Catalytic scaffolding ligands: An efficient strategy for directing reactions

Article abstract of DOI:10.1021/ja803011d

The design and application of a scaffolding ligand that promotes branch and diastereoselective hydroformylation of terminal olefins as well as the regio- and diastereoselective hydroformylation of disubstituted olefins is reported. It is shown that the ligand covalently and reversibly bonds to the substrate, allowing for directed hydroformylation. As the substrate ligand interaction is dynamic, hydroformylations are catalytic in ligand and do not require any additional synthetic steps to add or remove the directing group. Using a catalytic quantity of a scaffolding ligand (20-25 mol %), excellent regioselectivity for disubstituted olefins (up to 98:2) and high branch selectivity (up to 88:12) for terminal olefins were obtained. Copyright

Full text of DOI:10.1021/ja803011d

Published on Web 06/25/2008
Catalytic Scaffolding Ligands: An Efficient Strategy for Directing Reactions
Thomas E. Lightburn, Michael T. Dombrowski, and Kian L. Tan*
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467
Received April 23, 2008; E-mail: kian.tan.1@bc.edu
Scheme 1. Mechanism of Catalytic Scaffold-Directed Reactions
In organic synthesis, directing groups are used to control selectivity
in a range of reactions from asymmetric epoxidation to C-H
activation.1,2 Ideally, a directing group serves as an efficient ligand as
well as a functional group handle for future synthetic steps.3 The
structural requirements for these two features are often at odds with
each other and require chemical transformations to convert the
“functional group” into a “directing group” and vice versa. Inspired
by the work in the area of C-H functionalization,4 we have designed
a scaffolding ligand that simultaneously and reversibly binds alcohol
substrates, as well as a metal-based catalyst (Scheme 1). Consequently,
the directed reaction can be performed with a catalytic amount of
ligand, and we are able to tune the ligand for efficient catalysis without
haVing to change the nature of the substrate. Herein, we applied this
strategy to the challenging problem of branch-selective hydroformyla-
tion.3b,5 Using a catalytic quantity of a scaffolding ligand (20-25 mol
%), we obtained excellent regioselectivity for disubstituted olefins (up
to 98:2) and high branch selectivity (up to 88:12) for terminal olefins.
Current methods for performing branch-selective hydroformylation
include modifying the olefin substrate electronically to favor C-C bond
formation at the more substituted site of terminal alkenes.6 Another
approach is to use phosphorus-based auxiliary directing groups, which
can deliver high regio-, diastereo-, and enantioselectivity.3b,7 Most
recently, supramolecular catalysts have been introduced to address this
problem; however, this approach gives rise to only moderate levels of
branch selectivity (branched:linear of 67:33).8
Scheme 2. Synthesis of Scaffolding Ligands 2a-c
Our investigation began with the synthesis of scaffolding ligands
2a-c (Scheme 2). Starting from N-methylaniline, ligand 2a is
synthesized in a three-step sequence that requires no column chroma-
tography, making it amenable to large-scale synthesis.9 The ligand is
isolated as one major diastereomer (as judged by 1H and 31P NMR).10
An X-ray crystal structure of 2b confirmed that the stereochemistry
of the ligand was anti.
Table 1. Optimization of Branch-Selective Hydroformylationa
Synthesis of 2b and 2c is achieved by mixing 2a with the appropriate
alcohol and 1 mol % of p-TsOH. The mild conditions under which
this reaction occurs suggest that exchange of alcohols is facile.
Equilibration occurs with primary, secondary, and even tertiary alcohols
at 45 °C with catalytic acid (as monitored by 1H and 31P NMR
spectroscopy, eq 1).11 The Keq depends largely on the sterics of the
alcohol, with isopropanol showing a 10-fold decrease in binding to
the ligand as compared to methanol, and tert-butanol exhibiting >100-
fold change.12
entry
ligand
rrb
dr (4:5)
yield (%)
1
4% PPh3
20% 2a
20% 2b
20% 2c
5% 2b
25:75
81:19
84:16
84:16
60:40
77:23
42:58
88:12
88:12
88:12
79:21
85:15
>98
80
>98
92
53
71
2c
3c
4c
5
6
10% 2b
a Yields and selectivities determined by GC using hexamethylbenzene
as an internal standard; reaction time 16 h; see Supporting Information
for experimental details. b rr ) ratio of five- to six-membered ring
lactones. c Yields and selectivities are an average of two runs.
Having established that the ligand reversibly exchanges with
alcohols, we tested 2 as a ligand in the hydroformylation of terminal
olefin 3.13 When reactions are performed with PPh3 as a control ligand,
75:25 regioselectivity favoring lactone 6 is observed (Table 1, entry
1). Furthermore, the γ-lactone formed as the minor regioisomer is
obtained as a mixture of diastereomers. Application of 2a leads to a
reversal in the regioselectivity and a significant enhancement of the
diastereoselectivity (88:12) in favor of anti-4 (Table 1, entry 2).14 Use
of 2b improves the yield of the reaction (Table 1, entry 3); this is
likely due to an increase in the concentration of the substrate-bound
ligand since free isopropanol competes less effectively for binding to
the ligand than methanol. Use of 2c results in a decrease in yield (Table
1, entry 4). This result may be due in part to decreased stability of the
9
9210 J. AM. CHEM. SOC. 2008, 130, 9210–9211
10.1021/ja803011d CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Evaluation of Substrates in the Hydroformylation
Reaction
this hypothesis, we investigated the reaction of a Z-disubstituted olefin.
As shown in entry 6 of Table 2, this hydroformylation proceeds with
excellent diastereoselectivity (>98:2) and regioselectivity (98:2).
Concerned that these high selectivities may be unique to a substrate
that bears an allylic phenyl group, the transformation in entry 7 of
Table 2 was performed: even with the small methyl group, excellent
regio- and diastereoselectivity is observed. Consistent with the
importance of A1,3-strain, there is diminished diastereoselectivity in
the catalytic hydroformylation of the E olefin (Table 2, entry 8).
In summary, we have achieved branch-selective hydroformylation
through the use of an appropriately designed scaffolding ligand. We
are currently developing this concept to include other functional groups
as well as synthesizing enantioenriched ligands for applications to
asymmetric catalysis. We plan to implement this strategy toward the
development of catalytic processes.
Acknowledgment. We thank Dr. Bo Li for determining the
X-ray structure for 2b. We thank Jillian Thayer for experimental
assistance. We also thank Boston College for providing funding
for this research project.
Supporting Information Available: Experimental details and
compound characterization, cif file of 2b. This material is available
free of charge via the Internet at http://pubs.acs.org.
References
(1) For a review on substrate-directed reactions, see: Hoveyda, A. H.; Evans,
D. A.; Fu, G. C. Chem. ReV. 1993, 93, 1307.
(2) For reviews on directed C-H functionalization, see: (a) Ritleng, V.; Sirlin,
C.; Pfeffer, M. Chem. ReV. 2002, 102, 1731. (b) Kakiuchi, F.; Murai, S.
Acc. Chem. Res. 2002, 35, 826. (c) Dick, A.; Sanford, M. Tetrahedron
2006, 62, 2439. (d) Kakiuchi, F.; Chatani, N. AdV. Synth. Catal. 2003,
345, 1077.
(3) For examples of removable directing groups in late-metal-catalyzed
reactions, see ref 1 and: (a) Breit, B.; Seiche, W. Synthesis 2001, 1, 1. (b)
Itami, K.; Yoshida, J. Synlett 2006, 2, 157. (c) Oestreich, M. Eur. J. Org.
Chem. 2005, 5, 783.
(4) For examples of catalytic directing groups in C-H functionalization
reactions, see: (a) Lewis, L. N.; Smith, J. F. J. Am. Chem. Soc. 1986, 108,
2728. (b) Park, Y. J.; Park, J. W.; Jun, C. H. Acc. Chem. Res. 2008, 41,
222. (c) Jun, C.; Moon, C.; Lee, D. Chem.sEur. J. 2002, 8, 2423. (d)
Bedford, R. B.; Betham, M.; Caffyn, A.; Charmant, J.; Lewis-Alleyne, L.;
Long, P.; Polo-Ceron, D.; Prashar, S. Chem. Commun. 2008, 990. (e)
Bedford, R.; Limmert, M. J. Org. Chem. 2003, 68, 8669. (f) Lewis, J.;
Wu, J.; Bergman, R.; Ellman, J. Organometallics 2005, 24, 5737.
(5) For leading references on hydroformylation, see: (a) Rhodium Catalyzed
Hydroformylation; Van Leeuwen, P. W. N. M., Claver, C., Eds.; Springer-
Verlag: New York, 2002. (b) Frohning, C. D. Kohlpaintner, C. W. Bohnen,
H. W. In Applied Homogeneous Catalysis with Organometallic Compounds;
Cornils, B., Herrmann, W. A., Eds.; Wiley: Weinheim, Germany, 2002;
Vol. 1, p 31.
(6) For reviews of branched hydroformylation in asymmetric catalysis, see:
(a) Agbossou, F.; Carpentier, J.; Mortreaux, A. Chem. ReV. 1995, 95, 2485.
(b) Diegeuz, M.; Pamies, O.; Claver, C. Tetrahedron: Asymmetry 2004,
15, 2113. (c) Claver, C.; Dieguez, M.; Pamies, O.; Castillon, S. Top.
Organomet. Chem. 2006, 18, 35. (d) Klosin, J.; Landis, C. R. Acc. Chem.
Res. 2007, 40, 1251.
a Unless otherwise noted, isolated yield of all lactone products.
b Regio- (five- to six-membered lactones) and diastereoselectivities
(anti:syn) were determined by GC of the crude reaction mixtures;
reaction time 16 h. c With 2 mol % of Rh(acac)(CO)2, benzene, 200 psi
CO/H2, 20 mol % of 2b, 45 °C, 0.2 mol % of p-TSA; PCC, NaOAc, 3
Å sieves. d With 2 mol % of Rh(acac)(CO)2, 4 mol % of PPh3, benzene,
200 psi CO/H2, 45 °C; PCC, NaOAc, 3 Å sieves. e With 6 mol % of
Rh(acac)(CO)2, benzene, 200 psi CO/H2, 25 mol % of 2b, 65 °C, 0.2
mol % of p-TSA; PCC, NaOAc, 3 Å sieves. f Isolated yield of only
five-membered ring lactones. g With
6 mol % of Rh(acac)(CO)2,
benzene, 200 psi CO/H2, 12 mol % of PPh3, 65 °C; PCC, NaOAc, 3 Å
sieves.
ligand. Lowering the ligand loading of 2b to 10 mol % results in a
decrease in selectivity and yield of the lactone products (Table 1, entry
6).
(7) (a) Krauss, I. J.; Wang, C. C. Y.; Leighton, J. L. J. Am. Chem. Soc. 2001,
123, 11514. (b) Leighton, J. L.; O’Neil, D. N. J. Am. Chem. Soc. 1997,
119, 11118. (c) Breit, B. Acc. Chem. Res. 2003, 36, 264. (d) Breit, B.;
Breuninger, D. J. Am. Chem. Soc. 2004, 126, 10244.
With the optimal conditions in hand, we investigated the substrate
scope. Rh-catalyzed directed hydroformylation of alcohol substrates
with an electron-rich and electron-deficient aromatic ring at the allylic
position affords good regio- and diastereoselectivities (Table 2, entries
2 and 3). Subjection of a compound with a silyl ether at the allylic
position results in improved regioselectivity (Table 2, entry 4).
Substitution of the phenyl substituent with the more electron-rich
cyclohexyl group provides lower regio- (65:35) and high diastereo-
selectivity (Table 2, entry 5). The latter finding suggests that the
reaction is proceeding through a directed hydroformylation rather than
an unselective background reaction. The lower regioselectivity reflects
the difficulty in overcoming the significant preference for the linear
aldehyde, which is evident by comparing the selectivity of the reaction
with PPh3 (b:l ) 16:84; Table 2, entry 5).
(8) (a) Smejkal, T.; Breit, B. Angew. Chem., Int. Ed. 2008, 47, 311. (b) Kuil,
M.; Soltner, T.; van Leeuwen, P. W. N. M.; Reek, J. N. H. J. Am. Chem.
Soc. 2006, 128, 11344. (c) Slagt, V. F.; Kamer, P. C. J.; van Leeuwen,
P. W. N. M.; Reek, J. N. H. J. Am. Chem. Soc. 2004, 126, 1526.
(9) In the Supporting Information, a more detailed discussion of the synthesis
is presented.
(10) 1H and 31P NMR analysis showed a minor compound (∼3%) which we
have assigned as the minor syn-diastereomer. DFT calculations suggest
that the anti-diastereomer is 2 kcal/mol more stable than the syn.
(11) Keq values are an average of three runs; all values deviated by <15% of
the average value. See Supporting Information for details.
(12) For all three alcohols, the time to reach half the equilibrium concentrations
is less than 2 h, showing that the exchange is rapid. Without the acid
catalyst, the exchange with isopropanol had a t1/2 > 10 h.
(13) Hydroformylation of 3 leads to spontaneous formation of lactols under the
reaction conditions. Because the lactols have an additional stereocenter,
they are oxidized to the lactones for ease of analysis and isolation.
(14) Hydroformylation of the methyl ether of 3 with 2b leads to a linear:branched
ratio of 74:26, demonstrating the necessity of a free alcohol for branch
selectivity. See Supporting Information for details.
The levels of diastereoselectivity in the hydroformylation reactions
correlate well with the size of the substituent at the allylic position.
The high anti selectivity in five-membered ring lactone formation can
be rationalized based on minimization of A1,3-strain.1,15 To support
(15) Hoffmann, R. W. Chem. ReV. 1989, 89, 1841.
JA803011D
9
J. AM. CHEM. SOC. VOL. 130, NO. 29, 2008 9211