Radical carbonylations using a continuous microflow system

Article abstract of DOI:10.3762/bjoc.5.34

Radical-based carbonylation reactions of alkyl halides were conducted in a microflow reactor under pressurized carbon monoxide gas. Good to excellent yields of carbonylated products were obtained via radical formylation, carbonylative cyclization and threecomponent coupling reactions, using tributyltin hydride or TTMSS as a radical mediator.

Full text of DOI:10.3762/bjoc.5.34

Radical carbonylations using a continuous
microflow system
Takahide Fukuyama, Md. Taifur Rahman, Naoya Kamata and Ilhyong Ryu*
Preliminary Communication
Open Access
Address:
Beilstein Journal of Organic Chemistry 2009, 5, No. 34.
Department of Chemistry, Graduate School of Science, Osaka
Prefecture University, Sakai, Osaka 599-8531, Japan
doi:10.3762/bjoc.5.34
Received: 14 April 2009
Accepted: 02 July 2009
Published: 13 July 2009
Email:
Ilhyong Ryu* - ryu@c.s.osakafu-u.ac.jp
*
Corresponding author
Guest Editor: A. Kirschning
Keywords:
© 2009 Fukuyama et al; licensee Beilstein-Institut.
License and terms: see end of document.
continuous flow system; microreactor; radical carbonylation; radical
mediator; V-65
Abstract
Radical-based carbonylation reactions of alkyl halides were conducted in a microflow reactor under pressurized carbon monoxide
gas. Good to excellent yields of carbonylated products were obtained via radical formylation, carbonylative cyclization and three-
component coupling reactions, using tributyltin hydride or TTMSS as a radical mediator.
Introduction
Placing a reaction mixture fluid inside a microstructured Seeberger group reported reduction and hydrosilylation using
channel network helps gain a high surface area to volume ratio TTMSS in a microflow system [13]. In our study, we found that
that in turn ensures rapid heat and mass transfer [1-3]. Precise the combination of a rapidly decomposing radical initiator with
control of reaction temperature and residence time, excellent a microreaction device allowed the reactions to be completed in
mixing properties for reactants/reagents as well as a flow nature a very short period of time giving good yields of the desired
of the microreaction system, often result in higher conversion, products. Carbon monoxide is an important feedstock and our
greater yields, superior product selectivity and safety. In recent group has actively pursued carbonylation reactions [14-17].
years, the potential of this new technology for organic synthesis Thermally induced radical carbonylations using tin hydride
have been recognized and many applications have been demon- usually require pressurized CO conditions to ensure that the
strated by our group [4-6] as well as others [7-11].
concentration of CO around the radical centers is high enough
to compete with the premature quenching by tin hydride
In our recent report, we demonstrated that excellent thermal (Scheme 1). Encouraged by our previous successes with both
efficiency of the microflow system would lead to effective radical reactions [12] and metal-catalyzed carbonylation reac-
execution of tin hydride and TTMSS (tris(trimethylsilyl)silane)- tions using microflow devices [18-20], we decided to examine a
mediated radical reduction and cyclization reactions [12]. The continuous microreaction system for radical carbonylation reac-
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Beilstein Journal of Organic Chemistry 2009, 5, No. 34.
Scheme 1: Tin-mediated radical carbonylation and the competing reduction.
tions, for which we typically used stainless-steel autoclaves as radical initiator. This was attributed to the rather slow decom-
the reactor in batch systems.
position rate of the AIBN (half-life time: 90 min at 85 °C) in
light of the time frame employed for the microflow reaction
(residence time, 12 min). When we switched AIBN to a more
Results and Discussion
The microflow system we employed was simple, yet robust rapidly decomposing V-65 (2,2′-azobis(2,4-dimethylvaleroni-
enough to withstand high CO pressures (ca. 80 atm) (Figure 1). trile), half-life time: 12 min at 80 °C), 100% conversion was
A metered stream of CO gas was fed in a controlled manner attained to give tridecanal (2) in a 77% yield (Table 1, entry 1).
into the system and was mixed with the toluene solution Microflow carbonylation of bromocyclohexane (3) and
containing a radical mediator, a radical initiator and a substrate 1-bromoadamantane (5) also worked well to furnish the corres-
in a T-shaped micromixer (stainless steel, internal diameter: ponding aldehydes 4 and 6 in good yields (entries 2 and 3). The
1
000 μm). This biphasic (gas-liquid) mixture was then guided judicious choice of a radical initiator is important for high
through a stainless steel tubular reactor (internal diameter: 1000 conversion in a short reaction time for carbonylation reactions,
μm), acting as the residence time unit (RTU), under heated which is in accordance with our previous experience with
conditions using an oil bath. A back pressure control valve was microflow radical reduction and cyclization of organic halides
connected at the end of the RTU to regulate and maintain the using tributyltin hydride [12].
pressure of the reactor system. Reaction time was adjusted via
the flow rates of CO and the liquid.
Tin-mediated radical carbonylation has a wide range of applica-
tions including carbonylative cyclization and multi-component
Using the microflow system depicted by Figure 1, we carried coupling reactions. In this regard, we again chose stannylcar-
out the radical formylation of 1-bromododecane (1) with CO in bonylation using 1,6-azaenyne 7 as a model for cyclization [22,
the presence of tributyltin hydride (bath temp. 80 °C) [21]. 23]. Using a similar microflow system but with an extended
However, we encountered incomplete conversion of the starting reaction time, we were able to obtain the desired six-membered
bromide when we used AIBN (2,2′-azobisisobutyronitrile) as a ring lactam 8 in good yield (entry 4). Using a similar micro-
Figure 1: Microflow system available for radical carbonylation using pressurized CO.
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Beilstein Journal of Organic Chemistry 2009, 5, No. 34.
Table 1: Radical carbonylation in a microflow system.a
entry
1
substrate
conditions
.02 M in toluene,
Bu3SnH (1.2 equiv),
V-65 (10 mol%),
CO 83 atm
product/yieldb
0
12 min
0.02 M in toluene,
Bu3SnH (1.2 equiv),
V-65 (10 mol%),
CO 85 atm
2
3
12 min
0.02 M in toluene,
Bu3SnH (1.2 equiv),
V-65 (10 mol%),
CO 85 atm
12 min
0.05 M in toluene,
Bu3SnH (1.1 equiv),
V-65 (10 mol%),
CO 79 atm
4
27 min
0.017 M in toluene,
Bu3SnH (1.5 equiv),
H2C=CH-COCH3 (4 equiv)
V-65 (10 mol%),
5
6
7
CO 85 atm
29 min
0.025 M in toluene,
(TMS)3SiH (1.5 equiv),
H2C=CH-COCH3 (1.2 equiv)
V-65 (30 mol%),
CO 20 atm
30 min
0.025 M in toluene,
(TMS)3SiH (1.5 equiv),
H2C=CH-CN (1.2 equiv)
V-65 (30 mol%),
CO 20 atm
30 min
aConditions: substrate (1 mmol, 0.017–0.05 M in toluene), Bu3SnH or TTMSS (1.1–1.5 equiv), V-65 (10–30 mol%), CO (20–85 atm), T-shaped micro-
mixer (1000 μm i.d.), residence time unit (1000 μm i.d. length: 8 m for entries 1–3, 18 m for entries 4–7). bYields were determined by GC analysis using
decane as an internal standard.
flow system, we then carried out a three-component coupling Since tris(trimethylsilyl)silane (TTMSS) delivers a hydrogen
reaction comprised of 1-iodooctane (9), CO, and methyl vinyl atom to a carbon-centered radical at a slower rate than
ketone in the presence of tributyltin hydride [24], which also tributyltin hydride [25], carbonylation reactions with TTMSS
worked well to give 2,5-tridecandione (10) in 78% yield can be carried out at lower CO pressure without being plagued
(
entry 5).
by the premature reduction of the key radical. Hence, we anti-
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Beilstein Journal of Organic Chemistry 2009, 5, No. 34.
3
4
5
.
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cipated that the combination of low pressure CO/V-65 could be
successfully applied to the TTMSS-mediated three component
carbonylative-coupling reaction of 1-iodooctane (9) [26,27] in a
microflow system using methyl vinyl ketone and acrylonitrile as
acyl radical traps (entries 6 and 7 ). Gratifyingly, in both cases,
good yields of the three-component coupling products were
formed by using reduced CO pressure.
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Conclusion
We have developed a facile platform to conduct radical
carbonylation under CO pressure in a flow system comprised of
a T-shaped mixer and a tabular residence time unit. Using V-65
as a radical initiator, we were able to carry out typical tin- or
silicon-based radical carbonylation reactions leading to alde-
hydes, unsymmetrical ketones, and a lactam, in a continuous
microflow system.
8
9
1
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Experimental
Typical procedure for radical carbonylation in a microflow
system. The radical formylation of 1-bromododecane (1).
1
2
-Bromododecane (1, 1 mmol, 249.5 mg), V-65 (0.1 mmol,
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as an internal standard were dissolved in toluene (50 mL). The
toluene solution was placed in a syringe (17 mL), which was
then attached to a syringe pump. The system was pressurized
with CO (83 atm) by means of the pressure control valve. The
flow rate of CO was controlled at 0.14 mL/min by the mass
flow controller. The toluene solution was introduced at a flow
rate of 0.37 mL/min, then was mixed with CO in the T-shaped
micromixer (i.d. = 1000 μm). The reaction was then fed into the
residence time unit, which was immersed in an oil bath and
heated at 80 °C. The time needed for the reaction mixture to
travel through the residence time unit was expressed as the
residence time (12 min). The mixture of products was collected
at the outlet. The initial effluent exiting the microflow reactor
was discarded (ca. 20 min) until a stable gas-liquid mixing was
achieved, and the following portion was collected for a 10 min
period. The yield was determined by GC analysis, and the
product was identified by comparison of 1H NMR spectrum and
a retention time for GC analysis with those of authentic sample.
1
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Acknowledgments
We thank JSPS/MEXT Japan and MCPT/NEDO for their finan-
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