Increasing rates and scope of reactions: Sluggish amines in microwave-heated aminocarbonylation reactions under air

Article abstract of DOI:10.1021/jo034382d

Commercially available molybdenum hexacarbonyl serves as a convenient and solid carbon monoxide source in palladium-catalyzed aminocarbonylations of aryl bromides and iodides. This improved microwave protocol, relying on DBU as base and THF as solvent, enables rapid couplings using otherwise sluggish anilines, tert-butylamine, and free amino acids. In addition, Cr(CO)₆ and W(CO)₆ were found to be useful alternative CO-releasing reagents. Altogether, 16 different aromatic amides were synthesized under air in 35-95% yield after only 15 min of controlled microwave irradiation.

Full text of DOI:10.1021/jo034382d

A recent report from our laboratory describes a pal-
ladium-catalyzed amidation protocol employing in situ
generation of carbon monoxide from easily handled
molybdenum hexacarbonyl (Mo(CO)6).15 This aminocar-
bonylation16-18 procedure affords good yields of benza-
mides from aryl iodides and bromides provided nonhin-
dered primary and secondary aliphatic amines are em-
ployed. Herein, we report an improved tandem carbon
monoxide release/amidation methodology relying on the
use of DBU as base and THF as solvent. With this new
and more general method, successful palladium-catalyzed
aminocarbonylations can be accomplished also with
anilines, the sterically hindered tert-butylamine, and
amino acids. The reactions are performed under air in
sealed vessels without external carbon monoxide gas,
giving moderate to high yields after only 15 min of
microwave irradiation.19-21
In cr ea sin g Ra tes a n d Scop e of Rea ction s:
Slu ggish Am in es in Micr ow a ve-Hea ted
Am in oca r bon yla tion Rea ction s u n d er Air
J ohan Wannberg and Mats Larhed*
Department of Organic Pharmaceutical Chemistry,
Uppsala University, Biomedical Centre, Box-574,
SE-751 23 Uppsala, Sweden
mats@orgfarm.uu.se
Received March 25, 2003
Abstr a ct: Commercially available molybdenum hexacar-
bonyl serves as a convenient and solid carbon monoxide
source in palladium-catalyzed aminocarbonylations of aryl
bromides and iodides. This improved microwave protocol,
relying on DBU as base and THF as solvent, enables rapid
couplings using otherwise sluggish anilines, tert-butylamine,
and free amino acids. In addition, Cr(CO)6 and W(CO)6 were
found to be useful alternative CO-releasing reagents. Alto-
gether, 16 different aromatic amides were synthesized under
air in 35-95% yield after only 15 min of controlled micro-
wave irradiation.
In a lead optimization program,22 we needed access to
certain aspartic protease inhibitors with aromatic amides
in the ortho position of the benzylic P1/P1′ side chains.
A basic study on high-speed aminocarbonylations using
anilines and other sluggish amines was therefore com-
menced.
Initial experiments to convert aryl halides into benz-
anilides, using the previously reported conditions for
molybdenum hexacarbonyl mediated couplings,15 met
with little success. The low reactivity encountered with
anilines encouraged us to improve the methodology with
the ultimate goal to extend the scope of the process to
include weakly nucleophilic amines as well. To circum-
vent precipitation of molybdenum metal on the wall of
the borosilicate vessel (avoiding subsequent microwave-
induced thermal cracking and vessel rupture), the previ-
ously reported in situ aminocarbonylations were con-
ducted with diglyme as a coordinating solvent. The high-
boiling and water-soluble diglyme was, however, difficult
to remove and complicated the isolation of the carbony-
lated products.
2-Iodotoluene (1d ) and aniline (2b) were selected as
model substrates for a series of optimization experiments.
Different solvents, palladium precatalysts, and bases
were examined. We aimed to obtain full conversion of 1d
in less than 15 min and adjusted the reaction tempera-
ture accordingly. All carbonylations were conducted
under air with controlled microwave heating in sealed
borosilicate vessels. After some experimentation,23 it was
discovered that THF served as a convenient solvent in
Today, a future view of combinatorial synthesis emerges
where solid- and liquid-phase methods complement each
other.1 In particular, the recent utilization of novel solid-
supported reagents and scavengers in multistep synthe-
sis demonstrates this powerful direction.2,3 Still, signifi-
cant limitations remain in the combinatorial chemistry
arena, one of which is often reaction speed.4,5 A second
limitation concerns the efficient utilization of reactive
gases. Specifically, the difficult handling of toxic carbon
monoxide in high-throughput or parallel chemistry has
created interest in exploring alternative sources of CO.6-8
The desire to eliminate the use of gases has resulted in
the development of modified gas-free aminocarbonylation
protocols,9-12 especially in the preparation of N,N-di-
methylbenzamides.13,14
(1) Combinatorial Chemistry: A Practical Approach; Fenniri, H., Ed.;
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Synthesis; Loupy, A., Ed.; Wiley-VCH: Weinheim, 2002; pp 387-388.
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science: New York, 2002; pp 2313-2332.
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Chem. 2002, 67, 6232-6235.
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2001, 57, 9225-9283.
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Chem. 2003, 5, 82-84.
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717-727.
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Chem. Lett. 2003, 32, 154-155.
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Today 2002, 7, 373-380.
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10.1021/jo034382d CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/06/2003
5750
J . Org. Chem. 2003, 68, 5750-5753

TABLE 1. Exa m in a tion of Differ en t Solid -CO Sou r ces
(µ-acetato)bis[o-(di-o-tolylphosphino)benzyl]dipalladium-
(II), 4)26,27 was an effective palladium(0) source at 150
°C. As shown in Table 2, this precatalyst delivered
reaction conditions (B) sufficiently general to tolerate not
only the presence of the o-methyl substituent on the aryl
bromide 1e but also other electron-donating (entries 5,
7, and 8) as well as electron-withdrawing groups (entries
17, 19, and 20). Thus, upon controlled microwave treat-
ment the transformations of all amines, except the
2-aminothiazole, were completed within 15 min in 35-
92% isolated yield. In accordance with the results with
aryl iodide 1d , low yields (35-44%) were obtained with
aryl bromides and tert-butylamine (2d ) (entries 8, 14, and
20).
in th e Am in oca r bon yla tion Rea ction
entrya
CO source
isolated yield of 3h (%)
1
2
3
4
5
6
Cr(CO)6
Mo(CO)6
W(CO)6
Fe(CO)5
Fe3(CO)12
Co2(CO)8
80
84
77
0b
0b
28
a
Aminocarbonylations of aryl iodides were also per-
formed with traditional heating in preheated metal
blocks (100 °C, 15 min). These reactions resulted in the
same high yields as those observed after microwave
irradiation (Table 2, entries 9 and 11). Despite this
additional possibility of performing the amidation reac-
tions, the microwave protocol was adopted because of
practical convenience, excellent reaction control, and
safety reasons. With aryl bromides, we did not investigate
the 150 °C sealed procedure using conventional heating
with standard glass vessels due to the risk of vessel
rupture at the relatively high pressures experienced at
this temperature (THF, bp 65-67 °C).
The flash heated aminocarbonylation reaction also
worked smoothly with resin-bound 4-iodobenzenesulfona-
mide (Polystyrene-Rink amide) (eq 1).28-30 Full conversion
to the carbonic anhydrase II inhibitor 531 was ac-
complished within 30 min of heating with an isolated
yield of 64% (calculated from the loading of the resin).
Reactions performed according to general procedure A, but
b
with different metal-CO complexes. Less than 5% conversion
of 1d .
combination with the strong amine base DBU,24 Mo(CO)6,
and palladium acetate. Under these conditions, full
conversion of 1d was obtained within 15 min of irradia-
tion at 100 °C reaction temperature, affording 84%
isolated yield of the benzamide 3h (Table 1, entry 2). The
selected conditions (A) were thereafter investigated with
other potential solid sources of carbon monoxide (Table
1). Pressure curves from these reactions indicated gas
release in all cases, and although Mo(CO)6 produced the
highest yield (entry 2), the other metal carbonyls of the
same group (Cr(CO)6, W(CO)6) proved almost equally
efficient.
Preparative aminocarbonylations with Mo(CO)6 as the
source of CO and with a variety of aryl iodides (1a , 1b,
1d , and 1f) and amines (2a -h ) are summarized in Table
2. The previously investigated piperidine (2a ) produced
improved yields,15 and aniline (2b) and benzylamine (2c)
also coupled easily with these aryl iodides (Table 2,
entries 1-4, 6, 9, and 11), whereas the sterically hindered
tert-butylamine and the labile 2-aminothiazole afforded
lower yields of products 3i and 3j (entries 13 and 15). In
addition, protected and nonprotected glycine could con-
veniently be benzoylated (entries 21 and 22), and impor-
tantly, nonprotected L-leucine reacted without racemiza-
tion under the accelerated conditions.25 The relatively low
yields of acidic products 3o and 3p are partly explained
by loss of material during preparative RP-LC-MS
purification.
The aminocarbonylation pathway utilizing DBU as
base is probably very similar to the one proposed with
weaker bases, but one obvious difference concerns the
release of carbon monoxide from the molybdenum hexa-
carbonyl complex. Addition of DBU to the reaction
mixture at room temperature immediately induces a
chemical liberation of carbon monoxide. At higher tem-
peratures, this occurs instantly. This reactivity is clearly
demonstrated in the temperature-pressure profiles pro-
To increase the scope of the reaction, we decided to
investigate aryl bromides as coupling partners. In these
aminocarbonylations, Herrmann’s palladacycle (trans-di-
(23) Investigation of the reaction parameters showed that the choice
of base was crucial in the aminocarbonylation of 2-iodotoluene with
aniline. Inorganic carbonate bases and tertiary aliphatic amines were
nonproductive at the temperatures investigated here (50-150 °C). The
nucleophilic catalysts imidazole and DMAP were effective at high
temperatures (150 °C), but the use of DBU as base furnished a
dramatically improved reaction rate, which allowed substantially lower
temperatures. Palladium acetate afforded a slightly superior catalytic
system compared to Pd/C and phosphine containing pre-catalysts. The
etherous solvents diglyme, DME, dioxane, and THF were all more
efficient than DMF, MeCN, or toluene. THF was the preferred choice
because of the easy access to freshly distilled solvent and the simple
removal from the reaction mixture.
(26) Herrmann, W. A.; Brossmer, C.; Reisinger, C. P.; Riermeier,
T. H.; Ofele, K.; Beller, M. Chem.-Eur. J . 1997, 3, 1357-1364.
(27) Herrmann, W. A.; Bohm, V. P. W.; Reisinger, C. P. J . Orga-
nomet. Chem. 1999, 576, 23-41.
(28) Beaver, K. A.; Siegmund, A. C.; Spear, K. L. Tetrahedron Lett.
1996, 37, 1145-1148.
(29) J ames, I. W. Tetrahedron 1999, 55, 4855-4946.
(30) Guillier, F.; Orain, D.; Bradley, M. Chem. Rev. 2000, 100, 2091-
2157.
(24) Perry, R. J .; Wilson, B. D. Macromolecules 1993, 26, 1503-
1508.
(25) Optical rotation compared to commercially available sample
(Fluka).
(31) J ain, A.; Whitesides, G. M.; Alexander, R. S.; Christianson, D.
W. J . Med. Chem. 1994, 37, 2100-2105.
J . Org. Chem, Vol. 68, No. 14, 2003 5751

TABLE 2. Ra p id P a lla d iu m -Ca ta lyzed Am in oca r bon yla tion Rea ction s w ith Mo(CO)6 a s a CO Sou r ce
a
The reactions were performed in 0.40 mmol scale. Method A: A reaction vessel was charged with dry THF (1.0 mL), Ar-I (1.0 equiv),
amine (3.0 equiv), Mo(CO)6 (1.0 equiv), DBU (3.0 equiv), and Pd(OAc)2 (10 mol %). The reaction mixture was thereafter microwave heated
to 100 °C for 15 min. Method B: As method A but with Ar-Br (1.0 equiv), palladacycle 4 (5.0 mol %), and microwave heating to 150 °C
b
for 15 min. Isolated yield, >95% pure according to GC-MS or 1H NMR. c Synthesized with conventional heating (metal heating block,
d
100 °C, 15 min). DBU (6.0 equiv). Acids 3o and 3p purified by LC-MS. e No racemization detected.
vided in Figure 1. In the presence of both DBU and Mo-
(CO)6 (A and B), the pressure increases to almost 4 bar
upon heating to 100 °C. For the preparative palladium-
catalyzed reaction B, the pressure increased extremely
rapidly.32 The decrease in pressure with irradiation time
indicates the consumption of CO in the carbonylation
reaction (Table 2, entry 11). Control experiments C and
D revealed that the pressure without DBU or Mo(CO)6
never exceeded 2.0 bar.
sions and yields obtained with poor amino nucleophiles
using the DBU-based conditions might partly be ex-
plained by an accelerated liberation of carbon monoxide.
In particular, the aminocarbonylations performed at 100
°C (condition A) require DBU as base.
In an attempt to study the CO-liberation process, Mo-
(CO)6 was heated in a large excess of DBU until gas
release subsided. With addition of isohexane, a labile
yellow molybdenum complex precipitated. Infrared spec-
troscopy and combustion elemental analysis indicate that
structure 6 was formed (eq 2). Unfortunately, the de-
composition of the CO-liberating complex 6 in solution
prevented a thorough NMR and MS analysis but analyti-
cal LC-MS of reaction mixtures from Table 1 display a
peak with the same retention time as complex 6. Fur-
thermore, direct high-resolution FAB-MS of precipitated
6 identifies two ions corresponding to (6 - DBU)+ and
(6 - DBU - CO)+ respectively. Against this background,
With other investigated bases,33 much lower reaction
pressures were observed. Therefore, the higher conver-
(32) Repeated experiments clearly proved that the precatalyst, Pd-
(OAc)2, was responsible for the immediate CO-release illustrated in
Figure 1, profile B. The omission of 1d or 2b did not affect the pressure.
(33) Using aqueous potassium carbonate, triethylamine, 1,2,2,6,6-
pentamethylpiperidine, or 2c as base in the aminocarbonylation of 1d
with 2c at 100 °C, 15 min, afforded less than 10% conversion of 1d
and little or no increase in pressure. DMAP was able to release CO,
but the conversion was still low under these conditions.
5752 J . Org. Chem., Vol. 68, No. 14, 2003

with a Teflon septum under air and irradiated with microwaves
to 100 °C for 15 min. After cooling, the reaction mixture was
filtered through a short Celite pad, and the solvent, excess DBU,
and if possible, excess amine were removed under reduced
pressure. The residue was purified by silica gel flash chroma-
tography (0-1% MeOH in CHCl3) to give the desired pure
amides 3 (>95% by GC-MS or 1H NMR).
Gen er a l P r oced u r e B. Am in oca r bon yla tion of Ar yl
Br om id es. A 0.5-2.0 mL process vial was charged with an aryl
bromide (0.40 mmol) and palladacycle 4 (18.8 mg, 0.020 mmol),
Mo(CO)6 (0.106 g, 0.40 mmol), amine (1.2 mmol), DBU (0.180
mL, 1.2 mmol), and dry THF (1.0 mL). The vial was immediately
capped with a Teflon septum under air and irradiated with
microwaves to 150 °C for 15 min. After cooling, the reaction
mixture was filtered through a short Celite pad, and the solvent,
excess DBU, and if possible, excess amine were removed under
reduced pressure. The residue was purified by silica gel flash
chromatography (0-1% MeOH in CHCl3) to give the desired
pure amides 3 (>95% by GC-MS or 1H NMR).
F IGURE 1. Pressure profiles from microwave heating at 100
°C with a power of 0-300 W: (A) Mo(CO)6 (0.40 mmol), DBU
(3 equiv) in THF (1 mL); (B) preparative synthesis of 3h , entry
11 (conditions A); (C) as B but without Mo(CO)6; (D) as B but
without DBU.
2-Meth yl-N-th ia zol-2-ylben za m id e (3j). The title com-
pound was obtained as a colorless solid in 42% yield (36.7 mg)
from 1d : MS m/z (relative intensity, 70 eV) 218 (M+, 9), 203
1
(11), 119 (100), 91 (83); H NMR (400 MHz, CDCl3) δ 7.64 (dd,
J ) 7.6 Hz, 1.8 Hz, 1H), 7.47 (dt, J ) 7.6 Hz, 1.8 Hz, 1H), 7.28-
7.37 (m, 2H), 6.85 (d, J ) 3.8 Hz), 6.46 (d, J ) 3.8 Hz), 2.51 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 167.9, 160.4, 137.4, 135.9,
it seems reasonable that 6 is formed as a labile CO-
releasing intermediate in the DBU-promoted aminocar-
bonylation reaction.
134.2, 131.4, 131.2, 127.9, 126.1, 113.1, 20.0; IR (KBr, cm-1
)
3160, 1685, 1560. Anal. Calcd for C11H10N2OS: C, 60.53; H, 4.62;
N, 12.83. Found: C, 60.5; H, 4.9; N, 12.6.
N-Ben zyl-4-tr iflu or om eth ylben za m id e (3k ) The title com-
pound was obtained as a white solid in 95% yield (106 mg) from
1g: MS m/z (relative intensity, 70 eV) 279 (M+, 65), 173 (100),
145 (61); 1H NMR (400 MHz, CDCl3) δ 7.88 and 7.67 (AA′BB′
system, 4H), 7.25-7.39 (m, 5H), 6.60 (br s, 1H), 4.64 (d, J ) 5.7
Hz); 13C NMR (400 MHz, CDCl3) δ 166.2, 137.8, 137.7, 133.4 (q,
∆
Mo(DBU) (CO)
Mo(CO)6 + DBU (excess)
98
+ 2CO
4
2
6
(2)
3
2J C-F ) 33 Hz), 129.0, 128.0, 127.9, 127.6, 125.7 (q, J C-F ) 4
The formation of 6, and its relatively poor stability
compared to Mo(CO)6,34 explains the DBU-accelerated CO
release from the reaction cocktail. We have at present
no viable theory for the mechanism of the extremely rapid
CO-liberation in the presence of both DBU and palladium
acetate (Figure 1, profile B).
In reactions with weakly nucleophilic amines and aryl
iodides or bromides, this improved high-speed aminocar-
bonylation method affords useful yields of benzamides
after only 15 min reaction time. The base DBU acceler-
ates the CO release from Mo(CO)6 and improves the
outcome of the reaction. In addition, a possible explana-
tion for the effect of DBU on the rate of CO liberation
from Mo(CO)6 is suggested. Given the experimental
convenience by employing a condensed carbon monoxide
source and the combination of THF and DBU, this
microwave protocol should be of importance for sluggish
high-throughput carbonylation applications.
Hz), 123.7 (q, 1J C-F ) 273 Hz), 44.4; IR (neat, cm-1) 3270, 1640.
Anal. Calcd for C15H12F3NO: C, 64.51; H, 4.33; N, 5.02. Found:
C, 64.5; H, 4.4; N, 5.0.
N-Ben zyl-4-su lfam oylben zam ide (5)31 4-Iodobenzenesulfona-
mide Rink amide resin (Novabiochem; 200 mg, loading 0.59
mmol/g, 0.12 mmol), Mo(CO)6 (158 mg, 0.60 mmol), Pd(OAc)2
(13.5 mg, 0.060 mmol), benzylamine (0.47 mL, 3.6 mmol), and
2.0 mL of THF were added to a 2.0-5.0 mL process vial. The
vial was capped with a Teflon septum under air, DBU (0.54 mL,
3.6 mmol) was added by syringe through the septum, and the
reaction was irradiated with microwaves to 100 °C for 30 min.
After cooling, the resin was filtered and washed with DMF (4×)
and CH2Cl2 (4×). The resin was treated with 20% TFA/CH2Cl2
for 15 min and filtered, and the eluent was evaporated under
reduced pressure. The crude was washed with a small amount
of isohexane to remove traces of the linker and then dried under
reduced pressure to give the title compound as a white solid in
64% yield (21.8 mg).
Ack n ow led gm en t. We thank Dr. Kristofer Olofsson
and Dr. Nils-Fredrik Kaiser for help with the manu-
script. We also thank the Swedish Research Council and
Knut and Alice Wallenberg Foundation. We thank
Personal Chemistry for providing the Smith microwave
synthesizer.
Exp er im en ta l Section
Gen er a l P r oced u r e A. Am in oca r bon yla tion of Ar yl
Iod id es. A 0.5-2.0 mL process vial was charged with an aryl
iodide (0.40 mmol) and Pd(OAc)2 (9.0 mg, 0.040 mmol), Mo(CO)6
(0.106 g, 0.40 mmol), amine (1.2 mmol), DBU (0.180 mL, 1.2
mmol), and dry THF (1.0 mL). The vial was immediately capped
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails, spectroscopic data and references for compounds 3a -
i,3l-p , 5, and 6. This material is available free of charge via
the Internet at http://pubs.acs.org.
(34) CRC Handbook of Chemistry and Physics, 83rd ed.; Lide, D.
R., Ed.; CRC Press: Boca Raton, FL, 2002; pp 3-384, 4-43.
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