α-Tetrasubstituted Aldehydes through Electronic and Strain-Controlled Branch-Selective Stereoselective Hydroformylation

Article abstract of DOI:10.1021/acs.joc.8b01431

Hydroformylation utilizes dihydrogen, carbon monoxide, and a catalyst to transform alkenes into aldehydes. This work applies chiral bisdiazaphospholane (BDP)- and bisphospholanoethane-ligated rhodium complexes to the hydroformylation of a variety of alkenes to produce chiral tetrasubstituted aldehydes. 1,1′-Disubstituted acrylates bearing electron-withdrawing substituents undergo hydroformylation under mild conditions (1 mol % of catalyst/BDP ligand, 150 psig gas, 60 °C) with high conversions and yields of tetrasubstituted aldehydes (e.g., 13:1 regioselectivity, 85% ee, and <1% hydrogenation for 1-fluoromethyl acrylate). The scope also encompasses both acyclic 1,1′-disubstituted and trisubstituted, electron-poor alkenes as well as di- and trisubstituted alkenes composed of small rings with exocyclic and endocyclic unsaturation. For example, 1-methylene-β-lactam furnished the tetrasubstituted aldehyde with 98% selectivity and up to 83% ee. Notably, chiral trisubstituted bicyclic methyleneaziridines are transformed with >99% regioselectivity and >19:1 diastereoselectivity to tetrasubstituted aldehydes at rates >50 catalyst turnovers/hour. NMR studies of the noncatalytic reaction of HRh(BDP)(CO)₂ with methyl 1-fluoroacrylate enable interception of tertiary alkylrhodium intermediates, demonstrating migratory insertion to acyl species is slower than formation of secondary and primary alkylrhodium intermediates. Overall, these investigations reveal how the interplay of sterics, electronics, and ring strain are harnessed to provide access to valuable α-tetrasubstituted aldehyde synthetic building blocks by promoting branched-selective hydroformylation.

Full text of DOI:10.1021/acs.joc.8b01431

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Article
#-Tetrasubstituted aldehydes through electronic and strain-
controlled branch-selective stereoselective hydroformylation
Josephine Eshon, Floriana Foarta, Clark R. Landis, and Jennifer M Schomaker
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01431 • Publication Date (Web): 02 Aug 2018
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The Journal of Organic Chemistry
α-Tetrasubstituted aldehydes through electronic and strain-controlled branch-selective
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stereoselective hydroformylation
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Josephine Eshon, Floriana Foarta, Clark R. Landis* and Jennifer M. Schomaker*
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Department of Chemistry, University of Wisconsin-Madison, 1101 University Avenue, Madison,
WI 53706 (USA)
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Corresponding authors: landis@chem.wisc.edu, schomakerj@wisc.edu
Abstract
Hydroformylation utilizes dihydrogen, carbon monoxide, and a catalyst to transform alkenes
into
aldehydes.
This
work
applies
chiral
bisdiazaphospholane
(BDP) and
bisphospholanoethane (BPE)-ligated rhodium complexes to the hydroformylation of a variety
of alkenes to produce chiral tetrasubstituted aldehydes. 1,1'-Disubstituted acrylates bearing
electron-withdrawing substituents undergo hydroformylation under mild conditions (1 mol%
catalyst/BDP ligand, 150 psig gas, 60 °C) with high conversions and yields of tetrasubstituted
aldehydes (e.g., 13:1 regioselectivity, 85% ee, and <1% hydrogenation for 1-
fluoromethylacrylate). The scope also encompasses both acyclic 1,1'-disubstituted and
trisubstituted, electron-poor alkenes, as well as di- and trisubstituted alkenes comprised of
small rings with exocyclic and endocyclic unsaturation. For example, 1-methylene--lactam
furnished the tetrasubstituted aldehyde with 98% selectivity and up to 83% ee. Notably, chiral
trisubstituted bicyclic methyleneaziridines are transformed with >99% regioselectivity and
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>19:1 diastereoselectivity to tetrasubstituted aldehydes at rates >50 catalyst turnovers/hour.
NMR studies of the non-catalytic reaction of HRh(BDP)(CO)2 with methyl 1-fluoroacrylate
enable interception of tertiary alkyl-rhodium intermediates, demonstrating migratory insertion
to acyl species is slower than formation of secondary and primary alkyl-rhodium intermediates.
Overall, these investigations reveal how the interplay of sterics, electronics, and ring strain are
harnessed to provide access to valuable α-tetrasubstituted aldehyde synthetic building blocks
by promoting branched-selective hydroformylation.
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Introduction
Hydroformylation is a well-established commodity process for the synthesis of linear
aldehydes from alkenes, carbon monoxide and dihydrogen.1 However, applications of the
branch-selective asymmetric hydroformylation (AHF) to the syntheses of chiral aldehydes,
which serve as useful synthons in the production of pharmaceuticals and fine chemicals, are
underdeveloped. More recently, successful AHF of diverse monosubstituted alkenes2 have
been reported using Rh complexes supported by chiral ligands (Figure 1) that include
BisDiazaphos3 (L1), Ph-BPE (L2), Chiraphos (L3), DIOP (L4), BINAP (L5) and P-chirogenic
ligands such as QuinoxP* (L6).4
Figure 1. Common ligands for asymmetric hydroformylation.
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In comparison to AHF reactions of monosubstituted alkenes, the analogous
transformations of 1,1'- and 1,2-disubstituted alkenes have been significantly more challenging
and display limited scope.5 In particular, 1,1'-alkene AHF reactions are scarcely reported,
proceed more slowly than those of mono- or 1,2-disubstituted alkenes, and tend to favor linear
selectivity (according to Keuleman’s rule).6 Despite the volume of literature describing
enantioselective hydroformylation, only four examples of distinct 1,1'-disubstituted alkenes
undergoing branch-selective AHF have been reported (Scheme 1).7 The groups of Gladiali,8
Alper,9 and Breit10 achieved successful AHF reactions of N-acylaminoacrylate, α-methylene-γ-
butyrolactone and 1,3-dichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene, respectively. These
reactions proceed with high branch-selectivity, but require high pressures and furnish only
modest enantioselectivities. Alkene hydrogenation is a common side reaction, especially in the
case of the acrylate derivatives. Buchwald11 found that Rh(CO)2acac supported by a (R,R)-
QuinoxP* ligand promotes AHF of 1-(trifluoromethyl)ethenyl acetate to deliver the aldehyde in
91% ee; further oxidation furnished the 2-trifluoromethyl lactic acid in 99% ee. Finally, Zhang12
achieved the same transformation of 1-(trifluoromethyl)ethenyl acetate using a BIBOP ligand
to give aldehyde in 80% ee (not shown).
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Scheme 1. Known examples of AHF of 1,1'-disubstituted alkenes.
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The lack of branch-selective AHF reactions for the construction of tetrasubstituted,
stereogenic centers is unfortunate, as this remains a formidable challenge in organic
synthesis. The prevalence of quaternary methyl-bearing stereocenters in numerous drug
candidates (Figure 2) and bioactive natural products inspired us to target α-tetrasubstituted
aldehydes as particularly attractive intermediates, due to the synthetic versatility of the
carbonyl group and the inability of the stereogenic center to racemize via enolization. Methods
reported to generate enantioenriched α-tetrasubstituted aldehydes include organocatalysis13,
chiral auxiliary-controlled14 or Pd-catalyzed asymmetric alkylations,15 reactions of prochiral
enol derivatives,16 and stereocontrolled cycloadditions.17 However, these approaches
generally suffer from limited substrate scope, lack of predictable regio- and stereoselectivity,
and/or low cost-efficiency. Thus, branch-selective AHF of 1,1'-disubstituted or trisubstituted
alkenes might offer a convenient strategy to produce enantioenriched α-tetrasubstituted
aldehydes, provided the scope of the chemistry can be expanded.
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Figure 2. Representative examples of drugs and bioactive molecules with quaternary
stereocenters.
Previous studies of AHF from the Landis group showed that 1,2-disubstituted alkenes
bearing groups that withdraw electron density through the σ framework, including enol esters,
enamides, vinyl arenes, vinyl fluorides or acrylates, did not follow the general steric preference
for the linear aldehyde products and instead favored the branched regioisomer.2b,5 We
hypothesized that strong electron-withdrawing groups might also promote the branched-
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selective AHF of a range of 1,1'-disubstituted alkenes to give tetrasubstituted aldehydes, a
proposal that is supported by the results in Scheme 1. As a complement to electronic control,
we were also curious to explore the potential of ring strain to improve the reactivity and
branch-selectivity of Rh-catalyzed hydroformylations. Herein, we report highly selective and
practical AHF reactions of diverse 1,1'-disubstituted and 1,1',2-trisubstituted alkenes to furnish
enantioenriched α-tetrasubstituted aldehydes.
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Results and discussion
Electronic control of regioselectivity for the AHF of 1,1'-disubstituted alkenes to produce α-
tetrasubstituted aldehydes. Initial studies focused on methyl 2-fluoroacrylate 1 (Table 1), a
commercially available compound expected to furnish the tetrasubstituted aldehyde 1b, due to
the presence of the two electron-withdrawing substituents on the alkene. The α-fluoroaldehyde
1b has high synthetic value as a β-fluoroamine precursor, a motif occurring in several drug
candidates.18 Current approaches to 1b rely on stereoselective, organocatalytic fluorination
methods, but these strategies display limited scope and utilize expensive catalysts and non-
atom-economic fluorinating agents.19 Successful branch-selective AHF would provide a
selective and efficient route to 1b from commercially available starting materials.
Ligands L1-L6 (Figure 1) were investigated for the AHF of 1 in the presence of a
Rh(CO)2acac catalyst precursor at 400 psi CO/H2 (7:1) and 60 °C. Under these mild reaction
conditions, L1 and L2 display high regio- and enantioselectivities (entries 1-2), with L1
delivering a conversion of 96% of 1 after 3 h. Ligands L4 and L6 (entries 4, 6) afford high
branch-selectivity, but modest ee; L3 and L5 (entries 3, 5) show no appreciable conversion of
1 and only starting material was recovered. Given these results, L1 and L2 were chosen for
further investigations.
Table 1. Ligand screening in AHF of Me-2-fluoroacrylate 1.
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The effects of CO/H2 ratios and temperature on the AHF of 1 using L1 are highlighted in
Table 2. A general problem with AHF of 1,1'-disubstituted alkenes is competing hydrogenation;
we hypothesized that a gas mixture enriched in CO, as compared to H2, would favor reaction
of tetrasubstituted Rh-alkyl intermediate to give the aldehyde, rather than the hydrogenation,
product. Higher CO partial pressures (entry 1 vs. entries 2-3) and lower temperatures (entry 3)
do lead to higher hydroformylation:hydrogenation ratios, with a slight increase in ee noted at
the lower temperature. Because the results at 150 psi (entry 1) revealed selectivities similar to
350 psi, all remaining studies were conducted at 150 psi in glass pressure bottles, a more
practical and less expensive alternative to metal bomb reactors.
Table 2. CO pressure and temperature effect in the AHF of 1.
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Using the conditions established in Tables 1-2, we examined the scope of α-substituted
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acrylates, many of which are commercially available, in AHF (Table 3). This substrate class
was chosen due to previous results showing that ester groups in 1,2-disubstituted alkenes
could direct the regioselectivity in hydroformylation.5 Acrylates 1-10 were tested in the
presence of both (S,S,S)-BisDiazaphos (L1) and (S,S)-Ph-BPE (L2). As previously mentioned,
the methyl ester of 2-fluoropropenoic acid 1 (entry 1) gave excellent selectivity for the
branched aldehyde 1b and a good ee of 85% using L1. In contrast, ligand L2 exhibits poor
selectivity and conversion. With L1, replacement of the F substituent with the CF3 group of
trifluoromethyl acrylate 2 (entry 2) affords modest selectivity for the branched aldehyde 2b;
however, significant amounts of 2h were also observed. Comparison between 1 and 2
suggests that smaller electron-withdrawing groups are required for branch-selective
hydroformylation; larger groups may slow the rate of desired CO migratory insertion in the
alkyl-Rh intermediate in favor of competing hydrogenation.
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Table 3. AHF of α,β-unsaturated esters.
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The use of α-acetoxy acrylate 3 (entry 3) also results in excellent branched selectivity to
deliver 3b in 98% yield over 2 h in the presence of Rh/L1; although Rh/L2 gives good
branched selectivity, the yield of 3b is modest and significant hydrogenation to 3h is observed.
Lowering the temperature from 60 to 40 °C improves the ee from 73% (entry 2) to 85% ee.
Interestingly, the nature of the group on the enol ester has a significant impact on the ee; while
the Me group in 3 gives 73% ee, replacing Me with Ph lowers the ee of the branched product
to 16% ee with L1 (see the SI for details). Replacement of the enol ester with an amido group
in 4 (entry 4) gives poor reactivity and selectivity, yielding significant hydrogenation product 4h
in addition to the desired 4b. AHF of phenyl acrylate 5 (entry 5) proceeds predominantly with
branched selectivity to give 5b in the presence of Rh/L1 (65% conversion after 24 h), but with
poor enantiocontrol (13% ee). Rh/L2 largely gives hydrogenation to 5h under the same
conditions. These results again point to the need for a small R group to achieve good
selectivity for hydroformylation over hydrogenation.
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The exclusive linear selectivity using 6 (Table 3, entry 6) gave us an opportunity to
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examine the reason behind the lack of branched product 6b (Scheme 2). Two general
scenarios can be envisioned; in the first, only the linear Rh-alkyl intermediate is formed, which
goes on to form the linear aldehyde 6l (Scheme 2A). A second scenario involves formation of
both linear and branched alkyl intermediates, but only the linear one goes on to form 6l, while
the branched one undergoes β-hydride elimination to regenerate 6. To probe if formation of the
branched Rh-alkyl intermediate is reversible, deuterioformylation of 6 was conducted (Scheme
2B). This technique has been used to probe the reversibility of intermediate formation in
similar reactions of 1,1'-diphenylethene20 and monosubstituted alkenes.21
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Incorporation of deuterium at the terminal vinyl position of 6 to yield 6-D would be
indicative of reversible formation of the branched alkyl intermediate. Indeed, analysis of the
crude deuterioformylation mixture at low conversion of 6 (3%) revealed two major products:
Scheme 2. Linear-selective hydroformylation (A) and deuterioformylation of 6 (B).
the expected deuterated linear aldehyde 6l-D and the deuterated alkene 6-D, in an
approximate ratio of 1.2:1. Scrambling of D into the substrate indicates that the tertiary alkyl-
Rh intermediate forms, but reverts via β-hydride elimination more rapidly than the desired
migratory insertion of CO that would produce the tetrasubstituted aldehyde product.
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The scope of AHF to give tetrasubstituted aldehydes is not limited to alkenes bearing two
electron-withdrawing groups. The methoxy-substituted acrylate 7 (entry 7) proceeds with
excellent branched selectivity and 90% ee with both L1 and L2, displaying 73% and 53%
conversion of 7 after 72 h, respectively. Hydroformylation of the less electronically activated
methyl methacrylate22 8 (entry 8) provides excellent regioselectivity in the presence of Rh/L2.
The AHF again proved sensitive to increased steric demand, as reaction of ethyl methacrylate
9 (entry 9) leads to poor branched selectivity, due to isomerization of the starting material to a
trisubstituted alkene. Hydroformylation of 9 at 40 °C increased the extent of isomerization.
Interestingly, hydroformylation of 8-10 with L2 results in greater reactivity and a higher
branched-to-linear selectivity than with L1, although the reasons for this are not yet clear. In
the case of 10 (entry 10), Rh/L2 afforded the highest reported ee to date for this alkene at 95%
ee, contrasting with the 36% ee reported by Alper with the same substrate (see Scheme 1).9
Vinyl acetate derivatives also produce tetrasubstituted aldehydes under AHF conditions
(Table 4). As shown in Table 3, entry 3 and Table 4, entry 1, AHF of methyl-2-acetoxyacrylate
3 with Rh/L1 proceeds with excellent selectivity for the tetrasubstituted aldehyde 2b and >70%
ee. AHF of 1-(trifluoromethyl)vinyl acetate 11 (entry 2), previously investigated by Buchwald
using ligand L6,11 affords high regioselectivity with both L1 and L2 (entry 2) and good ee of
85% and 92%, respectively. The AHF of 1-cyanovinyl acetate 12 (entry 3) gave 95%
conversion to the tetrasubstituted aldehyde in 61% ee in the presence of Rh/L1, lower than the
85% ee observed for 11; however, lower reaction temperatures would be expected to increase
the ee. Lastly, AHF of isopropenyl acetate 13 (entry 4) with Rh/L1 resulted in modest reactivity
and selectivity for the tetrasubstituted aldehyde (29%), illustrating the importance of having at
least one moderately electron-withdrawing group installed on the alkene precursor to achieve
good branched selectivity and ee.
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Table 4. AHF of enol ester 1,1'-disubstituted alkenes.
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The data in Tables 3 and 4 are helpful in determining which substituents efficiently yield α-
tetrasubstituted aldehydes in AHF. General reactivity trends reveal that electron-deficient
alkenes with small substituents result in the best reaction rates, regioselectivity and ee. The
presence of the -CO2Me and –OAc groups on the alkene of 3 (Table 3, entry 3; Table 4, entry
1) give excellent b:l ratios with L1, along with promising ee. A direct comparison of the effect of
–CO2Me vs. –OAc as a directing group was made between 2 (Table 3, entry 2) and 11 (Table
4, entry 2); both substrates exhibit good branched-to-linear selectivity, albeit with significant
hydrogenation of 2 to 2h. The ee of 2b (15%) is also low, compared to the ee for 11b (85%
with L1, 92% with L2). Another direct comparison could be made between 8 (Table 3, entry 8)
and isopropenyl acetate 13 (Table 4, entry 4). In this case, the lower electronic activation
provided by the Me substituent resulted in a better 8b:8l ratio (>40:1 with L2) as compared to
13b:13l (~2:1-4:1 at low conversion), again pointing to the benefit of having at least one
strongly electron-withdrawing group present on the alkene.
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Enol esters and vinyl fluorides conjugated with ester and cyano groups (Table 3, entries 1,
3; Table 4, entries 1, 3) show remarkably fast rates; full conversion of starting material is
achieved within 2 h. In contrast, acrylates substituted with aryl, ether or alkyl groups require 24
h or more for satisfactory conversion at 1 mol % catalyst loading and 60 °C. Interestingly, rates
obtained with 1,1'-alkenes (up to 50 turnovers/h, Table 3, entries 1, 3) can surpass those
previously observed for 1,2-disubstituted enol esters and enamides (up to 17 turnovers/h)
under the same conditions.5
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In general, ligand L1 yields faster and more selective AHF than L2, although L2 shows
better selectivity for alkyl-substituted acrylates, such as 8-9 (Table 3, entries 8-9) and α-
methylene-ɣ-butyrolactone (entry 10). Thus, when screening new substrates, it is advisable to
try both L1 and L2.
Attempted hydroformylation of 1,1',2-trisubstituted alkenes. A limitation of the AHF of 1,1'-
disubstituted alkenes is that a methyl substituent is always present in the aldehyde product.
Given the fast reaction rates in the AHF of 1,1'-disubstituted alkenes 3 and 12, we thought that
electronically activated trisubstituted alkenes might perhaps be transformed to tetrasubstituted
Table 5. Attempted AHFs of trisubstituted alkenes.
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aldehydes under similar reaction conditions. Unfortunately, our initial attempts with a series of
electronically activated alkenes were unsuccessful (Table 5). Entries 1 and 2 showed no
appreciable conversion of either 14 or 15 to the desired tetrasubstituted aldehyde, while 16
formed only the hydrogenation product in excellent yield (entry 3).
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7
8
9
Exploration of ring strain to produce α-tetrasubstituted aldehydes via regioselective AHF.
The disappointing results in Table 5 required us to either identify a more active catalyst or
improve the reactivity of the alkene. We hypothesized that ring strain might both decrease the
steric burden on the reaction and increase alkene reactivity. Exocyclic alkenes 17-18 (Table 6,
entries 1-2) gave no branched selectivity and only linear products were observed. However, 19
gave small amounts (13%) of the tetrasubstituted aldehyde product (entry 3), suggesting that
strain may play some role in controlling the regioselectivity of the hydroformylation reaction.
The corresponding acyclic versions of these alkenes gave either poor conversion to the linear
aldehyde product or significant isomerization (see compounds 39-40 in the Supporting
Information for further details), due to the high preference for β-hydride elimination of the alkyl-
Rh intermediate, as compared to productive CO insertion to form the branched aldehyde.
The results in entries 1-3 demonstrated that ring strain alone is not sufficient to promote
effective branch-selective hydroformylation. We therefore examined the addition of electron-
withdrawing substituents to a series of strained 1,1'- disubstituted alkenes (Table 6, entries 4,
6-20). In many cases, these substrates exhibit enhanced reactivity in hydroformylation,
typically reaching full conversion within 2 h using 1 mol % of catalyst. For example,
hydroformylation of the β-lactam 20 gave excellent branched selectivity (98%) with Rh/L1 and
Rh/L2 (entry 4); the ee of 20α using Rh/L2 increases from 71% to a promising 83% when the
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°
temperature is decreased from 60 °C to 40 C. AHF of the analogous linear 2-methyl-N-
phenylacrylamide 21 (entry 5) was conducted for the purposes of comparison, but resulted in
both low reactivity (16-18% conversion) and poor branched selectivity, highlighting the
influence of ring strain on the success of branch selective hydroformylation.
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To further test the limits of this chemistry, a series of 1,1',2-trisubstituted cyclobutenes (Table
6, entries 6-8) were tested to assess whether combining ring strain and electronic activation
would enable a substrate class previously resistant to hydroformylation to undergo successful
reaction (Table 5, vide supra). To our delight, hydroformylation of 2-ethylidene-cyclobutan-1-
one 22 (Table 6, entry 6) exhibits complete conversion within 24 h and afforded the
tetrasubstituted aldehyde in 85% yield. However, increasing the bulk of the alkene substituent
from Me in 22 to cyclohexyl in 23 (entry 7) affords only 6% of the tetrasubstituted aldehyde,
along with 89% of the hydrogenated product. Presumably, the CO migratory insertion step
slows as a result of the increased steric bulk of the tertiary alkyl-Rh, thus favoring
hydrogenolysis. Finally, the competing effects of strain and electronics in four-membered rings
are highlighted using 24 (entry 8). The reaction produces only 24β in poor yields, suggesting
that electronics may overrule ring strain in terms of dictating the regioselectivity of the
hydroformylation event.
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As cyclobutenes in general did not provide sufficient ring strain to strongly favor production
of the α-tetrasubstituted aldehyde with broad scope, we turned our attention to
methylenecyclopropanes. Interestingly, the aryl-substituted cyclopropenes 25-27 showed
promise for dictating regioselectivity. Hydroformylation of 25 with the Rh/L1 catalyst affords
61% yield of the racemic tetrasubstituted aldehyde 25α and 39% of linear aldehyde 25β in
excellent dr (>19:1), favoring the syn diastereomer via substrate control. While the
regioselectivity was modest, greater selectivity (85% 26α) and dr (17.5:1 syn:anti) is observed
using Rh/L2 (entry 9). Similar selectivity is observed for 26-27 (entries 10-11). The aryl group
can be viewed as having an electronic, albeit remote, effect on the reaction; thus, we were
surprised to discover AHF of the electronically unactivated alkenes 7-methylenebicyclo-
[4.1.0]heptane 28 and 8-methylenebicyclo-[5.1.0]octane 29 (entries 12-13) yields 45% and
57% of the branched aldehydes 28α and 29α, respectively, using the Rh/L1 catalyst.
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1
The Journal of Organic Chemistry
Table 6. Exploring combinations of electronic effects and ring strain to control the
regioselectivity of hydroformylation.
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Furthermore, 84% and 83% of the same products are observed with the Rh/L2 catalyst
system. This impressive level of branched selectivity unique for electronically unactivated
alkenes and clearly emphasizes the important role that ring strain plays in influencing the
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regioselectivity in 1,1'-disubstituted alkenes. To further test the limits of this chemistry, two
1,1',2-trisubstituted methylenecyclopropanes 30 and 31 (Table 6, entries 14-15) were tested.
Increasing the steric bulk in 30 results in low conversion to the branched product (entry 14);
isomerization of the alkene and subsequent hydroformylation of the resulting disubstituted
alkene comprises the remaining mass balance. However, strained alkenes that cannot
isomerize, such as 31 (entry 15), provide good b:l selectivity using Rh/L1, although the results
were poor with Rh/L2 for reasons that are not yet clear.
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Finally, a series of chiral bicyclic methyleneaziridines (MA), reported by the Schomaker23-25
group as key intermediates en route to a variety of complex amine stereotriads, were tested in
the hydroformylation. The calculated ring strain of bicyclic MAs (~42 kcal/mol), coupled with
the unusual enamide-type substituent on the alkene, led us to propose that MA
hydroformylation would likely afford tetrasubstituted aldehydes with good rates. Indeed,
hydroformylation of 32 (entry 16) affords the desired aldehyde 32α in 2 h using 1 mol % of
Rh/L1. Hydroformylation can occur either syn or anti to the stereogenic carbon in 32 (Figure 3)
to give two possible diastereomers. The reaction preferentially occurs anti to the more
sterically demanding stereogenic carbon under the auspices of substrate control to give the
Figure 3. Stereoselective hydroformylation of 32.
anti diastereomer in >19:1 dr. Varying the R group in trisubstituted MAs (-Me vs. -C5H11 vs. -
CH2CH2Ph vs -iPr, entries 16-19, 32-35) does not have a detrimental effect on the
i
regioselectivity or dr of the reaction. However, slower rates are observed for the Pr-MA
substrate 35. Tetrasubstituted aldehydes 32α-35α are obtained in excellent yields and >19:1
dr in favor of the anti stereoisomer. Effective transfer of axial-to-point chirality from the original
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The Journal of Organic Chemistry
allene precursor enables these compounds to be accessed in enantioenriched form. However,
attempts to push the hydroformylation using a bicyclic methyleneaziridine containing a
tetrasubstituted alkene 36 (entry 20) were not successful and only intractable mixtures of
unidentifiable products were obtained.
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9
Investigating catalyst speciation using low temperature NMR. The presence of hydrogenated
alkene by-products, particularly in the case of the trisubstituted alkene 23 (Table 6, entry 7),
suggests a relatively slow CO migratory insertion step for sterically congested tertiary alkyl-Rh
intermediates. This situation leads to competitive trapping of the Rh-alkyl intermediate III.5
(Figure 4) with H2 to give III.6 before migratory insertion can occur to ultimately furnish the
desired III.8 through the intermediacy of III.7. We hypothesized that the alkyl intermediate may
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1
accumulate in high enough concentrations to be detectable by H NMR spectroscopy in the
absence of H2. This hypothesis was tested by direct NMR observation of the reaction of pre-
formed Rh(H)(CO)2(L7) catalyst 37 and 10 equiv of 1 as monitored by 31P{1H} NMR in the
absence of H2 at 0 °C and under 1 atm CO (Figure 5). Under passive gas-liquid mixing
conditions in a standard NMR tube, 37 (~83 ppm) was rapidly consumed and replaced by two
major species, each with two distinct 31P resonances.26 One species comprises a doublet-of-
Figure 4. Mechanistic model to rationalize the observed hydrogenation pathway during alkene
hydroformylation.
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doublet (dd) resonance at 71 ppm (1J P-Rh = 80 Hz, 2J P-P = 21 Hz) and a ddd resonance at 60
ppm (1JP-Rh = 167 Hz, 2JP-P = 21 Hz, 4JP-F = 12 Hz) whereas the second species exhibits a ddd
resonance at 75 ppm (1J P-Rh = 81 Hz, 2J P-P = 11 Hz, 3JP-F = 36 Hz) and a ddd at 43 ppm (1JP-Rh
1
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= 143 Hz, JP-P = 11 Hz, 3JP-F = 29 Hz). The resonances at 71 and 60 ppm were assigned to
9
the branched Rh-acyl species 38acyl and the resonances at 75 and 43 ppm to the branched
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Rh-alkyl species 38alkyl
.
The larger differences in the 31P chemical shifts of 38alkyl vs. 38acyl are consistent with
previous observations.21b,c The 1JP-Rh values of 80 and 143 Hz for 38alkyl and 81 and 167 Hz for
38acyl, respectively, are consistent with both intermediates existing as five-coordinate, trigonal
bipyramidal complexes. Characteristics of 19F, 19F{1H} and 19F{31P} NMR spectra distinguish
31
Figure 5. P{1H} monitoring of reaction of [Rh(H)(CO)2(rac-L7)] 37 with 1 (10 equiv) at 0 °C
under 1 atm CO in CD2Cl2. Spectra were taken every 3.5 min. Under actual AHF conditions,
L7 is slower than L1, but both ligands display similar selectivity (1% Rh/L7, CO/H2 150 psi 1:1,
40 °C, 3 h, [1] = 1.4 M in CH2Cl2: 17% conversion of starting material, >50:1 branched to
linear, 11:1 AHF to hydrogenation).
3
between the branched and linear isomers. The presence of quartets corresponding to JF-H
=
21 Hz and 23 Hz for 38acyl and 38alkyl, respectively, are indicative of branched hydrocarbonyls;
2
the linear complexes would display a JF-H coupling. In addition to 38acyl and 38alkyl, minor
resonances are visible at 74 and 42 ppm (both ddd) that are slightly upfield from the 38alkyl
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The Journal of Organic Chemistry
resonances. The resemblance in chemical shift and coupling constants to 38alkyl suggest that
this minor species is the diastereomer of 38alkyl
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.
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9
Further details of the reaction progress are revealed by cooling a mixture of 38alkyl and
38acyl to -30 °C and following the changes that occur upon warming (Figure 6). At -30 °C, the
resonances for the alkyl species 38alkyl sharpens to reveal two sets of resonances that we
interpret as diastereomeric alkyls in a ratio of approximately 3:1. Upon slow warming, these
peaks broaden somewhat and slowly transform to acyl resonances.26 Acyl formation is not
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Figure 6. 31P{1H} monitoring the reaction between [Rh(H)(CO)2(rac-L7)] 37 (83 ppm, 20 mM)
with 1 (10 equiv) while temperature increases from -30°C to room temperature. Spectra were
collected every 3.5 min.
complete unless more CO is added (established by separate experiments), because it is
limited by the amount of CO dissolved in solution under passive gas-liquid conditions.
Although the diastereomers of the 38acyl are not clearly resolved, it is clear that the major
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38alkyl diastereomer is converted to 38acyl faster than the minor diastereomer. These studies
establish a rare example of the interception of a trialkyl metal complex intermediate in a
catalytic reaction and establish that, compared with secondary and primaryl alkyl-Rh
intermediates, CO insertion into the tertiary alkyl-Rh bond is substantially slower. These
studies suggest that more detailed kinetic and mechanistic analyses of hydroformylation
processes to produce tetrasubstituted aldehydes are feasible.
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Conclusions
Tetrasubstituted stereogenic centers occur in numerous drug candidates and natural
products that are challenging to synthesize. AHF of 1,1'-disubstituted or 1,1',2-trisubstituted
alkenes is a convenient, atom-efficient strategy for making novel α-tetrasubstituted aldehydes.
To date, branched-selective AHF of these substrate classes has been fraught with issues
pertaining to control over the regio- and/or stereoselectivity of the reaction. In this work, we
have shown that fast and selective hydroformylations of 1,1'-disubstituted alkenes bearing
electron-withdrawing groups can be achieved using Rh catalysts supported by either
BisDiazaphos or Ph-BPE ligands. Acrylates and acetates in particular displayed
unprecedented rates (up to 50 turnovers/h) and selectivities (up to 95% ee and >50:1
branched selectivity) under mild conditions (150 psi CO/H2, 60 °C). NMR studies suggested
that alkene insertion to form a branched Rh-alkyl intermediate is fast; however, the CO
migratory insertion step is slow, leading to competitive trapping of this species by H2.
We have also reported the first examples to date of selective hydroformylations of 1,1',2-
trisubstituted alkenes, using a combination of ring strain and electronic effects and Rh
catalysts supported by either BisDiazaphos or Ph-BPE ligands. The desired α-tetrasubstituted
aldehyde products are furnished in good-to-excellent yields. Many of the 1,1',2-trisubstituted
alkenes show fast rates (up to 50 turnovers/h) and selectivities (>50:1 αβ, >19:1 dr) under mild
conditions (150 psi CO/H2, 60 °C). NMR studies suggested that the hydroformylation proceeds
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The Journal of Organic Chemistry
through a tetrasubstituted Rh-alkyl intermediate; rapid migratory insertion of CO leads to the
aldehyde in preference to competing hydrogenation products.
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Branch-selective hydroformylation occurs in competition with simple hydrogenation. This
work establishes correlations of substrate structure with hydrogenation vs. hydroformylation
tendencies. Such correlations will inform future efforts directed towards expanding the scope
of AHF of challenging substrates, exploring changes to the reaction conditions to further
improve selectivity and decrease hydrogenation and investigations of further mechanistic
details of these valuable transformations.
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Experimental section
I. General information. All glassware was either oven-dried overnight at 130 °C or flame-
dried, cooled under vacuum and purged with nitrogen before use. Unless otherwise specified,
reagents were used as obtained from the vendor without further purification. Mesitylene and
(carbethoxymethylene)-triphenylphosphorane were purchased from Sigma. (S)-(+)-1-Methoxy-
2-propylamine was obtained from Alfa Aesar. The (S,S)-Ph-BPE ligand (L2) was purchased
from either Strem Chemicals or Sigma Aldrich. Synthesis gas (1:1 CO:H2) and CO gas were
obtained from Airgas. The asymmetric hydroformylation (AHF) reactions were run in glass
pressure bottles purchased from Ace Glass Inc. Reactors were assembled as previously
reported.27 The bis-(S,S,S)-DiazaPhos ligand L1 and the Rh complex 37 were synthesized as
previously reported.21b
Diethyl ether was distilled from purple Na/benzophenone ketyl. Tetrahydrofuran was distilled
from purple Na/benzophenone ketyl or dried over alumni safety columns before use.
Dichloromethane, acetonitrile and toluene were dried over CaH2 and distilled before use. All
other solvents were purified using “Purification of Laboratory Chemicals”.28 All air- and
moisture- sensitive reactions were performed using standard Schlenk techniques under an
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atmosphere of nitrogen. Analytical thin layer chromatography (TLC) was performed utilizing
pre-coated silica gel 60 F254 plates containing a fluorescent indicator. Columns were
conducted using a gradient method. KMnO4 was used as stains reagent. Rh(acac)(CO)2] was
received from Dow Chemical and purified by passing it through cold toluene. Purified
[Rh(acac)(CO)2] was stored in a N2-filled glovebox. Syngas as a 1:1 CO:H2 was obtained from
Airgas. All pressures given are gauge pressures unless otherwise noted.
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1H NMR, 13C NMR, and 19F NMR spectra were obtained using Bruker-300, Varian-300,
13
Avance III 400, Varian Inova-500, or Varian Unity-500 spectrometers. C NMR spectra were
1
obtained using 125 MHz or 75 MHz instruments. H NMR spectra chemical shifts were
reported in accordance to residual protiated solvent peaks ( 77.2, 39.5, 128.0 and 137.9 ppm
for CDCl3, (CD3)2SO, C6D6, and CD3C6D5, respectively). Accurate mass measurements were
acquired at the University of Wisconsin, Madison using a Micromass LCT (electrospray
ionization, time-of-flight analyzer or electron impact methods). The NMR and Mass
Spectrometry facilities are funded by the NSF CHE-1048642 and NIH 1S10OD020022-1. GC
data was obtained on chiral BetaDex 225 column on a Shimadzu analytical GC-2010 Plus
equipped with an FID detector. Optical rotation data were obtained on a Randolph digital
polarimeter using a 1 mL cell with 0.5 dm path length at room temperature. The sign of the
optical rotation is reported for products after Wittig olefination. Silica gel flash column
chromatography was performed on Silicycle Siliaflash P60 230-400 mesh, 40-63 µm.
1
Conversion and regioselectivity were determined by crude H NMR. Isolated yields are
reported after 2 steps: AHF, followed by Wittig olefination of the crude AHF mixture with
(carbethoxymethylene)triphenylphosphorane.
Methyl 2-fluoroprop-2-enoate (1). The alkene was purchased from Alfa Aesar.
Methyl 2-(trifluoromethyl)-propenoate (2). The alkene was purchased from Alfa Aesar.
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Methyl 2-acetoxyacrylate (3). The alkene was prepared according to a reported literature
procedure.29
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5
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7
8
9
Methyl 2-acetamidoacrylate (4) The alkene was purchased from sigma Aldrich.
2-Phenyl-acrylic acid methyl ester (5). The alkene was prepared according to a reported
literature procedure.30
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Methyl 2-(2-methylphenyl)acrylate (6). The alkene was prepared according to a reported
literature procedure.30
Methyl 2-methoxylacrylate (7). The alkene was prepared according to a reported literature
procedure.31
Methacrylic acid methyl ester (8). The alkene was purchased from sigma Aldrich.
Methyl 2-ethylacrylate (9). The alkene was prepared according to a reported literature
procedure.32 1H NMR (500 MHz, CDCl3) δ 6.14 – 6.12 (m, 1H), 5.55 – 5.52 (m, 1H), 3.76 (s,
3H), 2.33 (qt, J = 7.3, 1.3 Hz, 2H), 1.08 (t, J = 7.4 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ
168.0, 142.3, 123.7, 51.9, 25.0, 12.8. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C6H11O2
115.0754, Found 115.0752.
α-Methylene-γ-butyrolactone (10). The alkene was purchased from Sigma Aldrich.
1,1,1-Trifluoro-2-(acetyloxy)-2-propene (11). The alkene was purchased from Alfa Aesar.
2-Acetoxyacrylonitrile (12). The alkene was purchased from TCI.
Isopropenyl acetate (13). The alkene was purchased from Sigma Aldrich.
Methyl (Z)-2-acetyloxybut-2-enoate (14). The alkene was purchased from Sigma Aldrich.
(Z)-Methyl 3-(4-bromophenyl)-2-fluoroacrylate (15). The alkene was prepared according to a
reported literature procedure.33
3-Methylfuran-2,5-dione (16). The alkene was purchased from Sigma Aldrich.
Methylenecyclohexane (17). The alkene was purchased from Acros Organics.
Methylenecyclopentane (18). The alkene was purchased from TCI.
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Methylenecyclobutane (19). The alkene was purchased from Sigma Aldrich.
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5
3-Methylene-1-phenylazetidin-2-one (20). The alkene was prepared according to a reported
literature procedure.34
6
7
8
2-Methyl-N-phenylacrylamide (21). The alkene was purchased from TCI.
9
2-Ethylidenecyclobutan-1-one (22). The alkene was prepared according to a reported literature
procedure.35
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(E)-2-Cyclohexylcyclobutanone (23). The alkene was prepared according to a reported
literature procedure.35
(Z)-Ethyl 2-(2-oxocyclobutylidene)acetate (24). The alkene was prepared according to a
reported literature procedure.36 1H NMR (500 MHz, CDCl3) δ 5.58 (pentet, J = 2.3 Hz, 1H),
4.14 (q, J = 7.1 Hz, 2H), 3.13 (m, 2H), 2.87 – 2.78 (m, 2H), 2.09 (pentet, J = 8.0 Hz, 2H), 1.27
(t, J = 7.1 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 168.0, 142.3, 123.7, 51.9, 25.0, 12.8. HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C8H13O2 141.0910; Found 141.0908.
1-Methylene-2-phenylcyclopropane (25). The alkene was prepared according to a reported
literature procedure.37 1H NMR (500 MHz, CDCl3) δ 7.29 – 7.23 (m, 2H), 7.17 – 7.13 (m, 3H),
5.59 – 5.55 (m, 2H), 2.60 (ddt, J = 9.4, 4.8, 2.0 Hz, 1H), 1.74 (tt, J = 9.2, 2.3 Hz, 1H), 1.21
(ddt, J = 9.3, 4.9, 2.3 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 142.1, 135.6, 128.5, 126.5, 126.0,
104.6, 20.3, 14.7. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C10H11 131.0855; Found 131.0853.
2-(4-Chlorophenyl)-1-methylenecyclopropane (26). The alkene was prepared according to a
reported literature procedure.37 1H NMR (500 MHz, CDCl3) δ 7.24 – 7.18 (m, 2H), 7.12 – 7.03
(m, 2H), 5.60 – 5.55 (m, 2H), 2.56 (ddt, J = 9.2, 4.6, 2.0 Hz, 1H), 1.75 (tt, J = 9.2, 2.3 Hz, 1H),
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1.17 (ddt, J = 9.2, 4.9, 2.3 Hz, 1H). C NMR (126 MHz, CDCl3) δ 140.6, 135.1, 131.6, 128.5,
127.9, 105.0, 19.7, 14.9. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C10H10Cl 165.0466; Found
165.0464.
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The Journal of Organic Chemistry
1-(p-Methoxyphenyl)-2-methylenecyclopropane (27). The alkene was prepared according to a
reported literature procedure.37 1H NMR (400 MHz, CDCl3) δ 7.13 – 7.03 (m, 2H), 6.86 – 6.75
(m, 2H), 5.57 (q, J = 2.1 Hz, 2H), 3.77 (s, 3H), 2.56 (ddt, J = 9.1, 4.3, 1.9 Hz, 1H), 1.69 (tt, J =
9.2, 2.2 Hz, 1H), 1.20 – 1.06 (m, 1H). 13C NMR (126 MHz, CDCl3) δ 158.0, 135.7, 133.9,
127.0, 113.9, 104.5, 55.4, 19.6, 14.3. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C11H13O
161.0961; Found 161.0460.
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7-Methylenebicyclo[4.1.0]heptane (28). The alkene was prepared according to a reported
literature procedure.37 1H NMR (400 MHz, CDCl3) δ 5.35 (t, J = 2.1 Hz, 2H), 1.86 – 1.71 (m,
2H), 1.71 – 1.59 (m, 2H), 1.57 – 1.46 (m, 2H), 1.31 – 1.16 (m, 4H). 13C NMR (126 MHz,
CDCl3) δ 142.9, 101.4, 22.9, 21.4, 12.9. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C8H13
109.1012; Found 109.1011.
9-Methylidenebicyclo[6.1.0]nonane (29). Prepared according to a reported literature
procedure.37 1H NMR (500 MHz, CDCl3) δ 5.29 (t, J = 2.1 Hz, 2H), 1.97 (dq, J = 14.7, 3.4 Hz,
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2H), 1.76 – 1.64 (m, 2H), 1.63 – 1.50 (m, 2H), 1.47 – 1.27 (m, 4H), 1.11 – 0.97 (m, 2H). C
NMR (126 MHz, CDCl3) δ 142.1, 101.1, 29.3, 26.4, 25.6, 19.4. HRMS (ESI-TOF) m/z: [M+H]+
Calcd for C10H17 137.1325; Found 137.1323.
Dodecylidenecyclopropane (30). The alkene was prepared according to a reported literature
procedure.38 1H NMR (500 MHz, CDCl3) δ 5.81 – 5.69 (m, 1H), 2.16 (m, 2H), 1.43 (m, 2H),
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1.36 – 0.98 (m, 20H), 0.88 (t, J = 6.9 Hz, 3H). C NMR (126 MHz, CDCl3) δ 121.0, 118.6,
32.1, 32.0, 29.8, 29.8, 29.8, 29.7, 29.6, 29.5, 29.5, 22.9, 14.3, 2.3, 2.0.
Ethyl cyclopropenylideneacetate (31). The alkene was prepared according to a reported
literature procedure.36 1H NMR (500 MHz, CDCl3) δ 6.22 (p, J = 2.0 Hz, 1H), 4.21 (q, J = 7.2
Hz, 2H), 1.49 – 1.41 (m, 2H), 1.30 (t, J = 7.1 Hz, 3H), 1.27 – 1.18 (m, 2H). 13C NMR (126 MHz,
CDCl3) δ 166.4, 145.1, 111.1, 60.3, 14.5, 4.7, 2.2. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C7H11O2 127.0754; Found 127.0752.
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(7E)-7-Ethylidene-3-oxa-1-azabicyclo[4.1.0]heptan-2-one (32). The alkene was prepared
according to a reported literature procedure. 39
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(7E)-7-Hexylidene-3-oxa-1-azabicyclo[4.1.0]heptan-2-one (33). The alkene was prepared
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(7E)-7-Benzylidene-3-oxa-1-azabicyclo[4.1.0]heptan-2-one-ethene (1/1) (34). The alkene was
prepared according to a reported literature procedure. 39
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II. General method for hydroformylation.
In a nitrogen-filled glovebox, a 15 mL Ace Glass glass pressure bottle equipped with a
magnetic stir bar was charged with a THF stock solution of (0.1 M) Rh(acac)(CO)2 and either
the bisdiazaphospholane ligand L1 or the (S,S)-Ph-BPE ligand L2 (0.04 or 0.05 M,
respectively) using 1000 μL and 200 μL Eppendorf® pipets. The glass bottle was attached to a
pressure reactor head and the apparatus was removed from the glovebox. The apparatus was
placed inside a fume hood and was charged with 5 pressurization (150 psi)/depressurization
(0 psi) cycles to completely replace the nitrogen atmosphere with syngas. The apparatus was
filled with either 150 psi of a 1:1 CO:H2 syngas mixture or 90 psi of CO and an additional 60
psi of syngas. The apparatus was placed in an oil bath and the reaction mixture stirred
vigorously for 30-60 min to ensure formation of the pre-activated catalyst. The reaction
apparatus was then removed from the oil bath and cooled for 5 min. The pressure was
reduced to 0 psi and a solution of the alkene in THF or a solution of alkene and mesitylene
(1/3 eq) in THF was injected with a gas-tight syringe using a 12" needle. The reaction was
then charged using 3 x 150 psi pressurization/0 psi depressurization cycles, taken to a final
pressure of 150 psi and placed in the oil bath at the desired temperature. The reaction mixture
was vigorously stirred for the specified period of time. The reactor was then removed from the
oil bath, cooled to room temperature and depressurized. A crude NMR sample was taken in
CDCl3 using 5 or 10 μL of mesitylene as an internal standard. The same crude NMR was used
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The Journal of Organic Chemistry
for GC analysis. Since CO is very toxic and H2 is flammable, a well-ventilated fume hood
should be used at all times.
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III. General procedure for asymmetric hydroformylations with pressures greater than
150 psi.
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A CAT24 reactor is charged with either a 100 mM stock solution of Rh(acac)(CO)2 (1%
catalyst loading, 48 µL) in toluene or THF, a 20 mM stock solution of ligand (1.2%, 264 µL) in
either toluene or THF and the alkene substrate (0.48 mmol) inside a N2 glove box. The reactor
is sealed and pressurized inside a fume hood, heated at the desired temperature with stirring
at 700 rpm. At the end of the indicated reaction time, the reactor is allowed to cool down for
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30 min and then depressurized. The crude reaction mixture is analyzed by H NMR and chiral
GC analysis.
IV. General Procedure for Wittig olefination of the aldehydes.
The crude mixture of aldehydes from the hydroformylation reaction is transferred to a 50 mL
oven-dried Schlenk flask. Under a flow of N2, (carbethoxymethylene)triphenylphosphorane
(1.2 eq) is added as a solution in dichloromethane (7 mL) at room temperature. The mixture is
allowed to stir at room temperature overnight under N2. The mixture is concentrated under
reduced pressure and the residue purified via silica gel chromatography using 20%
EtOAc/hexanes as the eluent.
V. General procedure for deuterioformylation.
An oven-dried, 15 mL glass pressure bottle equipped with a stir bar is charged with a 100
mM stock solution of Rh(acac)(CO)2 (1.0 mol% catalyst loading, 56.76 µL) in THF and a 30
mM stock solution of L1 (1.2 mol%, 189.2 µL) in THF inside a N2 glove box. The pressure
bottle was then attached to a pressure gauge and placed inside a fume hood. The reactor
was subjected to three pressurization (100 psig)/depressurization (20 psig) cycles with CO,
taken to a final pressure of 120 psig CO/30 psig D2 and placed in an oil bath at 60 °C for 1 h.
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The reactor was allowed to cool for 5 min and depressurized to 10 psig. The alkene 2-(2-
methylphenyl)acrylic acid methyl ester 6 (0.57 mmol, 100 mg) and the 1,4-bis-
trimethylsilylbenzene internal standard (0.1 eq, 6.31 mg) in THF were injected into the reactor
using a syringe (the amount of THF was adjusted to furnish a 1.6 M solution of the alkene).
The reactor was then pressurized/depressurized 3 times with CO, taken to a final pressure of
120 psig CO/30 psig D2 and placed in the oil bath set at 60 °C for 19 h. The mixture was
stirred vigorously, with the stir bar serving to break the gas-liquid interface for good gas-liquid
mixing. After the specified reaction time, the reactor was allowed to cool for 30 min and then
depressurized. An aliquot of the crude mixture was used for NMR analysis.
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VI. General Procedure for Low Temperature Non-catalytic Experiments.27
An oven-dried, 15 mL glass pressure bottle equipped with a stir bar was charged with 37 (60
mg) and 1 mL CD2Cl2 inside a N2 glove box and then attached to a pressure gauge. Inside a
fume hood, the reactor was subjected to three pressurization (150 psig)/depressurization (20
psig) cycles with syngas, then pressurized to 150 psig syngas and placed in an oil bath at 60
°C for 3 h. The reactor was allowed to cool for 5 min and depressurized to 10 psig. The
reactor was pressurized-depressurized 5 times with CO to ensure complete removal of any
remaining H2, then depressurized to 15 psig. The reactor was connected to an oven-dried and
septum-capped NMR tube via a cannula and the system purged with CO for 2 min. The
solution in the pressure bottle was then transferred to the NMR tube using the same cannula.
The NMR tube was then sealed with parafilm and placed in an NMR spectrometer cooled to 0
°C. An initial NMR spectrum of the Rh(H)(L7)(CO)2 solution was obtained, the tube ejected
from the spectrometer and methyl 2-fluoroacrylate 1 (18.26 µL) injected quickly through the
septum using a gas-tight syringe. The NMR tube was inverted 3 times, quickly returned to the
spectrometer and the 31P spectra collected immediately.
VII. Data for Hydroformylation of Alkenes.
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Methyl (2R)-2-fluoro-2-methyl-3-oxopropanoate (1b). 1H NMR (500 MHz, CDCl3) δ 9.65 (d, J =
5.7 Hz, 1H), 3.85 (s, 3H), 1.70 (d, J = 21.6 Hz, 3H). 19F NMR (377 MHz, CDCl3) δ -167.30. The
chiral separation was carried out via GC: 80 °C, hold 6 min, ramp 2 °C/min to 90 °C, hold 6
min, ramp 2 °C/min to 100 °C, hold 6 min, ramp 2 °C/min to 110 °C, hold 5 min, ramp 3 °C/min
to 120 °C, hold 5 min, tR (S) 14.8 min, tR (R) 21.1 min. The crude aldehyde was oxidized to a
carboxylic acid via a previously reported procedure,40 and the optical rotation [α]20D = +19.4 (c
= 1.00, MeOH) compared to that of a previously reported41 (S)-(-)-α-fluoro-α-methylmalonic
acid monoethyl ester, [α]20D = -22.5 (c = 2.20, MeOH).
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1-Ethyl 5-methyl (2E)-4-fluoro-4-methylpent-2-enedioate (1c). Hydroformylation was
conducted on a 1.92 mmol scale. After completion of the reaction, the crude material was
treated with (carbethoxymethylene)triphenylphosphorane to facilitate 72% (0.28 g) isolation of
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1c. H NMR (500 MHz, CDCl3) δ 7.01 (dd, J = 20.2, 15.7 Hz, 1H), 6.19 (d, J = 15.7 Hz, 1H),
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NMR (126 MHz, CDCl3) δ 169.6, 165.5, 143.4, 121.8, 93.1, 60.9, 53.2, 24.1, 14.2. F NMR
(377 MHz, CDCl3) δ -158.20. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C9H13FO4Na
227.0690; Found 227.0690.
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Methyl 3,3,3-trifluoro-2-formyl-2-methylpropanoate ( 2b). H NMR (400 MHz, CDCl3) δ 9.74 (s,
1H), 3.84 (s, 3H), 1.56 (s, 3H).
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Methyl 2-(acetyloxy)-2-methyl-3-oxopropanoate (3b). H NMR (500 MHz, CDCl3) δ 9.87 (s,
1H), 3.83 (s, 3H), 2.17 (s, 3H), 1.60 (s, 3H). Chiral separation via GC: 50 °C, ramp 2 °C/min to
100 °C, hold 2 min, ramp 6 °C/min to 150 °C, hold 2 min tR (major) 12.7 min, tR (minor) 14.9
min.
1-Ethyl 5-methyl (2E)-4-(acetyloxy)-4-methylpent-2-enedioate (3c). 1H NMR (500 MHz, CDCl3)
δ 7.16 (d, J = 15.9 Hz, 1H), 6.04 (d, J = 15.9 Hz, 1H), 4.21 (q, J = 7.1 Hz, 2H), 3.76 (s, 3H),
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2.13 (s, 3H), 1.68 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H). C NMR (126 MHz, CDCl3) δ 170.3, 169.5,
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