Photoredox-initiated α-alkylation of imines through a three-component radical/cationic reaction

Article abstract of DOI:10.1002/chem.201103062

Radical-polar crossover reaction: The photoredox-mediated alkylation of enamides with diethyl bromomalonate in the presence of alcohols has been developed. This multicomponent domino process affords β-alkylated α-carbamido ethers as stables imine surrogat

Full text of DOI:10.1002/chem.201103062

COMMUNICATION
DOI: 10.1002/chem.201103062
Photoredox-Initiated a-Alkylation of Imines through a Three-Component
Radical/Cationic Reaction
Thibaut Courant and Gꢀraldine Masson*[a]
The a-alkylation of imines is a valuable carbon–carbon
bond-forming strategy, which is still an underdeveloped
area[1–3] despite the synthetic potential of its a-branched
resulting alkyl radical 5 reacts with enamide 1 to produce a-
amidoalkyl radical 6. The oxidative radical-polar crossover
reaction[15] then furnishes an N-acyliminium cation 7, which
can be trapped by a suitable nucleophile. Alcohol 3 was the
nucleophile of choice to generate b-alkylated a-amido ether
4, which is a stable precursor of a-alkylated imines[16,14f] and
can be found in a number of biologically important natural
products.[17,18] To initiate this radical/cationic domino pro-
cess, a free-radical redox initiator, which was compatible
with the nucleophile, was selected. As visible-light photore-
dox catalysis[19] has emerged as an efficient tool to promote
single-electron-transfer (SET) redox transformations since
the success of MacMillan et al.,[20] Yoon et al.,[21] Stephenson
et al.,[22] and others,[23] environmentally friendly photoredox
catalysts were chosen.[24]
imine products.[4] The direct C H bond functionalization of
À
imines with alkyl halides has proven challenging, owing to
competing side reactions, such as Mannich condensation, N-
alkylation, and hydrolysis.[1,5] The indirect approach, based
on the intermolecular nucleophilic alkylation reaction of en-
amine[6] or enamide[7] derivatives, was not found to be more
efficient. Moreover, the only corresponding products report-
ed were a-alkylated carbonyl compounds.[8] To the best of
our knowledge, there is no efficient method for the prepara-
tion of a-alkylated imines. Herein, we disclose a novel a-al-
kylation reaction of imines, which can be achieved by photo-
À
redox-mediated direct intermolecular C H functionalization
of enamide derivatives, involving a radical/cationic domino
process.
Initial studies focused on examining the reaction of (E)-
benzyl prop-1-enylcarbamate (1a), diethyl bromomalonate
(2a), and ethanol (3a) in the presence of Et3N (2 equiv),
Recently, Friestad et al.[9] reported an interesting tin-
mediated, non-reductive radical alkylation of tertiary enam-
ides, forming two-carbon-elongated homologues by oxida-
tion and proton transfer through N-amido radical intermedi-
ates.[10–12] Based on this, we envisaged that the same radical/
cationic process in the presence of a nucleophile might pro-
vide an expedient synthesis of a-alkylated imines. The prin-
ciple of this multicomponent domino process is depicted in
Scheme 1.[13,14] After radical reduction of alkyl halide 2, the
[RuACTHNURTGNE(NUG bpy)3]Cl2 (8, 1.5 mol%, bpy=bypyridine), and light
from a 25 W compact fluorescent lamp. As described in
Table 1, we were able to obtain the desired three-compo-
nent adduct 4a as a 3:2 mixture of diastereomers, although
the reaction was not clean. To optimize the reaction, differ-
ent photoredox catalysts, alcohols, and solvents were
screened. To our delight, a change from Ru-containing pho-
tocatalyst 8 to [IrACHTNUTRGENNUG(ppy)2ACHTUGNTREN(NUNG dtbbpy)]PF6 (9, dtbbpy=4,4’-di-tert-
butyl-2,2’-dipyridyl) gave the product in higher yield (79%,
Table 1, entry 1 vs. 2). The change in the nature of the base
(DIPEA=N,N-diisopropylethylamine instead of Et3N) low-
ered the yield (entry 3). The reaction proceeds in various
solvents, except DMF. Dichloromethane was found to be
the solvent of choice regarding both the yield and the reac-
tion rate to give product 4a in almost quantitative yield
within 3 h (entry 7). A reduced reaction time to less than
1 h was observed under the same conditions, but in sunlight
(entry 7 vs. 8). Additional alcohols, namely MeOH and
iPrOH, were also found to be suitable nucleophiles, albeit
slightly lower in yield, to give the corresponding b-alkylated
a-carbamido ethers 4b and 4c, respectively (entries 11 and
12).
Scheme 1. Rational design for a three-component radical/cationic reac-
tion of enamide 1, alkyl halide 2 and alcohol 3.
[a] T. Courant, Dr. G. Masson
Centre de Recherche de Gif
After having identified the optimal conditions of the
three-component radical/cationic process, the scope of the
enamide substrates 1 was investigated (Table 2). We were
pleased to find that the reaction conditions developed were
applicable to a range of enamides to provide good to excel-
lent yields of a-alkylated imine adducts 4 in short reaction
Institut de Chimie des Substances Naturelles CNRS
Avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex (France)
Fax : (+33)1-6907-7247
E-mail: masson@icsn.cnrs-gif.fr
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201103062.
Chem. Eur. J. 2012, 18, 423 – 427
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
423

Table 1. Survey of reaction conditions for the photoredox-initiated three-
component radical/cationic reaction.
Table 2. Photoredox-initiated alkylation of enamide derivatives.
Entry
1
Product
4
Yield [%]/ACHTUNGTRENNUNG
(d.r.)[a,b,c]
Entry
3
Cat.
Solvent
Et3N
[equiv]
4
t [h]
Yield [%][a,b]
4d
>99 (1:1)
AHCTUNGTRENNUNG
1
2
3
4
5
6
7
8
9
3a
3a
3a
3a
3a
3a
3a
3a
3b
3b
3b
3c
8
9
9
9
9
9
9
9
9
9
9
9
CH3CN
CH3CN
CH3CN
toluene
EtOH
2
2
4a
4a
4a
4a
4a
4a
4a
4a
4b
4b
4b
4c
24
12
12
12
12
12
3
1
1
1
1
60
79
65
79
78
2
3
4e
4 f
95 (3:2)
84 (1:1)
2[c]
2
2
2
2
2
–
1
2
2
DMF
0[d]
>99
>99[e]
–
–
88
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
4
4g
92 (1:1)
10
11
12
5
6
4h
4i
62
1
62
[a] Reaction conditions: enecarbamate 1a (0.1 mmol), diethyl 2-bromo-
malonate (2a, 0.2 mmol), 3 (1.0 mmol), 8 or 9 (0.001 mmol), c=0.10m at
RT. [b] Isolated yield after column chromatography. [c] Et3N was re-
placed by DIPEA. [d] Non-reductive, radical-alkylated enecarbamate
was isolated. [e] Sunlight was used.
60 (1:1)
7
4j
45 (1:1)
times (1 to 3 h). It is worth noting that no side products,
such as homocoupling products or those derived from reduc-
tion of the malonyl radical or the a-amidoalkyl radical, were
detected.[22j] Several protecting groups at the nitrogen of 1,
such as Boc (entry 3), alloc (entry 6), acetate (entry 8), and
8
9
4k
4l
74 (1:1)
62
methylcarbonate (entry 9), were tolerated. However,
a
slightly lower yield was noted with a triple bond bearing a
carbamate protecting group, even when an excess of enecar-
bamate was used (entry 7). This method was also compatible
with silylated alcohols (entries 2 and 3). In addition, a b-
branched cyclopropyl enecarbamate participated successful-
ly in the reaction to afford 4g in 92% yield (entry 4). Most
remarkably, the radical-polar crossover process worked well
with aliphatic ketone-derived enamides. This was demon-
strated, as the N-acyl enamide from cyclohexanone was con-
verted into the quaternary-carbon-containing, b-alkylated a-
amido ether 4k, which is a corresponding a-alkylated keta-
mine (entry 8). Interestingly, the endocyclic enecarbamate
reacted readily to afford a suitable framework 4m for the
construction of a number of nitrogen-containing heterocy-
cles (entry 10).
10
4m
48 (1:1)
[a] Reaction conditions: enecarbamate 1 (0.1 mmol), diethyl 2-bromomal-
onate (2a, 0.2 mmol), Et3N (0.2 mmol), 3 (1.3 mmol), 9 (0.001 mmol), c=
0.10m at RT. [b] Isolated yield after column chromatography. [c] Diaste-
reomeric ratio (d.r.) was determined by 1H NMR analysis of crude mix-
tures.
The photoredox-initiated a-alkylation of enamides provid-
ed a convenient synthesis to highly functionalized precursors
of a-alkylated imines 4, which are important synthetic inter-
mediates for several transformations.[15] To illustrate this, 4a
was easily prepared on a 5 mmol scale using 0.5 mol% of
iridiumACHTUNGTRENNUNG(III) catalyst 9 (4 mg). Its reduction using triethylsi-
lane (TES) and AgOTf proceeded smoothly to afford amine
10 in quantitative yield (Scheme 2). The cyanation of 4a was
also carried out using AgOTf and TMSCN to give easy
access to a highly functionalized precursor of amino acid
11.[25] Finally, a Friedel–Crafts alkylation[26] of indole 12 was
Scheme 2. Synthetic application of b-alkylated a-carbamido ethers 4.
424
www.chemeurj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 423 – 427

a-Alkylation of Imines
COMMUNICATION
performed with 10 mol% of phosphoric acid catalyst 14 in
toluene at 608C. The desired product 13 was isolated as a
2:1 mixture of diastereomers with 86% yield over two steps.
Additionally, no undesired bisindolyl by-product was isolat-
ed.[27]
Control experiments were carried out to investigate if an
ionic pathway was involved in this three-component reac-
tion. It was found that no reaction proceeded in the absence
K2CO3, or lutidine. To investigate this issue, we hypothe-
sized that, since the oxidation potential of iridiumACHTUNGTRENNUNG(III) is
high (1.60 V vs. NHE in CH3CN, NHE=normal hydrogen
electrode),[31] it might oxidize enamide derivatives 1 in the
absence of Et3N.[32–34] On this basis, a second mechanism,
which involves the reductive quenching of the excited state
of *Ir3+ by Et3N to produce the reducing Ir2+ species
(À1.51 V vs. SCE in CH3CN, SCE=saturated calomel elec-
trode)[24b,35] and the ammonium radical cation,[20c,22i] was
postulated (path B). Then, alkyl radical 5, formed by the
Ir2+-mediated reduction of 2, reacts with 1 to provide a-
amido radical 6. Reduction of *Ir3+ or radical propagation
and subsequent addition of alcohol affords the desired prod-
uct 4. In this case, only a catalytic amount of tertiary amine
is required, and the excess of the base neutralizes HBr,
formed in the reaction media.
of any of the reaction partners, including [Ir
ACHTUNGERTN(NUNG ppy)2-
ACHTUNGTRENNUNG
of TEMPO (TEMPO=2,2,6,6-tetramethylpiperidine N-
oxide) suppressed the reaction completely. These control ex-
periments confirm that the alkylation of enamides proceeds
through a radical/cationic pathway and two possible mecha-
nistic pathways are proposed in Scheme 3. In the first mech-
In summary, we have described a photoredox-initiated
three-component domino synthesis of N-carbamoyl a-alky-
lated imines from easily accessible starting materials. Key
features of this approach are its operational simplicity, high
atom-economy, wide substrate scope and good to excellent
chemical yields. The easy accessibility of a-alkylated imines,
which are stable precursors in many useful synthetic trans-
formations, makes this methodology particularly attractive
in organic synthesis. Synthetic potentials have also been il-
lustrated by various transformations into functionalized
amines.
Experimental Section
General protocol: A flame-dried tube under argon atmosphere (1 atm)
was charged with [IrACHTNUTRGENNUG(ppy)2ACHTUGNTREN(NUNG dtbbpy)]PF6 catalyst (9, 1.3 mg, 1.5 mmol) in
dry dichloromethane (1 mL) or dry acetonitrile (1 mL). Enecarbamate 1
(0.1 mmol), diethyl bromomalonate (2a, 37 mL, 0.2 mmol), Et3N (28 mL,
0.2 mmol) and alcohol 3 (1 mmol) were added in this order. The hetero-
geneous solution was degassed by three freeze–pump–thaw cycles and
the tube was irradiated with a 25 W fluorescent lamp. After the reaction
was complete, as monitored by TLC, the solvent was removed in vacuo
and the residue was purified by flash chromatography on silica gel (hep-
tane/EtOAc 7:3) to afford the corresponding product 4.
Scheme 3. Proposed mechanistic pathways for the radical/cationic alkyla-
tion of enamides.
anism (path A), a strong reductant *Ir3+ is formed from the
photoredox initiator after its excitation with weak fluores-
cent light.[20b,22e] Then, the reduced iridium species carries
out a single electron transfer (SET) to activate the carbon–
bromine bond, forming the electron-deficient alkyl radical 5
and a bromide ion and regenerating the Ir4+ catalyst. Enam-
ide 1 then reacts with the electrophilic radical generated to
give nucleophilic a-amido radical intermediate 6,[28] which
can be rapidly oxidized to N-acyliminium cation 7, either by
SET from Ir4+ or by bromine atom transfer, and subse-
quently trapped by the ethanol component.[29] On the basis
of previously proposed mechanisms, the radical propagation
probably occurs through an atom-transfer mechanism.[30]
However, this mechanism does not explain the role of Et3N,
which does not seem to be limited solely to trapping HBr.[30]
Indeed, only a complex mixture was observed, when the re-
action was conducted with one equivalent or without a terti-
ary amine (Table 1, entries 9 and 10). Similar results were
also obtained with bases other than Et3N, such as NaHCO3,
Acknowledgements
Financial supports from CNRS are gratefully acknowledged. T. C. thanks
MESR for a doctoral fellowship, University of Paris XI.
Keywords: alkylation
· domino reactions · enamides ·
photoredox catalysis · radicals
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Received: September 29, 2011
Published online: December 9, 2011
Chem. Eur. J. 2012, 18, 423 – 427
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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