Regioselective and enantioselective hydroformylation of dialkylacrylamides

Article abstract of DOI:10.1002/adsc.200900871

Dimethylacrylamide can be hydroformylated with very high chemo- and regioselectivity. Asymmetric hydroformylation of this substrate is possible, provided steps are taken to minimise racemisation of the aldehyde products, and this work demonstrates the eff

Full text of DOI:10.1002/adsc.200900871

FULL PAPERS
DOI: 10.1002/adsc.200900871
Regioselective and Enantioselective Hydroformylation of
Dialkylacrylamides
Gary M. Noonan,a David Newton,a Christopher J. Cobley,b Andrꢀs Suꢁrez,c
Antonio Pizzano,c and Matthew L. Clarkea,*
a
School of Chemistry, University of St Andrews, EaStCHEM, St Andrews, KY16 9ST, Fife, U.K.
Fax : (+44)-(0)1334-463-808; e-mail: mc28@st-andrews.ac.uk
Chirotech Technology Limited, Dr. Reddyꢂs Laboratories, 162 Cambridge Science Park, Milton Road, Cambridge, CB4
b
0GH, U.K.
c
Instituto de Investigaciones Quꢃmicas, Consejo Superior de Investigaciones Cientꢃficas and Universidad de Sevilla, Avda
Amꢀrico Vespucio n8 49, Isla de la Cartuja, 41092 Sevilla, Spain
Received: December 17, 2009; Revised: March 10, 2010; Published online: April 7, 2010
Abstract: Dimethylacrylamide can be hydroformylat- droformylated under mild conditions giving similar
ed with very high chemo- and regioselectivity. Asym- or better enantioselectivities, including the Weinreb
metric hydroformylation of this substrate is possible, amide of acrylic acid (71% ee), and the asymmetric
provided steps are taken to minimise racemisation of hydroformylation of diethylacrylamide producing the
the aldehyde products, and this work demonstrates chiral aldehyde with up to 82% ee.
the effect of various conditions and variables on rac-
emisation. Using the Landis diazaphospholane li- Keywords: aldehydes; asymmetric carbonylation; hy-
gands up to 68% ee can be realised under very mild droaminomethylation; hydroformylation; racemiza-
conditions. Other dialkylacrylamides were also hy- tion
Introduction
We have recently reported that Rh catalysts de-
rived from the monodentate phosphorus cage ligand
Rhodium-catalysed hydroformylation is one of the denoted MeCgPPh show significantly enhanced reac-
most industrially important carbon-carbon bond- tivity, chemo- and a-selectivity in the hydroformyla-
forming reactions, especially in the commodity chemi- tion of various unsaturated ester substrates,[15] The
cals industry, where the use of cheap feedstocks (al- highly efficient a-selective hydroformylation reactions
kenes and syngas) and the potential for near perfect of a,b-unsaturated esters are only viable for the syn-
atom economy makes it an especially desirable meth- thesis of racemic compounds since formyl esters
odology.[1] Hydroformylation has been investigated in [RCH
ACTHUNTRGNE(NUG CHO)CO2R’)] are in an observable equilibri-
the synthesis of more complex molecules for many um with their enol form and configurationally unsta-
years, but due to selectivity problems in many early ble. The products from the a-selective hydroformyla-
publications, the true potential of the reaction has not tion of a,b-unsaturated amides are formyl amides that
yet been exploited to any great extent. This situation should exhibit less enol character due to the delocali-
À
is beginning to change, since the last two decades sation between the C=O and C N bonds and steric
have seen some significant developments in the repulsion in the enol form. We felt that the catalytic
design of linear-selective catalysts,[2] more reactive asymmetric synthesis of these potentially delicate
catalyst systems,[3] tandem procedures using hydrofor- chiral building blocks represented an interesting chal-
mylation[4,5] and the discovery of new effective chiral lenge with regard to both control of selectivity, and
ligands for asymmetric hydroformylation.[1,6–14] These the development of a methodology that enables the
improvements result in the sort of levels of selectivity aldehyde products to be isolated or utilised without
that make this reaction of immediate potential in aca- racemisation. In addition, a-formyl amides have the
demic and industrial-scale organic synthesis. The hy- potential to be very easily transformed into b-amino
droformylation of more functionalised and challeng- acids, hydroxy esters, 1,3 diamines and g-amino alco-
ing alkene substrates with the new generation of cata- hols. A publication reporting the R&D synthesis of
lysts can now be tackled with some reasons for opti- drug candidates in clinical trials used a-formyl amides
mism.
[RCHACTHGNUTREN(NUG CHO)ACHTUNGTERN(NUNG CONEt2)] as the key chiral building
Adv. Synth. Catal. 2010, 352, 1047 – 1054
ꢄ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1047

Gary M. Noonan et al.
FULL PAPERS
blocks.[16] The synthesis used produced the desired was not known if this substrate would react or its
compounds with no serious problems, but required regio-chemical preference, we carried out some stud-
nine reactions from enantio-pure phenylalanine to ies with achiral ligands. These studies show that this is
produce the more substituted compounds and five a slightly deactivated substrate relative to active sub-
steps from the enantio-pure Roche ester building strates like styrene, since all of the ligands studied
block for the simplest aldehyde (R=methyl). A would give high conversion for an easier substrate
number of unpleasant stoichiometric reagents includ- under these reaction conditions, but in this case gave
ing alkyl halides, TiCl4, BuLi, periodanes and TBTU quite low conversions. The lower selectivity observed
were required. Asymmetric hydroformylation could with Xantphos (Table 1, entry 11) reflects that the
deliver the same building blocks in one step from ligand directs towards the linear aldehyde, while the
cheap achiral starting materials with potentially no substrate under these conditions prefers the branched
waste. All these factors made it clear to us that this product. The ligand denoted MeCgPPh performed
was a particularly interesting class of substrate for best, giving high yields and regioselectivity (Table 1,
study. Hydroformylation of a,b-unsaturated amides entry 8). The hydroformylation predominantly yielded
À
[RC=CH C(=O)NRR’] has, thus far, been limited to the branched a-formyl amide with lower temperature
studies on methacrylamide, acrylamide and N-benzyl- improving selectivity for this product (Table 1 runs 1–
ACHTUNGTRENNUNGacrylamide, with no reports of highly enantioselective 3). A pressure of 20 bar or above is desirable to main-
processes. This is most likely due to difficulty in con- tain good conversion and regioselectivity using this
trolling the selectivity for these functionalised sub- specific catalyst (Table 1, entry 3 vs. entry 6 and
strates, since significant amounts of side products entry 1 vs. entry 7). Hydroformylation of unsaturated
were observed on the hydroformylation of these sub- esters and amides has a far greater dependence be-
strates under certain conditions.[17] In this paper, we tween regioselectivity and temperature and pressure
report our promising initial findings on the achiral than in other alkenes. Our data suggest that the in-
and asymmetric hydroformylation of dialkylacryl- built preference for all catalysts is a-selectivity, but
A
conditions that promote isomerisation can erode or
even reverse this. In this case, although lower pres-
sures and temperatures reduce regioselectivity, this is
not as pronounced as in the case of methyl acrylate
where the selectivity can be reversed.[15] There is no
Results and Discussion
Commercially available N,N-dimethylacrylamide was further gain in selectivity if pressure is increase
selected as the model substrate for this work. Since it beyond 20 bar, and for this ligand productivity is sig-
Table 1. Regioselective hydroformylation of N,N-dimethylacrylamide.[a]
Entry
Ligand
T [oC]
P [bar]
Conv. [%]
2B+2L [%]
B:L
1
2
3
4
5
6
MeCgPPh
MeCgPPh
MeCgPPh
MeCgPPh
MeCgPPh
MeCgPPh
MeCgPPh
MeCgPPh
PPh3
100
80
60
80
60
60
100
60
60
60
60
20
20
20
50
50
10
10
20
20
20
20
>99
>99
96
>99
92
52
54
95
12
>99 (69)[b]
10:1
30:1
50:1
33:1
36:1
14:1
3:1
82:1
47:1
>99:1
1.5:1
>99 (76)[b]
84
>99
80
35
48
95
12
10
8
7
8[c]
9
10
11
dppe
Xantphos
10
8
[a]
Conditions: see general procedure (A). Conv. refers to conversion of alkene consumed relative to standard. % aldehyde
refers to the proportion of the reaction mixture that is branched or linear HF products. Low levels of hydrogenation and
aldol side products were detected in some cases and make up the remaining mass balance.
Numbers in brackets refer to yields of pure branched aldehyde after chromatography.
[b]
[c]
Runs 8–11 in separate vials in the same pressure vessel, t=90 min.
1048
asc.wiley-vch.de
ꢄ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 1047 – 1054

Regioselective and Enantioselective Hydroformylation of Dialkylacrylamides
nificantly reduced below 20 bar initial pressure. We
have observed other instances of this positive pressure
effect using this ligand system, that is in contrast to
many hydroformylation catalysts that operate best at
very low pressures (and show kinetics with negative
order in [CO]).[1a]
An additional experiment, carried out using real-
time gas uptake monitoring, showed that the reaction
had gone to completion after approximately 40 min at
608C and 20 bar syngas with no significant induction
period (average TOF ~800 mol prod/mol cat/h), to
produce essentially pure branched aldehyde. Chiral
HPLC method development on the aldehyde proved
problematic, as we have experienced for other alde-
hyde products. However the aldehyde can be readily
reduced with NaBH4 at À788C to give the alcohol
(79% isolated yield on a preparative example) that
can be analysed by HPLC even if a crude reaction
mixture containing the alkene starting material is
used. Alternatively, the aldehyde can be converted to
the diastereomeric imines (see Experimental Section)
by adapting the protocol of Gellman and Chi; the
enantiomeric excess is easily measured from the dia-
1
stereomeric imine CH resonances in the H NMR.[18]
Both methods returned essentially the same result on
samples produced under similar conditions providing
the imine-based method was analysed within one
hour of imine formation. This result, along with other
precedents for both methods, is highly consistent with
both analysis protocols not causing racemisation
under the conditions described.
The chiral ligands chosen for initial studies on the
hydroformylation of dimethylacrylamide were (R,R)-
PhBPE,[13] (R,R)-Chiraphite,[7,10] (R,R)-Kelliphite,[7,8]
the phosphine-phosphite ligands denoted POP,[14]
while later studies used the (S,S,S) or (R,R,S)-Diaza-
phos-SPE ligand, developed by Landis and co-work-
ers[12] (see Figure 1). The ligand to Rh ratio was
Figure 1. Ligands used in this study.
1.25:1, since in many many experiments with a wide
variety of alkenes, we have observed that ratios of
1.1–1.5 generally give the best results. In our initial formed under the reaction conditions prior to the 2-
experiments, even after reducing the reaction temper- hour reaction, a reasonable conversion and an im-
ature to 608C, racemic mixtures were produced for all proved ee of 37% was possible (Table 2, entry 9). No
ligands after 24 h, even if the reactions were found to improvement using pre-formed catalysts was observed
be completely regio-selective (Table 2, entries 1, 4, using Chiraphite.
and 6).
A control experiment in which [RhACTHNGUTERNN(UG acac)(CO)2]
It was thought that the disappointing lack of enan- was used as a catalyst without a ligand present con-
tioselectivity might in part be due to racemisation firmed that unmodified catalysts do not promote this
under the reaction conditions. A shorter reaction time reaction under the conditions used. With a variety of
of 5 h was therefore used with the Rh/Kelliphite cata- substrates, it is our experience that unmodified cata-
lyst, in which an ee of 18% was recorded (Table 2, lysts are poorly active hydroformylation catalysts rela-
entry 7). The above results imply that in order to tive to those derived from the more reactive ligands
achieve a significant ee for this substrate at 608C a using functionalised substrates at moderate pressures
short reaction time is needed. Therefore, a 2-hour hy- and temperatures. Our working hypothesis was there-
droformylation was attempted at 20 bar and 608C for fore that the catalysts were fairly selective, but the
Rh/Kelliphite. This initially gave reduced enantiose- product was racemising under the reaction conditions,
lectivity, but when the Rh/Kelliphite catalyst was pre- possibly with unmodified Rh hydrido-carbonyl com-
Adv. Synth. Catal. 2010, 352, 1047 – 1054
ꢄ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1049

Gary M. Noonan et al.
FULL PAPERS
Table 2. Asymmetric hydroformylation of dimethylacrylamide.[a]
Run
Ligand
L:Rh
T [oC]
P [bar]
t [h]
Conv. [%]
Aldehydes [%]
B:L
ee [%]
1
2
3
4
5
6
7
8
N
1.25
1.25
1.25
1.25
1.25
1.25
1.25
1.25
1.25
1.25
1.25
1.25
1.25
1.25
–
60
60
60
60
60
60
60
60
60
35
35
35
35
25
60
100
60
60
60
60
20
60
35
35
35
20
20
20
20
20
20
20
20
24
5
2
24
5
24
5
2
2
4
4
4
4
26
2
2
0.66
2[e]
5[e]
1.33
20
1.33
1.5
0.5
20
>99
>99
>99
>99
>99
>99
>99
>99
n.d.
9
67
18
27
28
10
29
n.d.
n.d.
n.d
>99
>99
>99
98
73
>100:1
>100:1
>100:1
>100:1
>100:1
>100:1
>100:1
>100:1
>100:1
>100:1
>100:1
>100:1
>100:1
>100:1
8:1
0
85(33)[b]
82
17 (+)
15 (+)
0
13 (+)
0
18 (À)
7 (À)
37 (À)
15 (+)
18 (À)
21 (+)
25 (+)
46 (+)
n.d.
68
89
87
81 (25)[b]
70
9
20
59
9
64
17
10
11
12
13
14
15
16
17
18
19
20[g]
21[g]
22[g]
23[g]
24[g]
25[g]
4.5
4.5
4.5
4.5
4.5
20
50
20
20
20
3.5
4.5
3.5
3.5
3.5
4.5
27
28
1[d]
9
–
6:1
n.d.
1.25
1.25
1.25
1.25
1.25
1.25
1.25
1.25
1.25
36
55
70
93
89
96
96
n.d.
>99
>100:1
>100:1
>100:1
16:1
32:1
13:1
49:1
49:1
15:1
47 (À)
40 (À)
17 (À)
47 (+)
46
53 (À)
62 (À)
68 (À)
43 (À)
n.d.
100
[a]
[b]
[c]
[d]
[e]
[f]
[g]
plexes aiding this process. An experiment in which this ligand class at just 358C and around 4 bar pres-
samples of aldehyde were removed, reduced and ana- sure. Comparing entries 22 and 25 to entry 23 shows
lysed demonstrated that after 40 min an ee of 47% that longer reaction times and temperatures are both
was possible at 36% conversion. However, as the en- detrimental to selectivity. Based on our findings de-
tries 18 and 19 illustrate, the ee decreased rapidly as scribed above, the catalysts were pre-formed by stir-
the reaction proceeded. The “POP” ligands did not ring [RhACTHNUTRGNEN(UG acac)CO2] with the ligands under a syngas
improve the enantioselectivity for hydroformylation atmosphere, which has been established to quantitive-
of this substrate and tended to have somewhat lower ly convert the Rh precursor to the ligand-modified
reactivity. However, a reasonable ee of 46% could be species. We propose that 68% is the optimised ee for
realised at low conversion (Table 2, entry 17). We also this substrate with this catalyst, since various experi-
note that the phosphite and phosphine-phosphite li- ments suggested that under these conditions product
gands are almost completely regioselective.
The diazaphospholane ligands developed by Landis quired to obtain perfect enantioselectivity.
and co-workers have been shown to not only yield Tandem hydroformylation–imine formation reac-
racemisation was minimised. New catalysts will be re-
high ee but very high reactivity in the hydroformyla- tions in the presence of (S)-2-methoxypropylamine
tion of several substrates, and we therefore felt it were also carried out, since this potentially might act
could give improved results at lower temperatures as a method to trap sensitive aldehydes as more con-
and short reaction times. These ligands were therefore figurationally stable imines. Amines and Michael ac-
investigated next, and we were pleased to obtain the ceptor alkenes can undergo competing Michael addi-
highest selectivities for this class of substrate using tion reactions in related processes,[19] but the lower
1050
asc.wiley-vch.de
ꢄ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 1047 – 1054

Regioselective and Enantioselective Hydroformylation of Dialkylacrylamides
Scheme 2. Asymmetric hydroformylation of other dialkyl-
AHCTUNGTREGUNaNN crylamides.
to be less prone to racemisation than the dimethyl an-
alogue, since the enol potentially formed from these
products is sterically hindered in its planar conforma-
Scheme 1. Tandem hydroformylation–imine formation.
Michael acceptor character of unsaturated amides tion. In addition, extra bulk might facilitate stereo-dif-
and the high reactivity of catalysts derived from the ferentiation in the hydroformylation reaction. Gratify-
Diazaphos ligands enable these reactions to proceed ingly these substrates also underwent branched selec-
cleanly to give the imine products with slightly re- tive hydroformylation with good conversions ach-
duced ee to that observed when the amine is not pres- ieved, with the stereo-induction either similar, or in
ent (Scheme 1).
the case of diethylacrylamide significantly better than
To investigate the configurational stability further, that for the dimethyl analogue.
we measured the tendencies of the aldehyde and
imine to racemise. Aldehyde samples were found to
Asymmetric hydroformylation of N,N-diethylacryl-
AHCTUNGTREGUNaNN mide gave good conversions to branched aldehyde
racemise if left in chlorinated solvents for several with up to 82% ee. An interesting observation is that
hours, but could be stored dilute in toluene for ex- between two otherwise identical runs increased con-
tended periods. The imines were found to be more version was seen for run 6, for which a preactivation
stable to racemisation in chlorinated solvents than the (stirring under 5 bar syn gas) of the catalyst was car-
aldehydes. An initial ee of 62% for the aldehyde, ried out at elevated temperature (508C) compared to
dropped to 30% after standing in CDCl3 for 24 h, run 5 where preactivation was carried out at room
meanwhile for the imine remained relatively constant temperature. Thus, preactivation of the Rh complexes
dropping from 52% to 42% ee after standing in of the Landis ligands should be carried out slightly
CDCl3 for 24 h.
above a Scottish room temperature! As discussed,
Preliminary investigations into the hydrogenation there is no advantage in using large L/Rh ratios under
of the enantio-enriched imine revealed that racemisa- these conditions; a hydroformylation of diethylacyl-
tion occurs under hydrogenation conditions. Transi-
ACHTUNGTRENUNaNG mide (not shown) run using an L/Rh ratio of 5:1
tion metal catalysts must promote isomerisation to gave only 13% conversion under the conditions of
enamines (that are possibly also reduced more rapid- Table 3, run 5 with a similar 77% ee. In one of the ex-
ly) during the reaction. Thus treatment of imine 4B periments (Table 3, run 2) a sample was reduced to
(48% ee) with hydrogen in the presence of catalysts the corresponding alcohol and isolated as a single
derived from [IrClACHTNUGTRNEUNG(COD)]2 and dppf or 1,1’-diisopro- regio-isomer using NaBH4 (54% from alkene). HPLC
pylphosphine-ferrocene, which we have previously analysis confirmed no racemisation took place and
found to be excellent C=N reduction catalysts results the absolute configuration was determined to be R by
in both diastereomers of the amine being formed comparison of the optical rotation value with that
even at room temperature. The long-desired hypo- from the literature.[16] It is proposed that the other di-
thetical asymmetric hydroaminomethylation reaction alkylacrylamide hydroformylations are also likely to
via an asymmetric hydroformylation will only be pos- be R-selective when using (R,R,S)-Diazaphos as
sible if catalysts can be designed that can reduce ligand. This corresponds to the same sense of enantio-
imines without racemisation or reduce by dynamic ki- selection as has been observed in the asymmetric hy-
netic resolution. A more promising approach may droformylation of vinyl acetate using this ligand (sty-
well be formation of enamines by hydroformylation- rene also hydroformylates on the same face of the
enamine formation followed by asymmetric hydroge- alkene, although the configuration changes due to the
nation of enamines, and is being pursued in this labo- priority rules).[12] The N,N-diisopropylamine deriva-
ratory.[19]
tive, 6, was found to be hydroformylated more slowly,
The reaction scope was then examined with three but with similar levels of enantioselectivity as the di-
other dialkylacrylamides studied in this reaction methyl analogue (Table 3, runs 7–13). The N,N-diiso-
(Scheme 2 and Table 3). The aldehydes produced propylacrylamide was also found to racemise at a sim-
from these more bulky derivatives might be expected ilar rate to the N,N-dimethyl analogue, a drop in ee of
Adv. Synth. Catal. 2010, 352, 1047 – 1054
ꢄ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1051

Gary M. Noonan et al.
FULL PAPERS
Table 3. Asymmetric hydroformylation of other dialkylacrylamides.[a]
Run
Alkene
T [oC]
P [bar]
t [h]
Conv. [%]
Aldehydes [%]
B:L
ee [%]
1
2
3
5
5
5
5
5
5
6
6
6
6
6
6
6
7
7
7
7
50
50
35
35
r.t.
r.t.
50
50
35
35
50
35
r.t.
60
35
35
r.t.
4.5
4.5
4.5
4.5
4.5
4.5
5.5
8
4.5
4.5
4.5
4.5
4.5
4.5
4.5
4.5
4.5
5
3
5
5
>99
>99
78
68
50
87
75
62
16
85
13:1
28:1
33:1
19:1
30:1
38:1
24:1
24:1
>99:1
24:1
n.d.
25:1
56:1
49:1
77:1
71:1
56:1
57
62
68
79
82
75
46
46
56
66
42
70
74
40
63
65
71
69 (54)[c]
73
65
50
4[b]
5[b]
6[b,d]
7
20
20
0.83
0.83
0.83
5
2.5
5
20
2
87 (56)[c]
71
8
9
10
11
55
10
21
26
n.d
>99
65
72
100
85
78(56)[c]
>99
65
12[b]
13[b,d]
14
64
88
85
86
15
5
5
20
16[b]
17[b,d]
87
[a]
General procedure (C) followed, 0.2 mol% RhACTHNUGTRENUNG(acac)[CO]2, 0.25 mol% of (R,R,S)-Diazaphos-SPE. Dry, degassed toluene
used as solvent (3 mL). Conversion refers to the substrate consumed, with selectivity to aldehydes referring to the NMR
yield of aldehyde isomers measured with reference to 1-methylnapthalene or tetraethylsilane internal standard unless
1
stated otherwise. B:L determined by H NMR, >100:1 refers to no linear aldehyde detected (we estimate <100:1 would
be detectable).
[b]
[c]
Reactions carried out as above but with (S,S,S)-Diazaphos-SPE as ligand.
Number in brackets refers to yield of single regio-isomer of pure alcohol after reduction with NaBH4 and column chro-
matography with no loss of ee In the case of entry 8, a repeat run gave 50% ee aldehydes and 43% yield of pure alcohol
of 52% ee.
[d]
Catalyst preactivated at 508C for 1 h, autoclave cooled, then substrate was added and autoclave repressurised.
56% to 38% was noted upon standing in CDCl3 over dium hydride species. At present, using a selection of
24 h. The l-valine methyl ester-derived imine of this some of the state-of-the-art ligands for asymmetric
substrate was found to be more configurationally hydroformylation up to 82% ee can be realised. Fur-
stable in chlorinated solvents with no drop in ee upon ther studies on the branched selective and asymmetric
standing for 24 h in CDCl3. The Weinreb amide of hydroformylation of other classes of functionalised al-
acrylic acid, 7, was also hydroformylated in high yield kenes are currently underway.
to give the enantioenriched aldehyde in up to 71% ee
(Table 3, runs 14–17)
Experimental Section
Conclusions
General
Solvents were obtained from commercial sources. Dry tolu-
ene used directly from stills without degassing. N,N-dime-
thylacrylamide, acryloyl chloride and the secondary amines
were obtained from Aldrich. Dialkylacrylamides 1b, 1c and
1d were prepared according to literature procedures.[20,21]
In summary, hydroformylation of dialkylacrylamides
tends to be branched selective, with the substrates un-
dergoing hydroformylation more slowly than unfunc-
tionalised substrates such as styrene. Reactive cata-
lysts such as Rh/MeCgPPh enable a fast regioselective MeCgPPh and the POP ligands were prepared according to
the literature.[3b,14] Other chiral ligands were donated by Chi-
reaction to occur. We have shown that asymmetric hy-
rotech. Syngas was obtained from BOC. Purification and
droformylation of dialkylacrylamides is a viable reac-
separation by flash chromatography were conducted with
tion for development, provided reaction times are
1
Silica Flash P60 by SILICYCLE. H and 13C NMR analyses
kept short, temperatures are minimised, and products
were carried out on Bruker Avance spectrometers at 300 or
are either diluted in toluene or reduced to alcohol
400 MHz NMR at room temperature. The symbols s, d, t, q,
products shortly after the reaction. Although many
studies have shown favourable results using pre-
formed catalysts, this study provides results entirely
consistent with pre-formed catalysts preventing race-
1
and m used to assign H NMR spectra refer to singlet, dou-
blet, triplet, quartet and multiplet, respectively. Assignments
were assisted by 1H-1H COSY, and 1H-13C HSQC experi-
ments where necessary. IR: by thin film on NaCl plates
misation of the sensitive aldehydes by unmodifed rho- unless otherwise stated. Electrospray mass spectrometry
1052
asc.wiley-vch.de
ꢄ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 1047 – 1054

Regioselective and Enantioselective Hydroformylation of Dialkylacrylamides
(ES-MS) and high-resolution mass spectrometry were car-
ried out on a Micromass LCT orthogonal acceleration time-
of-flight (TOF) mass spectrometer. Enantiomeric excess of
chiral aldehydes found using a literature method which in-
volves use of a chiral amine as a derivatising agent[18] (2B):
(S)-1-methoxy-2-propylamine in toluene-d8, (8B): l-valine
methyl ester in toluene-d8, (9B): l-valine methyl ester in
CDCl3, (10B): l-valine methyl ester in CDCl3. ee found
using derivitisation method for (2B) was checked using
chiral GC and results correlate. Enantiomeric excess of (3B)
measured using HPLC, ChiralPakꢅ AD column, eluent
97:3 hexane:propan-2-ol, flow rate 1 mLminÀ1.
Products were isolated using flash chromatography, or can
be reduced to the corresponding alcohols and isolated using
flash chromatography.
(C) General Procedure for Rhodium-Catalyzed
Hydroformylation using Air-Sensitive Ligands with
Catalyst Preactivation
As for (B), but the ligand and metal precursor were stirred
together under reaction conditions in an autoclave (i.e., syn
gas pressure and heat) for one hour, before addition of the
required amount of alkene substrate. The autoclave was
then repressurised and heated to the reaction temperature
for the desired time. (Note: all transfers were carried out
under an inert atmosphere.)
(A) General Procedure for Rhodium-Catalyzed
Hydroformylation using Phenylphosphatrioxa-
adamantane Ligand
1
(2B): Yield: 297 mg (76%). H NMR (300 MHz, CDCl3):
d =9.57 (d, J=1.9 Hz, 1H), 3.51 (qd, J=7.1, 1.9 Hz, 1H),
3.0 (s, 3H), 2.92 (s, 3H), 1.31 (d, J=7.1 Hz, 3H); 13C NMR
(300 MHz, CDCl3): d =198.9, 137.9, 49.7, 37.3, 35.6, 19.5;
MS (ES+): m/z=152.04 [M+1]+, C6H1NO2Na requires
152.07.
[RhACHTUNGTRENNUNG(acac)ACHTUNGTRENNUNG
(CO2)] (0.2 mol%), MeCgPPh (0.25 mol%), inter-
nal standard (methylnaphthalene, 33 mol% except en-
tries 1,2 and 4 in Table 1, standard omitted to ease isolation)
and a stirrer bar were placed in a clean dry microwave tube,
the tube capped and placed under an inert atmosphere and
toluene added. The alkene was added (1 mmol of alkene per
3 mL toluene) and the tube pierced with two disposable
needles and transferred to an autoclave under a flow of N2.
The autoclave was pressurised with syn gas (1:1), isolated
from the gas supply (the pressure drop on completion of re-
action is less than 1 bar) and heated to the desired tempera-
ture using a heating jacket. For the cage-phosphine catalysts,
activation and reaction rates are so fast that no pre-activa-
tion is neccessary. After 2 h stirring (stirring bead) the auto-
clave was allowed to cool and depressurised in the fume
1
(8B): Yield: 88 mg (56%). H NMR (300 MHz, CDCl3): d
=9.57 (d, J=2.3 Hz, 1H), 3.42 (qd, J=7.2, 2.3 Hz, 1H),
3.16–3.38 (m, 4H), 1.32 (d, J=7.2 Hz, 3H), 1.14 (t J=
7.2 Hz, 3H), 1.06 (t, J=7.2 Hz, 3H); 13C NMR (300 MHz,
CDCl3): d =199.4, 168.8, 51.2, 48.7, 46.2, 20.6, 20.5, 12.2; MS
(CI+): m/z=158.12 [M+1]+, C10H20NO2 requires 158.12.
1
(9B): Yield: 46 mg (25%). H NMR (300 MHz, CDCl3): d
=9.65 (d, J=2.3 Hz, 1H), 3.94 (septet, J=6.8 Hz, 1H), 3.55
(septet, J=6.8 Hz , 1H), 3.47 (qd, J=7.1, 2.3 Hz, 1H), 1.31–
1.44 (m, 9H), 1.19–1.27 (m, 6H); 13C NMR (300 MHz,
CDCl3): d =199.4, 168.8, 51.2, 48.7, 46.2, 21.2, 20.6, 20.5,
12.2; MS (CI+): m/z=186.15 [M+1]+, C10H20NO2 requires
1
cupboard. The product was analysed by H NMR to obtain
% conversion and selectivity and products isolated through
flash chromatography if required.
186.15.
1
(10B): Yield: 90 mg (21%). H NMR (400 MHz, CDCl3):
d =9.64 (d, J=1.9 Hz, 1H), 3.63–3.77 (m, 4H), 3.22 (s, 3H),
1.34 (d, J=7.2 Hz, 3H); 13C NMR (400 MHz, CDCl3): d=
196.9, 169.7, 60.5, 48.6, 31.2, 10.2; HR-MS (CI+): m/z=
146.0815 [M+1]+, C6H12NO3 requires 146.0817.
(B) General Procedure for Rhodium-Catalyzed
Hydroformylation using Air-Sensitive Ligands
A 1 mgmLÀ1 stock solution of [Rh
ACTHNUTRGNEUGN(acac)(CO)2] (0.2 mol%)
in dry, degassed toluene (3 mL) was prepared under an inert
atmosphere. The required amount of air-sensitive phospho-
rus ligand (0.25 mol%) was added to a microwave vial con-
taining a stirring bead, the vial capped and purged under an
inert atmosphere. The desired volume of rhodium stock so-
lution (1 mL for 1 mmol of substrate) was added to the li-
gands under inert conditions. A stock solution in dry, de-
gassed toluene of the alkene substrate and tetraethylsilane
(or methylnaphthalene) internal standard was prepared and
the required amount added to the microwave vial containing
the catalyst. This vial was pierced with two disposable nee-
dles and placed in an autoclave under a flow of N2. The au-
toclave was pressurised using syn gas (1:1) and heated to the
desired temperature using a heating jacket with magnetic
stirring. When the required reaction time was complete the
autoclave was allowed to cool to room temperature, then
depressurised in the fume cupboard. The product was ana-
General Procedure for Reduction of Aldehyde
Products to Alcohols
Solvent was removed from a crude hydroformylation reac-
tion under reduced pressure. The remaing residue (~1 mmol
of aldehydes) was then dissolved in ethanol (3 mL) and
cooled to À788C. NaBH4 (1 mmol) was then added and the
reaction mixture was stirred overnight. HCl (1M) was
added dropwise until pH ~6. Dichloromethane (15 mL) and
water (10 mL) were then added sequentially. The water
layer was extracted with 3ꢆ15 mL portions of dichlorome-
thane and the combined organics dried over anhydrous
MgSO4. The solvent was removed under reduced pressure
and the resulting residue purified by flash chromatography.
(3B) (alcohol derived from 2B): Yield: 401 mg (79%);
[a]2D0: À14.7 (c 0.75, CDCl3, ee=43%); IR (nujol): nmax
=
1
1
lysed by H NMR using tetraethylsilane as internal standard
2933, 1653, 1467, 1261, 1036, 800 cmÀ1; H NMR (300 MHz,
CDCl3): d=3.62 (m, 2H), 2.96 (s, 3H), 2.87 (s, 3H), 2.75 (m,
1H), 1.06 (d, J=7.1 Hz, 3H); 13C NMR (300 MHz, CDCl3):
d=175.0, 63.9, 36.6, 36.1, 34.3, 18.3; HR-MS (CI+): m/z=
132.1027 [M+1]+, C6H14NO2 requires 132.1025.
to obtain % conversion. Conversion refers to the substrate
consumed, with selectivity to aldehydes referring to the
NMR yield of aldehyde isomers measured with reference to
1-methylnapthalene or tetraethylsilane as internal standard.
Adv. Synth. Catal. 2010, 352, 1047 – 1054
ꢄ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1053

Gary M. Noonan et al.
FULL PAPERS
A
Pringle, A. M. Ward, D. A. Zambrano-Williams, Dalton
Trans. 2005, 1079; c) B. Breit, E. Fuchs, Chem.
Commun. 2004, 694; d) A. van Rooy, E. N. Orji, P. C. J.
Kamer, P. W. N. M. van Leeuwen, Organometallics
1995, 14, 34.
two steps, one isolation); [a]2D0: À22.2 (c 4.0, CDCl3, ee=
62%) [Lit.[16] À33.58 (c 1.15 CHCl3, pure R-enantiomer); IR:
nmax =3408, 2974, 2935, 2876, 1617, 1464, 1381, 1264, 1219,
1150, 1123, 1040 cmÀ1 1H NMR (400 MHz, CDCl3): d=
;
3.62–3.71 (m, 2H), 3.14–3.50 (m, 5H), 2.7–2.83 (m, 1H),
1.16 (t, J=7.0 Hz, 3H) 1.13 (d, J=7.0 Hz, 3H), 1.07 (t, J=
7.0 Hz, 3H); 13C NMR (400 MHz, CDCl3): d=175.6, 65.1,
41.8, 40.0, 37.5, 14.7, 14.3, 13.0; HR-MS (ES+): m/z=
182.1163 [M+Na]+, C8H17NO2Na requires 182.1157.
[4] Some recent tandem processes: a) P. S. Bꢇuerlein, I. A.
Gonzalez, J. J. M. Weemers, M. Lutz, A. L. Spek, D.
Vogt, C. Mꢈller, Chem. Commun. 2009, 4944; b) S.
Chercheja, T. Rothenbꢈcher, P. Eilbracht, Adv. Synth.
Catal. 2009, 351, 339; c) S. Chercheja, P. Eilbracht, Adv.
Synth. Catal. 2007, 349, 1897; d) O. Abillard, B. Breit,
Adv. Synth. Catal. 2007, 349, 1891.
[5] Reviews on tandem processes: a) P. Eilbracht, L. Bꢇr-
facker, C. Buss, C. Hollmann, B. E. Kitsos-Rzychon,
C. L. Kranemann, T. Rische, R. Roggenbuck, A.
Schmidt, Chem. Rev. 1999, 99, 3329; b) P. Eilbracht, A.
Schmidt, Top. Organomet. Chem. 2006, 18, 65.
[6] M. Dieguez, O. Pamies, A. Ruiz, S. Castillon, C.
Claver, Chem. Eur. J. 2001, 7, 3086.
ACHTUNGTRENNUNG(12B) (alcohol derived from 9B): Yield: 105 mg (56%
over two steps, one isolation); [a]2D0: À12.2 (c 2.1, CDCl3,
ee=50%). IR: nmax =3422, 2967, 1617, 1444, 1371, 1210,
1
1137, 1028 cmÀ1; H NMR (400 MHz, MeOD): d=3.97–4.21
(m, 1H), 3.62 (dd, J=10.6, 7.4 Hz, 1H), 3.54 (m, 1H), 3.37
(dd, J=10.6, 6 Hz, 1H), 2.77–2.89 (m, 1H), 1.21–1.32 (m,
6H), 1.10–1–21 (m, 6H), 0.97 (d, J=6.8 Hz, 3H); 13C NMR
(400 MHz, CDCl3): d==174.4, 64.2, 47.1, 44.8, 37.8, 20.1,
20.0, 19.7, 19.5, 13.2; HR-MS (ES+): m/z=210.1464 [M+
Na]+, C10H21NO2Na requires 210.1470; anal. calcd. for
C10H21NO2: C 64.13, H 11.30, N 7.48; found: C 64.02, H
11.26, N 7.50.
[7] C. J. Cobley, K. Gardner, J. Klosin, C. Praquin, C. Hill,
G. T. Whiteker, A. Zanotti-Gerosa, J. L. Petersen,
K. A. Abboud, J. Org. Chem. 2004, 69, 4031.
[8] C. J. Cobley, J. Klosin, C. Qin, G. T. Whiteker, Org.
Lett. 2004, 6, 3277.
