Manganese catalyzed α-methylation of ketones with methanol as a C1 source

Article abstract of DOI:10.1039/c8cc08064j

The direct α-methylation of ketones with methanol under hydrogen borrowing conditions using a well-defined manganese PN³P complex as a pre-catalyst was, for the first time, achieved. The reactions typically proceed at 120 °C for 20 h with 3 mol% pre-catalyst loading and in the presence of NaOtBu (50 mol%) as base. The scope of the reaction was extended to the α-methylation of esters.

Full text of DOI:10.1039/c8cc08064j

ChemComm
View Article Online
View Journal | View Issue
COMMUNICATION
Manganese catalyzed a-methylation of ketones
with methanol as a C1 source†
Cite this: Chem. Commun., 2019,
55, 314
ab
b
Antoine Bruneau-Voisine,
Lenka Pallova,b Stephanie Bastin,
´
b
bc
Received 9th October 2018,
Accepted 30th November 2018
Vincent Cesar
and Jean-Baptiste Sortais
*
´
DOI: 10.1039/c8cc08064j
rsc.li/chemcomm
The direct a-methylation of ketones with methanol under hydrogen
The potential of manganese in (de)-hydrogenation reactions
borrowing conditions using a well-defined manganese PN3P complex as as an alternative to noble metals16 has been demonstrated with
a pre-catalyst was, for the first time, achieved. The reactions typically the seminal works of Beller in hydrogenation17 and Milstein in
proceed at 120 8C for 20 h with 3 mol% pre-catalyst loading and in the dehydrogenative coupling of amines with alcohols.18 Since then,
presence of NaOtBu (50 mol%) as base. The scope of the reaction was several reactions based on hydrogen borrowing processes involving
extended to the a-methylation of esters.
alcohols have been developed19 and a few well defined homo-
geneous manganese-based catalysts (Chart 1) proved their ability to
a-Methylated carbonyl functions are often encountered in promote complete dehydrogenation of methanol,20 N-formylation,21
biologically active molecules.1 Characteristically, a-alkylation aminomethylation22 and N-methylation reactions,19a,23 demonstrat-
of ketones is achieved by reaction of the corresponding enolate ing that MeOH associated with manganese can be efficiently used
with an alkyl halide, thus generating stoichiometric amounts of as a C1 source via a partial oxidation. In line with our interest in
wastes. In the prospect of sustainable chemistry, new strategies manganese organometallic catalysis,24 we report here, for the first
to introduce a methyl group under catalytic conditions starting time, the a-methylation of carbonyl compounds using methanol as
from renewable resources and in an atom economical manner an alkylating reagent.
are indeed highly desirable.2 In this respect, alkylation at the
The optimisation of the reaction conditions was carried out
a-position of carbonyl derivatives with alcohols under hydrogen considering the methylation of propiophenone a1 with methanol
borrowing conditions providing water as the sole by-product (Scheme 1) as the model reaction (Table 1). Initial assessments were
constitutes an inviting strategy.3 Complementarily, methanol, performed in sealed ACEs pressure tubes at 120 1C for 20 h.
which is produced on an industrial scale from a wide variety of
In the presence of catalyst 5 (5 mol%) and NaOtBu (20 mol%),
sources including renewable ones,4,5 represents a very attrac- the ketone was converted in 93% yield, the major product being
tive C1 source for an environmentally benign, inexpensive, and the desired isobutyrophenone b1, isolated in 55% yield (entry 1).
abundant alkylating agent.6
It is worth noting that 1,5-diphenyl-2,4-dimethylpenta-1,5-dione
Yet, although alkylation of ketones with alcohols in the c1 resulting from the Michael addition of the enolate onto the
presence of homogeneous catalysts based on precious metals,3a,b transient enone e1 is the sole by-product observed at the end of
including Ru,7 Rh,8 Ir,9 and Re,10 is well established, a-methylation the reaction, indicating that the hydrogenation step is relatively slow
using methanol still remains challenging11 due to its higher compared to the Michael addition.25 None of the possible side
activation barrier for the dehydrogenation step into aldehydes products (i.e. alcohol d1, resulting from transfer hydrogenation,26
compared to heavier alcohols.12 In this context, the implemen- enone e1, or methyl ether f1) were detected by 1H NMR or GC-MS in
tation of an efficient system based on inexpensive and abundant the crude mixture. Diluting the reaction mixture and increasing the
base metals constitutes an additional challenge,13 with some amount of base to 0.5 equivalent finally allowed full conversion and
successes being recently reported by Liu14 then Morril15 using
cobalt or iron-based catalysts, respectively.
a Univ Rennes, CNRS, ISCR – UMR 6226, F-35000 Rennes, France
b
´
LCC-CNRS, Universite de Toulouse, CNRS, UPS, Toulouse, France.
E-mail: jean-baptiste.sortais@lcc-toulouse.fr
c Institut Universitaire de France, 1 rue Descartes, F-75231 Paris Cedex 05, France
† Electronic supplementary information (ESI) available: Experimental procedures
and characterization of the products. See DOI: 10.1039/c8cc08064j
Chart 1 Manganese catalysts promoting reactions with methanol.
314 | Chem. Commun., 2019, 55, 314--317
This journal is ©The Royal Society of Chemistry 2019

View Article Online
Communication
ChemComm
Table 2 Scope of the a-methylation of ketones with methanol in the
presence of 5 as a precatalyst. Typical reaction conditions: in a glovebox,
an Aces pressure tube was charged with ketone (0.5 mmol), MeOH (2 mL),
toluene (4 mL), 5 (3 mol%, 8.4 mg) and NaOtBu (50 mol%, 24.0 mg), in that
order. The closed pressure tube was then heated at 120 1C for 20 h. Yields
1
were determined by H NMR analysis of the crude mixture and confirmed
by GC-MS analysis
Scheme 1 Methylation of propiophenone a1 with MeOH.
Table 1 Optimization of the parameters of the a-methylation of a1
catalysed by 5
NMR yield (%)
Yieldc
Entry Substrate
1
Product
(isolated yield)
tBuONa
(mol%)
CH3OH
(mL)
Toluene
(mL)
Conv.
(%)
Entry
b1
c1
87 (64)
1a
2a
3
20
50
50
50
50
50
100
100
1
2
2
6
6
2
0.5
2
1
4
4
12
0
4
93
98
99
50
99
29
99
o5
55 (55)
90
87 (64)
44
84
11
39 (14)
10
13
6
16
18
66 (63)
o5
4b
5
2
3
67 (43)
82 (38)
6d
7d
8e
0.5
4
33
o5
Reaction conditions: in a glovebox, an Aces pressure tube was charged
with propiophenone a1 (0.5 mmol, 66 mL), MeOH, toluene, Mn complex
5 (3 mol%, 8.4 mg), and base, in that order. The closed pressure tube
was then heated at 120 1C for 20 h.a 5 mol% of Mn complex 5 (14 mg).
4
85 (79)
b
Propiophenone a1 (1.5 mmol, 198 mL) and Mn complex 5 (1.5 mol%,
16 mg). c NMR yield determined by 1H NMR spectroscopy and compared
with GC/MS of the crude mixture. Isolated yields in parentheses. d 100 1C.
e No Mn catalyst.
5
95 (46)
73 (51)
92 (66)
80 (71)
65 (56)
45 (40)
80 (78)
6
good selectivity toward the desired methylated ketone b1 (90% NMR
yield, entry 2).
7
The catalyst loading could be decreased to 3 mol% while
maintaining high conversion and good selectivity (entry 3), but
further lowering to 1.5 mol% had a detrimental effect on
conversion (entry 4). This model reaction could be carried out in
pure MeOH with comparable results (entry 5), but during the
reaction scope development, it appeared that toluene greatly
improved the solubility of most substrates (vide infra, Table 2).
Lowering the temperature to 100 1C resulted in a drastic
decrease of the conversion rate to 29% (entry 6). Different
alternative bases such as tBuOK, KHMDS, and K3PO4 have been
evaluated, leading to similar conversions and selectivities
(Table S1, ESI†).
8
9
10
11
Finally, reasoning that 1,5-diketones are valuable products
as starting materials for the synthesis of pyridines27 or cyclic
alkenes,28 the formation of c1 was tentatively optimized. Carrying
out the reaction at higher concentration in the presence of catalyst
5 (3 mol%) and a stoichiometric amount of base at 100 1C afforded
the 1,5-diphenyl-2,4-dimethyl-penta-1,5-dione c1 in 66% yield
(Table 1, entry 7).29 A blank test omitting the manganese catalyst
(Table 1, entry 8) led to no conversion.
12
13
14
n.d. (46)
87 (41)
n.d. (34)
With the optimized conditions in hand, a series of ketones
were methylated with methanol (Table 2). Propiophenone a1
and acetophenone a2 led to the same product, namely, iso-
butyrophenone b1, in 87% and 67% NMR yield, respectively.
It is worth noting that in the case of acetophenone a2, which is
less sterically hindered than a1, more 1,5-diketone was formed;
15
30 (23)
This journal is ©The Royal Society of Chemistry 2019
Chem. Commun., 2019, 55, 314--317 | 315

View Article Online
ChemComm
Communication
Table 2 (continued)
4-tert-Butylcyclohexanone a15 was dimethylated in moderate
yield (30%) due to the formation of the corresponding undesired
1,5-diketone. The methylation of propiophenone a1 also proceeded
well in the presence of competing substrates such as fluoro- and
trifluoromethyl-benzene, 1-octene or 4-nitrotoluene (Table S2, ESI†).
Dihydrochalcone a16, in which the transient enolate and
enone are stabilized by the phenyl ring, was methylated in very
high yield (95%). A series of dihydrochalcone derivatives
a17–a21 were subsequently methylated. The presence of a pyridinyl
moiety in a19 had a detrimental impact on the yield of the reaction
(60%). Interestingly, the catalytic system tolerated brominated sub-
strate a20, but dehalogenation (about 10%) was observed with the
iodo derivative a21. Finally, deuterated methanol CD3OD was
successfully employed as an alkylating agent, allowing the
introduction of the deuterated CD3 fragment in b22 (82%
isolated yield).
The scope of the reaction was finally extended to the catalytic
a-methylation of esters (Table 3),31 which has barely been achieved,
even using noble metal precatalysts.11d Under the same reaction
conditions as above yet in the presence of one equivalent of base,
several aryl acetic esters a23–a26 were methylated with methanol in
moderate to good yields (Table 3), including the brominated sub-
strate (a26) and deuterated product (b27). It is worth noting that
isolation of the methylated esters as pure products was difficult,
thus leading to low yields.
NMR yield (%)
(isolated yield)
Entry Substrate
16
Product
95 (80)
99 (93)
17
18
19
20
21
93 (86)
60 (51)
82 (82)
67 (42a)
84 (82b)
Table 3 Scope of the a-methylation of esters with methanol in the
presence of 5 as a precatalyst. Conditions: in a glovebox, an Aces pressure
tube was charged with ester (0.5 mmol), MeOH (2 mL), toluene (4 mL),
5 (3 mol%, 8.4 mg) and NaOtBu (100 mol%, 48.1 mg), in that order. The closed
pressure tube was then heated at 120 1C for 20 h. Yields were determined by
1H NMR analysis of the crude mixture and confirmed by GC/MS analysis
22
a
b
10% of the deiodination product was identified. CD3OD instead of
MeOH.
cyclic ketones including a-tetralone a3, 2,3-dihydrophenanthren-
4(1H)-one a4, 1-indanone a5, and 2-benzylidenecyclohexanone a6
were methylated in moderate to good yields (82%, 85%, 95%, and
73%, respectively). Steric hindrance actually disfavored the formation
of the undesired 1,5-diketones, allowing the double methylation of
20,40,60-trimethylacetophenone a7 and 20-methylacetophenone a8 in
high yields (92%, and 80%, respectively). This protocol is also
tolerant toward chlorinated substrate a9 to afford the corresponding
4-chloroisobutyrophenone b9 (65%), this being in line with the
functional group tolerance observed for the hydrogenation of
ketones.30 In the case of 20-aminoacetophenone a10, the methylation
occurred at the a-position of the carbonyl function, with the
isobutyrophenone derivative being obtained as the major product.
This result contrasts with the N-methylation of 40-aminoaceto-
phenone using the same catalyst under similar reaction conditions
where the methylation occurred at the nitrogen.23b It is likely that
intramolecular hydrogen bonds N–HꢀꢀꢀO favor the formation of the
enolate and direct the selectivity. Besides, we have previously noticed
that ortho-substituted anilines were more difficult to methylate.23b
2-Acetylbenzofuran a12 and thiophene derivatives a13 and a14
were a-methylated under these conditions (entries 12–14).
NMR yield (%)
(isolated yield)
Entry
1
Substrate
Product
95
2
95 (31)
3
4
50 (37)a
68 (35)
5
n.d. (20)b
a
b
50 mol% of tBuOK (24 mg) was used. CD3OD instead of MeOH, 48 h.
316 | Chem. Commun., 2019, 55, 314--317
This journal is ©The Royal Society of Chemistry 2019

View Article Online
Communication
ChemComm
15 K. Polidano, B. D. W. Allen, J. M. J. Williams and L. C. Morrill, ACS
Catal., 2018, 8, 6440–6445.
16 (a) D. A. Valyaev, G. Lavigne and N. Lugan, Coord. Chem. Rev., 2016,
308, 191–235; (b) F. Kallmeier and R. Kempe, Angew. Chem., Int. Ed.,
2018, 57, 46–60.
17 S. Elangovan, C. Topf, S. Fischer, H. Jiao, A. Spannenberg, W. Baumann,
R. Ludwig, K. Junge and M. Beller, J. Am. Chem. Soc., 2016, 138,
8809–8814.
18 A. Mukherjee, A. Nerush, G. Leitus, L. J. W. Shimon, Y. Ben David,
N. A. Espinosa Jalapa and D. Milstein, J. Am. Chem. Soc., 2016, 138,
4298–4301.
In conclusion, the manganese-catalyzed a-alkylation of ketones
using methanol as a green alkylating reagent was, for the first time,
achieved in the presence of a manganese catalyst based on a
2,6-diaminopyridine scaffold. The defined protocol could be
successfully extended to the even more challenging ester derivatives,
demonstrating further the great potential of manganese catalysis in
the field of (de)-hydrogenation reactions.
¨
We thank Noel Lugan for discussions, and the Centre
´
National de la Recherche Scientifique (CNRS), the Universite
19 (a) S. Elangovan, J. Neumann, J.-B. Sortais, K. Junge, C. Darcel and
M. Beller, Nat. Commun., 2016, 7, 12641; (b) N. Deibl and R. Kempe,
Angew. Chem., Int. Ed., 2017, 56, 1663–1666; (c) F. Kallmeier, B. Dudziec,
T. Irrgang and R. Kempe, Angew. Chem., Int. Ed., 2017, 56, 7261–7265;
Paul Sabatier, the Institut Universitaire de France (IUF) and the
Agence Nationale de la Recherche (ANR Agency, grant JCJC
ANR-15-CE07-0001).
¨
(d) M. Mastalir, M. Glatz, N. Gorgas, B. Stoger, E. Pittenauer, G. Allmaier,
L. F. Veiros and K. Kirchner, Chem. – Eur. J., 2016, 22, 12316–12320;
(e) M. Mastalir, M. Glatz, E. Pittenauer, G. Allmaier and K. Kirchner,
˜
´
J. Am. Chem. Soc., 2016, 138, 15543–15546; ( f ) M. Pena-Lopez, P. Piehl,
S. Elangovan, H. Neumann and M. Beller, Angew. Chem., Int. Ed., 2016,
55, 14967–14971; (g) N. V. Kulkarni, W. W. Brennessel and W. D. Jones,
ACS Catal., 2018, 8, 997–1002; (h) U. K. Das, Y. Ben-David, Y. Diskin-
Posner and D. Milstein, Angew. Chem., Int. Ed., 2018, 57, 2179–2182;
(i) M. K. Barman, S. Waiba and B. Maji, Angew. Chem., Int. Ed., 2018, 57,
9126–9130; ( j) D. H. Nguyen, X. Trivelli, F. Capet, J.-F. Paul, F. Dumeignil
and R. M. Gauvin, ACS Catal., 2017, 7, 2022–2032.
Conflicts of interest
There are no conflicts to declare.
Notes and references
1 E. J. Barreiro, A. E. Ku¨mmerle and C. A. M. Fraga, Chem. Rev., 2011,
111, 5215–5246.
2 (a) C. S. Yeung and V. M. Dong, Chem. Rev., 2011, 111, 1215–1292;
(b) P. T. Anastas and J. C. Warner, Green Chemistry: Theory and
Practice, Oxford University Press, 2000.
´
´
20 M. Anderez-Fernandez, L. K. Vogt, S. Fischer, W. Zhou, H. Jiao,
M. Garbe, S. Elangovan, K. Junge, H. Junge, R. Ludwig and M. Beller,
Angew. Chem., Int. Ed., 2017, 56, 559–562.
21 S. Chakraborty, U. Gellrich, Y. Diskin-Posner, G. Leitus, L. Avram
and D. Milstein, Angew. Chem., Int. Ed., 2017, 56, 4229–4233.
3 (a) Y. Obora, ACS Catal., 2014, 4, 3972–3981; (b) M. H. S. A. Hamid,
P. A. Slatford and J. M. J. Williams, Adv. Synth. Catal., 2007, 349, 22 M. Mastalir, E. Pittenauer, G. Allmaier and K. Kirchner, J. Am. Chem.
´
1555–1575; (c) G. Guillena, D. J. Ramon and M. Yus, Chem. Rev.,
Soc., 2017, 139, 8812–8815.
2010, 110, 1611–1641; (d) A. Corma, J. Navas and M. J. Sabater, Chem. 23 (a) J. Neumann, S. Elangovan, A. Spannenberg, K. Junge and
Rev., 2018, 118, 1410–1459.
4 (a) G. A. Olah, Angew. Chem., Int. Ed., 2013, 52, 104–107; (b) G. A. Olah,
Angew. Chem., Int. Ed., 2005, 44, 2636–2639.
M. Beller, Chem. – Eur. J., 2017, 23, 5410–5413; (b) A. Bruneau-
Voisine, D. Wang, V. Dorcet, T. Roisnel, C. Darcel and J.-B. Sortais,
J. Catal., 2017, 347, 57–62.
5 http://www.methanol.org, retrieved June 29th 2018.
6 (a) C. Chauvier and T. Cantat, ACS Catal., 2017, 7, 2107–2115;
(b) K. Natte, H. Neumann, M. Beller and R. V. Jagadeesh, Angew.
Chem., Int. Ed., 2017, 56, 6384–6394.
7 (a) C. S. Cho, B. T. Kim, T.-J. Kim and S. C. Shim, J. Org. Chem., 2001,
66, 9020–9022; (b) A. R. Sahoo, G. Lalitha, V. Murugesh, C. Bruneau,
G. V. M. Sharma, S. Suresh and M. Achard, J. Org. Chem., 2017, 82,
10727–10731.
8 R. Grigg, T. R. B. Mitchell, S. Sutthivaiyakit and N. Tongpenyai,
J. Chem. Soc., Chem. Commun., 1981, 611–612.
9 K. Taguchi, H. Nakagawa, T. Hirabayashi, S. Sakaguchi and Y. Ishii,
J. Am. Chem. Soc., 2004, 126, 72–73.
24 (a) D. Wei, A. Bruneau-Voisine, D. A. Valyaev, N. Lugan and J.-B.
Sortais, Chem. Commun., 2018, 54, 4302–4305; (b) D. Wei, A. Bruneau-
Voisine, T. Chauvin, V. Dorcet, T. Roisnel, D. A. Valyaev, N. Lugan and
J.-B. Sortais, Adv. Synth. Catal., 2018, 360, 676–681; (c) H. Li, D. Wei,
A. Bruneau-Voisine, M. Ducamp, M. Henrion, T. Roisnel, V. Dorcet,
´
C. Darcel, J.-F. Carpentier, J.-F. Soule and J.-B. Sortais, Organometallics,
2018, 37, 1271–1279; (d) D. Wang, A. Bruneau-Voisine and J.-B. Sortais,
Catal. Commun., 2018, 105, 31–36; (e) A. Bruneau-Voisine, D. Wang,
V. Dorcet, T. Roisnel, C. Darcel and J.-B. Sortais, Org. Lett., 2017, 19,
3656–3659; ( f ) J. Zheng, S. Chevance, C. Darcel and J.-B. Sortais, Chem.
Commun., 2013, 49, 10010–10012; (g) J. Zheng, S. Elangovan, D. A.
´
Valyaev, R. Brousses, V. Cesar, J.-B. Sortais, C. Darcel, N. Lugan and
10 P. Piehl, M. Pena-Lopez, A. Frey, H. Neumann and M. Beller, Chem.
Commun., 2017, 53, 3265–3268.
11 (a) L. K. M. Chan, D. L. Poole, D. Shen, M. P. Healy and T. J. Donohoe,
G. Lavigne, Adv. Synth. Catal., 2014, 356, 1093–1097; (h) D. A. Valyaev,
D. Wei, S. Elangovan, M. Cavailles, V. Dorcet, J.-B. Sortais, C. Darcel and
N. Lugan, Organometallics, 2016, 35, 4090–4098.
Angew. Chem., Int. Ed., 2014, 53, 761–765; (b) S. Ogawa and Y. Obora, 25 For the proposed mechanism, see the ESI†.
Chem. Commun., 2014, 50, 2491–2493; (c) X. Quan, S. Kerdphon and 26 In contrast, using n-butanol or benzyl alcohol instead of methanol
P. G. Andersson, Chem. – Eur. J., 2015, 21, 3576–3579; (d) T. T. Dang and
led to 1-phenylpropan-1-ol as the main product.
A. M. Seayad, Adv. Synth. Catal., 2016, 358, 3373–3380; (e) S. M. A. H. 27 T. W. Bell and S. D. Rothenberger, Tetrahedron Lett., 1987, 28, 4817–4820.
´
Siddiki, A. S. Touchy, M. A. R. Jamil, T. Toyao and K.-i. Shimizu, ACS 28 A. Fu¨rstner and B. Bogdanovic, Angew. Chem., Int. Ed. Engl., 1996, 35,
¨
Catal., 2018, 8, 3091–3103; ( f ) R. L. Wingad, E. J. E. Bergstrom,
2442–2469.
M. Everett, K. J. Pellow and D. F. Wass, Chem. Commun., 2016, 52, 29 Under the same conditions, 2,20-methyleneditetralone c3 was
5202–5204; (g) K. Chakrabarti, M. Maji, D. Panja, B. Paul, S. Shee,
G. K. Das and S. Kundu, Org. Lett., 2017, 19, 4750–4753.
obtained starting from a-tetralone in 38% isolated yield, see the
ESI†.
12 (a) W.-H. Lin and H.-F. Chang, Catal. Today, 2004, 97, 181–188; 30 A. Bruneau-Voisine, D. Wang, T. Roisnel, C. Darcel and J.-B. Sortais,
(b) M. Qian, M. A. Liauw and G. Emig, Appl. Catal., A, 2003, 238,
211–222.
13 R. M. Bullock, Science, 2013, 342, 1054–1055.
14 Z. Liu, Z. Yang, X. Yu, H. Zhang, B. Yu, Y. Zhao and Z. Liu, Org. Lett.,
2017, 19, 5228–5231.
Catal. Commun., 2017, 92, 1–4.
31 In the case of amides: for acetanilide, only N-methylaniline (ca. 25%)
resulting from trans-esterification/methylation was detected. In
contrast, the lactam 2-oxindole a28 was methylated in good isolated
yield (b28, 71%). See the ESI†.
This journal is ©The Royal Society of Chemistry 2019
Chem. Commun., 2019, 55, 314--317 | 317