ϫ7.3 (m, 10 H) ppm.[42b]
13C NMR: δ ϭ 42.4, 47.2, 126.6, 127.7, 128.6, 143.6, 173.4 ppm.
N,N-Diethyl-3,3-diphenylpropionamide (11e). Method a: A mixture
of AlCl3 (0.6 g, 4.5 mmol) and 10e (0.4 g, 2 mmol) in benzene
(4 mL) was stirred at 25 °C for 0.5 h and after workup gave 11e
(0.554 g, 100%) as a white crystalline solid: M.p. 77Ϫ78 °C, ref.[43]
1
m.p. 76 °C. H NMR: δ ϭ 0.99 (t, J ϭ 7.2 Hz, 3 H), 1.06 (t, J ϭ
7.2 Hz, 3 H), 3.01 (d, J ϭ 7.5 Hz, 2 H), 3.16 (q, J ϭ 7.2 Hz, 2 H),
3.29 (q, J ϭ 7.2 Hz, 2 H), 4.75 (t, J ϭ 7.5 Hz, 1 H), 7.1Ϫ7.3 (m,
10 H) ppm. 13C NMR: δ ϭ 12.7, 14.2, 38.9, 40.2, 41.7, 47.1, 126.1,
127.8, 128.2, 144.1, 169.9 ppm. Method b: Compound 10e (0.2 g,
1 mmol) was introduced into a mixture of triflic acid (1 g,
6.7 mmol) and benzene (1 mL) and the mixture was stirred at 25
°C for 15 h. After the reaction mixture had been poured over
several grams of ice, the resulting mixture was extracted with di-
ethyl ether. The organic phase was washed with water and aqueous
ammonia, dried (Na2SO4) and concentrated to give 11e (0.274 g,
99%).
3-(3,4-Dichlorophenyl)-3-phenylpropionamide (12d-1) and 3-(2,3-Di-
chlorophenyl)-3-phenylpropionamide
(12d-2):
Ratio
5:1.
C15H13Cl2NO (294.2): calcd. C 61.2, H 4.5, N 4.8; found C 61, H
1
4.6, N 4.5. Compound 12d-1: H NMR: δ ϭ 2.88 (dd, J ϭ 8.1 Hz,
1 Hz, 2 H), 4.51 (t, J ϭ 8.1 Hz, 1 H), 5.7 (br. s, 1 H), 5.9 (br. s, 1
H), 7Ϫ7.3 (m, 8 H) ppm. 13C NMR: δ ϭ 41.8, 46.2, 126.7, 127,
127.6, 128.7, 128.9, 129.7, 130.5, 132.5, 142.5, 144, 173.2 ppm.
Compound 12d-2: 1H NMR: δ ϭ 2.91 (dd, J ϭ 8.1 Hz, 1 Hz, 2 H),
5.05 (t, J ϭ 8.1 Hz, 1 H), 5.8 (br. s, 1 H), 6 (br. s, 1 H), 7Ϫ7.3 (m,
8 H) ppm.
3-(3,4-Dichlorophenyl)-N,N-diethyl-3-phenylpropionamide (12e-1)
and 3-(2,3-Dichlorophenyl)-N,N-diethyl-3-phenylpropionamide (12e-
2): Ratio 7:1. C19H21Cl2NO (350.3): calcd. C 65.1, H 6, N 4; found
C 64.9, H 6.2, N 3.7. Compound 12e-1: 1H NMR: δ NMR: δ ϭ
0.99 (t, J ϭ 7.2 Hz, 3 H), 1.08 (t, J ϭ 7.2 Hz, 3 H), 2.98 (dd, J ϭ
7.5 Hz, 1 Hz, 2 H), 3.21 (q, J ϭ 7.2 Hz, 2 H), 3.31 (q, J ϭ 7.2 Hz,
2 H), 4.7 (t, J ϭ 7.5 Hz, 1 H), 7Ϫ7.3 (m, 8 H) ppm. 13C NMR:
δ ϭ 12.9, 14.4, 38.8, 40.4, 46.3, 126.8, 127.5, 127.8, 128.5, 128.7,
4-(3,3-Diphenylpropionyl)morpholine (11f): A mixture of AlCl3
(0.29 g, 2.15 mmol) and 10f (0.15 g, 0.69 mmol) in benzene (3 mL)
was stirred at 25 °C for 0.5 h and after usual workup gave 11f
(0.2039 g, 100%) as a white crystalline solid: M.p. 144Ϫ146 °C. 1H
NMR: δ ϭ 3.04 (d, J ϭ 7.6 Hz, 2 H), 3.29 (s, 4 H), 3.52 (s, 4 H),
4.67 (t, J ϭ 7.6 Hz, 1 H), 7.15Ϫ7.3 (m, 10 H) ppm. 13C NMR: δ ϭ
38.5, 42, 46.2, 47.5, 66.4, 66.8, 126.5, 127.9, 128.6, 144, 169.9 ppm.
C19H21NO2 (295.4): calcd. C 77.3, H 7.2, N 4.7; found C 77.2, H
7.3, N 4.5.
1
129.8, 130.3, 132.3, 143.2, 144.7, 169.4 ppm. Compound 12e-2: H
NMR: δ ϭ 0.99 (t, J ϭ 7.2 Hz, 3 H), 1.08 (t, J ϭ 7.2 Hz, 3 H),
3.01 (d, J ϭ 7.5 Hz, 2 H), 3.21 (q, J ϭ 7.2 Hz, 2 H), 3.31 (q, J ϭ
7.2 Hz, 2 H), 5.21 (t, J ϭ 7.5 Hz, 1 H), 7Ϫ7.3 (m, 8 H) ppm.
3-(4-Methoxyphenyl)-3-phenylpropionamide (11g): A mixture of
AlCl3 (0.4 g, 3 mmol) and 10g (0.1 g, 0.57 mmol) in benzene (3 mL)
was vigorously stirred at 25 °C for 5 h and after workup gave 11g
(0.141 g, 98%) as a white solid: M.p. 141Ϫ143 °C, ref.[44] m.p. 140
°C. 1H NMR: δ ϭ 2.91 (d, J ϭ 7.8 Hz, 2 H), 3.76 (s, 3 H), 4.51 (t,
J ϭ 7.8 Hz, 1 H), 5.25 (br. s, 1 H), 5.36 (br. s, 1 H), 6.81 (d, J ϭ
8.1 Hz, 2 H), 7.1Ϫ7.3 (m, 7 H) ppm. 13C NMR: δ ϭ 42.7, 46.4,
55.2, 114.1, 126.5, 127.6, 128.6, 128.7, 135.6, 143.9, 158.2, 173.4
ppm.
3-(3,4-Dichlorophenyl)-3-(4-methoxyphenyl)propionamide
(12g-1)
and 3-(2,3-Dichlorophenyl)-3-(4-methoxyphenyl)propionamide (12g-
2): Ratio 5:1. C16H15Cl2NO2 (324.2): calcd. C 59.3, H 4.7, N 4.3;
1
found C 58.7, H 4.9, N 3.9. Compound 12g-1: H NMR: δ ϭ 2.83
(dd, J ϭ 7.7, 1.5 Hz, 2 H), 3.76 (s, 3 H), 4.47 (t, J ϭ 7.7 Hz, 1 H),
5.5 (br. s, 1 H), 5.7 (br. s, 1 H), 6.8Ϫ7.3 (m, 7 H) ppm. 13C NMR:
δ ϭ 42.1, 45.4, 55.3, 114.2, 127.2, 128.6, 128.9, 129.5, 130.5, 132.5,
134.4, 144.4, 158.5, 173 ppm. Compound 12g-2: 1H NMR: δ ؍ 2.92
(dd, J ϭ 7.7, 1.5 Hz, 2 H), 3.75 (s, 3 H), 4.97 (t, J ϭ 7.7 Hz, 1 H),
5.5 (br. s, 1 H), 5.8 (br. s, 1 H), 6.8Ϫ7.3 (m, 7 H) ppm.
3,3,3-Triphenylpropionamide (11h): A mixture of AlCl3 (0.34 g,
2.5 mmol) and 10h (0.09 g, 0.62 mmol) in benzene (2 mL) was
stirred at 25 °C for 1.5 h. After usual workup the obtained residue
was recrystallized from ethanol to provide 11h (0.103 g, 55%) as a
Reactions with Cyclohexane
1
white crystalline solid: M.p. 193Ϫ194 °C, ref.[45a] m.p. 192 °C. H
NMR: δ ϭ 3.61 (s, 2 H), 4.8 (br. s, 1 H), 5.4 (br. s, 1 H), 7.2Ϫ7.3
(m, 15 H) ppm .[45b] 13C NMR: δ ϭ 48.5, 55.9, 126.6, 128.2, 129.2,
146.1, 173.4 ppm.[45b]
Propionamide (13a): A mixture of AlCl3 (1.4 g, 10.5 mmol) and 10a
(0.3 g, 3.5 mmol) in cyclohexane (4 mL) was stirred at 130 °C for
15 h. After cooling, the mixture was poured over several grams of
ice and extracted with diethyl ether. The aqueous phase was sepa-
rated and then concentrated to a volume of 4 mL, followed by ex-
traction with CHCl3 (5 ϫ 10 mL). The organic phase was dried
(Na2SO4) and concentrated to give a mixture of 10a and 13a
(0.12 g, ratio 1:1). The mixture was separated by silica gel chroma-
tography with CH2Cl2/acetone to provide 13a (0.05 g, 16%): M.p.
80Ϫ81 °C (benzene/hexane), ref.[46a] m.p. 80.5Ϫ81.5 °C. 1H NMR:
Reactions with o-Dichlorobenzene were carried out similarly to the
procedures described above (compound 10a reacted at 130 °C).
Subsequent silica gel chromatographic purification with CH2Cl2
gave products 12 (mixtures of isomers 12-1 and 12-2) as colourless
solids or viscous liquids.
3-(3,4-Dichlorophenyl)propionamide (12a-1) and 3-(2,3-Dichlorophe-
nyl)propionamide (12a-2): Ratio 2:1. C9H9Cl2NO (218.1): calcd. C δ ϭ 1.09 (t, J ϭ 7.1 Hz, 3 H), 2.2 (q, J ϭ 7.1 Hz, 2 H), 5.9 (br. s,
Eur. J. Org. Chem. 2004, 4039Ϫ4047
www.eurjoc.org  2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 4045

K. Y. Koltunov, S. Walspuger, J. Sommer
FULL PAPER
[6]
[7]
1 H), 6.3 (br. s, 1 H) ppm.[46b] 13C NMR: δ ϭ 9.5, 28.9, 177.3
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2-Methylpropionamide (13b): A mixture of AlCl3 (1.4 g, 10.5 mmol)
and 10b (0.3 g, 3.5 mmol) in cyclohexane (4 mL) was stirred at 130
°C for 5 h. After cooling, the mixture was poured over several
grams of ice and extracted with CH2Cl2. The organic phase was
separated, dried (Na2SO4) and concentrated to give the residue,
which was washed with hexane to provide a mixture of 10b and
13b (ratio 2:1). The mixture was separated by silica gel chromatog-
raphy with CH2Cl2/CHCl3 to give 13b (0.083 g, 27%): M.p.
128Ϫ130 °C, ref.[46a] m.p. 129.5Ϫ130 °C. 1H NMR: δ ϭ 1.15 (d,
J ϭ 7 Hz, 6 H), 2.39 (m, J ϭ 7 Hz, 1 H), 5.9 (br. s, 2 H) ppm.[46c]
13C NMR: δ ϭ 18.6, 34.9, 179.9 ppm.[46c]
[8]
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[11]
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Butyramide (13c): A mixture of AlCl3 (0.7 g, 5.2 mmol) and 10c
(0.11 g, 1.3 mmol) in cyclohexane (3 mL) was stirred at 130 °C for
1 h to provide, after usual workup and chromatographic purifi-
cation, compound 13c (0.105 g, 93%): M.p. 115Ϫ116 °C (benzene),
ref.[46a] m.p. 115Ϫ116 °C. 1H NMR: δ ϭ 0.96 (t, J ϭ 7.4 Hz, 3 H),
1.65 (m, 2 H), 2.19 (t, J ϭ 7.3 Hz, 2 H) 5.5 (br. s, 1 H), 5.7 (br. s,
1 H) ppm.[46d] 13C NMR: δ ϭ 13.7, 18.9, 37.8, 175.7 ppm.
[15]
[16]
[17]
[18]
[19]
[20]
[21]
[22]
3-(4-Methoxyphenyl)propionamide (13g): Compound 10g (0.1 g,
0.57 mmol) was added to a stirred mixture of AlCl3 (0.37 g,
2.8 mmol) and CH2Cl2 (3 mL), followed by cyclohexane (1 mL).
The resulting mixture was stirred at 25 °C for 7 h to give, after
usual workup and chromatographic purification, compound 13g
(0.079 g, 78%): M.p. 126Ϫ127 °C (CHCl3), ref.[47a] m.p. 125Ϫ126
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°C. H NMR: δ ϭ 2.45 (t, J ϭ 7.4 Hz, 2 H), 2.86 (t, J ϭ 7.4 Hz,
[23]
[24]
2 H), 3.73 (s, 3 H), 5.7 (br. s, 2 H), 6.77 (d, J ϭ 11.7 Hz, 2 H), 7.07
(d, J ϭ 11.7 Hz, 2 H) ppm.[47b] 13C NMR: δ ϭ 30.5, 37.7, 55.2,
113.9, 129.2, 132.8, 158, 174.7 ppm.
[25]
[26]
[27]
[28]
4-Phenylcarbostyril (15). Method a: A mixture of AlCl3 (0.07 g,
0.52 mmol) and 10i (0.025 g, 0.11 mmol) in CH2Cl2 (4 mL) was
stirred at 25 °C for 10 h. After usual workup, the obtained residue
was purified by silica gel chromatography with CHCl3 to give 15
(0.0153 g, 61%) as a white crystalline solid: M.p. 260 °C, ref.[23]
m.p. 259Ϫ261 °C. 1H NMR: δ ϭ 6.75 (s, 1 H), 7.19 (t, J ϭ 8.1 Hz,
1 H), 7.4Ϫ7.6 (m, 8 H) ppm.[48] 13C NMR: δ ϭ 117.1, 119.8, 120,
123, 126.8, 128.7, 128.9, 129, 131, 136.9, 138.7, 154.1, 163.9
ppm.[48]
[29]
[30]
[31]
[32]
[33]
[34]
Method b: A mixture of triflic acid (3 g, 20 mmol) and 10i (0.12 g,
0.54 mmol) was stirred at 25 °C for 100 h. After the reaction mix-
ture had been poured over several grams of ice, the resulting pre-
cipitate was filtered off and washed with water to provide 15
(0.1164 g, 97%).
[35]
[36]
[37]
Acknowledgments
Financial support of the work by the Loker Hydrocarbon Institute,
U.S.C., Los Angeles, and the ‘‘CNRS’’ is gratefully acknowledged.
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