Ruthenium pincer-catalyzed cross-dehydrogenative coupling of primary alcohols with secondary alcohols under neutral conditions

Article abstract of DOI:10.1002/adsc.201200438

Cross-dehydrogenative coupling of primary alcohols with secondary alcohols to obtain mixed esters with the liberation of molecular hydrogen is achieved in high yield and good selectivity under neutral conditions, using a bipyridyl-based PNN ruthenium(II) pincer catalyst. Copyright

Full text of DOI:10.1002/adsc.201200438

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DOI: 10.1002/adsc.201200438
Ruthenium Pincer-Catalyzed Cross-Dehydrogenative Coupling
of Primary Alcohols with Secondary Alcohols under Neutral
Conditions
Dipankar Srimani,a Ekambaram Balaraman,a,b Boopathy Gnanaprakasam,a
Yehoshoa Ben-David,a and David Milsteina,*
a
Department of Organic Chemistry, Weizmann Institute of Science, 76100 Rehovot, Israel
Fax : (+972)-8-934-6569; e-mail: david.milstein@weizmann.ac.il
Present address: SRM Research Institute, SRM University, Kattankulathur – 603 203, Tamil Nadu, India
b
Received: May 24, 2012; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200438.
Abstract: Cross-dehydrogenative coupling of pri-
mary alcohols with secondary alcohols to obtain
mixed esters with the liberation of molecular hydro-
gen is achieved in high yield and good selectivity
under neutral conditions, using a bipyridyl-based
PNN ruthenium(II) pincer catalyst.
alkylation of secondary alcohols with primary alcohol
is known.[7]
We have developed several environmentally benign
reactions catalyzed by pincer complexes of ruthenium
based on pyridine[8] and acridine backbones,[9] includ-
ing dehydrogenative coupling of primary alcohols to
give esters,[8b,d,g] the dehydrogenation of secondary al-
cohols to give ketones,[8a,d] the hydrogenation of esters
to give alcohols,[8c,g] efficient synthesis of amides[8e,g]
and imines[10] from alcohols and amines, acylation of
alcohols using esters,[8h] and amidation of esters.[8i] Re-
cently we have prepared the Ru-bipyridine-based
pincer complex 1 (Figure 1) and explored its catalytic
activity toward the hydrogenation of amides,[11a] bio-
Keywords: cross-esterification; dehydrogenation;
homogeneous catalysis; oxidative coupling; rutheni-
um pincer complexes
Alcohol esterification is one of the most fundamental mass-derived cyclic diesters,[11b] and urea derivatives[12]
reactions in synthetic organic chemistry.[1] It has vari- as well as organic carbonates, carbamates and for-
ous applications in the production of synthetic inter- mates.[13] These reactions are thought to involve
mediates, biologically active natural products, fragran- a new mode of metal-ligand cooperation based on
ces, polymers, polyesters, plasticizers, fatty acids, ligand aromatization–dearomatization which has also
paints and pharmaceuticals.[2] The reaction is usually led to C H activation
and N H activation
re-
[14a,b]
[14c]
À
À
performed by coupling of a carboxylic acid or its de- actions, and to consecutive water splitting.[14d]
rivative (acid chloride or acid anhydride) with an al-
Here we report on the dehydrogenative cross-cou-
cohol.[3] Transesterification is also a very useful reac- pling of primary alcohols with secondary alcohols cat-
tion.[4] In recent years, much attention has been di- alyzed by complex 1 under mild, neutral conditions
rected at the search for environmentally benign (Scheme 1).
esterification methods.[5] Although several catalytic
Complex 1 was prepared as described in our previ-
dehydrogenative esterifications of primary alcohols to ous report.[11a] When a toluene solution containing
esters have been reported so far,[5f,k-r,7b,d] less attention
has been paid to the oxidative cross-esterification re-
actions. Available oxidative cross-esterification meth-
ods are limited to methyl esterification of primary al-
cohols[6] and palladium-catalyzed oxidative cross-
esterification of primary alcohols using oxygen.[5c,d]
None of these cross-esterification reactions is based
on the generation of molecular hydrogen, or use of
a secondary alcohol, which, being more bulky, is ex-
pected to be less reactive. The ruthenium-catalyzed b- plex.
Figure 1. Dearomatized Bipy-PNN ruthenium pincer com-
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hexanol and cyclohexanol (3 mmol each) and
0.03 mmol of complex 1 was refluxed under an argon
atmosphere, cyclohexyl hexanoate was obtained in
79% yield, together with 16% hexyl hexanoate (by
the self-esterification of hexanol) and 12% of cyclo-
hexanone (by dehydrogenation of cyclohexanol), as
Scheme 1. Cross-esterification between primary and secon-
dary alcohols.
Table 1. Dehydrogenative cross-coupling of primary and secondary alcohols cata-
lyzed by 1.[a]
[a]
Complex
1 (0.03 mmol), primary alcohol (3 mmol), secondary alcohol
(7.5 mmol) and toluene (2 mL) were refluxed (oil bath temperature 1358C)
under argon. Yields of products were determined by GC using m-xylene as in-
ternal standard.
The yield in parenthesis was obtained when equimolar amounts of hexanol and
cyclohexanol were employed.
[b]
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Ruthenium Pincer-Catalyzed Cross-Dehydrogenative Coupling of Primary Alcohols
determined by GC and confirmed by GC-MS cyclohexanol and with 3-pentanol only
a trace
(Table 1, entry 1). The relatively selective formation amount of butyl butyrate was noted by GC-MS.
of the ester of the secondary alcohol is noteworthy. Excellent yields of the cross-esterification products
Although use of equivalent amounts of the secondary were obtained also with the primary alcohols 3-
and primary alcohols resulted in good yield of the methyl-1-butanol and 2-methoxyethanol (entries 12,
cross-esterification product, a higher yield was ob- 13, and 14). Reaction of benzyl alcohol with cyclohex-
tained when excess of the secondary alcohol was anol resulted in a 91% yield of cyclohexyl benzoate
used, as expected. Thus, when a toluene solution con- (entry 15) together with 34% of cyclohexanone.
taining 3 mmol hexanol, 7.5 mmol of cyclohexanol
Interestingly, the dehydrogenation of the secondary
and 0.03 mmol of complex 1 was refluxed under an alcohols to the corresponding ketones is slower than
argon atmosphere, a 93% yield of cyclohexyl hexan- the dehydrogenative coupling of the alcohol to ester,
ACHTUNGTRENNUNGoate (based on hexanol) was obtained (Table 1, generally resulting in the desired cross-esters in excel-
entry 1). Cyclohexanone (34%) was also formed. Pure lent yields. In addition, the self-esterification product
cyclohexyl hexanoate was isolated by evaporation of is observed only as a minor product, if at all.
the solvent followed by silica gel chromatography and
analysis by NMR and GC-MS.
A possible catalytic cycle for the cross-esterification
of primary and secondary alcohols likely involves O
À
Studying the scope of this reaction with regard to H activation of the primary alcohol followed by H2
cyclic secondary alcohols, the reaction of 1-hexanol elimination to give an intermediate aldehyde, which
with cyclopentanol in the presence of 1 mol% of forms a hemiacetal with the secondary alcohol. Dehy-
1 (entry 2) resulted after 26 h reflux in toluene in the drogenation of the hemiacetal yields the cross-ester,
formation of cyclopentyl hexanoate (63% yield), ac- similar to the proposed mechanism of dehydrogena-
companied by hexyl hexanoate as side product (25% tive self-coupling of primary alcohols to esters.[8b,g]
yield). Reaction of 1-hexanol with cycloheptanol The self-esterification product of the primary alcohol,
under the same conditions gave cycloheptyl hexa- if formed, can be converted to the desired cross-ester
noate in 90% yield (entry 3) and hexyl hexanoate by transesterification.[8h]
(8%).
In conclusion, the new cross-esterification reaction
Expanding the scope of the reaction to acyclic sec- of primary alcohols with secondary alcohols is effi-
ondary alcohols, the optimized reaction conditions ciently catalyzed by the dearomatized complex
were applied to 3-pentanol and 1-phenylethanol. Re- 1 under neutral conditions. In most of the cases the
action of 3-pentanol with 1-hexanol gave the cross- yield of the cross-ester is excellent, although in some
ester in 93% yield (entry 4), while in the case of 1- cases a small amount of the homocoupling product of
phenylethanol the cross-ester was formed in 58% the primary alcohol is observed. In most of the cases
yield (entry 5) in addition to hexyl hexanoate (25% a ketone side product, generally obtained in low yield
yield). The lower yield of the cross-esterification by dehydrogenation of the secondary alcohol was ob-
product is a result of facile dehydrogenation of 1-phe- served. This reaction offers an efficient, mild method
nylethanol to acetophenone (46%).
for the dehydrogenative cross-coupling of primary
Next we studied the reaction of 1-pentanol with and secondary alcohols under neutral conditions.
various secondary alcohols. Reaction of 3 mmol of 1-
pentanol with 7.5 mmol cyclohexanol led to a 95%
yield of cyclohexyl pentanoate after 25 h (entry 6).
Experimental Section
Upon refluxing of 1-pentanol with 3-pentanol in tolu-
ene, a 96% yield of the cross-ester were formed
(entry 7). Only a trace of pentyl pentanoate was de-
tected by GC-MS, while in both cases cyclohexanone
was formed in 35% yield. The reaction of 1-pentanol
with 1-phenylethanol after 38 h gave the cross-ester
(46% yield) (entry 8) and acetophenone (58% yield).
Exploring further the scope with regard to the pri-
mary alcohol, 1-butanol was reacted with cyclohexa-
nol, resulting in a 95% yield of cyclohexyl butyrate
(entry 9) after 25 h. In a similar reaction with 3-penta-
nol and cycloheptanol 93% and 70% yields of the
cross-esterification products, respectively, were
formed after 26 h (entries 10 and 11). In the case of
cycloheptanol, butyl butyrate (28% yield) was also
formed but in the cases of reactions of butanol with
General Procedure for the Cross-Esterification
Reaction
Complex 1 (0.03 mmol), primary alcohol (3 mmol), secon-
dary alcohol (7.5 mmol) and toluene (2 mL) were added to
a
Schlenk flask under an atmosphere of nitrogen in
a Vacuum Atmospheres glovebox. The flask was equipped
with a condenser and the solution was refluxed with stirring
in an open system under argon for the specified time
(Table 1) at 1358C oil bath temperature. The reaction prod-
ucts were analyzed by GC-MS. After cooling to room tem-
perature, m-xylene (1 mmol) was added as internal standard
to the reaction mixture and the products were quantitatively
analyzed by GC using a Carboxen 1000 column on an HP
690 series GC system or HP-5 cross linked 5% PH ME Si-
loxane column (30 mꢁ0.32 mmꢁ0.25 mm film thickness) on
an HP 6890 series GC system. Pure esters were obtained by
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silica gel chromatography. Characterization data are avail-
able in the Supporting Information.
er, ChemCatChem 2009, 1, 72; p) M. Bertoli, A. Choua-
leb, D. G. Gusev, A. J. Lough, Q. Major, B. Moore,
Dalton Trans. 2011, 40, 8941; q) K. Oded, S. Musa, D.
Gelman, J. Blum, Catal. Commun. 2012, 20, 68;
r) G. E. Dobereiner, R. H. Crabtree, Chem. Rev. 2010,
110, 681.
Acknowledgements
[6] a) N. Yamamoto, Y. Obora, Y. Ishii, J. Org. Chem.
2011, 76, 2937; b) D. I. Enache, D. W. Knight, G. J.
Hutchings, Catal. Lett, 2005, 103, 43; c) N. A. Owston,
A. J. Parker J. M. J. Williams, Chem. Commun. 2008,
624; d) F. Su, J. Ni, H. Sun, Y. Cao, H. He, K. Fan,
Chem. Eur. J. 2008, 14, 7131; e) I. S. Nielsen, E. Taarn-
ing, K. Egeblad, R. Madsen, C. H. Christensen, Catal.
Lett, 2007, 116, 35.
This research was supported by the European Research
Council under the FP7 framework (ERC No 246837), by the
Israel Science Foundation, and by the Helen and Martin
Kimmel Center for Molecular Design. D. M. holds the Israel
Matz Professorial Chair of Organic Chemistry.
References
[7] a) K. Fujita, C. Asai, T. Yamaguchi, F. Hanasaka, R.
Yamaguchi, Org. Lett. 2005, 7, 4017; b) M. Viciano, M.
Sanaffl, E. Peris, Organometallics 2007, 26, 6050.
[8] a) J. Zhang, M. Gandelman, L. J. W. Shimon, D. Mil-
stein, Organometallics 2004, 23, 4026; b) J. Zhang, G.
Leitus, Y. Ben-David, D. Milstein, J. Am. Chem. Soc.
2005, 127, 10840; c) J. Zhang, G. Leitus, Y. Ben- David,
D. Milstein, Angew. Chem. 2006, 118, 1131; Angew.
Chem. Int. Ed. 2006, 45, 1113; d) J. Zhang, M. Gandel-
man, L. J. W. Shimon, D. Milstein, Dalton Trans. 2007,
107; e) C. Gunanathan, Y. Ben-David, D. Milstein, Sci-
ence 2007, 317, 790; f) L. Schwartsburd, M. A. Iron, Y.
Konstantinovski, Y. Diskin-Posner, G. Leitus, L. J. W.
Shimon, D. Milstein, Organometallics 2010, 29, 3817;
g) D. Milstein, Top. Catal. 2010, 53, 915; h) B. Gnanap-
rakasam, Y. Ben-David, D. Milstein, Adv. Synth. Catal.
2010, 352, 3169; i) B. Gnanaprakasam, D. Milstein J.
Am. Chem. Soc. 2011, 133, 1682; j) C. Gunanathan, D.
Milstein, Acc. Chem. Res. 2011, 44, 588.
[9] a) C. Gunanathan, L. J. W. Shimon, D. Milstein, J. Am.
Chem. Soc. 2009, 131, 3146; b) C. Gunanathan, D. Mil-
stein, Angew. Chem. 2008, 120, 8789; Angew. Chem.
Int. Ed. 2008, 47, 8661.
[10] B. Gnanaprakasam, J. Zhang, D. Milstein, Angew.
Chem. 2010, 122, 1510; Angew. Chem. Int. Ed. 2010, 49,
1468.
[11] a) E. Balaraman, B. Gnanaprakasam, L. J. W. Shimon,
D. Milstein, J. Am. Chem. Soc. 2010, 132, 16756; b) E.
Balaraman, E. Fogler, D. Milstein, Chem. Commun.
21012, 48, 1111.
[12] E. Balaraman, Y. Ben-David, D. Milstein, Angew.
Chem. 2011, 123, 11906; Angew. Chem. Int. Ed. 2011,
50, 11702.
[1] R. C. Larock, in: Comprehensive Organic Transforma-
tions, VCH, New York, 1989; p 966 and references
cited therein.
[2] a) Comprehensive Organic Synthesis, (Eds.: B. M. Trost,
I. Fleming), Pergamon Press, New York, 1992; b) R. C.
Larock, in: Comprehensive Organic Transformations,
2nd edn., Wiley-VCH, New York, 1996; c) J. Otera, in:
Esterification Methods, Reactions and Applications,
Wiley-VCH, Weinheim, 2003.
[3] J. Otera, J. Nishikido, in: Esterification: Methods, Reac-
tions, and Applications; Wiley-VCH: Weinheim, Ger-
many, 2010.
[4] For reviews on transesterification, see: a) J. Otera,
Chem. Rev. 1993, 93, 1449; b) J. Otera, Acc. Chem. Res.
2004, 37, 288; c) G. A. Grasa, R. Singh, S. P. Nolan,
Synthesis 2004, 985; d) H. E. Hoydonckx, D. E. De Vos,
S. A. Chavan, P. A. Jacobs, Top. Catal. 2004, 27, 83.
[5] For selected examples, see: a) K. Ishihara, S. Ohara, H.
Yamamoto, Science 2000, 290, 1140; b) A. Corma, L. T.
Nemeth, M. Renz, S. Valencia, Nature 2001, 412, 423;
c) S. Gowrisankar, H. Neumann, M. Beller, Angew.
Chem. 2011, 123, 5245; Angew. Chem. Int. Ed. 2011, 50,
5139; d) C. Liu, J. Wang, L.-K. Meng, Y. Deng, Y. Li,
A.-W. Lei, Angew. Chem. 2011, 123, 5250; Angew.
Chem. Int. Ed. 2011, 50, 5144; e) X.-F. Wu, C. Darcel,
Eur. J. Org. Chem. 2009, 1144; f) T. Zweifel, J.-V. Nau-
bron, H. Grꢂtzmacher, Angew. Chem. 2009, 121, 567;
Angew. Chem. Int. Ed. 2009, 48, 559; g) A. Sakakura,
K. Kawajiri, T. Ohkubo, Y. Kosugi, K. Ishihara, J. Am.
Chem. Soc. 2007, 129, 14775; h) R. S. Reddy, J. N.
Rosa, L. F. Veiros, S. Caddick, P. M. P. Gois, Org.
Biomol. Chem. 2011, 9, 3126; i) R. Lerebours, C. Wolf,
J. Am. Chem. Soc. 2006, 128, 13052; j) Y. Leng, J.
Wang, D. Zhu, X.-Q. Ren, H.-Q. Ge, L. Shen, Angew.
Chem. 2009, 121, 174; Angew. Chem. Int. Ed. 2009, 48,
168; k) S.-I. Murahashi, T. Naota, K. Ito, Y. Maeda, H.
Taki, J. Org. Chem. 1987, 52, 4319; l) A. Sølvhøj, R.
Madsen, Organometallics 2011, 30, 6044; m) D. Spa-
syuk, S. Smith, D. G. Gusev, Angew. Chem. 2012, 124,
2826; Angew. Chem. Int. Ed. 2012, 51, 2772; n) E.
Kossoy, Y. Diskin-Posner, G. Leitus, D. Milstein, Adv.
Synth. Catal. 2012, 354, 497; o) A. Friedrich, S. Schneid-
[13] E. Balaraman, C. Gunanathan, J. Zhang, L. J. W.
Shimon, D. Milstein, Nature Chem. 2011, 3, 609.
[14] a) E. Ben Ari, G. Leitus, L. J. W. Shimon, D. Milstein,
J. Am. Chem. Soc. 2006, 128, 15390; b) M. Iron, E.
Ben-Ari, R. Cohen, D. Milstein, Dalton Trans. 2009
9433; c) E. Khaskin, M. A. Iron, L. J. W. Shimon, J.
Zhang, D. Milstein, J. Am. Chem. Soc. 2010, 132, 8542;
d) S. W. Kohl, L. Weiner, L. Schwartsburd, L. Konstan-
tinovski, L. J. W. Shimon, Y. Ben-David, M. A. Iron, D.
Milstein, Science 2009, 324, 74.
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Ruthenium Pincer-Catalyzed Cross-Dehydrogenative
Coupling of Primary Alcohols with Secondary Alcohols
under Neutral Conditions
5
Adv. Synth. Catal. 2012, 354, 1 – 5
Dipankar Srimani, Ekambaram Balaraman,
Boopathy Gnanaprakasam, Yehoshoa Ben-David,
David Milstein*
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
5
ÞÞ
These are not the final page numbers!