Iridium-catalysed direct C-C coupling of methanol and allenes

Article abstract of DOI:10.1038/nchem.1001

Methanol is an abundant (35 million metric tons per year), renewable chemical feedstock, yet its use as a one-carbon building block in fine chemical synthesis is highly underdeveloped. Using a homogeneous iridium catalyst developed in our laboratory, meth

Full text of DOI:10.1038/nchem.1001

ARTICLES
PUBLISHED ONLINE: 27 FEBRUARY 2011 | DOI: 10.1038/NCHEM.1001
Iridium-catalysed direct C–C coupling
of methanol and allenes
Joseph Moran, Angelika Preetz, Ryan A. Mesch and Michael J. Krische
*
Methanol is an abundant (35 million metric tons per year), renewable chemical feedstock, yet its use as a one-carbon
building block in fine chemical synthesis is highly underdeveloped. Using a homogeneous iridium catalyst developed in our
laboratory, methanol engages in a direct C–C coupling with allenes to furnish higher alcohols that incorporate all-carbon
quaternary centres, free of stoichiometric by-products. A catalytic mechanism that involves turnover-limiting methanol
oxidation, a consequence of the high energetic demand of methanol dehydrogenation, is corroborated through a series of
competition kinetics experiments. This process represents the first catalytic C–C coupling of methanol to provide discrete
products of hydrohydroxymethylation.
he development of catalytic C–C bond formations, free of by- discrete products of hydrohydroxymethylation, as demonstrated
products, that use abundant, renewable feedstocks represents by the regioselective conversion of the 1,1-disubstituted allenes
T
an important step in defining sustainable paradigms for bulk 1a–1l into the homoallylic neopentyl alcohols 2a–2l. Notably,
and fine chemical manufacture1–4. With an annual global pro- these transformations promote the direct conversion of methanol
duction estimated at 35 million metric tons per year (close to 12 into higher alcohols in the absence of stoichiometric by-products.
billion gallons), methanol is vastly abundant5. However, use of
Results
methanol as a C1-feedstock in catalytic C–C coupling is restricted
to dehydrative oligomerizations, such as the methanol-to-gasoline6
and methanol-to-olefins7 processes6–11, and to methanol carbonyla-
tion (the Monsanto and Cativa processes)12–15, the latter being the
second largest volume application of homogenous catalysis.
Homogenous catalytic C–C couplings of methanol beyond the car-
In an initial series of experiments, ruthenium21–26 and iridium27–34
complexes that proved effective in catalytic C–C couplings of
p-unsaturated reactants to higher alcohols were assayed in corre-
sponding couplings of methanol. Consistent with prior obser-
vations39, the ruthenium complexes established thus far18,39 were
inefficient in the attempted catalytic C–C couplings of methanol.
bonylative processes remain highly uncommon6–16
.
Alkene hydroformylation is the largest volume application of
homogenous metal catalysis and may be viewed as the prototypical
‘C–C bond-forming hydrogenation’17. In the course of developing
hydrogen-mediated C–C couplings beyond hydroformylation, our
laboratory uncovered a broad class of catalytic transformations in
which alcohols and p-unsaturated reactants are converted directly
into products of formal carbinol C–H functionalization or ‘hydro-
hydroxyalkylation’18–20. In such transformations, the removal of
hydrogen from an alcohol reactant (an oxidation) generates an alde-
hyde and a metal hydride, which triggers the reductive generation of
a transient organometallic nucleophile through the hydrometalla-
tion of a p-unsaturated reactant. The resulting electrophile–nucleo-
phile pair combine to form products of carbonyl addition21–34. In
this way, carbonyl addition is achieved from the alcohol oxidation
level in the absence of stoichiometric by-products. Further, by
merging alcohol oxidation and C–C bond construction events,
one circumvents discrete alcohol oxidation and the use of pre-
metallated nucleophiles (which typically are required for carbonyl
additions of non-stabilized carbanions) and provides access to
more tractable synthetic building blocks in the form of alcohols.
Although catalytic C–C couplings of various p-unsaturated
reactants were achieved using higher alcohols21–34, direct C–C
couplings of methanol proved elusive, probably due to the relatively
high energetic demand of methanol dehydrogenation (DH ¼
þ84 kJ mol21) compared to the dehydrogenation of higher alco-
hols, such as ethanol (DH ¼ þ68 kJ mol21) (refs 35–38). Here,
using a homogenous iridium catalyst developed in our laboratory,
we report the first catalytic C–C couplings of methanol to furnish
Table 1 | Iridium-catalysed C–C coupling of CH3OH to allene 1a.
Ph2
P
P
Ph2
HO
Ir
O
Ir-complex (5 mol%)
Me
HOCH3
(equiv.)
Solvent (M)
T (°C), 24h
O
PMBO
Me
PMBO
X
1a
(100 mol%)
2a
NO2
Ir-complex
Entry Ligand, X
MeOH
Solvent (M) T(8C) Yield 2a
(equiv.)
(%)
1
2
3
4
5
BIPHEP, H
BIPHEP, H
BIPHEP, H
10
15
20
PhMe (1)
PhMe (1)
PhMe (1)
PhMe (1)
PhMe (1)
PhMe (1)
PhMe (1)
PhMe (2)
THF (2)
80
80
80
80
80
80
80
80
80
80
100
70
29
39
36
37
39
44
63
67
55
34
61
BIPHEP, OMe 15
BIPHEP, CN
BIPHEP, Cl
DPPF, Cl
DPPF, Cl
DPPF, Cl
DPPF, Cl
DPPF, Cl
DPPF, Cl
15
15
15
15
15
Neat
15
6
7
8
9
10
11
12
MeOH (1)
PhMe (2)
PhMe (2)
15
42
Selected optimization data are given. Yields are of material isolated by silica-gel chromatography and
represent the average of two runs (see Supplementary Information for further details). PhMe ¼
toluene, PMBO ¼ p-methoxybenzyl ether.
Department of Chemistry and Biochemistry, University of Texas at Austin, Austin, Texas 78712, USA. e-mail: mkrische@mail.utexas.edu
*
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1001
ARTICLES
Ph2
P
NO2
NO2
R
O
O
Ir
Fe
P
O
Ph2
Cl
Cl
R
O
O
P
P
O
P
P
IrIII
IrIII
O
H
Cl
NO2
NO2
H
H
NO2
O
O
O
H
Cl
Cl
HO CH3
DPPF-I (X-ray)
O
H
O
P
P
IrIII
R
IrIII
P
P
H
O
H
Me
H
H
R
Ir1
P1
NO2
NO2
OH
01
O
O
Fe1
P2
Cl
Cl
R
02
O
P
P
O
P
P
R
R
CH3OH
IrIII
IrIII
O
R
R
Hexacoordinate,
18-electron complex
R
Cl1
N1
03
04
Figure 1 | Mechanism for the iridium-catalysed C–C coupling of methanol and the structure of DPPF-I. The structure was determined by single-crystal
X-ray diffraction analysis. Entry into the catalytic cycle occurs by methanolysis of the p-allyl moiety of the precatalyst. b-Hydride elimination of the resulting
iridium methoxide generates a transient iridium hydride with the concomitant release of formaldehyde. Allene hydrometallation followed by addition of the
resulting allyliridium intermediate to formaldehyde furnishes the homoallylic iridium alkoxide, which on methanolysis closes the catalytic cycle. Further
oxidation of the coupling product is prohibited by coordination of the homoallylic olefin to the iridium centre.
In contrast, the ortho-cyclometallated p-allyl iridium C,O-benzoate However, deuterium incorporation at the interior vinylic position
2
complex29 derived from (Ir(cycoloctadiene)Cl)2, allyl acetate, was incomplete (82% H) and also deuterium incorporation at the
3-nitrobenzoic acid and 2,2′-bis(diphenylphosphino)biphenyl vinylic terminus (9% H) was observed. These data suggest revers-
2
(BIPHEP) catalysed the C–C coupling of methanol to the 1,1-disub- ible allene hydrometallation to form a transient vinyl iridium
2
stituted allene 1a to provide the homoallylic neopentyl alcohol 2a in species. In contrast, only trace quantities of deuterium (,1% H)
29% isolated yield (Table 1, entry 1). By adjusting the loading of were detected at the carbinol methylene when the experiment was
methanol and tuning the electronic features of the C,O-benzoate carried out using CH3OD (Fig. 2b). In an effort to uncover the
moiety, the yield of 2a was increased to 44% (Table 1, entry 6). turnover-limiting step of the catalytic cycle, a series of competition
After screening various chelating triarylphosphine ligands, we kinetic experiments were performed (Fig. 2c,d). The product
found that the catalyst modified by 1,1′-bis(diphenylphosphino)fer- obtained on exposure of allene 1g to equimolar quantities of
rocene (DPPF), designated DPPF-I, was superior, and ultimately d1-methanol and d4-methanol incorporated a lower proportion of
2
provided 2a in 67% isolated yield (Table 1, entry 12). The structural deuterium at the carbinol methylene (33% H), consistent with a
assignment of DPPF-I was corroborated by single crystal X-ray dif- normal primary kinetic isotope effect (kH/kD ¼ 2.0, where kH and
fraction analysis (Fig. 1).
kD are the rate constants for d1- and d4-methanol). However, corre-
Optimal conditions for the precatalyst DPPF-I were applied to sponding competition kinetic experiments that involved benzyl
diverse 1,1-disubstituted allenes (1a–1l). The corresponding homo- alcohol and d2-benzyl alcohol revealed no significant kinetic effect
allylic neopentyl alcohols (2a–2l) were isolated in yields that ranged (kH/kD ¼ 1.1) (Fig. 2c,d)40–45. These data suggest that dehydrogena-
from 59 to 70% (Table 2). As allenes 1a–1l were used as limiting tion–oxidation is the turnover-limiting step in the catalytic C–C
reagents, the relatively modest yields resulted from competitive pro- coupling of methanol and 1,1-disubstituted allenes.
tonolysis of the transient allyliridium complex to furnish products
of allene-transfer hydrogenation, which could be isolated from the Discussion
reaction mixture. Remarkably, although dehydrogenation of the Turnover-limiting dehydrogenation–oxidation steps in the catalytic
primary alcohol products 2a–2l was anticipated to be less endother- C–C coupling of methanol and 1,1-disubstituted allenes, as corro-
mic than the dehydrogenation of methanol35–38, further oxidation of borated by competition kinetics (Fig. 2c,d), are consistent with
the alcohol products 2a–2l to give the corresponding aldehydes was several empirical observations. For example, the temperature
not observed. At the stage of the homoallylic iridium alkoxide, a required for methanol C–C coupling (80–95 8C) is significantly
hexacoordinate 18-electron complex, the olefin moiety of the higher than the temperatures used in related hydrohydroxyalkyla-
product occupied the final remaining coordination site required tions of allylic or benzylic primary alcohols (30–40 8C)34. The col-
for b-hydride elimination and disabled the kinetic pathway for lective data suggest that, although dehydrogenation–oxidation is
product oxidation (Fig. 1).
the turnover-limiting event in C–C couplings of methanol, carbonyl
Deuterium-labelling experiments gave further insight into the addition is probably the turnover-limiting event in reactions of
catalytic mechanism (Fig. 2). Exposure of 1,1-disubstituted allene higher alcohols. This assertion is made despite the absence of a
1g to standard conditions for iridium-catalysed hydrohydroxy- detectable secondary inverse isotope effect in the competition
methylation using d4-methanol produced deuterio-2g (Fig. 2a). As kinetic experiments that involved benzyl alcohol and d2-benzyl
determined by 1H and 2H NMR analyses, complete deuterium alcohol (Fig. 2d), as such isotope effects are often too small to
incorporation (.99% 2H) was observed at the carbinol methylene. detect easily. This divergence in turnover-limiting events stems
288
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1001
ARTICLES
DPPF-I (5 mol%)
PhMe (2.0M)
80°C, 48h
a
Table 2 | Iridium-catalysed C–C coupling of CH3OH to 1a–1l.
(82%) 2
2H
H
HO
2H
Me
>99%
Ph2
P
P
Ph2
DOCD3
(15 equiv.)
2H
HO
R1
Ir
DPPF-I (5 mol%)
2H
R1
9%
Fe
O
Me
NPhth
HOCH3
(15 equiv.)
NPhth
PhMe (2.0 M)
80°C, 24h
R2
O
1g
R2
1a–1l
deuterio-2g, 59% yield
(100 mol%)
Cl
2a–2l
b
c
DPPF-I
(100 mol%)
NO2
(6%) 2
H
HO
2H
2H
As above
1a, R1 ¼ Me,
1b, R1 ¼ n-Pr,
R2 ¼ OPMB
1e, R1 ¼ c-Pent,
R2 ¼ OPMB
1h, R1 ¼ n-Pr,
R2 ¼ NPhth
1c, R1 ¼ i-Pr,
1g
2H
<1%
(100 mol%)
R2 ¼ OPMB
R2 ¼ OPMB
1f, R1 ¼ Bn,
R2 ¼ OPMB
1i, R1 ¼ i-Pr,
R2 ¼ NPhth
1l, R1 ¼ Bn,
R2 ¼ NPhth
DOCH3
(15 equiv.)
1d, R1 ¼ c-Pr,
R2 ¼ OPMB
1g, R1 ¼ Me,
R2 ¼ NPhth
1j, R1 ¼ c-Pr,
R2 ¼ NPhth
Me
2H
9%
NPhth
deuterio-2g, 64% yield
1k, R1 ¼ c-Pent,
R2 ¼ NPhth
(30%) 2
2H
H
HO
As above
2H
2H
1g
33%
HO
HO
HO
(100 mol%)
DOCH3/DOCD3
(1:1, 15 equiv.)
2H
Me
10%
PMBO
Me
PMBO
PMBO
Me
NPhth
Me
Me
2c, 65% yield
2a, 67% yield
deuterio-2g, 66% yield
2b, 64% yield
d
(31%) 2
2H
H
HO
HO
HO
HO
2H
As above
(47%)
1g
(100 mol%)
Ph
PhCD2OH/
PhCH2OH
(1:1, 15 equiv.)
PMBO
PMBO
PMBO
Bn
2H
Me
2%
2f, 68% yield
NPhth
2d, 60% yield
2e, 59% yield
deuterio-3, 68% yield,
1.2:1 dr
*HO
HO
HO
Figure 2 | Deuterium labelling and competition kinetics experiments.
a,b, Experiments that corroborate reversible allene hydrometallation.
c,d, Experiments that corroborate turnover-limiting methanol
dehydrogenation. dr ¼ diastereomeric ratio
PhthN
Me
PhthN
PhthN
Me
Me
Me
2g, 70% yield*
2h, 65% yield*
HO
2i, 65% yield*
HO
HO
studies, including competition kinetics experiments, corroborate
reversible allene hydrometallation and turnover-limiting methanol
dehydrogenation–oxidation steps. Future studies will focus on the
development of second-generation catalysts for enantio- and diaster-
eoselective alcohol C–C couplings, including enantioselective variants
of the present transformation.
PhthN
PhthN
PhthN
Bn
2l, 65% yield
2j, 67% yield*
†
2k, 66% yield
Methods
Yields are of material isolated by silica-gel chromatography and represent the average of two runs
(see Supplementary Information for further details). *Reaction was conducted at 95 8C for
48 hours. †Reaction was conducted at 95 8C for 72 hours. NPhth ¼ phthalimido, c-Pentyl ¼
cyclopentyl, c-Pr ¼ cyclopropyl.
DPPF-I (14.8 mg, 0.0150 mmol, 5 mol%) and allene 1g (0.0642 g, 0.300 mmol,
100 mol%) were added to an oven-dried sealed pressure tube equipped with a
magnetic stir bar. The tube was capped with a rubber septum and purged with argon
for five minutes. Toluene (0.15 ml, 2.0 M) and methanol (0.120 ml, 4.50 mmol,
1,500 mol%) were added by syringe. The rubber septum was removed and the
pressure tube was sealed immediately with a plastic screwcap. The reaction mixture
was stirred at 95 8C for 48 hours. The tube was cooled to room temperature and
solvents were removed in vacuo. The reaction mixture was subjected to column
chromatography (SiO2, 12% ethyl acetate/hexanes) to provide neopentyl alcohol 2g
as a white powder (0.052 g, 70%).
not only from the relative energetic demands of methanol versus
higher alcohol oxidation, but also from the relative electrophilicities
of the resulting aldehydes: monomeric formaldehyde is far more
reactive towards carbonyl addition than the substituted aldehydes.
The ability of iridium- versus ruthenium-based catalysts to
promote catalytic C–C couplings of methanol is consistent with
the observed change in turnover-limiting events. The high energetic
demand of methanol dehydrogenation can be attenuated through
stabilization of the resulting metal hydride. Third-row transition
metals, such as iridium, generally form stronger metal–hydrogen
bonds than those of second-row transition metals46. Formation of
a strong Ir–H bond compensates for the loss of a strong methanol
C–H bond, which may, in accordance with Hammond’s postulate,
make the activation barrier of the methanol dehydrogenation
event less endothermic.
Received 7 October 2010; accepted 19 January 2011;
published online 27 February 2011
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Acknowledgements
Acknowledgement is made to the Robert A. Welch Foundation (F-0038), the Texas Higher
Education Coordinating Board (NHARP Award 01849), the University of Texas Center for
Green Chemistry and Catalysis and the National Science Foundation (CHE-1021640). The
Natural Sciences and Engineering Research Council of Canada and the German Research
Foundation are thanked for partial support of J.M. and A.P., respectively.
Author contributions
J.M., A.P. and R.A.M. carried out the experiments. M.J.K. directed the study. M.J.K. and
J.M. co-wrote the manuscript.
29. Kim, I. S., Ngai, M.-Y. & Krische, M. J. Enantioselective iridium-catalyzed
carbonyl allylation from the alcohol or aldehyde oxidation level using
allyl acetate as an allyl metal surrogate. J. Am. Chem. Soc. 130,
6340–6341 (2008).
Additional information
30. Kim, I. S., Ngai, M.-Y. & Krische, M. J. Enantioselective iridium-catalyzed
carbonyl allylation from the alcohol or aldehyde oxidation level via transfer
hydrogenative coupling of allyl acetate: departure from chirally modified
allyl metal reagents in carbonyl addition. J. Am. Chem. Soc. 130,
14891–14899 (2008).
The authors declare no competing financial interests. Supplementary information and
chemical compound information accompany this paper at www.nature.com/
naturechemistry. Reprints and permission information is available online at http://npg.nature.
com/reprintsandpermissions/. Correspondence and requests for materials should be
addressed to M.J.K.
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