Convenient Reductive Methylation of Amines with Carbonates at Room Temperature

Article abstract of DOI:10.1002/chem.201502917

Methylation of amines is a fundamental and commonly used reaction in organic synthesis. Many methods are known including various reductive methylations using formaldehyde, formic acid, or carbon dioxide in the presence of reductants. However, several of these methods suffer from limited substrate scope and chemoselectivity because of the different nucleophilicities of substrates. In this respect, the combination of carbonates and hydrosilanes is a valuable methylation source in the presence of Pt-based catalysts. This highly tunable method allows for methylation of both aromatic and aliphatic amines, and chemoselective methylation of aminoalcohols and diamines. Notably, the in situ-formed catalyst can also be used for the reduction of carbonates to methanol at room temperature. Mechanistic insights on intermediates formed during the reaction pathway were obtained by using ESI mass spectrometry.

Full text of DOI:10.1002/chem.201502917

DOI: 10.1002/chem.201502917
Communication
&
Methylation |Hot Paper|
Convenient Reductive Methylation of Amines with Carbonates at
Room Temperature
Yuehui Li,[a] Ivµn Sorribes,[a] Cristian Vicent,[b] Kathrin Junge,[a] and Matthias Beller*[a]
carbonates also attracted interest in the context of reductive
Abstract: Methylation of amines is a fundamental and
CO2 valorization. In this regard, the hydrogenation of organic
commonly used reaction in organic synthesis. Many meth-
carbonates to methanol, as reported by the groups of Milstei-
ods are known including various reductive methylations
n[6a] and Ding,[6b] is noteworthy. Although the use of dimethyl
using formaldehyde, formic acid, or carbon dioxide in the
carbonate as a green methylation reagent is an important
presence of reductants. However, several of these meth-
issue for a sustainable chemical industry,[7a–d] only one example
ods suffer from limited substrate scope and chemoselec-
of reductive methylation of amines by carbonates is known,
tivity because of the different nucleophilicities of sub-
which interestingly employed photoactivation in the presence
strates. In this respect, the combination of carbonates and
of Fe complexes.[7e] Nevertheless, we assumed that under the
hydrosilanes is a valuable methylation source in the pres-
appropriate catalytic conditions, the C=O moiety could be
ence of Pt-based catalysts. This highly tunable method
used for efficient methylation of amines by selective substitu-
allows for methylation of both aromatic and aliphatic
tion and reduction reactions in the absence of photoactivation.
amines, and chemoselective methylation of aminoalcohols
Herein, we report a general and selective homogeneous
and diamines. Notably, the in situ-formed catalyst can also
system for this type of reaction under mild conditions. Com-
be used for the reduction of carbonates to methanol at
pared to the recent work with CO2 or formaldehyde, the use of
room temperature. Mechanistic insights on intermediates
different carbonates allows the performance of reductive
formed during the reaction pathway were obtained by
methylation under ambient conditions without any specific
using ESI mass spectrometry.
high-pressure equipment (Scheme 1).
N-methyl amines are key intermediates and important building
blocks in organic synthesis. Hence, the discovery of more effi-
cient and selective methylation methods continuously attracts
the attention of chemists.[1] Other than the use of toxic formal-
dehyde or activated methylation reagents, recently CO2,[2]
CH3OH,[3] and HCO2H[4] have been disclosed as interesting C1
building blocks for the synthesis of N-methylamines. Despite
these important developments, improvements are desired due
to drawbacks such as limited substrate scope, inconvenient
employment of pressure operations, or the necessity to apply
high temperatures or acidic conditions.
Organic carbonates (carbonic acid esters) constitute an im-
portant and versatile class of compounds that are easily avail-
able from CO or CO2. These “nontoxic”, biodegradable com-
Scheme 1. N-Methylation methods: A) and B) Known methods; C) use of
carbonates as methylating reagents under reductive conditions (this work).
pounds are used more and more in chemical and material in-
dustries, for example, as solvents even in organic (reduction)
reactions.[5] Nonetheless, recently the selective reduction of
At the start of our work, we investigated the reaction of N-
methylaniline (1a) and dimethyl carbonate (2a) in toluene in
the presence of transition metals and silanes as a model sys-
tem.[8a,b] To identify effective catalysts, different metal precur-
sors, including Ru, Ir, Rh, Ni, Pd, In, and Pt complexes, were
tested by using phenylsilane as a reducing agent (Table 1 and
Table S5 in the Supporting Information). Commercially avail-
able Pt complexes proved to be the most active catalyst pre-
cursors, giving dimethylaniline (3a) in near 70% yield (Table 1,
entries 7–9), whereas no reaction took place in the absence of
[a] Dr. Y. Li,+ Dr. I. Sorribes,+ Dr. K. Junge, Prof. Dr. M. Beller
Leibniz-Institut für Katalyse e.V.
Albert-Einstein-Str. 29a, 18059 Rostock (Germany)
E-mail: matthias.beller@catalysis.de
[b] Dr. C. Vicent
Serveis Centrals d’Instrumentació Científica, Universitat Jaume I
Av. Sos Baynat s/n, 12071 Castelló de la Plana (Spain)
[+] Both authors contributed equally to this work.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201502917.
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observed for the reduction of dimethyl carbonate to methanol
within 20 h in the presence of 0.5 mol% catalyst and 2.5 equiv-
alents of PhSiH3.[9] Furthermore, 63% yield of MeOH could be
obtained after acidic work-up in the reduction of NaHCO3
[Eq. (1)].
Table 1. Transition metal-catalyzed methylation of 1a with 2a and
phenysilane.[a]
Entry
[M]
Ligand
T [8C]
Conv. [%][b]
Yield [%][b]
1
2
3
4
5
6
7
8
9
[RuCl2(dmso)4]
[{Ir(cod)Cl}2]
[RhCl(PPh3)3]
[Ni(cod)2]
[Pd(OAc)2]
In(OTf)3
–
–
–
–
–
–
–
–
–
80
80
80
80
80
80
80
80
80
80
RT
RT
RT
RT
100
26
46
34
35
8
25
46
33
34
6
Hence, bicarbonate and propylene carbonate were also
tested for reductive methylation of amines. Whereas bicarbon-
ate gave only a low yield of 3a (24%), in the presence of pro-
pylene carbonate excellent activity (93% yield) was observed
(Table 1, entries 14 and 15). However, given its easy availability,
dimethyl carbonate (DMC) was used for the subsequent mech-
anistic studies and the evaluation of the substrate scope.
2
2
H2PtCl6
[Pt(PPh3)4]
73
72
72
76
78
39
96
99
26
66
66
67
71
76
37
92
93
24
Karstedt [Pt]
Karstedt [Pt]
Karstedt [Pt]
Karstedt [Pt]
Karstedt [Pt]
Karstedt [Pt]
Karstedt [Pt]
10
11[c,d]
12[c,e]
13[c,d,f]
14[g]
15[h]
–
tpy
tpy
tpy
tpy
tpy
Mechanistic insights on this multicomponent catalytic reac-
tion were gathered from electrospray ionization mass spec-
trometry (ESI-MS) experiments.[10] 1a and 3a and proton ad-
ducts of potential carbamate or amide intermediates might be
easily detected by ESI(+)-MS. Thus, we envisaged this tech-
nique as a highly sensitive analytical tool for reaction monitor-
ing in the present system. Performing the model reaction in
THF under optimized conditions (Table 1, entry 13 and Fig-
ure S1 in the Supporting Information) gave almost full conver-
sion of the substrate after 4 h. After 30 min, prominent peaks
had formed in the mass spectrum that were assigned to
proton adducts of carbamate 4a and formamide 5a,[11] as well
as the iminium 6a cation (Scheme 2). However, Pt-containing
[a] Reaction conditions (unless otherwise stated): 1a (0.5 mmol), 2a
(2 equiv), PhSiH3 (2.5 equiv), solvent (1 mL); Karstedt [Pt]=platinum(0)
1,3-divinyl-1,1,3,3-tetramethyldisiloxane; entries 1–9: solvent=toluene;
entries 10–13: solvent=nBu2O; [b] determined by GC using n-hexadecane
as an internal standard; [c] t=18 h; [d] 1 mol% [Pt] and tpy; [e] 0.1 mol%
[Pt] and tpy; [f] 2a (4 equiv), PhSiH3 (5 equiv); [g] carbon source=propyl-
ene carbonate; [h] carbon source=NaHCO3, t=24 h.
catalyst (see the Supporting Information, Table S1).[8c] A moder-
ate improvement in the conversion and yield was observed on
changing the solvent to nBu2O (Table 1, entry 10). Next, to im-
prove the product yield various commercially available ligands
were tested in combination with Karstedt’s complex ([Pt(CH2=
CHSiMe2)2O]; see the Supporting Information, Table S2). The
most effective catalyst was formed by using 2,2’:6’,2’’-terpyri-
dine (tpy) as a ligand, with which 76% yield of 3a was ob-
tained at room temperature (Table 1, entry 11).[8d,e] Notably,
even at 0.1 mol% catalyst loading, this system showed signifi-
cant activity (Table 1, entry 12). Next, the methylation of 1a
was investigated in the presence of different silanes (see the
Supporting Information, Table S3). Basically, all tested silanes
proved to be less active than PhSiH3. For example, with poly-
methylhydrosiloxane (PMHS) and Ph2SiH2, 10% and 9% yields
were observed, respectively, and no reaction occurred with
other silanes under the otherwise same conditions. However,
by using phenyl silane and adjusting the amount of dimethyl
carbonate (2a) and reductant to 4 and 5 equivalents, respec-
tively, 96% conversion of 1a was achieved affording dimethyl-
aniline (3a) in 92% yield (Table 1, entry 13). Reaction monitor-
ing over time revealed the formation of 3a in 62% yield in 1 h,
whereas after 4 h the reaction was almost finished (>85%
yield; see the Supporting Information, Scheme S1). In the
meantime, 0.8 mmol of methanol could be produced by
quenching the reaction solution with acidic aqueous solution.
Without amine present, smooth reduction of various carbo-
nates, such as dimethyl carbonate or ethylene carbonate, to
methanol was achieved at room temperature (see the Support-
ing Information, Scheme S2). For example, full conversion was
Scheme 2. Reaction intermediates 4a–6a under catalytic conditions and
species detected from reactivity studies of the Karstedt’s complex with tpy
and PhSiH3.
species could not be detected by ESI-MS, due to strong ion-
suppression effects.[12] The effect of each component ([Pt], tpy,
1a, DMC, PhSiH3) on the chemical speciation was investigated
separately and is summarized in Scheme 2 (see also the Sup-
porting Information, Figures S2–S5). The reaction of Karstedt’s
complex and tpy afforded the [Pt(tpy)(CH2=CHSiMe2)2O)] com-
plex [(CH2=CHSiMe2)2O=1,3-divinyl-1,1,3,3-tetramethyl disilox-
ane].
Upon reaction of Karstedt’s complex with tpy and PhSiH3,
besides the PtII hydride [Pt(tpy)H]+ cation (m/z 429.1), the hy-
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dridoplatinum silyl complex [Pt(tpy)H(PhSiH2)] is also detected
as the proton adduct (m/z 537.1), which supports oxidative ad-
dition of the silane to the Pt0 complex. In this respect, it is in-
teresting to note that hydridometal silyl complexes and imini-
um 6a cations are key intermediates in the Ir–[13] or Pt–silane[14]
mediated reduction of tertiary amides to amines (a transforma-
tion formally corresponding to the 5a to 3a step). Based on
the detection of intermediates 1a–6a, we propose an initial
addition of 1a to DMC to form the carbamate intermediate
4a. Subsequent Pt-catalyzed reduction of 4a by formamide 5a
and iminium cation 6a should afford amine 3a.
Table 2. Pt-catalyzed methylation of amines from DMC.[a]
Entry
Substrate
Product
T
Conv. Yield
[8C] [%][b] [%][b]
1
2
3
4
5
1b
1c
1d
1e
1 f
3b
3c
3d
3e
3 f
RT 93
RT 94
RT 81
RT 88
RT 92
87
93
Meanwhile, a control experiment of the model reaction
using MeOH as the carbon source was carried out. Even at
1008C, no methylated product was formed in the presence of
phenylsilane [Eq. (2)].
(70)
82
90
After investigating the model reaction, the substrate scope
and limitation of various amines were tested (Table 2). In gen-
eral, arylalkylamines showed higher methylation reactivity
compared to diaryl, dialiphatic or primary amines (see also the
Supporting Information, Table S6). When using aromatic secon-
dary amines as substrates, in most cases the methylation reac-
tion worked at room temperature affording the corresponding
N-methylated anilines in up to 94% yield (Table 2, entries 1–9).
However, an increased temperature and higher amount of
DMC (2a) were needed for primary amines, as well as benzylic
and aliphatic amines (58–95% yield; Table 2, entries 10–15).
