Synthesis of 3-substituted tetrahydrofuran and 4-substituted tetrahydropyran derivatives by cyclization of dicarboxylic acids with InBr 3/TMDS

Article abstract of DOI:10.1002/ejoc.201200727

An efficient reduction followed by cyclization of diacid compounds with the InBr₃/TMDS system is reported. This system allows the formation of five- and six-membered ring ethers substituted in the 3- or 4-position. Copyright

Full text of DOI:10.1002/ejoc.201200727

Job/Unit: O20727
/KAP1
Date: 25-07-12 16:13:42
Pages: 6
SHORT COMMUNICATION
DOI: 10.1002/ejoc.201200727
Synthesis of 3-Substituted Tetrahydrofuran and 4-Substituted Tetrahydropyran
Derivatives by Cyclization of Dicarboxylic Acids with InBr3/TMDS
Leyla Pehlivan,[a] Estelle Métay,[a] Dominique Delbrayelle,[b] Gérard Mignani,[c] and
Marc Lemaire*[a]
Keywords: Cyclization / Indium / Oxygen heterocycles / Carboxylic acids / Reduction
An efficient reduction followed by cyclization of diacid com-
pounds with the InBr3/TMDS system is reported. This system
allows the formation of five- and six-membered ring ethers
substituted in the 3- or 4-position.
with activated MnO2 and Et3SiH/CF3COOH.[4] The heat-
ing of dihalogenated compounds in the presence of alumina
allows the formation of five-, six-, or seven-membered rings
in moderate to good yields.[5] The synthesis of 3- or 4-sub-
stituted cyclic ethers was also described under radical con-
ditions. Thus, the cyclization of 1,6-dienes by using CCl4 in
the presence of diethylphosphite or diphenylphosphane ox-
ide permits access to 3,4-substituted THF;[6] radical cycliza-
tions of β-allyloxyalkylphenyl selenides[7] and those of bi-
s(allenes)[8] or iodoalkenes[9] are also described. A highly
enantioselective “ene”-type cyclization of 1,6-enyne cata-
lyzed by the BINAP-Pd complex leads to a 3,4-substituted
THF.[10] A palladium complex was also described by Yama-
moto for a two-component alkoxyallylation reaction be-
tween an activated olefin and hydroxylated allylic carbon-
ate, which leads to five-membered rings in 29 to 76% yield
according to the initial olefin.[11] At last, a three-component
reaction catalyzed by a Pd complex was developed for the
synthesis of 3-arylidene (or 3-alkylidene) THF, but the
methodology also requires substitution at the 2-position.[12]
THF can also be prepared by hydrogenation from maleic
acid or succinic acid by using a Pd/Re/C[13] or Ru/Re cata-
lyst.[14] However, in addition to a high temperature and
pressure, these methodologies lead to a mixture of THF
and alcohols. Recently, a ruthenium–Triphos complex was
found to reduce levulinic acid at 100 bar and 160 °C into
the corresponding diol and a small amount of 2-MeTHF
was observed. If the same conditions were applied to a lac-
tone, the corresponding THF was obtained as the major
product.[15]
Introduction
Cyclic ethers, such as substituted tetrahydrofurans, tetra-
hydropyrans, oxepans, and so on are present in the struc-
tures of natural products and drugs. For example, the mole-
cule A-834,735 developed by Abbot Laboratories is a po-
tent cannabinoid receptor (Scheme 1).[1]
Scheme 1. Structure of A-834,735.
Numerous methods have been described for the synthesis
of tetrahydrofurans (THFs) and tetrahydropyrans (THPs)
in racemic or asymmetric versions substituted in the 2- and
5-positions or the 6-position.[2] However the synthesis of
THF and THP derivatives substituted in the 3-position (for
THF) and the 3- or 4-position (for THP) is less described.
The formation of these five- and six-membered rings can
be performed from diols, activated by iodine,[3] or proceed
through a unique oxidation–reduction step of orthodiols
[a] Laboratoire de Catalyse et Synthèse Organique, Institut de
Chimie et Biochimie Moléculaires et Supramoléculaires
(ICBMS), CNRS, UMR 5246, Université Lyon 1,
43 boulevard du 11 novembre 1918, bat. CPE,
69622 Villeurbanne, France
To the best of our knowledge, an indium catalyst has
never been employed with a source of hydride for the syn-
thesis of cyclic ethers such as THF and THP substituted in
the 3- or 4-position. However, during our investigation
Sakai and co-workers described the reduction of carboxylic
acids into alcohols by using an indium catalyst and TMDS.
This methodology requires the use of InBr3 (5 mol-%) and
occurs in chloroform.[16] In our laboratory, TMDS (tet-
Fax: +33-4-72431408
E-mail: marc.lemaire@univ-lyon1.fr
Homepage: http://www.icbms.fr
[b] Minakem SAS,
145 Chemin des Lilas, 59310 Beuvry la Foret, France
[c] Rhodia, Lyon Research center,
85 Avenue des Frères Perret, BP 62, 69192 Saint-Fons Cedex,
France
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200727.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1

Job/Unit: O20727
/KAP1
Date: 25-07-12 16:13:42
Pages: 6
L. Pehlivan, E. Métay, D. Delbrayelle, G. Mignani, M. Lemaire
SHORT COMMUNICATION
ramethyldisiloxane, Scheme 2) has been used a source of was observed (Table 1, entry 9). When the hydride source
hydride and employed for several reductive systems associ- was switched to PMHS (polymethylhydrosiloxane), a gel
ated with a metal catalyst.[17] This use is interesting, as un- was formed and the reaction proceeded slowly; conversion
like other reducing agents (NaBH4, LiAlH4, etc.), a large into 1-octanol reached only 58% for the same reaction time
excess amount of hydride is not necessary and treatment frame. Unlike InBr3, no transformation was noticed with
does not require hydrolysis or specific attention. Moreover, In(acac)3 (Table 1, entry 11). Finally, reaction with GaBr3
no toxicity has been reported and its cost is easily afford- gave 75% conversion, but the selectivity was less interesting,
able. Herein is described the association of InBr3 and as an alcohol/ether ratio of 60:15 was obtained (Table 1,
TMDS for the synthesis of THF and THP derivatives.
entry 12).
The InBr3/TMDS reductive system applied to octanoic
acid in toluene at 60 °C gave the best result (Scheme 3),
and under these conditions, different aliphatic acids were
efficiently reduced with good selectivity and conversions.
Scheme 2. Structure of TMDS.
Results and Discussion
At the beginning of this study, the goal was to reduce
carboxylic acids by using a hydrosiloxane as the hydride
source. Different catalysts were tested with octanoic acid
(Table 1), although publication of similar conditions were
reported by Sakai during our study.
Scheme 3.
As a consequence, we decided to test the reactivity of
diacids to prepare cyclic ethers. 3-Phenylglutaric acid was
first tested under our reductive conditions. Because two
carboxylic acid functions needed to be reduced, 2 mol-% of
InBr3 and 3 equiv. of TMDS were added in toluene at
60 °C. After 15 h, the cyclization occurred with complete
conversion (Scheme 4).
Table 1. Reduction of octanoic acid with different metals.
Entry
[M] (mol-%)
Si-H (equiv.)
Conversion[a] [%]
(alcohol/ether)
1
2
3
4
5
6
7
8
Pd(OAc)2 (5)
V(O)(OiPr)3 (5)
Cu(OTf)2 (5)
Ce(OTf)x (5)
Bi(OTf)3 (5)
In(OTf)3 (1)
In(OAc)3 (1)
InBr3 (5)
InBr3 (1)
InBr3 (1)
In(acac)3 (1)
GaBr3 (1)
TMDS (1)
TMDS (1.5)
TMDS (1.5)
TMDS (1.5)
TMDS (1.5)
TMDS (1.5)
TMDS (1.5)
TMDS (3)
TMDS (1.5)
PMHS (3)
TMDS (1.5)
TMDS (1.5)
0
0
26 (26:0)
36 (36:0)
Scheme 4.
0
0
0
100 (97:3)
100 (100:0)
58
Under these conditions, 4-phenyltetrahydropyran was
isolated in high yield (Table 2, entry 1). Consequently, dif-
ferent diacids were then considered to synthesize four-,
five-, six-, or seven-membered rings (Table 2).
9
10
11
12
0
With chlorine in the para-position of the aromatic ring,
the conversion was still complete. The isolated yield of THP
2b reached 53% (Table 2, entry 2). With the cyclopentane
75(60:15)
1
[a] Determined by H NMR spectroscopy.
