Modernized low pressure carbonylation methods in batch and flow employing common acids as a CO source

Article abstract of DOI:10.1021/ol401092a

Carbonylation reactions, such as Heck, Sonogashira, and radical carbonylations, were successfully carried out in a two-chamber reactor where carbon monoxide was produced ex situ by the Morgan reaction (dehydration of formic acid by sulfuric acid). By a subsequent application in a microflow system using a tube-in-tube reactor where gas-permeable Teflon AF2400 was used as the inner tube, it is demonstrated that formic acid/sulfuric acid can be employed concomitantly with an amine base such as triethylamine in the Heck aminocarbonylation of aryl iodide.

Full text of DOI:10.1021/ol401092a

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Modernized Low Pressure Carbonylation
Methods in Batch and Flow Employing
Common Acids as a CO Source
†
,†
†
‡
ꢀ
Celia Brancour, Takahide Fukuyama,* Yu Mukai, Troels Skrydstrup, and
Ilhyong Ryu*,†
Department of Chemistry, Graduate School of Science, Osaka Prefecture University,
Sakai, Osaka 599-8531, Japan, and Center for Insoluble Protein Structure (inSPIN),
Interdisciplinary Nanoscience Center and Department of Chemistry, Aarhus University,
Gustav Wieds Vej 14, 8000 Aarhus, Denmark
fukuyama@c.s.osakafu-u.ac.jp; ryu@c.s.osakafu-u.ac.jp
Received April 23, 2013
ABSTRACT
Carbonylation reactions, such as Heck, Sonogashira, and radical carbonylations, were successfully carried out in a “two-chamber reactor” where
carbon monoxide was produced ex situ by the Morgan reaction (dehydration of formic acid by sulfuric acid). By a subsequent application in a
microflow system using a “tube-in-tube” reactor where gas-permeable Teflon AF2400 was used as the inner tube, it is demonstrated that formic
acid/sulfuric acid can be employed concomitantly with an amine base such as triethylamine in the Heck aminocarbonylation of aryl iodide.
Carbon monoxide (CO) has proven to be a practical
carbonyl source for the preparation of a wide variety of
carbonyl compounds, which involve aldehydes, ketones,
carboxylic acids, and their derivatives.1 However, both
academic and industrial research have demonstrated a
certain reluctance to study such reactions, due to the
difficulty in handling the odorless, toxic, and flammable
CO gas. Nevertheless, methods have been developed for
carrying out carbonylation reactions without the direct use
of gaseous CO.2 Such transformations exploit in situ gener-
ated carbon monoxide from a variety of CO precursors,3
including aldehydes,3aÀc formates,3d formamides,3eÀg and
metal carbonyls such as Mo(CO)6 and W(CO)6.3h How-
ever, these alternative reagents have been involved in pro-
tocols that include the mixing of substrates, catalysts, and
other additives in the same reaction vessels, which could
limit the applications of carbonylation reactions.
† Osaka Prefecture University.
‡ Aarhus University.
ꢀ
(1) (a) Kollar, L. Modern Carbonylation Methods; Wiley-VCH:
Weinheim, 2008. (b) Beller, M. Catalytic Carbonylation Reaction;
Springer-Verlag: Berlin, 2006. (c) Fukuyama, T.; Ryu, I. Carbon Monoxide.
e-eros, Encyclopedia of Reagents for Organic Synthesis; John Wiley &
Sons: DOI: 10.1002/047084289X.rc013.pub2.
(2) For reviews, see: (a) Morimoto, T.; Kakiuchi, K. Angew. Chem.,
Int. Ed. 2004, 43, 5580. (b) Morimoto, T.; Fujioka, M.; Fuji, K.;
Tsutsumi, K.; Kakiuchi, K. Pure Appl. Chem. 2008, 80, 1079.
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Chang, S. Org. Lett. 2003, 5, 2687. (e) Hosoi, K.; Nozaki, K.; Hiyama, T.
Org. Lett. 2002, 4, 2849. (f) Wan, Y.; Alterman, M.; Larhed, M.;
Hallberg, A. J. Org. Chem. 2002, 67, 6232. (g) Ko, S.; Lee, C.; Choi,
M.-G.; Na, Y.; Chang, S. J. Org. Chem. 2003, 68, 1607. (h) Wieckowska,
A.; Fransson, R.; Odell, L. R.; Larhed, M. J. Org. Chem. 2011, 76, 978.
Recently, one of us has reported a new and practical
approach for carbonylation reactions, consisting of using a
two-chamber reactor (COware) with two new solid CO
precursors. This reactor allowed the ex situ generation of
CO (in the decarbonylation chamber) while the gas was
consumed in the other chamber during the carbonylation
reaction.4 This concept was exemplified with a number of
r
10.1021/ol401092a
XXXX American Chemical Society

Pd-catalyzed carbonylation transformations and, interest-
ingly, demonstrated that stoichiometric or substoichio-
metric amounts of CO (1.0À1.5 equiv) could be used.
This easy-to-use and safe reactor has paved the way for a
new age of low-pressure carbonylation reactions, whereby
CO gas can be delivered by decarbonylation reactions, or
by decomplexation from a metal carbonyl complex.5
In contrast, we were interested in more common re-
agents that are cheap and readily available. From this
perspective, our idea was to exploit the well-known dehy-
drationofformicacidinsulfuricacidatelevatedtemperatures
(Morgan reaction)6 for CO generation (Figure 1). Herein, we
report selected examples of carbonylation reactions with
CO issued from formic acid decomposition in both the two-
chamber reactor and in a microflow tube-in-tube reactor.
Furthermore, we demonstrate for the first time that radical
mediated carbonylations can also be run effectively in a
two-chamber system, COware.
equivalents of acids to 3 also provided the amide 3 in
high yield, whereas this yield significantly decreased with
2 equiv of acids, which caused a pressure drop to ca. 2 atm
(entries 2 and 3). An excess of sulfuric acid allowed the
formation of the carbonylated product in a good yield of
89% (entry 4). In light of these results, we have confirmed
that the internal pressure was not the limiting factor for
obtaining the product in high yields, whereas a sufficient
volumeofsulfuricacidwasessentialtoleadtothecomplete
decomposition of formic acid, and thereby allowing for a
continuous consumption of the diatomic reagent during
the Heck carbonylation reaction.
Table 1. Conditions for Decarbonylation Reaction in the
Two-Chamber Reactor
entrya
1:H2SO4:HCO2H
pressure (atm)
yield of 3 (%)b
1
2
3
4
1:4:4
1:3:3
1:2:2
1:4:2
3.3
2.6
2.0
2.0
quant.
97
59c
89
a Reaction conditions: 4-Iodoanisole (0.5 mmol), n-hexylamine
Figure 1. CO generation from formic acid in two-chamber reactor.
(2 equiv), dioxane (1.5 mL). b Isolated yield. c NMR yield.
We first focused our attention on the Heck aminocar-
bonylation of aryl iodide that has previously been reported
by Skrydstrup and co-workers and later by the Larhed
group, investigating the amount of acid necessary for
proper CO delivery (Table 1).4,5 For this, we examined
the carbonylation of 4-iodoanisole (1) with n-hexylamine
(2) in the presence Pd(dba)2 and triethylamine for our
CO-generator system based on the Morgan reaction. We
were pleased to see that the desired amide 3 was obtained in
quantitative yield after only 2 h of the reaction (entry 1)
with 4 equiv of formic acid and sulfuric acid. The internal
pressure inside the reactor could be measured by applying
a pressure monitor connected to the reactor.7 With the
4 equiv of formic acid and sulfuric acid, the pressure inside
the reactor increased to 3.3 atm (entry 1). Lowering the
The setup was then tested for the carbonylative
Sonogashira reaction. Inspired by quality work from the
Yang group,8 describing the efficient carbonylative coupling
between an aryl iodide and a terminal alkyne in water, we
attempted to carry out this reaction in the two-chamber
reactor (Scheme 1). Thus, iodobenzene (4) and 1-octyne(5)
were placed in the carbonylation chamber in the presence
of palladium chloride. Yang and co-workers report that
this coupling reaction reaches completion at room tem-
perature, but in our system, the decarbonylation chamber
required heating at 80 °C for 15 min in order to encourage
the generation of CO. Then, the decarbonylation chamber
was cooled to room temperature by a water bath, and the
coupling reaction was carried out at room temperature for
24 h. The desired alkynyl ketone 6 was obtained in a high
yield of 91%.
