Iron/tetramethylethylenediamine-catalyzed ambient-temperature coupling of alkyl grignard reagents and aryl chlorides

Article abstract of DOI:10.1021/jo4016612

Tetramethylethylenediamine (TMEDA) acts as cheap and readily removed ligand in the iron-catalyzed coupling of alkyl Grignard reagents and activated aryl chlorides. The use of TMEDA allows for low ligand and iron catalyst loading as well as an increased reaction concentration and an ambient reaction temperature on a mole scale.

Full text of DOI:10.1021/jo4016612

Note
pubs.acs.org/joc
Iron/Tetramethylethylenediamine-Catalyzed Ambient-Temperature
Coupling of Alkyl Grignard Reagents and Aryl Chlorides
Philip J. Rushworth,† David G. Hulcoop,‡ and David J. Fox*,†
†Department of Chemistry, University of Warwick, Coventry CV4 7AL, U.K.
‡Research and Development, GlaxoSmithKline, Gunnelswood Road, Stevenage SG1 2NY, U.K.
S
* Supporting Information
ABSTRACT: Tetramethylethylenediamine (TMEDA) acts as cheap and
readily removed ligand in the iron-catalyzed coupling of alkyl Grignard
reagents and activated aryl chlorides. The use of TMEDA allows for low
ligand and iron catalyst loading as well as an increased reaction
concentration and an ambient reaction temperature on a mole scale.
ore than 60% of carbon−carbon bond-forming reactions
alkyl Grignard reagent. More recently, the use of N-heterocyclic
Mperformed currently in medicinal chemistry are carbene (NHC)-type ligands has been reported for the cross-
coupling of both aryl halides with aryl Grignard reagents12 and
phenol derivatives (aryl tosylates, sulfamates, or carbamates)
with alkyl Grignard reagents.13 These reactions require
conditions more forcing than those previously described
(long reaction times and high temperatures) and are again
limited to relatively unfunctionalized substrates. Herein, we
describe our initial results in the pursuit of a broad-spectrum
catalyst/ligand system for carbon−carbon bond formation by
cross-coupling of a carbon−halogen functionality with a
Grignard reagent.
catalyzed by palladium species.1 However, these reactions
often require the addition of costly and structurally complex
ligands, and the palladium species often present toxicity and
price issues. Following the seminal publication by Kochi in
1971,2 in which he described C−C bond formation between a
vinyl halide and an alkyl Grignard reagent, the field of iron-
catalyzed cross-coupling reactions has garnered considerable
attention as an alternative to these palladium-catalyzed cross-
coupling reactions, especially over the past decade.3 As well as
being considerably cheaper, less toxic, and more abundant than
many transition metals, iron complexes are being increasingly
used in a wide range of applications in catalysis, including drug
and natural product syntheses.3i,4 A number of catalyst and
ligand systems have been reported for the coupling reaction
between a carbon−halogen bond and a Grignard reagent. In
1998, Cahiez and co-workers demonstrated that by employing
1-methyl-2-pyrollidinone (NMP) as a cosolvent, the equiv-
alents of the vinyl halide coupling partner could be dramatically
reduced from those reported4d while maintaining high yields.5
The discovery that the same cosolvent could be used to
similarly improve the reactions of aryl chlorides and triflates
with alkylmagnesium halides was subsequently published by
Initial investigations for the comparison of the variety of
catalytic systems were based upon a model reaction. Fe(acac)3
was selected as a cheap, readily available, and relatively
nonhydroscopic source of iron. It has been proposed that
Fe(III) salts are reduced to lower-oxidation state active catalysts
by Grignard reagents.2,6,11,14 Furstner reports excellent yields
̈
from the reaction of methyl 4-chlorobenzoate 1 and alkyl
Grignard reagents (>95%; ligand, 600 mol % NMP) using 5
mol % Fe(acac)3.6 With readily available starting materials, this
was selected as our model substrate in the coupling reaction
with ethylmagnesium chloride (Table 1).
Initially, five ligand combinations were screened at 0 °C,
along with the reaction with no ligand, all with 5 mol %
Furstner et al.6 Interestingly, the coupling of chloroheterocycles
̈
does not always require NMP as a cosolvent.6,7 These reaction
conditions are tolerant of a variety of substrates with excellent
selectivities and yields. However, NMP is a less-than-desirable
reagent, because of the issues associated with both its removal
from the products and its status as a possible reproductive
toxin.8 For the “reverse” reaction, i.e., that of an alkyl halide and
an aryl Grignard reagent, the use of 1.2 equiv of
tetramethylethylenediamine (TMEDA) gave good yields of
the coupled product.9 It has also been reported that
substoichiometric quantities (10 mol %) of TMEDA can be
used, either alone10 or with hexamethylenetetraamine
(HMTA),11 while still giving excellent yields.11 However,
these conditions have not been applied to functionalized
substrates or tested in the reaction of an aryl chloride and an
Fe(acac)3 (Table 1, entries 1−8). As expected, Furstner’s
̈
conditions using NMP gave excellent results, with complete
conversion of starting material to clean coupled product 2 with
no impurities apart from NMP visible by 1H NMR
spectrometry (entries 2 and 3). The use of amine-based
chelating ligands also gave good results (entries 4−7), with 50
mol % TMEDA giving the highest level of conversion. The
NHC precursor ligand SIPr-HCl gave the lowest level of
conversion of the reactions that included ligands (entry 8), but
this value was still significantly higher than that of the reaction
with no ligand (entry 1). In all of these reactions, the only
Received: July 30, 2013
Published: August 29, 2013
© 2013 American Chemical Society
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The Journal of Organic Chemistry
Note
TMEDA at 20 °C]. In these reactions, the levels of conversion
to 4-ethylbenzoate ester 2 were significantly lower than for the
aryl chloride (99%), with values of 23% for the aryl bromide
and 51% for the aryl triflate.
Table 1. Optimization of the Synthesis of Ester 2
Despite a number of esters that are reported to undergo
these coupling reactions, there are few examples in the
literature of the application of this chemistry to p-
chloroamides.15 We subjected tertiary amide 3 to a similar
range of catalyst−ligand combinations and conditions and were
pleased to find not only that the reactions were successful but
also that the TMEDA ligand gave results comparable to those
of NMP for the synthesis of amide 4 (Table 2, entries 1−5).
Fe(acac)3
(mol %)
T
conversion
entry
ligand (mol %)
none
(°C)
(% by NMR)
1
2
3
4
5
6
7
5
5
5
5
5
5
5
0
0
0
0
0
0
0
55
>99
93
NMP (600)
NMP (300)
TMEDA (50)
TMEDA (10)
HMTA (5)
76
75
66
Table 2. Optimization of the Synthesis of Amide 4
TMEDA (10)/
HMTA (5)
70
8
5
5
5
5
SIPr-HCl (15)
NMP (300)
0
20
20
20
60
88
9
10
11
TMEDA (10)
>99
93
TMEDA (10)/
HMTA (5)
Fe(acac)3
(mol %)
T
conversion
entry
ligand (mol %)
none
(°C)
(% by NMR)
12
13
14
2
TMEDA (10)
TMEDA (10)
TMEDA (10)
20
20
20
>99
>99
18
1
2
3
4
5
5
5
5
5
5
0
0
50
88
94
87
85
1
NMP (600)
0.1
TMEDA (50)
TMEDA (10)
0
20
0
TMEDA (10)/
HMTA (5)
materials visible in the NMR spectra were the coupled product,
residual starting material, and, in the case of Furstner’s
conditions, residual NMP, with no discernible carbonyl
addition products from the reaction of the Grignard reagent
with the ester functionality. These results also demonstrate that
̈
6
7
8
2
TMEDA (10)
TMEDA (10)
TMEDA (10)
20
20
20
94
96
97
1
0.1
the high levels of NMP loading used by Furstner are necessary
̈
for complete conversion (entries 2 and 3). However, when the
level of TMEDA was decreased from 50 to 10 mol %, there was
no significant decrease in the level of conversion (entries 4 and
5). Many of the reported literature reactions are performed at
low temperatures (≤0 °C). It would be preferable to perform
these reactions at ambient temperature, especially if the
reactions are to be performed on a larger scale. Pleasingly,
the three best results from the initial screen gave comparable
results when the reactions were performed at 20 °C, and in the
cases of the amine-based ligands, the levels of conversion were
significantly improved (entries 9−11) to the point where the
use of TMEDA at 10 mol % gave complete conversion (>99%)
with an 85% isolated yield (entry 10). While Fe(acac)3 is not
reported to be hygroscopic, it was noted that upon drying of
the catalyst under vacuum, the level of conversion for this
reaction (entry 10) increased from 95 to >99%. All of the
subsequent reactions were therefore performed with vacuum-
dried catalyst. The catalyst loadings typically used for these
reactions are relatively high, especially when compared to the
initial catalyst loadings of 0.06 mol % reported by Kochi et al.2
Investigations into the loading of catalyst revealed that when
using 10 mol % TMEDA, the loading of catalyst could be
significantly reduced to 1 mol %, without any loss of conversion
(entries 13 and 14). However, when the reaction was
performed with 0.1 mol % Fe(acac)3, the major product
recovered (50%) was the tertiary alcohol from double addition
at the carbonyl of the ester functionality (entry 14). By way of
comparison with the aryl chloride starting material, the
equivalent aryl bromide (methyl 4-bromobenzoate) and aryl
triflate (methyl 4-trifluoromethylsulfonyloxybenzoate) (not
shown) were reacted with EtMgCl using the conditions
described for entry 10 [1 mol % Fe(acac3) and 10 mol %
The optimized conditions for ester 2 [1 mol % Fe(acac)3 and
10 mol % TMEDA at 20 °C] gave good conversion (entry 4),
with no side reactions observed. Because of the less reactive
nature of amides toward Grignard reagents, the loading of the
iron catalyst could be lowered from 5 to 0.1 mol % (entries 6−
8), leading, surprisingly, to a slight increase in the overall level
of conversion.
Having defined a robust set of conditions that gave excellent
results without the requirement for the use of NMP, we applied
the same conditions to some of the other aryl chloride−
Grignard reagent combinations (Figure 1). In most cases, levels
of conversion were high (>90%) and gave clean products.
Lower levels of conversion were seen with phenethyl side
chains and the generally less reactive benzotrifluoride system
(12−15). Interestingly, 2-chloropyridine and 4-chlorobenzoni-
trile (not shown) did not react using TMEDA as a ligand,
unlike the case in which NMP is used when yields of up to 91%
are reported.17
With a view to possible industrial applications of this
chemistry, we were interested in the performance of this
reaction on scale. We were able to perform the reaction on a
much larger scale, successfully coupling 1 mol (210 g) of N-(4-
chlorobenzoyl)pyrrolidine 3 with ethylmagnesium chloride and
0.1 mol % Fe(acac)3 at 20−30 °C. This was done at a total aryl
halide concentration of 0.625 M, a concentration significantly
higher than those previously reported. This reaction gave a
1
crude yield of 99% (200.5 g), with H NMR spectrometry
showing 98% conversion to product 4.
In conclusion, we have developed a clean, effective ambient-
temperature protocol for the coupling of a number of activated
aryl chlorides with alkyl Grignard reagents using TMEDA as
the ligand and loadings of iron catalyst lower than those
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Note
(CONR2), 758 (C−Cl) cm−1; HRMS (ESI) m/z [M + H+] calcd for
C11H13ClNO 210.0680, found 210.0676. These data are consistent
with those previously reported.17
N-(4-Chlorobenzoyl)morpholine. To a solution of morpholine
(0.87 mL, 10 mmol) in CH2Cl2 (10 mL) was added 4-chlorobenzoyl
chloride (0.64 mL, 5 mmol) at 0 °C. The reaction mixture was allowed
to warm to ambient temperature and stirred for 16 h. The reaction
mixture was diluted with pH 2 buffer (20 mL). The organic layer was
collected, washed with Na2CO3, dried (Na2SO4), and concentrated in
vacuo to afford the product as a colorless oil that crystallized on
standing to give a white solid (1.05 g, 93%): mp 75−76 °C; δH (400
MHz, CDCl3) 7.42−7.33 (4H, m, 4 × ArH), 4.02−3.25 (8H, m, 4 ×
CH2); δC (100 MHz, CDCl3) 169.2 (CO), 135.9 (quat.), 133.5
(quat.), 128.7 (ArCH), 128.6 (ArCH), 66.7 (NCH2), 48.1 (OCH2),
42.7 (OCH2); IR (ATR) 1620 (CONR2), 1111 (C−O), 754 (C−Cl)
cm−1; HRMS (ESI) m/z [M + H+] calcd for C11H13ClNO2 226.0629,
found 226.0632. These data are consistent with those previously
reported.17
1-(4-Chlorobenzoyl)-4-methylpiperazine. To a solution of N-
methylpiperazine (2.22 mL, 20 mmol) in CH2Cl2 (20 mL) was added
4-chlorobenzoyl chloride (1.28 mL, 10 mmol) at 0 °C. The reaction
mixture was allowed to warm to ambient temperature and stirred for
16 h. The reaction mixture was concentrated in vacuo and partitioned
between pH 2 buffer (20 mL) and EtOAc (20 mL). The aqueous layer
was collected, basified (Na2CO3), and extracted with EtOAc. The
organic layers were combined, washed with a saturated aqueous
Na2CO3 solution, dried (Na2SO4), and concentrated in vacuo to afford
the product as a yellow oil that crystallized on standing to give a light
yellow solid (2.124 g, 89%): mp 68−69 °C; δH (400 MHz, CDCl3)
7.39 (2H, d, J 8.5, 2 × ClCCH), 7.35 [2H, d, J 8.5, 2 × (CO)CCH],
4.00−3.15 [4H, m, (CO)NCH2], 2.55−2.18 (4H, m, MeNCH2), 2.32
(3H, s, CH3); δC (100 MHz, CDCl3) 169.1 (CO), 135.7 (quat.), 134.1
(quat.), 128.7 (ArCH), 128.5 (ArCH), 55.0 [(CO)NCH2], 54.7
[(CO)NCH2], 47.6 (MeNCH2), 46.0 (CH3), 42.1 (MeNCH2); IR
(ATR) 2798 (NCH2), 1615 (CONR2), 752 (C−Cl) cm−1; HRMS
(ESI) m/z [M + H+] calcd for C12H16ClN2O 239.0946, found
239.0943. This compound is known but has previously been reported
without spectroscopic data.18
Coupling Reactions. General Procedure A. To a solution of
methyl 4-chlorobenzoate 1 (0.170 g, 1 mmol), Fe(acac)3 (3.5 mg, 0.01
mmol), and TMEDA (14.9 μL, 0.1 mmol) in dry THF (1 mL) in an
oven-dried flask under an inert atmosphere at room temperature was
added the alkyl Grignard reagent (1.2 mmol, solution in THF) in 0.1
mmol portions every 30 s. Upon completion of the addition, the
reaction mixture was stirred for an additional 1 min before the reaction
was quenched with a pH 2 buffer solution (2.5 mL). The reaction
mixture was diluted with EtOAc (2.5 mL). The organic layer was
collected, dried (MgSO4), and concentrated in vacuo to afford the
crude product.
General Procedure B. To a solution of N-(4-chlorobenzoyl)-
pyrrolidine 3 (0.210 g, 1 mmol), Fe(acac)3 (0.35 mg, 0.1 mol %), and
TMEDA (14.9 μL, 0.1 mmol) in dry THF (1 mL) in an oven-dried
flask under an inert atmosphere at room temperature was added the
alkyl Grignard reagent (1.2 mmol, solution in THF) in 0.1 mmol
portions every 30 s. Upon completion of the addition, the reaction
mixture was stirred for a further 1 min before the reaction was
quenched with a pH 2 buffer solution (2.5 mL). The reaction mixture
was diluted with EtOAc (2.5 mL). The organic layer was collected,
dried (MgSO4), and concentrated in vacuo to afford the crude product.
General Procedure C. To a solution of 4-chlorobenzotrifluoride
(0.133 mL, 1 mmol), Fe(acac)3 (0.35 mg, 0.1 mol %), and TMEDA
(14.9 μL, 0.1 mmol) in dry THF (1 mL) in an oven-dried flask under
an inert atmosphere at room temperature was added the alkyl
Grignard reagent (1.3 mmol, solution in THF) in 0.1 mmol portions
every 60 s. Upon completion of the addition, the reaction mixture was
stirred for a further 5 min before the reaction was quenched with a pH
2 buffer solution (2.5 mL). The reaction mixture was diluted with
EtOAc (2.5 mL). The organic layer was collected, dried (MgSO4), and
concentrated in vacuo to afford the crude product.
Figure 1. Conversions by 1H NMR (and isolated yields) for the
coupling of aryl chlorides with Grignard reagents. Reaction conditions:
ArCl (1 mmol), RMgCl in THF (1.2 mmol), TMEDA (0.1 mmol),
THF (1 mL), and dried Fe(acac)3 (0.001 mmol for amides and ArCF3
and 0.01 mmol for esters) at 20 °C under N2.
previously reported. We have also demonstrated that these
types of reactions are amenable to scale, increasing the
likelihood that this chemistry could be adopted as an alternative
to precious metal catalysis in an industrial setting.
EXPERIMENTAL SECTION
■
1H, 13C, and 19F NMR spectra were recorded at 400, 100, and 376
MHz, respectively, in CDCl3, and shifts are given relative to Me4Si.
Coupling constants (J) are rounded to the nearest 0.5 Hz. 1H and 13
C
1
assignments were based on H−1H COSY, HSQC, and HMBC two-
dimensional NMR spectra. HRMS measurements were performed on
an ion trap spectrometer. All starting materials are commercially
available and were used without any further purification. Grignard
reagents were titrated before being used versus menthol in THF using
1,10-phenanthroline as an indicator. pH 2 buffer is an aqueous solution
(0.25 M H2SO4 and 0.75 M Na2SO4).
Synthesis of Aryl Chlorides. Methyl 4-Chlorobenzoate 1. Acetyl
chloride (17.77 mL, 0.25 mol) was added to MeOH (100 mL)
dropwise at 0 °C. To the resultant solution was added a suspension of
4-chlorobenzoic acid (15.65 g, 0.1 mol) in MeOH (100 mL) dropwise
at 0 °C. The reaction mixture was stirred at 65 °C for 16 h. The crude
reaction mixture was concentrated in vacuo to give the product (15.12
g, 88%) as a white solid: mp 43−44 °C; δH (400 MHz, CDCl3) 7.97
[2H, d, J 8.5, 2 × (CO)CCH], 7.41 (2H, d, J 8.5, 2 × ClCCH), 3.92
(3H, s, CO2CH3); δC (100 MHz, CDCl3) 166.3 (CO), 139.4 (ClC),
131.0 [(CO)CCH], 128.7 (ClCCH), 128.6 [(CO)C], 52.3
(CO2CH3); IR (ATR) 1718 (CO2Me), 760 (C−Cl) cm−1; LRMS
(GC−MS) m/z calcd for C8H7ClO2 170.0, found 170.0. These data
are consistent with those previously reported.16
N-(4-Chlorobenzoyl)pyrrolidine 3. To a solution of pyrrolidine
(159 mL, 1.91 mol) in CH2Cl2 (600 mL) was added 4-chlorobenzoyl
chloride (122 mL, 0.95 mol) at 0 °C. The reaction mixture was
allowed to warm to ambient temperature and stirred for 16 h. The
reaction mixture was diluted with pH 2 buffer (600 mL). The organic
layer was collected, washed with Na2CO3, dried (Na2SO4), and
concentrated in vacuo to afford the product as a colorless oil that
crystallized on standing to give white needles (192 g, 96%): mp 73−74
°C; δH (400 MHz, CDCl3) 7.47 [d, 2H, J 8.5, 2 × (CO)CCH], 7.37
(2H, d, J 8.5, 2 × ClCCH), 3.62 (2H, t, J 7.0, NCH2), 3.40 (2H, t, J
6.5, NCH2), 1.94 (2H, sext, J 7.0, NCH2CH2), 1.88 (2H, sext, J 6.5,
NCH2CH2); δC (100 MHz, CDCl3) 168.3 (CO), 135.5 (quat.), 135.4
(quat.), 128.5 [(CO)CCH], 128.3 (ClCCH), 49.4 (NCH2), 46.1
(NCH2), 26.2 (NCH2CH2), 24.2 (NCH2CH2); IR (ATR) 1623
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Note
Methyl 4-Ethylbenzoate 2. Prepared according to General
Procedure A using EtMgCl: conversion 95% (by HPLC), >99% (by
NMR); isolated yield 0.140 g, 85%, yellow oil; δH (400 MHz, CDCl3)
7.96 [2H, d, J 8.0, 2 × (CO)CCH], 7.27 (2H, d, J 8.0, 2 × CH2CCH),
3.91 (3H, s, OCH3), 2.71 (2H, q, J 7.5, CH2CH3), 1.26 [3H, t, J 7.5,
CH2CH3]; δC (100 MHz, CDCl3) 167.2 (CO), 149.7 (CH2C), 129.7
[(CO)CCH], 127.9 (CH2CCH), 127.6 [(CO)C], 51.9 (OCH3), 28.9
(CH2CH3), 15.2 (CH2CH3); IR (ATR) 1719 (CO2Me) cm−1; HRMS
(ESI) m/z [M + H+] calcd for C10H13O2 165.0910, found 165.0912.
These data are consistent with those previously reported.19
Methyl 4-Butylbenzoate 7. Prepared according to General
Procedure A using n-BuMgCl: conversion 93% (by HPLC), >99%
(by NMR); isolated yield 0.174 g, 91%, yellow oil; δH (400 MHz,
CDCl3) 7.94 (2H, d, J 8.0, 2 × COCCH), 7.22 (2H, d, J 8.0, 2 ×
CH2CCH), 3.88 (3H, s, OCH3), 2.64 (2H, t, J 7.5, CCH2), 1.60 (2H,
quint., J 7.5, CCH2CH2), 1.34 (2H, sext., J 7.0, CH3CH2), 0.92 (3H, t,
J 7.0, CH3CH2); δC (100 MHz, CDCl3) 167.0 (CO), 148.3 (CH2C),
129.5 [(CO)CCH], 128.3 (CH2CCH), 127.5 [(CO)C], 51.8 (OCH3),
35.6 (CCH2), 33.1 (CCH2CH2), 22.2 (CH2CH3), 13.8 (CH2CH3); IR
(ATR) 1720 (CO2Me) cm−1; HRMS (ESI) m/z [M + H+] calcd for
C12H17O2 193.1223, found 193.1226. These data are consistent with
those previously reported.20
Methyl 4-Hexylbenzoate 8. Prepared according to General
Procedure A using n-hexylMgCl: conversion 95% (by HPLC), 98%
(by NMR); isolated yield 0.196 g, 89%, yellow oil; δH (400 MHz,
CDCl3) 7.94 [2H, d, J 8.0, 2 × (CO)CCH], 7.23 (2H, d, J 8.0, 2 ×
CH2CCH), 3.89 (3H, s, OCH3), 2.65 (2H, t, J 7.5, CCH2), 1.62 (2H,
quint., J 7.5, CCH2CH2), 1.37−1.24 (6H, m, 3 × alkyl CH2), 0.88
(3H, t, J 6.5, CH2CH3); δC (100 MHz, CDCl3) 167.2 (CO), 148.5
(CH2C), 129.6 [(CO)CCH], 128.4 (CH2CCH), 127.6 [(CO)C], 51.9
(OCH3), 36.0 (CCH2), 31.6 (alkyl CH2), 31.0 (CCH2CH2), 28.9
(alkyl CH2), 22.5 (alkyl CH2), 14.0 (CH2CH3); IR (ATR) 1720
(CO2Me) cm−1; HRMS (ESI) m/z [M + H+] calcd for C14H21O2
221.1536, found 221.1538. These data are consistent with those
previously reported.21
Methyl 4-Phenethylbenzoate 9. Prepared according to General
Procedure A using PhCH2CH2MgCl: conversion 88% (by NMR);
isolated yield 0.180 g, 75%, yellow oil; δH (400 MHz, CDCl3) 7.94
[2H, d, J 8.0, 2 × (CO)CCH], 7.30−7.14 (5H, m, 5 × ArH), 7.14
(2H, d, J 7.0, 2 × o-Ph), 3.90 (3H, s, OCH3), 3.01−2.91 (m, 4H,
CH2CH2); δC (100 MHz, CDCl3) 167.1 (CO), 147.2 [(CO)-
CCHCHC], 141.1 (i-Ph), 129.7 [(CO)CCH], 128.5 [(CO)CCHCH],
128.4 (Ph), 128.4 (Ph), 128.0 [(CO)C], 126.1 (p-Ph), 52.0 (CH3),
37.9 (PhCH2CH2), 37.4 (PhCH2); IR (ATR) 1717 (CO2Me) cm−1;
HRMS (ESI) m/z [M + H+] calcd for C16H17O2 241.1223, found
241.1224. These data are consistent with those previously reported.22
N-(4-Ethylbenzoyl)pyrrolidine 4. Prepared according to General
Procedure B using EtMgCl: conversion 97% (by NMR); isolated yield
0.183 g, 92%, off-white solid; mp 85−86 °C; δH (400 MHz, CDCl3)
7.45 [2H, d, J 8.0, 2 × (CO)CCH], 7.21 (2H, d, J 8.0, 2 × CH2CCH),
3.64 (2H, t, J 7.0. NCH2), 3.45 (2H, t, J 6.5, NCH2), 2.67 (2H, q, J 7.5,
CCH2), 1.95 (2H, quint., J 6.5, NCH2CH2), 1.86 (2H, quint., J 6.5,
NCH2CH2), 1.24 (3H, t, J 7.5, CH2CH3); δC (100 MHz, CDCl3)
169.8 (CO), 146.1 (CH2CCH), 134.5 [(CO)C], 127.6 (CH2CCH),
127.2 [(CO)CCH], 49.6 (NCH2), 46.1 (NCH2), 28.7 (CH2CH3),
26.4 (NCH2CH2), 24.4 (NCH2CH2), 15.3 (CH2CH3); IR (ATR)
1605 (CONR2) cm−1; HRMS (ESI) m/z [M + H+] calcd for
C13H18NO 204.1383, found 204.1383. These data are consistent with
those previously reported.23
13.8 (CH3); IR (ATR) 1620 (CONR2) cm−1; HRMS (ESI) m/z [M +
H+] calcd for C15H22NO 232.1696, found 232.1693. This compound
has not previously been reported.
N-(4-Hexylbenzoyl)pyrrolidine 11. Prepared according to General
Procedure B using n-hexylMgCl: conversion 94% (by HPLC), 94%
(by NMR); isolated yield 0.230 g, 89%, yellow oil; δH (400 MHz,
CDCl3) 7.44 [2H, d, J 8.0, 2 × (CO)CCH], 7.19 (2H, d, J 8.0, 2 ×
CH2CCH), 3.64 (2H, t, J 7.0, NCH2), 3.45 (2H, t, J 6.5, NCH2), 2.62
(2H, t, J 7.5, CCH2), 1.95 (2H, quint., J 6.5, NCH2CH2), 1.86 (2H,
quint., J 6.5, NCH2CH2), 1.60 (2H, quint., J 7.5, CCH2CH2), 1.38−
1.24 (6H, m, 3 × alkyl CH2), 0.88 (3H, t, J 6.5, CH3); δC (100 MHz,
CDCl3) 169.8 (CO), 144.8 (CH2CCH), 134.5 [(CO)C], 128.1
(CH2CCH), 127.1 [(CO)CCH], 49.6 (NCH2), 46.1 (NCH2), 35.8
(CCH2), 31.6 (alkyl CH2), 31.2 (CCH2CH2), 28.9 (alkyl CH2), 26.4
(NCH2CH2), 24.4 (NCH2CH2), 22.5 (CH2CH3), 14.0 (CH3); IR
(ATR) 1621 (CO2Me) cm−1; HRMS (ESI) m/z [M + H+] calcd for
C17H26NO 260.2009, found 260.2008. This compound has not
previously been reported.
N-(4-Ethylbenzoyl)morpholine 5. Prepared according to General
Procedure B using EtMgCl: conversion 93% (by NMR); isolated yield
0.185 g, 84%, colorless oil; δH (400 MHz, CDCl3) 7.33 [2H, d, J 8.0, 2
× (CO)CCH], 7.23 (2H, d, J 8.0, 2 × CH2CCH), 4.00−3.35 [m, 8H,
N(CH2CH2)O], 2.67 (2H, q, J 7.5, CH2CH3), 1.24 (2H, t, J 7.5,
CH2CH3); δC (100 MHz, CDCl3) 170.6 (CO), 146.3 (CH2CCH),
132.6 [(CO)C], 128.0 (CH2CCH), 127.3 [(CO)CCH], 66.9
(NCH2CH2O), 28.7 (CH2CH3), 15.4 (CH3); IR (ATR) 1628
(CONR2) 1111 (C−O) cm−1; HRMS (ESI) m/z [M + H+] calcd
for C13H18NO2 220.1332, found 220.1330. This compound is known
but has previously been reported without characterization data.
1-(4-Ethylbenzoyl)-4-methylpiperazine 6. Prepared according to
General Procedure B using EtMgCl: conversion >99% (by NMR);
isolated yield 0.123 g, 53%, colorless oil; δH (400 MHz, CDCl3) 7.33
[2H, d, J 8.0, 2 × (CO)CCH], 7.22 (2H, d, J 8.0, 2 × CH2CCH),
4.05−3.25 [4H, m, (CO)NCH2], 2.67 (2H, q, J 7.5, CH2CH3), 2.57−
2.22 (m, 4H, CH2NCH3), 2.32 (3H, s, NCH3), 1.24 (3H, t, J 7.5,
CH2CH3); δC (100 MHz, CDCl3) 170.5 (CO), 146.1 (CH2CCH),
133.1 [(CO)C], 127.9 (CH2CCH), 127.2 [(CO)CCH], 46.0 (NCH3),
28.7 (CH2CH3), 15.4 (CH2CH3); IR (ATR) 2792 (NCH2), 1628
(CONR2) cm−1; HRMS (ESI) m/z [M + H+] calcd for C14H21N2O
233.1648, found 233.1650. This compound is known but has
previously been reported without characterization data.
4-Ethylbenzotrifluoride 12. Prepared according to General
Procedure C using EtMgCl: conversion 93% (by NMR), 97% (by
HPLC); compound not isolated; δH (400 MHz, CDCl3) 7.53 (2H, d, J
8.0, 2 × F3CCCH), 7.30 (2H, d, J 8.0, 2 × CH2CCH), 2.71 (2H, q, J
7.5, CH2), 1.26 (3H, t, J 7.5, CH3); δC (100 MHz, CDCl3) 148.3
(CH2CCH), 128.2 (CH2CCH), 128.0 (q, F3CCCH, JCF 32.2), 125.2
(q, F3CCCH, JCF 3.7), 124.2 (q, F3C, JCF 271.7), 28.8 (CH2), 15.3
(CH3); δF (376 MHz, CDCl3) −62.3; IR (ATR) 1323 (C-F) cm−1;
LRMS (GC−MS) m/z [M] calcd for C9H9F3 174.1, found 174.0.
These data are consistent with those previously reported.24
4-Butylbenzotrifluoride 13. Prepared according to General
Procedure C using n-BuMgCl: conversion 97% (by NMR), 96% (by
HPLC); isolated yield 140 mg, 69%, yellow oil; δH (400 MHz, CDCl3)
7.52 (2H, d, J 8.0, 2 × F3CCCH), 7.27 (2H, d, J 8.0, 2 × CH2CCH),
2.66 (2H, t, J 8.0, CCH2), 1.66−1.55, (2H, m, CCH2CH2), 1.35 (2H,
sext., J 7.5, CH2CH3), 0.93 (3H, t, J 7.5, CH3); δC (100 MHz, CDCl3)
147.0 (CH2CCH), 128.7 (CH2CCH), 128.0 (q, F3CC, JCF 32.2), 125.1
(q, F3CCCH, JCF 3.8), 124.4 (q, F3C, JCF 271.6), 35.5 (CCH2), 33.3
(CCH2CH2), 22.3 (CH2CH3), 13.9 (CH3); δF (376 MHz, CDCl3)
−62.3; IR (ATR) 1323 (C-F) cm−1; LRMS (GC−MS) m/z [M] calcd
for C11H13F3 202.1, found 201.9. These data are consistent with those
previously reported.25
N-(4-Butylbenzoyl)pyrrolidine 10. Prepared according to General
Procedure B using n-BuMgCl: conversion 95% (by HPLC), 96% (by
NMR); isolated yield 0.172 g, 75%, yellow oil; δH (400 MHz, CDCl3)
7.44 [2H, d, J 8.0, 2 × (CO)CCH], 7.19 (2H, d, J 8.0, 2 × CH2CCH),
3.64 (2H, t, J 7.0, NCH2), 3.44 (2H, t, J 6.5, NCH2), 2.62 (2H, t, J 7.5,
CCH2), 1.94 (2H, quint., J 7.0, NCH2CH2), 1.85 (2H, quint., J 6.5,
NCH2CH2), 1.60 (2H, quint., J 7.5, CCH2CH2), 1.35 (2H, sext., J 7.5,
CH3CH2), 0.92 (3H, t, J 7.5, CH3); δC (100 MHz, CDCl3) 169.7
(CO), 144.7 (CH2CCH), 134.4 [(CO)C], 128.0 (CH2CCH), 127.0
[(CO)CCH], 49.5 (NCH2), 46.0 (NCH2), 35.3 (CCH2), 33.3
(CCH2CH2), 26.3 (NCH2CH2), 24.3 (NCH2CH2), 22.1 (CH2CH3),
4-Hexylbenzotrifluoride 14. Prepared according to General
Procedure C using n-hexylMgCl: conversion 87% (by NMR), 93%
(by HPLC); isolated yield 192 mg, 83%, yellow oil; δH (400 MHz,
CDCl3) 7.51 (2H, d, J 8.0, 2 × F3CCCH), 7.26 (2H, d, J 8.0, 2 ×
CH2CCH), 2.65 (2H, t, J 7.5, CCH2), 1.61 (2H, quint., J 7.5,
CCH2CH2), 1.37−1.24 (6H, m, 3 × alkyl CH2), 0.88 (3H, t, J 6.5,
CH3); δC (100 MHz, CDCl3) 147.0 (CH2C), 128.7 (CH2CCH), 128.0
9520
dx.doi.org/10.1021/jo4016612 | J. Org. Chem. 2013, 78, 9517−9521

The Journal of Organic Chemistry
Note
(q, F3CC, JCF 32.2), 125.1 (q, F3CCCH, JCF 3.8), 124.4 (q, F3C, JCF
271.5), 35.8 (CCH2), 31.7 (alkyl CH2), 31.2 (CCH2CH2), 28.9 (alkyl
CH2), 22.6 (alkyl CH2), 14.0 (CH3); δF (376 MHz, CDCl3) −62.3; IR
(ATR) 1323 (C-F) cm−1; LRMS (GC−MS) m/z [M] calcd for
C13H17F3 230.1, found 230.0. These data are consistent with those
previously reported.26
4-Phenethylbenzotrifluoride 15. Prepared according to General
Procedure C using PhCH2CH2MgCl: conversion 48% (by NMR),
56% (by HPLC); isolated yield 62 mg, 25%, yellow oil; δH (400 MHz,
CDCl3) 7.52 (2H, d, J 8.0, F3CCCH), 7.31−7.24 (m, 4H, ArH), 7.20
(1H, t, J 7.5, p-PhH), 7.15 (2H, d, J 7.5, 2 × o-PhH), 3.02−2.89 (m,
4H, CH2CH2); δC (100 MHz, CDCl3) 145.8 (i-Ar), 141.0 (i-Ar),
128.8, 128.4, 126.1, 125.2 (q, F3CCCH, JCF 3.8), 37.6 (CH2), 37.5
(CH2); δF (376 MHz, CDCl3) −62.3; IR (ATR) 1322 (C-F) cm−1;
LRMS (GC−MS) m/z [M] calcd for C15H13F3 250.1, found 249.3.
These data are consistent with those previously reported.27
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mmol), and TMEDA (15.0 mL, 0.1 mol) in dry THF (800 mL) was
added EtMgCl (600 mL, 2 M solution in THF, 1.2 mol) via cannula at
a rate that kept the internal temperature of the reaction mixture below
30 °C (roughly 1 h). Immediately following the completion of the
addition, the reaction mixture was added via cannula to a pH 2 buffer
solution (1.6 L) (over 45 min) and stirred at room temperature for 16
h. The organics were collected. The aqueous was extracted with
EtOAc, and organics were combined, washed with a saturated aqueous
NaCl solution, dried (Na2SO4), and concentrated in vacuo to give the
crude product as a yellow solid (200.5 g, 99%). The purity (by NMR)
was >98%. A sample was recrystallized for characterization: mp 85−86
°C. Characterization data are consistent with those listed above.
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ASSOCIATED CONTENT
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̈
■
Chem.Eur. J. 2011, 17, 11991−11993.
S
* Supporting Information
1H, 13C, and 19F NMR spectra for all products. This material is
available free of charge via the Internet at http://pubs.acs.org.
(15) The coupling of an amide-containing aryl iodide utilizing an iron
catalyst has been reported, but with the use of a magnesium-derived
copper reagent rather than a Grignard reagent. See: Sapountzis, I.; Lin,
W.; Kofink, C. C.; Despotopoulou, C.; Knochel, P. Angew. Chem., Int.
Ed. 2005, 44, 1654−1657.
AUTHOR INFORMATION
Corresponding Author
*E-mail: d.j.fox@warwick.ac.uk.
■
(16) Ushijima, S.; Moriyama, K.; Togo, H. Tetrahedron 2012, 68,
4701−4709.
(17) Li, J.; Xu, F.; Zhang, Y.; Shen, Q. J. Org. Chem. 2009, 74, 2575−
Notes
2577.
The authors declare no competing financial interest.
(18) Kalyanasundaram, M.; Mathew, N.; Paily, K. P.; Prabakaran, G.
Acta Trop. 2009, 111, 168−171.
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(20) Das, A.; Chaudhuri, R.; Liu, R.-S. Chem. Commun. 2009, 4046−
4048.
ACKNOWLEDGMENTS
We thank the EPSRC and GSK Ltd. for funding.
■
(21) Furstner, A.; Leitner, A. Angew. Chem., Int. Ed. 2002, 41, 609−
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