Catalytic enantioselective Grignard Nozaki-Hiyama methallylation from the alcohol oxidation level: Chloride compensates for π-complex instability

Article abstract of DOI:10.1039/c1cc14392a

Methallyl chloride serves as an efficient allyl donor in highly enantioselective Grignard Nozaki-Hiyama methallylations from the alcohol or aldehyde oxidation level via iridium catalyzed transfer hydrogenation. Under identical conditions, methallyl acetat

Full text of DOI:10.1039/c1cc14392a

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COMMUNICATION
Catalytic enantioselective Grignard Nozaki–Hiyama methallylation from
the alcohol oxidation level: chloride compensates for p-complex instabilitywz
Abbas Hassan, Ian A. Townsend and Michael J. Krische*
Received 20th July 2011, Accepted 20th July 2011
DOI: 10.1039/c1cc14392a
Methallyl chloride serves as an efficient allyl donor in highly
enantioselective Grignard Nozaki–Hiyama methallylations from
the alcohol or aldehyde oxidation level via iridium catalyzed
transfer hydrogenation. Under identical conditions, methallyl
acetate does not react efficiently. Double methallylation of
1,3-propanediol provides the C2-symmetric adduct as a single
enantiomer, as determined by HPLC analysis.
The reductive coupling of allylic chlorides to carbonyl compounds
is typically conducted under Grignard conditions employing
elemental magnesium as a terminal reductant.1 To achieve
enantioselective reductive coupling of allylic chlorides to carbonyl
compounds, asymmetric variants of Furstner’s modification2
¨
of the Nozaki–Hiyama reaction may be used.3,4 In more recent
studies, hydrogen exchange between alcohols and p-unsaturated
reactants was found to trigger generation of electrophile–
nucleophile pairs, enabling a variety of enantioselective carbonyl
allylation processes.5,6 A remarkable feature of these transforma-
Scheme 1 Better leaving groups compensate for decreased p-complex
stability, facilitating p-allyl formation.
tions resides in the ability to perform carbonyl addition directly
from the alcohol oxidation level in the absence of stoichiometric
allylmetal reagents or (organo)metallic reductants.
destabilization of the transient p-complex arising from higher
degrees of olefin substitution (Scheme 1).
One restriction associated with such iridium catalyzed carbonyl
allylations relates to the requirement of allyl donors that
incorporate monosubstituted olefins: higher degrees of olefin
substitution are not tolerated. It has been established that the
stability of late transition metal–olefin p-complex decreases with
increasing olefin substitution.7 As olefin coordination is
a prerequisite to ionization, the requirement of allyl donors
that incorporate monosubstituted olefins likely stems from
the shorter lifetime of more highly substituted iridium–olefin
p-complexes. However, in prior studies on vinylogous aldol
addition,6i LUMO-lowering substituents were found to increase
the degree of p-backbonding8,9 thus compensating for steric
To enable efficient reactions of more highly substituted allyl
donors in the absence of electronic effects, one may compensate
for the shorter lifetime of the iridium–olefin p-complexes by
employing a more reactive leaving group. For example,
whereas methallyl acetate does not participate in efficient
enantioselective iridium catalyzed carbonyl addition, methallyl
chloride might serve as a feasible allyl donor.10–12 Given the
paucity of studies devoted exclusively to enantioselective carbonyl
methallylation,10h,11g,12a this class of carbonyl additions was
selected for investigation. In this account, we report that
methallyl chloride does indeed participate in efficient enantio-
selective carbonyl methallylation from the alcohol or aldehyde
oxidation level, whereas methallyl acetate does not. More signifi-
cantly, this work reveals key structural–interactional features
of the catalytic system that should accelerate development of
hitherto inaccessible C–C bond forming transfer hydrogenations.
Our studies began with an assay of various methallyl
carboxylates, sulfonates and halides employing as a catalyst
the chromatographically isolated cyclometallated iridium
p-allyl complex ‘‘(R)-I’’, which is prepared from [Ir(cod)Cl]2,
(R)-Cl,MeO-BIPHEP, allyl acetate and 4-cyano-3-nitrobenzoic
acid (Scheme 2).
Department of Chemistry and Biochemistry, University of Texas at
Austin, Austin, TX 78712, USA. E-mail: mkrische@mail.utexas.edu;
Fax: +1 613 9418447; Tel: +1 512 2325892
z This article is part of the ChemComm ‘Advances in catalytic C–C
bond formations via late transition metals.
w Electronic supplementary information (ESI) available: Characteri-
zation data for all new compounds (1H NMR, 13C NMR, IR, HRMS,
[a]). Absolute stereochemical assignments of 3g via single crystal
X-ray diffraction are provided. CCDC 835997. For ESI and crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/
c1cc14392a
c
10028 Chem. Commun., 2011, 47, 10028–10030
This journal is The Royal Society of Chemistry 2011

alcohols 1a–1i. The products of methallylation 3a–3i were
produced in good to excellent yields and with uniformly high
levels of enantioselectivity. Notably, aliphatic alcohols 1a–1d
undergo methallylation to form adducts 3a–3d with virtually
complete suppression of further oxidation to form enones
4a–4d (Table 1).
In the presence of isopropanol (200 mol%), but under
otherwise identical conditions an equivalent set of adducts
3a–3i can be generated from aldehydes 2a–2i. In most cases,
comparable isolated yields and enantioselectivities are observed.
Thus, carbonyl methallylation is achieved with equal facility
from the alcohol or aldehyde oxidation level. As previously
observed, competing enone formation is most evident in the
case of adducts that embody allylic and benzylic secondary
alcohols, which are more susceptible to b-hydride elimination
(Table 1). The absolute stereochemistry of methallylation
products 3a–3i was made in analogy to that determined for
bromide containing adduct 3g by single crystal X-ray diffraction
analysis using the anomalous dispersion method.
Scheme 2 Synthesis of iridium complex (R)-I.
Using benzylic alcohol 1g as a test reactant, it was found
that methallyl carboxylates delivered only trace quantities of
C–C coupling product 3g. In contrast, under identical conditions,
much higher conversions were observed using methallyl chloride,
an inexpensive commercial material. However, these initial
experiments, which were conducted at 70 1C over 48 hours,
also revealed a major side-reaction: oxidation of the initially
formed methallylation product 3g to form the conjugated
dimethyl enone 4g.13 The formation of enone 4g corroborates
the poor coordinating ability of the methyl-substituted homo-
allylic olefin. Olefin dissociation at the stage of the homoallylic
iridium alkoxide opens a coordination site, which induces
b-hydride elimination to form a transient b,g-enone that
isomerizes to the conjugated enone 4g.
To showcase the utility of this methodology, double enantio-
selective methallylation of 1,3-propanediol was attempted
under standard conditions.14 The corresponding C2-symmetric
diol 6 is produced in 66% isolated yield as a single enantiomer,
as the minor enantiomer of the mono-adduct is transformed to
the meso-stereoisomer of the product.15 Diol 6 was converted
to acetonide 7 and subjected to ozonolysis to provide the
formal product of double acetone aldol addition 8 (Scheme 3).
The present study suggests that methallyl acetate does not
serve as an efficient allyl donor due to the lower stability and,
hence, shorter lifetime of the iridium–olefin p-complex that
precedes formation of the requisite p-allyliridium complex.
It was found that oxidation of the initially formed methallyl-
ation product 3g to form enone 4g is suppressed at lower
temperature (50 1C) and shorter reaction times (24 hours). Under
optimal conditions involving the use of catalyst (R)-I (5 mol%),
methallyl chloride (300 mol%) and potassium phosphate
(100 mol%) in THF (1 M) at 50 1C, benzylic alcohol 1g
is transformed to the adduct 3g in 83% isolated yield and
96% enantiomeric excess. These conditions were applied to
Table 1 Enantioselective carbonyl allylation from the alcohol or aldehyde oxidation levela
1a, R = (CH2)7Me 1b, R = (CH2)2OBn 1c, R = CMe2CH2OPMB 2a, R = (CH2)7Me 2b, R = (CH2)2OBn 2c, R = CMe2CH2OPMB
1d, R = c-C6H11
1g, R = 4-BrC6H4 1h, R = piperonyl
1e, R = CHQCHPh 1f, R = geranyl
2d, R = c-C6H11
2g, R = 4-BrC6H4 2h, R = piperonyl
2e, R = CHQCHPh 2f, R = geranyl
1i, R = 2-benzothienyl
2i, R =2-benzothienyl
a
b
c
See ESIw for detailed experimental procedure. 200 mol% isopropanol. 400 mol% isopropanol.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 10028–10030 10029

6 For enantioselective carbonyl allylation via iridium catalyzed C–C
bond forming transfer hydrogenation, see: (a) I. S. Kim, M.-Y. Ngai
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J. Org. Chem., 2011, 76, 2350; (k) X. Gao, Y. J. Zhang and
M. J. Krische, Angew. Chem., Int. Ed., 2011, 50, 4173.
Scheme 3 Double methallylation of propanediol to form the
C2-symmetric adduct 8.
7 (a) R. Cramer, J. Am. Chem. Soc., 1967, 89, 4621; (b) A. C. Jesse,
E. H. P. Cordfunke and W. Ouweltjes, Thermochim. Acta, 1979,
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10 For isolated examples of enantioselective carbonyl methallylation
employing chirally modified methallylmetal reagents (withstanding
ref. 10h), see: (a) Boron: R. W. Hoffmann and T. Herold, Chem.
Ber., 1981, 114, 375; (b) P. K. Jadhav, K. S. Bhat, T. Perumal and
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D. G. Hall, Synthesis, 2004, 1290; (g) W. Chen, Y. Liu and
Through the use of methallyl chloride, which incorporates a
more reactive leaving group, ionization to form the p-allyliridium
complex becomes more rapid, compensating for the shorter
lifetime of the more highly substituted olefin p-complex. Based
on this insight into the requirements of the catalytic process,
highly enantioselective Grignard-Nozaki–Hiyama methallylation
is achieved from the alcohol or aldehyde oxidation levels in the
absence of stoichiometric metallic reagents or reductants.
Future studies will focus on the development of related
alcohol–alkyl halide C–C couplings.
Acknowledgment is made to the Robert A. Welch Foundation
(F-0038) and the NIH-NIGMS (RO1-GM069445) for partial
support of this research. The Higher Education Commission of
Pakistan is acknowledged for graduate student fellowship
support (AH).
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´
J. A. Soderquist, J. Org. Chem., 2007, 72, 9772; (i) Titanium:
R. O. Duthaler, A. Hafner, P. L. Alsters, P. Rothe-Streit and
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´
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11 For isolated examples of enantioselective methallyl employing
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¨
4 For selected examples of enantioselective carbonyl allylation and
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13 Under the conditions of ruthenium catalysis, alcohols and allylic
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Y. Lu and M. J. Krische, Org. Lett., 2009, 11, 3108 and ref. 6e.
15 This mechanism for enantiomeric enrichment has been documented
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This journal is The Royal Society of Chemistry 2011