Preparation of amides mediated by isopropylmagnesium chloride under continuous flow conditions

Article abstract of DOI:10.1039/c2gc35037h

A safe, green and functional-group-tolerant flow version of the direct amide bond formation mediated by Grignard reagents (the Bodroux reaction) is described. The procedure can be applied to a wide variety of primary and secondary amines and anilines, as well as to aromatic and aliphatic esters. The flow approach leads to improved yields and selectivities in the reaction, which has a sustainable purification procedure and a simple scale-up. This reaction represents an efficient and green alternative to the use of alkylaluminium and metal-catalyzed procedures.

Full text of DOI:10.1039/c2gc35037h

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PAPER
Preparation of amides mediated by isopropylmagnesium chloride under
continuous flow conditions†
Juan de M. Muñoz,a Jesús Alcázar,*a Antonio de la Hoz,b Ángel Díaz-Ortizb and Sergio-A. Alonso de Diegoa
Received 9th January 2012, Accepted 20th February 2012
DOI: 10.1039/c2gc35037h
A safe, green and functional-group-tolerant flow version of the direct amide bond formation mediated by
Grignard reagents (the Bodroux reaction) is described. The procedure can be applied to a wide variety of
primary and secondary amines and anilines, as well as to aromatic and aliphatic esters. The flow approach
leads to improved yields and selectivities in the reaction, which has a sustainable purification procedure
and a simple scale-up. This reaction represents an efficient and green alternative to the use of
alkylaluminium and metal-catalyzed procedures.
Although this procedure is environmentally benign, it is limited
to the use of alkyl esters and alkyl amines.
Introduction
The development of new and improved chemical processing
techniques that are economically viable and have greater
environmental compatibility is of great importance to the chemi-
cal industry. The ability to conduct complex and routine chemi-
cal transformations in a safe, reproducible and scalable way
without recourse to costly route modification or redevelopment
is highly desirable nowadays.
Amide bond formation is a common transformation in organic
and medicinal chemistry.1 An attractive procedure is the syn-
thesis starting from esters, as they are stable and abundant in
nature.2 A three-step sequence of hydrolysis, activation and treat-
ment with an amine is usually required to obtain the correspond-
ing amide.
Taking into consideration the precedents, it seems clear
that more sustainable procedures are required to produce amides
in a single step in a more general way. In fact, the American
Chemical Society Green Chemistry Institute Pharmaceutical
Roundtable has labelled this transformation as a high priority
research field.6 In this sense, tert-butoxide-assisted amidation
of esters has been lately described.7 The procedure is
general although it employs a high concentration of a strong
base and, more important, oxygen is needed to complete
the reaction, which may compromise its use at larger scales,
because batch reactors are poorly equipped to ensure
efficient gas–liquid mixing and high concentrations of dissolved
O2.8
In an effort to avoid this three-step procedure, direct trans-
formation has been widely studied. Among the alternative
approaches, the use of trimethylaluminium has become the gold
standard.3 However, this reagent is highly pyrophoric, hazardous
and potentially thermally unstable. With the aim of improving
the safety of this transformation, especially on a large scale, a
continuous flow procedure has recently been described.4 Current
alternatives involve more atom-economical catalytic syntheses.
For instance, in a recent article a dearomatized ruthenium–pincer
complex was described as a catalyst for the direct synthesis of
amides from esters and amines with the liberation of H2.5
Grignard-mediated amide formation, i.e. the Bodroux reac-
tion,9 can be considered as one of these procedures as all
reagents involved in this reaction are inexpensive and environ-
mentally inert. The enhanced reactivity of these magnesium
reagents could be attributed to a ‘push–pull’ mechanism orig-
inating from the nucleophilicity of the magnesium amide
coupled with the Lewis acid activation of the magnesium salt.
Although this reaction has been known since the 1950s, its use
has been limited by two main factors. On the one hand, the
scope and limitations of this reaction have not been systemati-
cally studied. On the other hand, the high reactivity of Grignard
reagents can compromise the selectivity of the reaction. These
two drawbacks have restricted the use of this reaction over the
alternatives mentioned above. For instance, in the synthesis of
Weinreb’s amide this approach has frequently been used as an
alternative when trimethylaluminium-based conversion failed.10
An efficient conversion of nitriles to amides using ethylmagne-
sium bromide has recently been described, although the pro-
cedure only works with aromatic nitriles.11
aJanssen Research and Development, Janssen-Cilag, S.A., C/ Jarama
75, Toledo, Spain. E-mail: jalcazar@its.jnj.com; Fax: +34 925245771;
Tel: +34 925245750
bFacultad de Ciencias Químicas, Universidad de Castilla-La Mancha,
Ciudad Real, Spain. E-mail: Antonio.Hoz@uclm.es; Fax: +34
926295318; Tel: +34 926295300
†Electronic supplementary information (ESI) available: Experimental
procedures, GC/MS of representative crude mixtures, GC/MS of the
selectivity assays and NMR spectra for all compounds. See DOI:
10.1039/c2gc35037h
In recent years flow chemistry and microreactors have
appeared as novel technologies that, among other advantages,
allow much better control of reactions in which unstable and
This journal is © The Royal Society of Chemistry 2012
Green Chem., 2012, 14, 1335–1341 | 1335

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highly reactive intermediates are involved, as these species are
produced and reacted in line.12 Microreactors have a high
surface-to-volume ratio in microchannels and this permits very
efficient heat transfer and, as a consequence, good control of the
reaction temperature, thus avoiding the problems associated with
highly exothermic reactions. Mass transfer is also enhanced and
the use of dangerous or air- and moisture-sensitive compounds is
improved due to the lower reaction volume. Optimization of
reaction conditions is performed by control of residence time
and the scalability of this kind of reaction is simply a matter of
pumping, mixing and quenching the reagents continuously
through the microreactor. This approach permits rapid exper-
imentation and scale-up, thus shortening the time from research
to development and production. From an environmental point of
view, continuous flow reactors are considered as a sustainable
alternative in chemical research and production as the levels of
hazardous waste are reduced.13 The use of Grignard reagents
in flow conditions have been previously described in the
literature.14
inserted into the glass microreactors.‡ The reaction mixture was
finally connected to a column filled with Amberlyst A-15, thus
enhancing the green character of the procedure. However, in
order to facilitate the scalability of the process, quenching of the
reaction can also be performed with 1 M HCl.
Reaction optimization
This simple set up outlined above was used to optimize the con-
ditions for the reaction of 2,4-difluoroaniline 2a with ethyl ben-
zoate 1a (Table 1). Aniline 2a was selected due to its lower
carcinogenicity in comparison to other analogues of this family.
The procedure was first applied in batch (Table 1, entry 1) in
order to assess the feasibility of the reaction in flow using an
excess of amine and isopropylmagnesium chloride as described
in the literature.11 The presence of solid was not detected at any
point of the reaction and the flow procedure was therefore tried
using a 1 : 1 : 2 ratio of ester, aniline and Grignard reagents
respectively (Table 1, entry 2). A higher yield was obtained in
this flow procedure despite the lower excess of amine and the
much shorter reaction time.
Results and discussion
Following this promising result, yields were further improved
by optimization of the reaction temperature, time and number of
equivalents of aniline and alkylmagnesium chloride, always
keeping the ester as the limiting reagent and adapting the con-
centration of amine and Grignard reagent to it. The use of longer
retention times (i.e. reaction times) clearly improved the yield
(entries 3 and 4), but the temperature could not be increased as
the system became blocked by a black slurry observed in the
magnesium amide line (entry 5). The use of 1.5 equivalents of
aniline 1a was required to complete the reaction (entry 6) but
without reducing the aniline : Grignard reagent ratio. This
Description of the instrument
As part of our efforts to apply flow approaches to typical medic-
inal chemistry problems, we considered the application of this
technology to the Bodroux reaction as a greener alternative for
the preparation of amides in a single step. In order to achieve
this goal, a simple and inexpensive set up was built based on
two 1 ml Sigma-Aldrich Starter KitTM microreactors connected
to two standard dual syringe pumps from Harvard Apparatus
(Fig. 1). In the first microreactor, one line with isopropylmagne-
sium chloride and another with the amine, connected to the first
syringe pump, were mixed to form the corresponding mag-
nesium amide. The end of this line was fixed to the second
microreactor, where the magnesium amide was mixed with the
ester, coming from the second syringe pump. A 5 ml coil was
added at the end of this second reactor in order to increase the
residence time as this step was found to be the limiting one. Con-
sequently, the time for the formation of the aminomagnesium
chloride was adapted to the time set for the second reactor.
All tubing, glass reactor and coils used have a 0.1 mm internal
diameter. The reaction temperature can be monitored by sensors
Table 1 Reaction optimization using ethyl benzoate 1a and 2,4-
difluoroaniline 2a
Entry 2a i-PrMgBr T (°C) Rt1 (min) Rt2 (min) Yielda (%)
1
2
3
4
5
6
7
8
9
1.5
1
1
1
1
1.5
1.5 1.5
1.5
1.5
3
2
2
2
2
3
0, rt
Rt
Rt
Rt
40
Rt
Rt
Rt
Rt
60
2
4
6
6
6
6
6
6
60
5
45b
61
67
76
—
90
10
14
14
14
14
20
14
c
88
3
3
87
95 (92%)d
a Yield by GCMS. b Batch reaction. c System blocked. d Reaction
performed on an 18 mmol scale (isolated yield).
‡For further information about elements used in the flow system set up
the following web pages can be visited: microreactors (www.sigmaal-
drich.com), syringe pumps (www.harvardapparatus.com) and 5 ml coil
and tubing (www.vapourtec.co.uk).
Fig. 1 Experimental set up of the flow system.
1336 | Green Chem., 2012, 14, 1335–1341
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Table 2 Combination of esters 1a and 1b with amines 2a–f
Table 3 General exploration of the scope
Entry
Ester
Amine
Compounda
Entry
R1
Amine
Compounda
1
2
3
4
5
6
7
8
9
PhCO2Et (1a)
PhCO2Et (1a)
PhCO2Et (1a)
PhCO2Et (1a)
n-PrCO2Et (1b)
n-PrCO2Et (1b)
n-PrCO2Et (1b)
n-PrCO2Et (1b)
PhCO2Et (1a)
n-PrCO2Et (1b)
2,4-diF-C6H3NH2 (2a)
PhNHMe (2b)b
3aa (88%)
3ab (93%)
3ac (92%)
3ad (83%)
3ba (95%)
3bb (92%)
3bc (82%)
3bd (80%)
3ae (65%)c
3bf (88%)
1
2
3
4
5
6
7
8
9
p-F-C6H4 (1c)
2a
2a
2a
2a
2bb
2a
2a
2a
2a
2bb
3ca (92%)
3da (90%)
3ea (52%)
3fa (95%)
3gb (84%)
3ha (91%)
3ia (61%)
3ja (91%)
3ka (73%)
3lb (62%)
p-MeO-C6H4 (1d)
p-NO2-C6H4 (1e)
m-CN-C6H4 (1f)
PhCH2 (1g)
2-Furyl (1h)
2-Pyrrolyl (1i)
5-Me-3-isoazolyl (1j)
5-ClCH2-2-furyl (1k)
2-Br-5-thienyl (1l)
n-BuNH2 (2c)
Piperidine (2d)b
2,4-diF-C6H3NH2 (2a)
PhNHMe (2b)b
n-BuNH2 (2c)
Piperidine (2d)b
2-Aminopyridine (2e)
4-Br-aniline (2f)
10
10
a Compound number (isolated yield). b Ratio ester–amine–i-PrMgCl
(1 : 1.5 : 1.5). c Reaction performed at 0.108 M of 1a.
a Compound number (isolated yield). b Ratio ester–amine–i-PrMgCl
(1 : 1.5 : 1.5).
reduction did not improve the yield and the crude product was
less clean (entry 7). Similar results were observed on further
extending the reaction time to 20 minutes (entry 8).
The optimized conditions shown in entry 6 can be easily
scaled up by a factor of 22.5 (entry 9). Concentration of reagents
and flow rates are given in Fig. 1. The higher yield obtained
in this case can be explained by the longer steady state. Using
this flow procedure up to 1.2 g h−1 of amide were produced.
Quenching of the crude mixture was performed using 1 M HCl.
Scheme 1
Scope of the reaction
The conditions reported in entry 6 (Table 1), with concentrations
and flow rates given in Fig. 1, were selected to explore the scope
of the reaction. Firstly, an alkyl and an aryl ester were selected in
conjunction with alkyl, aryl, primary and secondary amines in
order to test all possible combinations (Table 2, entries 1–8). All
compounds were isolated in good to excellent yields. It is worth
noting that for secondary amines a 1 : 1.5 : 1.5 ester–amine–
Grignard reagent ratios were used. Two additional examples are
included in Table 2 and these represent two potentially proble-
matic situations: 2-aminopyridine 2e as an example of a hetero-
cyclic amine with low nucleophilicity and 4-bromoaniline 2f to
assess the potential interaction with the trans-metallation reac-
tion. Both examples afforded the corresponding amides in good
to excellent yields.
In a second approach, the reaction was performed with a
wider range of amines and esters including heterocyclic systems
and other functional groups. All of the examples were carried
out using the same general conditions shown in Fig. 1. Excellent
functional group tolerance was found (Table 3). Electron-donat-
ing and electron-withdrawing groups are compatible with the
reaction, although strong electron-withdrawing groups conju-
gated with the ester function, such as the nitro group, led to a
decrease in the yield of the reaction (Table 3, entries 1–4).
It is worth noting the high chemoselectivity of the reaction.
For example, the reactivity of the ester group is higher than that
of the cyano group in compound 1f, despite the fact that both
groups can react under the same conditions.11 Benzylic and
heterocyclic esters also provided the corresponding amides in
good yield (entries 5–10). Pyrrolyl analogue 1i reacted in the
absence of a suitable protecting group on the nitrogen atom to
give the desired product in good yield (entry 7). This is a clear
improvement over the tert-butoxide procedure, very sensitive to
hydrogen donating groups.7
The last two examples in Table 3 show chemoselective amide
formation over nucleophilic aliphatic and aromatic substitution
reactions. In both examples the expected amide was obtained in
good yield and the substitution by-product was not found in the
crude mixture. This represents an excellent example of chemos-
electivity, especially considering the high reactivity of benzyl
halides. In a third approach, ring opening and ring closure reac-
tions were tried with esters 1m and 1n using the standard pro-
cedure as described in Table 1 entry 6 and shown in Fig. 1.
These compounds provided amides 3ma and 3na, respectively,
in good yields (Scheme 1).
Selectivity assays
Encouraged by the results obtained so far, two experiments were
designed to explore further the selectivity of the reaction:
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7683 Series injector and autosampler, J&W HP-5MS column
(20 m × 0.18 mm, 0.18 μm) from Agilent Technologies coupled
to a 5973N MSD Mass Selective Detector (single quadrupole,
Agilent Technologies). The MS detector was configured with an
electronic impact ionization source/chemical ionization source
(EI/CI). EI low-resolution mass spectra were acquired by scan-
ning from 50 to 550 at a rate of 14.29 scan. The source tempera-
ture was maintained at 230 °C. Helium was used as the nebulizer
gas. Data acquisition was performed with Chemstation-Open
1
Action software. H-NMR and 13C-NMR spectra were recorded
on a Bruker DPX-400 with standard pulse sequence, operating at
400 MHz and 100 MHz, respectively. Chemical shifts (δ) are
reported in parts per million (ppm) downfield from tetramethyl-
silane (TMS), which was used as internal standard. Reactions
were performed in Sigma-Aldrich Starter KitTM microreactors
connected to syringe pumps from Harvard Apparatus. Unless
otherwise specified, reagents were obtained from commercial
sources and used without further purification.
Scheme 2
Selective reaction of a single ester group in a diester compound
and selective reaction between ethyl and isopropyl esters
(Scheme 2).
In the first example, the selective reaction of one ester group
in diester 1o, was achieved easily in flow under the standard con-
ditions shown in Fig. 1 using one equivalent of amine 2a. The
ratio between monosubstituted 3oa and disubstituted product 4
was 6 : 1. In batch the selectivity was reversed, i.e. diamide 4
was the major product, in a 1 : 2 ratio.
In the second example, selectivity between ethyl and isopro-
pyl esters, was tested with compounds 1c and 1p. To the best of
our knowledge, selective amide formation between isopropyl
and ethyl esters has not been described previously in the litera-
ture. Under Bodroux reaction conditions the isopropyl ester
reacted faster to form amide 3aa. This selectivity was enhanced
under flow conditions, where the ratio between compounds 3aa
and 3ca was 6 : 1, whereas in batch the ratio decreased to 3 : 1.
In both examples the reaction in batch was only complete after
2 h whereas the flow reaction was complete in 15 min, thus
demonstrating the efficiency of the flow approach.
General procedure for Bodroux reaction in flow
Two solutions, amine 2 (1.5 equiv) in THF and an isopropyl-
magnesium chloride lithium chloride complex solution 1.3 M in
THF (3 equiv), were pumped at 0.1 mL min−1 (each solution)
through a Sigma-Aldrich microreactor using a syringe pump. At
the same time a third solution of ester 1 (1 equiv) in THF was
pumped at 0.2 mL min−1 with a second syringe pump and
mixed with the previous solution in a Sigma-Aldrich micro-
reactor and then passed through a 5 mL coil (Rt = 14 min). The
outlet solution was poured into 1 M HCl and extracted with
diethyl ether. The organic layer was separated, dried (MgSO4),
filtered and the solvents were evaporated in vacuo to yield the
corresponding product.
On-line work-up
The output of the coil was directed to a 10 mm diameter Omnifit
column filled with Amberlyst A-15 (2 g). The collected solution
was evaporated to dryness to yield the product.
Conclusions
In summary, acylation of amides using esters as acylating agents
is effectively mediated by Grignard reagents. The reaction can
be performed using a cheap, safe and environmentally benign
reaction medium. The procedure proved to be very general, func-
tional-group-tolerant, selective and easily scalable. The examples
reported here cover many different situations that can be found
typically in organic synthesis and medicinal chemistry. The use
of microreactors in flow allows the Bodroux amide formation to
be performed in a safer, more sustainable and selective manner
that traditional batch approaches. These examples demonstrate
the applicability of the reaction and show that this route may be
considered as a primary approach in amide synthesis in academia
and industrial processes instead of the use of alkylaluminium
and metal-catalyzed procedures.
1-Benzamido-2,4-difluorobenzene (3aa).15 White solid; m.p.:
1
170.1–171.1 °C. H-NMR (CDCl3, δ ppm): 6.88–6.96 (m, 2H),
7.49–7.54 (m, 2H), 7.58 (t, 1H, J = 7.4 Hz), 7.86–7.90 (m, 2H),
7.94 (br s, 1H), 8.38–8.45 (m, 1H). 13C-NMR (CDCl3, δ ppm):
104.0 (dd, J = 26.7, 23.5 Hz, CH), 118.8 (dd, J = 21, 3.5 Hz,
CH), 122.7 (C), 122.9 (dd, J = 9, 2 Hz, CH), 127.5 (2 × CH),
129.3 (2 × CH), 132.6 (CH), 153.3 (dd, J = 246, 12 Hz, C–F),
134.7 (C), 159.0 (dd, J = 246, 12 Hz, C–F), 165.9 (CvO). m/z
C13H9F2NO calc.: 233.06. Found (EI): 233.05.
N-Methyl-N-phenylbenzamide (3ab).16 Yellow oil. 1H-NMR
(CDCl3, δ ppm): 3.50 (s, 3H), 7.02–7.06 (m, 2H), 7.11–7.19
(m, 3H), 7.20–7.25 (m, 3H), 7.27–7.31 (m, 2H). 13C-NMR
(CDCl3, δ ppm): 38.7 (CH3), 126.9 (CH), 127.3 (2 × CH), 128.1
(2 × CH), 129.1 (2 × CH), 129.5 (2 × CH), 130.0 (CH), 136.3,
145.3 (C), 170.6 (CvO). m/z C14H13NO calc.: 211.10. Found
(EI): 211.09.
Experimental section
GC measurements were performed using a 6890 Series Gas
Chromatograph (Agilent Technologies) system comprising a
1338 | Green Chem., 2012, 14, 1335–1341
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1
N-Butylbenzamide (3ac).17 Pale yellow oil. H-NMR (CDCl3,
(2 × CH), 136.9 (C), 171.2 (CvO). m/z C10H12BrNO calc.:
δ ppm): 0.96 (t, 3H, J = 7.4 Hz), 1.42 (qt, 2H, J = 7.2, 7.6 Hz),
1.61 (tt, 2H, J = 7.2, 7.2 Hz), 3.46 (dt, 2H, J = 6.8, 6.4 Hz), 6.14
(br s, 1H), 7.40–7.45 (m, 2H), 7.47–7.51 (m, 1H), 7.74–7.78 (m,
2H). 13C-NMR (CDCl3, 100 MHz, δ ppm): 13.8 (CH3), 20.2
(CH2), 31.8 (CH2), 39.8 (CH2), 126.8 (2 × CH), 128.5 (2 × CH),
131.3 (CH), 134.9 (C), 167.6 (CvO). m/z C11H15NO calc.:
177.11. Found (EI): 177.11.
241.01. Found (EI): 241.01.
N-(2,4-Difluorophenyl)-4-fluorobenzamide (3ca). White solid
1
m.p.: 134.4–135.4 °C. H-NMR (CDCl3, δ ppm): 6.90–6.96 (m,
2H), 7.17–7.22 (m, 2H), 7.87 (br s, 1H), 7.88–7.93 (m, 2H),
8.37 (m, 1H). 13C-NMR (CDCl3, δ ppm): 103.6 (dd, J = 26.8,
24.0 Hz, CH), 111.4 (dd, J = 21.9, 3.5 Hz, CH), 115.9 (CH),
116.1 (CH), 123.0 (dd, J = 8.5, 2.1 Hz, CH), 129.4 (CH), 129.5
(CH), 130.4 (d, J = 3.5 Hz, C), 152.6 (dd, J = 245.8, 12 Hz,
C–F), 158.6 (dd, J = 247.2, 12.0 Hz, C–F), 163.8 (C), 164.4
(C), 166.3 (CvO). m/z C13H8F3NO calc.: 251.06. Found (EI):
251.05.
1-Benzoylpiperidine (3ad).18 Colourless oil. 1H-NMR (CDCl3,
δ ppm): 1.52 (br s, 2H), 1.67 (br s, 4H), 3.34 (br s, 2H), 3.71 (br
s, 2H), 7.39 (br s, 5H). 13C-NMR (CDCl3, δ ppm): 24.6 (CH2),
25.7 (CH2), 26.6 (CH2), 43.1 (CH2), 48.8 (CH2), 126.8
(2 × CH), 128.4 (2 × CH), 129.3 (CH), 136.4 (C), 170.2
(CvO). m/z C12H15NO calc.: 189.11. Found (EI): 189.10.
N-(2,4-Difluorophenyl)-4-methoxybenzamide
(3da). White
solid. m.p.: 132.7–133.7 °C. 1H-NMR (CDCl3, δ ppm): 3.88
(s, 3H), 6.88–6.94 (m, 2H), 6.97–7.01 (m, 2H), 7.83–7.87
(m, 3H), 8.37–8.43 (m, 1H). 13C-NMR (CDCl3, δ ppm): 55.5
(CH3), 103.5 (dd, J = 26.8, 23.3 Hz, CH), 111.3 (dd, J = 21.9,
3.5 Hz, CH), 114.1 (2 × CH), 122.8 (dd, J = 9.2, 2.1 Hz, CH),
123.4 (C), 126.4 (Cq), 129.0 (2 × CH), 152.6 (dd, J = 245.1, 12
Hz, C–F), 158.3 (dd, J = 246.5, 12.0 Hz, C–F), 162.8 (C), 164.9
(CvO). m/z C14H11F2NO2 calc.: 263.08. Found (EI): 263.07.
N-(2,4-Difluorophenyl)butyramide (3ba). Pale yellow solid.
1
m.p.: 112–113 °C. H-NMR (CDCl3, δ ppm): 1.02 (t, 3H, J =
7.4 Hz), 1.77 (qt, 2H, J = 7.2, 7.6 Hz), 2.38 (t, 2H, J = 7.6 Hz),
6.82–6.90 (m, 2H), 7.22 (br s, 1H), 8.22–8.31 (m, 1H).
13C-NMR (CDCl3, δ ppm): 13.7 (CH3), 19.0 (CH2), 39.6 (CH2),
103.4 (dd, J = 26.8, 24.0 Hz, CH), 111.2 (dd, J = 21.2, 3.5 Hz,
CH), 122.8 (dd, J = 9.0, 3.0 Hz, CH), 152.6 (dd, J = 246.0, 12.0
Hz, C–F), 158.4 (dd, J = 246.0, 12.0 Hz, C–F), 122.9 (C), 171.2
(CvO). m/z C10H11F2NO calc.: 199.08. Found (EI): 199.08.
N-(2,4-Difluorophenyl)-4-nitrobenzamide (3ea). Pale yellow
solid. m.p.: 159.4–160.4 °C. 1H-NMR (CDCl3, δ ppm):
6.93–6.99 (m, 2H), 7.95 (br s, 1H), 8.05–8.08 (m, 2H),
8.36–8.40 (m, 3H). 13C-NMR (CDCl3, δ ppm): 103.8 (dd, J =
26.8, 23.3 Hz, CH), 111.6 (dd, J = 21.9, 3.5 Hz, CH), 123.2
(d, J = 8.5 Hz, CH), 124.1 (2 × CH), 128.3 (2 × CH), 128.4 (C),
139.7 (C), 152.6 (dd, J = 245.1, 12 Hz, C–F), 158.3 (dd, J =
246.5, 12.0 Hz, C–F), 162.8 (C), 164.9 (CvO). m/z
C13H8F2N2O3 calc.: 278.05. Found (EI): 278.05.
N-Methyl-N-phenylbutyramide
(3bb).19 Colourless
oil.
1H-NMR (CDCl3, δ ppm): 0.82 (t, 3H, J = 7.2 Hz), 1.55–1.65
(m, 2H), 2.05 (t, 2H, J = 6.6 Hz), 3.27 (s, 3H), 7.16–7.20 (m,
2H), 7.31–7.38 (m, 1H), 7.39–7.45 (m, 2H). 13C-NMR (CDCl3,
δ ppm): 13.8 (CH3), 18.9 (CH2), 35.9 (CH2), 37.3 (CH3), 127.3
(2 × CH), 127.6 (CH), 129.6 (2 × CH), 144.2 (C), 173.0
(CvO). m/z C11H15NO calc.: 177.11. Found (EI): 177.11.
N-(n-Butyl)butyramide (3bc).20 Colourless oil. 1H-NMR
(CDCl3, δ ppm): 0.97 (t, 3H, J = 7.2 Hz), 1.50–1.60 (m, 4H),
1.60–1.69 (m, 4H), 2.32 (t, 2H, J = 7.2 Hz), 3.45–3.55 (m, 4H).
13C-NMR (CDCl3, δ ppm): 13.7 (2 × CH3), 19.3 (CH2), 20.0
(CH2), 31.6 (CH2), 38.4 (CH2), 39.4 (CH2), 173.6 (CvO). m/z
C8H17NO calc.: 143.13. Found (EI): 143.12.
3-Cyano-N-(2,4-difluorophenyl)-benzamide
(3fa). White
solid. m.p.: 146.7–147.7 °C. 1H-NMR (CDCl3, δ ppm):
6.92–6.99 (m, 2H), 7.67 (t, 1H, J = 7.9 Hz), 7.87 (dt, 1H, J =
7.9, 1.4 Hz), 7.92 (br s, 1H), 8.11 (dt, 1H, J = 8.1, 1.2 Hz), 8.19
(t, 1H, J = 0.9 Hz), 8.31–8.37 (m, 1H). 13C-NMR (CDCl3, δ
ppm): 103.8 (dd, J = 26.8, 23.3 Hz, CH), 111.5 (dd, J = 21.9,
3.5 Hz, CH), 113.4 (C), 117.7 (C), 123.3 (dd, J = 9.2, 2.1 Hz,
CH), 129.9 (CH), 130.9 (CH), 131.1 (CH), 135.3 (CH), 135.4
(C), 152.8 (dd, J = 246.5, 12.0 Hz, C–F), 159.2 (dd, J = 247.2,
12.0 Hz, C–F), 163.3 (CvO). m/z C14H8F2N2O calc.: 258.06.
Found (EI): 258.05.
1-(Piperidin-1-yl)butan-1-one
(3bd).5 Colourless
oil.
1H-NMR (CDCl3, δ ppm): 0.97 (t, 3H, J = 7.2 Hz), 1.50–1.60
(m, 4H), 1.60–1.69 (m, 4H), 2.32 (t, 2H, J = 7.2 Hz, 2H),
3.45–3.55 (m, 4H). 13C-NMR (CDCl3, δ ppm), 14.0 (CH3), 18.9
(CH2), 24.5 (3 × CH2), 35.3 (CH2), 40.4 (CH2), 43.7 (CH2),
171.4 (CvO). m/z C9H17NO calc.: 155.13. Found (EI): 155.12.
N-Methyl-N-phenylphenylacetamide (3gb).23 Yellow oil.
1H-NMR (CDCl3, δ ppm): 3.28 (s, 3H), 3.46 (s, 2H), 7.05
(d, 2H, J = 7.2 Hz), 7.12 (d, 2H, J = 7.7 Hz), 7.17–7.26
(m, 3H), 7.32–7.43 (m, 3H). 13C-NMR (CDCl3, δ ppm): 37.6
(CH3), 40.9 (CH2), 126.5 (CH), 127.6 (2 × CH), 127.9 (CH),
128.3 (2 × CH), 129.0 (2 × CH), 129.7 (2 × CH), 135.4, 143.9
(C), 171.0 (CvO). m/z C15H15NO calc.: 225.11. Found (EI):
225.10.
N-Pyridin-2-yl-benzamide (3ae).21 Colourless oil. 1H-NMR
(CDCl3, δ ppm): 7.01 (ddd, 1H, J = 7.2, 4.9, 0.9 Hz), 7.44–7.49
(m, 2H), 7.52–7.57 (m, 1H), 7.71–7.76 (m, 1H), 7.91–7.94
(m, 2H), 8.09–8.12 (m, 1H), 8.41 (dt, 1H, J = 8.3, 0.9 Hz), 9.27
(br s, 1H). 13C-NMR (CDCl3, δ ppm): 114.3 (CH), 119.8 (CH),
127.3 (2 × CH), 128.6 (2 × CH), 132.1 (CH), 134.3 (C), 138.4
(CH), 147.7 (CH), 151.7 (C), 166.0 (CvO). m/z C12H10N2O
calc.: 198.08. Found (EI): 198.07.
N-(2,4-Difluorophenyl)furan-2-carboxamide
(3ha). White
1
N-(4-Bromophenyl)butanamide (3bf).22 White solid. m.p.:
125–126 °C (lit. 126 °C). 1H-NMR (CDCl3, δ ppm): 1.01 (t, 3H,
J = 7.4 Hz), 1.71–1.78 (m, 2H), 2.33 (t, 2H, J = 7.4 Hz), 7.25
(br s, 1H), 7.42 (s, 4H); 13C-NMR (CDCl3, δ ppm): 13.7 (CH3),
18.9 (CH2), 39.6 (CH2), 116.7 (C), 121.3 (2 × CH), 131.9
solid. m.p.: 82.6–83.6 °C. H-NMR (CDCl3, δ ppm): 6.57–6.59
(dd, 1H, J = 3.5, 1.6 Hz), 6.85–6.94 (m, 2H), 7.26–7.28
(m, 1H), 7.54 (dd, 1H, J = 1.9, 0.9 Hz), 8.20 (br s, 1H),
8.37–8.42 (m, 1H). 13C-NMR (CDCl3, δ ppm): 103.6 (dd, J =
26.8, 23.3 Hz, CH), 111.3 (dd, J = 21.9, 4.24 Hz, CH), 112.6
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(CH), 115.7 (CH), 122.6 (dd, J = 26.8, 23.3 Hz, CH), 144.6
(CH), 152.6 (dd, J = 245.8, 12 Hz, C–F), 158.6 (dd, J = 247.2,
12.0 Hz, C–F), 163.8 (C), 164.4 (C), 166.3 (CvO). m/z
C11H7F2NO2 calc.: 223.04. Found (EI): 223.04.
(m, 1H), 7.58–7.62 (m, 1H), 7.67–7.69 (m, 2H), 7.89–7.91
(d, 1H, J = 7.63 Hz). 13C-NMR (CDCl3, δ ppm): 83.96 (CH),
105.5 (dd, J = 26.8, 23.3 Hz, CH), 112.3 (dd, J = 21.9, 4.2 Hz,
CH), 122.6 (C), 123.9 (CH), 124.5 (CH), 130.7 (CH), 131.3 (dd,
J = 9, 2 Hz, CH), 133.5 (CH), 152.4 (dd, J = 247.9, 12.0 Hz,
C–F), 156.9 (C), 158.2 (C), 158.8 (dd, J = 258.5, 11.3 Hz, C–F),
171.81 (CvO). m/z C14H9F2NO2 calc.: 261.06. Found (EI):
261.05.
N-(2,4-Difluorophenyl)-1H-pyrrole-2-carboxamide(3ia). White
solid. m.p.: 169.2–170.2 °C. 1H-NMR (CDCl3, δ ppm):
6.30–6.33 (m, 1H), 6.74–6.75 (m, 1H), 6.88–6.93 (m, 2H), 7.01
(dt, 1H, J = 1.4, 1.1 Hz), 7.64 (br s, 1H), 6.29–6.35 (m, 1H),
9.57 (br s, 1H). 13C-NMR (CDCl3, δ ppm): 103.6 (dd, J = 26.8,
23.3 Hz, CH), 110.0 (CH), 110.4 (CH), 111.3 (dd, J = 21.9, 4.2
Hz, CH), 122.6 (dd, J = 8.5, 2.1 Hz, CH), 122.7 (CH), 125.4
(C), 155.4 (dd, J = 246.5, 12.0 Hz, C–F), 158.5 (dd, J = 246.1,
11.2 Hz, C–F), 158.7 (C), 161.3 (CvO). m/z C11H8F2N2O calc.:
222.06. Found (EI): 222.05.
Ethyl 4-[(2,4-difluorophenyl)carbamoyl]furan-3-carboxylate
(3oa). White solid. m.p.: 92.7–93.7 °C. 1H-NMR (DMSO, δ
ppm): 1.26 (t, 3H, J = 9.3 Hz), 4.23 (m, 2H), 7.09–7.13
(m, 1H); 7.32–7.38 (m, 1H); 8.14–8.20 (m, 1H), 8.47 (d, 1H,
J = 1.62 Hz), 8.57 (d, 1H, J = 1.62 Hz), 11.11 (s, 1H).
13C-NMR (DMSO, δ ppm): 21.4 (CH3), 61.5 (CH2), 104.1 (dd,
J = 26.8, 24.0 Hz, CH), 111.2 (dd, J = 21.9, 3.53 Hz, CH),
115.3 (C), 117.8 (C), 122.6 (dd, J = 11.3, 3.5 Hz, C), 124.2 (dd,
J = 9.2, 2.1 Hz, CH), 150.7 (CH), 151.6 (CH), 153.3 (dd, J =
247.9, 12.0 Hz, C–F), 158.4 (dd, J = 244.4, 12.0 Hz, C–F),
159.1 (CvO), 161.0 (CvO). m/z C14H11F2NO4 calc.: 295.06.
Found (EI): 295.06.
N-(2,4-Difluorophenyl)-5-methyl-1,2-oxazole-3-carboxamide
(3ja). White solid. m.p.: 97.6–98.6 °C. 1H-NMR (CDCl3, δ
ppm): 2.53 (s, 3H), 6.53 (s, 1H), 6.92 (m, 2H), 8.31–8.37
(m, 1H), 8.64 (br s, 1H). 13C-NMR (CDCl3, δ ppm): 12.4
(CH3), 101.4 (CH), 103.8 (dd, J = 26.8, 23.3 Hz, CH), 111.3
(dd, J = 21.9, 4.2 Hz, CH), 121.8 (dd, J = 10.6, 4.2 Hz, C),
122.8 (dd, J = 9.2, 2.1 Hz, CH), 152.6 (dd, J = 247.9, 12.0 Hz,
C–F), 156.9 (C), 158.2 (C), 158.8 (dd, J = 258.5, 11.3 Hz, C–F),
171.81 (CvO). m/z C11H8F2N2O2 calc.: 238.05. Found (EI):
238.05.
N,N’-Bis(2,4-difluorophenyl)furan-3,4-dicarboxamide (4).
1
White solid. m.p.: 209.6–210.6 °C. H-NMR (DMSO, δ ppm):
7.10–7.16 (m, 2H); 7.34–7.40 (m, 2H), 7.87–7.93 (s, 2H), 8.60
(s, 2H), 11.25 (s, 2H). 13C-NMR (DMSO, δ ppm): 104.4 (dd, J
= 26.8, 24.0 Hz, 2 × CH), 111.4 (dd, J = 21.9, 3.5 Hz, 2 × CH),
119.6 (2 × C), 121.87 (dd, J = 12.0, 3.53 Hz, 2 × Cq), 126.4
(dd, J = 9.9, 2.1 Hz, 2 × CH), 150.2 (2 × CH), 154.6 (dd, J =
249.4, 12.72 Hz, 2 × C–F), 159.1 (dd, J = 244.4, 11.3 Hz, 2 ×
C–F), 161.1 (2 × CvO). m/z C18H10F4N2O3 calc.: 378.06.
Found (EI): 378.06.
1-[5-(Chloromethyl)fur-2-yl]-2-(2,4-difluorophenyl)ethanone
1
(3ka). White solid. m.p.: 101.6–102.6 °C. H-NMR (CDCl3, δ
ppm): 4.64 (s, 2H), 6.55 (d, 1H, J = 3.5 Hz), 6.89–6.96 (m, 2H),
7.21 (d, 1H, J = 3.5 Hz), 8.15 (br s, 1H), 8.32–8.38 (m, 1H).
13C-NMR (CDCl3, δ ppm): 37.7 (CH2), 103.7 (dd, J = 26.8,
23.3 Hz, CH), 111.4 (dd, J = 21.9, 3.5 Hz, CH), 112.3 (CH),
116.6 (CH), 122.8 (dd, J = 9.2, 2.1 Hz, CH), 147.6 (C), 152.4
(C), 152.5 (dd, J = 246.5, 12.0 Hz, C–F), 155.5 (C), 158.8 (dd,
J = 246.5, 11.3 Hz, C–F), 170.5 (CvO). m/z C12H8ClF2NO2
calc.: 271.02. Found (EI): 271.02.
Acknowledgements
The authors acknowledge financial support from the Spanish
Ministerio de Ciencia e Innovación (project CTQ2011-22410)
and the Junta de Comunidades de Castilla-La Mancha (Program
HITO 2010-54 and project PII2I09-0100).
2-Bromo-N-methyl-N-phenyl-1,3-thiazole-5-carboxamide (3lb).
Yellow pale solid. m.p.: 97.4–98.4 °C. 1H-NMR (CDCl3, δ
ppm): 3.50 (s, 3H), 7.31 (s, 1H), 7.35–7.37 (m, 2H), 7.57–7.56
(m, 3H). 13C-NMR (CDCl3, δ ppm): 38.7 (CH3), 128.2 (2 ×
CH), 129.3 (CH), 130.3 (2 × CH), 136.7 (C), 141.1 (C), 142.5
(C), 146.7 (CH), 159.8 (CvO). m/z C11H9BrN2OS calc.:
295.96. Found (EI): 295.95.
Notes and references
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N-(2,4-Difluorophenyl)-5-hydroxypentanamide (3ma). White
1
solid. m.p.: 45.4–46.4 °C. H-NMR (CDCl3, δ ppm): 1.55–1.75
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(m, 2H), 1.75–1.90 (m, 2H); 2.12 (br s, 1H), 2.47 (t, 2H, J = 7
Hz), 3.70 (t, 2H, J = 6 Hz), 6.82–6.85 (m, 2H), 7.56 (br s, 1H),
8.15–8.26 (m, 1H). 13C-NMR (CDCl3, δ ppm): 21.8 (CH2), 31.6
(CH2), 36.9 (CH2), 62.2 (CH2), 103.5 (dd, J = 26.1, 23.3 Hz,
CH), 111.1 (dd, J = 21.9, 3.5 Hz, CH), 122.5 (dd, J = 10.6,
4.2 Hz, C), 123.1 (dd, J = 9.2, 2.1 Hz, CH), 152.5 (dd, J =
245.8, 12.0 Hz, C–F), 158.4 (dd, J = 246.5, 11.3 Hz, C–F),
171.5 (CvO). m/z C11H13F2NO2 calc.: 229.05. Found (EI):
229.04.
2-(2,4-Difluorophenyl)-3-hydroxy-2,3-dihydro-1H-isoindol-1-
1
one (3na). White solid. m.p.: 198–199 °C. H-NMR (CDCl3, δ
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1340 | Green Chem., 2012, 14, 1335–1341
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