Tertiary amine synthesis: Via reductive coupling of amides with Grignard reagents

Article abstract of DOI:10.1039/c7sc03613b

A new iridium catalyzed reductive coupling reaction of Grignard reagents and tertiary amides affording functionalised tertiary amine products via an efficient and technically-simple one-pot, two-stage experimental protocol, is reported. The reaction-which can be carried out on gram-scale using as little as 1 mol% Vaska's complex [IrCl(CO)(PPh₃)₂] and TMDS as the terminal reductant for the initial reductive activation step-tolerates a broad range of tertiary amides from (hetero)aromatic to aliphatic (branched, unbranched and formyl) and a wide variety of alkyl (linear, branched), vinyl, alkynyl and (hetero)aryl Grignard reagents. The new methodology has been applied directly to bioactive molecule synthesis and the high chemoselectivity of the reductive coupling of amide has been exploited in late stage functionalization of drug molecules. This reductive functionalisation of tertiary amides provides a new and practical solution to tertiary amine synthesis.

Full text of DOI:10.1039/c7sc03613b

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Tertiary Amine Synthesis via Reductive Coupling of Amides with
Grignard Reagents
§Received 00th January 20xx,
Accepted 00th January 20xx
Lan-Gui Xie and Darren J. Dixon*
A new iridium catalyzed reductive coupling reaction of Grignard reagents and tertiary amides affording functionalised
tertiary amine products via an efficient and technically-simple one-pot, two-stage experimental protocol, is reported. The
reaction – which can be carried out on gram-scale using as little as 1 mol% Vaska’s [IrCl(CO)(PPh3)2] complex and TMDS as
the terminal reductant for the initial reductive activation step – tolerates a broad range of tertiary amides from
(hetero)aromatic to aliphatic (branched, unbranched and formyl) and a wide variety of alkyl (linear, branched), vinyl,
alkynyl and (hetero)aryl Grignard reagents. The new methodology has been applied directly to bioactive molecule
synthesis and the high chemoselectivity of the reductive coupling of amide has been exploited in late stage
functionalization of drug molecules. This reductive functionalisation of tertiary amides provides a new and practical
solution to tertiary amine synthesis.
DOI: 10.1039/x0xx00000x
www.rsc.org/
Reductive functionalisation of amide functionality to generate
carbon-carbon bonds alpha to nitrogen has also been
demonstrated as a viable approach for amine synthesis.6-8 In
Introduction
Tertiary amines are chemical motifs commonly found in
molecules of importance to chemistry, biology and medicine.
Their Lewis basic properties arising from the lone pair of
electrons make them ideal as ligands for transition metal
catalysts and organometallic complexes. Moreover, the
Brønsted basicity of the tertiary amine moiety has been
exploited extensively for sequestering acidic side products in
coupling reactions, and, in metal-free catalysts exploiting
acid/base equilibria for substrate activation in enantioselective
carbon-carbon bond formation.1 In nature they are often
found contained within alkaloid secondary metabolites
produced by organisms such as bacteria, fungi, and plants.
Classical synthetic routes typically rely on C-N bond forming
reactions such as amine-carbonyl reductive amination, amine
alkylation and C-N cross-coupling.1,2 However, amine synthesis
through carbon-carbon bond formation alpha to nitrogen
offers complementarity especially for accessing α-branched
products, and, as such, the synthetic utility of the Petasis-
Mannich reaction3 as well as the directed amine lithiation /
functionalisation approach of Beak, Hoppe, and others, are
well-documented.4 Furthermore, α-functionalisation of amines
via radical intermediates produced through photoredox
activation have recently been achieved.5
this context, approaches using stoichiometric amounts of
strongly electrophilic reagents, such as Tf2O and POCl3, for
amide pre-activation prior to reductive functionalisation, have
been described9 (Scheme 1, A). Weinreb amides have also
been demonstrated as alternative substrates for reductive pre-
activation, using stoichiometric DIBAL-H or Schwartz’s reagent
(Cp2ZrHCl), affording alkoxy amine products after, for example,
allylation and cyanation reactions in the presence of Lewis
acids for reactive iminium ion formation10 (Scheme 1, B).
