β-Amidoaldehydes via oxazoline hydroformylation

Article abstract of DOI:10.1039/b913698c

4-Substituted oxazolines, which are readily synthesized from naturally occurring α-amino acids, are converted efficiently and stereospecifically to β-amidoaldehydes in the presence of synthesis gas and catalytic dicobalt octacarbonyl.

Full text of DOI:10.1039/b913698c

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b-Amidoaldehydes via oxazoline hydroformylationwz
David S. Laitar, John W. Kramer, Bryan T. Whiting, Emil B. Lobkovsky
and Geoffrey W. Coates*
Received (in College Park, MD, USA) 9th July 2009, Accepted 10th August 2009
First published as an Advance Article on the web 1st September 2009
DOI: 10.1039/b913698c
4-Substituted oxazolines, which are readily synthesized from
naturally occurring a-amino acids, are converted efficiently
and stereospecifically to b-amidoaldehydes in the presence of
synthesis gas and catalytic dicobalt octacarbonyl.
Enantiomerically pure N-protected b-aminoaldehydes are
useful building blocks for addition of b-amino functionality
in a stereospecific fashion. This method has been utilized
for the synthesis of b-peptide derivatives1 as well as other
bioactive molecules.2 Maraviroc, a promising antiretroviral,
uses a b-amidoaldehyde as a key intermediate in its synthesis.3
Given the utility of enantiopure N-protected b-aminoaldehydes,
there has been interest in their efficient synthesis. Two general
strategies can be employed: enantioselective coupling of
two prochiral substrates4–9 or synthetic transformation of a
naturally occurring chiral molecule.10
The Mannich reaction is frequently used for the enantio-
Scheme 1 Proposed catalytic cycle for the hydroformylation of
selective synthesis of N-protected b-aminoaldehydes, either
through the coupling of imines with aldehydes4 or indirectly
through the coupling of imines with esters5 or Weinreb amides6
followed by reduction. Enantioenriched b-aminoaldehydes
have also been synthesized by the organocatalytic conjugate
addition of nitrogen nucleophiles to a,b-unsaturated aldehydes;7
by the cyclization of N-acyl imines with chiral vinyl ethers
followed by hydrolysis;8 and by using an enantioselective
aza-Petasis–Ferrier rearrangement of vinyl hemiaminals.9
a-Amino acids are the most common chiral precursors for
the synthesis of enantiomerically pure b-amidoaldehydes, and
are first converted to b-amino acids using the Arndt–Eistert
protocol followed by reduction.10 This route uses the
hazardous reagent diazomethane as well as stoichiometric
amounts of silver salts, precluding its use on large scale.
For the past several years, our group has studied the
carbonylation of heterocycles using cobalt catalysts.11,12
Recently, inspired by work of Jia and co-workers,13 we have
developed an efficient method for the carbonylation of 4- and
5-substituted oxazolines to oxazinones using the catalyst
HCo(CO)4.14 Given that HCo(CO)4 is an effective olefin
hydroformylation catalyst,15 we hypothesized that the reaction
oxazolines to b-amidoaldehydes.
conditions used for the carbonylation of oxazolines to
oxazinones might be adapted to favor the formation of
b-amidoaldehydes through addition of hydrogen. Herein, we
report that 4-substituted oxazolines, prepared in one step from
commercially available a-amino alcohols, are efficiently
converted to b-amidoaldehydes using hydrogen, carbon monoxide
and the inexpensive precatalyst dicobalt octacarbonyl.
The reaction is presumed to proceed through a catalytic
cycle similar to that of oxazoline carbonylation to oxazinones,
where initial protonation of an oxazoline by HCo(CO)4 is
followed by ring opening to form a cobalt alkyl intermediate A
(Scheme 1). Upon migratory insertion of CO, production
of the desired b-amidoaldehyde would depend on a faster
reaction of the resulting cobalt acyl complex B with hydrogen
than intramolecular ring closure to form oxazinone [eqn (1)].
(1)
Department of Chemistry and Chemical Biology, Baker Laboratory,
Cornell University, Ithaca, NY 14853-1301, USA.
E-mail: gc39@cornell.edu; Fax: +1 607-255-4137;
On the basis of this proposed mechanism, we hypothesized
that it would be critical to find reaction conditions that provided
selectivity for b-amidoaldehyde over oxazinone formation. We
have previously shown that solvent choice is important for
achieving optimal rates and product selectivities in epoxide
carbonylation16 and began by screening the hydroformylation
of 4-methyl-2-phenyloxazoline in solvents of varying polarity
and donicity (Table 1). The optimized reaction conditions for
oxazoline carbonylation to oxazinones under a pressure of
Tel: +1 607-255-5447
w Electronic supplementary information (ESI) available: Experimental
procedures, characterization data for all new compounds, and X-ray
tabular data for 3. CCDC 739579. For ESI and crystallographic data
in CIF or other electronic format see DOI: 10.1039/b913698c
z This article is part of a ChemComm ‘Catalysis in Organic Synthesis’
web-theme issue showcasing high quality research in organic
chemistry. Please see our website (http://www.rsc.org/chemcomm/
organicwebtheme2009) to access the other papers in this issue.
ꢀc
This journal is The Royal Society of Chemistry 2009
5704 | Chem. Commun., 2009, 5704–5706

Table 1 Effect of solvent on oxazoline hydroformylationa
Table 2 Hydroformylation of oxazolines to b-amidoaldehydesa
Entry
Solvent
[Oxazoline]/M
Conversionb (%)
Oxazoline
1
2
3
4
5
6
7
8
9
DME
0.50
0.50
0.50
0.50
0.50
0.50
0.50
1.00
0.25
15
0
Cpd Ar
R
Entry
trxn/h Yieldb (%) eec (%)
CH3CN
THF
Et2O
1,4-Dioxane
Toluene
Hexanes
Toluene
Toluene
1d
2d
3d
4dg
5
6
7
8
9
1a
1b
1c
1d
Ph
H
H
H
6
6
81e
83e
64e
71
85
84
88
89
63
82
90
naf
naf
naf
94
53
45
68
80
11
38
95
p-FC6H4
p-MeOC6H4
Ph
6
6
Me
Et
1eh Ph
6
99
99
99
99
1f
Ph
Ph
Ph
Ph
Ph
iPr
20
20
20
20
6
1g
1h
1ih
1j
iBu
(S)-sBu
Ph
a
b
H2/CO (1 : 1, 82 atm). Conversion determined by 1H NMR
spectroscopy relative to an internal standard.
10
96
10
11
CH2Ph
1ki p-tBuC6H4
CH2OTBSj 20
naf
a
b
Conditions: [oxazoline] = 0.25 M; H2/CO (1 : 1, 82 atm). Isolated
hydrogen and carbon monoxide gave a complicated mixture of
products and only a small amount of the desired b-amidoaldehyde
was formed (entry 1). Other solvents of moderate donicity such as
tetrahydrofuran (entry 3), diethyl ether (entry 4) and 1,4-dioxane
(entry 5) also provided only modest yields of the desired product,
while the strongly coordinating solvent acetonitrile (entry 2)
completely inhibited the reaction. Of the solvents screened,
toluene (entry 6) proved to be the highest yielding. The yield of
3-benzamidobutanal was also significantly impacted by reaction
concentration (entries 6, 8 and 9), where reactions run under more
dilute conditions resulted in higher yields. Under optimized
conditions, 3-benzamidobutanal was formed in 95% conversion.
With optimized reaction conditions established, the hydro-
formylation of a wide range of 4-substituted oxazolines was
attempted (Table 2). Variation at the 2-position with aryl
groups containing both electron-donating and -withdrawing
substituents was tolerated (entries 1–3). A number of oxazolines
derived from naturally occurring a-amino acids including
glycine (entry 1), alanine (entry 4), valine (entry 6), leucine
(entry 7), isoleucine (entry 8), and phenylalanine (entry 10) were
hydroformylated to their corresponding b-amidoaldehydes in
good to excellent isolated yield. For oxazolines possessing
4-substituents with groups larger than methyl, higher catalyst
loadings and longer reaction times were required to reach full
conversion. The serine-derived oxazoline required protection of
the alcohol group (entry 11) for clean hydroformylation to the
corresponding b-amidoaldehyde. The reactions generally
produced minimal byproducts, however for oxazolines that
lacked substitution at the 4-position (entries 1–3) small amounts
(5%) of the branched aldehyde isomer were formed.17 In the
case of phenyl-substituted oxazoline 1i (entry 9), a significant
amount of 1-phenylethylbenzamide (B15%) was detected in
the crude reaction mixture by 1H NMR spectroscopy.
yield, average of two runs. %ee determined by 1H NMR spectroscopy
c
d
e
mol% Co2(CO)8 used. Yield determined
using (+)-Eu(tfc)3.
by 1H NMR spectroscopy relative to an internal standard. na: not
2
f
g
h
applicable. Reaction run at 70 1C. Enantiomeric compound used.
Racemic substrate used. TBS = tert-butyldimethylsilyl.
i
j
alkyl intermediate A (Scheme 1) followed by hydroformylation
of the resulting ene-amide (Fig. 1). Hydroformylation of
optically pure 5-methyl-2-phenyloxazoline led to partially
racemized b-amidoaldehyde product.w
Alkyl cobalt tetracarbonyl compounds were shown to
undergo reversible b-hydrogen elimination more than 40 years
ago by Heck and Breslow.18 They found that the rate of
elimination is more rapid at elevated temperatures and low
pressures of carbon monoxide. The degree of racemization in
oxazoline hydroformylation is also impacted by temperature
and pressure (Table 3). As the reaction temperature is lowered,
Fig. 1 Proposed racemization pathway.
Table 3 Effect of temperature on the hydroformylation of oxazoline 1da
In contrast to the carbonylation of oxazolines to
oxazinones, optical purity was not always transferred from
oxazolines to their b-amidoaldehyde products. Racemization
was particularly problematic with the oxazoline bearing a
phenyl substituent at the 4-position (Table 2, entry 9), and some
racemization was observed with methyl and benzyl-substituted
substrates (entries 4 and 10). We hypothesize that this
racemization is the result of b-hydride elimination from cobalt
Entry
Temperature/1C
H2/CO Pressure/atm
eeb (%)
1
2
3
4
90
80
80
70
82
82
55
82
70
87
53
94
a
b
Conditions: [oxazoline] = 0.25 M; 1 : 1 H2/CO. %ee determined
1
by H NMR spectroscopy using (+)-Eu(tfc)3.
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This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 5704–5706 | 5705

Fig. 2 Proposed formation of 3 (left), ORTEP of 3 drawn with 50% thermal ellipsoids (top right), and structurally-related pharmaceuticals (bottom right).
an increase in the enantiomeric excess of b-amidoaldehyde was
observed (entries 1, 3 and 4). Also, an increase in %ee was
observed when the total pressure of H2/CO was increased
(entry 2 and 3). Hydroformylation at temperatures below
70 1C led to formation of significant amounts of oxazinone.
While exploring the substrate scope of oxazolines derived
from naturally occurring a-amino acids, hydroformylation of
the tryptophan-derived oxazoline 1l led to a product whose
1H NMR spectrum was inconsistent with formation of a
b-amidoaldehyde. Further spectroscopic studies supported
the formation of the tetrahydrocarbazole product 3 (Fig. 2),
which was confirmed by single-crystal X-ray crystallography.w
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a reaction pathway where the expected
b-amidoaldehyde product is initially formed, followed by
intramolecular Friedel–Crafts hydroxyalkylation. The intra-
molecular reaction of the indole p system at the 2-position
with electrophiles is well precedented,19 including aldehydes.20
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In conclusion, we have developed an efficient route to
b-amidoaldehydes from oxazolines using the inexpensive,
commercially available precatalyst Co2(CO)8 with relatively
high levels of stereochemical retention. Efforts to further
optimize stereospecificity and substrate scope of oxazoline
hydroformylation are underway.
We are grateful to the Department of Energy for funding
(DE-FG02-05ER15687). We thank Dr Christopher M. Byrne
for the preparation of oxazoline starting materials and
Dr Sze-Sze Ng for helpful discussions.
17 We believe hydroformylation of the enamide formed after
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´
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This journal is The Royal Society of Chemistry 2009
5706 | Chem. Commun., 2009, 5704–5706