Regioselective Rh-Catalyzed Hydroformylation of 1,1,3-Trisubstituted Allenes Using BisDiazaPhos Ligand

Article abstract of DOI:10.1021/acs.joc.7b01140

The efficient hydroformylation of 1,1,3-trisubstituted allenes is accomplished with low loadings of a Rh catalyst supported by a BisDiazaPhos (BDP) ligand. The ligand identity is key to achieving high regioselectivity, while the mild reaction conditions m

Full text of DOI:10.1021/acs.joc.7b01140

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Featured Article
Regioselective Rh-catalyzed hydroformylation of 1,1,3-
trisubstituted allenes using BisDiazaPhos ligand
Josephine Eshon, Clark R. Landis, and Jennifer M Schomaker
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 16 Jun 2017
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Regioselective Rh-catalyzed hydroformylation of 1,1,3-trisubstituted allenes
using BisDiazaPhos ligand
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Josephine Eshon, Clark R. Landis* and Jennifer M. Schomaker*
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Department of Chemistry, University of WisconsinꢀMadison, 1101 University Avenue,
Madison, WI 53706 (USA)
Corresponding authors: landis@chem.wisc.edu, schomakerj@wisc.edu
Abstract
The efficient hydroformylation of 1,1,3ꢀtrisubstituted allenes is accomplished with low
loadings of a Rh catalyst supported by a BisDiazaPhos (BDP) ligand. The ligand identity
is key to achieving high regioselectivity, while the mild reaction conditions minimize
competing isomerization and hydrogenation to produce β,ɤꢀunsaturated aldehydes and
their derivatives in excellent yields.
Introduction
Rhꢀcatalyzed hydroformylation is a powerful and atomꢀeconomical method to
introduce valuable aldehyde functionality into a range of unsaturated substrates.1 While
hydroformylations of alkene2,3 and 1,3ꢀdiene4ꢀ7 substrates have been wellꢀexplored, only
a handful of reports describe the analogous reactions of allenes. Over 40 years ago,
Fell and Beutler reported a single example of the hydroformylation of a terminal allene
catalyzed by HRh(CO)(PPh3)3 to produce complex mixtures of monoꢀ and dialdehydes
as products.8 Nearly three decades after this initial report, Jiao et al. carried out
computational studies of Coꢀcatalyzed allene hydroformylation and surmised that
addition of H to the central carbon of the allene to give an η3–allyl complex is both
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kinetically and thermodynamically preferred.9 This prediction was borne out in 2015,
when the Breit group demonstrated the hydroformylation of 1,1ꢀdisubstituted allenes
using catalytic Rh(acac)(CO)2 supported by a 6ꢀDPPon ligand (Table 1) at 430 psi,
producing β,γ–unsaturated aldehydes in good yields and varying Z:E ratios.10
The ability to employ trisubstituted allenes in hydroformylation reactions would yield
valuable chiral β,γꢀunsaturated aldehydes not accessible from typical 1,3ꢀdienes or
terminal allenes. Chiral β,γꢀunsaturated aldehydes are useful building blocks that have
been employed in strategies directed towards the total synthesis of diverse natural
products that include premonensin, palmerolide C, matsone and the eicosanoids.10
However, the additional substitution and chirality at the carbon in the αꢀposition to the
aldehyde makes these compounds particularly susceptible to migration of the double
bond to place it into conjugation with the carbonyl group. This can render purification by
standard techniques, such as flash column chromatography, untenable. Thus, mild
methods that yield pure aldehydes under neutral conditions that minimize isomerization
are highly desirable.
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There are several challenges associated with the hydroformylation of trisubstituted
allenes, due to multiple competing reaction pathways that can be envisaged (Scheme
1). For example, hydroformylation can occur at either of the two double bonds of the
allene with two different regioselectivities to produce four different potential aldehyde
products. In addition to issues of regioselectivity, competing alkene hydrogenation and
secondary hydroformylation products must also be considered.11 Finally, isomerization
of the desired β,γꢀunsaturated aldehydes to α,βꢀunsaturated aldehydes must be
avoided. In this paper, we discuss our strategies to address these issues and achieve
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high regioselectivity under mild reaction conditions, while minimizing competing
isomerization and hydrogenation to produce β,ɤꢀunsaturated aldehydes and their
derivatives in excellent yields.
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Scheme 1. Possible reaction pathways for trisubstituted allenes under hydroformylation
conditions.
Results and Discussion
Initial optimization studies were carried out with the 1,1,3ꢀtrisubstituted allene 1 (Table
1), which is available in three simple steps from the corresponding aldehyde.12,13
A
selection of phosphineꢀbased ligands previously demonstrated to promote the
hydroformylation of alkenes and terminal allenes were tested.14,15 The ligands 6ꢀDPPon,
iPrꢀDuPhos, PhꢀBPE and BINAP all failed to yield significant conversion to aldehyde
products. Limited conversion to the desired 1a was achieved using the (R,R)ꢀQuinoxP*
and (+)ꢀDIOP ligands (entries 6ꢀ7), although small amounts of minor aldehydes were
also observed. Unique among the tested ligands was BisDiazaPhos (BDP) (entry 8),
which gave 64% conversion of 1 to 1a. In all cases, the formyl group was installed at the
less substituted terminal allene carbon; no addition of the formyl group to the central
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allenic carbon was detected in the reactions of 1a. While we do not fully understand the
reasons for the superior performance of BDP compared to other ligands in Table 1, we
speculate that the highly sterically congested environment of BDP yields a quadrant
map that places the less substituted allene carbon in an orientation that enables
delivery of the H to the central allene carbon, with the formyl group installed at the
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Table 1. Influence of ligand structure on the conversion and selectivity for
hydroformylation of 1.
0.1 mol % Rh(acac)(CO)2
0.12 mol % ligand[b]
Me Ph
1b
H
Me
Me
O
minor
aldehydes
+
Me
150 psig (1:1) CO/H2, 45 min
1a
1a
Ph
H
H
60 oC, THF or C7D8
entry
ligand
conversion[c]
selectivity 1a:1b
1
2
3
6ꢀDPPon
< 5%
< 5%
< 5%
1:1
1:1
1:1
(R,R)ꢀiPrꢀDuPhos
(S,S)ꢀPhenꢀBPE
4
5
6
7
8
(R)ꢀBINAP
(S,S)ꢀChiraphos
(R,R)ꢀQuinoxP*
(+)ꢀDIOP
< 5%
6%
12%
14%
64%
b
1:1
5:1
11:1
13:1
>64:1
(rac)ꢀBisDiazaphos
aConditions: 0.588 mmol 1 was used. Conditions: 1:1.2 Rh:ligand for
bidentate ligands; 1:2.4 Rh:ligand for monodentate ligands. cConditions:
Determined by 1H NMR of the crude reaction mixture using 5 L of
mesitylene as an internal standard.
iPr
Ph2P
Ph
P
P
P
Ph
N
6-DPPon
PPh2
PPh2
iPr
iPr
H
O
CH3
P
Ph
Ph
PPh2
iPr
Ph2P
CH3
(R,R)-iPr-DuPhos (S,S)-Ph-BPE
(R)-BINAP
(S,S)-
HN
Chiraphos
NH
Ph
CH3
P
Ph
Ph2P PPh2
O
O
O
O
O
O
N
N
N
N
t-Bu
t-Bu
N
N
P
P
O
O
P
O
O
Ph
Ph
H3C
CH3
CH3
HN
NH
(R,R)-
(rac)-BisDiazaPhos-SPM
(+)-DIOP
QuinoxP*
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carbon proximal to the least substituted terminal allene carbon.
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The influence of reaction conditions on the Rhꢀcatalyzed hydroformylation of 1 in the
presence of BDP ligand is summarized in Table 2. Variation of the ligand loading from
1.0 mol % to 0.1 mol % (entries 2ꢀ5) indicates that complete conversion of 1 to primarily
the β,γꢀunsaturated aldehyde 1a is achievable with only 0.1 mol % Rh loading if the
reaction time was increased to 2 h. However, longer reaction times resulted in
significant isomerization of 1a to the corresponding α,βꢀunsaturated aldehyde.
Increasing the reaction temperature to 80 °C (entry 6) resulted in competing allene
hydrogenation, yielding 18% of hydrogenation product 1c in addition to the desired 1a.
Because racemic BDP is not soluble in toluene, the ligand was switched to the more
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Table 2. Hydroformylation results for 1 given as % NMR yield (% conversion) under
varying reaction conditions (mol % of BDP and Rh, solvent, syngas pressure (psig),
temperature (°C), and reaction time (hours).
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soluble (S,S,S)ꢀBisDiazaPhos (entry 7) to test the influence of solvent polarity; slightly
higher yields were obtained in THF solvent than toluene. Variations in the pressure of a
1:1 mixture of CO:H2 (compare entry 5 to entries 8ꢀ10) showed interesting selectivity
between hydroformylation 1a and hydrogenation 1c. At 120 psig, excellent yields of 1a
were obtained, however lower pressures yielded increasing amounts of 1c via
competing allene hydrogenation. Based on these results, optimized conditions of 0.1
mol % Rh(acac)(CO)2, 0.12 mol % BisDiazaPhos and 150 psig 1:1 CO:H2 in THF at 60
°C were chosen for subsequent studies.
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The scope of the Rhꢀcatalyzed allene hydroformylation was first explored with a series
of 1,1ꢀdialkylꢀ3ꢀarylꢀtrisubstituted allenes 1-12 (Table 3). Variations in the electronics of
the para substituents of the aryl groups in 2ꢀ4 did not appear to influence either the yield
or selectivity, delivering the desired aldehydes 2aꢀ4a in good isolated yields.
Substitution of the dimethyl substituents in 1-4 with a cyclohexyl group in 5 gave 5a in
82% yield, although the reaction required an additional 0.5 h to ensure complete
conversion was achieved. A series of racemic, chiral allenes 6-8 produced the β,ɤꢀ
unsaturated aldehydes 6a-8a in good yields with varying Z:E ratios, depending on the
steric differences in the two substituents at the allene terminus. As the size of the alkyl
group increased from Et to iPr to tBu, the Z:E ratio improves from 1.5 to 5 to >20,
suggesting that control of the alkene stereoselectivity is kinetic in nature.11
Substitution of the phenyl group of the allene with other aromatic rings, including the
naphthyl and heterocyclic groups in 9-13, provided aldehydes 9a-12a with excellent
regioselectivity under the standard hydroformylation conditions, although increased
catalyst loadings and reaction times were necessary for high conversion in some cases.
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The aldehyde of 12a was observed to decompose upon isolation. Therefore, in situ
HornerꢀWadsworthꢀEmmons (HWE) derivatization was carried out to give 60% yield of
the olefinated product over two steps. The only unsuccessful substrate was the furan
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Table 3. Results for hydroformylation of arylꢀsubstituted allenes given as % isolated
yield (% conversion) for the indicated reaction conditions.
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13; while complete conversion was noted, complex product mixtures were obtained,
presumably because both the substrate and the product 13a are susceptible to Dielsꢀ
Alder reactions.
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The data in Table 3 establish high regioselectivity for the hydroformylation of aryl
allenes. To investigate the regioselective hydroformylation of nonꢀaryl allenes, the
trialkyl substituted allenes 15-21 (Table 4) were examined. Substrates 15-18 were
prepared through an orthoꢀClaisen rearrangement of the parent propargyl alcohol; these
substrates introduce another useful functional group in the product aldehyde.16 In
keeping with results observed for the hydroformylation of aryl alkenes and allylic
alcohols, the regiodirecting influence of the aryl substituents proved greater than those
of the hydroxymethyl or carboethoxymethyl groups. As a result, the hydroformylation of
15 yields 89% of 15b, 4% of 14 (see Scheme 2) and 7% of two minor aldehydes (one of
the minor aldehydes results from formylation at the central carbon of the allene). In
principle, the aldehyde product 15a may result from isomerization of 15 to the diene 14,
which then undergoes hydroformylation (Scheme 2). The hydroformylation of 14 was
performed to test the viability of this pathway. Hydroformylation of 14 under standard
conditions produced only a 9% yield of 15a, along with several other byꢀproducts (see
the Supplementary Information for further details). This result supports direct
hydroformylation of the allene as the primary pathway for the production of 15a.
Scheme 2. Hydroformylation of 1,3ꢀdiene 14.
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The scope of the homoallenylic ester was explored (Table 4, 15-18). Due to low yield
in the isolation of 15a, the aldehydes were converted to the corresponding unsaturated
esters 15b-18b using an in situ HWE reaction. In this manner, 15b was furnished in
62% yield over the two steps and 18b in 64% isolated yield. Hydroformylation of the
chiral allenes 16-17 resulted in 60% and 63% isolated yields over the two steps, with
Z:E ratios similar to those noted for the analogous Phꢀsubstituted allenes 6ꢀ7 (Table 3).
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The conjugated allenic ester precursor 19 was readily synthesized through a Wittig
reaction of a ketene with a stabilized phosphonium ylide.17 While 19 (Table 4)
undergoes successful hydroformylation, the product 19a rapidly tautomerizes to yield
the enol. Reducing the ester of 19 to an alcohol18,19 in 20 mitigated tautomerization of
the aldehyde; however, the tendency of the βꢀhydroxyaldehyde product to dimerize
upon concentration of the reaction mixture complicated isolation efforts.20 Thus, the
aldehyde 20a was protected as a pinacol acetal 20b to facilitate isolation in 75% yield
over the two steps. Similarly, hydroformylation of the allene 21 delivered 21b in 72%
yield after the pinacol synthesis.
The data presented thus far indicate that hydroformylation of trisubstituted allenes is
particularly fast and selective when: (1) BisDiazaphos (BDP) ligands are used and (2)
the monosubstituted terminus of the allene (R3 in Scheme 1) bears an inductively
electronꢀwithdrawing group (such as aryl, carboethoxymethyl, or hydroxymethyl). To
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Table 4. Results for hydroformylation of allenes bearing hydroxymethyl and
carboethoxymethyl substituents given as % isolated yield of the HWE derivatives (%
NMR yield) for the indicated reaction conditions.
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further explore the influence of the R3 substituent, the hydroformylation of 22 was
performed (Scheme 3). In the event, only a 60% yield of 22a was observed, resulting
from formylation at the less substituted terminal allene carbon. Furthermore, a 31%
yield of product 22b was observed, a result of formylation at the central carbon of the
allene 22. The observation of large amounts of 22b when R3 is substituted with an
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electronꢀdonating group (C5H11) suggests that electronic effects are primarily
responsible for controlling the regioselectivity of the hydrogen addition to the central
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1 mol % Rh(acac)(CO)2
1.2 mol % BDP
Me C5H11
Me
H
H
H
Me
Me
minor
aldehydes
O
Me
Me
H11C5
22b
O
150 psig (1:1) CO/H2
C5H11
H
H
60 oC, THF, 1 h
22a
60%
22c
9%
22
31%
Scheme 3. Hydroformylation of trisubstituted allene 22.
carbon of the allene in hydroformylations of trisubstituted allenes using our RhꢀBDP
catalyst system.
We have previously proposed a stereoelectronic mnemonic that summarizes the
empirical observations regarding the asymmetric hydroformylations of 1ꢀ and 1,2ꢀ
substituted alkenes with BisDiazaPhos ligands.21 To place the reactivity and selectivity
patterns for allene hydroformylation in the proper context, we have extended this
mnemonic as shown in Figure 1. Note that the allene hydroformylation results are for
racemic catalysts only; at this point, no experimental data regarding the enantiofacial
selectivity of allene hydroformylation is implied, although studies directed towards this
goal are ongoing in our labs. Placement of the EWG in the lower rightꢀhand quadrant
enables delivery of the H to the central allene carbon, with the formyl group installed at
the carbon proximal to the EWG. Also shown in Figure 1 are approximate catalyst
turnover frequencies (TOFs) for the different substrates at 60°C and 150 psig synthesis
gas; these data highlight the high TOFs obtained with allenes and the BisDiazaPhos
ligands.
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Figure 1. Quadrant mnemonic diagrams showing (a) the metal coordination geometry,
and approximate catalyst rates (TOFs) and preferred substrate orientations for (b) 1ꢀ
alkenes (c) (Z)-1,2ꢀalkenes and (d) trisubstituted allenes. (EWG=electronꢀwithdrawing
group).
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(a)
(b)
(c)
(d)
R
H
H
H
H
P
Rh CO
EWG
P
Rh CO
P
Rh CO
P
P
Rh CO
EWG
EWG
P
P
P
TOF 102ꢀ103 hꢀ1
TOF 101ꢀ102 hꢀ1
TOF 103ꢀ104 hꢀ1
In conclusion, Rhꢀcatalyzed hydroformylation supported by a BisDiazaPhos ligand
offers a practical and efficient synthetic route to useful β,ɤꢀunsaturated aldehyde
building blocks. A variety of trisubstituted aryl allenes, heterocyclic allenes,
homoallenylic esters and allenols undergo hydroformylation with high conversions and
regioselectivities using loadings as low as 0.1 mol % catalyst. For substrates containing
an inductively EWG, the data indicate a kinetic preference for the addition of H to the
central carbon of the allene. The results reported here suggest hydroformylation can
successfully be extended to diꢀ and tetrasubstituted allenes, including enantioselective
transformations and kinetic resolutions of racemic allenes.
Experimental section
General information. All glassware was either ovenꢀdried overnight at 130 °C or flameꢀ
dried immediately before use. Flameꢀdried glassware was cooled under vacuum while
purging with nitrogen. Unless otherwise specified, reagents were used as obtained from
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the vendor without further purification. Diethyl ether was freshly distilled from purple
Na/benzophenone ketyl. Tetrahydrofuran was either distilled from purple
Na/benzophenone ketyl or dried over alumni 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”.22 Analytical thin
layer chromatography (TLC) was performed utilizing preꢀcoated silica gel 60 F254 plates
containing a fluorescent indicator. Columns were conducted using a gradient method.
KMnO4 was used as stains reagent. Bisdiazaphospholane ligands were prepared as
reported in the literature.23 [Rh(acac)(CO)2] was received from Dow Chemical and
purified by passing it through cold toluene; the purified [Rh(acac)(CO)2] was stored in a
N2ꢀfilled glovebox. The 1:1 CO:H2 was obtained from Airgas. All pressures given are
gauge pressures, unless otherwise noted. Carbon monoxide (CO) is very toxic and
hydrogen is flammable; therefore, reactions should be conducted in a flame hood with
adequate airflow. CO detectors should be present in case of a CO leak.
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1H NMR, 13C NMR, and 19F NMR spectra were obtained using Brukerꢀ300, Varianꢀ300,
Avance III 400, or Varian Inovaꢀ500, or Varian Unityꢀ500 spectrometers. 13C NMR
1
spectra were obtained using 125 MHz or 75 MHz instruments. H NMR spectra
chemical shifts were reported in accordance to residual protiated solvent peaks (δ 77.2,
39.5, 128.0 and 137.9 ppm for CDCl3, (CD3)2SO, C6D6, and CD3C6D5, respectively).
Synthesis and characterization of allene substrates.13,24
Method I: General procedure for the synthesis and characterization of aryl allenes. The
syntheses of the aryl allene substrates were based on a reported literature procedure.
Slight modifications to this procedure were made as necessary, as indicated in the
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following typical experimental setꢀup. An ovenꢀdried, round bottom flask was cooled to rt
under vacuum. Benzaldehyde (1.0 g, 9.4 mmol) and freshly distilled diethyl ether (8.8
mL) were added to the flask and the mixture cooled to 0 °C. A solution of 1ꢀ
propynylmagnesium bromide (0.5 M in tetrahydrofuran, 28.3 mL, 14.1 mmol) was added
dropwise, the reaction mixture warmed to rt and monitored by TLC. Once complete
consumption of the starting material was noted, the reaction mixture was quenched with
a saturated NH4Cl(aq) solution. The organic layer was extracted with portions of diethyl
ether, the combined organics washed with brine, then dried over Na2SO4. The solvent
was removed under reduced pressure and the crude material was used in the next step
without any further purification.
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An ovenꢀdried round bottom flask was charged with the crude propargylic alcohol
prepared above, distilled dichloromethane (7.3 mL), and triethylamine (2.6 mL, 18.8
mmol) at room temperature. To this mixture were added acetic anhydride (1.8 mL, 18.8
mmol) and 4ꢀdimethylaminopyridine (0.58 g, 4.7 mmol). The reaction mixture was
stirred at room temperature until TLC indicated complete consumption of the substrate,
then quenched with water. The organic layer was extracted with portions of
dichloromethane (20 mL x 3), the combined organics washed with brine and dried over
Na2SO4. The solvent was removed under reduced pressure and the crude material was
purified by column chromatography (20% ethyl acetate/ hexane).
A cooled, ovenꢀdried round bottom flask was charged with purified CuCN (3.2 g, 35.2
mmol) and dried THF (57 mL). The mixture was cooled to 0 °C and a solution of
MeMgBr (3.0 M in tetrahydrofuran, 11.7 mL, 35.2 mmol) was added dropwise. The
reaction mixture was stirred at 0 °C for 1 h, a solution of the acylated propargylic alcohol
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in THF was added and the reaction mixture stirred at rt for an additional 48 h. The
reaction was quenched with a 1:1 volume of saturated Na2CO3(aq) and hexane,
extracted with three portions of ethyl acetate and the combined organic layers dried with
Na2SO4. The crude material was purified via column chromatography (10% ethyl
acetate/hexane). The yield reported is the yield of the organocuprate reaction.
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(4-Methylpenta-2,3-dien-1-yl)benzene (1). The organocuprate reaction was run on a
12.25 mmol scale. The product was purified by silica gel flash chromatography (9:1
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hexane/ethyl acetate) to yield 1 as a colorless oil in 73% (1.3 g) isolated yield. H NMR
(500 MHz, CDCl3) δ 7.31 – 7.26 (m, 4H), 7.18 – 7.14 (m, 1H), 5.98 (hept, J = 2.9 Hz,
1H), 1.82 (d, J = 2.9 Hz, 6H). 13C NMR (126 MHz, CDCl3) δ 203.3, 136.1, 128.6, 126.8,
126.5, 99.3, 92.6, 20.4. HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for C11H13 145.1012; found
145.1010.
1-Fluoro-4-(4-methylpenta-2,3-dien-1-yl)benzene (2). The organocuprate reaction was
run on a 0.97 mmol scale. The product was purified by silica gel flash chromatography
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(9:1 hexane/ethyl acetate) to yield 2 as a colorless oil in 55% (0.09g) isolated yield. H
NMR (400 MHz, CDCl3) δ 7.25 – 7.18 (m, 2H), 7.02 – 6.93 (m, 2H), 5.95 (hept, J = 2.9
13
Hz, 1H), 1.82 (d, J = 2.9 Hz, 6H). C NMR (101 MHz, CDCl3) δ 203.0, 163.0, 160.5,
19
132.0, 132.0, 128.1, 128.0, 115.6, 115.4, 110.1, 99.6, 91.7, 20.4. F NMR (377 MHz,
CDCl3) δ ꢀ116.4. HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for C11H12F 163.0918; found
163.0916.
1-Bromo-4-(4-methylpenta-2,3-dien-1-yl)benzene (3). The organocuprate reaction was
run on a 9.89 mmol scale. The product was purified by silica gel flash chromatography
(9:1 hexane/ethyl acetate) to yield 3 as a colorless oil in 73% (1.61 g) isolated yield. 1H
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NMR (500 MHz, CDCl3) δ 7.41 – 7.38 (m, 2H), 7.15 – 7.06 (m, 2H), 5.92 (hept, J = 2.9
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Hz, 1H), 1.81 (d, J = 2.9 Hz, 6H). C NMR (126 MHz, CDCl3) δ 203.3, 135.0, 131.5,
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128.1, 119.9, 99.7, 91.7, 20.2. HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for C11H12Br
223.0117; found 223.0111.
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1-Methoxy-4-(4-methylpenta-2,3-dien-1-yl)benzene (4). The organocuprate reaction
was run on a 6.20 mmol scale. The product was purified by silica gel flash
chromatography (9:1 hexane/ethyl acetate) to yield 4 as a colorless oil in 77% (0.83 g)
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isolated yield. H NMR (500 MHz, CDCl3) δ 7.23 – 7.14 (m, 2H), 6.87 – 6.78 (m, 2H),
5.94 (hept, J = 2.9 Hz, 1H), 3.80 (s, 3H), 1.81 (d, J = 2.9 Hz, 6H).13C NMR (126 MHz,
CDCl3) δ 201.9, 136.4, 128.6, 126.4, 126.4, 112.8, 94.2, 34.4, 29.3, 14.8. HRMS (ESIꢀ
TOF) m/z: [M+H]+ calcd for C12H15O 175.1116; found 175.1146.
(2-Cyclohexylideneethenyl) benzene (5). The organocuprate reaction was run on a 9.96
mmol scale. The compound was made following a reported literature procedure.25 The
product was purified by silica gel flash chromatography (9:1 hexane/ethyl acetate) to
yield 5 as a colorless oil in 82% (1.52 g) isolated yield. 1H NMR (500 MHz, CDCl3) δ
7.31 – 7.27 (m, 4H), 7.19 – 7.12 (m, 1H), 5.99 (p, J = 2.2 Hz, 1H), 2.30 – 2.24 (m, 2H),
13
2.23 – 2.16 (m, 2H), 1.75 – 1.55 (m, 6H). C NMR (126 MHz, CDCl3) δ 199.8, 136.3,
128.6, 126.6, 126.4, 106.6, 92.5, 31.5, 27.8, 26.3. HRMS (ESIꢀTOF) m/z: [M+H]+ calcd
for C14H17 185.1325; found 185.1325.
(4-Methylhexa-2,3-dien-1-yl)benzene (6). The organocuprate reaction was run on a 5.31
mmol scale. The product was purified by silica gel flash chromatography (9:1
hexane/ethyl acetate) to yield 6 as a colorless oil in 92% (0.77 g) isolated yield. 1H NMR
(500 MHz, CDCl3) δ 7.30 – 7.26 (m, 4H), 7.21 – 7.11 (m, 1H), 6.08 (h, J = 3.0 Hz, 1H),
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2.09 (m, 2H), 1.82 (d, J = 2.8 Hz, 3H), 1.06 (t, J = 7.4 Hz, 3H). C NMR (126 MHz,
CDCl3) δ 202.5, 136.3, 128.6, 126.6, 126.5, 105.6, 94.5, 27.3, 18.9, 12.4. HRMS (ESIꢀ
TOF) m/z: [M+H]+ calcd for C12H15 159.1168; found 159.1167.
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(4,5-Dimethylhexa-2,3-dien-1-yl)benzene (7). The organocuprate reaction was run on a
5.31 mmol scale. The product was purified by silica gel flash chromatography (9:1
hexane/ethyl acetate) to yield 7 as a colorless oil in 89% (0.81 g) isolated yield. 1H NMR
(400 MHz, CDCl3) δ 7.28 (d, J = 5.5 Hz, 4H), 7.20 – 7.13 (m, 1H), 6.08 (p, J = 2.8 Hz,
1H), 2.25 (heptd, J = 6.8, 2.3 Hz, 1H), 1.81 (d, J = 2.9 Hz, 3H), 1.10 (dd, J = 8.3, 6.8 Hz,
6H). 13C NMR (101 MHz, CDCl3) δ 201.7, 136.1, 128.5, 126.4, 126.2, 109.8, 94.6, 32.5,
21.7, 21.5,17.1. HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for C13H17 173.1325; found
173.1313.
(3Z)-4,5,5-Trimethyl-2-phenylhex-3-enal (8). The organocuprate reaction was run on a
20.43 mmol scale. The product was purified by silica gel flash chromatography (9:1
hexane/ethyl acetate) to yield 8 as a colorless oil in 74% (2.81 g) isolated yield. 1H NMR
(500 MHz, CDCl3) δ 7.31 – 7.24 (m, 4H), 7.20 – 7.11 (m, 1H), 6.05 (q, J = 2.8 Hz, 1H),
1.81 (d, J = 2.8 Hz, 3H), 1.13 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 201.9, 136.4, 128.6,
126.4, 126.4, 112.8, 94.2, 34.4, 29.3, 14.8. HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for
C14H19 187.1481; found 187.1480.
1-(4-Methylpenta-2,3-dien-1-yl)naphthalene (9). The organocuprate reaction was run on
a 10.76 mmol scale. The product was purified by silica gel flash chromatography (9:1
hexane/ethyl acetate) to yield 9 as a white solid in 83% (1.73 g) isolated yield. m.p. 62ꢀ
o
65 C. 1H NMR (500 MHz, CDCl3) δ 7.81 – 7.70 (m, 3H), 7.65 – 7.57 (m, 1H), 7.50 –
7.35 (m, 3H), 6.16 (hept, J = 2.9 Hz, 1H), 1.86 (d, J = 2.9 Hz, 6H). 13C NMR (126 MHz,
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CDCl3) δ 203.9, 133.9, 133.7, 132.6, 128.2, 127.8, 127.7, 126.2, 125.5, 125.2, 125.0,
99.6, 93.0, 20.5. HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for C15H15 195.1168; found
195.1169. The characterization data match the reported data.29
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4-(4-Methylpenta-2,3-dien-1-yl)-2H-1,3-benzodioxole (10). The organocuprate reaction
was run on a 11.00 mmol scale. The product was purified by silica gel flash
chromatography (9:1 hexane/ethyl acetate) to yield 10 as a colorless oil in 86% (1.79 g)
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isolated yield. H NMR (500 MHz, CDCl3) δ 6.79 (d, J = 1.7 Hz, 1H), 6.73 (d, J = 7.9 Hz,
13
1H), 6.69 (dd, J = 8.0, 1.6 Hz, 1H), 5.96 – 5.89 (m, 3H), 1.80 (d, J = 2.9 Hz, 6H). C
NMR (126 MHz, CDCl3) δ 202.3, 147.9, 146.3, 130.2, 120.2, 108.2, 106.5, 100.9, 99.4,
92.3, 20.4. HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for C12H13O2 189.0910; found
189.0911.
4-(4-Methylpenta-2,3-dien-1-yl)-2H-1,3-benzodioxole (11). The organocuprate reaction
was run on a 5.91 mmol scale. The product was purified by silica gel flash
chromatography (9:1 hexane/ethyl acetate) to yield 11 as a colorless oil in 75% (0.89 g)
isolated yield. 1H NMR (500 MHz, CDCl3) δ 7.98 (dd, J = 7.6, 1.7 Hz, 1H), 7.78 – 7.74
(m, 1H), 7.32 – 7.24 (m, 2H), 7.13 (s, 1H), 6.27 (hept, J = 3.1 Hz, 1H), 1.80 (d, J = 3.1
Hz, 6H). 13C NMR (126 MHz, CDCl3) δ 203.5, 140.8, 137.5, 130.6, 124.4, 124.2, 122.8,
122.6, 122.6, 98.1, 86.1, 20.8. HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for C13H13S
201.0733; found 201.0733.
3-(3-Methylbuta-1,2-dien-1-yl)pyridine (12). The organocuprate reaction was run on a
8.50 mmol scale. The product was purified by silica gel flash chromatography (9:1
hexane/ethyl acetate) to yield 12 as a brown oil in 78% (0.96 g) isolated yield. 1H NMR
(400 MHz, CDCl3) δ 8.49 (d, J = 2.2 Hz, 1H), 8.39 (dd, J = 4.8, 1.6 Hz, 1H), 7.55 (dt, J =
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7.9, 2.0 Hz, 1H), 7.20 (ddd, J = 7.9, 4.8, 0.9 Hz, 1H), 5.96 (hept, J = 2.9 Hz, 1H), 1.83
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(d, J = 2.9 Hz, 6H). C NMR (101 MHz, CDCl3) δ 203.8, 148.4, 147.6, 133.5, 132.0,
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123.5, 100.2, 89.5, 20.3. HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for C10H12N 146.0964;
found 146.0963.
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2-(3-Methylbuta-1,2-dien-1-yl)furan (13). The organocuprate reaction was run on a
10.35 mmol scale. The product was purified by silica gel flash chromatography (9:1
hexane/ethyl acetate) to yield 13 as a yellow oil in 38% (0.53 g) isolated yield. 1H NMR
(500 MHz, CDCl3) δ 7.33 (dd, J = 1.9, 0.8 Hz, 1H), 6.35 (dd, J = 3.3, 1.9 Hz, 1H), 6.14
(dd, J = 3.3, 0.8 Hz, 1H), 5.96 (hept, J = 3.0 Hz, 1H), 1.81 (d, J = 3.0 Hz, 6H).13C NMR
(126 MHz, CDCl3) δ 202.2, 145.0, 141.7, 111.4, 106.5, 100.00, 83.4, 20.7. HRMS (ESIꢀ
TOF) m/z: [M+H]+ calcd for C9H11O 135.0804; found 135.0804.
Method II: General procedure for the synthesis and characterization of homoallenylic
ester substrates.16 All allenyl esters were prepared according to a reported literature
procedure. A cooled, ovenꢀdried round bottom flask was charged with 2ꢀmethylbutꢀ3ꢀ
yneꢀ2ꢀol (4.9 mL, 50.6 mmol), triethyl orthoacetate (11.2 mL, 60.7 mmol) and propanoic
acid (0.38 mL, 5.1 mmol). The reaction mixture was heated to 100ꢀ150 °C under
nitrogen until TLC indicated complete consumption of the starting material. The mixture
was cooled to rt, diluted with ethyl acetate, washed with 0.1 M HCl (2x), aqueous
NaHCO3, then brine. The combined organics were dried over Na2SO4, the solvent
removed under reduced pressure and the crude material purified by column
chromatography (10% ethyl acetate or 20% ether/hexane) to give the desired
homoallenic ester.
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Ethyl 5-methylhexa-3,4-dienoate (15). The product was purified by silica gel flash
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chromatography (8:2 hexane/ether) to yield 15 as a yellow oil. H NMR (500 MHz,
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CDCl3) δ 5.15 – 5.03 (m, 1H), 4.15 (q, J = 7.2 Hz, 2H), 2.97 (d, J = 7.1 Hz, 2H), 1.69 (d,
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J = 2.9 Hz, 6H), 1.27 (t, J = 7.1 Hz, 4H). C NMR (126 MHz, CDCl3) δ 203.0, 172.0,
96.4, 82.0, 60.6, 35.4, 20.5, 14.3. HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for C8H13O2
141.0910; found 141.0910.
Ethyl 5-methylhepta-3,4-dienoate (16). The product was purified by silica gel flash
chromatography (9.5:0.5 hexane/ethyl acetate) to yield 16 as a yellow oil. 1H NMR (500
MHz, CDCl3) δ 5.22 – 5.15 (m, 1H), 4.15 (q, J = 7.2 Hz, 2H), 2.98 (d, J = 7.1 Hz, 2H),
1.94 (qd, J = 7.4, 3.2 Hz, 2H), 1.69 (d, J = 2.8 Hz, 3H), 1.26 (t, J = 7.1 Hz, 3H), 0.99 (t, J
= 7.4 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 202.3, 172.1, 102.8, 84.1, 60.7, 35.7, 27.0,
19.0, 14.3, 12.3. HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for C10H17O2 169.1223; found
169.1222.
Ethyl 5,6-dimethylhepta-3,4-dienoate (17). The product was purified by silica gel flash
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chromatography (9:1 hexane/ethyl acetate) to yield 17 as a yellow oil. H NMR (500
MHz, CDCl3) δ 5.21 – 5.14 (m, 1H), 4.15 (q, J = 7.1 Hz, 2H), 2.97 (d, J = 7.1 Hz, 2H),
2.10 (hept d, J = 6.8, 2.3 Hz, 1H), 1.69 (d, J = 2.8 Hz, 3H), 1.26 (t, J = 7.1 Hz, 3H), 1.01
(d, J = 6.8 Hz, 6H).13C NMR (126 MHz, CDCl3) δ 201.6, 171.9, 107.0, 84.1, 60.5, 35.6,
31.9, 21.4, 21.3, 17.2, 14.2. HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for C11H19O2
183.1380; found 183.1381.
Ethyl 4-cyclohexylidene-3-butenoate (18). The product was purified by silica gel flash
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chromatography (9:1 hexane/ethyl acetate) to yield 18 as a colorless oil. H NMR (400
MHz, CDCl3) δ 5.09 (tp, J = 6.5, 2.1 Hz, 1H), 4.15 (q, J = 7.1 Hz, 2H), 2.98 (d, J = 7.1
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Hz, 2H), 2.21 – 2.06 (m, 4H), 1.64 – 1.45 (m, 6H), 1.27 (t, J = 7.2 Hz, 3H).13C NMR (126
MHz, CDCl3) δ 199.7, 172.1, 103.7, 81.9, 60.7, 35.8, 31.4, 27.4, 26.2, 14.3. HRMS
(ESIꢀTOF) m/z: [M+H]+ calcd for C12H19O2 195.1380; found 195.1379.
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Ethyl 4-methylpenta-2,3-dienoate (19). The compound was made following a reported
literature procedure. The NMR data matched the published data.26
Method III: General procedure for the synthesis and characterization of allenols.18,19 All
allenol substrates were prepared according to a reported literature procedure. A cooled,
ovenꢀdried round bottom flask was charged with pꢀtoluenesulfonate (1.78 g, 7.10 mmol,
5 mol %), CH2Cl2 (60 mL), 2ꢀmethylbutꢀ3ꢀyneꢀ2ꢀol (12.0 g, 143 mmol) and 3,4ꢀ
dihydropyran (50.0 g, 594 mmol). The reaction was stirred at rt until complete
conversion of the substrate was observed by TLC. The solvent was removed under
reduced pressure, diethyl ether was added and the organics washed with water. The
organic layer was dried with MgSO4 and the solvent was removed. The crude material
was distilled under reduced pressure to give pure 1,1ꢀdimethylpropꢀ2ꢀynyl
tetrahydropyranꢀ2ꢀylꢀether.
An ovenꢀdried round bottom flask was charged with the protected propargyl alcohol
prepared above (0.5 g, 2.9 mmol) and distilled diethyl ether (2.96 mL) and the mixture
cooled to ꢀ78 °C. A solution of nꢀbutyllithium (2.64 M, 1.7 mL, 4.4 mmol) was added
dropwise to the reaction mixture and stirred at ꢀ78 °C for 45 min. A solution of
paraformaldehyde (0.27 g, 8.9 mmol) in ether was added dropwise, the reaction mixture
warmed to rt and vigorously stirred until TLC indicated complete consumption of the
substrate. The reaction was quenched with an ice water, extracted with ether (20 mL x
3) and the combined organics dried with MgSO4. The solvent was removed under
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reduced pressure and the product was purified via column chromatography (40% ethyl
acetate/hexane) to give 4ꢀmethylꢀ4ꢀ[(tetrahydroꢀ2Hꢀpyranꢀ2ꢀyl)oxy]pentꢀ2ꢀynꢀ1ꢀol.
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An ovenꢀdried round bottom flask was charged with lithium aluminium hydride (LAH,
0.28 g, 7.6 mmol) and distilled diethyl ether (10.1 mL) and cooled to 0 °C. A solution of
the propargyl alcohol substrate (0.50 g, 2.52 mmol) in distilled ether (2.5 mL) was added
dropwise to the suspension of LAH. The reaction was warmed to rt and stirred
overnight. Once TLC indicated complete consumption of the propargyl alcohol, the
reaction mixture was diluted with ether and cooled to 0 °C. Quenching was carried out
carefully according to the method of Fieser and Fieser using sequential addition of 0.3
mL of water, 0.3 mL of 15% aqueous NaOH, and 3 x 0.3 mL of water.27 The mixture
was warmed to rt and stirred until a white precipitate was observed. A portion of MgSO4
was added and stirring continued for an additional 30 min. The solids were filtered, the
solvent removed under reduced pressure and the residue purified by column
chromatography to give the allenic alcohol product.
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4-Methylpenta-2,3-dien-1-ol (20). The reduction with LiAH4 was run on a 10.53 mmol
scale. The product was purified by silica gel flash chromatography (8:2 hexane/ethyl
acetate) to afford 20 as a colorless oil in 72% (0.74 g) isolated yield. 1H NMR (500 MHz,
CDCl3) δ 5.24 – 5.16 (m, 1H), 4.07 (t, J = 5.7 Hz, 2H), 1.73 (d, J = 2.9 Hz, 6H). 13C NMR
(126 MHz, CDCl3) δ 200.5, 98.6, 89.9, 61.0, 20.6. HRMS (ESIꢀTOF) m/z: [M+H]+ calcd
for C6H11O 99.0810; found 99.0804.
3-Cyclohexylidene-2-propen-1-ol (21). The product was purified by silica gel flash
chromatography (8:2 hexane/ethyl acetate) to afford 21 as a colorless oil. 1H NMR (500
MHz, CDCl3) δ 5.25 – 5.15 (m, 1H), 4.07 (t, J = 5.5 Hz, 2H), 2.14 (m, 4H), 1.65 – 1.49
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(m, 6H).13C NMR (126 MHz, CDCl3) δ 197.3, 105.9, 89.8, 61.3, 31.6, 27.5, 26.1. HRMS
(ESIꢀTOF) m/z: [M+H]+ calcd for C9H15O3 139.1117; found 139.1117.
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2-Methylnona-2,3-diene (22). The compound was made following a reported literature
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procedure.25
General method for hydroformylation. In a nitrogenꢀfilled glovebox, a 15 mL Ace
Glass glass pressure bottle equipped with a magnetic stir bar was charged with a THF
stock solution of (0.005 M or 0.1 M) Rh(acac)(CO)2 and (0.005 M or 0.05 M)
bisdiazaphospholane ligand using 1000 ꢁL and 200 ꢁL 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
pressurizations (150 psi)/ depressurization (0 psi) cycle with 1:1 CO:H2. This allows for
complete replacement of nitrogen with syngas. The apparatus was filled with 150 psi of
syngas and placed in an oil bath at desired temperature. The solution was stirred
vigorously for 30ꢀ60 min to ensure formation of the preꢀactivated catalyst. The reaction
apparatus was removed from the oil bath and cooled for 5 min. The pressure was
reduced to 0 psi syngas and a solution of allene in THF was injected with a gasꢀtight
syringe using a 12’’ needle. The reaction was charged with 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 until
completion. Completion was determined by taking crude NMR sample of the
hydroformylation mixture. Once the reaction was complete, the reactor was removed
from the oil bath for 5 minutes, cooled to rt and depressurized. A crude NMR sample
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was taken in CDCl3 using 5 ꢁL of mesitylene as an internal standard. The allene peak
and the aldehyde peak were used to mentor reaction progress.
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4-Methyl-2-phenylpent-3-enal (1a). The hydroformylation was run on a 0.588 mmol
scale at 40 °C. After completion of the hydroformylation, the crude mixture was filtered
through a plug of silica and washed with dichloromethane to give 82% (0.08 g) isolated
yield of 1a as a yellow oil. 1H NMR (500 MHz, CDCl3) δ 9.51 (d, J = 2.5 Hz, 1H), 7.33 –
7.27 (m, 2H), 7.24 – 7.19 (m, 1H), 7.18 – 7.15 (m, 2H), 5.52 – 5.40 (m, 1H), 4.34 (dd, J
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= 9.0, 2.5 Hz, 1H), 1.75 (d, J = 1.4 Hz, 3H), 1.63 (d, J = 1.3 Hz, 3H). C NMR (126
MHz, CDCl3) δ 198.5, 138.1, 136.9, 129.2, 128.6, 127.5, 118.5, 58.3, 26.2, 18.7. HRMS
(ESIꢀTOF) m/z: [M+H]+ calcd for C12H15O 175.1123; found 175.1115.
2-(4-Fluorophenyl)-4-methylpent-3-enal (2a). The hydroformylation reaction was run on
a 1.18 mmol scale at 60 oC. After completion of the hydroformylation reaction, the crude
mixture was filtered through a plug of silica and washed with dichloromethane to give
82% (0.21 g) isolated yield of 2a as a yellow oil. 1H NMR (500 MHz, CDCl3) δ 9.56 (d, J
= 2.4 Hz, 1H), 7.20 (dd, J = 8.6, 5.4 Hz, 2H), 7.06 (t, J = 8.7 Hz, 2H), 5.52 – 5.45 (m,
1H), 4.40 (dd, J = 9.0, 2.3 Hz, 1H), 1.83 (d, J = 1.3 Hz, 3H), 1.69 (d, J = 1.3 Hz, 3H). 13C
NMR (126 MHz, CDCl3) δ 198.0, 198.0, 163.1, 161.1, 138.4, 132.4, 132.4, 118.1, 116.0,
115.8, 57.3, 26.0, 18.6. 19F NMR (377 MHz, CDCl3) δ ꢀ115.2. HRMS (ESIꢀTOF) m/z: [Mꢀ
H]ꢀ calcd for C12H12FO 191.0872; found 191.0878.
2-(4-Bromophenyl)-4-methylpent-3-enal (3a). The hydroformylation was run on a 0.588
mmol scale at 60 °C. After completion of the hydroformylation, the crude mixture was
filtered through a plug of silica and washed with dichloromethane to give 86% (0.13 g)
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isolated yield of 3a as a yellow oil. H NMR (500 MHz, CDCl3) δ 9.49 (d, J = 2.4 Hz,
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1H), 7.42 (d, J = 8.5 Hz, 2H), 7.04 (d, J = 8.4 Hz, 2H), 5.40 (m, 1H), 4.30 (dd, J = 9.0,
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2.3 Hz, 1H), 1.76 (d, J = 1.3 Hz, 3H), 1.62 (d, J = 1.3 Hz, 3H). C NMR (126 MHz,
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CDCl3) δ 197.7, 138.7, 135.7, 132.1, 130.1, 121.4, 117.8, 57.5, 26.0, 18.6. HRMS (ESIꢀ
TOF) m/z: [M+H]+ calcd for C12H13OBr 253.0223; found 253.0218.
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2-(4-Methoxyphenyl)-4-methylpent-3-enal (4a). The hydroformylation was run on a
0.588 mmol scale at 60 °C. The crude hydroformylation mixture was filtered through a
plug of silica and washed with dichloromethane to give 4a in 86% (0.10 g) isolated yield
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as a yellow oil. H NMR (400 MHz, CDCl3) δ 9.55 (d, J = 2.5 Hz, 1H), 7.15 (d, J = 8.7
Hz, 2H), 6.91 (d, J = 8.7 Hz, 2H), 5.54 – 5.46 (m, 1H), 4.35 (dd, J = 8.9, 2.5 Hz, 1H),
3.80 (s, 3H), 1.82 (d, J = 1.4 Hz, 3H), 1.69 (d, J = 1.4 Hz, 3H). 13C NMR (126 MHz,
CDCl3) δ 198.5, 159.0, 137.7, 129.6, 128.7, 118.72, 114.6, 57.4, 55.3, 26.1, 18.6.
HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for C13H17O2 205.1223; found 205.1223.
3-Cyclohexylidene-2-phenylpropanal (5a). The hydroformylation reaction was run on a
0.588 mmol scale at 60 °C. The crude mixture was filtered through a plug of silica and
washed with dichloromethane to give 80% (0.10 g) isolated yield of 5a as a yellow oil.
1H NMR (500 MHz, CDCl3) δ 9.52 (d, J = 2.6 Hz, 1H), 7.30 (s, 2H), 7.24 – 7.19 (m, 1H),
7.19 – 7.16 (m, 2H), 5.38 (m, 1H), 4.40 (dd, J = 8.8, 2.6 Hz, 1H), 2.21 – 2.03 (m, 5H),
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1.57 – 1.34 (m, 5H). C NMR (126 MHz, CDCl3) δ 198.6, 146.1, 137.1, 129.1, 128.6,
127.5, 115.0, 57.3, 37.4, 29.8, 28.7, 27.7, 26.7. HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for
C15H19O 215.1430; found 215.1429.
(3Z)-4-Methyl-2-phenylhex-3-enal (6a). The hydroformylation reaction was run on a
0.588 mmol scale at 60 °C. The crude mixture was filtered through a plug of silica and
washed with dichloromethane to give 82% (0.09 g, Z:E 1.5:1) isolated yield of 6a as a
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yellow oil. 1H NMR (400 MHz, CDCl3) δ 9.59 (d, J = 2.6 Hz, 1H, major), 9.58 (d, J = 2.7
Hz, 1H, minor), 7.41 – 7.35 (m, 4H), 7.33 – 7.25 (m, 2H), 7.25 – 7.22 (m, 4H), 5.55 –
5.51 (m, 1H, minor), 5.51 – 5.47 (m, 1H, major), 4.43 (ddd, J = 7.7, 4.8, 2.6 Hz, 2H),
2.16 – 2.07 (m, 4H), 1.82 (d, J = 1.4 Hz, 3H, major), 1.69 (d, J = 1.4 Hz, 3H, minor),
1.05 (t, J = 7.4 Hz, 3H, minor), 0.96 (t, J = 7.6 Hz, 3H, major). 13C NMR (126 MHz,
CDCl3) δ Major: 198.5, 143.5, 136.9, 129.0, 128.4, 127.4, 117.9, 58.0, 25.5, 23.2, 12.5.
Minor: 198.3, 143.5, 136.8, 129.0, 128.5, 127.4, 116.8, 57.8, 32.6, 16.9, 12.5. HRMS
(ESIꢀTOF) m/z: [M+H]+ calcd for C13H17O 189.1274; found 189.1273.
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(3Z)-4,5-Dimethyl-2-phenylhex-3-enal (7a). The hydroformylation was run on a 0.588
mmol scale at 60 °C. The crude mixture was filtered through a plug of silica and washed
with dichloromethane to give 82% (0.1 g, Z:E 5:1) isolated yield of 7a as a yellow oil. 1H
NMR (500 MHz, CDCl3) δ 9.58 (d, J = 2.6 Hz, 1H, major), 9.56 (d, J = 2.8 Hz, 1H,
minor), 7.39 – 7.34 (m, 4H), 7.31 – 7.27 (m, 2H), 7.26 – 7.22 (m, 4H), 5.56 (m, 1H,
minor), 5.48 – 5.39 (m, 1H, major), 4.51 (dd, J = 9.1, 2.5 Hz, 1H, major), 4.41 (dd, J =
8.7, 2.8 Hz, 1H, minor), 2.82 (hept, J = 6.8 Hz, 1H, major), 2.41 – 2.33 (m, 1H, minor),
1.73 (d, J = 1.4 Hz, 3H, major), 1.65 (d, J = 1.4 Hz, 1H, minor), 1.05 (dd, J = 6.9, 4.8 Hz,
2H, minor), 1.01 (d, J = 6.8 Hz, 3H, major), 0.89 (d, J = 6.9 Hz, 3H, major).13C NMR
(126 MHz, CDCl3) δ Major: 198.6, 147.8, 137.1, 129.2, 128.6, 127.5, 117.4, 57.4, 29.6,
20.9, 20.6, 18.5. Minor: 198.3, 147.1, 136.9, 129.1, 128.6, 127.5, 115.9, 57.9, 37.3,
21.5, 14.60. HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for C14H19O 203.1436; found
203.1429.
(3Z)-4,5,5-Trimethyl-2-phenylhex-3-enal (8a). The hydroformylation reaction was run
on a 0.588 mmol scale at 60 °C. After hydroformylation, the crude hydroformylation
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mixture was filtered through a plug of silica and washed with dichloromethane to give
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88% (0.11 g, Z:E >20:1) isolated yield of 8a as a yellow oil. H NMR (500 MHz, CDCl3)
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δ 9.57 (d, J = 2.7 Hz, 2H), 7.37 (m, 4H), 7.31 – 7.27 (m, 2H), 7.24 (m, 4H), 5.63 (dd, J =
8.6, 1.3 Hz, 1H, minor), 5.50 (dq, J = 10.7, 1.5 Hz, 1H, major), 4.81 (dd, J = 10.6, 2.7
Hz, 1H,major), 4.40 (dd, J = 8.5, 2.8 Hz, 1H, minor), 1.87 (d, J = 1.4 Hz, 3H, major),
1.67 (d, J = 1.3 Hz, 3H, minor), 1.15 (s, 9H), 1.09 (s, 9H). 13C NMR (126 MHz, CDCl3) δ
Major: 198.7, 148.8, 137.1, 129.2, 128.6, 127.5, 118.7, 58.7, 35.9, 30.8, 24.8. HRMS
(ESIꢀTOF) m/z: [M+H]+ calcd for C15H21O 217.1587; found 217.1584.
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4-Methyl-2-(naphthalen-2-yl)pent-3-enal (9a). The hydroformylation reaction was run on
a 0.588 mmol scale at 60 °C. The crude mixture was filtered through a plug of silica
and washed with dichloromethane to give 70% (0.09 g) isolated yield of 9a as a yellow
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oil. H NMR (500 MHz, CDCl3) δ 9.67 (d, J = 2.4 Hz, 1H), 7.88 – 7.78 (m, 3H), 7.72 –
7.69 (m, 1H), 7.51 – 7.45 (m, 2H), 7.35 (dd, J = 8.5, 1.8 Hz, 1H), 5.65 (m, 1H), 4.57 (d, J
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= 2.4 Hz, 1H), 1.86 (d, J = 1.4 Hz, 3H), 1.73 (d, J = 1.3 Hz, 3H). C NMR (126 MHz,
CDCl3) δ 198.5, 138.3, 134.3, 133.8, 132.7, 129.0, 127.9, 127.8, 127.4, 126.5, 126.5,
126.2, 118.4, 58.4, 26.2, 18.8. HRMS (ESIꢀTOF) m/z: [M+H]+ + calcd for C16H17O
225.1274; found 225.1270.
2-(2H-1,3-Benzodioxol-5-yl)-4-methylpent-3-enal (10a). The hydroformylation reaction
was run on a 0.588 mmol scale at 60 °C. The crude mixture was filtered through a plug
of silica and washed with dichloromethane to give 90% (0.23 g) isolated yield of 10a as
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a yellow oil. H NMR (500 MHz, CDCl3) δ 9.53 (d, J = 2.5 Hz, 1H), 6.80 (d, J = 8.0 Hz,
1H), 6.73 – 6.67 (m, 2H), 5.95 (s, 2H), 5.48 (m, 1H), 4.31 (dd, J = 8.9, 2.4 Hz, 1H), 1.82
(d, J = 1.4 Hz, 3H), 1.68 (d, J = 1.5 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 198.3, 148.4,
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147.1, 138.1, 130.5, 121.8, 118.5, 108.9, 108.9, 101.3, 57.8, 26.2, 18.7. HRMS (ESIꢀ
TOF) m/z: [M+H]+ calcd for C13H15O3 219.1016; found 190.1013.
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2-(1-Benzothiophen-2-yl)-4-methylpent-3-enal (11a). The hydroformylation reaction was
run on a 0.588 mmol scale at 60 °C. The crude mixture was filtered through a plug of
silica and washed with dichloromethane to give 88% (0.12 g) isolated yield of 11a as a
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yellow oil. H NMR (500 MHz, CDCl3) δ 9.56 (d, J = 2.7 Hz, 1H), 7.95 – 7.77 (m, 1H),
7.79 – 7.69 (m, 1H), 5.59 (m,1H), 4.77 (dd, J = 8.8, 2.7 Hz, 1H), 1.84 (d, J = 1.4 Hz,
3H), 1.75 (d, J = 1.4 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 197.0, 140.5, 138.8, 138.0,
131.0, 124.7, 124.3, 124.1, 123.0, 121.8, 117.0, 52.6, 26.1, 18.7. HRMS (ESIꢀTOF) m/z:
[M+H]+ calcd for C14H15OS 231.0838; found 231.0835.
The HornerꢀWadsworthꢀEmmons reactions were run following a reported literature
procedure.28
Ethyl (2E)-6-methyl-4-(pyridin-3-yl)hepta-2,5-dienoate (12b). The hydroformylation
reaction was run on a 2.94 mmol scale at 60 °C with 4:1 CO:H2 and then a Hornerꢀ
WadsworthꢀEmmons reaction was carried out to facilitate isolation of 12b. A solution of
NaH (0.14 g, 3.23 mmol) in dry THF (5 mL) at 0 °C was treated with dropwise addition of
triethyl phosphonoacetate (0.64 mL, 3.23 mmol). The mixture was stirred at 0 °C for 45
min. Dry THF (5 mL) was added to the crude hydroformylation mixture and this solution
added slowly to the ylide solution. The mixture was warmed to rt, stirred overnight, then
quenched by the addition of an aqueous saturated solution of NH4Cl. The mixture was
extracted with three portions of ethyl acetate, the combined organic layers dried over
MgSO4, concentrated under reduced pressure and purified by column chromatography
(40% ethyl acetate /hexanes) to furnish a 60% (0.40 g) isolated yield of 12a as a yellow
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oil. 1H NMR (500 MHz, CDCl3) δ 8.64 (d, J = 2.2 Hz, 1H), 8.58 – 8.44 (m, 2H), 7.68 (dt,
J = 7.9, 2.0 Hz, 1H), 7.25 – 7.22 (dd, 1H), 6.13 (dd, J = 7.1, 1.3 Hz, 1H), 5.84 – 5.81 (m,
1H), 4.20 (q, J = 7.1 Hz, 3H), 3.25 – 3.17 (m, 1H), 1.92 (d, J = 1.4 Hz, 4H), 1.54 (d, J =
1.2 Hz, 4H), 1.31 (t, J = 7.1 Hz, 4H). 13C NMR (126 MHz, CDCl3) δ 171.7, 148.3, 148.1,
138.9, 137.6, 136.6, 133.7, 123.0, 122.2, 120.7, 60.8, 35.3, 25.5, 19.8, 14.2. HRMS
(ESIꢀTOF) m/z: [M+H]+ calcd for C15H20NO2 246.1489; found 246.1489.
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Diethyl (2E)-4-(2-methylprop-1-en-1-yl)hex-2-enedio-ate (15b). The hydroformylation
reaction was run on a 2.94 mmol scale at 60 °C and then a HornerꢀWadsworthꢀEmmons
reaction was carried out to facilitate isolation of 12b. To a solution of NaH (0.14 g, 3.23
mmol) in dry THF (5 mL) at 0 °C was added triethyl phosphonoacetate (0.64 mL, 3.23
mmol) dropwise. The mixture was stirred at 0 °C for 45 min. Dry THF (5 mL) was added
to the crude hydroformylation mixture and this added slowly to the solution of the ylide.
The mixture was warmed to rt, stirred overnight, then quenched by the addition of an
aqueous saturated solution of NH4Cl. The mixture was extracted with ethyl acetate
(3x), the combined organic layers dried over MgSO4, concentrated under reduced
pressure and purified by column chromatography (20% ether /hexanes) to furnish a
62% (0.46 g) isolated yield of 15b as a yellow oil. 1H NMR (500 MHz, CDCl3) δ 6.84 (dd,
J = 15.7, 6.7 Hz, 1H), 5.80 (dd, J = 15.6, 1.5 Hz, 1H), 4.95 (heptd, J = 9.3, 1.5 Hz, 1H),
4.18 (q, J = 7.1 Hz, 2H), 4.12 (q, J = 7.2 Hz, 2H), 3.61 (dddd, J = 14.5, 9.3, 6.8, 1.5 Hz,
1H), 2.47 (dd, J = 15.0, 6.9 Hz, 1H), 2.37 (dd, J = 15.0, 7.8 Hz, 1H), 1.71 (d, J = 1.5 Hz,
3H), 1.65 (d, J = 1.4 Hz, 3H), 1.28 (t, J = 7.1 Hz, 3H), 1.24 (t, J = 7.1 Hz, 3H).13C NMR
(126 MHz, CDCl3) δ 171.5, 166.7, 149.5, 135.2, 123.0, 120.5, 60.5, 60.3, 39.4, 37.7,
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