Although the above stoichiometric approaches are
demonstrably successful, catalysed variants of these reductive
functionalization processes offer
a number of potential
benefits, especially in terms of chemoselectivity and functional
group tolerance. For example, in presence of Vaska’s complex
and (Me2HSi)2O (TMDS), Chida/Sato11 demonstrated the
formation of hemiaminal intermediates from Weinreb amide
substrates, which with the assistance of stoichiometric
BF3.Et2O, undergo substitution by preformed nucleophiles such
as silyl ketene acetals and allyltin reagents. Our group, and
others, have been exploring amine synthesis through
exploitation of enamine and iminium ion intermediates
formed by catalytic partial reduction of tertiary amides.12 In
this respect, we have reported the iridium catalysed reductive
intramolecular nitro-Mannich reaction of lactams for the
synthesis of bicyclic nitroamines, and the broad-scope iridium
catalysed reductive Strecker reaction of tertiary amides for the
efficient synthesis of α-amino nitrile products.
[*]
Dr. L.-G. Xie, Prof. Dr. D. J. Dixon
Department of Chemistry, Chemistry Research Laboratory
University of Oxford
Mansfield Road, Oxford OX1 3TA, UK.
E-mail: darren.dixon@chem.ox.ac.uk
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benzoylamide with benzyl magnesium chloride.a
A) Preactivation approaches
O
OX
R4H
R4M
Tf2O or P2O5
R2
R2
R2
R1
N
R1
N
R1
N
R3
activation
reagents
R3
then [H]
R3
B) Stoichiometric approaches:
Entry
Cat.
loading
(mol %)
Solvent
Concentration
(M)
Yield
(%)b
O
M
R3H
O
R3M
DIBAL
OMe
R1
N
OMe
H
OMe
R1
N
R1
N
R2
R2
R2
or Cp2ZrHCl
Lewis acid
1
2
3
4
5
6
7
8
1
tetrahydrofuran
toluene
CH2Cl2
0.05
0.05
0.05
0.05
0.05
0.1
54
C) This work:
1
64
R4H
cat. IrCl(CO)(PPh3)3
TMDS
O
R4MgX
O[Si]
R2
R2
R2
R1
N
R1
N
R1
N
1
82
R4 = Alkyl, vinyl,
R3
R3
R3
alkynyl, (hetero)aryl, etc
3.3
0.5
1
CH2Cl2
85
broad (sp, sp2, sp3) carbon nucleophiles
functionalised Grignard reagents
drug-molecule synthesis
late-stage functionalisation
user friendly
CH2Cl2
53
chemoselective
95 (89)c
35
Scheme 1. Reductive functionalisation of amides with carbon-centered
nucleophiles.
CH2Cl2
1
CH2Cl2
0.025
0.5
In a continuation of our program, and with the ultimate aim of
expanding the range of amine products accessible using the
two stage reductive activation approach, we considered a
reductive coupling of tertiary amides and Grignard reagents
(Scheme 1, C). Grignard reagents are widely available
commercial organometallic reagents and are simply and
reliably prepared in the laboratory. Similarly, tertiary amides
are commonly found in biologically active natural products and
drug compounds, and are widespread throughout
pharmaceutical and agrochemical companies. When combined
with the ease at which they can be prepared through standard
amide coupling reactions,13 a mild reductive coupling protocol
that could efficiently and chemoselectively target this
functional group to generate tertiary amine products from
Grignard reagents would likely find numerous applications in
preparative scale synthesis, library generation, late-stage
functionalisation, and total synthesis alike. Herein we wish to
report our findings.
1
CH2Cl2
80
aReactions were performed on 0.3 mmol of amide; bNMR yields with 3,5-
dibromoanisole as internal standard; cIsolated yield.
With optimised conditions in hand the scope of the reductive
benzylation reaction with respect to the tertiary amide was
assessed (Scheme 2). Benzoylamides derived from cyclic
amines pyrrolidine, azepine, azocane, morpholine and 6,7-
dimethoxytetrahydroisoquinoline respectively, all furnished
the target tertiary amines (2-6) in good to excellent yields (70-
90%). Methylbenzylbenzoylamide was also a good substrate
yielding benzylamine (7) in excellent yield and thus expanding
the potential application of the protocol to secondary amine
synthesis via subsequent hydrogenolysis. The Weinreb amide
of benzoic acid was an excellent substrate and afforded α-
benzylated methoxyamine product
8
in 87% yield.
Methylaniline derived benzoyl amide was also amenable to
reductive benzylation, and furnished a substituted aniline
Results and discussion
product 9. The acceptable yield of 57% in this case required
the use of an increased loading of Vaska’s complex (5 mol%) in
the initial reductive activation step to overcome diminished
substrate reactivity. Great tolerance with respect to the arene
moiety of the dimethylamide was witnessed under the
optimised reaction conditions. Thus electron deficient,
electron-rich and halogen-substituted benzoic acid derivatives
gave the respective tertiary amine products (14-18) in yields
ranging from 84 to 97%. Similarly a 2-furanyl substrate gave
the desired amine product (19) in 94% yield. Aliphatic dimethyl
amides, derived from n-decanoic acid, cyclohexane carboxylic
acid and pivalic acid were all good substrates for the reductive
alkylation protocol and yielded tertiary amine products 10-12
in respectable yields. N-Formyl piperidine was also an
excellent substrate and gave product 13 in 82% yield. The
ability to dialkylaminomethylate organomagnesium reagents
using tertiary formamides should find many synthetic
We chose the reductive benzylation of dimethyl benzoylamide
as a model reaction and selected Vaska’s catalyst and
tetramethyldisiloxane (TMDS) for the key reductive activation
step (Table 1). Initial investigations employing THF or toluene
as the reaction solvent were encouraging; in both cases a two-
stage protocol – where the reductive activation step (using 1
mol% Vaska’s catalyst and 2 eq of TMDS) was allowed to run to
completion prior to addition of benzylmagnesium chloride (1
M in THF) – afforded moderate yet encouraging yields of the
desired tertiary amine
1 (entry 1 and 2). Further studies
identified dichloromethane as the solvent of choice and the
ideal concentration of amide starting material to be 0.1 M.
Following optimisation, our two-stage one-pot protocol
enabled the synthesis of
1 in 89% isolated yield after flash
column chromatography (entry 6).
applications
within
target
synthesis,
methodology
Table 1. Discovery and optimization of reductive functionalisation of dimethyl
2 | J. Name., 2012, 00, 1-3
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development and drug discovery programs. Unfortunately, amount of Grignard reagent in the second stage was lowered
under the current reaction conditions, reductive coupling of to 1.2 equivalents and the reaction temperature kept below 0
lactams with Grignard reagents were not successful.14
°C. The ability to tolerate halide functionality and pinacol
Despite the use of a relatively reactive organometallic coupling boronate esters establishes this transformation as fully
partner (BnMgCl) the functional group tolerance of the compatible with other cross-coupling reactions, indicating its
reductive functionalisation reaction was found to be high. potential for the synthesis of amine derived building blocks.
Nitrile, aryl ketone, pinacol boronate ester, tert-butyl
carbamate and ester functionality all survived when the
Scheme 2. Scope with respect to the tertiary amide. Standard condition: amide 0.3 mmol, IrCl(CO)(PPh3)2 1 mol%, TMDS 0.6 mmol, CH2Cl2 3 mL, BnMgCl 0.6
mmol; isolated yields are given; Bpin = pinacol boronate; Boc = t-Butyloxy carbonyl. a5 mol% of IrCl(CO)(PPh3)2 was used; bperformed at 0 ˚C for 6 h after the
addition of BnMgCl (1.2 eq.); cPd/C catalysed hydrogenolysis of the N-benzyl group was performed on the tertiary amine product and overall yield is given.
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To demonstrate the synthetic utility of this newly developed yield using phenylmagnesium bromide in the carbon-carbon
reductive carbon-carbon bond forming methodology, we bond-forming step.
selected several amine-containing drug molecules as targets. Encouraged by the high reactivity of the silylated hemiaminal
NMDA
receptor
antagonists,
diphenidine
(25), intermediates towards organomagnesium reagents, we then
methoxphenidine
(
26
)
and fluorolintane (
27), which are chose to apply Knochel-type Grignard reagents to the new
generally used as dissociative anesthetics,15 were obtained reductive carbon-carbon bond forming methodology. The
directly and efficiently by submitting the corresponding and diversity of organomagnesium reagents accessible by the
readily prepared parent amides to the standard protocol. Knochel procedure is impressive and would therefore boost
Likewise ephenidine (28), a secondary amine drug molecule,16 the nature and type of amine products accessible using this
was synthesised by partial hydrogenolysis of the initially approach.19 To this end, para-trifluoromethylphenyl
generated tertiary amine from its benzylethyl benzoylamide organomagnesium reagent, prepared by magnesium/iodide
precursor, in 67% yield over the two steps. Furthermore, exchange with isopropylmagnesium bromide, was investigated
piperazine-derived opioid analgesic drug MT-4517 was in the reductive arylation of the pyrrolidine amide of benzoic
prepared in near quantitative yield.
acid and indeed was found to be compatible with our protocol,
The scope with respect to the Grignard reagent was also found yielding 39 in 65% yield. Similarly a range of aryl and
to be broad. As depicted in Scheme 3, methyl, linear-alkyl and pyrimidine-based heteroaryl Knochel-type Grignard reagents
branched-alkyl magnesium reagents were compatible with this were successfully generated, then reacted with
N-formyl
protocol and yielded amine products (30-32) in good to piperidine following our standard protocol, furnishing
excellent yields. (Trimethylsilyl)methylmagnesium chloride was homologated amine products (40-42) in satisfactory yields.
also an excellent reagent for new carbon-carbon bond Furthermore, organomagnesium reagents derived from α-D-
formation under the standard conditions. Importantly, a glucofuranose and cholesterol derivatives using the Knochel
reductive methylation of N,N-dimethyl-
carried out on gram scale following the standard protocol and The synthetic utility of this chemistry was further
afforded methylated product 34 in 85% yield. Reductive demonstrated through the late stage reductive
p-toluamide was procedure were also compatible.
vinylation using vinylmagnesium bromide and reductive functionalisation of drug molecules. Thus, piperine20 (an
alkynylation using hexynyl magnesium bromide yielded extract of black pepper used as traditional medicine and
allylamine 35 and propargylamine 36 in 74% and 86% yield, insecticide) was successfully modified by benzylation (45, 93%)
respectively. Phenyl magnesium bromide was also found to be and butenylation (46, 83%). Also, the psychoactive drug
a competent nucleophilic coupling partner and afforded fipexide21 underwent
a reductive coupling reaction with
benzylic tertiary amine product 37 in 66% respectively. benzylmagnesium chloride affording 47 in 73% yield. While by
Reductive phenylation [or (hetero)arylation] of amides will magnesium/proton exchange of the acetylenic proton of
likely find many applications within the pharmaceutical sector pargyline22 (an irreversible selective monoamine oxidase MAO-
and here we have exemplified it through the synthesis of the B inhibitor) and then homologation with N-formyl piperidine,
antiemetic piperazine-containing drug cinnarizine (38).18 Using amine derivative 48 was obtained in 54% yield.
the two-step protocol 38 was successfully synthesised in 67%
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1 mol% IrCl(CO)(PPh3)2
O
R
2.0 eq. RMgX
O[Si]
N
R3
2.0 eq. TMDS
R2
R2
R2
R1
N
R3
R1
N
R2
R1
H
CH2Cl2 0.1 M
rt, 20 min
-78 °C to rt, 4 h
Alkyl, vinyl and alkynyl Grignard reagents
Me
Si
N
Me
N
N
N
N
N
N
32, 52%
dr 1:1
34, 85%a
36, 86%
33, 84%
35
, 74%
30, 64%
31, 88%
Phenyl and functionalised (hetero)aryl Grignard reagents
N
N
N
N
N
N
N
N
N
Cl
EtOOC
Cl
N
Cl
N
F3C
39, 65%b,c,d
Cinnarizine
40, 85%b,c,d
41, 74%b,c,d
37
42, 86%b,c,d
, 66%
38, 67%
O
O
O
O
O
H
H
H
O
O
H
H
O
N
N
44, 51%b,d,e
43, 46% b,e
Late stage functionalisation of drug molecules
N
O
O
O
N
O
N
N
N
N
O
O
O
Cl
c
48
, pargyline derivative, 54%
47, fipexide derivative, 73%
46, piperine derivative, 83%
45
, piperine derivative, 93%
Scheme 3. Scope with respect to the Grignard reagent. Standard condition: amide 0.3 mmol, IrCl(CO)(PPh3)2 1 mol%, TMDS 0.6 mmol, CH2Cl2 3 mL, RMgX 0.6
mmol; isolated yields are given. aPerformed on 1.01 gram of amide with no additional optimisation; bGrignard reagent prepared by Mg/I exchange with i-PrMgBr;
cwith 1.5 eq. Grignard reagent; dperformed at 0 ˚C for 6 h after Grignard reagent addition; eyield based on Grignard reagent (0.67 eq).
methodology should find many synthetic applications in
research laboratories within both industry and academia.
Conclusions
A new two-stage, iridium catalysed reductive coupling of
Acknowledgements
tertiary amides and Grignard reagents has been developed.
Due to its good functional group tolerance, high We thank Marie Curie Actions for a fellowship to L.-G.X. (H2020-
MSCA-IF-2015, 707559). We also thank Heyao Shi, Dr. Angel L.
Fuentes de Arriba, Dr. Amber L. Thompson and Dr. Kirsten E.
chemoselectivity and broad scope with respect to both the
amide and Grignard coupling partners, this new and practical
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O
Ph
N
N
O
Me
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1-methylquinolin-2(1H)-one
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