Octanoic acid (1 m in toluene) at 60 °C in the presence derivative, the cyclization occurred with complete conver-
of Pd(OAc)2 or V(O)(OiPr)3 associated with TMDS was sion, and spirotetramethyleneTHP 3b was isolated in 73%
not reduced in 24 h (Table 1, entries 1 and 2). Some interest- yield (Table 2, entry 3). The transformation of homo-
ing results were noticed when Cu(OTf)2 and Ce(OTf)x were phthalic acid (4a) allowed the formation of isochroman (4b)
used. However, conversions into alcohol were not complete in 80% yield (Table 2, entry 4). The formation of 4-hy-
(Table 1, entries 3 and 4). Because the triflate ligand seemed droxytetrahydropyran was then envisaged. From 1,3-ace-
favorable with copper and cerium, Bi(OTf)3 and In(OTf)3 tonedicarboxylic acid (5a), the main product appeared to
were also tested, but only the starting material was reco- be the volatile 4-hydroxyTHP (5b), which was isolated after
vered (Table 1, entries 5 and 6). Other indium catalysts were silica gel chromatography in only 17% yield (Table 2, en-
tested including In(OAc)3, InBr3, and In(acac)3. With the try 5). Therefore, the protection of the hydroxy group was
acetate derivative (Table 1, entry 7), no interesting result envisaged to improve the yield of the final molecule. Several
was observed; however, with InBr3 (5 mol-%) a complete approaches were studied (oxime, tosyl, etc.) and finally the
conversion was noticed (Table 1, entry 8). Under these con- preparation of the benzyl derivative was obtained
ditions, 97% yield of the expected alcohol was obtained (Scheme 5).
along with 3% yield of the ether. When decreasing the
Following a literature procedure, the protection of diethyl
amount of indium and TMDS to 1 mol-% and 1.5 equiv. 3-hydroxyglutarate (6a1) allowed the formation of benzyl
respectively, the conversion was still complete and no ether derivative 6a2 in 78% isolated yield. The next step consisted
2
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20727
/KAP1
Date: 25-07-12 16:13:42
Pages: 6
Cyclization of Dicarboxylic Acids
Table 2. Cyclization of different dicarboxylic diacids.[a]
[a] Conditions: Diacid (5 mmol), InBr3 (2 mol-%, 0.1 mmol.), TMDS (3 equiv.), anhydrous toluene (c = 1 m), 60 °C, 15 h. [b] Determined
by 1H NMR spectroscopy. [c] Isolated yield after purification by flash chromatography. [d] Reaction was carried out with 5 mol-% InBr3.
[e] Low UV sensibility and lack of reactivity with different dips. [f] Very soluble in water and can form an azeotrope with solvents used
for purification.
in the preparation of diacid 6a, which was obtained in 89% was followed for the synthesis of 3-benzylTHF (9b,
yield. Conditions for the cyclization were then applied on Scheme 6).
6a and 4-benzyloxyTHP (6b) was isolated in 76% yield
(Table 2, entry 6).
The synthesis started from the preparation of diester 9a2
from malic acid (9a1). The hydroxy function was then pro-
The synthesis of five-membered rings was then studied. tected with a benzyl group to give compound 9a2. After
The reaction of 2-cyclohexylsuccinic acid (7a) was almost saponification, diacid 9a underwent cyclization to give THF
complete after 15 h, and 3-cyclohexylTHF (7b) was isolated derivative 9b in 26% yield (Table 2, entry 9). In this case,
in 40% yield (Table 2, entry 7). The cyclohexyl group was the conversion reached only 46%. Compound 9a was ob-
then replaced by a phenyl group, and corresponding THF tained as a very viscous oil, in which some ethyl acetate
8b was collected in 34% yield. As detailed above for the (solvent of purification) was trapped. This could explain the
preparation of the benzyl derivative, the same procedure low reactivity in the cyclization step.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3

Job/Unit: O20727
/KAP1
Date: 25-07-12 16:13:42
Pages: 6
L. Pehlivan, E. Métay, D. Delbrayelle, G. Mignani, M. Lemaire
SHORT COMMUNICATION
entry 10). The formation of the cycle was not detected,
which could be due to the strained conformation of oxetans.
Applying the conditions to 1,2-phenylenediacetic acid (11a)
led to the formation of both seven-membered ring 11b and
diol 11bЈ. Diol 11bЈ was isolated in 65%.
From a mechanistic point of view and by analogy with
the Sakai proposition, the formed silyl ether reacts intramo-
lecularly with a second molecule of the carboxylic acid.[17]
The resulting ester is then reduce. The Lewis acid properties
of indium should assist the cyclization step.
Conclusions
Scheme 5.
A new method for the preparation of five- and six-mem-
bered cyclic ethers was described. The reductive InBr3/
TMDS system allowed formation of THP derivatives in
good yields and the formation of THF derivatives in mod-
erate yields. Oxepan can also be formed but the correspond-
ing diol is also observed.
Experimental Section
Procedure for the Cyclization of Diacid Compounds: To a solution
of diacid compound a (5 mmol) in anhydrous toluene (c = 0.5–1
m) was added InBr3 (2 mol-%, 0.05 equiv., 35.5 mg). TMDS was
then added very carefully and slowly (formation of bubbles) over
several minutes. The solution turned bright orange in color. The
reaction mixture was heated to 60 °C. After 15 h, 1H NMR spectro-
scopic analysis of an aliquot was made to check for complete con-
version of the starting material. Toluene was then evaporated, and
the crude material was purified by column chromatography on sil-
ica gel. Cyclic ethers were in general apolar so the purification was
done with pure cyclohexane. UV light and Pancaldi were used for
analysis of the TLC plates. After evaporation, cyclic ether b was
obtained as an oil or a solid.
Scheme 6.
Access to THF and 3-MeTHF from succinic acid and
itaconic acid was also controlled under these conditions,
but because of their volatility they were not isolated. H
NMR revealed complete conversion for the preparation of
THF after a reaction time of 1 h, but the presence of a
minor unidentified product was also detected. The conver-
sion rate of itaconic acid reached 50%. The reduction of
the activated double bond finally led to 3-methylTHF
(Scheme 7).
1
Supporting Information (see footnote on the first page of this arti-
cle): Characterization data, NMR spectra, and GC–MS analyses.
Acknowledgments
This work was supported by the Fond Unique Interministériel
“REDSUP”.
[1] J. M. Frost, M. J. Dart, K. R. Tietje, T. R. Garrison, G. K.
Grayson, A. V. Daza, O. F. El-Kouhen, L. N. Miller, L. Li,
B. B. Yao, G. C. Hsieh, M. Pai, C. Z. Zhu, P. Chandran, M. D.
Meyer, J. Med. Chem. 2008, 51, 1904–1912.
[2] M. C. Elliott, J. Chem. Soc. Perkin Trans. 1 2002, 2301–2323.
[3] B. G. Roy, A. Roy, B. Achari, S. B. Mandal, Tetrahedron Lett.
2006, 47, 7783–7787.
[4] B. Panda, T. K. Sarkar, Tetrahedron Lett. 2008, 49, 6701–6703.
[5] M. Mihara, Y. Ishino, S. Minakata, M. Komatsu, Synlett 2002,
9, 1526–1528.
[6] J. M. Barks, B. C. Gilbert, A. F. Parsons, B. Upeandran, Tetra-
hedron Lett. 2001, 42, 3137–3140.
[7] C. Ericsson, L. Engman, Org. Lett. 2001, 3, 3459–3462.
[8] S. K. Kang, Y. H. Ha, D. H. Kim, Y. Limb, J. Jung, Chem.
Commun. 2001, 1306–1307.
Scheme 7.
Preparation of the THF derivatives was less efficient than
the preparation of THP derivatives. Although conversions
were good, the probable formation of the diol limits the
yield of the cyclic ethers. Moreover, certain cyclic com-
pounds are not visible under UV light or with staining solu-
tions, which make purification more difficult.
At last, the preparation of oxetan and oxepan was con-
sidered. Some tests on phenylmalonic acid (10a) were made,
which led to diol 10b after complete conversion (Table 2,
[9] Y. Kita, H. Nambu, N. G. Ramesh, G. Anilkumar, M. Matsugi,
Org. Lett. 2001, 3, 1157–1160.
4
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20727
/KAP1
Date: 25-07-12 16:13:42
Pages: 6
Cyclization of Dicarboxylic Acids
[10] M. Hatano, M. Terada, K. Mikami, Angew. Chem. 2001, 113,
255; Angew. Chem. Int. Ed. 2001, 40, 249–253.
[11] M. Sekido, K. Aoyagi, H. Nakamura, C. Kabuto, Y. Yamam-
oto, J. Org. Chem. 2001, 66, 7142–7147.
[12] M. Bottex, M. Cavicchioli, B. Hartmann, N. Monteiro, G.
Balme, J. Org. Chem. 2001, 66, 175–179.
[13] M. A. Mabry, W. W. Prichard, S. B. Ziemecki (E. I. Dupont
De Nemours and Company), Patent US No. 0147219A2, 1984.
[14] O. S. Fruchey, L. E. Manzer, D. Dunuvila, B. T. Keen, B. A.
Albin, N. A. Clinton, B. D. Dombek (BioAmber S.A.S), Patent
EP 2371797A1, 2011.
[15] F. M. A. Geilen, B. Engendahl, M. Hölscher, J. Klankermayer,
W. Leitner, J. Am. Chem. Soc. 2011, 133, 14349–14358.
[16] a) N. Sakai, Y. Usui, R. Ikeda, T. Konakaharaa, Adv. Synth.
Catal. 2011, 353, 3397–3401; b) N. Sakai, K. Kanawa, Y.
Nakaike, T. Konakahara, Eur. J. Org. Chem. 2011, 3178–3183;
c) N. Sakai, T. Moriya, K. Fujii, T. Konakahara, Synthesis
2008, 21, 3533–3536.
[17] a) M. Berthod, A. Favre-Réguillon, J. Mohamad, G. Mignani,
G. Docherty, M. Lemaire, Synlett 2007, 1545–1548; b) C. Petit,
A. Favre-Réguillon, B. Albela, L. Bonneviot, G. Mignani, M.
Lemaire, Organometallics 2009, 28, 6379–6382; c) C. Petit, A.
Favre-Réguillon, G. Mignani, M. Lemaire, Green Chem. 2010,
12, 326–330; d) S. Laval, W. Dayoub, A. Favre-Reguillon, M.
Berthod, P. Demonchaux, G. Mignani, M. Lemaire, Tetrahe-
dron Lett. 2009, 50, 2092–2094; e) S. Laval, W. Dayoub, L.
Pehlivan, E. Métay, A. Favre-Réguillon, D. Delbrayelle, G.
Mignani, M. Lemaire, Tetrahedron Lett. 2011, 52, 4072–4075;
f) S. Laval, W. Dayoub, A. Favre-Reguillon, M. Berthod, P.
Demonchaux, G. Mignani, M. Lemaire, Tetrahedron Lett.
2010, 51, 7005–7007; g) L. Pehlivan, E. Métay, S. Laval, W.
Dayoub, P. Demonchaux, G. Mignani, M. Lemaire, Tetrahe-
dron Lett. 2010, 51, 1939–1941; h) L. Pehlivan, E. Métay, S.
Laval, W. Dayoub, P. Demonchaux, G. Mignani, M. Lemaire,
Tetrahedron 2011, 67, 1971–1976; i) Y. Shi, W. Dayoub, G.-R.
Chen, M. Lemaire, Tetrahedron Lett. 2011, 52, 1281–1283; j)
L. Pehlivan, E. Métay, O. Boyron, P. Demonchaux, G. Mig-
nani, M. Lemaire, Eur. J. Org. Chem. 2011, 4687–4692; k) L.
Pehlivan, E. Métay, S. Laval, W. Dayoub, D. Delbrayelle, G.
Mignani, M. Lemaire, Eur. J. Org. Chem. 2011, 7400–7406; l)
L. Pehlivan, E. Métay, D. Delbrayelle, G. Mignani, M. Le-
maire, Tetrahedron 2012, 68, 3151–3155.
Received: May 31, 2012
Published Online: ᭿
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O20727
/KAP1
Date: 25-07-12 16:13:42
Pages: 6
L. Pehlivan, E. Métay, D. Delbrayelle, G. Mignani, M. Lemaire
SHORT COMMUNICATION
Oxygen Heterocycles
L. Pehlivan, E. Métay, D. Delbrayelle,
G. Mignani, M. Lemaire* ................. 1–6
Synthesis of 3-Substituted Tetrahydrofuran
and 4-Substituted Tetrahydropyran Deriva-
tives by Cyclization of Dicarboxylic Acids
with InBr3/TMDS
The efficient preparation of THF and THP
derivatives from dicarboxylic acids is de-
scribed. The reducing system used is InBr3/
TMDS. Oxygenated rings were isolated in
17 to 98% yield.
Keywords: Cyclization / Indium / Oxygen
heterocycles / Carboxylic acids / Reduction
6
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0