Conventional and Tandem Hydroformylation

Abstract

Transition-metal-catalyzed hydroformylation has become an essential tool for the synthesis of aldehydes. In this paper, we highlight several examples of synthetically useful applications of homogeneous and heterogeneous rhodium-catalyzed hydroformylation, as well as several examples of tandem processes involving hydroformylation as a reaction step developed in our laboratory.

The reaction of an olefin with carbon monoxide and hydrogen effected by a transition metal catalyst to give a homologous aldehyde defines the hydroformylation reaction. Since its discovery by O. Roelen in 1938, [¹] the hydroformylation reaction has become a useful tool for the synthesis of aldehydes as a laboratory-scale method, as well as an industrial process, representing one of the most important chemical manufacturing processes today with capacity amounting to more than 9 million tons of hydroformylated products worldwide per year. [²] The method has been evolving over the years as the complexes of transition metals other than cobalt, notably rhodium, platinum, and ruthenium, were found to catalyze the reaction. [¹b] [c] [³] Advances in hydroformylation reactions resulting from catalyst design and better mechanistic understanding have been utilized broadly, including applications to several types of asymmetric hydroformylation. [¹b] [c] [³] [4]

In this paper, we survey the homogeneous and heterogeneous hydroformylation of alkenes, as well as hydroformylative tandem transformations with a focus on recent work from our own laboratory using rhodium complexes to effect these transformations.

Although rhodium-catalyzed homogeneous hydroformylation of alkenes most typically involves the use of mono- or bidentate phosphine ligands and a rhodium source, or a preformed complex of rhodium with these ligands, we found that the ionic rhodium(I) diamine complexes 1 and 2 (Figure  [¹] ) effectively catalyze hydroformylation reaction of terminal alkenes at ambient temperature providing aldehyde products with excellent regioselectivity. [5]

As shown in Table  [¹] , reaction of aryl alkenes bearing electron-donating or -withdrawing functional groups with complex 2 afforded branched aldehydes in excellent selectivity. Oct-1-ene gave a mixture of branched (b) and linear (l) aldehyde products in equal amounts. [5]

Table 1 Hydroformylation of Alkenes with Ionic Rhodium(I) Complex 2

R	Conv. (%)	Ratio b/l
4-ClC6H4	99	21
4-i-BuC6H4	99	26
C6H13	99	1

The regio- and stereoselective hydroformylation of the 4-vinyl-β-lactams catalyzed by a zwitterionic rhodium(I) complex 3 (Figure  [²] ) in the presence of (S,S)-2,4-bis(diphenylphosphino)pentane [(S,S)-BDPP] provides easy access to the corresponding branched aldehydes, which are the key synthetic precursors for the synthesis of 4-methylcarbapenem antibiotic framework 4 (Figure  [²] ). [6]

As illustrated in Table  [²] , 4-vinyl-β-lactams 5a-c were converted into the corresponding branched aldehydes 6a-c in moderate to high regioselectivity, and with excellent stereoselectivity. The results using 5c as the reactant are particularly impressive. In contrast to the hydroformylation effected in the presence of (S,S)-BDPP ligand, the use of (R)-BINAP ligand in a similar reaction provides the desired aldehyde 6c in significantly lower yield and poor regioselectivity. [6]

Table 2 Regio- and Stereoselective Hydroformylation of 4-Vinyl-β-lactams 5a-c

5	R¹	L	Conv. (%)	Ratio 6/7	Ratio R/S
a	Boc	(S,S)-BDPP	98	76:24	99:1
b	OAc	(S,S)-BDPP	>99	82:18	92:8
c	Me	(S,S)-BDPP	70	>99:1	>99:1
c	Me	(R)-BINAP	30	60:40	>99:1

One of the directions of the research towards the development of environmentally more benign and economically sustainable processes is the heterogenization of homogeneous catalytic systems. The reason why this direction of research has and is receiving much attention lies in many obvious advantages of heterogeneous over homogeneous catalysts including facile separation, easy recycle, and the fact that they have potential applications in continuous processes. [7]

One of the strategies used for the heterogenization of homogeneous catalysts is the use of dendrimers as a support for transition metal complexes. [8] In this context, we recently demonstrated that rhodium complexes supported on resin having dendritic extensions terminated with phosphine functional groups (Figure  [³] ) are efficient catalysts for the hydroformylation of olefins, affording the branched aldehydes with excellent yields, and in exceptionally high regioselectivity. Table  [³] illustrates some examples for the hydroformylation of styrenes and vinyl esters catalyzed by generation 1 (G1) and generation 2 (G2) rhodium dendrimer-grafted resin complexes. [9]

Table 3 Hydroformylation of Styrene and Vinyl Benzoate Effected by G1 and G2 Rhodium Dendrimer-Grafted Resin Complexes

Gn	R	Cycle	Conv. (%)	Ratio b/l
G1	Ph	1	>99	36:1
G1	Ph	2	>99	36:1
G1	Ph	8	95	34:1
G1	PhC(O)O	1	>99	32:1
G1	PhC(O)O	2	>99	31:1
G1	PhC(O)O	6	93	32:1
G2	Ph	1	>99	39:1
G2	Ph	2	>99	38:1
G2	Ph	8	>99	36:1
G2	PhC(O)O	1	>99	33:1
G2	PhC(O)O	2	>99	33:1
G2	PhC(O)O	8	>99	32:1

The reactions shown in Table  [³] occur at ambient temperature and the dendritic catalysts can be recycled by simple filtration and reused without loss of activity and selectivity. [9]

Despite many advantages, resins, as most organic polymers, have potential problems associated with the lack of mechanical stability and tendency to swell in organic solvents. In order to avoid these drawbacks we used a method in which polyamidoamine (PAMAM) dendrimers were grown divergently on the aminopropyl silica gel support. Terminal amino groups of the dendrons were then functionalized with diphenylphosphinomethyl groups serving as ligands to rhodium(I) (Figure  [4] ). [¹0]

Results, presented in Table  [4] , demonstrate that rhodium(I) phosphine PAMAM-on-SiO₂ catalyst of zero and first generations, G0 and G1, are highly active and regio­selective catalysts for the hydroformylation of aryl olefins and vinyl esters. In contrast, higher generation catalysts displayed significantly lower catalytic activity. One of the reasons for the observed decrease in catalytic activity as the generation increases is an incomplete phosphination of the dendrimer arising from steric crowding. To relieve the steric strain and allow for increased catalyst loading at higher generations the chain length was extended by the use of 1,4-diaminobutane, 1,6-diaminohexane, and 1,12-diaminododecane instead of the ethylenediamine linker (Figure  [4] , n = 3, 5, 11). [¹0]

As the spacer length increases, the reactivity and recyclability of the rhodium(I) phosphine PAMAM-on-SiO₂ catalysts increases; however, the selectivity for the branched chain aldehyde decreases somewhat at elevated reaction temperatures (Table  [4] ). [¹0]

Table 4 Hydroformylation of Alkenes with Rhodium(I) Phosphine PAMAM-on-SiO₂ Catalyst of Different Generations and Spacer Lengths

R	Cycle	Gn	Conv. (%)	Ratio b/l
Ph		G0	98	25:1
Ph		G1	98	27:1
Ph		G2	99	30:1
Ph		G3	5	n.d.
PhC(O)Oa		G2	99	19:1
PhC(O)Oa		G3	99	18:1
Phb	1	G3, n = 3	99	9:1
Phb	2	G3, n = 3	90	7:1
Phb	4	G3, n = 3	6	n.d.
Phb	1	G3, n = 5	99	10:1
Phb	2	G3, n = 5	92	12:1
Phb	4	G3, n = 5	80	11:1
Phb	1	G3, n = 11	99	8:1
Phb	2	G3, n = 11	99	11:1
Phb	4	G3, n = 11	76	10:1
a At 75 ˚C. b At 65 ˚C.

A valuable alternative to the rhodium dendrimer-grafted resin complexes and rhodium(I) phosphine PAMAM-on-SiO₂ catalysts are the rhodium-phosphine heterogeneous complexes prepared by complexation of rhodium(I) with phosphine ligands attached to the PAMAM dendrons of various generations divergently grown on silica-coated magnetic nanoparticles. The reactivity, selectivity, and recyclability of the catalysts are illustrated by the examples shown in Table  [5] . [¹¹]

Although the reactions shown in Table  [5] were carried out at slightly elevated temperature than those effected by rhodium dendrimer-grafted resin complexes (Table  [³] ), they afforded the hydroformylation product in higher selectivity for the branched aldehyde. However, the catalytic activity of the rhodium-dendronized nanoparticles complex G0 shows a decrease in activity with an increasing number of runs. [¹¹]

The high reactivity of the carbonyl group introduced by the hydroformylation reaction allows the development of the reaction sequences (tandem processes) in which the carbonyl compound formed becomes subject to nucleophilic attack or, as in the form of the corresponding enolate, to electrophilic attack. [¹²] Moreover, tandem reactions involving a hydroformylation process can also include reactions of intermediates of the hydroformylation reaction, such as metal alkyl and metal acyl species, which can undergo coupling, isomerization, or elimination processes (metal alkyls), or can be attacked by a nucleophile (metal acyls) (Scheme  [¹] ). [¹²]

In the most typical cases the hydroformylation tandem reactions involve hydroformylation as the first step of the reaction sequence. An interesting exception to this is synthesis of 4-carbaldehydepyrrolin-2-ones 10 from α-imino alkynes 8 catalyzed by rhodium(I) zwitterionic complex 9 in the presence of a triphenyl phosphite ligand under carbon monoxide and hydrogen gas atmosphere as illustrated in Scheme  [²] . In this reaction a hydrocyclocarbonylation step giving rise to a pyrrolinone, precedes the formylation process. [¹³]

Table 5 Hydroformylation of Styrene with Rhodium-Dendronized Magnetic Nanoparticle Complexes of Generations G0 and G1

Dendronized magnetic nanoparticles	Cycle	Conv. (%)	Ratio b/l
G0	1	>99	45:1
	2	>99	41:1
	5	69	43:1
G1	1	>99	48:1
	2	>99	48:1
	5	98	42:1

The scope of the reaction covers α-imino alkynes with both alkyl and aryl substituents at imine carbon, and a variety of alkyl substituents at imine nitrogen and the alkyne terminus making it an excellent preparative method. [¹³]

A new type of tandem reaction, hydroaminovinylation, occurring under hydroformylation conditions, was observed when vinyl sulfones and vinyl phosphonates were subjected to hydroformylation conditions using rhodium complex 9 as the catalyst and (±)-BINAP as the ligand. The reaction is generally selective for the corresponding enamines (e.g., 12a-c), affording products in good isolated yields. Some examples of vinyl sulfones hydroamino­vinylation are shown in Table  [6] . [¹4]

Table 6 Rhodium-Catalyzed Hydroaminovinylation of Vinyl Sulfones

11	12	R¹	R²	Yield (%)
11a	12a	MeSO2	t-Bu	89
11a	12b	MeSO2	Ph	73
11b	12c	PhSO2	i-Pr	68

Hydroformylation of styrene catalyzed by the zwitterionic complex 9 in the presence of amine resulted in hydroformylation-reductive amination tandem sequence (overall hydroaminomethylation) producing predominantly branched secondary amines as exemplified in Table  [7] . [¹5]

Table 7 Hydroaminomethylation of Styrene Catalyzed by Zwitter­ionic Complex 9

13	R	Isolated yield (%) of 13	Ratio 13/13′	Pressure CO/H2 (psi)
a	i-Pr	85	11.5	200
b	n-Bu	68	15	600
c	Bn	78	14	1000

The scope of the hydroaminomethylation tandem reaction is not restricted only to intermolecular processes, as it can also occur intramolecularly. This strategy was successfully used in the development of a practical method for the construction of tetrahydroquinolines from 2-(prop-1-en-2-yl)anilines 14, using ionic rhodium(I) diamine complexes 1 as the catalyst (Table  [8] ). [¹6]

Table 8 Synthesis of Tetrahydroquinolines by Rhodium-Catalyzed Hydroaminomethylation

14/15	R¹	R²	Yield (%) of 15
a	H	H	89
b	H	Bn	98
c	8-Me	H	85
d	8-MeO	H	80
e	6-Me	H	80

The intramolecular hydroaminomethylation strategy was further extended to the synthesis of seven-membered ring heterocycles, tetrahydro-1H-2-benzazepines 17, from 2-(prop-1-en-2-yl)benzylamines under similar reaction conditions (Table  [9] ). [¹6]

An efficient synthesis of 2,3,4,5-tetrahydro-1H-2-benz­azepines 17 from prop-2-enylbenzaldehyde (18) and anilines illustrated in Table  [9] , method B extends the utility of intramolecular hydroaminomethylation even further, allowing for the reaction to occur in one pot via a five-step cascade. [¹7]

The scope of the one-pot reaction was found to be quite general and the synthetic protocol tolerates 2-(prop-1-en-2-yl)benzaldehyde 18 and anilines of diverse nature affording 2,3,4,5-tetrahydro-1H-2-benzazepines 17 in excellent yields.

Table 9 Synthesis of Tetrahydro-1H-2-benzazepines by Hydroaminomethylation from Presynthesized Benzylamine (Method A) and a Five-Steps-In-One-Pot Cascade (Method B)

17	R	Method A yield (%)	Method B yield (%)
a	H	91	90
b	MeO	94	89
c	Ph	98	96

We found that cyclic N,O-acetals can be prepared diastereoselectively by a hydroformylation-SiO₂-induced deformylation reaction sequence starting from the easily accessible chiral N-(allyl)oxazolidines 19. [¹8] The method made it possible to synthesize the five-membered 5-unsubstituted oxazabicycloalkane ring systems, which were not previously accessible by hydroformylation-acetalization of 2-(alkenylamino)ethanols and prepared previously only by a stoichiometric oxidative cyclization of 2-pyrrolidino-1-ethanol derivatives. [¹9] An example of the developed hydroformylation-SiO₂-induced deformylation reaction is shown in Table  [¹0] , where hydroformylation of (4R)-3-allyl-4-phenyloxazolidine (19a), followed by a silica-induced diastereoselective deformylative cyclization affords (3R,7aS)-3-phenylhexahydropyrrolo[2,1-b]oxazole (20a) in 87% yield. [¹8]

We examined the scope of the cyclization reaction of N-(allyl)oxazolidines 19a-d. As one may see from the results­ presented in Table  [¹0] , the hydroformylation-deformylation­ reaction sequence gave hexahydropyrrolo[2,1-b]oxazoles 20a-d in good yields with a variety of substituents located at the 3-position of the hexahydropyr­rolo[2,1-b]oxazole. [¹8]

Table 10 Synthesis of Hexahydropyrrolo[2,1-b]oxazoles by Hydroformylation-SiO₂-Induced Deformylation Reaction Sequence

20	R	Config. at C-7a	dr	Isolated yield (%)
a	(R)-Ph	S	25:1	87
b	(R)-i-Bu	S	6:1	63
c	(R)-Bn	S	9:1	85
d	(S)-i-Pr	R	10:1	73

In conclusion, we have presented results demonstrating the application of homogeneous and supported rhodium catalysts for regio- and in some cases the stereoselective hydroformylation of alkenes. Additionally, we have demonstrated an application of rhodium-catalyzed tandem hydroformylation reactions for the synthesis of five-, six- and seven-membered heterocycles.

Solution ^¹H NMR and ^¹³C NMR were recorded in CDCl₃, containing TMS as internal standard, on a Bruker Avance spectrometer at 300 MHz (or 400 MHz). Chemical shifts (δ) are reported in ppm with the solvent signals as reference (^¹H NMR at 7.26 ppm and ^¹³C NMR at 77.1 ppm), and coupling constants (J) are given in hertz (Hz). Flash column chromatography was undertaken with silica gel (60 Å, 200-430 mesh) supplied by VWR. IR spectra were obtained with a Shimadzu FTIR8400S spectrometer. Mass spectra were determined using a VG 7070E spectrometer.

Hydroformylation of 5a-c; [6] General Procedure

The hydroformylation reaction was carried out in a 45 mL Parr autoclave fitted with a glass liner and a stirring bar. The 4-vinyl-β-lactam (0.5 mmol), Rh complex 3 (5 mmol%), and phosphorus ligand (10 mmol%) were placed in the glass liner, which was then protected with a septum. CO was bubbled through a needle for several min prior to the addition of benzene (5 mL). The glass liner was transferred into the autoclave, and the system was purged three times with CO and subsequently pressurized with CO and H₂. The autoclave was heated in an oil bath; at the end of the reaction time, it was cooled to r.t., the gas was vented, and the reaction mixture was filtered through Flurosil to remove the catalyst. The conversion of the starting material was determined by GC. After evaporation of the solvent, the branched/linear ratio of the isomeric aldehydes and the stereoselectivity were determined by ^¹H NMR by integration of the resonances corresponding to the aldehyde protons.

(3 S ,4 R )- tert -Butyl 3-[( R )-1-methoxyethyl]-2-oxo-4-[( R )-1-oxopropan-2-yl]azetidine-1-carboxylate (6c) [6]

IR (CH₂Cl₂): 1830 cm^-¹ (C=O, carbamate), 1737 (C=O, lactam), 1694 (C=O, aldehyde).

^¹H NMR (300 MHz, CDCl₃): δ = 1.12-1.20 (m, 6 H), 1.45 (s, 9 H), 2.5-2.6 (m, 1 H), 3.5-3.6 (m, 1 H), 4.0-4.2 (m, 1 H), 4.5-4.6 (m, 1 H), 9.625-9.630 (d, J = 1.0 Hz, 1 H).

^¹³C NMR (100 MHz, CDCl₃): δ = 9.32, 20.27, 28.16, 51.91, 54.04, 65.33, 70.43, 80.13, 148.51, 165.91, 201.10.

HRMS: m/z calcd for C₁₄H₂₃NO₅: 285.1576; found: 285.1570.

Cyclohydrocarbonylative/CO Insertion of Acetylenic Imines 8; [¹³] General Procedure

In a 45 mL autoclave containing a glass liner and stirring bar was placed zwitterionic rhodium complex 9 (0.03 mmol), P(OPh)₃ (0.12 mmol), acetylenic imine 8a,b (1.5 mmol), and CH₂Cl₂ (10 mL). The autoclave was flushed three times with CO, pressurized from 17.5 to 38.5 atm followed by the introduction of H₂ to a total pressure of 21-42 atm. The autoclave was placed in an oil bath at 75-100 ˚C for 18-36 h and then allowed to cool to r.t. The autoclave was depressurized, the reaction mixture filtered through Celite, and the solvent removed by rotary evaporation. The resulting residue was purified by silica gel chromatography using an EtOAc-hexanes gradient ranging from 33:67 to 50:50 as the eluent.

1-Butyl-4-carbaldehyde-3-ethyl-5-methyl-3-pyrrolin-2-one (10a) [¹³]

Purification by flash chromatography provided the title compound in 82% yield.

IR (neat): 1727 (C=O), 1644 cm^-¹ (C=O).

^¹H NMR (500 MHz, CDCl₃): δ = 9.71 (s, 1 H), 3.55 (t, J = 7.7 Hz, 1 H), 3.45 (t, J = 7.7 Hz, 1 H), 3.30 (m, 1 H), 2.38 (br, 3 H), 2.01 (m, 2 H), 1.52 (q, J = 7.7 Hz, 2 H), 1.32 (sext, J = 7.7 Hz, 2 H), 0.92 (t, J = 7.4 Hz, 3 H), 0.71 (t, J = 7.5 Hz, 3 H).

^¹³C NMR (200 MHz, CDCl₃): δ = 182.9, 180.1, 159.9, 118.8, 46.0, 40.5, 31.9, 22.5, 20.7, 14.3, 11.4, 9.6.

MS (EI): m/z = 209 [M⁺].

HRMS: m/z calcd for C₁₂H₁₉NO₂ [M⁺]: 209.14158; found: 209.14173.

Hydroaminomethylation of 14a-e; [¹6] General Procedure

A glass liner, equipped with a magnetic stirring bar, containing the olefin 14a-e (1.00 mmol), catalyst 1 (5.0 mol%, 25.6 mg), and toluene (2 mL) was placed in a 45 mL autoclave. The autoclave was flushed three times with CO and pressurized to 700 psi of CO and then 300 psi of H₂. The autoclave was then placed in an oil bath preset to 120 ˚C on a stirring hot plate. The total pressure increased to 1200 psi. After 48 h, the autoclave was removed from the oil bath and cooled to r.t. prior to the release of excess CO. The solvent was concentrated and the residue was purified by silica gel chromatography with a mixture of hexane and EtOAc (9:1) as the eluent to afford the desired products.

4-Methyl-1,2,3,4-tetrahydroquinoline (15a) [¹6]

Purification by flash chromatography provided the title compound in 89% yield.

^¹H NMR (300 MHz, CDCl₃): δ = 1.28 (d, J = 6.9 Hz, 3 H), 1.62-1.72 (m, 1 H), 1.92-2.02 (m, 1 H), 2.85-2.96 (m, 1 H), 3.21-3.35 (m, 2 H), 3.82 (br s, 1 H), 6.45-6.65 (m, 2 H), 6.93-7.06 (m, 2 H).

^¹³C NMR (75.4 MHz, CDCl₃): δ = 22.7, 29.9, 30.3, 39.0, 114.2, 117.0, 126.6, 126.8, 128.5, 144.3.

Hydroaminomethylation of 16a-c; [¹7] Method A; General Procedure

A glass liner, equipped with a magnetic stirring bar, containing the benzylamine 16a-c (0.50 mmol), catalyst 1 (7.5 mol%), and toluene (2.5 mL) was placed in a 45 mL autoclave. The autoclave was flushed three times with CO and pressurized to 700 psi of CO and then 100 psi of H₂. The autoclave was then placed in an oil bath preset to 120 ˚C on a stirring hot plate. The total pressure increased to 1200 psi. After 48 h, the autoclave was removed from the oil bath and cooled to r.t. prior to the release of excess CO. The solvent was concentrated and the residue was purified by silica gel chromatography with a mixture of hexane and EtOAc (9:1) as the eluent to afford the desired products.

Hydroaminomethylation of 18; Method B; One-Pot Procedure

A glass liner, equipped with a magnetic stirring bar, containing the olefin 18 (0.50 mmol), suitable aniline (0.50 mmol), catalyst 1 (7.5 mol%, 19 mg), and toluene (2.5 mL) was placed in a 45 mL autoclave. The procedure continues as described for olefins 16a-c.

5-Methyl-2-phenyl-2,3,4,5-tetrahydro-1 H- benzo[ c ]azepine (17a) [¹7]

Purification by flash chromatography provided the title compound in 91% yield (Method A) (in 90% using the one-pot procedure, Method B).

^¹H NMR (400 MHz, CDCl₃): δ = 1.35 (d, J = 7.1 Hz, 3 H), 1.50-1.59 (m, 1 H), 2.10-2.18 (m, 1 H), 3.09-3.18 (m, 1 H), 3.57-3.68 (m, 2 H), 4.54 (q, J = 14.9 Hz, 2 H), 6.63 (t, J = 7.2 Hz, 1 H), 6.78 (d, J = 8.0 Hz, 2 H), 7.10-7.23 (m, 5 H), 7.28 (d, J = 7.2 Hz, 1 H).

^¹³C NMR (100 MHz, CDCl₃): δ = 19.7, 33.5, 36.6, 47.0, 54.8, 112.3, 116.0, 125.8, 126.7, 127.6, 129.2, 129.4, 137.3, 144.7, 148.0.

HRMS: m/z calcd for C₁₇H₁₉N: 237.1517; found: 237.1509.

Catalytic Hydroformylation-Decarbonylation Reaction of 19a-d; [¹8] General Procedure

Xanthphos (0.2 mmol) and Rh(CO)₂(acac) (0.05 mmol) were dissolved in anhyd THF (10 mL) under an atmosphere of argon in a glass liner equipped with a magnetic stirring bar. The solution was stirred for 2 min until the evolution of CO had ceased. To this solution was added N-(allyl)oxazolidine 19a-d (1 mmol) and the liner was inserted into a 45 mL autoclave, which was then sealed. CO, 25 atm, was introduced to the autoclave by the two consecutive pump-release cycles. Finally, H₂ gas was introduced into the autoclave bringing the overall pressure to 35 atm. The autoclave was placed in a thermostated oil bath at 100 ˚C and the reaction was carried out for 24 h. The autoclave was then cooled, and pressure was released. The reaction mixture was concentrated and the residue was subjected to flash chromatography using the indicated eluent.

(3 R ,7a S )-3-Phenylhexahydropyrrolo[2,1- b ]oxazole (20a) [¹8]

Purification by flash chromatography with 20% of EtOAc in hexanes used as eluent provided the title compound in 87% yield; [α]_D ^²² -95.3 (c = 1.29, CHCl₃).

^¹H NMR (400 MHz, C₆D₆): δ = 1.5 (m, 1 H), 1.7 (m, 2 H), 1.9 (m, 1 H), 2.5 (dt, J = 9.8, 6.9 Hz, 1 H), 2.9 (dt, J = 9.7, 6.3 Hz, 1 H), 3.5 (dd, J = 7.6, 8.1 Hz, 1 H), 3.8 (t, J = 7.2 Hz, 1 H), 4.1 (dd, J = 7.9, 6.8 Hz, 1 H), 5.0 (dd, J = 5.1, 1.9 Hz, 1 H), 7.1 (tt, J = 7.3, 2.0 Hz, 1 H), 7.2 (m, 2 H), 7.3 (m, 2 H).

^¹³C NMR (101 MHz, C₆D₆): δ = 24.2, 31.9, 55.4, 70.1, 73.7, 98.9, 126.9, 127.1, 128.6, 143.2.

HRMS: m/z calcd for C₁₂H₁₅NO: 189.1154; found: 189.1132.

Acknowledgment

The work carried out by the authors of this manuscript benefited from generous support by the Natural Sciences and Engineering Research Council of Canada and by Sasol Technology.

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