Koch-Haaf reaction of adamantanols in an acidtolerant hastelloy-made microreactor

Article abstract of DOI:10.3762/bjoc.7.149

The Koch-Haaf reaction of adamantanols was successfully carried out in a microflow system at room temperature. By combining an acid-tolerant hastelloy-made micromixer, a PTFE tube, and a hastelloy-made microextraction unit, a packaged reaction-toworkup system was developed. By means of the present system, the multigram scale synthesis of 1-adamantanecarboxylic acid was achieved in ca. one hour operation.

Full text of DOI:10.3762/bjoc.7.149

Koch–Haaf reaction of adamantanols in an acid-
tolerant hastelloy-made microreactor
Takahide Fukuyama*, Yu Mukai and Ilhyong Ryu*
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2011, 7, 1288–1293.
Department of Chemistry, Graduate School of Science, Osaka
Prefecture University, Sakai, Osaka 599-8531, Japan
doi:10.3762/bjoc.7.149
Received: 16 June 2011
Email:
Accepted: 16 August 2011
Published: 15 September 2011
Takahide Fukuyama* - fukuyama@c.s.osakafu-u.ac.jp; Yu Mukai -
y_mukai@c.s.osakafu-u.ac.jp; Ilhyong Ryu* - ryu@c.s.osakafu-u.ac.jp
This article is part of the Thematic Series "Chemistry in flow systems II".
Guest Editor: A. Kirschning
*
Corresponding author
Keywords:
continuous flow system; hastelloy; Koch–Haaf reaction; microreactor
© 2011 Fukuyama et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
The Koch–Haaf reaction of adamantanols was successfully carried out in a microflow system at room temperature. By combining
an acid-tolerant hastelloy-made micromixer, a PTFE tube, and a hastelloy-made microextraction unit, a packaged reaction-to-
workup system was developed. By means of the present system, the multigram scale synthesis of 1-adamantanecarboxylic acid was
achieved in ca. one hour operation.
Introduction
The recent evolution of microreactor technology has allowed Carbonylation reactions are a powerful tool for the introduction
synthetic chemists to use this precisely sophisticated reaction of carbon monoxide into organic molecules, and we also
apparatus in place of the well-established glassware batch flask reported that Pd-catalyzed carbonylation [13] and radical
[
1-10]. Microreactors are expected to have a significant impact carbonylation [16] could be successfully carried out in a contin-
on chemical synthesis and production because of their many ad- uous microflow system with higher efficiency than in a batch
vantageous characteristics, such as highly efficient mixing, effi- autoclave system. In this study, we focused on the carbonyla-
cient heat transfer ability, precise control over the residence tion of carbocation intermediates carried out in a continuous
time, and high operational safety. We have studied and devel- microflow system [22-24]. The Koch–Haaf reaction [25], that is
oped practical organic syntheses using flow microreactors, and the carbonylation of alcohols or olefins with formic acid in the
we have reported thus far examples of Pd-catalyzed coupling presence of a strong acid, is an important reaction for the
reactions [11-13], radical reactions [14-16], and photoreactions preparation of carboxylic acids, which are widely used in
[
17-21].
organic synthesis [26-31]. Since the Koch–Haaf reaction is
1288

Beilstein J. Org. Chem. 2011, 7, 1288–1293.
highly exothermic, the reaction is typically carried out at
controlled temperature by means of a cooling bath, such as an
ice bath, and with carefully controlled slow addition of reagents
through an addition funnel. The temperature control causes a
serious problem especially for large scale synthesis. Herein, we
report that the Koch–Haaf reaction in a microflow reactor can
be carried out at room temperature without any cooling equip-
ment. The employed hastelloy-made microreactor system was
compatible with corrosive (strongly acidic) conditions and
confirmed for gram scale (7.1 g) synthesis of 1-adamantanecar-
boxylic acid in ca. 1 h operation.
Results and Discussion
The carbonylation reaction of 1-adamantanol (1a) was investi-
gated in a microflow system as a model reaction. Since the
Koch–Haaf reaction requires the use of concentrated sulfuric
acid, an acid-tolerant system is essential. For this study, we
employed a combination of a hastelloy-made micromixer
(
MiChS, β-150H) having 150 μm reactant inlet holes and
00 μm × 300 μm channels (Figure 1), and a PTFE tube
1.0 mm i.d. × 3 m, inner volume: 2.36 mL) as a residence time
2
(
unit. To this reactor system, a hastelloy-made microextraction
unit (a flow-workup system) was attached (Figure 2 and
Figure 3). The microextraction unit has three inlets and one
outlet (channel size: 1 mm i.d. × 14 cm). The reaction mixture
was mixed at T-shaped junctions with Et2O and water, and a
biphasic mixture was collected from the outlet.
Figure 2: Hastelloy-made microextraction unit.
Figure 3: Acid-tolerant microflow system used for the Koch–Haaf
reaction.
Figure 1: Hastelloy-made micromixer (MiChS β-150H).
product and remove excess acids (Scheme 1). The biphasic mix-
1
0
-Adamantanol (1a) dissolved in HCOOH (flow rate: ture was collected in a flask and the ether layer was concen-
.30 mL/min) and 98% H2SO4 (flow rate: 0.88 mL/min) were trated in vacuo. 1-Adamantanecarboxylic acid (2a) was
mixed in the micromixer at room temperature, and the resulting obtained in 89% isolated yield after purification by silica gel
reaction mixture was fed into the PTFE tube and then into the column chromatography. While the residence time was a priori
extraction unit, in which Et2O (flow rate: 2.5 mL/min) and expected to be 2 min based on the total flow rate of the reagents
water (2 mL/min) were introduced to extract the carbonylation and inner volume of the residence time unit, the observed
1289

Beilstein J. Org. Chem. 2011, 7, 1288–1293.
Scheme 1: Synthesis of 1-adamantanecarboxylic acid (2a) in a
microflow system.
residence time was 1.5 min due to a plug flow by the CO gas
generated.
For comparison, we also carried out the batch reaction in a
5
0 mL glass flask on 4 mmol scale to give 2a in 92% yield. In
the batch reaction, the careful addition of a solution of 1a in
formic acid over a period of 5 min and cooling in an ice bath
were necessary to achieve good results. Indeed, without a
cooling bath, we observed that the temperature of the reaction
mixture rose up to 50–60 °C. It is therefore remarkable that the
reaction in the microflow system can be performed success-
fully at room temperature without any cooling unit.
Scheme 2: Koch–Haaf reaction of 1b and 1c in a microflow system.
We then investigated the reaction of some other adamantanols,
such as that of 2-adamantanol (1b) and 2-methyl-2-adaman-
tanol (1c) (Scheme 2). The reaction of 1b in a microflow system
gave a mixture of 2-adamantanecarboxylic acid (2b) and
1
5
-adamantanecarboxylic acid (2a) (82% total yield, 2b:2a =
8:42), in which the latter compound originated from the
isomerized tertiary cation, which derived from the initially
formed secondary cation. The batch reaction gave a mixture of
2
b and 2a in 65% total yield with a greater proportion of the
rearranged product (2b:2a = 14:86). The reaction of 2-methyl-
-adamantanol (1c) resulted in a mixture of the carboxylated
products, 2c, 2c', and 2c'' in 97% total yield (2c:2c':2c'' =
3:53:24). The batch reaction resulted in an inferior yield with
more of the rearranged products (83% yield, 2c:2c':2c'' =
9:62:19). All results are summarized in Table 1.
2
Scheme 3: Multigram scale flow synthesis of 1-adamantanecarboxylic
acid (2a).
2
1
Conclusion
In this work, we demonstrated that the Koch–Haaf reaction of
Multigram scale synthesis of 2a from 1a was carried out in a adamantanols was successfully carried out in an acid-tolerant
continuous flow reaction. When the reaction of 1a (45 mmol) microflow system comprising a hastelloy-made micromixer, a
was performed for 55 min, 7.1 g of 2a was obtained in 88% PTFE tube, and a hastelloy-made microextraction unit. Unlike
yield, demonstrating that the present microflow system can be in the batch system, the reaction could be carried out at room
used for multigram scale synthesis without any problems temperature without any cooling equipment. The employed
(
Scheme 3).
reaction-to-workup system was useful for the multigram scale
1290

Beilstein J. Org. Chem. 2011, 7, 1288–1293.
Table 1: Koch–Haaf reactions of adamantanols.a
Entry
1
Reactor
Conditions
Product (yield)b
T: 20 °C
flow rate (1a/HCO2H): 0.30 mL/min
flow rate (H2SO4): 0.88 mL/min
residence time: 2 minc
residence time: 1.5 mind
1
microflow
T: 15–20 °C
2
3
batch
addition time: 5 min
reaction time: 2 min
T: 20 °C
flow rate (1b/HCO2H): 0.30 mL/min
flow rate (H2SO4): 0.88 mL/min
residence time: 2 minc
residence time: 1 mind
microflow
T: 17–20 °C
4
5
batch
addition time 5 min
reaction time 1 min
T: 20 °C
flow rate (1c/HCO2H): 0.01 mL/min
flow rate (H2SO4): 0.3 mL/min
residence time: 20 minc
residence time: 2.5 mind
microflow
T: 17–20 °C
6
batch
addition time: 3 min
reaction time: 10 min
a1 (4 mmol), HCOOH (6 equiv), H2SO4 (20 equiv); bisolated yield after column chromatography on SiO2; ccalculated; dobserved.
synthesis of 1-adamantanecarboxylic acid (2a). We are now observed to be 1.5 min. The mixture of products was fed into
expanding the system to other cationic systems and the results the hastelloy-made extraction unit, which was cooled by an ice/
will be published in due course.
water bath. Et2O (2.5 mL/min) and water (2 mL/min) were fed
into the extraction unit. The mixture that was eluted during the
first 5 min was discarded and the portion that followed was
Experimental
Typical procedure for Koch–Haaf reaction in a microflow collected for 55 min (1a: 45 mmol). The ethereal layer was sep-
system. Multigram scale synthesis of 1-adamantanecar- arated, and washed with 1.4 N KOH aq. The aqueous layer was
boxylic acid (2a). 1-Adamantanol (1a, 60 mmol, 9.2 g) was acidified with 1 N HCl and extracted with Et2O. The organic
dissolved in 96% HCOOH (360 mmol, 16.6 g), and the solu- layer was dried over MgSO4, filtered, and evaporated.
tion was placed in a 50 mL syringe (22.3 mL), which was then 1-Adamantanecarboxylic acid (2a) was obtained in 88% yield
attached to a syringe pump. Concentrated H2SO4 (99%) as a white solid (7.1 g, mp 171–172 °C). The obtained product
(
1.2 mol, 64 mL) was placed in 100 mL syringe. These liquids was identified by comparison of the 1H NMR and 13C NMR
were mixed in the hastelloy micromixer (150 μm) (flow rate: 1a spectra with those of commercially available authentic samples.
in HCOOH = 0.3 mL/min, H2SO4 = 0.88 mL/min). The All other products, 2b, 2c, 2c', and 2c'' were identified by
resulting reaction mixture was then fed into the residence time means of NMR spectroscopy by comparison with literature data
unit (PTFE tube, 1 mm i.d. × 3 m). The residence time was [32,33].
1291

Beilstein J. Org. Chem. 2011, 7, 1288–1293.
Typical procedure for Koch–Haaf reaction in
17.Fukuyama, T.; Hino, Y.; Kamata, N.; Ryu, I. Chem. Lett. 2004, 33,
1430–1431. doi:10.1246/cl.2004.1430
a batch reaction system
In a 50 mL two-necked round bottom flask, 99% H2SO4
18.Sugimoto, A.; Sumino, Y.; Takagi, M.; Fukuyama, T.; Ryu, I.
Tetrahedron Lett. 2006, 47, 6197–6200.
(
80 mmol, 7.85 g) was placed. A solution of 1-adamantanol (1a,
mmol, 613 mg) in 96% HCOOH (24 mmol, 1.01 g) was
doi:10.1016/j.tetlet.2006.06.153
4
19.Sugimoto, A.; Fukuyama, T.; Sumino, Y.; Takagi, M.; Ryu, I.
added through a dropping funnel over a period of 5 min, while
the temperature of the reaction mixture was maintained at
Tetrahedron 2009, 65, 1593–1598. doi:10.1016/j.tet.2008.12.063
2
0.Matsubara, H.; Hino, Y.; Tokizane, M.; Ryu, I. Chem. Eng. J. 2011,
67, 567–571. doi:10.1016/j.cej.2010.08.086
1
1
5–20 °C in an ice/water bath. The reaction mixture was stirred
2
1.Tsutsumi, K.; Terao, K.; Yamaguchi, H.; Yoshimura, S.; Morimoto, T.;
Kakiuchi, K.; Fukuyama, T.; Ryu, I. Chem. Lett. 2010, 39, 828–829.
doi:10.1246/cl.2010.828
at 15–20 °C for an additional 2 min, poured into ice/water and
extracted with Et2O. The ethereal layer was washed with 1.4 N
KOH aq, and the aqueous layer was acidified with 1 N HCl and
extracted with Et2O. The organic layer was dried over MgSO4,
evaporated and purified by column chromatography on SiO2.
Compound 2a was obtained in 92% yield (667 mg). The reac-
tion of 1b and 1c was carried out by a similar procedure.
22.Suga, S.; Nagaki, A.; Yoshida, J. Chem. Commun. 2003, 354–355.
doi:10.1039/B211433J
For Friedel–Crafts alkylation with carbocation intermediates using a
microreator.
2
3.Tanaka, K.; Motomatsu, S.; Koyama, K.; Tanaka, S.; Fukase, K.
Org. Lett. 2007, 9, 299–302. doi:10.1021/ol062777o
For acid-catalyzed dehydration of alcohols via carbocation
intermediates in a mircoflow system.
Acknowledgements
2
4.Brandt, J. C.; Elmore, S. C.; Robinson, R. I.; Wirth, T. Synlett 2010,
The authors thank MCPT and NEDO for financial support of
this work. IR acknowledges the Grant-in-Aid for Scientific
Research on Innovative Areas (No. 2105) from the MEXT
Japan for funding.
3099–3103. doi:10.1055/s-0030-1259075
For Ritter reaction in a microflow system.
2
2
2
5.Koch, H.; Haaf, W. Justus Liebigs Ann. Chem. 1958, 618, 251–266.
doi:10.1002/jlac.19586180127
6.Hoffmann-Emery, F.; Hilpert, H.; Scalone, M.; Waldmeier, P.
J. Org. Chem. 2006, 71, 2000–2008. doi:10.1021/jo0523666
7.Sorensen, B.; Rohde, J.; Wang, J.; Fung, S.; Monzon, K.; Chiou, W.;
Pan, L.; Deng, X.; Stolarik, D.; Frevert, E. U.; Jacobson, P.; Link, J. T.
Bioorg. Med. Chem. Lett. 2006, 16, 5958–5962.
References
1.
2.
3.
Wirth, T., Ed. Microreactors in Organic Synthesis and Catalysis;
Wiley-VCH: Weinheim, Germany, 2008. doi:10.1002/9783527622856
Hessel, V.; Renken, A.; Schouten, J. C.; Yoshida, J. Micro Process
Engineering; Wiley-VCH: Weinheim, Germany, 2009.
Mason, B. P.; Price, K. E.; Steinbacher, J. L.; Bogdan, A. R.;
McQuade, D. T. Chem. Rev. 2007, 107, 2300–2318.
doi:10.1021/cr050944c
doi:10.1016/j.bmcl.2006.08.129
2
8.Becker, C. L.; Engstrom, K. M.; Kerdesky, F. A.; Tolle, J. C.;
Wagaw, S. H.; Wang, W. Org. Process Res. Dev. 2008, 12,
1114–1118. doi:10.1021/op800065q
2
9.Wan, Z.; Laine, D. I.; Yan, H.; Zhu, C.; Widdowson, K. L.;
4.
5.
6.
7.
Yoshida, J.; Nagaki, A.; Yamada, T. Chem.–Eur. J. 2008, 14,
Buckley, P. T.; Burman, M.; Foley, J. J.; Sarau, H. M.; Schmidt, D. B.;
Webb, E. F.; Belmonte, K. E.; Palovich, M. Bioorg. Med. Chem. Lett.
7
450–7459. doi:10.1002/chem.200800582
Lin, W.-Y.; Wang, Y.; Wang, S.; Tseng, H.-R. Nano Today 2009, 4,
70–481. doi:10.1016/j.nantod.2009.10.007
2009, 19, 4560–4562. doi:10.1016/j.bmcl.2009.07.006
4
3
0.Barton, V.; Ward, S. A.; Chadwick, J.; Hill, A.; O’Neill, P. M.
J. Med. Chem. 2010, 53, 4555–4559. doi:10.1021/jm100201j
1.Shmailov, A.; Alimbarova, L.; Shokova, E.; Tafeenko, V.; Vatsouro, I.;
Kovalev, V. Tetrahedron 2010, 66, 3058–3064.
McMullen, J. P.; Jensen, K. F. Annu. Rev. Anal. Chem. 2010, 3, 19–42.
doi:10.1146/annurev.anchem.111808.073718
3
Webb, D.; Jamison, T. F. Chem. Sci. 2010, 1, 675–680.
doi:10.1039/C0SC00381F
doi:10.1016/j.tet.2010.02.043
8
.
.
Yoshida, J. Chem. Rec. 2010, 10, 332–341. doi:10.1002/tcr.201000020
Wegner, J.; Ceylan, S.; Kirschning, A. Chem. Commun. 2011, 47,
3
2.Mukherjee, A.; Wu, Q.; le Noble, W. J. J. Org. Chem. 1994, 59,
9
3270–3274. doi:10.1021/jo00091a010
4583–4592. doi:10.1039/c0cc05060a
3
3.Alford, J. R.; Cuddy, B. D.; Grant, D.; McKervey, M. A.
J. Chem. Soc., Perkin Trans. 1 1972, 2707–2713.
doi:10.1039/P19720002707
1
1
1
1
1
1
1
0.Fukuyama, T.; Rahman, M. T.; Sato, M.; Ryu, I. Synlett 2008, 151–163.
doi:10.1055/s-2007-1000884
1.Fukuyama, T.; Shinmen, M.; Nishitani, S.; Sato, M.; Ryu, I. Org. Lett.
2
002, 4, 1691–1694. doi:10.1021/ol0257732
2.Liu, S.; Fukuyama, T.; Sato, M.; Ryu, I. Org. Process Res. Dev. 2004,
, 477–481. doi:10.1021/op034200h
8
3.Rahman, M. T.; Fukuyama, T.; Kamata, N.; Sato, M.; Ryu, I.
Chem. Commun. 2006, 2236–2238. doi:10.1039/B600970K
4.Fukuyama, T.; Kobayashi, M.; Rahman, M. T.; Kamata, N.; Ryu, I.
Org. Lett. 2008, 10, 533–536. doi:10.1021/ol702718z
5.Wienhöfer, I. C.; Studer, A.; Rahman, M. T.; Fukuyama, T.; Ryu, I.
Org. Lett. 2009, 11, 2457–2460. doi:10.1021/ol900713d
6.Fukuyama, T.; Rahman, M. T.; Kamata, N.; Ryu, I.
Beilstein J. Org. Chem. 2009, 5, No. 34. doi:10.3762/bjoc.5.34
1292

Beilstein J. Org. Chem. 2011, 7, 1288–1293.
License and Terms
This is an Open Access article under the terms of the
Creative Commons Attribution License
(http://creativecommons.org/licenses/by/2.0), which
permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
(http://www.beilstein-journals.org/bjoc)
The definitive version of this article is the electronic one
which can be found at:
doi:10.3762/bjoc.7.149
1293