Acknowledgements
[9] S. Breeden, D. J. Cole-Hamilton, D. F. Foster, G. J.
Schwarz, M. Wills, Angew. Chem. 2000, 112, 4272;
Angew. Chem. Int. Ed. 2000, 39, 4106.
[10] J. E. Babin, G. T. Whiteker, Patent WO93/03839, 1993.
[11] a) K. Nozaki, N. Sakai, T. Nanno, T. Higashijima, S.
Mano, T. Horiuchi, H. Takaya, J. Am. Chem. Soc. 1997,
119, 4413; b) Y. Yan, X. Zhang, J. Am. Chem. Soc.
2006, 128, 7198; c) M. M. H. Lambers-Verstappen, J. G.
De Vries, Adv. Synth. Catal. 2003, 345, 478.
The authors thank Chirotech and EPSRC–Chemistry Innova-
tion Knowledge Transfer Network for funding (GMN), The
Royal Society of Edinburgh for the award of a “supports Re-
search” fellowship (MLC), and the European Union Interna-
tional Training Network (NANOHOST) for supporting the
collaboration between AP and MLC. Technical assistance
from Mrs. Melanya Smith, Mr. Peter Pogorzelec, and Mrs.
Carolyn Horsburgh is also gratefully acknowledged.
[12] T. P. Clark, C. R. Landis, S. L. Feed, J. Klosin, K. A.
Abboud, J. Am. Chem. Soc. 2005, 127, 5040.
[13] A. T. Axtell, C. J. Cobley, J. Klosin, G. T. Whiteker, A.
Zanotti-Gerosa, K. A. Abhoud, Angew. Chem. 2005,
117, 5984; Angew. Chem. Int. Ed. 2005, 44, 5834.
[14] a) A. Suꢁrez, M. A. Mꢀndez-Rojas, A. Pizzano, Orga-
nometallics 2002, 21, 4611; b) S. Vargas, M. Rubio, A.
Suꢁrez, D. del Rꢃo, E. ꢉlvarez, A. Pizzano, Organome-
tallics 2006, 25, 961; c) M. Rubio, A. Suꢁrez, E. ꢉlvar-
ez, C. Bianchini, W. Oberhauser, M. Peruzzini, A. Piz-
zano, Organometallics 2007, 26, 6428.
[15] a) M. L. Clarke, G. J. Roff, Chem. Eur. J. 2006, 12,
7978; b) M. L. Clarke, Tetrahedron Lett. 2004, 45, 4043.
[16] F. Souscy, L. Grenier, M. Behnke, A. Destree, T. Mc-
Cormack, J. Adams, L. Plamondon, J. Am. Chem. Soc.
1999, 121, 9967.
References
[1] a) P. W. N. M. Van Leeuwen, C. Claver, Rhodium Cata-
lysed Hydroformylation, 2000, Kluwer Academic Pub-
lishers, Dordrecht; b) F. Ungvary, Coord. Chem. Rev.
2004, 248, 867; c) F. Agbossou, J. F. Carpentier, A. Mor-
treaux, Chem. Rev. 1995, 95, 2485; d) M. Dieguez, O.
Pamies, C. Claver, Tetrahedron: Asymmetry 2004, 15,
2113; e) M. L. Clarke, Curr. Org. Chem. 2005, 9, 701;
f) B. Breit, W. Seiche, Synthesis 2001, 1; g) J. Klosin,
C. R. Landis, Acc. Chem. Res. 2007, 40, 1251.
[2] a) P. C. J. Kamer, P. W. N. M. Van Leeuwen, J. N. H.
Reek, Acc. Chem. Res. 2001, 34, 895; b) C. P. Case, G.
T
Whiteker M. G. Melville, L. M. Petrovich, JA.
[17] a) G. Consiglio, L. Kollar, R. Kolliker, J. Organomet.
Chem. 1990, 396, 375; b) L. Garcia, C. Claver, M. Die-
guez, A. M. Masdeu-Bulto, Chem. Commun. 2006, 191.
[18] S. H. Gellman, T. J. Peelen, Y. Chi, Org. Lett. 2005, 7,
3469.
[19] a) M. L. Clarke and G. J. Roff, Green Chem. 2007, 9,
792; b) unpublished results.
[20] N. Kuhnert, A. Le Gresley, Org. Biomol. Chem. 2005,
3, 2175.
Gavney, D. R. Powell, J. Am. Chem. Soc. 1992, 114,
5535; c) G. D. Cuny, S. L. Buchwald, J. Am. Chem. Soc.
1993, 115, 2066; d) H. Klein, R. Jackstell, K. D. Wiese,
C. Borgmann, M. Beller, Angew. Chem. 2001, 113,
3505; Angew. Chem. Int. Ed. 2001, 40, 3408; e) M.
Beller, B. Cornils, C. D. Frohning, C. W. Kohlpainter, J.
Mol. Catal. A: Chemical 1995, 104, 17; f) B. Breit W.
Seiche, J. Am. Chem. Soc. 2003, 125, 6608.
[3] a) B. Breit, R. Winde, T. Mackewitz, R. Paciello, K.
Harms, Chem. Eur. J. 2001, 7, 3106; b) R. A. Baber,
M. L. Clarke, K. Heslop, A. Marr, A. G. Orpen, P. G.
[21] Y. Yoshitomi, K Makino, Y. Hamada, Org. Lett. 2007,
9, 2457.
1054
asc.wiley-vch.de
ꢄ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 1047 – 1054