(4) (a) Hermange, P.; Lindhardt, A. T.; Taaning, R. H.; Bjerglund, K.;
Lupp, D.; Skrydstrup, T. J. Am. Chem. Soc. 2011, 133, 6061. (b) Hermange,
P.; Gogsig, T. M.; Lindhardt, A. T.; Taaning, R. H.; Skrydstrup, T. Org.
Lett. 2011, 13, 2444. (c) Nielsen, D. U.; Taaning, R. H.; Lindhardt, A. T.;
Gogsig, T. M.; Skrydstrup, T. Org. Lett. 2011, 13, 4454. (d) Friis, S. D.;
Taaning, R. H.; Lindhardt, A. T.; Skrydstrup, T. J. Am. Chem. Soc. 2011,
133, 18114. (d) Gøgsig, T. M.; Taaning, R. H.; Lindhardt, A. T.; Skrydstrup,
T. Angew. Chem., Int. Ed. 2012, 51, 798.
(5) Mo(CO)6 was recently adapted as the CO source in the two-
chamber reactor; see: Nordeman, P.; Odell, L. R.; Larhed, M. J. Org.
Chem. 2013, 77, 11393.
(6) (a)Morgan, J. S. J. Chem. Soc., Trans 1916, 109, 274. For mechanistic
studies, see: (b) Kaushik, S. M.; Rich, R. L.; Noyes, R. M. J. Phys. Chem.
1985, 89, 5722. (c) Bowers, P. G.; Hodes, K. J. Phys. Chem. 1988, 92, 2489.
(7) The CO pressure was measured without carrying out the amino-
carbonylation reaction.
We are also pleased to report the first application of
radical carbonylation reactions using a two-chamber re-
actor, as it was possible to carry out thermal-initiated and
irradiation-initiated carbonylations of organo iodides
using formic acid as a CO-precursor (Scheme 2). In our
previous report about the hydroxymethylation of alkyl
iodides mediated by tetrabutylammonium borohydride,
we have demonstrated that an atmospheric pressure of CO
could lead to the desired homologated alcohols.9 In order
(8) Liang, B.; Huang, M.; You, Z.; Xiong, J.; Lu, K.; Fathi, R.; Chen,
J.; Yang, Z. J. Org. Chem. 2005, 70, 6097.
B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 1. Carbonylative Sonogashira Reaction in a
Two-Chamber Reactor
Scheme 2. Radical-Mediated Carbonylation in a Two-Chamber
Reactor
to apply this reaction in COware, 1-iodoadamante (7),
tetrabutylammonium borohydride, and AIBN were placed
in the carbonylation chamber and heated at 80 °C for
3 h. The homologated alcohol 8 was obtained in a 66%
yield. Further studies have led us to take advantage of the
transparent glass of the reactor in order to test the efficiency
of photoirradiation-initiated carbonylation in COware. In
our previous work, we have demonstrated the efficient
iodine transfer carbonylation of alkyl iodides in the presence
of amines under photoirradiation that could afford amides
in good yields.10,11 Thus, 1-iodoadamante (7), aniline (9),
and triethylamine were placed in the carbonylation chamber
and submitted to 500 W-Xenon lamp irradiation. After 14 h
of mixing at room temperature, the desired amide 10 was
obtained in a 59% yield. The pressure inside the reactor was
measured to be 6.5 atm for this amount of acids.
compounds, meanwhile allowing precise control of the
reaction conditions (temperature and residence time) and
improving yields and safety.12,13 Therefore, in recent years,
we14 and other groups15 reported carbonylation reactions
applying a microflow system. Here, we investigated the
Heck aminocarbonylation of an aryl halide in order to
estimate the efficiency of our microflow device with ex situ
generated CO based on the Morgan reaction. At first
sight, such a flow reaction would be incompatible with
the present CO generation system because it would involve
the mixingof sulfuricacidwithtriethylamine. Therefore, in
order to prevent this parasite acid/base reaction, a dual
flow system was applied. By analogy to the two-chamber
reactor, this dual flow system would provide one flow
dedicated to the CO generation reaction while the other
flow would allow the carbonylation reaction. For this, we
prepared a “tube-in-tube” reactor with an outside stainless
steel tube for the carbonylation flow and an inner PTFE
tube which is exclusively permeable to gas, for the decom-
position of formic acid (Figure 2). For the inner PTFE
tube, Teflon AF 2400 was employed, which has previously
been used in a microflow reaction by Ley and co-workers16
with gaseous CO,16a CO2,16b ozone,16c H2,16d and others.
Our continuous microflow “tube-in-tube” reactor is simple
to prepare and consists mainly of two Swagelock T-pieces, a
Hastelloy mixer (150 μm width, MiChS β 150),17 and two
sections of tubing (outer = stainless steel tube; 3.17 mm o.d.,
2.0 mm i.d., inner = Teflon AF-2400; 1 mm o.d., 0.8 mm i.d.,
53 cm length) as shown in Figure 3. Applying this apparatus,
we could easily carry out the aminocarbonylation of
Finally, we focused our attention on a microflow system
for the carbonylation reaction based on the Morgan reac-
tion. Advantageously, continuous-flow processes offer
the possibility to increase the production of desired
(9) Kobayashi, S.; Kawamoto, T.; Uehara, S.; Fukuyama, T.; Ryu, I.
Org. Lett. 2010, 12, 1548.
(10) For a review, see: Ryu, I. Chem. Soc. Rev. 2001, 30, 16.
(11) Ryu, I.; Nagahara, N.; Kambe, N.; Sonada, S.; Kreimerman, S.;
Komatsu, M. Chem. Commun. 1998, 1954.
(12) For recent reviews, see: (a) Wirth, T. Microreactors in Organic
Synthesis and Catalysis; Wiley-VCH: Weinheim, 2008. (b) Hessel, V.;
Renken, A.; Schouten, J. C. Yoshida, J. Micro Process Engineering;
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J. L.; Bogdan, A. R.; McQuade, D. T. Chem. Rev. 2007, 107, 2300. (d)
Yoshida, J.; Nagaki, A.; Yamada, T. Chem.;Eur. J. 2008, 14, 7450. (e)
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Webb, D.; Jamison, T. F. Chem. Sci. 2010, 675. (h) Yoshida, J. Chem.
Rec. 2010, 10, 332. (i) Wegner, J.; Ceylan, S.; Kirschning, S. Chem.
Commun. 2011, 47, 4583. (j) Hartman, R. L.; McMullen, J. P.; Jensen,
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I. Chem. Commun. 2006, 2236. (b) Fukuyama, T.; Rahman, M. T.;
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Org. Lett., Vol. XX, No. XX, XXXX
C

Figure 2. Principle of ex situ flow carbonylation using tube-
in-tube reactor and illustration of permeativity of Teflon AF
2400 with generated CO.
Figure 3. Microflow system for carbonylation reaction with
formic acid/sulfuric acid using “tube-in-tube” reactor.
permeable PTFE inner tube. The latter is an unprece-
dented example of Heck aminocarbonylation that com-
bines simultaneously a strong acid with a base. Moreover,
the decomposition of formic acid in sulfuric acid is a con-
venient reaction that gives rise to pure carbon monoxide,
along with water. Thus, in combination with safe and
easily handled equipment, common acids can serve as a
CO source so that chemists can avoid the use of CO
cylinders for low pressure carbonylation reactions.
4-iodoanisole 1 to obtain the amide 3 in a good yield of
81%. To our knowlegde, this is the first time that a micro-
flow Heck carbonylation could be performed in presence
ofsulfuric acid, thankstothe Teflon AF-2400 thathas high
chemical compatibility. It is noteworthy that the reaction
time was calculated as a function of the volume of the
outside tube; however, it was difficult to determine the
residence time for this reaction since CO was formed
progressively and consumed in the occurring carbonyla-
tion reaction. Nevertheless, the residence time inside the
reactor is less than 2 h 42 min for this particular system.
In summary, through these selected examples of Pd
catalyzed and radical carbonylations, we have demon-
strated that the classical CO-generation system based on
the Morgan reaction (HCOOH/H2SO4) is a useful tool
for carbonylation in a modern double chamber system
using COware. Furthermore, we have adapted the CO-
generation system to a continuous microflow system using
a modern “tube-in-tube” reactor, equipped with a CO gas
Acknowledgment. This work was supported by a
Grant-in-Aid for Scientific Research from the MEXT
and the JSPS.
Supporting Information Available. The experimental
procedure and compound characterization. This material
is available free of charge via the Internet at http://pubs.
acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX