High-efficiency aminocarbonylation by introducing CO to a pressurized continuous flow reactor

Article abstract of DOI:10.1021/ol7030894

Halogenated aryl carboxylic acids were efficiently converted to the corresponding dicarboxylic acid monoamides by a one-step Pd-catalyzed aminocarbonylation in a micro/meso fluidic continuous flow reactor (X-Cube) operated at high pressure and high temperature with CO gas introduction. Reaction parameters (solvent, base, catalyst, pressure, temperature) were rapidly optimized in the reactions, which required less than 2 min. The method gave improved results over comparable batch techniques and is also suited to automated parallel syntheses of compound libraries.

Full text of DOI:10.1021/ol7030894

ORGANIC
LETTERS
2008
Vol. 10, No. 8
1589-1592
High-Efficiency Aminocarbonylation by
Introducing CO to a Pressurized
Continuous Flow Reactor
Csaba Csaja´gi,* Bernadett Borcsek, Krisztia´n Niesz, Ildiko´ Kova´cs,
Zsolt Sze´kelyhidi, Zolta´n Bajko´, La´szlo´ U2rge, and Ferenc Darvas
ThalesNano Inc., H-1031, Budapest, Za´hony u. 7., Hungary
csaba.csajagi@thalesnano.com
Received February 5, 2008
ABSTRACT
Halogenated aryl carboxylic acids were efficiently converted to the corresponding dicarboxylic acid monoamides by a one-step Pd-catalyzed
aminocarbonylation in a micro/meso fluidic continuous flow reactor (X-Cube) operated at high pressure and high temperature with CO gas
introduction. Reaction parameters (solvent, base, catalyst, pressure, temperature) were rapidly optimized in the reactions, which required less
than 2 min. The method gave improved results over comparable batch techniques and is also suited to automated parallel syntheses of
compound libraries.
The syntheses of selectively derivatized dicarboxylic acids
hold considerable interest because of their common occur-
rence as biologically active compounds in medicinal chem-
istry, for example, 1,1-cyclohexanediacetic acid monoamide
(gabapentine) is an important neurological agent1 and tere-
phthalic acid monoamides have antiallergic effects,2,3 and
some dicarboxylic acids are inhibitors of dicarboxylate
monoamide aminohydrolases.4 In addition, they can often
be found in materials derived from natural sources.5,6 The
conventional synthesis of aryl dicarboxylic acid monoamides
is usually achieved via three steps,7,8 with selective depro-
tection of diesters9,10 followed by amidation and a second
deprotection.11 While the carbonylation of aryl halides, a
versatile reaction, is an important synthetic route for the
preparation of aromatic carboxylic acid derivatives, like
carboxylic amides,12-27 the direct aminocarbonylation of
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10.1021/ol7030894 CCC: $40.75
© 2008 American Chemical Society
Published on Web 03/22/2008

haloaryl acids for synthesis of a dicarboxylic acid monoamide
has only been mentioned in a single paper.28
Table 1. Results of Comparing Different Bases
We considered the one-step selective syntheses of dicar-
boxylic acid monoamides an important chemical problem
so we tried to solve it by direct CO gas introduction using
our continuous flow system. We selected the aminocarbo-
nylation of 4-iodobenzoic acid with pyrrolidine and carbon
monoxide as a model reaction to demonstrate the optimiza-
tion of the reaction conditions (Scheme 1) because this was
base
conversiona (%)
NMPY
TEA
DABCO
DBU
DMAP
EDIPA
68
83
47
0
44
33
a Conversion to 4-(pyrrolidine-1-carbonyl)benzoic acid.
Scheme 1. Model Reactiona
suitable for this flow based synthesis. Hence, a selection of
commercially available immobilized palladium catalysts was
used to fill the proprietary cartridges (CatCarts, a trade name
by ThalesNano, Inc., Hungary). The best results were
obtained with polymer-supported tetrakis(triphenylphos-
phine)palladium, which resulted in high conversion with no
detectable byproduct under the test conditions (Table 2).
a X-Cube is a trademark of ThalesNano Inc., Hungary. It is a
high-pressure continuous-flow reactor capable of reaching temper-
atures and pressures between room temperature and 200 °C and
up to 150 bar, respectively, and performing reactions with or without
gas introduction from an external source. The system works by
flowing substrates through a low-volume stainless steel reaction
line and reacting them continuously on preloaded catalyst/reagent
cartridges.
Table 2. Results of Comparing Different Immobilized
Catalysts
catalyst
conversiona (%)
b
Pd(TPP)4
83
25
9
20
2
the single example quoted in the literature.28 In this study,
we applied a continuous flow reactor.29
FibreCat 1001c,g
FibreCat 1007d,g
PdEnCat TPP 30e,h
PdEnCat 30f,h
This general-purpose flow chemistry instrument (X-Cube)
works by pressing the solution of substrates through a low-
volume stainless steel tube and reacting them continuously
on preloaded catalyst cartridges under high pressure, high
temperature, by optional continuous gas introduction.30-32
In our model reaction, we introduced carbon monoxide from
an external cylinder.
a Conversion to 4-(pyrrolidine-1-carbonyl)benzoic acid. b FibreCat 1001:
Pd(OAc)2/TPP on polymer fiber. c FibreCat 1007: Pd(OAc)2/tricyclohexyl-
phosphine on polymer fiber. e PdEnCat TPP 30: microencapsulated
Pd(TPP)4. f Pd EnCat 30: microencapsulated Pd(OAc)2. g FibreCat is a
registered trademark of Johnson Matthey, Inc., UK. h EnCat is a trademark
of Reaxa Ltd., UK.
Intelligent solvent selection is essential in flow chemistry
as precipitates can easily block the narrow tubes used. A
range of solvents often used for cross-coupling reactions was
tested, including acetonitrile, acetone, 1,4-dioxane, and
tetrahydrofuran (THF). THF was found to offer the best
solubility of both starting materials and products. Next, the
most effective base needed to be determined. Model reactions
were run using different organic bases such as N-methylpyr-
rolidine (NMPY), triethylamine (TEA), 1,4-diazabyciclo-
[2.2.0]octane (DABCO), 1,8-diazabicyclo[5.4.0]-undec-7-ene
(DBU), 4-dimethylaminopyridine (DMAP), and N-ethyldi-
isopropylamine (EDIPA). The results listed in Table 1
indicated TEA was the best base to be used in this reaction.
Several catalysts were also screened to find the one most
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2002, 67, 6232-6235.
Figure 1. Effect of pressure. Reaction conditions: 0.01 M of
4-iodobenzoic acid in 20 mL of THF, 1.5 equiv of pyrrolidine, 2.0
equiv of base, Pd(TPP)4 catalyst (CatCart), 100 °C, 0.5 mL/min
flow rate.
(27) Skoda-Fo¨ldes, R.; Kolla´r, L. Current Org. Chem. 2002, 6, 1097-
1119.
(28) Karimi, F.; Langstro¨m, B. Eur. J. Org. Chem. 2003, 2132-2137.
(29) Csaja´gi, C.; Szatzker, G.; To¨ke, R. E.; U¨ rge, L.; Darvas, F.; Poppe,
L. Tetrahedron: Asymmetry 2008, 19, 237-246.
(30) Jones, R.; Go¨do¨rha´zy, L.; Varga, N.; Szalay, D.; U¨ rge, L.; Darvas,
F. J. Comb. Chem. 2006, 8, 110-116.
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Commun. 2006, 21, 2236-2238.
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8, 442-446.
The effect of pressure up to 70 bar and of temperature
between 25 and 100 °C was also studied. Testing at higher
temperatures was limited due to the decomposition of the
applied polymer supported catalysts that can occur above
1590
Org. Lett., Vol. 10, No. 8, 2008

100 °C. Due to the high system pressure, all reactions could
be run in the liquid phase even above the boiling point of
tetrahydrofuran. Figures 1 and 2 summarize the effect of
Table 4. Results of Various Monoamide Syntheses
Figure 2. Effect of temperature. Reaction conditions: 0.01 M of
4-iodobenzoic acid in 20 mL of THF, 1.5 equiv of pyrrolidine, 2.0
equiv of base, Pd(TPP)4 catalyst (CatCart), 30 bar, 0.5 mL/min
flow rate.
temperature and pressure. The conversion (as defined by the
percentage transformation of the starting material to all new
compounds) was significantly increased at higher pressures
and temperatures and reached 100% above 40 bar and 90
°C respectively. The selectivity toward the desired product
was optimal at 30 bar CO pressure. The decline of selectivity
over 30 bar suggested that the reaction kinetics may change
at higher pressure, and there was a detectable byproduct
(terephthalic acid).
Table 3. Comparison of Flow and Batch Reactions
conversiona (%)
selectivityb (%)
autoclavef,i
balloong,j
flowh
22c
60d
35c
69d
96e
36c
20d
54c
75d
87e
a Conversion to all new compounds. b Percent of desired product (4-
(pyrrolidine-1-carbonyl)benzoic acid). c After a sampling at 30 min. d Reac-
tion time was 60 min. e Reaction time (i.e., residence time) was 1.5 min.
f Temperature 100 °C, pressure 30 bar. g Temperature 68 °C (reflux),
pressure ca. 1 bar. h Temperature 100 °C, pressure 30 bar, flow rate: 0.5
mL/min. i 4-Iodobenzoic acid (1 mmol, 0.248 g), pyrrolidine (1.5 mmol,
124 µL), and triethylamine (2 mmol, 278 µL) were dissolved in 50 mL of
tetrahydrofuran. The solution was placed into an ultrasonic degasser for 10
min. Then the solution was moved to a glovebox (under a nitrogen
atmosphere). The catalyst (0.4 g tetrakis(triphenylphosphine)palladium) was
added into the reaction mixture. The autoclave (with 250 mL volume) was
closed and filled to 30 bar with carbon monoxide and stirred at 100 °C for
1 h. The reaction mixture was then cooled to room temperature. The
autoclave was opened in a fume hood and the catalyst was filtered from
suspension. j The solution prepared as above was purged with carbon
monoxide in a balloon for 15 min. The catalyst was added and stirred under
a CO balloon at reflux (68 °C) for 1 h.
a After purification by preparative HPLC.
The typical protocol for aminocarbonylation when opti-
mizing the model reaction in X-Cube was the following:
4-iodobenzoic acid (1 mmol, 0.248 g), pyrrolidine (1.5 mmol,
124 µL), and triethylamine (2 mmol, 278 µL) were dissolved
Org. Lett., Vol. 10, No. 8, 2008
1591

in 50 mL of tetrahydrofuran. The solution was passed through
X-Cube with 0.5 mL/min flow rate at 100 °C and 30 bar.
Carbon monoxide gas from a cylinder was introduced to the
X-Cube, which mixed the CO gas with the solution in its
gas-liquid mixer unit. The gas-liquid mixture then was
pressed through the prefilled, preheated cartridge (CatCart,
containing 0.4 g of catalyst) where the reaction took place.
The reaction time (as calculated from the residence time)
was less than 2 min. The solvent was removed under reduced
pressure, resulting in a product of 75% purity and 96%
conversion. Preparative HPLC chromatography (with Waters
2545-ZQ 4000 system) purification afforded the product,
4-(pyrrolidine-1-carbonyl)benzoic acid (0.177 g) in 81%
yield in over 98% purity.
To compare our approach with traditional batch carbonyl-
ation methods,33 we carried out the same reaction (Scheme
1) in a pressurized autoclave and in a conventional flask
using a CO-filled balloon. Table 3 shows the results of the
comparative tests where we found a remarkable difference
in favor of the flow technique.
In summary, the flow chemistry provided higher selectivity
and conversion rate than conventional batch methods within
a shorter time. The efficiency of the synthesis in the flask
was also limited by the boiling point of tetrahydrofuran (68
°C) as the reaction temperature.
As an important factor of safety, the total volume of the
carbon monoxide present at a time of the system was 800
mL in the flow reaction with X-Cube vs 7500 mL in an
autoclave and 1000 mL in a glass flask.
The conversions and yields were acceptable (Table 4),
taking into consideration the large structural diversity of the
compounds studied (some halobenzoic and halonicotinic
acids with a collection of primary, secondary, and aromatic
amines). The amidocarbonylation by continuous flow works
well with iodobenzoic acid isomers and relatively reactive
amines (for example, pyrrolidine, benzylamine, and cyclo-
hexylamine), while bromonicotinic acids and iodobenzoic
acids with amines of low reactivity (tert-butylamine and
4-nitrophenylpiperazine) resulted in lower conversion and
yield. With three exceptions (e.g., in the formation of 3-[4-
(4-nitrophenyl)piperazine-1-carbonyl]benzoic acid, which
resulted in contaminants such as regioisomers), all the other
transformations showed high purity toward the desired
products.
In conclusion, we have shown that flow chemistry using
X-Cube gave remarkable results for carbonylative coupling
reactions of halobenzoic acids with amines. Reaction pa-
rameters (solvent, base, catalyst, pressure, temperature) were
rapidly optimized in the reactions, which required less than
2 min. The short time of optimization allowed to a large
number of optimizing reactions and facilitated generalization
of the experiences. The method gave improved results over
comparable batch techniques and is also suited to automated
parallel syntheses of combinatorial libraries.34
Acknowledgment. We thank Dr. Andra´s Kotschy from
Eo¨tvo¨s Lora´nd University and Tom Smith from the
Thalesnano UK office for their valuable contributions to the
preparation of this manuscript.
After optimizing the reaction conditions as described
above, a derivatized dicarboxylic acids series was synthesized
in the X-Cube reactor without further optimization, under
the conditions optimized for the synthesis of 4-(pyrrolidine-
1-carbonyl)benzoic acid.
Supporting Information Available: Experimental details
for the aminocarbonylation reactions. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
OL7030894
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