C-Alkylation of N-alkylamides with styrenes in air and scale-up using a microwave flow reactor

Article abstract of DOI:10.1039/c8ob02282h

C-Alkylation of N-alkylamides with styrenes is reported, proceeding in ambient air/moisture to give arylbutanamides and pharmaceutically-relevant scaffolds in excellent mass balance. Various amide and styrene derivatives were tolerated, rapidly affording molecular complexity in a single step; thus highlighting the future utility of this transformation in the synthetic chemistry toolbox. Reaction scalability (up to 65 g h^-1 product) was demonstrated using a Microwave Flow reactor, as the first example of a C-alkylation reaction using styrenes in continuous flow.

Full text of DOI:10.1039/c8ob02282h

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DOI: 10.1039/C8OB02282H.
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PAPER
C-alkylation of N-alkylamides with styrenes in air and scale-up
using a microwave flow reactor
Joshua P. Barham,*a,b Souma Tamaoki,a Hiromichi Egami,a Noriyuki Ohneda,b Tadashi Okamoto,b
Hiromichi Odajima,b and Yoshitaka Hamashima*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
C-alkylation of N-alkylamides with styrenes is reported, proceeding in ambient air/moisture to give
arylbutanamides and pharmaceutically-relevant scaffolds in excellent mass balance. Various amide and
styrene derivatives were tolerated, rapidly affording molecular complexity in a single step; thus highlighting
the future utility of this transformation in the synthetic chemistry toolbox. Reaction scalability (up to 65 g/h
product) was demonstrated using a Microwave Flow reactor, as the first example of a C-alkylation reaction
using styrenes in continuous flow.
rsc.li/obc
well known.10 Pines first reported the addition of
alkylpotassiums generated from alkyl-substituted heterocycles
(pyridines/pyrazines/thiophenes) to styrenes and the addition
of alkylpyridines to styrenes was extended in a recent report.11
Introduction
Synthesis of amides is fundamentally important in organic
chemistry and particularly within active pharmaceutical
ingredients (APIs).1-5 Amide synthesis from reactions of
carboxylic acids and amines involves pre-activation of the
carboxylic acid2 or generation of an activated intermediate in
situ by use of a coupling agent.3 Though highly versatile and
general, such bond formations typically require inefficient,
often expensive and hazardous reagents and generate large
quantities of waste.4 To this end, elegant catalytic methods
have been recently reported for direct condensation of amines
with carboxylic acids.5,6 However, novel and scalable methods
for amide synthesis are still desirable.7 A complementary
strategy is functionalization of simple amide feedstocks.
Knochel reported KOtBu-mediated α-C alkylation of nitriles,
imines and ketones to styrenes (Figure 1B).12 Almost five
decades ago, Pines et al. reported a curious KOtBu-mediated
transition metal-free C-alkylation of N-methyl-2-pyrrolidinone
(NMP) or N-methyl-2-piperidone with styrenes, which gave
rise to amide-styrene monoadducts and bisadducts depending
Previous reports
A. Addition of alkyllithiums to styrenes
Li
B. Addition of ketones, nitriles and alkyl-substituted heterocycles to styrenes
Historically, functionalization of amide
α-C positions is
R2
O
achieved via deprotonation employing a strong base (LDA,
BuLi, see Figure 1A),8 followed by C-alkylation, but these highly
reactive bases require handing under inert atmosphere,
moisture-free conditions at cryogenic temperatures. Related
to this is the potassium base-mediated addition of amides (and
cat. KOtBu
R'
CN
H
R1
R1
,
R2
R2 = alkyl
R''
R1
=
This work
N
C. Addition of alkylamides to styrenes
O
similar compounds) to
α,β-unsaturated carbonyl compounds,
R3 R2
N
reported by Kobayashi et al.,9 according with the natural
electronics. In this context, styrenes represent an interesting,
underexploited class of ‘electrophile’, because they are
electron-rich.
H
R1
cat. KOtBu
R1
(+ bisadduct)
N
R3 R2
R1, R2 = alkyl
O
R3 = H, alkyl, aryl
D. Pharmaceuticals containing an arylbutanamide core (top 200 by retail sales, 2016)
CF3
O
Addition of premade alkyllithium compounds to styrenes is
NH
O
O
F
F
N
O
NH
O
N
O
N
N
O
N
HN
HN
NH2
O
F
Sitagliptin
Carfilzomib
Fig. 1 Addition of carbanions to styrenes and pharmaceutically-relevant
compounds.
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on the conditions employed.13 The reaction appears to concentration of
Organic & Biomolecular Chemistry
2
to 0.23 M in DMA gave little selectivity
proceed via addition of a potassium amide enolate to styrene. improvement for 4a whilst addition of solubilizing agent 18-
For the two cyclic amides aforementioned, the constrained crown-6 drastically decreased 4a selectivity and allowed the
molecular geometry allows reactions to proceed compared to: reaction to proceed at rt. A control reaction with 18-crown-6
i) 7-membered cyclic amide N-methylcaprolactam (NMC), only gave no reaction. Interestingly, NaOtBu effected
o
which gave no reaction, ii) open-chain amides, which were not successful reaction in the presence of 18-crown-6 at 80 C but
reported by Pines. Aside from the two cyclic amide substrates not at rt. Control reactions (see ESI) revealed the reaction was
reported by Pines, this reaction has since featured merely as a shut down by addition of protic sources EtOH (10 eq.) or BHT
low-yielding (<10%) undesired side-reaction.12 The substrate (1 eq.) and was unaffected by light exclusion.
scope of this reaction in the amide and styrene coupling
partner had yet to be established. Moreover, for C-alkylations
with styrenes to be industrially viable in general, they require
proof of scalability yet multigram-scale and continuous flow
applications have not been reported. We reasoned use of
elevated reaction temperatures and additives (e.g. 18-crown-
6) may increase the reactivity of the potassium enolate,
allowing a wider scope of amide substrates to react. Herein,
we report a versatile C-alkylation of alkylamides using styrenes
Fig. 2 Preliminary studies of a transition metal-free Heck reaction in DMF vs.
DMA solvent and control reactions.
(Figure 1C) proceeds under ambient air and moisture in
excellent mass balance, under readily accessible conditions
Table 1 Optimization of C-alkylation Reaction of DMAa
and is scalable up to 65 g/h in continuous flow. This method
provides convenient and unique access to arylbutanamides;
pharmaceutically relevant cores (present, for example, in
Sitagliptin and Carfilzomib, Figure 1D).14
Entry
1b
Deviation from Reaction Conditions
Yield (%)a
4a 4b
Results and discussion
KOtBu (0.6 eq.), 80 oC, 1.90 M 2 in DMA (4.5
eq.), under Ar
39 51
[36] [47]
77 15
Preliminary results came serendipitously from studies of a
transition metal-free Heck reaction, reported by Shirakawa et
al. (Figure 2).15 Based on recent advancements in the
KOtBu (0.6 eq.), 80 oC, under Ar
2
3
KOtBu (0.6 eq.), 80 oC
KOtBu (1.5 eq.), 80 oC
KOtBu (3.0 eq.), 80 oC
KOtBu (1.5 eq.), rt
71 16
72 21
63 16
mechanistic understanding of reaction classes, it is likely that 4c
the solvent, DMF, undergoes deprotonation by KOtBu at
5
elevated temperature, leading to trace amounts of carbamoyl
23
2
6
7b
anions which ultimately initiate radical chain reactions of
haloarenes via single electron transfer.16,17 We elected to
KOtBu (1.5 eq.), 80 oC, 0.23 M 2 in DMA (47
75 11
[77] [7]
48 36
eq.)
examine the impact of DMA as solvent on the reaction, which
is blocked to formation of the carbamoyl anion.18 The reaction
8
KOtBu (1.5 eq.), 80 oC, 18-crown-6 (1.5 eq.)
KOtBu (1.5 eq.), rt, 18-crown-6 (1.5 eq.)
No base, 80 oC, 18-crown-6 (1.5 eq.)
NaOtBu (1.5 eq.), 80 oC
in DMA solvent gave a decreased yield of
3 (16%) compared to
9
39 45
DMF (49%) in our hands (Figure 2), but additionally yielded 4a
and 4b. Products 4a and 4b were favored by omission of EtOH
10
11
12
13
0
5
0
and iodoarene 1. Hence, heating a mixture of styrene and
0
KOtBu (0.6 eq.) in DMA gave 4a (39%) and 4b (49%) (Table 1,
entry 1). Here, we realized the opportunities to exploit this
curious reaction as an unconventional route to the synthesis of
arylbutanamides and hence began investigating the reaction
optimization. Selectivity for monoadduct 4a was promoted by
NaOtBu (1.5 eq.), 80 oC, 18-crown-6 (1.5 eq.)
NaOtBu (1.5 eq.), rt, 18-crown-6 (1.5 eq.)
65
0
9
0
Unless otherwise stated, reactions were conducted using 1.15 mmol
2
(0.50 M)
in DMA (25.0 eq.) and sealed under an air atmosphere. aYields determined by 1H
NMR (isolated yields in parenthesis). bYields are consistent with isolated yields,
decreasing concentration of
2 to 0.50 M in DMA. The reaction
see ESI. cAverage of 3 replicates, identified as conditions
A.
was almost unaffected by running under air instead of Ar.
KOtAm, KHMDS, NaHMDS and KOH were similarly effective
whilst NaOtBu, KF, K2CO3 and strong organic bases DBU and
DABCO gave no reaction (see ESI). That KOH was equally
effective as KOtBu may explain reaction tolerance to ambient
air/moisture, to which KOtBu is sensitive. The reaction was
sluggish at rt, highlighting the importance of elevated
temperature for reactions of open-chain amides compared to
room-temperature conditions reported by Pines. Decreasing
A range of both acyclic and cyclic alkylamides were
tolerated by the reaction with styrene (Figure 3), affording
good to excellent yields (72 - 91%) of monoadducts under
conditions
successfully despite the potential steric hinderance provided
by an -methyl-substituent, giving excellent selectivity for
A (Table 1, entry 4). The reaction proceeded
α
monoadduct 6a in 98% yield. When DMA was used as the
amide partner reacting with different styrenes, the reaction
2 | Org. Biomol. Chem., 2018, 00, 1-3
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electron-rich styrenes and their loss to thermal
polymerization. Electron-deficient styrenes afforded better
mass balance, yet selectivity shifted toward bisadducts. The
reaction proceeded using NMP,13 giving rise to monoadduct
(
14a) in notably higher selectivity than reactions using DMA.
Further studies revealed NMP was more reactive than DMA,
and that reactions proceeded smoothly in the presence of 18-
crown-6 (either with KOtBu or NaOtBu base) as a solubilizing
agent (see ESI for full investigations, including co-solvent
evaluation to allow amide equivalents to be decreased). An N-
benzyl group was tolerated as seen in the successful formation
of
16a
.
Interestingly,
the
N-methyl-substituted
diketopiperazine (sarcosine anhydride), oxindole and
caprolactam derivatives gave excellent yields and perfect
selectivity for the monoadducts 17a, 18a and 19a. Notably, our
conditions gave successful reaction of N-methylcaprolactam
which gave no reaction under conditions reported by Pines.13
A surprising and notable example was sarcosine anhydride,
which potentially could form up to
5 products, yet
monoadduct 17a was afforded as the sole product. As opposed
to acyclic amide DMAc, reactions of cyclic amide NMP as the
amide partner were insensitive to the electronics of the
styrene. Styrene, 4-methoxystyrene and 4-fluorostyrene gave
14a/14b, 20a/20b and 21a/21b in almost identical yields,
ratios and in >97% mass balance. Presumably, the higher
reactivity of NMP relative to DMAc outcompetes deleterious
side-reactions. We postulated whether the monoadduct
product could be re-subjected to the reaction conditions using
a different styrene partner to afford a compound with
interesting 3D geometry and
a differentially-substituted
quaternary center. To our delight, monoadduct 14a (2.0 eq.)
reacted with 4-fluorostyrene 22 (1.0 eq.) in DMSO solvent to
afford compound 23 in the presence of 18-crown-6 (1.5 eq.).
Notably, the addition of 18-crown-6 increased the reactivity
such that only 2.0 eq. of amide 14a were required to obtain 23
in good yield. This is important, since the absence of 18-crown-
6 necessitates high loadings of amide (15 - 25 eq.) in order for
reaction completion and satisfactory yields, which is
inefficient. Though the amide partners herein are readily
available and inexpensive, further optimisation of conditions is
necessary to decrease the amide loading for future application
of this method to complex systems (Figure 1D). A challenge is
that i) stoichiometric loadings of amide result in sluggish
conversion ii) 18-crown-6 increases the reactivity but
promotes the selectivity towards the bisadduct (see ESI for full
investigations of the reaction optimisation).
Fig. 3 Substrate scope for conditions A varying amide and styrene
components. Isolated yields are shown in parentheses. *Reaction performed
using
2
in 0.35 M DMSO and using 15 eq. of amide substrate.
Fig. 4 Reaction of product 14a with a different 4-fluorostyrene. Isolated yields
are shown in parentheses.
appeared to be sensitive to electronic variations in the styrene.
Monoadducts were observed in modest to high yields (36 -
78%), the reactions proceeded in variable mass balance (51 -
95%) and variable selectivity (1 : 0.06 to 1 : 0.60 mono- : bis-
adduct). Whilst 4-vinyltoluene smoothly afforded 8a/8b, 4-
vinylanisole which is more electron-rich afforded 7a in
excellent selectivity but mass balance was only 51%. Other
We sought to demonstrate reaction scalability via flow
processing (Table 2). Flow processing is globally recognized as
a promising technology within the pharmaceutical19-21 and
fine/commodity22 chemical industries. The NaOtBu/18-crown-
6 combination was found to be most suitable for flow due to
solubility. In batch mode, conditions gave high selectivity for
o
monoadduct 14a at 80 C but the reaction did not proceed at
electron-rich styrenes, such as
α
-methylstyrene,
β-
methylstyrene (see ESI) and 4-methyl-5-vinylthiazole gave low
rt.
A commercially available and previously reported
microwave (MW) flow reactor was employed.23 At rt, no
reaction was observed in flow. At 140 oC, a residence time (RT)
1
yields or failed to afford detectable products by H NMR. Such
results are attributed to the slower desired reaction of the
of 3 min gave yields of 14a/14b which matched those of the
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Organic & Biomolecular Chemistry
batch conditions, yet the g/h productivity was ca. 100 times oxygen), which undergoes protonation to form monoadduct
higher in flow.24 The optimum conditions for yield and 4a. Monoadduct 4a reacts with a second molecule of styrene
productivity were identified; affording 14a in 73% (64.9 g/h) via the same mechanism to afford bisadduct 4b. Alternatively,
and 14b in 7% (9.4 g/h). These conditions (RT = 0.4 min, T = 180 intramolecular proton transfer from the
α-position gives a
oC) were employed for 5 min in a multigram-scale reaction, potassium enolate which enters the catalytic cycle. Addition of
affording 5.2 g of 14a (70%) after work-up and isolation. styrene at the benzylic position of 24 to give oligomers was not
Results show a remarkable increase in productivity and observed.27 A radical mechanism was deemed unlikely due to
scalability opportunities in moving from batch to flow. MW the outcomes of experiments involving 1.0 eq. of radical traps
heating allowed the elevated temperatures necessary at such TEMPO and Galvinoxyl radical (see ESI for full details).
short residence times to sustain high yield and bolster
productivity at the reaction step. The benefits of MW towards
Conclusions
rapid, uniform heating and expedition of reaction optimization
have been previously disclosed.23
We report C-alkylation of alkylamides using styrenes to give a
Table 2 Reaction Scale-up using a Microwave Flow Reactor.a
range of pharmaceutically-relevant arylbutanamide scaffolds.
This underexploited reaction rapidly builds molecular
complexity, proceeds in excellent mass balance (with respect
to the styrene) and generally provides monoadducts
selectively and in good yield. Scalability was demonstrated in a
commercially available MW flow reactor. To our knowledge,
this is the first example of a C-alkylation reaction using
styrenes as the ‘electrophile’ in flow. Further studies are
ongoing in our laboratory.
Entry
RT
Tempb
Yield (%)c,d
Productivity (g/h)e
[method] (min) (oC)
14a
14b
14a
14b
1 [B, T]f
2 [B, T]
120
120
25
0
0
-
-
Conflicts of interest
80
88
0
10
0
0.10
-
0.02
-
There are no conflicts to declare.
3 [F, MW] 3.0
4 [F, MW] 3.0
5 [F, MW] 0.4
25
Acknowledgements
140
87
8
9.49
1.32
The authors gratefully acknowledge financial support from the
subsidy program for innovative business promotion of
Shizuoka Prefecture, Japan SAN-Pro, the Japan Trust
International Research Cooperation Project and the University
of Shizuoka.
180
73 [70] 7 [3] 64.86
9.40
aB, batch (
2, 0.45 M in NMP); reaction time (min) is shown in parenthesis. T,
thermal heating for 2 h reaction time (see ESI). F, flow (2, 0.44 M in NMP). MW,
microwave heating. RT, residence time. bReaction temperature measured at the
reactor tube exit upon reaching steady-state. cYield determined by 1H NMR
spectroscopic analysis of the crude reaction mixture using 1,3,5-
trimethoxybenzene (10 mol%) as an internal standard, see ESI for details.
dIsolated yields in parentheses; 5.17 g of 14a and 0.32 g of 14b isolated after
employing entry 5 conditions for 5.0 min. eBatch productivities are calculated
from NMR yield and total reaction time. Flow productivities are calculated from
NMR yield and flow rate. f1.5 eq. of NaOtBu was used.
Notes and references
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Proposed reaction mechanism.
A plausible reaction mechanism is proposed in Figure 5.
Deprotonation of DMA (pKa = 29.4 in H2O)25 by KOtBu (pKa
tBuOH = 16.6 in H2O)26 occurs via an equilibrium (heavily
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24 See ESI for step-by-step optimization of the reaction towards
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times showed this effect but bis-alkylation could not be
completely overcome within the range of flow rates
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