Enantioselective Formation of All-Carbon Quaternary Centers via C-H Functionalization of Methanol: Iridium-Catalyzed Diene Hydrohydroxymethylation

Article abstract of DOI:10.1021/jacs.6b09333

The first catalytic enantioselective C-C couplings of methanol (>30 × 10⁶ tons/year) are reported. Insertion of 2-substituted dienes into the methanol C-H bond occurs in a regioselective manner to form all-carbon quaternary centers with excellent levels of enantioselectivity using an iridium-PhanePhos catalyst. Mechanistic studies corroborate a Curtin-Hammett scenario in which methanol dehydrogenation triggers rapid, reversible diene hydrometalation en route to regioisomeric allyliridium-formaldehyde pairs, yet single constitutional isomers are formed.

Full text of DOI:10.1021/jacs.6b09333

Communication
pubs.acs.org/JACS
Enantioselective Formation of All-Carbon Quaternary Centers via C−
H Functionalization of Methanol: Iridium-Catalyzed Diene
Hydrohydroxymethylation
Khoa D. Nguyen, Daniel Herkommer, and Michael J. Krische*
Department of Chemistry, University of Texas at Austin, Austin, Texas 78712, United States
S
* Supporting Information
Scheme 1. Inverting Diene Reactivity via C−C Bond
Forming Transfer Hydrogenation: Enantioselective
Formation of All-Carbon Quaternary Centers
ABSTRACT: The first catalytic enantioselective C−C
couplings of methanol (>30 × 106 tons/year) are reported.
Insertion of 2-substituted dienes into the methanol C−H
bond occurs in a regioselective manner to form all-carbon
quaternary centers with excellent levels of enantioselectiv-
ity using an iridium−PhanePhos catalyst. Mechanistic
studies corroborate a Curtin−Hammett scenario in which
methanol dehydrogenation triggers rapid, reversible diene
hydrometalation en route to regioisomeric allyliridium−
formaldehyde pairs, yet single constitutional isomers are
formed.
espite impressive advances in the field of chemical
D
synthesis, catalytic enantioselective formation of all-
carbon quaternary stereocenters remains a daunting challenge.1
Ideally, it would be desirable to form all-carbon quaternary
stereocenters from inexpensive feedstocks in C−C bond
forming processes that circumvent generation of stoichiometric
byproducts. Indeed, the two largest volume applications of
homogeneous catalysis, hydroformylation2 and methanol
carbonylation (the Monsanto/Cativa processes),3 are by-
product-free C−C bond formations. In connection with our
development of catalytic C−C couplings that convert lower
alcohols to higher alcohols,4 processes that merge the
characteristics of transfer hydrogenation and carbonyl addition,
we became interested in the use of methanol as a C1 feedstock
in catalytic C−C coupling.4c,5 Toward this end, the direct
byproduct conversion of methanol to higher alcohols was
achieved using allene pronucleophiles.6a Methanol-mediated
couplings of more abundant π-unsaturated partners (dienes or
α-olefins) have hitherto proven elusive, and enantioselective
transformations of this type appeared especially implausible.6b,7
Here, we report an iridium−PhanePhos catalyst for the
enantioselective C−C coupling of methanol (>30 × 106 tons/
year) with 2-substituted dienes. Remarkably, mechanistic
studies corroborate rapid interconversion of regio- and
stereoisomeric allyliridium intermediates, yet a Curtin−
Hammett selection process enables formation of single isomeric
products bearing all-carbon quaternary stereocenters. Further-
more, enantiotopic π-facial discrimination for the reactive
allyliridium isomer is efficient, resulting in high levels of
enantioselectivity.8 Thus, by inverting the canonical behavior of
methanol in its reaction with unsaturates (etherification),
enantioselective C−H functionalization of methanol is achieved
for the first time (Scheme 1).
In an effort to develop enantioselective iridium-catalyzed C−
C couplings of primary alcohols with dienes to form
homoallylic secondary alcohols,9 diverse primary alcohols
were exposed to 2-phenyl-1,3-butadiene 1a in the presence of
the iridium catalyst generated in situ from [Ir(cod)Cl]2 and
various chelating chiral phosphine ligands. An astonishing
observation was made: whereas the iridium-PhanePhos
catalyzed reaction of ethanol with 2-phenyl-1,3-butadiene 1a
results in coupling at the diene C3-position to form iso-2a (R =
Me), the corresponding reaction of methanol results in
coupling at the diene C2-position to form 2a (R = H) in
93% ee (eq 1). For both reactions, complete partitioning of C2
vs C3 regioselectivity is observed. Underscoring the fortuitous
nature of these findings, an extensive ligand survey revealed that
PhanePhos was unique in its ability to promote efficient
formation of 2a (R = H).
Received: September 5, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.6b09333
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
The absolute stereochemistry of adducts 2b−2l was assigned in
analogy.
Table 1. Enantioselective Iridium-Catalyzed C−C Coupling
of 2-Substituted Dienes 1a−1l with Methanol To Form
a
The coupling of methanol with dienes bearing alkyl
substituents at the C2-position was investigated. As illustrated
in the coupling of cyclohexyl-substituted diene 1m under
standard reaction conditions (eq 2), complete levels of C2-
regioselectivity are accompanied by excellent levels of
enantioselectivity; however, a lower isolated yield is observed.
The development of improved conditions for the coupling of
C2-alkyl substituted dienes is currently underway.
Neopentyl Alcohols 2a−2l
To briefly illustrate how the present coupling products may
serve as building blocks in asymmetric synthesis, alcohol 2b was
converted to the corresponding p-toluenesulfonate and reacted
with sodium azide in DMSO. Although neopentyl electrophiles
2
are notoriously recalcitrant partners for SN reactions, azide 3b
was formed in good yield (eq 3). Additionally, Jones oxidation
of neopentyl alcohol 2b followed by Fischer esterification
provides the ester 4b (eq 4).
a
Yields of material isolated by silica gel chromatography. Enantiose-
Regarding the catalytic mechanism, the regiodivergence
observed in the coupling of diene 2a with methanol vs higher
alcohols suggests a Curtin−Hammett scenario wherein alcohol
dehydrogenation triggers rapid, reversible diene hydrometal-
ation to form regioisomeric allyliridium−formaldehyde pairs.10
To probe the veracity of this interpretation, deuterium labeling
experiments were performed. The coupling of diene 1b with d4-
methanol under otherwise standard conditions provides
deuterio-2b in 35% yield (eq 5). Deuterium is retained at the
lectivities were determined by chiral stationary phase HPLC analysis.
See Supporting Information for further experimental details.
Acetone/methanol (1:1).
b
The conditions indicated for the formation of 2a (eq 1) are
the result of extensive optimization (see Supporting Informa-
tion). Diene 1a is susceptible to formation of a Diels−Alder
dimerization byproduct, but this side reaction is largely
suppressed at lower temperature. Because diene 1a is far
more precious than methanol, it was used as the limiting
reagent even though higher yields are possible by inverting
stoichiometry. Application of these conditions to 2-aryl
substituted dienes 1a−1l illustrates the scope of this process
(Table 1). Dienes 1b and 1c, which incorporate electron-
withdrawing p-substituted phenyl moieties, are converted to the
products of hydrohydroxymethylation 2b and 2c, respectively,
with excellent levels of enantioselectivity. Dienes 1d−1g,
bearing phenyl groups with alkoxy substituents at the para-,
meta-, and ortho-positions, are converted to adducts 2d−2g
with uniformly high levels of enantioselectivity. Finally, dienes
incorporating halogenated phenyl moieties (1h−1j) and
heteroaromatic rings (1k−1l) perform equally well. The
absolute stereochemistry of the 4-bromobenzoate of adduct
2a was determined by single crystal X-ray diffraction analysis.
2
carbinol position (Hc = >95% H), suggesting deuterio-2b is
kinetically inert with respect to dehydrogenation. The
B
DOI: 10.1021/jacs.6b09333
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Scheme 2. General Catalytic Mechanism Accounting for Regiodivergence in the Iridium-Catalyzed Coupling of Diene 1a with
Methanol vs Higher Alcohols
incorporation of deuterium at the former diene C1, C3, and C4
positions is consistent with rapid, reversible diene hydro-
metalation-β-hydride elimination in advance of carbonyl
addition. Incomplete transfer of deuterium is observed, which
may be attributed to H−D exchange of the transient iridium
hydride with adventitious water.11 A competition kinetics
experiment was performed in which diene 1b was exposed to
equimolar quantities of methanol and d4-methanol (eq 6). The
incorporation of deuterium at the carbinol methylene (25%
2H) of the product deuterio-2b establishes a normal primary
kinetic isotope effect (kH/kD = 3.0). These data suggest
methanol dehydrogenation is turnover-limiting. This result is
not surprising given the relatively high energetic demand of
methanol dehydrogenation (ΔH = +84 kJ/mol) compared to
the dehydrogenation of higher alcohols, such as ethanol (ΔH =
+68 kJ/mol).12
Scheme 3. Diene Hydrometalation Delivers the Allyliridium
Isomer That Is Both Kinetically and Thermodynamically
Preferred
a
A catalytic mechanism consistent with the collective data has
been proposed (Scheme 2). Exposure of [Ir(cod)Cl]2 to
PhanePhos in the presence of methanol provides the methoxy-
bridged dimer I,12c,d,13 which exists in equilibrium with the
monomeric iridium methoxide complex II. β-Hydride elimi-
nation of II generates the iridium hydride III and form-
aldehyde.12 Reversible diene hydrometalation provides an
equilibrating mixture of regioisomeric allyliridium complexes
IV and V. Complexation of formaldehyde occurs exclusively by
way of the 1,1-disubstituted allyliridium isomers IV to form the
formaldehyde complex VI. Carbonyl addition then provides the
homoallylic iridium alkoxide complex VII, which upon
methanolysis releases the product of hydrohydroxymethylation
2a and regenerates the iridium methoxide complex I or II to
close the catalytic cycle. The regiodivergence observed in the
coupling of diene 2a with methanol vs higher alcohols may be
rationalized as follows. The 1,1-disubstituted allyliridium
species (E)-IV is both thermodynamically preferred and, in
the case of formaldehyde addition, kinetically more reactive.
Higher alcohols, and therefrom higher aldehydes, impose
greater steric congestion, raising the energy of the transition
state for carbonyl additions that form all-carbon quaternary
centers. Consequently, in addition to higher aldehydes, the 1,2-
disubstituted allyliridium isomers V are kinetically more
reactive. Rapid, reversible diene hydrometalation, as corrobo-
rated by deuterium labeling (eq 5), replenishes whichever
allyliridium isomer that is consumed.
a
Yields of material isolated by silica gel chromatography. Enantio-
selectivities were determined by chiral stationary phase HPLC analysis.
See Supporting Information for further experimental details.
High levels of enantioselectivity in the formation of adducts
2a−2m require intervention of a single allyliridium geometrical
isomer if carbonyl addition occurs in a stereospecific manner
through a closed 6-centered transition structure. As dienes
bearing sterically demanding groups at the 2-position
predominantly reside in the s-cis conformation,14 the hydro-
metalation of dienes 1a−1m should display a kinetic preference
for formation (E)-IV, which is presumed to be thermodynami-
cally more stable than (Z)-IV. The coupling of allene iso-1a
provides a unique opportunity to test this hypothesis (Scheme
3, eq 7). Hydrometalation of allene iso-1a should occur
predominantly from the olefin π-face that is “syn” with respect
C
DOI: 10.1021/jacs.6b09333
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Compounds; Cornils, B., Herrmann, W. A., Eds.; Wiley-VCH:
Weinheim, 1996; Vol. 1, pp 29−104. (c) Rhodium Catalyzed
Hydroformylation; van Leeuwen, P. W. N. M., Claver, C., Eds.; Kluwer
Academic Publishers: Norwell, MA, 2000. (d) Breit, B.; Seiche, W.
Synthesis 2001, 2001, 1. (e) Weissermel, K.; Arpe, H.-J. Industrial
Organic Chemistry, 4th ed.; Wiley-VCH: Weinheim, 2003; pp 127−
144. (f) Homogeneous Catalysis: Understanding the Art; van Leeuwen,
P. W. N. M., Ed.; Kluwer Academic Publishers: Dordrecht, 2004.
(3) For selected reviews on Monsanto/Cativa process, see: (a) Jones,
J. H. Platinum Met. Rev. 2000, 44, 94. (b) Thomas, C. M.; Suss-Fink,
G. Coord. Chem. Rev. 2003, 243, 125. (c) Haynes, A. Top. Organomet.
Chem. 2006, 18, 179. (d) Haynes, A. Adv. Catal. 2010, 53, 1.
(4) For selected reviews on C−C bond forming transfer hydro-
genation, see: (a) Ketcham, J. M.; Shin, I.; Montgomery, T. P.;
Krische, M. J. Angew. Chem., Int. Ed. 2014, 53, 9142. (b) Feng, J.;
Kasun, Z. A.; Krische, M. J. J. Am. Chem. Soc. 2016, 138, 5467.
(c) Sam, B.; Breit, B.; Krische, M. J. Angew. Chem., Int. Ed. 2015, 54,
3267.
(5) For selected examples of the use of methanol in catalytic C−C
coupling, see: (a) Chan, L. K. M.; Poole, D. L.; Shen, D.; Healy, M. P.;
Donohoe, T. J. Angew. Chem., Int. Ed. 2014, 53, 761. (b) Ogawa, S.;
Obora, Y. Chem. Commun. 2014, 50, 2491. (c) Li, Y.; Li, H.; Junge, H.;
Beller, M. Chem. Commun. 2014, 50, 14991. (d) Shen, D.; Poole, D.
L.; Shotton, C. C.; Kornahrens, A. F.; Healy, M. P.; Donohoe, T. J.
Angew. Chem., Int. Ed. 2015, 54, 1642. (e) Quan, X.; Kerdphon, S.;
Andersson, P. G. Chem. - Eur. J. 2015, 21, 3576.
(6) (a) Moran, J.; Preetz, A.; Mesch, R. A.; Krische, M. J. Nat. Chem.
2011, 3, 287. (b) Han, H.; Krische, M. J. Org. Lett. 2010, 12, 2844.
(7) Smejkal, T.; Han, H.; Breit, B.; Krische, M. J. J. Am. Chem. Soc.
2009, 131, 10366.
(8) Garza, V. J.; Krische, M. J. J. Am. Chem. Soc. 2016, 138, 3655.
(9) Bower, J. F.; Patman, R. L.; Krische, M. J. Org. Lett. 2008, 10,
1033.
(10) For a Curtin−Hammet scenario involving selection between
equilibrating (Z)- and (E)-allylruthenium isomers, see: Zbieg, J. R.;
McInturff, E. L.; Leung, J. C.; Krische, M. J. J. Am. Chem. Soc. 2011,
133, 1141.
to the relatively small methyl moiety. Thus, for allene iso-1a,
hydrometalation to form (Z)-IV is kinetically preferred.
Enantioselectivities in the coupling of allene iso-1a are
concentration dependent and improve with decreasing
concentration. These data corroborate a scenario wherein
isomerization of the kinetic allyliridium isomer (Z)-IV to the
more stable isomer (E)-IV occurs at a rate that is only slightly
faster than formaldehyde addition. For the corresponding diene
pronucleophile 1a, enantioselectivity is insensitive to concen-
tration, consistent with the hypothesis that (E)-IV is both
kinetically and thermodynamically preferred (Scheme 3, eq 8).
To summarize, by unlocking the native reducing ability of
methanol, one can override the canonical SN1 pathways
observed in reactions with dienes, that is, O-alkylation, and
instead activate catalytic mechanisms for C-alkylation. Fur-
thermore, as demonstrated by the regio- and enantioselectiv-
ities evident in the present report, mediation of the catalytic
process by transition metals enables unique isomer selectivities
manifesting in the asymmetric formation of all-carbon
quaternary centers, and the first enantioselective C−C
couplings of methanol.15 Future studies will focus on the
development of related transfer hydrogenative C−C bond
formations, including the byproduct-free coupling of alcohols
with α-olefins.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.6b09333.
■
S
Experimental procedures and spectral data. HPLC traces
corresponding to racemic and enantiomerically enriched
samples. Single crystal X-ray diffraction data for the 4-
bromobenzoate of compound 2a (PDF)
Crystallographic data (CIF)
(11) Ruthenium hydrides engage in H−D exchange with water: Tse,
S. K. S.; Xue, P.; Lin, Z.; Jia, G. Adv. Synth. Catal. 2010, 352, 1512.
(12) (a) Qian, M.; Liauw, M. A.; Emig, G. Appl. Catal., A 2003, 238,
211. (b) Lin, W.-H.; Chang, H.-F. Catal. Today 2004, 97, 181.
(c) Yamagata, T.; Iseki, A.; Tani, K. Chem. Lett. 1997, 26, 1215.
(d) Tani, K.; Iseki, A.; Yamagata, T. Chem. Commun. 1999, 1821.
(13) (a) Dorta, R.; Togni, A. Organometallics 1998, 17, 3423.
(b) Dorta, R.; Egli, P.; Zurcher, F.; Togni, A. J. Am. Chem. Soc. 1997,
119, 10857.
AUTHOR INFORMATION
Corresponding Author
*mkrische@mail.utexas.edu
■
Notes
The authors declare no competing financial interest.
(14) (a) Devaquet, A. J.; Townshend, R. E.; Hehre, W. J. J. Am.
Chem. Soc. 1976, 98, 4068. (b) Robiette, R.; Marchand-Brynaert, J.;
Peeters, D. J. Org. Chem. 2002, 67, 6823. (c) Pidaparthi, R. R.; Wright,
M. W.; Day, C. S.; Welker, M. E. Org. Lett. 2007, 9, 1623.
(15) The Minisci reaction of methanol provides achiral products. For
a review, see: Duncton, M. A. J. MedChemComm 2011, 2, 1135.
ACKNOWLEDGMENTS
■
The Robert A. Welch Foundation (F-0038), the NIH-NIGMS
(RO1-GM069445) and the Feodor Lynen postdoctoral fellow-
ship program administered by the Alexander von Humboldt
Foundation (D.H.) are acknowledged for partial support of this
research.
REFERENCES
■
(1) For selected reviews on the enantioselective formation of all-
carbon quaternary centers, see: (a) Corey, E. J.; Guzman-Perez, A.
Angew. Chem., Int. Ed. 1998, 37, 389. (b) Bella, M.; Gasperi, T.
Synthesis 2009, 2009, 1583. (c) Shimizu, M. Angew. Chem., Int. Ed.
2011, 50, 5998. (d) Hong, A. Y.; Stoltz, B. M. Eur. J. Org. Chem. 2013,
2013, 2745. (e) Minko, Y.; Marek, I. Chem. Commun. 2014, 50, 12597.
(f) Marek, I.; Minko, Y.; Pasco, M.; Mejuch, T.; Gilboa, N.; Chechik,
H.; Das, J. P. J. Am. Chem. Soc. 2014, 136, 2682. (g) Quasdorf, K. W.;
Overman, L. E. Nature 2014, 516, 181. (h) Zeng, X.-P.; Cao, Z.-Y.;
Wang, Y.-H.; Zhou, F.; Zhou, J. Chem. Rev. 2016, 116, 7330.
(2) For selected reviews on hydroformylation, see: (a) Beller, M.;
Cornils, B.; Frohning, C. D.; Kohlpaintner, C. W. J. Mol. Catal. A:
Chem. 1995, 104, 17. (b) Frohning, C. D.; Kohlpaintner, C. W.;
Bohnen, H.-W. In Applied Homogeneous Catalysis with Organometallic
D
DOI: 10.1021/jacs.6b09333
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX