Iron-Catalyzed Methylation Using the Borrowing Hydrogen Approach

: A general iron-catalyzed methylation has been developed using methanol as a C1 building block. This borrowing hydrogen approach employs a Kno ̈ lker-type (cyclopentadienone)iron carbonyl complex as catalyst (2 mol %) and exhibits a broad reaction scope. A variety of ketones, indoles, oxindoles, amines, and sulfonamides undergo mono-or dimethylation in excellent isolated yields (>60 examples, 79% average yield).

M ethylation is a fundamental transformation in synthetic chemistry that is widely used for the synthesis and functionalization of fine chemicals. 1Traditional methylation procedures often employ toxic and/or potentially explosive reagents including iodomethane, dimethyl sulfate, or diazomethane, among many others. 2In recent years, methanol, an abundant and biodegradable liquid, has emerged as an attractive alternative reagent for methylation. 3Borrowing hydrogen (BH), or hydrogen autotransfer, combines a transfer hydrogenation process with a concurrent reaction on the in situ-generated reactive intermediate. 4This one-pot oxidationreaction−reduction sequence has received much attention due to its inherent high atom economy and minimal waste generation, 5 allowing bench stable and inexpensive alcohols to be used as alkylating agents. 6In comparison with benzyl and long-chain n-alkyl alcohols, it is challenging to use methanol as the alkylating agent in BH processes, due partly to the increased energy of dehydrogenation (ΔH (MeOH) = +84 kJ mol −1 , cf.ΔH (EtOH) = +68 kJ mol −1 ) 7 to form the required transient reactive formaldehyde intermediate.
Following the pioneering work of Grigg on the rutheniumand rhodium-catalyzed methylation of arylacetonitriles and aromatic amines, 8 respectively, there have been a number of subsequent reports describing precious metal-catalyzed BH methylation (Scheme 1A). 9 Despite these advances, a key challenge in hydrogen transfer chemistry is the development and use of catalysts based on earth-abundant, inexpensive metals for more sustainable processes. 10Considerable progress has been made in this regard, with well-defined iron, manganese, and cobalt catalysts being employed for a variety of homogeneous BH alkylation processes. 11With the vast majority of reports primarily focusing on the use of benzyl alcohols as alkylating agents, Beller and Sortais have reported the methylation of aromatic amines using manganese pincer This is an open access article published under a Creative Commons Attribution (CC-BY) License, which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
complexes. 12Furthermore, Liu has recently a cobaltbased catalytic system for methylation. 13However, the catalytic BH methylation using iron, 14 the most abundant transition metal in the Earth's crust, remains an unsolved problem.Herein, we report an efficient and general ironcatalyzed methylation of ketones, indoles, oxindoles, amines, and sulfonamides using methanol as a sustainable C1 building block (Scheme 1B).
To commence our studies, we selected butyrophenone 1 as a model substrate (Table 1).After extensive optimization, 15 it was found that a BH system composed of Knolker-type (cyclopentadienone)iron carbonyl precatalyst 2 (2 mol %), 16 trimethylamine N-oxide (4 mol %) to activate the catalyst, 17 K 2 CO 3 (2 equiv) as base in MeOH ([1] = 0.5 M) at 80 °C for 24 h, enabled the methylation of 1, giving 3 in 98% NMR yield and 88% isolated yield (entry 1).No methylation occurs in the absence of the iron precatalyst 2 (entry 2), with a significant reduction in conversion observed in the absence of trimethylamine N-oxide (entry 3).Substituting Me 3 NO for PPh 3 as activator or lowering the loading of Me 3 NO to 2 mol %, both result in decreased NMR yield of 3 (entries 4 and 5).Employing KOH or KOt-Bu as base, or using substoichiometric quantities of K 2 CO 3 (0.5 equiv) all result in lower conversions to 3 (entries 6−8).Using methanol as solvent is crucial, with a mixed solvent system (MeOH:toluene (1:1)) resulting in only 40% NMR yield (entry 9).Altering the reaction concentration (entries 10 and 11), reaction temperature (entries 12 and 13), or reducing the catalyst loading to 1 mol % (entry 14), lowers the efficiency of the methylation of 1 to 3.
[1] = 0.5 M. b Yield after 24 h as determined by 1 H NMR analysis of the crude reaction mixture with 1,3,5-trimethylbenzene as the internal standard.Isolated yield given in parentheses.c 2 mol % of Me 3 NO.
Selecting the monomethylation of propiophenone as a representative reaction, a number of experiments were performed in order to obtain mechanistic insight (Scheme 3).First, the validity of several proposed intermediates (βhydroxy ketone 62, methyl ether 63, diketone 64, and enone 65) was probed by subjecting them to the "standard" methylation reaction conditions (Scheme 3A).Conjugate addition of methanol or the enolate of propiophenone to

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Letter enone would result in the formation of 63 and 64, respectively.Compounds 62, 63, and 65 were all converted to 4 in 85% NMR yield, indicating that they are all plausible reaction intermediates.The remaining mass balance in these reactions (∼15%) was diol 66, which likely forms via conjugate addition of the iron hydride species to 65, followed by trapping of the resulting enolate with formaldehyde and subsequent hydrogenation. 25Diketone 64 was returned after 24 h, indicating that this is a nonproductive reaction pathway and that 64 does not lead to the formation of 4. To gain further mechanistic insight, employing CD 3 OD as solvent under the otherwise standard reaction conditions, enone 65 was converted to 67 (74%, > 95% D) providing evidence for the proposed iron hydride species (Scheme 3B).Furthermore, propiophenone 68 was converted to 69 (>95%, > 95% D), confirming that methanol is the source of the methyl group.As such, the proposed mechanism begins with CO decoordination by Me 3 NO to form the active iron complex, which abstracts hydrogen from methanol in the presence of base to form the required transient reactive formaldehyde intermediate (Scheme 3C).A subsequent aldol reaction with propiophenone generates β-hydroxy ketone 62 that undergoes basecatalyzed dehydration to form enone 65, which may exist in equilibrium with 63.Finally, reduction of enone 65 by the iron−hydrogen complex gives methylated product 4 with regeneration of the active iron complex.
In conclusion, we have developed a general and efficient Fecatalyzed methylation using methanol as a sustainable C1 building block via the borrowing hydrogen approach.A diverse array of ketones, indoles, oxindoles, amines, and sulfonamides undergo mono-or dimethylation in excellent isolated yields (61 examples, 79% average yield).Mechanistic experiments provided evidence for plausible reaction intermediates, an ironhydride species, and methanol as themethylating agent in this catalytic process.Ongoing studies are focused on further applications of earth-abundant transition metals in catalysis, and these results will be reported in due course.Scheme 3. Mechanistic Considerations a Yield after 24 h as determined by 1 H NMR analysis of the crude reaction mixture with 1,3,5-trimethylbenzene as the internal standard.

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Letter P u blis h e r s p a g e : h t t p:// dx.doi.o r g/ 1 0. 1 0 2 1/ a c s c a t al. 8 b 0 2 1 5 8 < h t t p:// dx.doi.o r g/ 1 0. 1 0 2 1/ a c s c a t al. 8 b 0 2 1 5 8 > Pl e a s e n o t e: C h a n g e s m a d e a s a r e s ul t of p u blis hi n g p r o c e s s e s s u c h a s c o py-e di ti n g, fo r m a t ti n g a n d p a g e n u m b e r s m a y n o t b e r efl e c t e d in t his ve r sio n.Fo r t h e d efi nitiv e ve r sio n of t hi s p u blic a tio n, pl e a s e r ef e r t o t h e p u blis h e d s o u r c e.You a r e a d vis e d t o c o n s ul t t h e p u blis h e r's v e r sio n if yo u wi s h t o cit e t hi s p a p er. Thi s v e r sio n is b ei n g m a d e a v ail a bl e in a c c o r d a n c e wit h p u blis h e r p olici e s. S e e h t t p://o r c a .cf. a c. u k/ p olici e s. h t ml fo r u s a g e p olici e s.Co py ri g h t a n d m o r al ri g h t s fo r p u blic a tio n s m a d e a v ail a bl e in ORCA a r e r e t ai n e d by t h e c o py ri g h t h ol d e r s .

Scheme 2 .
Scheme 2. Scope of the Fe-Catalyzed BH Methylation Process §

Table 1 .
Optimization of Fe-Catalyzed BH Methylation a