Hydrogen Borrowing Catalysis with Secondary Alcohols: A New Route for the Generation of β-Branched Carbonyl Compounds

Article abstract of DOI:10.1021/jacs.6b12840

A hydrogen borrowing reaction employing secondary alcohols and Ph? (Me₅C₆) ketones to give β-branched carbonyl products is described (21 examples). This new C-C bond forming process requires low loadings of [Cp?IrCl₂]₂, relatively low temperatures, and up to 2.0 equiv of the secondary alcohol. Substrate-induced diastereoselectivity was observed, and this represents the first example of a diastereoselective enolate hydrogen borrowing alkylation. By utilizing the Ph? group, the β-branched products could be straightforwardly cleaved to the corresponding esters or amides using a retro-Friedel-Crafts reaction. Finally, this protocol was applied to the synthesis of fragrance compound (±)-3-methyl-5-phenylpentanol.

Full text of DOI:10.1021/jacs.6b12840

Communication
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Hydrogen Borrowing Catalysis with Secondary Alcohols: A New
Route for the Generation of β‑Branched Carbonyl Compounds
Wasim M. Akhtar,†,§ Choon Boon Cheong,†,§ James R. Frost,†,§ Kirsten E. Christensen,†
Neil G. Stevenson,‡ and Timothy J. Donohoe*,†
†Department of Chemistry, Chemical Research Laboratory, University of Oxford, Oxford, OX1 3TA, United Kingdom
‡GlaxoSmithKline, Medicines Research Centre, Stevenage, SG1 2NY, United Kingdom
S
* Supporting Information
and (b) from a synthetic perspective Ph* was extremely versatile
ABSTRACT: A hydrogen borrowing reaction employing
because treatment of the alkylated products with Br2 at −17 °C
secondary alcohols and Ph* (Me5C6) ketones to give β-
resulted in a retro-Friedel−Crafts acylation process to give an acid
branched carbonyl products is described (21 examples).
bromide, which could be trapped with nucleophiles to provide
carboxylic acid derivatives [Scheme 1(i)].9
This new C−C bond forming process requires low
loadings of [Cp*IrCl2]2, relatively low temperatures, and
up to 2.0 equiv of the secondary alcohol. Substrate-
induced diastereoselectivity was observed, and this
represents the first example of a diastereoselective enolate
hydrogen borrowing alkylation. By utilizing the Ph* group,
the β-branched products could be straightforwardly
cleaved to the corresponding esters or amides using a
retro-Friedel−Crafts reaction. Finally, this protocol was
applied to the synthesis of fragrance compound ( )-3-
methyl-5-phenylpentanol.
Scheme 1. Hydrogen Borrowing Alkylation with Secondary
Alcohols To Form β-Branched Products
ydrogen borrowing chemistry is an attractive method for
H
C−C bond formation under catalytic conditions.1 In this
reaction manifold a catalyst abstracts hydrogen from an alcohol to
generate the corresponding carbonyl compound in situ. After a
sequence involving C−C bond formation and elimination, the
catalyst “returns” the abstracted hydrogen to provide the C−C
coupled product and complete the catalytic cycle. This method is
popular for the formation of α-functionalized carbonyl
compounds via enolate intermediates because it avoids the use
of toxic alkyl halides and lithium amide bases/cryogenic
temperatures and generates water as the only byproduct.2
While the alkylation of ketones using primary alcohols is
widespread, the use of secondary alcohols is much more limited,
with most examples pertaining to Guerbet type dimerization3
processes of secondary alcohols themselves.4−7 In an important
contribution involving cross-condensation, Obora reported
several examples whereby MeCN was coupled with secondary
alcohols (48−88%), albeit using 10.0 equiv of MeCN at 130−
200°C.8 However, wearenotaware ofageneral procedure forthe
reaction of carbonyl substrates with secondary alcohols to
generate β-branched derivatives. Clearly, if we wish to involve
secondary alcohols in ketone alkylation then we must address
problems stemming from self-condensation of both the substrate
and the ketone derived from the secondary alcohol.
Herein, we report that Ph* ketones are especially active in
hydrogen borrowing alkylation with secondary alcohols [Scheme
1(ii)]. Two factors are essential for the success of this
methodology: (a) the Ph* group shields the adjacent carbonyl,
thereby preventing self-condensation of thesubstrate, and (b)the
catalytic oxidation of the secondary alcohol maintains a slow
release of the second ketone which is also unavailable for self-
condensation. Starting from commercially available Ph*COMe
(1) we have synthesized β-functionalized carbonyl products in
high yields. The ability of the Ph* group to be cleaved provides
ready access to the target β-functionalized ester or amide
compounds via a disconnection that does not involve conjugate
addition.
Our investigations began by studying the reaction between 1
and 3-pentanol in the presence of the most promising catalyst
Recently, we introduced Ph* ketones as novel substrates for
hydrogen borrowing alkylation with primary alcohols. Develop-
mentofthePh*groupwas key foranumberofreasons: (a)the di-
ortho-substitution of the aromatic ring alleviated steric hindrance
at the α-position by twisting out of conjugation with the ketone
Received: December 14, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.6b12840
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
[Cp*IrCl2]2 and KOH [see Supporting Information (SI) for an
extended optimization table]. After initial experimentation, the
desired β-alkylated product 4 could be isolated in 12−80% yield
depending on the temperature employed (Table 1, entries 1−3).
Scheme 2. Alkylation of ortho-Substituted Aryl Ketones
Table 1. Optimization Conditions for the Formation of β-
Branched Product 4
a
1.0 mol% [Cp*lrCl2]2, 3-pentanol (3.0 equiv), NaOtBu (4.0 equiv),
PhMe (4 M), 85 °C, 24 h, Ar.
incorporated (7, 8, and 9). Double alkylation was also efficient
when the reaction loadings were increased two-fold (10).
While the results in Scheme 2 show reasonable scope for the
structure of the aryl ketone, we decided to turn our attention to
Ph*COMe (1), since it not only was higher yielding but also held
greater potential for efficient removal and thereafter product
derivatization. A series of acyclic secondary alcohols were
employed, providing the desired β-branched products in good
to excellent yield (Scheme 3). As we screened variously
Scheme 3. Acyclic Secondary Alcohol Alkylation Scope
a
b
Isolated yields, 0.6 mmol scale. Reaction conducted on 5.3 mmol
c
1
(1.0 g) scale. Conversion measured by H NMR.
Reaction analysis indicated that the solubility of KOH in PhMe
may be a complicating factor, and so we assessed different bases
(entries 4−6). Pleasingly, KOtBu and NaOtBu (entries 5 and 6)
both resulted in complete conversion and improved isolated
yields (86% and 97% respectively) at 85 °C. The reaction was also
efficient at 65 °C, but gave the β-branched product in a reduced
yield(entry7, 68%of4). Atthislowertemperature wealsostarted
to observe enone 2 and skipped E/Z-enones (3), which were
isolated in a combined yield of 11%.
With the temperature fixed at 85 °C the amount of NaOtBu
could be reduced to 2.0 equiv, leading to complete reaction
(entries 8−9). The catalyst loading (entries 10−11) and amount
ofalcohol(entries12−13)couldalsobedecreased, with0.5mol%
of [Cp*IrCl2]2 and 1.5 equiv of 3-pentanol proving optimal. The
reaction also proved to be equally efficient on gram scale
(5.3 mmol of 1), giving 4 in 93% yield (entry 14). Control
experiments whereby [Cp*IrCl2]2 or NaOtBu were omitted
(entries 15−16) returned either starting material or partial
conversion to enones 2/3 (entry 15). Replacing the Ar
atmosphere with O2 (see SI) resulted in the recovery of 1 and
large quantities of insoluble polymeric material.
The scope of the aryl group was then explored with C−C
coupling attempted on a series of ortho-substituted aryl ketones
(Scheme 2). This study revealed that di-ortho methyl substituents
were optimal for successful alkylation, with complex mixtures and
CO reduction products often being observed without them.10
It appears that the di-ortho methyl groups are perfectly placed to
prevent self-condensation of the ketone substrate while also
protecting the product carbonyl from reduction in situ. Providing
that this condition was satisfied, several heteroatoms could be
a
2.0 mol % [Cp*lrCl2]2, RR′CHOH (2.0 equiv), NaOtBu (3.0 equiv),
b
PhMe (4 M), 85 °C, 24 h, Ar. Reaction performed at 105 °C.
functionalized alcohols, we found that 2.0 equiv of alcohol and
3.0 equiv of base were sometimes required to push the reaction to
completion. Pleasingly, secondary alcohols bearing heterocyclic
motifs (13 and 14) or heteroatoms (16, 17, and 18) were well-
tolerated.
We then moved to study a number of cyclic secondary alcohols
under these conditions. Experimentation revealed that these
alcohols gave superior yields when using KOtBu instead of
NaOtBu (Scheme 4). Interestingly, we observed that the size and
position of the substituent on the cyclohexane ring led to
substrate-induced diastereoselectivity (see 22, 23, 24, and 26). In
each case examined, the sense of diastereoselectivity can be
predicted by equatorial attack of an [Ir]−H species onto an
B
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Communication
providing trans-1,2-cyclopentane 31 in >95:5 d.r. (Scheme 5b).
With these results in hand, we also reacted 1 with 1,4-pentanediol
to test the feasibility of a one-step synthesis. Compound 31 was
once again produced in 49% yield as a single diastereomer
(Scheme 5c). Further studies relating to the use of unsymmetrical
diols and the diastereoselective synthesis of similar ring systems
are currently underway in our laboratory.
Scheme 4. Cyclic Secondary Alcohol Alkylation Scope
Next, we sought to remove the Ph* group by means of a retro-
Friedel−Crafts acylation reaction. A selection of β-branched
products were treated with Br2 (2.0 equiv) at −17 °C, generating
an acid bromide in situ (Scheme 6). Interception with either
Scheme 6. β-Branched Esters and Amides by Ph* Release
a
b
Reaction performed at 105 °C. d.r. determined from 1H NMR
c
analysis of the crude reaction mixture, major isomer shown. 0.5 mol %
[Cp*lrCl2]2, RR′CHOH (1.5 equiv), NaOtBu (2.0 equiv), PhMe (4
d
M), 85 °C, 24 h. The stereochemistry of 22 (major), 23 (minor), 24
(major), and 29 (major) were determined by X-ray crystallography.
exocyclic enone intermediate, although diastereoselectivity
during the reduction of a migrated (endocyclic) alkene (see 3)
cannot be ruled out.11,12
a
b
Having shown that acyclic and cyclic alcohols perform well in
this reaction manifold, we then attempted an intramolecular α-
alkylation to generate cyclic structures. Therefore, compound 16
was deprotected (see SI) to provide primary alcohol 30, which
was subjected to the alkylation conditions. Pleasingly, the desired
cyclopentaneproduct 31 wasformedin75%yieldat105 °Cas the
trans-1,2-diastereomer in d.r. > 95:5 by 1H NMR spectroscopic
analysis (Scheme 5a).13 In a similar fashion, isomeric alcohol 32
was also found to cyclize in slightly lower yield (65%), again
4.0 equiv of Br2 used. TMSCl (1.0 equiv), BuOH (3.0 equiv), HFIP,
40 °C, 24 h.
BuOH or BnNH2 gave the corresponding butyl esters and benzyl
amides in good to excellent yield, thereby expanding the utility of
this methodology.14 Compounds 23, 24, 29, and 31 (major
diastereomers) were straightforwardly converted to their
carboxylic acid derivatives with no erosion in stereochemical
1
purity (d.r. > 95:5 by H NMR analysis). Since thiophene-
containing 14 was incompatible with Br2, we also developed
alternative (electrophilic) conditions for Ph* cleavage. Treat-
ment of compound 14 with TMSCl (1.0 equiv) and BuOH (3.0
equiv) in HFIP at 40 °C provided the butyl ester 39 in good yield.
Interestingly, addition of Br2 to compound 16 resulted in
debenzylative lactonization to form β-substituted seven-mem-
bered lactone 42. Although debenzylative cycloetherification has
beenreportedforthesynthesisoftetrahydrofurans,15 thisstrategy
has not been employed for the synthesis of seven-membered
lactones and could prove to be useful for their synthesis.16 The
retro-Friedel−Crafts process was also shown to be applicable to
peptide coupling, with α-amino methyl esters coupled to give
compounds 45 and 46 in good yield.
Scheme 5. α-Alkylation Using an Intramolecular Hydrogen
Borrowing Approach
Finally, the hydrogen borrowing/Ph* cleavage sequence was
applied to the synthesis of ( )-3-methyl-5-phenylpentanol (48),
which is a common industrial fragrance compound used under
various brand names. Alkylation of 1 with 4-phenyl-2-butanol
provided 47 as a colorless solid in 92%. Treatment of this
C
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Journal of the American Chemical Society
Communication
44, 2305. (h) Nandakumar, A.; Midya, S. P.; Landge, V. G.; Balaraman, E.
Angew. Chem., Int. Ed. 2015, 54, 11022. (i) Leonard, J.; Blacker, A. J.;
Marsden, S. P.; Jones, M. F.; Mulholland, K. R.; Newton, R. Org. Process
Res. Dev. 2015, 19, 1400.
compound with Br2 followed by reduction of the acid bromide
withDIBAL-H provided ( )-3-methyl-5-phenylpentanol (48)in
70% yield in a one-pot process (Scheme 7).
(2)(a)Chan, L. M.K.;Poole, D.L.;Shen,D.;Healy,M. P.;Donohoe, T.
J. Angew. Chem., Int. Ed. 2014, 53, 761. (b) Shen, D.; Poole, D. L.;
Shotton, C. C.; Kornahrens, A. F.; Healy, M. P.; Donohoe, T. J. Angew.
Chem., Int. Ed. 2015, 54, 1642. (c) Frost, J. R.; Cheong, C. B.; Donohoe,
T. J. Synthesis 2017, 49, 910.
Scheme 7. Synthesis of ( )-3-Methyl-5-phenylpentanol
(3) (a) Musa, S.; Ackermann, L.; Gelman, D. Adv. Synth. Catal. 2013,
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(c) Chaudhari, C.; Siddiki, S. M. A. H.; Shimizu, K. Top. Catal. 2014, 57,
1042.
(4) For hydrogen borrowing reactions using secondary alcohols with
amines: (a) Tillack, A.; Hollmann, D.; Michalik, D.; Beller, M.
Tetrahedron Lett. 2006, 47, 8881. (b) Hollmann, D.; Tillack, A.;
Michalik, D.; Jackstell, R.; Beller, M. Chem. - Asian J. 2007, 2, 403.
(c) Fujita, K.; Enoki, Y.; Yamaguchi, R. Tetrahedron 2008, 64, 1943.
(d) Haniti, M.; Hamid, S. A.; Allen, C. L.; Lamb, G. W.; Maxwell, A. C.;
Maytum, H. C.; Watson, A. J. A.; Williams, J. M. J. J. Am. Chem. Soc. 2009,
131, 1766. (e) Marichev, K. O.; Takacs, J. M. ACS Catal. 2016, 6, 2205.
(5) For a related Meerwein−Pondorf−Verley-type process with
secondary alcohols, see: Black, P. J.; Harris, W.; Williams, J. M. J.
Angew. Chem., Int. Ed. 2001, 40, 4475.
(6) For the alkylation or formation of heterocycles using hydrogen
borrowing or related chemistry, see: (a) Tsuji, Y.; Huh, K.; Watanabe, Y.
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Org. Lett. 2015, 17, 4054. (e) Bartolucci, S.; Mari, M.; Di Gregorio, G.;
Piersanti, G. Tetrahedron 2016, 72, 2233.
In conclusion, we have shown that enolate alkylation using
secondary alcohols can be achieved under hydrogen borrowing
conditions to provide a number of β-branched products. The use
of Ph* as a design element was crucial to the success of this
methodology, preventing self-condensation of starting substrate
1. Slowoxidationof thesecondary alcoholcouplingpartner under
the catalytic conditions then enabled the formation of the desired
cross-coupled products. In several cases substrate-induced
diastereoselectivity was observed which is an area for further
development. Preliminary experiments have shown that an
intramolecular approach is feasible for allowing α-alkylation of
the β-branched products, delivering 1,2-disubstituted cyclo-
pentane 31 in good yield and as a single diastereoisomer. Finally,
the Ph* group was readily cleaved to provide a series of β-
branched esters and amides as well as the industrially important
compound ( )-3-methyl-5-phenylpentanol.
(7) For related processes using secondary alcohols, see: (a) Anxionnat,
B.; Pardo, D. G.; Ricci, G.; Cossy, J. Eur. J. Org. Chem. 2012, 2012, 4453.
(b) Lee, D.; Kwon, K.; Yi, C. S. J. Am. Chem. Soc. 2012, 134, 7325.
ASSOCIATED CONTENT
* Supporting Information
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/jacs.6b12840.
■
́
(c)Han,X.;Wu, J.Angew. Chem., Int.Ed.2013, 52, 4637.(d)Pena-Lopez,
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M.; Neumann, H.; Beller, M. Chem. Commun. 2015, 51, 13082.
(8) Sawaguchi, T.; Obora, Y. Chem. Lett. 2011, 40, 1055.
S
(9) Frost, J. R.; Cheong, C. B.; Akhtar, W. M.; Caputo, D. F. J.;
Stevenson, N. G.; Donohoe, T. J. J. Am. Chem. Soc. 2015, 137, 15664.
(10) Replacing 1 with acetophenone gave a complex mixture of self-
coupled and cross-coupled products. In contrast, substitution of 1 with
either Ph*COCH2CH3 or tert-butyl acetate under identical conditions
gave no alkylated product (see SI).
(11) (a) Sauvage, J.; Baker, R. H.; Hussey, A. S. J. Am. Chem. Soc. 1960,
82, 6090. (b) Huff, B. E.; Khau, V. V.; LeTourneau, M. E.; Martinelli, M.
J.; Nayyar, N. K.; Peterson, B. C. Tetrahedron Lett. 1997, 38, 8627.
(12)SinglecrystalX-raydiffractiondatawerecollectedusinga(Rigaku)
Oxford Diffraction SuperNova diffractometer and CrysAlisPro.
Structures were solved using ‘Superflip’ before refinement with
CRYSTALS as per the SI (CIF). Crystallographic data have been
deposited with the Cambridge Crystallographic Data Centre (CCDC
1521308−11) and can be obtained via www.ccdc.cam.ac.uk/data_
request/cif. For particular details concerning solving and refining these
structures, see:(a)Palatinus, L.;Chapuis, G. J. Appl. Crystallogr. 2007, 40,
786. (b) Parois, P.; Cooper, R. I.; Thompson, A. L. Chem. Cent. J. 2015, 9,
30. (c) Cooper, R. I.; Thompson, A. L.; Watkin, D. J. J. Appl. Crystallogr.
2010, 43, 1100.
Experimental procedures and spectroscopic data for all
new compounds (PDF)
Crystallographic data (CIF)
AUTHOR INFORMATION
Corresponding Author
*timothy.donohoe@chem.ox.ac.uk
■
ORCID
James R. Frost: 0000-0002-4966-0419
Timothy J. Donohoe: 0000-0001-7088-6626
Author Contributions
§W.M.A., C.B.C., and J.R.F. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(13) The relative stereochemistry of 43 was assigned by comparison of
its13CNMRdatatoverycloselyrelatedcyclopentanes.See:(a)Canonne,
P.; Plamondon, J. Can. J. Chem. 1989, 67, 555. (b) Gilbert, J. C.; Yin, J.;
Fakhreddine, F. H.; Karpinski, M. L. Tetrahedron 2004, 60, 51.
(c) Gilbert, J. C.; Yin, J. Tetrahedron 2008, 64, 5482.
(14) A selection of different nucleophiles will react with the in situ
generated acid bromide; see ref 9.
(15) Tikad, A.; Delbrouck, J. A.; Vincent, S. P. Chem. - Eur. J. 2016, 22,
We thank GlaxoSmithKline (W.M.A.), A*STAR, Singapore
(C.B.C.), and the EPSRC [J.R.F., T.J.D., Established Career
Fellowship (EP/L023121/1)] for financial support.
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DOI: 10.1021/jacs.6b12840
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX