Rhodium-catalyzed hydroformylation of alkynes employing a self-assembling ligand system

Article abstract of DOI:10.1039/c3sc50725d

Hydroformylation of alkynes is an underdeveloped atom-economic and redox-neutral method to prepare enals. Applying a new electron poor self-assembling ligand system provides the first general rhodium-catalyst for the chemo- and stereoselective hydroformylation of dialkyl- as well as diaryl-substituted alkynes to furnish enals in excellent chemo- and stereoselectivity.

Full text of DOI:10.1039/c3sc50725d

Chemical Science
View Article Online
View Journal
EDGE ARTICLE
Rhodium-catalyzed hydroformylation of alkynes
employing a self-assembling ligand system†
Cite this: DOI: 10.1039/c3sc50725d
*
Vladislav Agabekov, Wolfgang Seiche and Bernhard Breit
Received 15th March 2013
Accepted 11th April 2013
Hydroformylation of alkynes is an underdeveloped atom-economic and redox-neutral method to prepare
enals. Applying a new electron poor self-assembling ligand system provides the first general rhodium-
catalyst for the chemo- and stereoselective hydroformylation of dialkyl- as well as diaryl-substituted
alkynes to furnish enals in excellent chemo- and stereoselectivity.
DOI: 10.1039/c3sc50725d
www.rsc.org/chemicalscience
The hydroformylation of olens is one of the most important
Early studies on the hydroformylation of alkynes found that
industrial applications of homogeneous catalysis with about 9 the reaction occurred with poor chemoselectivity and low
million tons of oxo products produced annually. From a yields because the formation of hydrogenated products could
synthetic point of view, this reaction is highly attractive due to not be suppressed.12 During the past two decades, more effi-
its intrinsic atom economy, enabling the functionalization of an cient catalysts have been reported such as the rhodium/
alkene through carbon–carbon bond formation employing Biphephos system introduced by Buchwald et al.13 This catalyst
synthesis gas as an inexpensive carbon source.1 The aldehydes allows chemoselective hydroformylation of symmetrical dia-
generated are valuable intermediates that enable synthetic lkyl-substituted alkynes. However, with diaryl-substituted
transformations, and can even be used in tandem reactions.2 alkynes poor chemoselectivity is observed due to alkyne hydro-
Even though the hydroformylation reaction celebrates its 75th genation.
anniversary this year, being discovered in 1938 by Otto Roelen,3
many selectivity issues remain to be solved to unravel its full developed by Hidai et al.14 required harsh reaction conditions
synthetic potential. and suffered from chemoselectivity problems (hydrogenation)
A
heterobimetallic catalyst [PdCl2(PCy3)2]/[Co2(CO)8]
Inspired by DNA-base pairing, we have developed self- as well as problems with E/Z-selectivity. Alper and Van den
assembling bidentate ligand systems relying on complementary
hydrogen bonding. In particular, ligands based on the pyr-
idone/hydroxypyridine tautomer system form highly active and
regioselective rhodium catalysts for linear regioselective alkene
hydroformylation (Scheme 1).4 These catalysts enable extraor-
dinarily mild reaction conditions (ambient pressure and room
temperature) to be used,5 which has led to their application in
natural product synthesis.6
While hydroformylation of alkenes has been widely studied,
the corresponding hydroformylation of alkynes is less devel-
oped.7 Despite this, direct alkyne hydroformylation offers an
atom and redox economic approach for the production of
synthetically versatile enals.8 Most known synthetic approaches
employ either reduction and/or oxidation steps which are not
redox efficient.9,10 An exception is the elegant ruthenium-cata-
lyzed redox neutral isomerization of propargylic alcohols to
enals developed by Trost and Livingston (Scheme 2).11
¨
¨
Institut fur Organische Chemie, Albert-Ludwigs-Universitat Freiburg, Albertstrasse 21,
79104 Freiburg, Germany. E-mail: bernhard.breit@chemie.uni-freiburg.de; Fax: +49-
761-203 8715
† Electronic supplementary information (ESI) available: Experimental procedures
and detailed characterization data for all new compounds. CCDC 923423 and
923424. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c3sc50725d
Scheme 1 Self-assembling catalyst systems for the hydroformylation of alkenes
and alkynes.
This journal is ª The Royal Society of Chemistry 2013
Chem. Sci.

View Article Online
Chemical Science
Edge Article
Pleasingly, applying the para-uoro-substituted ligand L2, a
tenfold increase in catalyst activity compared to the 6-DPPon
ligand L1 was noted (Table 1, entry 3). Increasing the electron
withdrawing strength further (L3, L4) led to a further increase
in catalyst activity (entries 4 and 5), with ligand L4 providing
the most active catalyst. This new catalyst system is twice as
active as the best described previously (rhodium/Biphephos,
entry 6).13
Increasing the temperature to 55 ꢀC allowed the chemo- and
stereoselective hydroformylation of different dialkyl substituted
alkynes, including 2-butyne, to give the corresponding E-enals
2a–d in good to excellent yields (Table 2).
We next turned our attention to the challenging diary-
lalkynes. The hydroformylation of tolane (4a) was studied rst.
The rhodium/Biphephos system gave complete conversion,
however, a mixture of products was obtained (Scheme 3). In
addition to the desired enal 5a (58%), the corresponding satu-
rated aldehyde (14%) and cis-stilbene 6a (28%) were formed.
Conversely, employing our self-assembly ligand L4 under
otherwise identical conditions, the desired enal 5a was obtained
in 93% yield, while enal and alkyne hydrogenation were largely
suppressed (Scheme 3).
Scheme 2 Synthetic pathways to enals.
Hoven15 used
a zwitterionic rhodium/triphenylphosphite
complex to allow the selective hydroformylation of thiophenyl
substituted alkynes. However, a catalyst that enables chemo-
and stereoselective hydroformylation of diarylalkynes and
terminal arylalkynes is unknown.
We herein report that new electron-poor self-assembling
ligands (L2–L4, Scheme 1) based on the pyridone/hydroxypyr-
idine platform furnish a highly active rhodium catalyst that
enables the chemo- and stereoselective hydroformylation of
dialkyl-, diarylalkynes to produce E-enals in good to excellent
yields.
We commenced our investigation by studying the hydro-
formylation of 4-octyne. While rhodium catalysts derived from
triphenylphosphine did not show any reactivity under the
reaction conditions chosen, the 6-DPPon (L1) derived catalyst
furnished the desired enal with low conversion but high chemo-
and stereoselectivity (Table 1, entries 1 and 2). In order to
increase the catalyst activity, we speculated, whether analogous
to alkene hydroformylation, increasing the ligand’s p-acceptor
ability may increase the catalyst activity.1 We therefore prepared
and tested the acceptor substituted 6-DPPon ligands L2–L4
(Scheme 1).†
Table 2 Hydroformylation of symmetrical aliphatic substituted internal alkynesa
Table 1 Hydroformylation of 4-octyne (1a)a
a
Reaction conditions: CO/H2 (1 : 1) 5 bar, [Rh(CO)2acac]/L4/1a–d ¼
1 : 3 : 100 in 2 ml toluene, c0(1a–d) ¼ 0.6 M, 20 h at 55 ꢀC. The
conversion and product ratio were determined by GC and/or 1H-NMR
spectroscopy.
Entry
L
Conv. (%)c
2a : 3ac
1
2
3
4
PPh3
6-DPPon (L1)
L2
L3
0
2
20
54
95
51
— : —
100 : 0
100 : 0
98 : 2
97 : 3
95 : 5
5
L4
6b
Biphephos
a
Reaction conditions: CO/H2 (1 : 1) 5 bar, [Rh(CO)2acac]/L/4-octyne (1a)
b
¼ 1 : 3 : 100 in 2 ml toluene, c0(1a) ¼ 0.6 M, 20 h at 50 ꢀC. Reaction
conditions: CO/H2 (1 : 1)
5
bar, [Rh(CO)2acac]/L/4-octyne (1a)
¼
c
1 : 1.5 : 100 in 2 ml toluene, c0(1a) ¼ 0.6 M, 20 h at 55 ꢀC. The
conversion and 2a : 3a product ratio were determined by GC and/or
1H-NMR spectroscopy. 6-DPPon ¼ 6-diphenylphosphinopyridin-2(1H)-
one.
Scheme 3 Hydroformylation of tolane with rhodium/Biphephos and rhodium/
L4 catalysts.
Chem. Sci.
This journal is ª The Royal Society of Chemistry 2013

View Article Online
Edge Article
Chemical Science
Table 3 Hydroformylation of symmetrical aryl substituted internal alkynesa
To explore the generality of our catalyst for diarylalkyne
hydroformylation,
a series of diarylalkynes obtained via
Sonogashira coupling,16 was subjected to hydroformylation.
We were pleased to nd that on applying our rhodium/L4
catalyst all alkynes underwent efficient hydroformylation to
furnish the corresponding diaryl-substituted E-enals in gener-
ally excellent yields (Table 3). Alkyne hydrogenation was mostly
suppressed.
Only with electron poor aryl substituents was the amount of
hydrogenation product signicant (4l). Pleasingly, aryl
bromides are tolerated, allowing for subsequent derivatization.
The constitution and conguration of the enals were deter-
mined by NMR spectroscopy, and unambiguously conrmed in
two cases (5a and 5i) by X-ray crystallography.†
We also investigated the hydroformylation of terminal ary-
lacetylenes, which have never been successfully hydro-
formylated before. Subjection of terminal alkynes 7a–c to our
hydroformylation conditions provided for the rst time the
corresponding E-enals 8a–c in fair to good yields (Table 4). The
enals could be separated via chromatography from other side
products (saturated aldehydes, for details see the ESI†). In
particular enal 8c is of interest since it can be used for the
synthesis of the natural product boropinol B (Scheme 4).17
Boropinol B has been isolated from the dried roots of the
plant Boronia pinnata. Extracts from this plant, along with
boropinol B, contained a number of other phenylpropanoide
compounds displaying an inhibitory effect on tumor-promotion
as well as signicant inhibitory effects on Eppstein–Barr virus
early antigen (EBV-EA) activation.17
Our synthesis commenced from the commercially available
aryl iodide 9. Sonogashira cross coupling with TMS-acetylene
furnished alkyne 10. TMS-deprotection and hydroformylation
gave enal 8c in 62% isolated yield. Luche reduction of the
aldehyde and etherication yielded boropinol B, which repre-
sents its rst total synthesis.
In conclusion, we have reported the rst general catalyst for
the chemo- and stereoselective hydroformylation of dialkyl- as
well as diaryl-substituted alkynes. Furthermore, for the rst
time terminal alkynes could be reacted to furnish E-enals in
Table 4 Hydroformylation of terminal aryl substituted alkynesa
a
Reaction conditions: CO/H2 (1 : 1) 5 bar, [Rh(CO)2acac]/L4/4a–n ¼
1 : 3 : 200 in 2 ml toluene, c0(4a–n) ¼ 0.6 M, 20 h at 55 ꢀC. The
conversion and product ratio were determined by GC and/or 1H-NMR
spectroscopy.
a
Reaction conditions: CO/H2 (1 : 1) 5 bar, [Rh(CO)2acac]/L4/7a–c ¼
1 : 3 : 100 in 2 ml toluene, c0(7a–c) ¼ 0.6 M, 20 h at 55 ꢀC. The
conversion was determined by GC and/or 1H-NMR spectroscopy.
This journal is ª The Royal Society of Chemistry 2013
Chem. Sci.

View Article Online
Chemical Science
Edge Article
S. K. Nadakudity and P. Eilbracht, Adv. Synth. Catal., 2010,
¨
352, 637–643; (g) S. Chercheja, T. Rothenbucher and
P. Eilbracht, Adv. Synth. Catal., 2009, 351, 339–344; (h)
K. Takahashi, M. Yamashita, T. Ichihara, K. Nakano and
K. Nozaki, Angew. Chem., 2010, 122, 4590–4592; Angew.
Chem., Int. Ed., 2010, 49, 4488–4490; (i) J. Stiller,
A. J. Vorholt, K. A. Ostrowski, A. Behr and M. Christmann,
Chem.–Eur. J., 2012, 18, 9496–9499; (j) D. Fuchs,
G. Rousseau, L. Diab, U. Gellrich and B. Breit, Angew.
Chem., 2012, 124, 2220–2224; Angew. Chem., Int. Ed., 2012,
51, 2178–2182.
3 (a) O. Roelen, Chem. Abs., 1944, 38, 550; Patent DE, 849 548;
Patent US 2 327 066; (b) for a review, see: B. Cornils,
W. A. Herrmann and M. Rasch, Angew. Chem., 1994, 106,
2219–2238; Angew. Chem., Int. Ed. Engl., 1994, 33, 2144.
4 (a) B. Breit and W. Seiche, J. Am. Chem. Soc., 2003, 125, 6608–
6609; (b) B. Breit and W. Seiche, Angew. Chem., 2005, 117,
1666–1669; Angew. Chem., Int. Ed., 2005, 44, 1640–1643; (c)
C. Waloch, J. Wieland, M. Keller and B. Breit, Angew.
Chem., 2007, 119, 3097–3099; Angew. Chem., Int. Ed., 2007,
46, 3037–3039; (d) U. Gellrich, W. Seiche, M. Keller and
B. Breit, Angew. Chem., 2012, 124, 11195–11200; Angew.
Chem., Int. Ed., 2012, 51, 11033–11038; (e) for a review, see:
B. Breit, Angew. Chem., 2005, 117, 6976–6986; Angew.
Chem., Int. Ed., 2005, 44, 6816–6825.
Scheme 4 Synthesis of boropinol B.
preparatively useful amounts. This has enabled a short and
efficient rst total synthesis of boropinol B.
5 W. Seiche, A. Schuschkowski and B. Breit, Adv. Synth. Catal.,
2005, 347, 1488–1494.
Acknowledgements
6 H. H. Jung, J. R. Seiders II and P. E. Floreancig, Angew. Chem.,
2007, 119, 8616–8619; Angew. Chem., Int. Ed., 2007, 46, 8464–
8467.
This work was supported by the DFG, the International
Research Training Group “Catalysts and Catalytic Reactions for
Organic Synthesis” (IRTG 1038) and the Krupp Foundation. We
thank Umicore, BASF and Wacker for generous gis of chem-
icals. We also thank Andreas Filippi for technical support, Dr
Manfred Keller for solution of the X-ray crystal structure and Dr
´
´
7 S. Castillon and E. Fernandez, in Rhodium Catalysed
Hydroformylation, ed. P. W. N. M. van Leeuwen and
C. Claver, Kluwer, Dordrecht, 2000, pp. 178–182.
8 I. Escher and F. Glorius, in Science of Synthesis – Houben-Weyl
¨
Jorg Wieland for preliminary experiments.
¨
Methods of Organic Chemistry, ed. R. Bruckner, Thieme,
Stuttgart, New York, 2007, vol. 25, pp. 733–777.
9 For recent reviews on redox economy see: (a) N. Z. Burns,
P. S. Baran and R. W. Hoffmann, Angew. Chem., 2009, 121,
2896–2910; Angew. Chem., Int. Ed., 2009, 48, 2854–2867; (b)
T. Newhouse, P. S. Baran and R. W. Hoffmann, Chem. Soc.
Rev., 2009, 38, 3010–3021.
Notes and references
¨
1 (a) R. Franke, D. Selent and A. Borner, Chem. Rev., 2012, 112,
5675–5732; (b) B. Breit, Top. Curr. Chem., 2008, 279, 139–172;
(c) B. Breit, in Science of Synthesis – Houben-Weyl Methods of
¨
Organic Chemistry, ed. R. Bruckner, Thieme, Stuttgart, New
York, 2007, vol. 25, pp. 277–317; (d) K. Weissermel and 10 (a) For a tandem directed regioselective hydroformylation/b-
H.-J. Arpe, Industrial Organic Chemistry, Wiley-VCH,
Weinheim, 2003, pp. 127–144; (e) B. Breit and W. Seiche,
elimination reaction for the synthesis of 1,1-di- and
trisubstituted enals see: A. Bruch, A. Gebert and B. Breit,
Synthesis,
2001,
1–36;
(f)
Rhodium
Catalyzed
Synthesis, 2008, 2169–2176; (b) for
a
synthesis of
Hydroformylation, ed. P. W. N. M. van Leeuwen and C.
Claver, Kluwer Academic Publ., Dordrecht, 2000.
trisubstituted allylic alcohols by alkyne hydrohydroxy-
methylation with formaldehyde see: C. C. Bausch,
R. L. Patman, B. Breit and M. J. Krische, Angew. Chem., 2011,
123, 5805–5808; Angew. Chem., Int. Ed., 2011, 50, 5687–5690.
¨
2 (a) P. Eilbracht, L. Barfacker, C. Buss, C. Hollmann,
B. E. Kitsos-Rzychon, C. L. Kranemann, T. Rische,
R. Roggenbuck and A. Schmidt, Chem. Rev., 1999, 99, 11 B. M. Trost and R. C. Livingston, J. Am. Chem. Soc., 1995, 117,
3329–3365; (b) B. Breit and S. K. Zahn, Angew. Chem., 1999,
9586–9587.
111, 1022–1024; Angew. Chem., Int. Ed., 1999, 38, 969–971; 12 (a) B. Fell and M. Beutler, Tetrahedron Lett., 1972, 13, 4285–
(c) S. K. Zahn and B. Breit, Angew. Chem., 2001, 113, 1964–
1967; Angew. Chem., Int. Ed., 2001, 40, 1910–1913; (d)
4288; (b) C. Botteghi and C. Salomon, Tetrahedron Lett., 1974,
15, 4285–4288.
O. Abillard and B. Breit, Adv. Synth. Catal., 2007, 349, 13 J. R. Johnson, G. D. Cuny and S. L. Buchwald, Angew. Chem.,
¨
1891–1895; (e) P. Kohling, A. M. Schmidt and P. Eilbracht,
1995, 107, 1877–1879; Angew. Chem., Int. Ed. Engl., 1995, 34,
Org. Lett., 2003, 5, 3213–3216; (f) S. Chercheja,
1760.
Chem. Sci.
This journal is ª The Royal Society of Chemistry 2013

View Article Online
Edge Article
Chemical Science
14 Y. Ishii, K. Miyashita, K. Kamita and M. Hidai, J. Am. Chem. 16 M. J. Mio, L. C. Kopel, J. B. Braun, T. L. Gadzikwa, K. L. Hull,
Soc., 1997, 119, 6448–6449.
15 (a) B. G. Van den Hoven and H. Alper, J. Org. Chem., 1999, 64,
R. G. Brisbois, C. J. Markworth and P. A. Grieco, Org. Lett.,
2002, 4, 3199–3202.
3964–3968; (b) B. G. Van den Hoven and H. Alper, J. Org. 17 C. Ito, M. Itoigawa, T. Otsuka, H. Tokuda, H. Nishino and
Chem., 1999, 64, 9640–9645.
H. Furukawa, J. Nat. Prod., 2000, 63, 1344–1348.
This journal is ª The Royal Society of Chemistry 2013
Chem. Sci.