Notably, the presence of electron-donating or electron-with-
drawing groups in the para position of the aromatic ring in N-
methylanilines did not have a significant influence on the reac-
tivity. Nevertheless, ortho substituents on the aryl ring had
a major steric and electronic influence, lowering the general re-
activity under otherwise the same reaction conditions (Table 2,
entries 5–7).
6
1g
3g
RT 81
81
7
8
1h
1i
3h
3i
RT 57
RT 96
56
94
9
1j
3j
RT 88[c]
(81)
10[d] 1k
11[d] 1l
12[d] 1m
3k
3l
100 89
60 95
(76)
95
3m
100 59
58
13[d] 1n
14[d] 1o
15[e] 1p
3n
3o
3a
100 92
100 89
100 86
92
87
58
Of course, many bioactive amines contain other sensitive
functional groups, such as hydroxy or alkenyl groups. Selective
N-methylation of them might provide a useful route for effi-
cient amine modification in organic synthesis. For example, the
hydroxy group is well tolerated, even after 16 h of reaction
time, and 3q was obtained in 83% yield [Eq. (3)], whereas the
reduction of the unsaturated amine resulted in 3r in 41%
yield.
[a] Reaction conditions (unless otherwise stated): Substrate (0.5 mmol), 2a
(4 equiv), PhSiH3 (5 equiv), nBu2O (1 mL); [b] determined by GC using n-
hexadecane as an internal standard; yields in parentheses refer to isolated
products; [c] determined on isolation of the starting material after reac-
tion; [d] 2a (10 equiv), PhSiH3 (5 equiv); [e] 2a (20 equiv), PhSiH3
(10 equiv).
Selective monomethylation of di- and polyamines is chal-
lenging and often needs careful control of the reaction condi-
tions. As shown in Scheme 3, the desired monomethylated
product 8a was obtained from the heterocyclic diamine 7
(53%) after purification by simple column chromatography.
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change. After the mixture was stirred for 10 min, dimethylcarbon-
ate (169 mL, 2.0 mmol) and PhSiH3 (309 mL, 2.5 mmol) were added,
leading to the formation of a red precipitate, which progressively
disappeared with the fast addition of the amine substrate
(0.5 mmol) and n-hexadecane (50 mL) as internal standard. Next,
the reaction mixture was stirred at room temperature (or up to
1008C) for a given time period, diluted with ethyl acetate (15 mL),
and carefully quenched by aqueous NaOH solution (5 mL, 3m)
with vigorous stirring for 3 h at room temperature. Then, a sample
was taken to be injected into the GC to determine the yield. All
catalytic reactions were performed at least twice to ensure repro-
ducibility. To allow determination of the yields of the isolated me-
thylated amines, no internal standard was added. The mixture was
extracted with ethyl acetate (2”25mL) and the combined organic
layers were died over anhydrous MgSO4. Then, the organic phase
was filtered, concentrated and purified by column chromatography
on silica gel (eluent: n-heptane/ethyl acetate mixtures) to give the
corresponding methylated amines.
Scheme 3. Highly selective monomethylation of 7.
Notably, the main byproduct was the formamide derivative 9
and almost no formation of other methylated products was
observed. It should be noted here that higher methylation re-
activity was obtained for the dialkylamine site, which was fur-
ther established by competitive experiments between 1a and
1n. With respect to the results in Table 2, the presence of di-
alkylamines accelerates the reduction of carbonates to form
silyl methoxides, most likely through interaction with carbo-
nates and/or the Pt center. Hence, in these cases, considering
competitive reductions of the carbon source, higher amounts
of carbonates and higher temperatures were needed to ach-
ieve reasonable N-methylation yields.
Acknowledgements
We thank the state of Mecklenburg-Vorpommern and the
BMBF for financial support. Technical support from Bianca
Wendt is also acknowledged.
Finally, a domino reduction/methylation sequence of form-
amides was investigated. Due to the formation of formamides
as the reaction intermediate, such direct modification should
be possible. Indeed, the reaction of amide 10 at room temper-
ature for 16 h gave the desired product 3a in 77% yield
[Eq. (4)].
Keywords: alkylation · carbonates · platinum · reduction ·
silanes
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Experimental Section
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Chem. Eur. J. 2015, 21, 16759 – 16763
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Received: July 24, 2015
Published online on October 9, 2015
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