Preparation of useful building blocks, α-iodo- and bromoalkanols from cyclic ethers using the Dowex H+/NaX (X = I, Br) approach

Article abstract of DOI:10.1039/c5ra20813k

Our recently reported novel green chemistry tool was effectively used for opening cyclic ethers to produce α-iodo- and bromoalkanols. The synthesis of 4-iodobutanoic acid from γ-butyrolactone has also been described. The method is based on the use of a dried Dowex H⁺/NaX (X = Br, I)-system, which is effective at producing α-iodoalkanols and some α-bromoalkanols from commercially available cyclic ethers. Additionally, opening of three different crown ethers to form α-iodo(polyethylene)glycols with various chain lengths is demonstrated. Haloalkanols are important building blocks in synthetic chemistry e.g. for medicinal chemistry purposes.

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RSCPublishing
ARTICLE
Preparation of useful building blocks, αꢀiodoꢀ and
bromoalkanols from cyclic ethers using the Dowex
H+/NaX (X=I, Br) approach
Cite this: DOI: 10.1039/x0xx00000x
Petri A. Turhanena* and Jouko J. Vepsäläinena
Received 00th January 2012,
Accepted 00th January 2012
Our recently reported novel green chemistry tool was effectively used for opening cyclic ethers
to produce αꢀiodoꢀ and bromoalkanols. The synthesis of 4ꢀiodobutanoic acid from γꢀ
butyrolactone has also been described. The method is based on the use of a dried Dowex
H+/NaX (X = Br, I)ꢀsystem which is effective at producing αꢀiodoalkanols and some αꢀ
bromoalkanols from commercially available cyclic ethers. Additionally, opening of three
different crown ethers to form αꢀiodo(polyethylene)glycols with various chain lengths is
demonstrated. Haloalkanols are important building blocks in synthetic chemistry e.g. for
medicinal chemistry purposes.
DOI: 10.1039/x0xx00000x
www.rsc.org/
examples for the preparation of 5ꢀhalopentanol from
tetrahydrofuran (THF). However only a few reports can be
found in the literature which describe the synthesis of 5ꢀ
Introduction
We have recently discovered a powerful tool with which to
perform common organic addition and substitution reactions by
utilizing dried solid acidic material with the simultaneous use
of sodium iodide either as a catalyst or reagent.1 This report
details how the same approach can be applied for the
preparation of αꢀiodoꢀ and bromoꢀalkanols from cyclic ethers.
Haloalkanes and haloalkanols are important reagents and
building blocks which can be used in common reactions such as
alkylation of amines, etherification of alcohols and phenols,
esterification of carboxylic acid salts, MichaelisꢀArbuzov
reactions and esterification of phosphonates.2,3,4 In general,
iodoꢀ and bromoalkanols are much more reactive than
chloroalkanols which usually need elevated temperatures if
they are to react.2,5 αꢀIodoalkanols can be prepared from the
corresponding chloroꢀ or bromoderivatives by a common
halogen exchange reaction (NaI/acetone).6ꢀ8 However it is a
much more economical and environmentallyꢀfriendly way to
prepare αꢀiodoalkanols directly from starting materials not
containing a halogen such as cyclic ethers as will be described
in here.
halopentanol from tetrahydroꢀ2Hꢀpyran (THP). In fact, there is
only one paper which has described the synthesis of 5ꢀ
iodopentanol from THP by using the toxic NaI/BF3ꢀetherate
system9 and this can be avoided by adopting our method.1 The
Dowex H+/NaI approach also makes it possible to prepare 2ꢀ(2ꢀ
iodoꢀethoxy)ꢀethanol (10) from 1,4ꢀdioxane as we have recently
reported (see Scheme 1).1 Different size ethylene glycols are
very important compounds with which to optimize the
properties of a variety of biologically important molecules10ꢀ13
and 2ꢀ(2ꢀiodoꢀethoxy)ꢀethanol
(10) is precursor of the
diethylene glycol structure.14
Results and Discussion
In Table 1, we have collected the tested ring opening reactions
for commercially available starting materials. As shown, the
isolated yields for the bromide adducts 4b and 6b are moderate
but still reasonable, in fact in the case of 12b, the yield is quite
good. We also tested whether bromide adducts could be made
It is generally known that the ring opening reaction of a ring
containing a saturated ether bond depends to a great extent on
the ring size, because small, three or four atoms containing,
rings such as oxirane and oxetane can be quite easily opened
under acidic conditions. In addition, there are published
1
from
1
,
7
and
9
, but according to their H NMR spectra only a
few per cents of corresponding products were present in the
crude reaction mixtures.
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DOI: 10.1039/C5RA20813K
Scheme 1. Synthesis of 2ꢀ(2ꢀiodoꢀethoxy)ꢀethanol (10) from 1,4ꢀdioxane.
In the case of the iodide adducts, the isolated yields were xylene (ca. 142°C) for 24 h, products 18
, 20 and 22 were
generally reasonable or even high. Compound was isolated isolated with 32%, 22% and 14% yields, respectively. Although
2
with a 27% yield (the yield of crude product was 55% and these yields are not impressive, one has to bear in mind that in
purity ca. 91%, although adequate for its further use in most the method reported here, only one reaction step is needed,
cases), which was quite low, probably due to its rather low compared to the earlier method in the literature.18 Furthermore,
boiling point (volatility) and instability. Compounds 4a
,
6a
,
8
,
if one has to use either pentaethylene glycol or hexaethylene
10 and 12a were isolated at moderate to high yields, the most glycol as starting materials for the synthesis of compounds 20
interesting cases were the degradation of energetically stable and 22 according to the method reported in the literature18 then
sixꢀmembered rings
now we were able to improve the isolated yield of
to 47%.1 Compound 12a was isolated with a high 75% yield; starting from the corresponding crown ethers 19 and 21
7
and
9
which we demonstrated earlier, but the synthesis will be a much more costly procedure; these
8
from 33% materials are about 3.5 and 2.5 times more expensive than
,
this is a very interesting building block along with 12b for respectively (in fact, compound 20 has not been reported earlier
optimizing molecular properties e.g. for medicinal chemistry according to SciFinder). In addition, should the intent be to
use, since many drugs have a cyclohexyl structure.15,16 conduct a preliminary search for the optimal length of the
Interestingly, those building blocks have been sparingly ethylene glycol spacer without the need to synthesize more than
reported in the literature, e.g. experimental NMR spectral data 10ꢀ100 mg of the precursor, this method is definitely a
were not available and according to a SciFinder search, these convenient option. The main reason for the low yields of the
compounds are not commercially available. The 100% and 95% products 18
, 20 and 22 is believed be the degradation of the
conversions of the compounds 13 to 14 and 15 to 16 desired products during the reaction, since we were able to
,
respectively, were observed according to NMR samples isolate some of degradation products from the reaction mixture
measured from crude reaction mixtures. However, the isolated (as an example see the compounds isolated in the reaction
yield was only 36% and 33%, respectively, because of the mixture of 19 in Figure 1). All the isolated compounds 18, 23
presence of a “back reaction” (see Experimental section). The and 24 were confirmed by examining the 1H, 13C NMR and MS
degradation of 2,3ꢀdihydrobenzofuran (13) makes the method spectra. It is proposed that our method is also capable of
attractive because of its potential use in the destruction of degrading straight ethers, the formation of compound 24 was
samples containing chlorinated dibenzofurans which are not unexpected because the method can be used for the direct
extremely stable and highly toxic chemical compounds.17 The substitution of a hydroxyl group into iodide as we have reported
significance of different size ethylene glycols and the ability of earlier.1
our method to synthesize 10 from 1,4ꢀdioxane (
if we could degrade also crown ethers (17 19 and 21) and
produce corresponding ethylene glycol precursors (18 20 and
9) led us to test
,
,
22). When Crown ethers (17
,
19 and 21) were refluxed in
Table 1. Overview of the reactions
Conditionsa
Conditionsa
Yieldb
Product
Substrate
Yieldb
Product
Substrate
50°C, 18 h
50°C, 18 h
53% (4a)
29% (4b)
27%
(55%)c
70°C, 18 h
92°C, 18 h
47%
86% (6a)
34% (6b)
2 | J. Name., 2012, 00, 1-3
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60°C, 18 h
105°C, 18 h
68%d
75% (12a)
59% (12b)
122°C, 18 h
142°C, 24 h
36%
33%
(100%)e
(95%)e
O
142°C, 24 h
22%
O
O
O
O
142°C, 24 h
32%
O
O
O
O
17
19
142°C, 24 h
14%
a In the table, only the reaction time and temperature have been highlighted, all reactions were performed using the dried Dowex H+/NaX (X
= Br, I) system, detailed experimental procedures and conditions can be found in the supporting information; b isolated yields; c crude yield,
ca. 91% purity; d reported earlier1; e conversion.
Figure
1.
Some
of
the
sideꢀproducts
isolated
from
the
reaction
mixture
of
19.
and 10, no additional solvents were used, because the starting
The choice of the most appropriate solvent to be used in these materials ( , and ) are commonly used solvents and thus
reactions was far from straightforward. Our earlier experiences they were successfully exploited as such. Interestingly, when
with the reaction system used here indicated that alkylnitriles compounds 12a were synthesized using acetone as the
5
,
7
9
ꢀ
b
such as acetonitrile and butyronitrile would be the best solvents solvent, higher yields were obtained than with acetonitrile
to be used in all of these ring opening reactions, however this (crude yields were around the same as when using acetonitrile).
was not the case. It would have been theoretically possible to This was quite unexpected because acetone readily forms a
investigate the effect of different solvents individually in each selfꢀcondensation product under these kinds of acidic
1
of the reactions reported here, but that would be beyond the conditions, a fact confirmed from inspection of the H NMR
scope of this article. Many of the reported reactions were tested spectrum of the crude product (selfꢀcondensation of acetone
with at least two different solvents and the solvent which was observed also in the synthesis of 2). In the synthesis of 14,
achieved the best yields is described in the experimental section butyronitrile was used as the solvent, achieving a 100%
in the supporting information. As an example, there were very conversion yield, whereas acetonitrile resulted in only 41%
little differences in the isolated yields between acetonitrile and conversion. Probably the main reason for this difference is the
acetone in the synthesis of
2. In the case of 2a, acetonitrile was lower temperature which can be used with acetonitrile
better than 2ꢀpropanol, however, in the synthesis of 2b the use (acetonitrile b.p. 82°C and butyronitrile b.p. 118°C). Higher
of 2ꢀpropanol achieved a better yield. In the syntheses of
6
,
8
temperatures were needed to reach ca. 95% conversion of γꢀ
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DOI: 10.1039/C5RA20813K
butyrolactone (15) to 4ꢀiodobutanoic acid (16) and for this
reason xylene was selected as the solvent in this reaction. All
the Crown ether ring opening reactions were performed also in
xylene, because the use of butyronitrile resulted in lower yields.
In summary, it proved difficult to identify any direct
relationship between the solvent used in the reactions reported
here other than a temperature correlation. More strained rings
needs less energy (lower temperatures) than more stable rings
(higher temperatures).
6
7
8
9
M. Arseneault, I. Levesque and JꢀF. Morin, Macromolecules 2012,
45, 3687.
P.R. Bohländer and HꢀA. Wagenknech, Eur. J. Org. Chem. 2014, 34
,
7547.
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Z. Li. WeiꢀDong, D. WeiꢀGuo and Z. ChengꢀHan, Org. Lett., 2011,
13, 3538.
We also tested whether different equivalent amounts of NaI or
NaBr should be used in the reactions to obtain the best yields;
the amounts are reported individually for all reactions in the
experimental section in the supporting information as are the
amounts of Dowex H+ used in these reactions.
10 K. Sano, T. Nakajima, K. Miyazaki, Y. Ohuchi, T. Ikegami, P.L.
Choyke and H. Kobayashi, Bioconjugate Chem. 2013, 24, 811.
11 R. Watanabe, K. Sato, H. Hanaoka, T. Harada, T. Nakajima, I. Kim,
C. H. Paik, A.M. Wu, P.L. Choyke and H. Kobayashi, ACS Med.
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2012, No. 103973.
Conclusions
13 D. A. Sheik, L. Brooks, K. Frantzen, S. Dewhurst and J. Yang, ACS
Our very recently reported method1 was successfully applied to
prepare highly adaptable building blocks to be used in synthetic
chemistry with only one reaction step, starting from cyclic
ethers (or an ester in the case of 16). This new approach is
much more environmentallyꢀfriendly and economical than
published methods because the Dowex H+ resin can be
regerated and reused as we have earlier reported1 and there are
no need to use already halogenated starting materials (halogen
exchange reaction) and no need for the use of toxic reagents
such as NaI/BF3ꢀetherate system9. The reported yields for the
prepared compounds ranged from 14% to 86%, and although
these could probably be improved by optimizing the reaction
conditions, this would be a timeꢀconsuming process, since it
needs to be done on a caseꢀbyꢀcase basis.
Nano 2015, 9, 1829.
14 P.K. Poutiainen, T. Rönkkö, A.E. Hinkkanen, J.J. Palvimo, A.
Närvänen, P. Turhanen, R. Laatikainen, J. Weisell and J.T.
Pulkkinen, Bioconjugate Chem. 2014, 25, 4.
15 F.W. Muregi and A. Ishih, Drug Dev. Res. 2010, 71, 20.
16 I. Chopra and M. Roberts, Microbiol. Mol. Biol. Rev. 2001, 65, 232.
17 https://en.wikipedia.org/wiki/Polychlorinated_dibenzofurans
references therein, accessed June 25, 2015.
and
18 J.M. Song, A.M. DiBattista, Y.M. Sung, J.M. Ahn, R.S. Turner, J.
Yang, D.T.S. Pak, HꢀK. Lee and HꢀS. Hoe, Exp. Neurobiol. 2014,
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Acknowledgements
This research has been supported by strategic funding from the
University of Eastern Finland. The authors would like to thank
Mrs. Maritta Salminkoski for her expert technical assistance
and Dr. Jukka Leppänen and Mrs. Miia Reponen for
performing the MS measurements. Mrs. Tiina Koivunen is
acknowledged for her help with the elemental analyses.
Notes and references
a
University of Eastern Finland, School of Pharmacy, Biocenter Kuopio,
P.O. Box 1627, FINꢀ70211, Kuopio, Finland.
Electronic Supplementary Information (ESI) available: [Detailed
experimental procedures for all prepared compounds and 1H NMR
spectra for crude product and conversion of
2 and conversions of 14 and
16. 1H and 13C NMR spectra for the compounds 12aꢀb
,
18
,
20 and 22ꢀ24].
See DOI: 10.1039/b000000x/
1
2
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,
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,
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M. B. Smith and J. March, March’s Advanced Organic Chemistry:
Reactions, Mechanisms and Structure, Sixth Edition, John Wiley &
Sons, Inc. 2007.
3
Savignac, P.; Iorga, B. Modern Phosphonate Chemistry, CRC Press,
2003.
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N.S. Isaacs, Physical Organic Chemistry, Second Edition, Prentice
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4 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C5RA20813K
Economical and environmentallyꢀfriendly method for preparation of αꢀiodoꢀ and bromoalkanols
directly from cyclic ethers has been developed. Prepared compounds are highly important building
blocks in synthetic chemistry for the preparation of more complex molecules.