Strategic Application and Transformation of ortho-Disubstituted Phenyl and Cyclopropyl Ketones to Expand the Scope of Hydrogen Borrowing Catalysis

Article abstract of DOI:10.1021/jacs.5b11196

The application of an iridium-catalyzed hydrogen borrowing process to enable the formation of α-branched ketones with higher alcohols is described. In order to facilitate this reaction, ortho-disubstituted phenyl and cyclopropyl ketones were recognized as crucial structural motifs for C-C bond formation. Having optimized the key catalysis step, the ortho-disubstituted phenyl products could be further manipulated by a retro-Friedel-Crafts acylation reaction to produce synthetically useful carboxylic acid derivatives. In contrast, the cyclopropyl ketones underwent homoconjugate addition with several nucleophiles to provide further functionalized branched ketone products.

Full text of DOI:10.1021/jacs.5b11196

Communication
pubs.acs.org/JACS
Strategic Application and Transformation of ortho-Disubstituted
Phenyl and Cyclopropyl Ketones To Expand the Scope of Hydrogen
Borrowing Catalysis
James R. Frost,† Choon Boon Cheong,† Wasim M. Akhtar,† Dimitri F. J. Caputo,† Neil G. Stevenson,‡
and Timothy J. Donohoe*,†
†Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford OX1 3TA, United Kingdom
‡GlaxoSmithkline, Medicines Research Centre, Stevenage SG1 2NY, United Kingdom
S
* Supporting Information
Scheme 1. General Concept for the Design of Ketones that
enable α-Branched Products to form
ABSTRACT: The application of an iridium-catalyzed
hydrogen borrowing process to enable the formation of
α-branched ketones with higher alcohols is described. In
order to facilitate this reaction, ortho-disubstituted phenyl
and cyclopropyl ketones were recognized as crucial
structural motifs for C−C bond formation. Having
optimized the key catalysis step, the ortho-disubstituted
phenyl products could be further manipulated by a retro-
Friedel−Crafts acylation reaction to produce synthetically
useful carboxylic acid derivatives. In contrast, the cyclo-
propyl ketones underwent homoconjugate addition with
several nucleophiles to provide further functionalized
branched ketone products.
he use of hydrogen borrowing catalysis to allow the
Talkylation of functional groups such as amines or ketones
using alcohols has become a valuable method for organic
synthesis.1 Typically, this concept relies on the use of a transition-
metal catalyst to reversibly abstract hydrogen from an alcohol to
generate an aldehyde in situ. Subsequent reaction of the aldehyde
with a nucleophile (e.g., an enolate) results in bond formation.
The hydrogen is then returned to a reactive intermediate (e.g., an
enone) to complete the catalytic cycle and deliver alkylated
compounds.
The α-alkylation of a carbonyl group (typically a ketone) using
hydrogen borrowing chemistry is particularly attractive because it
avoids the use of strong bases, cryogenic temperatures, and alkyl
halides.2 However, most reports of this reaction pertain to the
monoalkylation of a methyl-substituted ketone. In contrast, the
formation of branched products by monoalkylation of a
methylene ketone is relatively underdeveloped.
Given that retro-aldol reactions are encouraged by a release of
steric strain,10 we set out to design a set of substrates that would
form branched products with a wider range of alcohols by
following two principles: (i) the ketones must be relatively
unhindered to prevent retro-aldol, and (ii) any new X group that
is introduced must be transformed or released easily afterward so
that the products have real synthetic value (Scheme 1).
Initially we focused on aryl ketones since they were particularly
effective substrates for hydrogen borrowing methylation. While
phenyl ketones were not good at forming branched products
with alcohols other than methanol, the addition of an ortho-
methyl group onto the aromatic ring improved matters
considerably. We rationalized this improvement to the lack of
planarity imposed on the Ar−CO system by the methyl group.
Recent contributions from the groups of Donohoe,3 Li,4
Andersson,5 and others6 have shown that methanol is uniquely
placed to form branched α-alkylated derivatives because of the
reactive nature of the formaldehyde generated in situ.7,8
However, to date few attempts to extend this protocol to other
alcohols have materialized.9 Our recent mechanistic studies
showed that the intermediate aldol adducts (see A, Scheme 1)
formed from reactions with substituted aldehydes were not stable
under the reaction conditions and reverted back to the
methylene ketones rather than alkylated products (i.e., the
retro-aldol reaction of A was more favorable than elimination).
Received: October 29, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.5b11196
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Optimization studies were performed using ortho-tolyl ketone
1, KOH, BnOH, and commercially available iridium catalysts at
85 °C (Table 1, 0.3 mmol of substrate, fixed equivalents of base
Scheme 2. α-Alkylation of ortho-Substituted Aryl Ketones
Table 1. Optimization Conditions for the α-Alkylation of
Ketone 1
a
yields %
entry
catalyst/ligand
2 mol % [CodlrCl]2
2
3
4
1
2
3
4
5
6
7
8
16
48
45
50
59
63
71
70
61
66
63
−
6
74
44
50
32
41
36
29
30
−
enhanced reactivity effect was also present on both electron-
deficient (8a) and electron-rich (9a) arenes. A crystal structure of
compound 7a was obtained by single crystal X-ray diffraction,
clearly indicating that the pentamethylphenyl group is twisted
out of conjugation with the carbonyl.14,15 We speculate that this
is beneficial for two reasons. First, the lack of steric hindrance
around the carbonyl α-carbon attenuates the rate of retro-aldol
reaction, allowing the elimination reaction to compete. Second,
the ortho-disubstitution on these aryl ketones shields the
carbonyl from reduction, with no trace of reduced starting
material (cf. 4) being observed. These effects were emphasized
when the lack of any ortho-substituent prevented efficient
formation of the desired branched product, instead providing
only unreacted or reduced starting material (see 10a, Scheme 2).
We selected two ortho-disubstituted aryl ketones that held
great potential for elaboration (2,4,6-trimethyl- and pentam-
ethylphenyl) and synthesized a variety of substrates bearing
different aliphatic side chains. These were then subjected to the
hydrogen borrowing alkylation conditions with different alcohols
(Scheme 3). Gratifyingly, these substrates were well tolerated
under the reaction conditions, with branched products formed in
consistently high yields.
Next, we sought to establish a method to functionalize these
aromatic ketones. We suspected that the twist of the ketone out
of the plane of the aromatic ring would facilitate ipso reaction
with an electrophile and a retro-Friedel−Crafts acylation
reaction would form an acylium ion. This reactive intermediate
could then be trapped to form alternative products.16 For
example, reaction of pentamethylphenyl (abbreviated as Ph*)
ketone 7a under acidic conditions led to formation of carboxylic
acid 11 (Scheme 4). The putative acylium ion intermediate could
also be trapped with nucleophiles other than water, such as an
electron-rich arene to give 12. While searching for milder
conditions to cleave the aryl ring, we discovered that ipso
bromination at low temperature was particularly efficient.
Reaction of 7a with bromine at −17 °C not only resulted in
release of the Ph* group but also formed the corresponding acid
bromide in situ [see Supporting Information (SI)].17 This could
then be quenched with many different nucleophiles in a one-pot
process. Ester 13,18 thioester 14, amides 15, 16, and alcohol 17
were all formed in this procedure, greatly expanding the scope of
α-branched carbonyl functional groups that can be prepared.
Additional studies indicated that the 2,4,6-trimethylphenyl
ketone products could also be cleaved using acid, with 6a
providing 11 (65%) and 12 (79%) under identical conditions to
that shown for 7a (see SI).
2 mol % [CodlrCl]2, 8 mol % PPh3
2 mol % [CodlrCl]2, 8 mol % cataCXium A
2 mol % [CodlrCl]2, 4 mol % BINAP
2 mol % [CodlrCl]2, 4 mol % DPPE
2 mol % [CodlrCl]2, 4 mol % DPPB
2 mol % [CodlrCl]2, 4 mol % DPPBz
1 mol % [CodlrCl]2, 2 mol % DPPBz
1 mol % [CodlrCl]2, 2 mol % DPPBz
0.5 mol % [CodlrCl]2,1 mol % DPPBz
2 mol % [Cp*lrCl2]2
6
5
13
−
1
−
−
−
4
b
9
10
11
30
34
−
−
62
c
12
1 mol % [CodlrCl]2, 2 mol % DPPBz, O2
a
All yields are of isolated material, reactions performed on 0.3 mmol
b
c
scale. Reaction conducted on 5 mmol scale. Reaction time was 12 h.
and alcohol are shown). The product distribution shows that,
along with desired product 2, the conjugate reduction process is
interrupted and leads to enone intermediate 3 being produced in
appreciable amounts. In addition to this, undesired ketone
reduction was also a problem,11 forming alcohol 4 in the process.
Initially, we showed that a commercially available Ir(I) catalyst
gave product 2 in 16% yield (Table 1, entry 1). The addition of a
monodentate ligand increased the yield from 16% to 48% (entry
2). While the hindered additive cataCXium A [di(1-adamantyl)-
n-butyl phosphine] did not change the product distribution, the
effect of a bidentate ligand was noticeable, with BINAP, DPPE,
and DPPB producing 2 in 50−63% yield (entries 4−6). Further
optimization of the bidentate ligand revealed DPPBz to be the
most effective, providing 2 in 70% yield using 1 mol % of Ir(I)
dimer (entry 8). Pleasingly the reaction was efficient on a 5 mmol
scale (entry 9), and reducing the catalyst loading to 0.5 mol % of
Ir(I) dimer still gave 66% of 2 (entry 10). We discovered that an
Ir(III) catalyst was viable for this alkylation forming 2 in good
yield (entry 11). Finally, in contrast to previous studies,3
performing the reaction under an O2 atmosphere under identical
conditions inhibited enone reduction to generate 3 exclusively
(entry 12).12 We postulate that the metal hydride reacts with the
O2 in preference to the enone, allowing 3 to accumulate and
recycling the Ir catalyst.13
With the optimization complete, we applied these conditions
to the alkylation of 1 with butanol. Pleasingly, this provided the
corresponding butylated product in 69% yield (5a, Scheme 2).
However, a breakthrough was made when we examined the
butylation of other ortho-substituted aryl ketones and discovered
that ortho-disubstituted aryl groups were superior to mono-
substituted compounds (compare 5a with 6a and 7a). The
B
DOI: 10.1021/jacs.5b11196
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Journal of the American Chemical Society
Communication
Scheme 3. Alcohol Scope with 2,4,6-Trimethyl- and
Pentamethylphenyl Ketones
Scheme 5. α-Alkylation of Cyclopropyl Ketones
range of different ketone side chains and alcohols were
compatible with this reaction, leading to diversity in the
branched products. The small size and inability to easily form
an enolate makes the cyclopropyl group an ideal substituent to
encourage the formation of branched products on the opposite
side of the ketone carbonyl.
The activated cyclopropyl groups contained in the products
were easily transformed into a more general set of alkyl
functionality by a homoconjugate addition reaction (Scheme
6). We discovered a variety of both carbon-based (see 19, 20)
Scheme 6. Homoconjugate Addition to Cyclopropyl Ketones
Scheme 4. Aryl Release under Acidic or Oxidative Conditions
and heteroatom nucleophiles (see 21, 22) that participated in
this process.19,20 Note that the use of cyclopropyl ketones in the
hydrogen borrowing procedure complements that of the
previously described aryl ketones in that (after ring opening)
they give access to functionalized ketones (rather than esters and
amides) bearing an α-branched center.
Finally, in the absence of metal catalyst, the alkylation of three
compounds (23−25) with BnOH gave the alkylated products
but in lower yields [Scheme 7, see 6f (18%) and 7b (11%) and
18c (49%)].21 We also observed a significant amount of enone
product that had not been reduced (cf. 3, 10−70%). We assume
that in the absence of catalyst a Meerwein−Ponndorf−Verley
type mechanism is operative which shifts a hydride between the
alcohol and the ketones/enones to facilitate the reaction.21
However, the catalyst free alkylation of substrates 23 (Ar =
Me3C6H2), 24 (Ar = Ph*), and 25 is not general, and when
nonbenzylic alcohols such as butanol and cyclopropylmethanol
were used, the reactions gave no alkylated product. In these cases
the reaction mixture consisted of mostly unreacted (Ar ketones)
or reduced starting material (cyclopropyl ketones).
Investigation of other ketones that might allow the formation
of branched products revealed that the cyclopropyl group was
also suitable (Scheme 5). In this case slightly different conditions
involving [Cp*IrCl2]2 (2 mol %) at 105 °C proved optimal,
providing the desired alkylated products in good yields. Again, a
In conclusion, we have shown that it is now possible to α-
alkylate various methylene ketones under hydrogen borrowing
conditions with higher alcohols to give branched products. In
C
DOI: 10.1021/jacs.5b11196
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Journal of the American Chemical Society
Communication
(2) For examples: (a) Taguchi, K.; Nakagawa, H.; Hirabayashi, T.;
Sakaguchi, S.; Ishii, Y. J. Am. Chem. Soc. 2004, 126, 72. (b) Kwon, M. S.;
Kim, N.; Seo, S. H.; Park, I. S.; Cheedrala, R. K.; Park, J. Angew. Chem.,
Int. Ed. 2005, 44, 6913. (c) Lofberg, C.; Grigg, R.; Whittaker, M.; Keep,
A.; Derrick, A. J. Org. Chem. 2006, 71, 8023. (d) Pridmore, S. J.;
Williams, J. M. J. Tetrahedron Lett. 2008, 49, 7413. (e) Iuchi, Y.; Obora,
Y.; Ishii, Y. J. Am. Chem. Soc. 2010, 132, 2536. (f) Guo, L.; Liu, Y.; Yao,
X.; Huang, Z. Org. Lett. 2013, 15, 1144.
Scheme 7. Catalyst-Free Control Experiments
(3) (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.
(4) Li, F.; Ma, J.; Wang, N. J. Org. Chem. 2014, 79, 10447.
(5) Quan, X.; Kerdphon, S.; Andersson, P. G. Chem. - Eur. J. 2015, 21,
3576.
(6) (a) Iuchi, Y.; Hyotanishi, M.; Miller, B. E.; Maeda, K.; Obora, Y.;
Ishii, Y. J. Org. Chem. 2010, 75, 1803. (b) Ogawa, S.; Obora, Y. Chem.
Commun. 2014, 50, 2491. (c) Yan, F.-X.; Zhang, M.; Wang, X.-T.; Xie,
F.; Chen, M.-M.; Jiang, H. Tetrahedron 2014, 70, 1193.
(7) For oxidative activation of MeOH, see: (a) Campos, J.;
Sharninghausen, L. S.; Manas, M. G.; Crabtree, R. H. Inorg. Chem.
2015, 54, 5079. (b) Nielsen, M.; Alberico, E.; Baumann, W.; Drexler, H.-
J.; Junge, H.; Gladiali, S.; Beller, M. Nature 2013, 495, 85. (c) Hu, P.;
Diskin-Posner, Y.; Ben-David, Y.; Milstein, D. ACS Catal. 2014, 4, 2649.
(8) For recent examples of C−N bond formation with MeOH, see:
(a) Dang, T. T.; Ramalingam, B.; Seayad, A. M. ACS Catal. 2015, 5,
4082. (b) Tsarev, V. N.; Morioka, Y.; Caner, J.; Wang, Q.; Ushimaru, R.;
Kudo, A.; Naka, H.; Saito, S. Org. Lett. 2015, 17, 2530.
(9) A recent report by Li has shown that arylacetonitriles can be
alkylated using several benzyl and aliphatic alcohols, see: Li, F.; Zou, X.;
Wang, N. Adv. Synth. Catal. 2015, 357, 1405.
(10) (a) Heathcock, C. In Asymmetric Synthesis; Morrison, J. D., Ed.; ,
Academic Press: San Diego, CA, 1984; Vol 3. (b) Mulzer, J.; Zippel, M.;
order to facilitate this reaction, ortho-disubstituted and cyclo-
propyl ketones were recognized as key structural motifs. These
proved to be very useful synthetic handles enabling product
functionalization following the catalysis step. Upon treatment
with bromine, the ortho-disubstituted ketones underwent a retro-
Friedel−Crafts reaction which, following the addition of
nucleophiles, resulted in an array of carboxylic acid derivatives.
Alternatively, the cyclopropyl ketone products could be opened
with several nucleophiles by a homoconjugate addition sequence
to give more functionalized ketones.
Bruntrup, G.; Segner, J.; Finke, J. Liebigs Ann. Chem. 1980, 1108.
(11) For an example, see: Wang, D.; Zhao, K.; Ma, P.; Xu, C.; Ding, Y.
Tetrahedron Lett. 2014, 55, 7233.
̈
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.5b11196.
■
S
(12) Lee, E. Y.; Kim, Y.; Lee, J. S.; Park, J. Eur. J. Org. Chem. 2009, 2943.
(13) (a) Gabrielsson, A. A.; van Leeuwen, P. P.; Kaim, W. W. Chem.
Commun. 2006, 4926. (b) Jiang, B.; Feng, Y.; Ison, E. A. J. Am. Chem. Soc.
2008, 130, 14462.
(14) Crystallographic data (excluding structure factors) have been
deposited with the Cambridge Crystallographic Data Center: 7a
(CCDC 1439711); S14 (CCDC 1439712) and can be obtained via
http://www.ccdc.cam.ac.uk/.
Experimental procedures and spectroscopic data (PDF)
Crystallographic data (CIF)
AUTHOR INFORMATION
Corresponding Author
*timothy.donohoe@chem.ox.ac.uk
Notes
■
(15) This effect can be observed in the IR spectra of aryl ketones, see
Fiedler, F.; Exner, O. Collect. Czech. Chem. Commun. 2004, 69, 797.
(16) (a) Schubert, W. M.; Latourette, H. K. J. Am. Chem. Soc. 1952, 74,
1829. (b) Bender, M. L.; Ladenheim, H.; Chen, M. C. J. Am. Chem. Soc.
1961, 83, 123. (c) Bender, M. L.; Chen, M. C. J. Am. Chem. Soc. 1963, 85,
37. (d) El-Khawaga, A. M.; Roberts, R. M.; Sweeney, K. M. J. Org. Chem.
1985, 50, 2055.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(17) An acid bromide has been observed by 13C NMR spectroscopy [δ
CO at 174.4 ppm (CD2Cl2)].
We thank the EPSRC (J.R.F., T.J.D., Established Career
Fellowship (EP/L023121/1)), GlaxoSmithKline (W.M.A.),
and A*STAR, Singapore (C.B.C.) for supporting this project.
D.F.J.C. is grateful to the EPSRC Centre for Doctoral Training in
Synthesis for Biology and Medicine (EP/L015838/1). Di Shen
and Lena Rakers are thanked for performing preliminary
experiments.
(18) Alkylation of tert-butyl esters has been reported: Guo, L.; Ma, X.;
Fang, H.; Jia, X.; Huang, Z. Angew. Chem. 2015, 127, 4095.
(19) Mioskowski, C.; Manna, S.; Falck, J. R. Tetrahedron Lett. 1983, 24,
5521.
(20) Lambert, J. B.; Napoli, J. J.; Kappauf Johnson, K.; Taba, K. N.;
Packard, B. S. J. Org. Chem. 1985, 50, 1291.
(21) (a) Veibel, S.; Nielson, J. I. Tetrahedron 1967, 23, 1723. (b) Allen,
L. J.; Crabtree, R. H. Green Chem. 2010, 12, 1362. (c) Liang, Y.-F.; Zhou,
X.-F.; Tang, S.-Y.; Huang, Y.-B.; Feng, Y.-S.; Xu, H.-J. RSC Adv. 2013, 3,
7739. (d) Xu, Q.; Chen, J.; Tian, H.; Yuan, X.; Li, S.; Zhou, C.; Liu, J.
Angew. Chem., Int. Ed. 2014, 53, 225.
REFERENCES
■
(1) For representative reviews, see: (a) Dobereiner, G. E.; Crabtree, R.
H. Chem. Rev. 2010, 110, 681. (b) Bahn, S.; Imm, S.; Neubert, L.; Zhang,
̈
M.; Neumann, H.; Beller, M. ChemCatChem 2011, 3, 1853. (c) Pan, S.;
Shibata, T. ACS Catal. 2013, 3, 704. (d) Gunanathan, C.; Milstein, D.
Science 2013, 341, 1229712. (e) Ketcham, J. M.; Shin, I.; Montgomery,
T. P.; Krische, M. J. Angew. Chem., Int. Ed. 2014, 53, 9142. (f) Obora, Y.
ACS Catal. 2014, 4, 3972. (g) Yang, Q.; Wang, Q.; Yu, Z. Chem. Soc. Rev.
2015, 44, 2305. (h) Nandakumar, A.; Midya, S. P.; Landge, V. G.;
Balaraman, E. Angew. Chem., Int. Ed. 2015, 54, 11022.
D
DOI: 10.1021/jacs.5b11196
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX