Visible-Light Photoredox-Catalyzed Amidation of Benzylic Alcohols

Article abstract of DOI:10.1021/acs.joc.0c01320

A new photocatalyzed route to amides from alcohols and amines mediated by visible light is presented. The reaction is carried out in ethyl acetate as a solvent. Ethyl acetate can be defined a green and bio-based solvent. The starting materials such as the energy source are easily available, stable, and inexpensive. The reaction has shown to be general and high yielding.

Full text of DOI:10.1021/acs.joc.0c01320

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Article
Visible-light photoredox catalyzed amidation of benzylic alcohols
Silvia Gaspa, Andrea Farina, Mariella Tilocca, Andrea Porcheddu,
Luisa Pisano, Massimo Carraro, Ugo Azzena, and Lidia De Luca
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01320 • Publication Date (Web): 14 Jul 2020
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Visible-light photoredox catalyzed amidation of benzylic alcohols
Silvia Gaspa,[a] Andrea Farina,[a] Mariella Tilocca,[a] Andrea Porcheddu, [b] Luisa Pisano,[a] Massimo Carraro,[a]
Ugo Azzena [a] and Lidia De Luca*[a]
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[a] Dipartimento di Chimica e Farmacia, Università degli Studi di Sassari, Via Vienna 2, 07100 Sassari, Italy
Fax: (+39)-079-229559; phone: (+39)-079-229494, e-mail: ldeluca@uniss.it
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[b]
Dipartimento di Scienze Chimiche e Geologiche, Università degli Studi di Cagliari, Cittadella Universitaria, 09042
Monserrato, Italy
Abstract: A new photocatalyzed route to amides from alcohols and amines mediated by visible light is
presented. The reaction is carried out in ethyl acetate as a solvent. Ethyl acetate can be defined a green and
bio-based solvent. The starting material such as the energy source are easily available, stable and
inexpensive. The reaction has shown to be general and high yielding.
Introduction
The amide bond is contained in many both synthetic compounds as drugs, polymers, detergent and natural
compounds as peptides and proteins.1 The amide bond formation reactions are among the most studied in
organic chemistry and the most frequent in biochemistry due to the widespread occurrence of these
compounds. Classically amide bonds are synthesized by acylation of amines with carboxylic acid derivatives
(activated esters, acyl chlorides, carboxylic anhydrides): indeed, this is the most common synthetical pathway
employed in the industrial synthesis of pharmaceuticals. This approach presents many disadvantages as two
additional steps with consequent increasing production of by-products and reduction of final products yields,
the use of highly hazardous reagents and the production of a stoichiometric amount of waste product.2 One
of the most challenging research topics in organic synthesis is the development of new methodologies
induced by visible light.3 Photosynthesis can be defined as the transformation of sunlight into chemical
energy effectively used to promote chemical reaction, allowing the development of sustainable and efficient
procedures. Visible light can be considered a clean reagent: it activates the substrates leaving no residues in
the reaction mixture, with considerable simplification of the work-up and purification processes. For these
reasons, visible-light-mediated organic synthesis has achieved strong priority, because of the development
of sustainable chemistry routes.4
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O2 (balloon)
a)
b)
O
rose bengal (3-6 mol%)
R2
R2
R1
N
R3
R1
N
R3
DBN (1.5- 2.5 eq.)
DMF
r.t., blue LED
ref. 5
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K2CO3 (6.8 eq.)
R2
O
O
R4 N
CCl4 : DCM (3 :1)
R2
R1 OH
( 1 eq.)
R1
N
R3
N2,
R3
( 7.5 eq.)
h (sun light)
ref.6
c)
O
R2
O
CCl3Br (1 eq.), CH3CN
R2
H N
R1
N
R3
R1
H
R3 Ir(dF(CF3)ppy)2(dtbbpy)PF6
( 1 eq.)
(2 mol%)
Ar, r. t., blue LED
ref.7
( 2 eq.)
this work :
Ru(bpy)3Cl2 5%mol,
TBHPaq (1.2 eq.)
CaCO3 (1.1 eq.)
O
H
*HCl
R2
(1.2 eq.)
Ar
OH
R2
N
R
N
R1
(1 eq.)
AcOEt
Ar, blue LED
R1
Scheme 1. Synthesis of amides mediated by visible light.
In this context the synthesis of amides mediated by visible light has recently been studied and few methods
have been mentioned in the literature. Recently, Das and co-workers have reported a α-oxygenation of
tertiary amines to tertiary amides (Scheme 1, path a).5 The methodology makes use of O2 as an oxidant, DBN
as a base, DMF as a solvent and rose Bengal as a photocatalyst. Even if the reaction scope is intimately linked
to the nature and availability of tertiary amines, the work is pioneering for the visible light-mediated amide
synthesis. In this context an interesting dealkylative condensation of tertiary amines with carboxylic acids to
amides has been proposed by Szpilman (Scheme 1, path b).6 The reaction proceeds through a charge-transfer
complex between the amine and carbon tetrachloride and the large excesses of reagents and solvents should
be easily recyclable in an industrial setting. Aldehydes have also been employed as starting materials for the
visible light-mediated synthesis of amides (Scheme 1, path c).7 Pandey has reported a direct amidation of
aldehydes by a cross-dehydrogenative coupling catalyzed by an Iridium-based catalyst in the presence of 1
equivalent of CCl3Br used as a stoichiometric oxidant. Aldehydes are normally obtained by selective oxidation
of alcohols, which are easily available and stable compounds, and are contained in many naturally occurring
organic molecules. For these reasons, the direct conversion of alcohols to amides is a highlight of green and
sustainable chemistry.8 The only paper reporting a visible light mediated conversion of alcohols to amides
was presented by Cai.9 It is an oxidative cross-coupling reactions of benzyl alcohols with N,N-dimethyl
acetamide, used both as a solvent and as a reagent, to obtain exclusively N,N-dimethyl cinnamides. In this
work we report a new photocatalyzed route to amides from alcohols and amines mediated by visible light.
Results and Discussion
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In relation to our interest in the synthesis of amides10 we have checked the possibility to explore a new visible
light-mediated method which would give a broaden access to amides from alcohols. We started our
investigation using benzyl alcohol 1a and N,N-dimethylamine hydrochloride 2a as the model substrates and
blue LEDS as the light source.
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Table 1. Screening of reaction conditions.
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O
photocatalyst (5.0 mol%),
oxidant (2.2 mmol)
OH
+
*HCl
N
HN
solvent (0.5 mL), rt, 72 h
CaCO3 (1.1. mmol)
blue LEDS
1 mmol
1.2 mmol
3aa
2a
1a
Entry[a]
Photocatalyst
Oxidant
Solvent
Yield
(%)[b]
1
2
[Ru(bpy)3Cl2]
[Ru(bpy)3Cl2]
[Ru(bpy)3Cl2]
[Ru(bpy)3Cl2]
[Ru(bpy)3Cl2]
[Ru(bpy)3Cl2]
[Ru(bpy)3Cl2]
[Ru(bpy)3Cl2]
[Ru(bpy)3Cl2]
Eosin Y
TBHPaq
TBHPaq
TBHPaq
TBHPdec
H2O2
acetonitrile
CPME
-
49
83
16
-
3
AcOEt
4
AcOEt
5
CPME
6
H2O2
acetonitrile
AcOEt
-
7
H2O2
-
8
O2
CPME
-
9
O2
AcOEt
-
10
11[c]
12
13
14
15d
TBHPaq
TBHPaq
TBHPaq
O2
AcOEt
36
35
7
Eosin Y
AcOEt
Rose Bengal
Rose Bengal
[Ru(bpy)3Cl2]
[Ru(bpy)3Cl2]
AcOEt
AcOEt
-
TBHPaq
TBHPaq
AcOEt
33
33
AcOEt
[a] General reaction conditions: 1a (1 mmol), 2a (1.2 mmol), photocatalyst (5.0 mol%), oxidant (2.2
mmol) and CaCO3 (1.1 mmol) in solvent (0.5 mL) at rt in argon for 72 h with 9 W blue LEDS. [b] Yield of
the isolated product. [c] The reaction was performed with 9 W green LEDS. [d] The reaction was carried
out for 96 h.
Benzyl alcohol (Table 1,1a, 1 mmol), N,N-dimethylamine hydrochloride (Table 1, 2a, 1.2 mmol), aqueous 70%
TBHP (Table 1, 2.2 mmol), CaCO3 (Table 1, 1.1 mmol) and [Ru(bpy)3Cl2] (Table 1, 5 mol%) in 0.5 mL of
acetonitrile were irradiated for 72 h with blue LEDS , but no product was formed (Table 1, entry 1). The same
reaction was carried out in cyclopentyl methyl ether (CPME) as a solvent, and the product 3aa was formed
in 49 % yield (Table 1, entry 2). In order to improve the yield AcOEt was employed as a solvent and the product
3aa was formed in 83 % yield (Table 1, entry 3). If the reaction was carried out by TBHP 5.5 M in decane as
an oxidant, the yield decreased to 16 % (Table 1, entry 4). A different oxidizing reagent as H2O2 was tested,
in respectively CPME (Table, 1, entry 5), acetonitrile (Table, 1, entry 6) and AcOEt (Table, 1, entry 7) but in
any case, no product was detected. Subsequently O2 was tested in CPME (Table 1, entry 8) and AcOEt (Table
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1, entry 9) but no product was formed. By using Eosin Y as a catalyst, instead of [Ru(bpy)3Cl2], both under
blue led (Table 1, entry 10) and green led (Table 1, entry 11) irradiation, the product was obtained in low
yields 36% and 35%, respectively. The reaction performed with Rose Bengal as a catalyst and respectively
TBHPaq and O2 as oxidants, the product was isolated only in traces (Table 1, entries 12 and 13). Finally, the
reaction was carried out in dark for 72 h (Table 1, entry 14) and for 96 h (Table 1, entry 15) and in both of
cases the product was obtained in low yield 33%.
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The use of AcOEt as a solvent is profitable. AcOEt highly is a recommended solvent by Sanofi’s solvent
selection guide,11 because of it is biodegradable and non bioaccumulable and has an ecotox > 100 mg/L, with
ICH limits (ppm) of 5000. It is included in the greener solvent GSK’s list12 too, and its use is high recommended.
Moreover, ethyl acetate is commercially available, easily accessible and inexpensive.
With the optimized conditions in hand (Table 1, entry 3), the reaction scope was investigated. An array of
substituted benzyl alcohols and amine hydrochloride was tested. In general, the corresponding amides were
obtained in good yields (Scheme 2, 3aa-bc). Different functional groups on aromatic rings both electron
donating and electron withdrawing were tested. Neither the electronic properties nor the steric effects of
substituents on the aromatic ring of benzylic alcohols were found to have any effect on the reaction and
products yield.
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O
[Ru(bpy)3Cl2] (5 mol%),
R1
HN
R2
2a
R1
TBHP, CaCO3
R
OH
+
*HCl
R
O
N
R2
AcOEt, rt, 72 h
blue LEDS
1a
3aa-3bc
O
N
O
O
O
O
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N
N
N
N
O
3aa
3ab
3ad
, 38%
, 83%
, 92%
3ac
3ae,
, 78%
41%
O
O
O
O
Cl
O
N
N
N
N
N
Cl
Br
3ag,
79%
3af
3ai,
3aj
, 79%
, 49%
39%
3ah
, 64%
O
O
O
N
O
N
N
N
, 60%
O
O
O
O
F3C
O
3an
, 85%
3ak
3al
3am
, 96%
, 91%
O
O
O
O
N
N
N
N
H
O
O
NH
3ao
O
S
S
3ap,
3aq,
, 74%
15%
70%
O
3ar
, 85%
O
O
O
Cl
N
N
N
N
H
O
O
O
Cl
Br
3av
, 79%
3at
3au
,78%
, 78%
3as
, 59%
O
O
O
Cl
N
H
N
H
N
H
O
Br
3aw
3ax
3ay,
, 20%
, 58%
69%
O
O
O
O
Cl
N
H
N
N
NH2
H
H
O2N
Cl
3bc
, 80%
3bb
, 59%
3ba
, 48%
3az
, 75%
O
O
O
N
H
N
N
H
H
Br
Br
a)
a)
a)
4a
4b
4c
, 46%
, 20%
, 24%
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a)
Scheme 2. Investigation of the alcohol scope of the reaction. Reaction condition: aliphatic aldehyde (1
mmol), amine hydrochloride salt (1.2 mmol), Ru(bpy)3Cl2*6H2O (0.05 mmol, 5.0 mol %), CaCO3 (1.1 mmol)
and tert-butyl hydroperoxide (70 wt % in H2O, 1.1 mmol) in ethyl acetate (0.5 mL), under argon atmosphere
and blue led for 48 h.
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Strong electron donating groups as OMe (Scheme 2, 3ac, 3ad, 3am and 3ax) showed good results. Benzyl
alcohols with moderate electron donating substituents as phenyl (Scheme 2, 3af, 3an and 3ay) and methyl
(Scheme 2, 3ae, 3ag and 3as) were tested with satisfactory results. Benzyl alcohols with halide substituents,
such as chlorine and bromide in different positions were subjected to this procedure giving the corresponding
amides, which could be further transformed by traditional cross-coupling reactions (Scheme 2, 3ah, 3ai, 3aj,
3at, 3au and 3az). Strong electron withdrawing groups such as NO2 (Scheme 2, 3ba) and CF3 (Scheme 2, 3ak)
were well tolerated providing the desired amides in good results. The reactions with sterically hindered
ortho-substituted benzylic alcohols were performed and the corresponding amides (Scheme 2, 3ad, 3ae and
3ai) were obtained in low yield as one would been expected because of steric hindrance. To prove the
synthetic utility of the procedure, (1H-pyrrol-2-yl) methanol, furan-2-ylmethanol and thiophen-2-ylmethanol
were subjected to optimized reactions conditions, giving the desired heteroaryl amides (Scheme 2, 3ao, 3ap,
3aq, 3ar).
To investigate the scope of the method, the reaction was investigated with an array of primary and secondary
hydrochloride ammines showing excellent tolerance. Secondary aliphatic acyclic amines as N,N-dimethyl
amine (Scheme 2, 3aa, 3ac, 3ad, 3ae, 3af, 3ag, 3ah, 3ai, 3aj, and 3ak), N,N-diethyl amine (Scheme 2, 3ab),
secondary aliphatic cyclic amines as morpholine (Scheme 2, 3al, 3am, 3an, 3ao, 3ap, 3aq, 3as, 3at, and 3au),
primary aliphatic amines as N-benzylamine (Scheme 2, 3ar, 3av and 3az), N-4-bromobenzylamine (Scheme
2, 3aw and 3ax), 2-chloroethylamine (Scheme 2, 3ay and 3ba), and tert-butylamine (Scheme 2, 3bb). The
reaction carried out with hydrochloride ammonium salts was performed and the corresponding primary
amide, benzamide (Scheme2, 3bc) was obtained in very good yield. The reaction was investigated with
aniline, but no product was detected. The procedure was applied to aliphatic alcohols but at the end of the
entire procedure the corresponding alcohols were recovered unreacted. Finally, aliphatic aldehydes were
tested, giving the desired amides in acceptable yields (Scheme 2, 4a, 4b and 4c).13
A plausible reaction mechanism is reported in Scheme 3. On the basis of previously published paper8c, 14
alcohol is oxidized, by TBHP to aldehyde. The aldehyde reacts with the amine to form hemiaminal.15
The reaction proceeds by photo-excitation of [Ru(bpy)3Cl2], which is known to undergo single electron
transfer (SET) in the presence of tert-butyl hydroperoxide, thus generating two species: tert-butoxy radical t-
BuO. and hydroxyl anion HO-. Subsequently t-BuO. may abstract by hydrogen atom transfer (HAT) a hydrogen
from the hemiaminal. The C-radical will be deprotonated to give the ketyl radical anion which then reduces
the Ru(III)-complex by a SET, which completes the photoredox catalytic cycle of Ru catalyst and hence its
regeneration.
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O
1)
t-BuOOH
t-BuOH
H2O
R
OH
R
R
H
H
O
OH
R1
NH
R2
R1
R1
base
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2)
3)
NH HCl
R
N
R2
R2
visible
light
Ru2+*
t-BuOOH
S E T
Ru2+
H
OH
O
O
H
R1
R1
SET
Ru3+
R
N
R2
t-BuO
R
N
R2
H A T
t-BuOH
O
R1
R
N
R2
H
OH
H2O
Scheme 3. Proposed reaction mechanism.
Quantum yield measurements were performed to provide insight into the effective reaction mechanism,16
and the results indicate a light-initiated chain propagation mechanism.
Briefly, standard chemical actinometry using potassium ferrioxalate allowed us to determine the photon flux
of a blue led at 455 nm. After 180 seconds of irradiation of reaction mixture 455 nm, 5 % conversion to amide
3aa is observed. This yield corresponds to 51 equivalents of product formed per absorbed photon (힍=51),
thus indicating that this reaction proceeds through a chain propagation mechanism.
Conclusions
In conclusion, the first example of photocatalyzed amides synthesis from alcohols and amines, mediated by
visible light was reported. The reaction is carried out in ethyl acetate as a green, eco sustainable and bio-
based solvent. The starting materials are stable, easily accessible and inexpensive. The reaction conditions
are mild, the stoichiometric ratio of the reactants is optimal and the use of visible light as a source of energy
is very appealing from an ecological point of view. The methodology has shown a big versatility and
applicability, while various functional groups, on both alcohols and amines, are well-tolerated, providing a
new approach to visible-light mediated amide synthesis.
Experimental Section
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All reagents and solvents were as obtained by commercial source. All solvents were dried by usual methods
and distilled under Argon. Column chromatography was generally performed on silica gel (pore size 60 Å, 32-
63 nm particle size) and reactions were monitored by thin-layer chromatography (TLC) analysis was
performed with Merck Kieselgel 60 F254 plates and visualized using UV light at 254 nm, KMnO4 and 2,4-DNP
staining. For irradiation with blue light OSRAM Oslon SSL 80 LDCQ7P-1U3U (blue, λ max = 455 nm, I max =
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1
13
1000 mA, 1.12 W) was used. H NMR and C NMR spectra were measured on a Bruker Avance III 400
spectrometer (400 MHz or 100 MHz, respectively) using CDCl3 solutions and TMS as an internal standard.
Chemical shifts are reported in parts per million (ppm, ) relative to internal tetramethylsilane standard (TMS,
 0.00). The peak patterns are indicated as follows: s, singlet; d, doublet; t, triplet; m, multiplet; q, quartet;
dd, doublet of doublets; brs, broad. The coupling constants, J, are reported in Hertz (Hz). High resolution
mass spectra HRMS (HESI-FT-ORBITRAP) were recorded on a Q-Exactive Thermo Scientific mass
spectrometer. UV-Vis spectra were obtained on a T80+ PG Instrument Ltd UV/VIS Spectrometer. Melting
points were determined in open capillary tubes and are uncorrected.
General Procedure to compounds 3aa-3bc:
To a mixture of amine hydrochloride salt (1.2 mmol), Ru(bpy)3Cl2*6H2O (37.4 mg, 0.05 mmol, 5.0 mol %) and
CaCO3 (110 mg, 1.1 mmol) in ethyl acetate (0.5 mL) were added alcohol (1 mmol) and tert-butyl
hydroperoxide (70 wt % in H2O, 0.31 mL, 2.2 mmol) under argon atmosphere at room temperature. The
reaction mixture was irradiated under blue led and stirred at room temperature for 72 h (monitored by TLC
until disappearance of the alcohol). Then the reaction mixture was quenched with water and extracted with
AcOEt. The combined organic layers were washed three times with a solution of 5 % citric acid and then three
times with a solution of 5 % NaHCO3; the organic phase was dried over anhydrous Na2SO4 and the solvent
was evaporated under reduced pressure. The crude products were purified by flash chromatography on silica
gel.
Compound characterizations:
17
1
N,N-dimethylbenzamide (3aa): Yellow oil; (124 mg, 83 % yield); Rf = 0.33 (hexane/ethyl acetate 2/3). H
NMR (400 MHz, CDCl3) δ: 7.40 – 7.39 (m, 5H), 3.11 (s, 3H), 2.97 (s, 3H). C{1H} NMR (100 MHz, CDCl3) δ:
13
171.7, 136.3, 129.5, 128.3, 127.0, 39.6, 35.3.
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N,N-diethylbenzamide (3ab): 18 Colorless oil; (163 mg, 92 % yield); Rf = 0.37 (hexane/ethyl acetate 2/3). H
NMR (400 MHz, CDCl3) δ: 7.35 – 7.31 (m, 5H), 3.49 (brs, 2H), 3.22 (brs, 2H), 1.22 – 1.08 (m, 6H). 13C{1H} NMR
(100 MHz, CDCl3) δ: 171.1, 137.1, 128.9, 128.2, 126.1, 43.1, 39.1, 14.0, 12.8.
4-methoxy-N,N-dimethylbenzamide (3ac): 19 Yellow oil; (140 mg, 78 % yield); Rf = 0.30 (hexane/ethyl acetate
2/3). 1H NMR (400 MHz, CDCl3) δ: 7.39 (d, J = 8.7 Hz, 2H), 6.89 (d, J = 8.7 Hz, 2H), 3.82 (s, 3H), 3.04 (s, 6H).
13C{1H} NMR (100 MHz, CDCl3) δ: 171.5, 160.6, 129.1, 128.3, 113.5, 55.3, 39.8, 35.6.
2-methoxy-N,N-dimethylbenzamide (3ad):20 Yellow oil; (68 mg, 38 % yield); Rf = 0.27 (hexane/ethyl acetate
2/3). 1H NMR (400 MHz, CDCl3) δ: 7.31 (t, J = 8.0 Hz, 1H), 7.20 (d, J = 7.4 Hz, 1H), 6.95 (t, J = 7.5 Hz, 1H), 6.88
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(d, J = 8.3 Hz, 1H), 3.81 (s, 3H), 3.09 (s, 3H), 2.82 (s, 3H). C NMR (100 MHz, CDCl3) δ: 169.3, 155.2, 130.2,
127.8, 126.2, 120.8, 110.8, 55.4, 38.1, 34.6.
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N,N,2-trimethylbenzamide (3ae):21 Yellow oil; (67 mg, 41 % yield); Rf = 0.37 (hexane/ethyl acetate 2/3). H
NMR (400 MHz, CDCl3) δ: 7.26 – 7.22 (m, 1H), 7.21 – 7.14 (m, 3H), 3.12 (s, 3H), 2.82 (s, 3H), 2.28 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3) δ: 171.5, 136.7, 133.9, 130.3, 128.7, 125.9, 125.8, 38.3, 34.5, 18.9.
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N,N-dimethyl-[1,1'-biphenyl]-4-carboxamide (3af): 22 White solid; (110 mg, 49 % yield); m.p. 104 - 105 °C,22
Rf = 0.26 (hexane/ethyl acetate 2/3). H NMR (400 MHz, CDCl3) δ: 7.63 - 7.59 (m, 4H), 7.53 – 7.42 (m, 4H),
7.39 - 7.35 (m, 1H), 3.09 (brs, 6H). 13C{1H} NMR (100 MHz, CDCl3) δ: 171.5, 142.4, 140.3, 135.0, 128.9, 127.7,
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127.7, 127.1, 127.0, 38.7, 35.3.
N,N,3,5-tetramethylbenzamide (3ag):23 Yellow oil; (140 mg, 79% yield); Rf = 0.41 (hexane/ethyl acetate 2/3).
1H NMR (400 MHz, CDCl3) δ: 7.00 (s, 1H), 6.98 (s, 2H), 3.07 (s, 3H), 2.96 (s, 3H), 2.31 (s, 6H). C NMR (100
MHz, CDCl3) δ: 172.0, 137.9, 136.2, 130.9, 124.5, 39.5, 35.2, 21.2.
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4-chloro-N,N-dimethylbenzamide (3ah): 19 Yellow oil; (117 mg, 64 % yield); Rf = 0.44 (hexane/ethyl acetate
2/3). 1H NMR (400 MHz, CDCl3) δ: 7.39 – 7.35 (m, 4H), 3.10 (s, 3H), 2.97 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3)
δ: 170.6, 135.6, 134.6, 128.6, 128.6, 39.6, 35.4.
2-chloro-N,N-dimethylbenzamide (3ai):24 Yellow oil; (72 mg, 39 % yield); Rf = 0.4 (hexane/ethyl acetate 2/3).
1H NMR (400 MHz, CDCl3) δ: 7.41 – 7.37 (m, 1H), 7.33 – 7.28 (m, 3H), 3.14 (s, 3H), 2.86 (s, 3H). 13C NMR (100
MHz, CDCl3) δ: 168.4, 136.4, 130.3, 130.0, 129.5, 127.8, 127.1, 38.0, 34.7.
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4-bromo-N,N-dimethylbenzamide (3aj): White solid; (180 mg, 79 % yield); m.p. 76 - 77 °C, Rf = 0.23
(hexane/ethyl acetate 2/3). 1H NMR (400 MHz, CDCl3) δ: 7.56 – 7.51 (m, 2H), 7.32 – 7.28 (m, 2H), 3.08 (s, 3H),
2.99 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ: 170.6, 135.0, 131.6, 128.8, 123.8, 39.5, 35.4.
N,N-dimethyl-4-(trifluoromethyl)benzamide (3ak): 19 Yellow solid; (198 mg, 91 % yield); m.p. 95 - 96 °C, Rf =
0.26 (hexane/ethyl acetate 2/3). 1H NMR (400 MHz, CDCl3) δ: 7.67 (d, J = 8.1 Hz, 2H), 7.53 (d, J = 8.0 Hz, 2H),
3.13 (s, 3H), 2.96 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ: 170.2, 139.8, 131.5 (q, J = 32.6 Hz), 127.4, 125.5
(q, J = 3.4 Hz), 123.7 (q, J = 266.3 Hz), 39.4, 35.3.
Morpholino(phenyl)methanone (3al): 18 Yellow oil; (115 mg, 60 % yield); Rf = 0.25 (hexane/ethyl acetate 2/3).
1H NMR (400 MHz, CDCl3) δ: 7.42 - 7.39 (m, 5H), 3.74 - 3.45 (m, 8H). 13C{1H} NMR (100 MHz, CDCl3) δ: 170.4,
135.3, 129.8, 128.5, 127.0, 66.9, 48.2, 42.6.
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(4-methoxyphenyl)(morpholino)methanone (3am):
Yellow oil; (212 mg, 96 % yield); Rf = 0.16
(hexane/ethyl acetate 2/3). 1H NMR (400 MHz, CDCl3) δ: 7.37 (d, J = 8.7 Hz, 2H), 6.90 (d, J = 8.7 Hz, 2H), 3.82
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(s, 3H), 3.68 - 3.62 (m, 8H). C{1H} NMR (100 MHz, CDCl3) δ: 170.4, 160.9, 129.1, 127.3, 113.7, 66.9, 55.3,
47.8, 43.9.
[1,1'-biphenyl]-4-yl(morpholino)methanone (3an): 27 White solid; (227 mg, 85 % yield); m.p. 86 - 87 °C, Rf =
0.25 (hexane/ethyl acetate 2.5/2.5). 1H NMR (400 MHz, CDCl3) δ: 7.64 (d, J = 8.3 Hz, 2H), 7.61 – 7.56 (m, 2H),
7.47 – 7.44 (m, 4H), 7.40 – 7.36 (m, 1H), 3.73 – 3.55 (m, 8H). 13C{1H} NMR (100 MHz, CDCl3) δ: 170.3, 142.9,
140.2, 134.0, 128.9, 127.9, 127.7, 127.3, 127.1, 66.9.
Morpholino(1H-pyrrol-2-yl)methanone (3ao): White solid; (133 mg, 74 % yield); m.p. 73 - 74 °C, Rf = 0.21
(hexane/ethyl acetate 3/2). 1H NMR (400 MHz, CDCl3) δ: 9.93 (brs, 1H), 6.92 (td, J = 2.7, 1.3 Hz, 1H), 6.51 (ddd,
J = 3.8, 2.5, 1.3 Hz, 1H), 6.23 (dt, J = 3.8, 2.6 Hz, 1H), 3.86 (t, J = 4.9 Hz, 4H), 3.75 – 3.72 (m, 4H). 13C{1H} NMR
(100 MHz, CDCl3) δ: 161.9, 124.1, 121.3, 112.2, 109.5, 66.8, 45.2. HRMS (HESI-FT-ORBITRAP) m/z: [M+H]+
Calcd for C9H13N2O2: 181,0972; Found 181,0972.
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Furan-2-yl(morpholino)methanone (3ap):28 Yellow oil; (27 mg, 15 % yield); Rf = 0.26 (hexane/ethyl acetate
2.5/2.5). 1H NMR (400 MHz, CDCl3) δ: 7.48 (s, 1H), 7.03 (d, J = 3.5 Hz, 1H), 6.49- 6.48 (m, 1H), 3.85 – 3.72 (m,
8H). 13C NMR (100 MHz, CDCl3) δ: 159.1, 147.7, 143.8, 116.8, 111.4, 67.0.
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Morpholino(thiophen-2-yl)methanone (3aq):29 Yellow oil; (138 mg, 70 % yield); Rf = 0.35 (hexane/ethyl
acetate 2.5/2.5). 1H NMR (400 MHz, CDCl3) δ: 7.45 (d, J = 4.8 Hz, 1H), 7.28 (d, J = 3.5 Hz, 1H), 7.06 – 7.02 (m,
1H), 3.77-3.75 (m, 4H), 3.73-3.71 (m, 4H). 13C{1H} NMR (100 MHz, CDCl3) δ:163.6, 136.6, 128.9 128.8, 126.7,
66.8, 45.9.
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N-benzylthiophene-2-carboxamide (3ar):8c White solid; (185 mg, 85 % yield); m.p. 114 - 115 °C, Rf = 0.29
(hexane/ethyl acetate 4/1). 1H NMR (400 MHz, CDCl3) δ:7.52 (d, J = 3.5 Hz, 1H), 7.47 (d, J = 4.9 Hz, 1H), 7.34
(d, J = 4.4 Hz, 4H), 7.30 (dd, J = 5.0, 3.6 Hz, 1H), 7.09 – 7.00 (m, 1H), 6.47 (s, 1H), 4.60 (d, J = 5.8 Hz, 2H). 13C
NMR (100 MHz, CDCl3) δ 161.9, 138.7, 138.0, 130.0, 128.7, 128.1, 127.9, 127.6, 43.9.
Morpholino(p-tolyl)methanone (3as): 26 Yellow oil; (121 mg, 59 % yield); Rf = 0.23 (hexane/ethyl acetate 2/3).
1H NMR (400 MHz, CDCl3) δ: 7.30 (d, J = 8.1 Hz, 2H), 7.20 (d, J = 7.8 Hz, 2H), 3.61 (m, 8H), 2.37 (s, 3H). 13C{1H}
NMR (100 MHz, CDCl3) δ: 170.6, 140.1, 132.3, 129.1, 127.2, 66.9, 48.3, 42.9, 21.3.
(4-chlorophenyl)(morpholino)methanone (3at): 30 White solid; (176 mg, 78 % yield); m.p. 74 - 76 °C, Rf = 0.26
(hexane/ethyl acetate 2/3). 1H NMR (400 MHz, CDCl3) δ: 7.36 – 7.30 (m, 4H), 3.65 - 3.40 (m, 8H). 13C{1H} NMR
(100 MHz, CDCl3) δ: 169.2, 135.8, 133.5, 128.7, 128.5, 66.6, 48.0, 42.6.
(3-chlorophenyl)(morpholino)methanone (3au): 31 Brown oil; (176 mg, 78 % yield); Rf = 0.48 (hexane/ethyl
acetate 2/3). 1H NMR (400 MHz, CDCl3) δ: 7.43 – 7.23 (m, 3H), 7.21 – 7.19 (m, 1H), 3.86 – 3.18 (m, 8H). 13C{1H}
NMR (100 MHz, CDCl3) δ: 168.8, 137.0, 134.7, 130.0, 129.9, 127.2, 125.1, 66.8, 48.1, 42.6.
N-benzylbenzamide (3av): 32 Brown solid; (167 mg, 79 % yield); m.p. 104 - 105 °C, Rf = 0.42 (hexane/ethyl
acetate 3.5/1.5). 1H NMR (400 MHz, CDCl3) δ: 7.79 (d, J = 7.3 Hz, 2H), 7.48 (d, J = 7.4 Hz, 1H), 7.40 (t, J = 7.5
Hz, 2H), 7.34 (d, J = 4.4 Hz, 4H), 7.31 – 7.26 (m, 1H), 6.68 (s, 1H), 4.62 (d, J = 5.7 Hz, 2H). 13C{1H} NMR (100
MHz, CDCl3) δ: 167.4, 138.2, 134.3, 131.5, 128.7, 128.5, 127.8, 127.5, 126.9, 44.0.
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N-(4-bromobenzyl)benzamide (3aw):
White solid; (58 mg, 20 % yield); m.p. 72 - 74 °C, Rf = 0.28
(hexane/ethyl acetate 4.5/0.5). 1H NMR (400 MHz, CDCl3) δ: 7.81 – 7.75 (m, 2H), 7.52 – 7.41 (m, 5H), 7.24 (d,
J = 8.4 Hz, 2H), 6.43 (s, 1H), 4.60 (d, J = 5.7 Hz, 2H). C{1H} NMR (100 MHz, CDCl3) δ: 167.4, 137.3, 134.1,
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131.8, 131.7, 129.5, 128.6, 126.9, 121.4, 43.4.
N-(4-bromobenzyl)-4-methoxybenzamide (3ax): 34 Yellow solid; (186 mg, 58 % yield); m.p. 176 - 177 °C, Rf =
0.28 (hexane/ethyl acetate 3/2). 1H NMR (400 MHz, CDCl3) δ: 7.75 (d, J = 8.8 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H),
7.22 (d, J = 8.4 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 6.36 (s, 1H), 4.58 (d, J = 5.7 Hz, 2H), 3.85 (s, 3H). 13C{1H} NMR
(100 MHz, CDCl3) δ: 166.9, 162.3, 137.5, 131.8, 129.5, 128.8, 126.4, 121.4, 113.8, 55.4, 43.4.
N-(2-chloroethyl)-[1,1'-biphenyl]-4-carboxamide (3ay): Yellow solid; (179 mg, 69 % yield); m.p. 123 - 124
°C,35 Rf = 0.28 (hexane/ethyl acetate 4.5/0.5). 1H NMR (400 MHz, CDCl3) δ: 7.87 (d, J = 8.4 Hz, 2H), 7.67 (d, J =
8.4 Hz, 2H), 7.66 – 7.61 (m, 2H), 7.47 (t, J = 7.5 Hz, 2H), 7.41 – 7.37 (m, 1H), 6.61 (s, 1H), 3.87 – 3.81 (m, 2H),
3.79 – 3.74 (m, 2H).35 13C{1H} NMR (100 MHz, CDCl3) δ: 167.3, 144.6, 139.9, 128.9, 128.1, 127.5, 127.3, 127.2,
44.2, 41.7. HRMS (HESI-FT-ORBITRAP) m/z: [M+H]+ Calcd for C15H15ClNO: 260,0837; Found 260,0835.
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N-benzyl-4-chlorobenzamide (3az): White solid; (184 mg, 75 % yield); m.p. 139 - 141 °C, Rf = 0.38
(hexane/ethyl acetate 3.7/1.3). 1H NMR (400 MHz, CDCl3) δ: 7.73 (d, J = 8.6 Hz, 2H), 7.40 (d, J = 8.6 Hz, 2H),
7.36 – 7.32 (m, 5H), 6.40 (s, 1H), 4.63 (d, J = 5.7 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ: 166.3, 137.9, 137.8,
132.7, 128.8, 128.4, 127.9, 127.7, 44.3.
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N-(2-chloroethyl)-4-nitrobenzamide (3ba): 37 White solid; (110 mg, 48 % yield); m.p. 123 - 124 °C,38 Rf = 0.29
(hexane/ethyl acetate 3/2). 1H NMR (400 MHz, CDCl3) δ: 8.30 (d, J = 8.8 Hz, 2H), 7.96 (d, J = 8.8 Hz, 2H), 6.66
(s, 1H), 3.87 – 3.81 (m, 2H), 3.79 – 3.74 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ: 165.6, 149.8, 139.6, 128.2,
123.9, 43.8, 41.9.
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N-(tert-butyl)benzamide (3bb):
Yellow solid; (105 mg, 59 % yield); m.p. 134 - 135 °C, Rf = 0.354
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(hexane/ethyl acetate 4/1). 1H NMR (400 MHz, CDCl3) δ: 7.71 (d, J = 6.9 Hz, 2H), 7.45 (d, J = 7.2 Hz, 1H), 7.40
(t, J = 7.2 Hz, 2H), 5.96 (s, 1H), 1.47 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3) δ: 166.9, 135.9, 131.0, 128.4, 126.7,
51.6, 28.8.
General Procedure to compounds 3bc:
To a mixture of NH4Cl (96.3 mg, 1.8 mmol), Ru(bpy)3Cl2*6H2O (37.4 mg, 0.05 mmol, 5.0 mol %) and CaCO3
(110 mg, 1.1 mmol) in CH3CN (0.5 mL) were added benzyl alcohol (108.1 mg, 1 mmol) and tert-butyl
hydroperoxide (70 wt % in H2O, 0.31 mL, 2.2 mmol) under argon atmosphere at room temperature. The
reaction vessel was capped and allowed to stir and irradiated under blue led at room temperature for 72 h
(monitored by TLC until disappearance of the alcohol). Then the reaction mixture was evaporated under
reduced pressure. The crude products were purified by flash chromatography on silica gel
Benzamide (3bc): White solid; (97 mg, 80 % yield); m.p. 126 - 127 °C, 39 Rf = 0.4 (hexane/ethyl acetate 1.5/3.5).
1H NMR (400 MHz, CDCl3) δ: 7.83 (d, J = 7.0 Hz, 2H), 7.53 (t, J = 7.4 Hz, 1H), 7.44 (t, J = 7.5 Hz, 2H), 6.46 (brs,
2H).40 13C{1H} NMR (100 MHz, CDCl3) δ: 169.9, 132.9, 132.2, 128.6, 127.4.40
The reaction was investigated with aliphatic aldehydes:
General Procedure to compounds 4a-4c:
To a mixture of amine hydrochloride salt (1.2 mmol), Ru(bpy)3Cl2*6H2O (37.4 mg, 0.05 mmol, 5.0 mol %) and
CaCO3 (110 mg, 1.1 mmol) in ethyl acetate (0.5 mL) were added aliphatic aldehyde (1 mmol) and tert-butyl
hydroperoxide (70 wt % in H2O, 0.156 mL, 1.1 mmol) under argon atmosphere at room temperature. The
reaction mixture was irradiated under blue led and stirred at room temperature for 48 h (monitored by TLC
until disappearance of the alcohol). Then the reaction mixture was quenched with water and extracted with
AcOEt. The combined organic layers were washed three times with a solution of 5 % citric acid and then three
times with a solution of 5 % NaHCO3; the organic phase was dried over anhydrous Na2SO4 and the solvent
was evaporated under reduced pressure. The crude products were purified by flash chromatography on silica
gel.
Compound characterizations:
N-(4-bromobenzyl)-3-phenylpropanamide (4a): Yellow oil; (63.6 mg, 20 % yield); Rf = 0.33 (hexane/ethyl
acetate 2.5/2.5). 1H NMR (400 MHz, CDCl3) δ:7.41 (d, J = 8.1 Hz, 2H), 7.29 (d, J = 7.0 Hz, 2H), 7.22 (dd, J = 16.2,
7.1 Hz, 3H), 6.99 (d, J = 8.1 Hz, 2H), 5.83 (s, 1H), 4.34 (d, J = 5.4 Hz, 2H), 3.00 (t, J = 7.4 Hz, 2H), 2.54 (t, J = 7.5
Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ: 172.0, 140.5, 137.2, 131.6, 129.3, 128.5, 128.4, 126.3, 121.2, 42.8,
38.4, 31.6. m/z: [M+H]+ Calcd for C16H17BrNO: 318,0488; Found 318,0491.
N-(2-bromobenzyl)isobutyramide (4b):41 Colorless oil; (61.5 mg, 24 % yield); Rf = 0.313 (hexane/ethyl acetate
3.5/1.5). 1H NMR (400 MHz, CDCl3) δ: 7.55 (d, J = 7.8 Hz, 1H), 7.36 (dd, J = 7.6, 1.8 Hz, 1H), 7.28 (t, J = 7.2 Hz,
1H), 7.14 (td, J = 7.7, 1.8 Hz, 1H), 6.16 (t, J = 6.3 Hz, 1H), 4.49 (d, J = 6.0 Hz, 2H), 2.45- 2.38 (m, 1H), 1.17 (d, J
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= 6.9 Hz, 6H). C {1H} NMR (100 MHz, CDCl3) δ: 176.8, 137.4, 132.7, 130.1, 129.0, 127.6, 123.6, 43.6, 35.5,
19.5.
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N-benzylcyclohexanecarboxamide (4c):42 White solid; (99.9 mg, 46 % yield); m.p. 112 – 114 °C, Rf = 0.44
(hexane/ethyl acetate 3.5/1.5). 1H NMR (400 MHz, CDCl3) δ: 7.26-7.17 (m, 5H), 5.82 (s, 1H), 4.34 (d, J = 5.6
Hz, 2H), 2.09 – 1.99 (m, 1H), 1.81 (dd, J = 13.1, 3.6 Hz, 2H), 1.72 - 1.68 (m, 2H), 1.62 – 1.55 (m, 1H), 1.45 –
1.33 (m, 2H), 1.22 – 1.13 (m, 3H). 13C NMR (100 MHz, CDCl3) δ 176.0, 138.5, 128.6, 127.6, 127.4, 45.5, 43.3,
29.7, 25.7.
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Scale up for the synthesis of 3aa:
To a mixture of dimethylamine hydrochloride (0.9 g, 11.04 mmol), Ru(bpy)3Cl2*6H2O (0.34 g, 0.46 mmol, 5.0
mol %) and CaCO3 (1.0 g, 10.12 mmol) in ethyl acetate (5 mL) were added benzyl alcohol (1.0 g, 0.95 mL, 9.2
mmol) and tert-butyl hydroperoxide (70 wt % in H2O, 2.80 mL, 20.2 mmol) under argon atmosphere at room
temperature. The reaction mixture was irradiated under blue led and stirred at room temperature for 72 h
(monitored by TLC until disappearance of the alcohol). Then the reaction mixture was quenched with water
and extracted with AcOEt. The combined organic layers were washed three times with a solution of 5 % citric
acid and then three times with a solution of 5 % NaHCO3; the organic phase was dried over anhydrous Na2SO4
and the solvent was evaporated under reduced pressure. The crude product was purified by flash
chromatography on silica gel and the product 3aa was obtained as a yellow oil (822 mg, 60% yield).
Determination of reaction quantum yield
The quantum yield calculation of the reaction was determined in two steps:16
1. Determination of the light intensity obtained from the Blue Led:
The photon flux of the blue Led was determined by standard potassium ferrioxalate actinometer method. 43
For the evaluation of the light intensity an experiment was set by preparing a 0.15 M solution of ferrioxalate
actinometer by dissolving 0.737 g of potassium trisoxalato ferrate trihydrate complex ([K3Fe(C2O4)3]*3H2O in
10 mL of a 0.05 M H2SO4 solution. A buffered solution of 1,10-phenanthroline was prepared by dissolving
0.025 g of 1,10-phenanthroline and 5.63 g of sodium acetate in 25 mL of a 0.5 M solution H2SO4. Both
solutions were stored in the dark.
For the actinometer measurement:
2.0 mL of ferrioxalate solution was placed in a cuvette and irradiated under blue led for 90 seconds. After
irradiation, 0.35 mL of the phenanthroline solution was added to ferrioxalate solution and the mixture was
allowed to stir in the dark for 1.0 h to allow the ferrous ions to completely coordinate to the phenanthroline.
The absorbance of the solution at λ 510 nm was measured. The similar procedure for a non-irradiated sample
was used (actinometer solution, buffer, and phenanthroline) and its absorbance at λ 510 nm was measured.
Conversion was determined according to the Beer’s Laws using equation:
푉 ∙ 훥퐴(510 푛푚)
푚표푙 퐹푒2 +
=
푙 ∙ 휀
0.00235 퐿 ∙ 2.592(510 푛푚)
1.00 푐푚 ∙ 11100 퐿푐푚 ―1푚표푙 ―1
푚표푙 퐹푒2 +
=
= 5.49 ∙ 10 ―7
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Where V is the total volume of the solution (0.00235 L) after addition of all reagents, ΔA is the difference in
absorbance at λ 510 nm between the irradiated and non-irradiated actinometer solutions (2.924 - 0.332), l is
the path length (1.00 cm), and ε is the molar absorptivity of the ferrioxalate actinometer at λ510 nm (11100
L cm-1 mol-1).44 The photon flux of the blue Led can be calculated using the following equation:
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푚표푙 퐹푒2 +
훷 ∙ 푡 ∙ 푓
5.49 ∙ 10 ―7
1.12 푒푖푛푠푡푒푖푛푠 ―1 ∙ 90 푠 ∙ 1.000
푃ℎ표푡표푛 푓푙푢푥 =
=
= 5.45 ∙ 10 ―9
Where Φ is the quantum yield for the ferrioxalate actinometer (1.12 einsteins-1), 43b t is the irradiation time
(90 s), and f is the fraction of light absorbed by the ferrioxalate actinometer. An absorption spectrum gave
an absorbance value of >3, indicating that the fraction of absorbed light f is > 0.999. The photon flux was thus
-9
-1
∙
calculated to be 5.45 10 einsteins s .
2.Determination of the reaction quantum yield:
To a mixture of dimethylamine hydrochloride (97.8 mg, 1.2 mmol), Ru(bpy)3Cl2*6H2O (37.4 mg, 0.05 mmol,
5.0 mol %) and CaCO3 (110 mg, 1.1 mmol) in ethyl acetate (0.5 mL) were added benzyl alcohol (108 mg, 1
mmol) and tert-butyl hydroperoxide (70 wt % in H2O, 0.31 mL, 2.2 mmol) under argon atmosphere at room
temperature. The reaction mixture was irradiated under blue led and stirred at room temperature for 180 s.
After irradiation, the yield of product 3aa formed was determined by 1H-NMR analysis. The yield of 3aa was
-5
∙
determined to be 5% (5 10 mol). The reaction quantum yield (Φ) was determined using following equation
-9
-1
∙
where the photon flux is 5.45 10 einsteins s (determined by actinometry as described in step 1), t is the
reaction time (180 s) and f is the fraction of incident light absorbed by the reaction mixture.
푚표푙 푝푟표푑푢푐푡
5.00 ∙ 10 ―5
5.45 ∙ 10 ―9 푒푖푛푠푡푒푖푛푠 ∙ 푠 ―1 ∙ 180 푠 ∙ 1.000
훷 =
=
= 51
푝ℎ표푡표푛 푓푙푢푥 ∙ 푡 ∙ 푓
The reaction quantum yield (Φ) was thus determined to be 51.
Associated content
Supporting Information
1H NMR and 13C NMR spectra of products
Keywords: amides • amidation • photocatalyzed reaction • alcohols • visible light
Acknowledgements
This work was financially supported by the Regione Autonoma della Sardegna within the project: ‘‘Green
Chemistry’’ in ‘‘Drug Discovery’’: sintesi sostenibili di nuovi inibitori di telomerase’’ (RASSR81788-Bando
‘‘INVITO A PRESENTARE PROGETTI DI RICERCA DI BASE -Annualità 2017’’).
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