Regioselective hydroformylation of allylic alcohols

Article abstract of DOI:10.1021/ol200782d

A highly regioselective hydroformylation of allylic alcohols is reported toward the synthesis of β-hydroxy-acid and aldehyde products. The selectivity is achieved through the use of a ligand that reversibly binds to alcohols in situ, allowing for a directed hydroformylation to occur. The application to trisubstituted olefins was also demonstrated, which yields a single diastereomer product consistent with a stereospecific addition of CO and hydrogen.

Full text of DOI:10.1021/ol200782d

ORGANIC
LETTERS
2011
Vol. 13, No. 10
2686–2689
Regioselective Hydroformylation of
Allylic Alcohols
Thomas E. Lightburn, Omar A. De Paolis, Ka H. Cheng, and Kian L. Tan*
Boston College, Merkert Chemistry Center, Chestnut Hill, Massachusetts 02467-3860,
United States
kian.tan.1@bc.edu
Received March 24, 2011
ABSTRACT
A highly regioselective hydroformylation of allylic alcohols is reported toward the synthesis of β-hydroxy-acid and aldehyde products. The
selectivity is achieved through the use of a ligand that reversibly binds to alcohols in situ, allowing for a directed hydroformylation to occur. The
application to trisubstituted olefins was also demonstrated, which yields a single diastereomer product consistent with a stereospecific addition
of CO and hydrogen.
Hydroformylation is an efficient means of generating
aldehyde products through the three-component coupling
of CO, H2, and an olefin. Hydroformylation is a comme-
rical process used to synthesize millions of tons of aldehyde
products per year.1,2 The vast majority of these products
are linear aldehydes due to their importance in commodity
chemical synthesis. The more difficult formation of the
aldehyde at a branchedcarbon can be achieved by using (1)
a symmetrical olefin, (2) an electronically activated olefin,
and/or (3) an olefin containing a directing group.3
Although directing groups are highly effective at control-
ling regio- and stereoselectivity, this strategy is syntheti-
cally inefficient because the directing group, often
phosphorus-based,4 must be added and removed in two
additional synthetic steps and generates a stoichiometric
(3) (a) Breit, B.; Seiche, W. Synthesis 2001, 1, 1–36. (b) Rousseau, G.;
Breit, B. Angew. Chem., Int. Ed. 2011, 50, 2450–2494.
(1) (a) Rhodium Catalyzed Hydroformylation; van Leeuwen, P. W. N.
M., Claver, C., Eds.; Springer-Verlag: New York, 2002; Vol. 22. (b)
Frohning, C. D.; Kohlpainter, C. W.; Gaub, A.; Seidel, A.; Torrence,
P.; Heymanns, P.; Hohn, A.; Beller, M.; Knifton, J. F.; Klausener, A.;
Jentsch, J. D.; Tafesh, A. M. In Applied Homogeneous Catalysis with
Organometallic Compounds; Cornils, B., Herrmann, W. A., Eds.; Wiley:
Weinheim, 2002; Vol. 1, Chapter 2.
(4) For selected examples of phosphorus-based directing groups in
hydroformylation, see: (a) Burke, S. D.; Cobb, J. E.; Takeuchi, K.
J. Org. Chem. 1985, 50, 3420–3421. (b) Burke, S. D.; Cobb, J. E.; Takeuchi,
K. J. Org. Chem. 1990, 55, 2138–2151. (c) Jackson, W. R.; Perlmutter, P.;
Tasdelen, E. E. J. Chem. Soc., Chem. Commun. 1990, 10, 763–764. (d)
Jackson, W. R.; Perlmutter, P.; Tasdelen, E. E. Tetrahedron Lett. 1990,
31, 2461–2462. (e) Breit, B. Acc. Chem. Res. 2003, 36, 264–275. (f) Breit,
B.; Breuninger, D. J. Am. Chem. Soc. 2004, 126, 10244–10245. (g) Breit,
B.; Breuninger, D. Eur. J. Org. Chem. 2005, 18, 3916–3929. (h) Breit, B.;
Breuninger, D. Eur. J. Org. Chem. 2005, 18, 3930–3941. (i) Rein, C.;
Demel, P.; Outten, R. A.; Netscher, T.; Breit, B. Angew. Chem., Int. Ed.
2007, 46, 8670–8673. (j) Bruch, A.; Gebert, A.; Breit, B. Synthesis 2008,
14, 2169–2176. (k) Bigot, A.; Breuninger, D.; Breit, B. Org. Lett. 2008,
10, 5321–5324. (l) Breit, B.; Bigot, A. Chem. Commun. 2008, 48, 6498–
6500. (m) Laemmerhold, K. M.; Breit, B. Angew. Chem., Int. Ed. 2010,
49, 2367–2370. (n) Krauss, I. J.; Wang, C. C. Y.; Leighton, J. L. J. Am.
Chem. Soc. 2001, 123, 11514–11515.
(2) For recent examples of hydroformylation applications, see: (a)
Dydio, P.; Dzik, W. I.; Lutz, M.; de Bruin, B.; Reek, J. N. H. Angew.
Chem., Int. Ed. 2011, 50, 396–400. (b) Vasylyev, M.; Alper, H. Synthesis
2010, 17, 2893–2900. (c) Takahashi, K.; Yamashita, M.; Ichihara, T.;
Nakano, K.; Nozaki, K. Angew. Chem., Int. Ed. 2010, 49, 4488–4490. (d)
Simaan, S.; Marek, I. J. Am. Chem. Soc. 2010, 132, 4066–4067. (e) Gual,
A.; Godard, C.; Castillon, S.; Claver, C. Tetrahedron: Asymmetry 2010,
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Int. Ed. 2010, 49, 4047–4050. (g) McDonald, R. I.; Wong, G. W.;
Neupane, R. P.; Stahl, S. S.; Landis, C. R. J. Am. Chem. Soc. 2010,
132, 14027–14029. (h) Chercheja, S.; Nadakudity, S. K.; Eilbracht, P.
Adv. Synth. Catal. 2010, 352, 637–643. (i) Noonan, G. M.; Newton, D.;
Cobley, C. J.; Suarez, A.; Pizzano, A.; Clarke, M. L. Adv. Synth. Catal.
2010, 352, 1047–1054. (j) Sherrill, W. M.; Rubin, M. J. Am. Chem. Soc.
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nylation Reactions. Topics in Organometallic Chemistry; Spinger-VER-
LAG: Berlin, 2006; Vol. 18, pp 65À95.
(5) (a) Lightburn, T. E.; Dombrowski, M. T.; Tan, K. L. J. Am.
Chem. Soc. 2008, 130, 9210–9211. (b) Worthy, A. D.; Gagnon, M. M.;
Dombrowski, M. T.; Tan, K. L. Org. Lett. 2009, 11, 2764–2767. (c) Sun,
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r
10.1021/ol200782d
Published on Web 04/19/2011
2011 American Chemical Society

byproduct in the process. In Rh catalyzed hydroformyla-
tion we5 and others6 have reported a means of circumvent-
ing this problem by developing ligands that reversibly and
covalently bind to organic substrates.7 We have termed
these compounds as scaffolding ligands due to their func-
tional similarity to scaffolding proteins,8 which are a class
of proteins whose major role is to localize multiple proteins
in a functional cluster. An important function of our
scaffolding ligand is to bring together the substrate and
catalyst. This induced intramolecularity allows for both
acceleration of the reaction as well as control of regio- and
stereochemistry.9
We recently reported that ligand 1 can be used in the
hydroformylation of 1,1-disubstituted olefins with excel-
lent regioselectivity for the quaternary aldehyde product.5c
Herein we report the extension of the methodology to 1,2-di-
and trisubstituted olefins as an alternative to the formal-
dehyde aldol process.
We initially investigated the hydroformylation of a
cinnamyl alcohol. Similar to our observations in the
hydroformylation of 1,1-disubstituted olefins, we found
it necessary to oxidize the product in situ using Pinnick
conditions because the β-hydroxy aldehyde was found to
dimerize during hydroformylation.10 During our optimi-
zation studies we found that variation of the CO/H2
pressure shows little effect on the conversion or selectivity
(Table 1). Using 1 mol % Rh(acac)(CO)2 and 10 mol % 1
the expected β-hydroxyacid product is formed in 83%
isolated yield and with excellent regioselectivity (rs =
95:5, Table 1, entry 2). The selectivity is in contrast to
other reports of hydroformylation of cinnamyl alcohol
yielding the aldehdye R to the aromatic ring.11
Both electron-donating and -withdrawing groups were
tolerated in the reaction without affecting the regioselec-
tivity (Table 2, entries 1 and 2). Ortho substitution on the
aromatic ring led to excellent regioselectivity as well as an
increase in the isolated yield of the desired carboxylic acid
product(Table2, entry 3). Both E and Z olefins substituted
with alkyl groups afford the desired products with high
regioselectivities (Table 2, entries 4À7). The hydroformy-
lation of a substrate with a phthalimide group yields the γ-
amino acid product. Phthalimides are known directing
groups for Rh-catalyzed hydroformylation,2f,g so this
result demonstrates that our scaffolding ligand can over-
ride internal substrate chelating groups even when em-
ployed in catalytic quantities. Hydroformylation of a
monoprotected diol affords the desired product in good
regioselectivity and yield (Table 2, entry 9). The TBDPS
group was used to protect the alcohol because silyl migra-
tion was observed when a TBS group was used.
We also investigated the hydroformylation of
3-methylbut-2-en-1-ol, a less reactive trisubstituted
olefin. Increasing the catalyst loading (2 mol % Rh
and 20 mol % 1) and temperature (55 °C) affords the
desired product in good yield (85%, Scheme 1). Hydro-
formylation of trisubstituted olefins is generally a
challenging reaction that requires more forcing condi-
tions. Ligand 1 operates under relatively mild condi-
tions for these types of substrates, albeit using higher
Rh loadings, suggesting it is one of the more reactive
hydroformylation catalyst systems.12,13 Because the
insertion of the Rh hydride into the olefin occurs
through a syn addition, hydroformylation of trisub-
stituted olefins presents the opportunity for forming
two stereocenters in a stereospecific fashion. This was
Table 1. Pressure Optimizationa
pressure
(psi)
regioselectivity
conversion
(%)
entry
(2:3)
1
2
3
4
50
100
200
400
96:4
95:5
95:5
95:5
85
90 (83)b
89
88
a (i) 10 mol % 1, 1 mol % Rh(acac)(CO)2, 45 °C, CO/H2, 0.05 mol %
p-TsOH benzene; (ii) NaClO2, NaH2PO4, 2-methyl-2-butene, H2O/t-
BuOH. b Isolated yield of 2, and H2O2 used in place of 2-methyl-2-
butene.
€
(6) (a) Grunanger, C. U.; Breit, B. Angew. Chem., Int. Ed. 2008, 47,
€
7346–7349. (b) Grunanger, C. U.; Breit, B. Angew. Chem., Int. Ed. 2010,
49, 967–970. (c) Usui, I.; Nomura, K.; Breit, B. Org. Lett. 2011, 612–615.
(d) Rousseau, G.; Breit, B. Angew. Chem., Int. Ed. 2011, 50, 2450–2494.
(7) For examples of the use of reversible covalent interactions in other
metal-catalyzed reactions, see: (a) Lewis, L. N. Inorg. Chem. 1985, 24,
4433–4435. (b) Lewis, L. N.; Smith, J. F. J. Am. Chem. Soc. 1986, 108,
2728–2735. (c) Preston, S. A.; Cupertino, D. C.; Palma-Ramirez, P.;
Cole-Hamilton, D. J. J. Chem. Soc., Chem. Commun. 1986, 977–978. (d)
Iraqi, A.; Fairfax, N. R.; Preston, S. A.; Cupertino, D. C.; Irvine, D. J.;
Cole-Hamilton, D. J. J. Chem. Soc., Dalton Trans. 1991, 1929–1935. (e)
Park, Y. J.; Park, J. W.; Jun, C. H. Acc. Chem. Res. 2008, 41, 222–234. (f)
Bedford, R. B.; Coles, S. J.; Hursthouse, M. B.; Limmert, M. E. Angew.
Chem., Int. Ed. 2003, 42, 112–114. (g) Bedford, R. B.; Limmert, M. E.
J. Org. Chem. 2003, 68, 8669–8682. (h) Bedford, R. B.; Haddow, M. F.;
Webster, R. L.; Mitchell, C. J. Org. Biomol. Chem. 2009, 7, 3119–3127.
(i) Oi, S.; Watanabe, S. I.; Fukita, S.; Inoue, Y. Tetrahedron Lett. 2003,
44, 8665–8668. (j) Carrion, M. C.; Cole-Hamilton, D. J. Chem. Commun.
2006, 4527–4529. (k) Lewis, J. C.; Wu, J.; Bergman, R. G.; Ellman, J. A.
Organometallics 2005, 24, 5737–5746.
(10) Boeckman, R. K.; Miller, J. R. Org. Lett. 2009, 11, 4544–4547.
(11) Nozaki, K.; Li, W.; Horiuchi, T.; Takaya, H. Tetrahedron Lett.
1997, 38, 4611–4614. Also see ref 2g.
(12) For examples of hydroformylation of trisubstituted olefins, see:
(a) da Silva, J. G.; Barros, H. J. V.; Balanta, A.; Bolanos, A.; Novoa,
M. L.; Reyes, M.; Contreras, R.; Bayon, J. C.; Gusevskaya, E. V.; dos
Santos, E. N. Appl. Catal., A 2007, 326, 219–226. (b) Clarke, M. L.; Roff,
G. L. Chem.;Eur. J. 2006, 12, 7978–7986. (c) Breit, B.; Winde, R.;
Mackewitz, T.; Paciello, R.; Harms, K. Chem.;Eur. J. 2001, 7, 3106–
3121. (d) Siegel, H.; Himmele, W. Angew. Chem., Int. Ed. 1980, 19, 178–
183. (e) Himmele, W.; Siegel, H. Tetrahedron Lett. 1976, 17, 907–910.
(13) For examples of hydroformylation of trisubstituted olefins using
(8) (a) Sheng, M.; Sala, C. Annu. Rev. Neurosci. 2001, 24, 1–29. (b)
Bhattacharyya, R. P.; Remenyi, A.; Yeh, B. J.; Lim, W. A. Annu. Rev.
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€
a stoichiometric phosphine directing group, see: Breit, B; Gruanger,
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Org. Lett., Vol. 13, No. 10, 2011
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Table 2. Regioselective Hydroformylation of Allylic Alcohols
a (i) 1 mol % Rh(acac)(CO)2, 10 mol % 1, 45 °C, 50 psi CO/H2, 0.0125 mol % p-TsOH; (ii) NaClO2, NaH2PO4, 2-methyl-2-butene, H2O/t-BuOH.
b Reaction performed 2 mol % Rh(acac)(CO)2, 20 mol % 1, 0.025 mol % p-TsOH. c Reaction performed at 35 °C and 200 psi CO/H2 d Reaction
performed at 35 °C, 200 psi CO/H2, 0.025 mol % pTsOH e Reaction performed at 45 °C, 100 psi CO/H2, 0.025 mol % p-TsOH. f Reaction performed with
0.2 mol % p-TsOH, 100 psi CO/H2. g Regioselectivities were determined by taking the crude 1H NMR after oxidation. The authentic lactone products
were independently synthesized and characterized by performing the hydroformylation with PPh3 as the ligand.
In order to extend the synthetic utility of the hydro-
formylation reaction we investigated methods of isolating
the product in the aldehyde oxidation state. This is readily
Scheme 1. Hydroformylation of Trisubstituted Olefins
achieved by forming the acetal of the product immediately
following hydroformylation. Reaction of cinnamyl al-
cohol and subsequent protection with pinacol affords
the acetal in 86% yield, and the selectivity is consistent
with the oxidation results (Scheme 2, eq 1). These
modified conditions also allowed for the hydroformyla-
tion of diene 4. Previous attempts to hydroformylate and
oxidize 4 resulted in a complex mixture of products.
Using the acetal protection conditions the olefin prox-
imal to the alcohol reacts selectively affording the de-
sired product in 84% yield (Scheme 2, eq 2). This
procedure was also used in the hydroformylation of allyl
alcohol, which formed the desired product in 80% yield
(rs = 87:13, Scheme 2, eq 3).
An attractive feature of hydroformylation is that it is an
atom economical reaction such that no byproducts
are formed. In order to improve the synthetic utility of
our method, we reoptimized the reaction conditions
focusing on lowering the catalyst and ligand loadings
as well as improving the volume efficiency. Under
the optimal conditions the concentration of the reaction
is increased from 0.1 to 0.5 M, while the rhodium
confirmed through the hydroformylation of both
E- and Z-3-methyloct-2-en-1-ol which form single
diastereomers as the sole products (Scheme 1).14
(14) The 1H and 13C NMR show that the products are nonidentical
(see Supporting Information for details). Based on a syn addition of
hydrogen and CO the E-olefin will form the anti product and the
Z-olefin will form the syn product.
2688
Org. Lett., Vol. 13, No. 10, 2011

slight decrease in the isolated yield (83% vs 86%,
Scheme 2, eq 4).
Scheme 2. Acetal Protection of Hydroformylation Products
In summary we have demonstrated that our scaffolding
strategycan beextended tothe hydroformylation of 1,2-di-
and trisubstituted olefins, providing an alternative discon-
nection to the formaldehyde aldol reaction. These reac-
tions are performed under mild conditions and yield highly
regioselective reactions. The extension to trisubstituted
olefins under mild conditions allows the generation of
two stereocenters in a stereospecific fashion. Furthermore,
we have improved the practicality of the reaction by
reducing the ligand and catalyst loading as well as increas-
ing the concentration of the reaction. We are currently
investigating enantioselective variants of this transforma-
tion and are continuing to develop ligands with increased
reactivity and stability.
Acknowledgment. We thank the ACS-PRF (DNI-
5001400) and NIGMS (RO1GM087581) for funding this
project. Mass spectrometry instrumentation at Boston
College is supported by funding from the NSF (DBI-
0619576).
Supporting Information Available.
Experimental
loading is reduced to 0.5 mol % and the ligand loading
to 5 mol %. Under the modified conditions the same
regioselectivity is observed in the reaction with only a
details, compound characterization. This material is
available free of charge via the Internet at http://
pubs.acs.org.
Org. Lett., Vol. 13, No. 10, 2011
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