N,N-carbonyldiimidazole-mediated amide coupling: Significant rate enhancement achieved by acid catalysis with imidazole - HCI

Article abstract of DOI:10.1021/op800226b

Over a series of 10 aromatic amines we show the rate of CDI mediated amidation to be significantly enhanced upon introduction of imidazole·HCI as a proton source for acid catalysis. Our work supports and provides an application for previous investigations into the imidazolium effect, thus increasing the scope of CDI as an amide-coupling reagent with aromatic amines. The influence of the relative pK_a of the amines studied on the rate of reaction was also investigated.

Full text of DOI:10.1021/op800226b

Organic Process Research & Development 2009, 13, 106–113
N,N′-Carbonyldiimidazole-Mediated Amide Coupling: Significant Rate Enhancement
Achieved by Acid Catalysis with Imidazole ·HCl
Emily K. Woodman, Julian G. K. Chaffey, Philip A. Hopes,* David R. J. Hose, and John P. Gilday*
AstraZeneca, Global PR&D, AVlon Works, SeVern Road, Hallen, Bristol BS10 7ZE, U.K.
Abstract:
our case the reduction in water content, reducing proton
availability, was the overriding factor. Following this, we
initiated a work programme on a model system in order to gain
a better understanding of the reaction mechanism and those
factors that would affect the robustness of the process.
The mechanism for the reaction of acyl-imidazole intermedi-
Over a series of 10 aromatic amines we show the rate of CDI
mediated amidation to be significantly enhanced upon introduction
of imidazole ·HCl as a proton source for acid catalysis. Our work
supports and provides an application for previous investigations
into the imidazolium effect, thus increasing the scope of CDI as
an amide-coupling reagent with aromatic amines. The influence
6
ates with nucleophilic reagents has been reported, and it has
been shown that significant rate improvements can be achieved
a
of the relative pK of the amines studied on the rate of reaction
was also investigated.
through use of a cationic imidazolide intermediate (7) (Scheme
7
4
2
) in reactions with nucleophiles. This imidazolium effect has
been applied in the case of aliphatic amines and demonstrated
to be beneficial to the rate of CDI-mediated amidations, due to
the increased reactivity of the intermediate containing a pro-
tonated or methylated imidazole leaving group. To our know-
ledge there is no precedent for the application of the imidazo-
lium effect to achieve rate enhancements in amide-coupling
reactions with aromatic amines.
Introduction
N,N′-Carbonyldiimidazole (CDI) is one of several commonly
used reagents for coupling carboxylic acids with aliphatic or
aromatic amines to form amides (Scheme 1). Since its initial
development as a reagent in 1960 its applicability has been
1
2
shown both in small-scale research and in large-scale manu-
Consideration of the literature led us to devise a hypothesis
that the addition of a weakly acidic compound to the amide
coupling reaction would have two advantageous effects. First,
it would act as a proton source that is required in the proton
transfer steps, and second it would result in the partial
protonation of the imidazolide (3), leading to the more reactive
intermediate (7a). Therefore, the weakly acidic compound
would not only lead to the required increased rate of reaction,
but it would also result in a more robust process. Whilst the
option of using methylating agent, such as methyl iodide, was
considered, it was not pursued as Jencks and co-workers have
previously shown that methylated and protonated intermediates
3
facture.
CDI (2) has several benefits as an amide-coupling reagent
in large-scale manufacture. It is relatively cheap and readily
available in kilogram quantities, and the only byproducts are
carbon dioxide and imidazole which, being relatively benign,
are unlikely to cause problems on scale up (Scheme 1). These
benefits make CDI (2) an excellent reagent for activating amide-
coupling reactions at scale; however, CDI (2) is not without its
drawbacks. Slow reaction rates between aromatic amines and
4
the CDI intermediates have limited the scope of the reaction
in the pharmaceutical and the fine chemicals industries.
CDI (2) was used recently for an amide coupling reaction
in an AstraZeneca project. The coupling, involving two aromatic
substrates, proceeded at a satisfactory rate in the laboratory,
but the rate was observed to be significantly retarded upon scale
up to the large-scale laboratory (LSL). Initial suggestions were
that scale-up factors such as changes in rate of carbon dioxide
removal and in batch water content had led to the rate retard-
ation. The influence of carbon dioxide on the rate of a CDI-
mediated amide coupling reaction has already been investigated
6,7
are equivalent in the case of weakly nucleophilic amines. In
addition, it is desirable to avoid the use of toxic alkylating
reagents such as methyl iodide.
Our choice of weakly acidic compound was required to meet
a number of criteria: it had to be cheap and readily available in
kilogram quantities; it must be easily removed from the reaction
mixture with little or no modifications to the current work-up
procedure; it must not lead to the formation of impurities that
may affect the downstream chemistry; and finally it must be
acidic enough to increase the concentration of the protonated
intermediate (7a), but not sufficiently acidic to significantly
protonate the nucleophilic amine. To this end, imidazole ·HCl
was selected as it meets all of the above requirements and
imidazole is already present in the reaction mixture. We
5
by Vaidyanathan and co-workers, but it was thought that in
*
To whom correspondence should be addressed. Telephone: +44 117
385456. Fax: +44 1179385081. E-mail: Philip.Hopes@astrazeneca.com;
John.Gilday@astrazeneca.com.
9
(
(
(
1) Montalbetti, C.A.G. N.; Falque, V. Tetrahedron 2005, 61, 10827.
2) Paul, R.; Anderson, G. W. J. Am. Chem. Soc. 1960, 82 (17), 4596.
3) Dale, D. J.; Dunn, P. J.; Golighty, C.; Hughes, M. L.; Levettt, P. C.;
Pearce, A. K.; Searle, P. M.; Ward, G.; Wood, A. S. Org. Process
Res. DeV. 2000, 4, 17.
hypothesised that the aqueous disassociation constant of
8
imidazole·HCl (pK
a
) 7.0) would be sufficiently acidic to
(
(
4) Grzyb, J. A.; Shen, M.; Yoshina-Ishii, C.; Chi, W.; Stanley Brown,
R.; Batey, R. A. Tetrahedron 2005, 61, 7153.
(6) Oakenfull, D. G.; Salvesen, K.; Jencks, W. P. J. Am. Chem. Soc. 1971,
93, 188.
5) Vaidyanathan, R.; Kalthod, V. G.; Ngo, D. P.; Manley, J. M.; Lapekas,
S. P. J. Org. Chem. 2004, 69, 2565–2568.
(7) Wolfenden, R.; Jencks, W. P. J. Am. Chem. Soc. 1961, 83, 4390.
1
06
•
Vol. 13, No. 1, 2009 / Organic Process Research & Development
10.1021/op800226b CCC: $40.75  2009 American Chemical Society
Published on Web 12/05/2008

Scheme 1
Scheme 2
the results for the heterocyclic amines deviate from the trend.
Table 2 lists each of the amines studied together with the
lifetimes (defined as time to >90% conversion by quantitative
HPLC) of their reactions with benzoic acid both with acid
catalysis and without acid catalysis at 50 and 100 °C where
applicable.
Using numerical methods,12 the rate constants for the
reactions of each amine under both acidic and nonacidic
conditions were determined (Table 3). It has been assumed for
the purposes of fitting the data that the reactions obey second-
order kinetics.
Only the results from the series of anilines (4a-4g) will be
considered initially, ignoring the heterocycles (4h-4j). Through-
out the series of anilines the rate constant is seen to increase
by 20-fold on average when the reaction is carried out under
acid catalysis compared to being carried out without acid
catalysis. This difference in rate demonstrates that using
imidazole·HCl as a proton source for acid catalysis in CDI-
mediated amide-coupling reactions does lead to an increase in
the rate of reaction between the imidazolide intermediate and
the amine within this series of anilines. The Brønsted-type plot
partially protonate the imidazolide intermediate (3) (predicted
9
pK
a
) 3.7) whilst ensuring sufficient unprotonated amine was
present to carry out efficient nucleophilic attack.
We chose to investigate a series of 10 aromatic and
a
heteroaromatic amines (Table 1) that span 12 pK units (based
upon aqueous pK predictions), which would cover a range of
a
reaction rates. This gave us the opportunity to investigate both
the effect of using imidazole ·HCl for acid catalysis and the
a
influence of the amine, or more specifically the pK of the amine
on the reaction. This paper reports the results of our investiga-
10
tions into these 10 amines (Table 1).
Results and Discussion
Each amine was investigated by carrying out the amidation
reaction with benzoic acid (8) in two steps (Scheme 3). In the
first step the imidazolide intermediate (3) was formed in greater
than 97% conversion. The reaction mixture was then heated to
(
Figure 2) demonstrates strong correlation between the aqueous
pK of the anilines and their corresponding logarithmic rates
of reaction.
The plot shows clearly that the rate of reaction, both in the
catalysed and uncatalysed cases, decreases as the pK of the
a
50 °C before the addition of the amine (4). The progress of the
amidation reaction was monitored by HPLC, using a butylamine
quench to facilitate analysis. In each case the reaction was
carried out both with and without acid catalysis in order to give
a direct comparison of rates. NMP was used as the reaction
solvent for all reactions to ensure complete dissolution of all
reactants and intermediates. Figure 1 shows a representative
a
amine decreases, reflecting the decreasing nucleophilicity of
2
the amine. The strong correlation (R > 0.97) in each of the
cases suggests that across the series of anilines the mechanism
and rate-determining step of the reaction is consistent. However,
the fact that the two correlations are distinct implies that the
rate-determining step differs between the two sets of conditions.
These observations support our suggestion that one rate-
determining step, in the presence of imidazole ·HCl, is controlled
by the protonated intermediate, whereas the other, without
imidazole·HCl present, is not.
11
example of the results collected.
Figure 1 demonstrates a significant decrease in reaction
lifetime on changing the noncatalysed reaction conditions (∼5
days) to those with acid catalysis (∼5 h). All of the reactions
involving anilines follow analogous reaction profiles, although
Whilst the results for the anilines clearly show an increase
in reaction rate when the reaction is carried out with acid
catalysis, the results for the heterocyclic amines are not as
conclusive. The rate of reaction increases by an order of
magnitude with acid catalysis compared to the rate of the
uncatalysed reaction in the case of 4-aminopyrimidine (4h),
which is consistent with the trend seen in the anilines. However,
in the case of 4-aminopyridine (4j) the trend is reversed, and
the rate of reaction is seen to decrease by 6-fold under acid
(
8) Bonvicini, P.; Levi, A.; Lucchini, V.; Modena, G.; Scorrano, G. J. Am.
Chem. Soc. 1973, 95, 5960.
(
9) ACD Labs pKa Database, Version 10.01; Advanced Chemistry
Developments Inc.: Toronto, Canada, 2007.
(
10) References for quoted pKa’s: (a) Willi, A. V.; Meirer, W. HelV. Chim.
Acta 1956, 39, 318. (b) Bolton, P. D.; Hall, F. M. Aust. J. Chem.
1
967, 20, 1797. (c) Bolton, P. D.; Hall, F. M. J. Chem. Soc. 1969, B,
2
59. (d) ACD Labs pKa Database, Version 10.01; Advanced Chemistry
Developments Inc.: Toronto, Canada, 2007. (e) Sheppard, W. A. J. Am.
Chem. Soc. 1962, 84, 3072. (f) Fickling, M. M.; Fischer, A.; Mann,
B. R.; Packer, J.; Vaughan, J. J. Am. Chem. Soc. 1956, 81, 4226. (g)
Gold, V.; Tomlinson, C. J. Chem. Soc. 1971, B, 1707. (h) Fischer,
A.; Galloway, W. J.; Vaughan, J. J. Chem. Soc. 1964, 3591. (i) Bender,
M.; Chow, Y. J. Am. Chem. Soc. 1959, 81, 3929. (j) Albert, A.;
Goldacre, R.; Phillips, J. N. J. Chem. Soc. 1948, 2240.
(12) The fitting of the experimental data was performed using Dynochem
Version 3.2.1.0.; Performance Fluid Dynamics (P.F.D.) Limited:
Dublin, Ireland, 2007.
(
11) A full set of reaction profiles can be found in the Supporting
Information.
Vol. 13, No. 1, 2009 / Organic Process Research & Development
•
107

Table 1. Amines investigated together with their aqueous
pK ’s and the amides formed
Scheme 3
a
chosen 4i is simply too unreactive. However, by increasing the
reaction temperature to 100 °C the reaction could be driven to
completion within 24 h with acid catalysis (6 times faster than
without acid catalysis).
a
The clear correlations seen between pK and reaction rate
in the Brønsted-type plot shown in Figure 2 are lost if the
heterocyclic amines are included. The loss of correlation could
imply that the heterocyclic amines react Via a different rate-
determining step from that of the anilines.
13
The Hammett plot (Figure 3) for the series of anilines
shows a reasonable linear relationship for both the acidic and
nonacidic processes. The 3-chloro-4-fluoroaniline is an obvious
and unexplained outlier. The gradients of the regression lines,
corresponding to F of the Hammett equation, are both negative
(-3.66 and -3.56 for the acidic and nonacidic processes,
respectively), indicating that electron-donating groups on the
aniline increases the rate of reaction through the stabilisation
of the developing positive charge at the reactive centre in the
transition state. The values of F are not dissimilar to F obtained
for the reaction of a series of anilines with benzoyl chloride in
14
benzene at 25 °C (F ) -2.69). The very similar values of F
obtained for the acidic and nonacidic processes suggest that,
from the perspective of the aniline, the reaction mechanism is
virtually identical in both regimes. This lends additional support
that the acidic conditions activate the benzoyl imidazolide to
attack (Table 4).
During our work, we have assumed that the imidazolium
effect proposed by Jencks, and named as such by Batey, is
correct. We decided to explore this further through density
functional theory (DFT) calculations. In principle the benzoyl
imidazolide could protonate either on the nitrogen atom (7a)
or the carbonyl oxygen (12) (Scheme 4). Either structure would
activate the carbonyl group to nucleophilic attack.
15
The gas-phase proton affinities of benzoyl imidazolide (9)
16
were calculated at the B3LYP/6-31+G*//B3LYP/6-31G* level
of theory. The results obtained indicate that the protonation of
-1
the nitrogen atom is preferred (940.7 kJ mol ) over protonation
-1
of the carbonyl oxygen (827.2 and 833.9 kJ mol for the Z-
a
a
Value in parentheses refers to the pK of the ring nitrogen.
(
(
13) Hammett, L. P. Chem. ReV. 1935, 17 (1), 125.
14) Sykes, P. A Guidebook to Mechanism In Organic Chemistry, 6th ed.;
Longman Group Ltd.: Harlow, 1986; p 364.
catalysis, implying that the proton source is retarding the
reaction rate rather than accelerating it.
No rate constants are reported for 2-aminopyrazine (4i) as,
at 50 °C, no reaction was seen either with or without acid
catalysis over a 6-day period. It seems that under the conditions
(
15) The proton affinity is defined as the negative of the enthalpy change
in the gas-phase reaction between a proton and the chemical species
concerned, usually an electrically neutral species, to give the conjugate
acid of that species.
(16) See Supporting Information for more details of the calculations.
1
08
•
Vol. 13, No. 1, 2009 / Organic Process Research & Development

Figure 1. Reaction profile showing amide formation over time for amine 4d.
Table 2. Experimental reaction times
quantum mechanically (QM) derived descriptors were
reaction time (h)a
obtained that represent aspects of the nucleophilicity of
the amine. The following descriptors relating to the
nucleophilic nitrogen atom were considered: partial atomic
charge, the occupancy and percentage of s-orbital character
of the lone-pair, molecular electrophilicity and softness,
as well as the condensed atom electrophilicity and softness
indices. The relationship between the logarithmic rate of
reaction and the QM-derived descriptors was examined
using the projection of latent structures (PLS) modelling
technique. Four models were built that examined the acidic
and nonacidic regimes for all of the compounds and the
aniline subset. All four models were refined through cross-
validation and model validation techniques to produce
non-acid
catalysis
acid
catalysis
amine
temperature (°C)
4
a
50
50
1
23
27
0
1
4
b
4
c
50
2
4
d
50
45
175
ND
3
4
4
4
4
e
e
f
f
50
29
100
50
3
.143
ND
143
10
100
50
100
50
100
100
50
4
g
g
.211
ND
.211
ND
140
114
>143
4
22
4
h
h
143
23
25
4
4
i
j
2
2
4
>120
single-component models with high R and Q values.
Figure 4 shows that virtually identical loadings plots were
obtained for the PLS models of the anilines under both acidic
and nonacidic conditions, indicating that the descriptors have
equal significance under each regime. This suggests that the
addition of imidazole ·HCl to the reaction mixture does not
unduly modify the intrinsic reactivity of the anilines compared
to that of the uncatalysed reaction, further supporting interpreta-
tion of the Hammett plots above.
a
Reaction time to greater than 90% conversion. ND ) Not Determined.
and the E-oxonium ions respectively). The energy difference
-1
of over 100 kJ mol indicates that the protonation of the oxygen
is virtually insignificant compared to that of the nitrogen atom
of the imidazole ring.
The Brønsted-type and Hammett plots show clear correla-
tions with the reaction rate for the anilines studied. However,
the heterocyclic amines do not obey these simple models. As
such we decided to examine a multiparameter, quantitative
structure activity relationship (QSAR) approach, which could
be used to predict the rates of reaction of all amines studied,
supporting our emphasis on improving the scope of CDI.
The geometry of each amine in turn was optimised at
the B3LYP/6-31G* level of theory. From these geometries
The PLS model encompassing both the anilines and
heterocyclic amines under nonacidic conditions is broadly
similar to those obtained for the anilines alone, the most
noticeable difference is in the loading for the percentage
s-orbital character.
The model that is most strikingly different is the one obtained
under acidic conditions, which includes both the anilines and
Table 3. Rate constants calculated for reactions at 50 °C
rate constant (mol/L ·s)
log (rate constant)
amine
non-acidic
acidic
non-acidic
acidic
3.808 × 10-
3
4
5
5
6
7
7
7
4.043 × 10
4.649 × 10
1.016 × 10
4.978 × 10
5.269 × 10
1.084 × 10
3.797 × 10
2.967 × 10
ND
-2
-3
-3
-4
-5
-5
-6
-6
-2.42
-3.74
-4.50
-4.58
-5.22
-6.43
-6.81
-6.54
ND
-1.39
-2.33
-2.99
-3.30
-4.28
-4.96
-5.42
-5.53
ND
4
-methoxyaniline
4a
4b
4c
4d
4e
4f
-
aniline
1.802 × 10
-
4
3
4
4
4
4
4
4
-chloroaniline
3.129 × 10
-
-chloro-4-fluoroaniline
-trifluoromethylaniline
-cyanoaniline
2.627 × 10
-
5.996 × 10
-
3.678 × 10
-
-nitroaniline
4g
4h
4i
1.545 × 10
-
-aminopyrimidine
-aminopyrazine
-aminopyridine
2.902 × 10
a
ND
2.527 × 10-
5
4.042 × 10
-6
-4.60
-5.39
4j
a
ND ) Not Determined.
Vol. 13, No. 1, 2009 / Organic Process Research & Development
•
109

Figure 2. Brønsted-type plot for the aniline series.
Figure 3. Hammett plot for the aniline series.
Table 4. Hammett plot parameters
nucleophiles upon adding acid to the system, indicating that
the heterocyclic amines do not fit the previously observed
model.
log (k
acidic
X H
/k )
amine
σ valuea
nonacidic
This behaviour can be readily explained in terms of the pK
a
4
-methoxyaniline
-0.27
0.00
0.94
0.00
1.32
0.00
aniline
of the nitrogen atoms in the heterocycle (Table 1). The aqueous
disassociation constant of the heterocyclic nitrogen in 4-ami-
nopyridine is 9.12, indicating that in the presence of the
imidazole ·HCl the ring nitrogen is protonated (Scheme 5). This
will result in the exocyclic nitrogen donating electron density
into the ring to stabilise the positive charge; thus, the exocyclic
nitrogen will have a lower propensity to undergo nucleophilic
attack. The QM descriptors fail to describe this behaviour
correctly, as the descriptors were calculated for the neutral and
not the protonated form.
4
3
4
4
4
-chloroaniline
0.23
-0.66
-0.97
-1.95
-2.63
-3.09
-0.76
-0.84
-1.48
-2.69
-3.07
b
-chloro-4-fluoroaniline
-trifluoromethylaniline
-cyanoaniline
0.43
0.54
0.66
0.78
-nitroaniline
a
b
σ values used were obtained from ref 18. The σ value used is the sum of the
σ
p-Cl and σm-F.
heterocyclic amines. The refined model does not include the
descriptors directly relating to the nitrogen lone-pair (occupancy
and s-orbital character), suggesting that as a complete group
the addition of acid has an effect on the nucleophilicity of the
amine as the regime changes. As demonstrated in the Hammett
plot, there is no effect upon the ability of the anilines to act as
Overall the models generated under the QSAR approach
support the experimental results obtained and provide a useful
a
model in the case of the anilines (within the pK range studied).
However, it can be seen that the heterocycles do not fit the
1
10
•
Vol. 13, No. 1, 2009 / Organic Process Research & Development

Scheme 4
Scheme 5
investigate how the rate of reaction changes as the number of
equivalents of imidazole·HCl is varied between 0 and 2 in 0.5
increments. For efficiency we carried out this final study using
17
an automated reaction system, which allowed us to investigate
the different reactions simultaneously. Although this forced us
to vary the conditions away from those used in the rest of this
paper, we were able to generate a self-consistent set of data
across five different concentrations of imidazole ·HCl. As
before, we made the assumption that the reaction followed
second-order kinetics in order to fit rate constants to the data.
From Figure 5, using the chosen aniline, it can be seen that
the rate of reaction increases linearly with the initial charge of
imidazole ·HCl. This is consistent with the overall rate equation
for the reaction being dependent upon acid concentration derived
from the imidazole ·HCl charge and that 7a forms part of the
aniline model and further work would be required, covering a
wider range of heterocycles in order to develop an alternative,
more appropriate model.
Having investigated the properties of the nucleophile we felt
that it would be useful to understand further the effect of acid
concentration on the rate of reaction. As such we undertook a
further experiment to demonstrate the change in rate as the
concentration of imidazole ·HCl is changed. Using 4-chloro-
aniline (4c) as a typical aniline, we designed an experiment to
Figure 4. Summary plot of PLS loadings.
Figure 5. Change in rate with initial charge of imidazole ·HCl.
Vol. 13, No. 1, 2009 / Organic Process Research & Development
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111

rate-determining step for the reaction. Together with the
evidence from the Hammett plot discussed above this leads us
to the conclusion that changing from a nonacidic regime to an
acidic regime enhances the rate by increasing the concentration
of 7a present without adversely affecting the level of unpro-
tonated amine.
The linear relationship obtained supports our hypothesis that
only a small proportion of the imidazolide is protonated under
these reaction conditions. Whilst additional rate enhancements
may be possible, we have restricted our investigation to practical
imidazole·HCl charges.
Generic Experimental Procedure. Without Acid Catalysis.
Benzoic acid (Aldrich >99.5%) (8, 1.00 g, 8.19 mmol); CDI
(Acros 97%) (2, 1.3 equiv, 1.76 g, 10.65 mmol); m-terphenyl
(Aldrich >98%) (200 mg, 0.86 mmol) and anhydrous NMP
(Aldrich 99.5%) (20 mL, 20 rel vols) were charged to a clean,
dry, three-necked, round-bottomed, 100 mL flask, fitted with
an overhead stirrer (200 rpm), nitrogen bubbler, and thermom-
eter. The reaction was allowed to proceed at ambient temper-
ature until at least 97% conversion to the imidazolide interme-
diate (9) was achieved based upon HPLC. Samples were
prepared for analysis by taking a 50 µL aliquot from the reaction
mixture, quenching it in 200 µL of butylamine. After holding
the quench mixture at ambient temperature for 5 min it was
diluted to 50 mL with 3:1 methanol/water and then analysed
Conclusions
Over the series of anilines screened, we have demonstrated
that the use of imidazole ·HCl significantly enhances the rate
of reaction. This observation supports previous investigations
into the imidazolium effect and suggests that protonation in situ
can be used effectively to increase the rate of reactions between
aromatic amines and the imidazolide intermediate generated in
CDI-mediated amidations. The anilines follow the trend of
17
using the HPLC method described above. Upon reaching
>
97% conversion, the reaction liquor was heated to 50 °C, and
the appropriate amine (all sourced from Acros or Aldrich
>98%) (4) (12.28 mmol, 1.5 equiv) was charged. Samples were
then taken using the method described above at regular time
intervals chosen according to the expected lifetime of the
reaction.
increasing reaction rate with increasing aqueous pK
a
, when
With Acid Catalysis. The reaction conditions were the same
as the uncatalysed reaction except that imidazole ·HCl (Aldrich
98%) (1.76 g, 12.28 mmol, 1.5 equiv) was charged to the
reaction at the same time as the benzoic acid.
reacting with the benzoyl imidazolide intermediate under either
acidic or nonacidic conditions. Furthermore, the logarithmic rate
constants for anilines can be modelled using quantum mechani-
cally derived descriptors under acidic and nonacidic regimes.
In conclusion we have shown that reactions, which under
standard conditions can take days to reach completion, can now
be carried out in a matter of hours upon addition of
imidazole ·HCl. Crucially, for large-scale manufacture this rate
enhancement can be achieved without the need for more forcing
conditions, thus maximising throughput for an otherwise slow
reaction with minimum impact on cost.
Work-Up. The reaction mixtures were drowned out into
water (20 mL) at ambient temperature. The precipitated white
solid was isolated by filtration and dried under vacuum at 40
°C. The dry solid was recrystallised from the minimum amount
of hot absolute ethanol and isolated by filtration at ambient
temperature. The white crystalline solid was dried under vacuum
at 40 °C. With the exception of two, all the amides synthesised
in the course of this study are known and characterised in the
literature. The two novel compounds synthesised have been fully
characterised, and the details are listed below. In the case of
Experimental Section
1
the known compounds structural identity was confirmed by H
General Considerations. All reagents were purchased from
commercial sources and used without any additional purifica-
tion. All experiments were carried out under a nitrogen
atmosphere to maintain anhydrous conditions. The reaction
profiles were followed quantitatively by HPLC on a Hewlett-
Packard series 1100 machine using a Hichrom ACE Phenyl
NMR; characterisation references for these compounds can be
found in Table 4.
4
h N-Pyrimidin-4-ylbenzamide: HPLC RT 2.98 min; mp
1
9
7-98 °C; H NMR (399.89 MHz, DMSO-d
6
) δ 11.22 (1H,
s), 8.93 (1H, s), 8.70 (1H, d, J)5.6 Hz), 8.19 (1H, d, J ) 6.8
13
Hz), 8.00 (2H, d, J)8.4 Hz), 7.60 (1H, m) 7.51 (2H, m); C
NMR: (100.55 MHz, DMSO-d ) δ 167.62, 158.38, 158.23,
33.40, 132.62, 128.64, 128.36, 126.09, 110.77; GC/MS-EI (m/
5
0 mm × 3.0 mm × 3 µm column at 45 °C; flow rate: 1.25
6
mL/min; injection volume: 2 µL; detection wavelength: 220
nm; mobile phase 5% methanol in water increasing to 95%
methanol in water over a 6 min period, 95% methanol in water
was then held for 1.5 min. Both the water and the methanol
eluent contained 0.03% trifluoroacetic acid. m-Terphenyl was
used as an internal standard for the HPLC analysis, and all
measurements were made within a previously defined linearity
range. H NMR and C NMR spectra were recorded on a
Varian Inova NMR 400 MHz spectrometer operating at 399.9
6
MHz in DMSO-d for H NMR and 100.55 MHz for C NMR.
1
+
+
z): Calcd for C11
9 3
H N O 199.0744 (M ) found 199.0738 (M ).
IR (ATR) 1682, 1568, 1504, 1459, 1394, 1308, 1265, 1176,
1
112, 1072, 1024, 997, 926, 897, 866, 834, 789, 718, 689,
-1
663 cm .
4
i N-Pyrazin-5-ylbenzamide: HPLC RT 2.90 min; mp
1
1
45-147 °C; H NMR: (399.89 MHz, DMSO-d ) δ 11.12 (1H,
6
1
13
s), 9.43 (1H, d, J)1.6), 8.49 (1H, m), 8.43 (1H, m), 8.06 (2H,
13
m), 7.63 (1H, m), 7.54 (2H, m); C NMR: (100.55 MHz,
1
13
6
DMSO-d ) δ 166.15, 149.05, 142.55, 139.94, 137.47, 133.36,
The chemical shifts, δ, were recorded relative to tetramethyl-
silane as an internal standard; all coupling constants, J, are
1
32.25, 128.39, 128.15; GC/MS-EI (m/z): Calcd for C11H N O
9 3
reported in Hz. All compounds were standardised against
(
17) The imidazolide intermediate (3) was not suitable for analysis by
HPLC; addition of the imidazolide intermediate to butylamine
facilitated analysis of the imidazolide by reacting to form the butyl
amide derivative, which was easily detected by HPLC.
1
2,3,5,6-tetrachloronitrobenzene (TCNB) by H NMR. GC/MS
was recorded on Agilent Micromass GC-TOF. IR was recorded
on a Perkin-Elmer UTAR spectrometer.
(18) Hansch, C.; Leo, A.; Taft, R. W. Chem. ReV. 1991, 91 (2), 165.
1
12
•
Vol. 13, No. 1, 2009 / Organic Process Research & Development

+
+
1
1
99.0744 (M ) found 199.0718 (M ). IR (ATR) 1671, 1530,
butylamine; after a 5 min hold take a 50 µL aliquot from the
quench and charge it into 1.5 mL of 3:1 methanol/water. The
samples collected were then analysed using the HPLC method
-1
410, 1292, 1258, 1054, 1010, 841, 801, 707 cm .
Experimental Procedure Investigation in the Automated
Reactor, SK233. N-Benzoylimidazole (Alfa Aesar 96%) (9,
16
described above.
7
4
.06 g, 41.0 mmol), imidazole (Acros >99%) (2.79 g, 1 equiv,
1.0 mmol), and m-terphenyl (1.06 g, 4.5 mmol) were made
Acknowledgment
up into 100 mL of stock solution with anhydrous NMP. The
stock solution was then divided into five 20 mL portions and
charged into five clean dry reaction tubes. Imidazole. HCl was
charged to the tubes as follows; Tube A: 0 g, 0 equiv; Tube B:
We thank Jonathan Moseley for his help in the preparation
of this manuscript. We also thank Ian Derrick for his support
and advice in running the SK233. We thank Gordon Plummer
and Richard Wisedale for additional analytical support.
0
.44 g, 4.10 mmol, 0.5 equiv; Tube C: 0.87 g, 8.20 mmol, 1
equiv; Tube D: 1.31 g, 12.30 mmol, 1.5 equiv; Tube E: 1.74 g,
6.40 mmol, 2 equiv. The tubes were then set up in the SK233
Supporting Information Available
1
Complete set of graphs to complement Figure 1, and a further
explanation of the computational work undertaken. This infor-
mation is available free of charge via the Internet at http://
pubs.acs.org.
instrument and heated to 46 °C. 4-Chloroaniline (4c, 16 g, 61.5
mmol) was made up into a 20 mL stock solution with anhydrous
NMP; this solution was then charged in 2.5 mL aliquots to each
of the five reaction tubes. The SK233 was programmed to
sample the reaction tubes at regular time intervals after the
amine charge. The sampling protocol was as follows: take 50
µL aliquot from the reaction tube and quench it into 200 µL of
Received for review September 12, 2008.
OP800226B
Vol. 13, No. 1, 2009 / Organic Process Research & Development
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