Synthesis of quaternary carbon centers via hydroformylation

Article abstract of DOI:10.1021/ja1036226

The application of hydroformylation to the synthesis of quaternary carbon centers is reported. The synthesis of the highly substituted carbon is achieved by applying a catalytic amount of 1. Ligand 1 serves as a catalytic directing group by covalently and reversibly binding to both the substrate and catalyst. The intramolecular nature of the directing group strategy accelerates the hydroformylation reaction such that the reaction is performed at mild temperatures (35-55 °C) and with excellent regioselectivity (b:l > 94:6).

Full text of DOI:10.1021/ja1036226

Published on Web 08/05/2010
Synthesis of Quaternary Carbon Centers via Hydroformylation
X. Sun, K. Frimpong, and K. L. Tan*
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467
Received April 28, 2010; E-mail: kian.tan.1@bc.edu
Table 1. Optimization Data for Hydroformylation of 2
Abstract: The application of hydroformylation to the synthesis
of quaternary carbon centers is reported. The synthesis of the
highly substituted carbon is achieved by applying a catalytic
amount of 1. Ligand 1 serves as a catalytic directing group by
covalently and reversibly binding to both the substrate and
catalyst. The intramolecular nature of the directing group strategy
accelerates the hydroformylation reaction such that the reaction
is performed at mild temperatures (35-55 °C) and with excellent
regioselectivity (b:l > 94:6).
pressure
(psi)
temperature
(°C)
yieldb
(%)
entry
ligand
b:la
c
1
2
3
4
5
6
7
8
PPh3
1d
400
200
200
200
50
100
400
400
75
35
45
55
45
45
45
45
<2:98
96:4
95:5
95:5
89:11
94:6
97:3
-
66e
54
61
50
1d
The application of directing groups in organic chemistry is a
powerful technique for controlling regio- and stereoselectivity.1 Often
the use of directing groups leads to an increase in the rate and substrate
scope of the reaction. Hydroformylation of disubstituted olefins has
been a challenge due to the difficulty in controlling regioselectivity
and the inherently poor reactivity of these substrates.2 Phosphorus-
based directing groups have been uniquely able to address these
challenges making it possible to obtain highly regioselective reactions,
while performing the reactions under mild conditions.3 The liability
of this strategy is the use of stoichiometric amounts of phosphorus-
based ligands; however, recently our group4 and the Breit group5 have
demonstrated that a catalytic amount of a directing group can be employed
if the directing group reversibly and covalently links to the substrate. We
have termed these catalytic directing groups “scaffolding ligands” due to
their ability to bind both the substrate and catalyst simultaneously. Using
this type of ligand allows for both regio- and diastereoselective hydro-
formylation of both mono- and disubstituted olefins.
1d
1d
38
53
1d
1d
70 (73)f
0
c
PPh3
a Regioselectivities determined by 1H NMR of crude reaction
mixtures. b Yields of the branched product determined by 1H NMR by
comparison to internal standard. c 8 mol % PPh3. d 20 mol % 1.
e Isolated yield of lactone. f Isolated yield of branched product.
We initiated our investigation by examining the hydroformylation
of 2. Though styrenyl-based substrates are known to have a
preference for the branched regioisomer,11 R-substituted styrenes
have been reported to be highly linear-selective.12 During the
course of our studies we found that the branched aldehyde product
is unstable to silica gel purification and also dimerizes to a small
extent to a cyclic acetal.13 To circumvent these problems we oxidize
the unpurified reaction mixture directly and isolate the carboxylic
acid product. When 2 is subjected to hydroformylation at 75 °C
with PPh3, only the linear product is formed (Table 1 entry 1). In
stark contrast when ligand 1 is used the branched product is
obtained (Table 1, entry 2). Performing a temperature screen using
ligand 1, we found that at 45 °C the branched product is formed in
61% yield and with excellent regioselectivity (b:l ) 95:5, Table 1,
entry 3). At higher temperatures and longer reaction times, a
decrease in yield is observed consistent with slow product
decomposition (Table 1, entry 4). Upon optimizing the pressure of
CO/H2 and reaction time, the desired product could be isolated in
73% yield with b:l ratio of 97:3 (Table 1, entry 7).14 As the CO/
H2 pressure is raised, the regioselectivity of the process increases
suggesting the selectivity-determining step may be changing with
pressure or higher pressure could be suppressing minor amounts
of background reaction.15 Under the same reaction conditions except
using PPh3, 2 is unreactive (Table 1, entry 8). A second control
reaction was performed with the methyl ether of 2 and ligand 1,
and again no reaction is observed (Figure SI-1). When a binding
study was performed by adding 2.5 equiv of 2 and 2.5 equiv of the
aldehyde product to 1, a 61:39 ratio of 2 bound to 1 over the product
bound to 1 was observed (eq 2).16 This experiment demonstrates
that there is only a slight preference for binding of 2 over the
product. These results are consistent with 1 serving as a catalytic
directing group that controls the regioselectivity of the reaction and
accelerates the overall process.
A significant challenge that remains for the area of hydroformylation
is the application toward the synthesis of quaternary carbon centers.
The formation of quaternary centers in hydroformylation is so
unfavorable that in 1948 Keulemans stated that “addition of the formyl
group to a tertiary C atom does not occur, so that no quaternary C
atoms are formed” (Keulemans’ rule).6 Though this rule has generally
been found to be true, there are a limited number of examples that
use hydroformylation for the synthesis of quaternary carbon centers.7-10
The majority of examples are with R,ꢀ-unsaturated esters, which are
both electronically activated toward forming the branched regioisomer
and which contain an ester that can serve as a chelating group. For
unactivated substrates, a sole example exists where a phosphorus
directing group facilitates formation of a quaternary center from a 1,1-
disubstituted olefin by hydroformylation.3d Inspired by this work we
report that catalytic quantities of 1 can be used for the efficient
generation of quaternary carbon centers (eq 1).
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C O M M U N I C A T I O N S
in the yield, while maintaining excellent regioselectivity (Table 2,
entry 3). Aromatic rings substituted with either a bromo or chloro
group function in the reaction (Table 2, entries 4-6). Furthermore,
π-electron-withdrawing groups such as nitriles and esters can be
used in the reaction with a b:l ratio of >98:2 (Table 2, entries 7
and 8). Heterocyclic aromatic rings and napthylene-based substrates
also yield the quaternary carbon products (Table 2, entries 9-12).
Attempts to hydroformylate an o-tolyl substrate led to minimal
conversion, suggesting that steric hindrance impedes the reaction.
Using 2-methyl-propen-1-ol results in the branched product being
formed as the major product (b:l ) 76:24; Table 2, entry 13). We
are currently investigating whether ligand modifications can be
made to improve the regioselectivity for aliphatic substituted olefins.
Next, we investigated the possibility of isolating the product in
the aldehyde oxidation state. This is achieved by treating the crude
hydroformylation reaction mixture with ethylene glycol and catalytic
p-TsOH to form the cyclic acetal (eq 3). Over the two steps the
product was isolated in 72% yield, matching the results obtained
from direct oxidation to the carboxylic acid.
With these initial promising results we investigated the substrate
scope of the reaction. The addition of electron-withdrawing groups
to the aromatic ring leads to an increase in the yields of the branched
product while maintaining high selectivity (Table 2, entries 1 and
2). An electron-rich aromatic ring is tolerated with a small decrease
Table 2. Substrate Scope
We have established that by using a catalytic directing group
formation of quaternary carbon centers via hydroformylation can
be achieved. These results demonstrate the power of directing
groups to overturn inherent selectivities of reactions. The fact that
these reactions are performed under mild temperatures further shows
the benefits of using directing groups. We will continue to develop
these scaffolding ligands and apply them to reactions that suffer
from poor selectivity or reactivity.
Acknowledgment. This work was supported by Boston College
and the ACS-PRF (DNI-5001400) and NIGMS (R01GM087581).
Mass spectrometry instrumentation at Boston College is supported
by funding from the NSF (DBI-0619576).
Supporting Information Available: Experimental details, exchange
data between 1 and 2 as well as with the aldehyde product, compound
characterization. This material is available free of charge via the Internet
at http://pubs.acs.org.
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