Flow Giese reaction using cyanoborohydride as a radical mediator

Article abstract of DOI:10.3762/bjoc.9.208

Tin-free Giese reactions, employing primary, secondary, and tertiary alkyl iodides as radical precursors, ethyl acrylate as a radical trap, and sodium cyanoborohydride as a radical mediator, were examined in a continuous flow system. With the use of an automated flow microreactor, flow reaction conditions for the Giese reaction were quickly optimized, and it was found that a reaction temperature of 70 °C in combination with a residence time of 10-15 minutes gave good yields of the desired addition products.

Full text of DOI:10.3762/bjoc.9.208

Flow Giese reaction using cyanoborohydride
as a radical mediator
Takahide Fukuyama, Takuji Kawamoto, Mikako Kobayashi and Ilhyong Ryu*
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 1791–1796.
Department of Chemistry, Graduate School of Science, Osaka
Prefecture University, Sakai, Osaka 599-8531, Japan
doi:10.3762/bjoc.9.208
Received: 02 July 2013
Email:
Accepted: 14 August 2013
Published: 03 September 2013
Ilhyong Ryu* - ryu@c.s.osakafu-u.ac.jp
* Corresponding author
This article is part of the Thematic Series "Chemistry in flow systems III".
Guest Editor: A. Kirschning
Keywords:
continuous flow system; cyanoborohydride; flow chemistry;
iodoalkanes; microreactor; tin-free Giese reaction
© 2013 Fukuyama et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
Tin-free Giese reactions, employing primary, secondary, and tertiary alkyl iodides as radical precursors, ethyl acrylate as a radical
trap, and sodium cyanoborohydride as a radical mediator, were examined in a continuous flow system. With the use of an auto-
mated flow microreactor, flow reaction conditions for the Giese reaction were quickly optimized, and it was found that a reaction
temperature of 70 °C in combination with a residence time of 10–15 minutes gave good yields of the desired addition products.
Introduction
Organo halides are among the most useful precursors to access radical carbonylation and hydroxymethylation reaction [11-
carbon radical species, and they have found numerous applica- 13,18] employing this methodology. In Scheme 1, a general
tions in chemical synthesis [1-5]. Alkyl radicals are classified as mechanism of a borohydride-based Giese reaction with the
nucleophilic radicals, and therefore they are able to add prefer- possible products is shown.
entially to alkenes possessing an electron-withdrawing
substituent [6,7]. This type of reductive radical addition reac- In recent years, microreaction technologies have made a signifi-
tion, better known as the Giese reaction, was historically carried cant impact on chemical synthesis and production in terms of
out most by using tributyltin hydride as the radical mediator their advantageous characteristics, which include efficient
[8,9]. Recently borane derivatives such as borohydride reagents mixing, efficient mass and heat transfer, and high operational
[10-13] or NHC-boranes [14-18] can be used in simple radical safety [19-23]. Radical reactions also benefit from these advan-
C–C bond forming reactions or radical reduction as efficient tages, and we have reported both photo- [24-26] and thermally-
substitutes for tin hydride reagents, whose toxicity is of great induced [27-30] radical reactions that are facilitated by flow
concern to organic chemists. Thus far we have demonstrated the reaction technology [31]. In this study, we report that
borohydride-based tin-free Giese reactions [10] and the related cyanoborohydride-based Giese reactions of primary, secondary,
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Beilstein J. Org. Chem. 2013, 9, 1791–1796.
Scheme 1: Giese reaction using borohydride-based radical mediators.
and tertiary iodoalkanes with ethyl acrylate can be carried out tion through the programming of temperature and flow rates
efficiently using a microflow system. Optimal conditions for (Figure 1).
each substrate were quickly determined by the use of an auto-
mated microflow reactor [32], which revealed that running the Initially, the reaction of 1-iodooctane (1a) with ethyl acrylate in
continuous flow reactions at 70 °C for 10–15 min gave good the presence of NaBH3CN (2 equiv) and 10 mol % AIBN (2,2’-
yields of Giese addition products with effective suppression of azobisisobutyronitrile) was investigated. A variety of different
the byproducts.
temperatures (90–110 °C) and residence times (2–10 min) were
screened. The reaction of 1a with ethyl acrylate was found to
give the desired Giese reaction product 3a together with two
Results and Discussion
We employed an automated microflow reactor system, MiChS® main byproducts, octane (2a) and the 1:2 addition adduct 4a. As
System X-1 [33], equipped with a fraction collector, which shown in Scheme 2, higher reaction temperatures tended to
allows screening of up to 20 reaction conditions in one opera- result in the formation of increased amounts of octane (2a).
Figure 1: Pictures of the flow microreactor system (MiChS® System X-1), a micromixer (MiChS β-150, channel width: 150 μm), and a fraction
collector used for this study.
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Beilstein J. Org. Chem. 2013, 9, 1791–1796.
Scheme 2: First screening for the reaction of 1a at different temperatures (90–110 °C) and residence times (2–10 min) in the presence of AIBN.
Under the same reaction conditions, the radical mediator To check the background hydride reduction of 1a with
Bu4NBH3CN gave similar results, whereas the reaction with NaBH3CN, we treated 1a with 2 equiv of NaBH3CN at various
Bu4NBH4 was found not to be suitable, since the competing temperatures (70–100 °C) for 10 min in the absence of a radical
reduction leading to 2a became the dominant product from the initiator and ethyl acrylate (Scheme 3). The reduction product
reaction.
2a was not formed in large amounts and we found that its for-
Scheme 3: Background reduction of 1a with NaBH3CN.
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Scheme 4: Second screening at 70 °C and residence time (5–20 min) in the presence of V-65.
mation was effectively suppressed by lowering the temperature
to 70 °C.
Setting the reaction temperature to 70 °C, we then further opti-
mize the other reaction conditions. Consequently we found that
the desired Giese product 3a could be obtained in 75% yield
(Scheme 4) when the reaction was carried out with 1.6 equiv of
ethyl acrylate and 3 equiv of NaBH3CN and 10 min residence
time in the presence of V-65 (2,2’-azobis(2,4-dimethylvaleroni-
Figure 2: Structures of V-65 and AIBN and their ten hour half-life
decomposition temperature.
trile)) as the radical initiator, which decomposes at a lower
temperature than AIBN (Figure 2). For comparison, we also
carried out a batch reaction using a 20 mL test tube on 0.5
mmol scale under similar reaction conditions (70 °C (bath these secondary and tertiary substrates, simple reduction to give
temp.), 10 min), which gave only 34% yield of 3a and a large octane (2b) or adamantane (2c) was hardly observed.
amount of recovered 1a. We assume that excellent thermal effi-
ciency inherent to tiny reaction channels would ensure efficient Conclusion
reaction in the microreactors.
The cyanoborohydride-mediated Giese reaction of alkyl iodides
1a, 1b, and 1c with ethyl acrylate was studied in a continuous
We then carried out the optimization of the reaction conditions microflow reaction system. Optimized conditions with
for the secondary and tertiary alkyl iodides, 2-iodooctane (1b) minimum formation of byproducts for the conversion of 1a to
and 1-iodoadamantane (1c), reacting with ethyl acrylate. We 3a were rapidly located by the use of an automated microflow
were pleased to find that under similar reaction conditions (70 system, MiChS® X-1, equipped with a static mixer having 150
°C, 10–15 min) these two flow Giese reactions worked well to μm width and an automated fraction collector. Using the opti-
give the corresponding addition products 3b and 3c in 88 and mized flow conditions (70 °C, 10–15 min), high yielding
81% yield, respectively (Scheme 5). It should be noted that for conversions of 1b to 3b and 1c to 3c were also obtained.
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Scheme 5: Cyanoborohydride mediated Giese reaction of 1b and 1c with ethyl acrylate.
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