Bronsted Acid Mediated Direct α-Hydroxylation of Cyclic α-Branched Ketones

Article abstract of DOI:10.1055/s-0037-1610292

We report a Bronsted acid mediated direct α-hydroxylation of cyclic α-branched ketones via a tandem aminoxylation/N-O bond-cleavage process. Nitrosobenzene is used as the oxidant and subsequently promotes the liberation of the free alcohol. The desired pr

Full text of DOI:10.1055/s-0037-1610292

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© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–C
letter
A
en
G. A. Shevchenko et al.
Letter
Synlett
Brønsted Acid Mediated Direct α-Hydroxylation of Cyclic α-Branched
Ketones
Grigory A. Shevchenko
O
O
PhNO (2.5 equiv)
Cl3CCO2H (3.0 equiv)
Stefanie Dehn
Benjamin List*
R
R
OH
0
0
0
0
0-
0
0
2
9-
8
0
4
5-
9
9
X
PhMe, r.t.
n
n
R = Ar, Alk
Max-Planck-Institut für Kohlenforschung,
Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr,
Germany
n = 0, 1, 2
O
R
O
Ph
N
list@kofo.mpg.de
O
PhNO
PhNO
N
Ph
HN Ph
n
Received: 21.08.2018
Accepted after revision: 02.09.2018
Published online: 26.09.2018
HO
O
O
(a)
OH
HO
O
DOI: 10.1055/s-0037-1610292; Art ID: st-2018-d0535-l
N
O
Abstract We report a Brønsted acid mediated direct α-hydroxylation
of cyclic α-branched ketones via a tandem aminoxylation/N–O bond-
cleavage process. Nitrosobenzene is used as the oxidant and subse-
quently promotes the liberation of the free alcohol. The desired prod-
ucts could be isolated in moderate to good yields at a maximum tested
scale of 10 mmol. Derivatizations of the obtained products are presented.
OH Me
O
O
paeonilactone B
oxymorphone
microstegiol
[Pd]; O2
Ritter et al. 2011
Jiao et al. 2015
[I2]; DMSO
(b)
Key words α-branched ketones, α-hydroxylation, aminoxylation,
α-functionalization of ketones, enolization, Brønsted acid mediated
[Cu]; O2
[Fe]; H2O/DDQ
Schoenebeck et al. 2016
Zhang et al. 2016
O
O
This work: acid, PhNO
R3
OH
R1
The direct α-hydroxylation of carbonyl compounds rep-
resents an efficient approach towards α-hydroxy carbonyls,
a ubiquitous motif in pharmaceuticals and natural products
(Scheme 1, a).1 Although α-hydroxylations of linear alde-
hydes and ketones are well established, such reactions of
their branched derivatives still remain a challenge.2 α-
Branched ketones are particularly difficult substrates be-
cause of the added challenge of controlling the branched vs.
unbranched regioselectivity. It is therefore not surprising
that a general solution does not exist and common synthet-
ic strategies towards α-hydroxy carbonyls rely on the oxida-
tion of prefunctionalized substrates, e.g., enol ethers and
enol esters.3 Few direct methods, which combine catalyt-
ic/substoichiometric amounts of (transition) metals, iodine,
or strong bases with oxygen, DDQ, or DMSO as the corre-
sponding oxidant, were recently reported (Scheme 1, b).4
Nitrosobenzene has been used as an oxidant in organo-
catalytic aminoxylations of aldehydes and ketones.5 In fact,
in the presence of a Brønsted acid, a second equivalent of
nitrosobenzene can additionally act as a reductant, giving
direct access to the desired hydroxy carbonyl compounds
via a tandem aminoxylation/N–O bond-cleavage process
with azoxybenzene as the side product.6
R1
R2 R3
R2
catalytic base or
PTC conditions
with O2
Jiao et al. 2014
Zhao et al. 2014
Scheme 1 (a) Natural products and pharmaceuticals containing the α-
hydroxy ketone motif. (b) Previous approaches for the direct α-hydrox-
ylation of branched ketones.
Given the dearth of direct α-hydroxylation methods and
based on our current interest in α-functionalizations of
branched ketones via Brønsted acid catalyzed enolizations
(enol catalysis),7 we pursued a complementary method for
the direct α-hydroxylation of branched ketones using nitro-
sobenzene. This reaction presents several challenges, i.e., i)
controlling the regioselectivity of the enolization, as well as
the ii) chemoselectivity (enol addition to O vs. N of nitroso-
benzene) and finally, iii) successfully completing the tan-
dem sequence.
We began our investigations using 2-phenylcyclohexa-
none (1a) as the model substrate (Table 1, for more details,
see the Supporting Information). Optimization of the reac-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–C

B
G. A. Shevchenko et al.
Letter
Synlett
tion conditions showed that an overstoichiometric amount
of a strong acid is necessary for the reaction to proceed,
with 3 equiv of trichloroacetic acid (TCA) giving the best re-
sult (Table 1, entry 4, 60% yield). Interestingly, weaker acids,
e.g. acetic acid, did not show any reactivity (Table 1, entry
1). While the yield remained the same, higher amounts of
TCA required additional purification steps to remove the
excess of acid (Table 1, entry 7). Since clean reaction profiles
were observed, we suspect the moderate yields to result
from the formation of an uncharacterized polymer in the
course of the reaction.
O
O
R
PhNO (2.5 equiv)
Cl3CO2H (3.0 equiv)
R
OH
PhMe, r.t., 16–24 h
2 n
1 n
O
O
O
O
O
O
OH
OH
OH
OH
2a
60%
54%a
2b
2c
58%
2d
40%
60%
R1
R1 = Me (2e, 51%)
CF3 (2f, 56%)
OMe (2g, 54%)
Ph (2h, 47%)
Cl (2i, 52%)
Table 1 Optimization of Reaction Conditionsa
R2
=
R2
OMe (2l, 54%)
Ph (2m, 56%)
Cl (2n, 42%)
Br (2o, 45%)
O
O
O
O
O
OH
PhNO (2.5 equiv)
acid (X equiv)
Ph
OH
OH
Ph
Br (2j, 45%)
F (2k, 41%)
PhMe, r.t., 16 h
MeO
1a
2a
O
O
OMe
O
OH
Entry
Acid
equiv
Yield (%)b
Cl
OH
OH
OH
1
2
3
4
5
6
7
AcOH
3
3
3
3
3
1
5
0
traces
28
ClCH2CO2H
Cl2CH2CO2H
Cl3CCO2H
F3CCO2H
2p
63%
2q
32%
2r
2s
57%
64%
O
O
(60)
(37)
27
O
O
Ph
OH
OH
OH
OH
Cl3CCO2H
Cl3CCO2H
2t
61%
2u
66%
2v
51%
2w
44%
(60)
a Reaction conditions: 1a (0.25 mmol, 1.0 equiv), acid, nitrosobenzene
(0.63 mmol, 2.5 equiv) in dry PhMe (2.5 mL).
Scheme 2 Scope of the α-hydroxylation of 2-substituted cyclic ketones,
indanone and tetralone. If not otherwise indicated the reactions were
performed using 0.25 mmol of 2. a Performed using 10 mmol of 2a.
b Determined by 1H NMR spectroscopy using Ph3CH as internal standard.
Isolated yield in parentheses.
With the optimized conditions in hand, we turned our
attention towards the scope of this transformation. Various
α-aryl cyclohexanones reacted readily under the reaction
conditions giving the desired products in moderate to good
yields (Scheme 2, 2a–q). Interestingly, no significant elec-
tronic effect was observed (2f, 56% yield vs. 2g, 54% yield).
To our delight, challenging ortho-substituted α-aryl cyclo-
hexanones (2b and 2p), a cycloheptanone (2r) and 2-alkyl
cyclohexanones (2u–w) could be transformed to their cor-
responding 2-hydroxy derivatives in similar yields. Further-
more, 2-methyl-indanone and 2-methyl-tetralone gave the
desired products with similarly good results (2s, 64% and
2t, 61%). However, when cyclopentanones or acyclic ke-
tones were used as substrates, no desired products were
obtained. Finally, the robustness of the method was demon-
strated by scale-up experiments of the model substrate.
Gratifyingly, 2a was obtained at a maximum tested scale of
10 mmol without deterioration of yield.
To demonstrate the utility of our developed method,
product 2a was derivatized to a variety of synthetically use-
ful functionalities (Scheme 3). Namely, amino alcohol 3 was
obtained via reductive amination. Reduction of ketone 2a
using K-Selectride® gave diol 4 in excellent yield and dia-
stereoselectivity. Notably, using NaBH4 as the reductant
resulted in similar yields, however, a dr of only 4:1 of the
resulting diol was observed. Treatment of product 2a with
methyl magnesium chloride resulted in the formation of
diol 5 as a single diastereomer. Elimination under acidic
conditions gave enone 6 in 54% yield, in addition to 16% of
the corresponding regioisomeric enone (see the Supporting
Information for details). Finally, treatment with the Best-
mann ylide8 afforded lactone 7, providing an efficient
access to dihydroactinidiolide-type structures.9
In summary, we have developed a simple and practical
Brønsted acid mediated direct hydroxylation of branched
ketones using nitrosobenzene as the oxygen source.10 The
scope includes various 2-aryl and 2-alkyl cyclohexanones,
which were converted into the corresponding products in
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–C

C
G. A. Shevchenko et al.
Letter
Synlett
(4) For selected publications regarding the direct α-hydroxylation
of α-branched ketones, see: (a) Schulz, M.; Kluge, R.; Sivilai, L.;
Kamm, B. Tetrahedron 1990, 46, 2371. (b) Ishikawa, T.; Hino, K.;
Yoneda, T.; Murota, M.; Yamaguchi, K.; Watanabe, T. J. Org.
Chem. 1999, 64, 5691. (c) Chuang, G. J.; Wang, W.; Lee, E.; Ritter,
T. J. Am. Chem. Soc. 2011, 133, 1760. (d) Liang, Y.-F.; Jiao, N.
Angew. Chem. Int. Ed. 2014, 53, 548. (e) Liang, Y.-F.; Wu, K.;
Song, S.; Li, X.; Huang, X.; Jiao, N. Org. Lett. 2015, 17, 876.
(f) Chen, T.; Peng, R.; Hu, W.; Zhang, F.-M. Org. Biomol. Chem.
2016, 14, 9859. (g) Tsang, A. S. K.; Kapat, A.; Schoenebeck, F. J. Am.
Chem. Soc. 2016, 138, 518. (h) Sim, S.-B. D.; Wang, M.; Zhao, Y.
ACS Catal. 2015, 5, 3609.
(5) For selected reviews on organocatalytic aminoxylations, see:
(a) Merino, P.; Tejero, T.; Delso, I.; Matute, R. Synthesis 2016, 48,
653. (b) Vilaivan, T.; Bhanthumnavin, W. Molecules 2010, 15,
917. (c) Janey, J. M. Angew. Chem. Int. Ed. 2005, 44, 4292.
(6) (a) Ramachary, D. B.; Barbas, C. F. Org. Lett. 2005, 7, 1577. (b) Lu,
M.; Zhu, D.; Lu, Y.; Zeng, X.; Tan, B.; Xu, Z.; Zhong, G. J. Am.
Chem. Soc. 2009, 131, 4562.
(7) For publications regarding enol catalysis by our group, see:
(a) Felker, I.; Pupo, G.; Kraft, P.; List, B. Angew. Chem. Int. Ed.
2015, 54, 1960. (b) Shevchenko, G. A.; Pupo, G.; List, B. Synlett
2015, 26, 1413. (c) Pupo, G.; Properzi, R.; List, B. Angew. Chem.
Int. Ed. 2016, 55, 6099. (d) Shevchenko, G. A.; Oppelaar, B.; List,
B. Angew. Chem. Int Ed. 2018, 57, 10756. For independent contri-
butions from other groups, see: (e) Pousse, G.; Le Cavalier, F.;
Humphreys, L.; Rouden, J.; Blanchet, J. Org. Lett. 2010, 12, 3582.
(f) Burns, A. R.; Madec, A. G. E.; Low, D. W.; Roy, I. D.; Lam, H. W.
Chem. Sci. 2015, 6, 3550. (g) Yang, X.; Toste, F. D. J. Am. Chem.
Soc. 2015, 137, 3205. (h) Yang, X.; Toste, F. D. Chem. Sci. 2016, 7,
2653. (i) Spanka, M.; Schneider, C. Org. Lett. 2018, 20, 4769. For
an account on heterodimeric activation in organocatalysis, see:
(j) Monaco, M. R.; Pupo, G.; List, B. Synlett 2016, 27, 1027.
(8) Bestmann, H. J. Angew. Chem., Int. Ed. Engl. 1977, 16, 349.
(9) (a) Rocca, J. R.; Tumlinson, J. H.; Glancey, B. M.; Lofgren, C. S. Tet-
rahedron Lett. 1983, 24, 1889. (b) Rubottom, G. M.; Juve, H. D.
J. Org. Chem. 1983, 48, 422. (c) Yao, S.; Johannsen, M.; Hazell, R.
G.; Jørgensen, K. A. J. Org. Chem. 1998, 63, 118. (d) Eidman, K. F.;
MacDougall, B. S. J. Org. Chem. 2006, 71, 9513.
O
O
O
Me
NH
i)
v)
OH
OH
2a
7
3
79%
4:1 dr
ii)
iv)
51%
iii)
O
OH
OH
OH
OH
6
54%
4
92%
>20:1 dr
5
85%
>20:1 dr
Scheme 3 Chemical derivatization of obtained products. i) MeNH2,
Ti(OiPr)4, PhMe, reflux, 24 h then NaBH4, MeOH, 0 °C, 1 h. ii) K-Selec-
tride®, THF, –78 °C to 0 °C, 2 h then NaOH, H2O2, r.t., overnight.
iii) MeMgCl, THF, –78 °C to r.t., overnight, the product was obtained as
a mixture with unreacted starting material (1H NMR ratio: 5.6:1).
iv) pTsOH, PhMe, reflux, overnight. v) Ph3PCCO, PhMe, reflux, 3 d.
moderate to good yields. The method is complementary to
published systems, easy to execute, and scalable and there-
fore might find application in chemical synthesis.
Funding Information
This work was partially supported by Max Planck Society and the DFG
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Acknowledgment
We are grateful for the generous support from the Max Planck Society
and the DFG (Leibnitz award to B. L.), as well as to the service depart-
ments of the MPI für Kohlenforschung.
(10) Exemplary Procedure
In a GC vial 2-phenylcyclohexanone (1a, 43.6 mg, 0.25 mmol,
1.0 equiv) was dissolved in a solution of trichloroacetic acid
(0.75 mmol, 3.0 equiv) in dry PhMe (2.5 mL) and nitrosoben-
zene (0.625 mmol, 2.5 equiv) was added. The vial was closed
with a screw cap, and the resulting mixture was stirred at r.t. for
16 h. The crude reaction mixture was directly purified by flash
column chromatography (SiO2, hexanes/EtOAc = 100:0 then
10:1) to give 2-hydroxy-2-phenylcyclohexan-1-one (2a) as an
orange oil (28.7 mg, 60%). 1H NMR (500 MHz, CDCl3): δ = 7.42–
7.27 (m, 2 H), 7.35–7.29 (m, 3 H), 5.04 (sbr, 1 H), 3.06–2.99 (m, 1
H), 2.59–2.51 (m, 1 H), 2.48–2.39 (m, 1 H), 2.11–2.02 (m, 1 H),
1.91–1.83 (m, 2 H), 1.82–1.68 (m, 2 H). 13C NMR (125 MHz,
CDCl3): δ = 212.9, 139.8, 129.3, 128.6, 126.5, 80.3, 39.0, 38.9,
28.5, 23.2. HRMS (ESI+): m/z calcd for C12H14O2Na [M + Na]+:
213.0886; found: 213.0885.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610292.
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References and Notes
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41, 4150. (c) Taj, R. A.; Green, J. R. J. Org. Chem. 2010, 75, 8258.
(2) Smith, A. M. R.; Hii, K. K. Chem. Rev. 2011, 111, 1637.
(3) For commonly applied methods, see: (a) Davis, F. A.; Chen, B. C.
Chem. Rev. 1992, 92, 919. (b) Rubottom, G. M.; Vazquez, M. A.;
Pelegrina, D. R. Tetrahedron Lett. 1974, 15, 4319.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–C