Oxidation and deprotection of primary benzylamines by visible light flavin photocatalysis

Article abstract of DOI:10.1055/s-0029-1218709

We report a photocatalytic oxidation procedure that can be used to convert benzylamines into their corresponding aldehydes under mild conditions without over-oxidation, using riboflavin tetraacetate as photocatalyst and blue emitting LEDs (440 nm) as light source. Oxygen is the terminal oxidant and H ²O² and NH³ appear as the only byproducts of the oxidation of primary benzylamines. Furthermore, we have developed a photocatalytic protocol for 4-methoxybenzyl (Mob) group deprotection of primary amines and alcohols. Double bonds, benzyl-protected esters and alcohols are tolerated under the applied conditions, whereas the deprotection of protected secondary amines is not applicable. Mob-protected carboxylic acids and carboxybenzoyl (Cbz) protected amines are inert under the photodeprotection conditions. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0029-1218709

1712
PAPER
Oxidation and Deprotection of Primary Benzylamines by Visible Light Flavin
Photocatalysis
Benzylamine
Ox
o
F
l
b
avin Photoca
e
talysis rt Lechner, Burkhard König*
Institute of Organic Chemistry, University of Regensburg, Universitätsstr. 31, 93040 Regensburg, Germany
Fax +49(941)9431717; E-mail: burkhard.koenig@chemie.uni-regenburg.de
Received 1 February 2010; revised 17 February 2010
mechanism of monoamine oxygenase enzymes and their
Abstract: We report a photocatalytic oxidation procedure that can
be used to convert benzylamines into their corresponding aldehydes
under mild conditions without over-oxidation, using riboflavin tet-
raacetate as photocatalyst and blue emitting LEDs (440 nm) as light
inhibition.9 Thermal aerobic oxidation of amines to N-ox-
ides using flavin catalysts has been accomplished,3 but, to
the best of our knowledge, no application of flavin-
source. Oxygen is the terminal oxidant and H2O2 and NH3 appear as mediated photooxidation of amines to aldehydes has been
the only byproducts of the oxidation of primary benzylamines. Fur-
described so far.
thermore, we have developed a photocatalytic protocol for 4-meth-
oxybenzyl (Mob) group deprotection of primary amines and
We report the scope and limitations of flavin-mediated
aerobic photooxidation of benzylamines to aldehydes.
The approach is used to cleave benzyl protecting groups
selectively by blue light irradiation. Riboflavin tetraace-
tate (RFT, see Scheme 1)10 is used as a readily available
and nontoxic photocatalyst; blue-light-emitting high-
power LEDs serve as a selective and efficient light source.
alcohols. Double bonds, benzyl-protected esters and alcohols are
tolerated under the applied conditions, whereas the deprotection of
protected secondary amines is not applicable. Mob-protected car-
boxylic acids and carboxybenzoyl (Cbz) protected amines are inert
under the photodeprotection conditions.
Key words: flavin, photooxidation, redox chemistry, electron
transfer, benzyl protecting group
440 nm
R
N
N
O
O
benzyl alcohol
or benzylamine
Flavins, acting as redox co-factors and photoreceptors, are
ubiquitous in nature, and occur mostly in the form of fla-
vin adenine dinucleotide (FAD) or flavin mononucleotide
(FMN) co-factors.1 Besides the application as flavoen-
zyme models for biochemical processes,2 flavins have
been used as organocatalysts in thermal3 and
photochemical4 oxidation reactions.
Flavin-mediated photooxidation of benzyl alcohols4 use
the increased oxidation power of the isoalloxazine chro-
mophore in its oxidized form 1 upon excitation by light.5
Subsequent two-electron reduction and protonation gives
dihydroflavin 2, which is oxidized back to 1 by molecular
air oxygen as the terminal oxidant, yielding hydrogen per-
oxide as sole stoichiometric byproduct (Scheme 1).4
H2O2
NH
N
1
R
N
H
N
O
aldehyde or
ketone
O2
NH
N
H
O
2
Scheme 1 Catalytic cycle of aerobic flavin-mediated photooxida-
tion of benzyl alcohols or benzylamines [riboflavin: R = C5H11O4;
riboflavin tetraacetate (RFT): R = C13H19O8].
Several methods for the oxidation of amines to their cor-
responding aldehydes have been reported in the literature.
However, the reaction conditions are rather harsh, require
the stoichiometric use of metallic reagents or suffer from
over-oxidation or lack of selectivity towards other func-
tional groups.6 The use of air oxygen as stoichiometric ox-
idant is particularly desirable from an environmental and
economical point of view. Some aerobic catalytic proce-
dures for amine oxidation are available,7 but examples of
visible light photocatalysis accelerating or mediating the
process are rare.8
Photooxidation of Benzylamines
4-Methoxybenzylamine (3a) was chosen as substrate to
optimize the reaction conditions for the RFT-mediated
photooxidation to 4a. The course of the reactions were
monitored by 1H NMR analysis. Upon irradiation of a so-
lution of benzylamine 3a (c = 4·10–3 mol/L) in 1 mL of
D2O (containing 4% of DMSO-d6 and 10 mol% of RFT)
with blue light (440 nm, 3 W LED), a decrease in intensity
of the benzylamine resonance signals and the appearance
of the aldehyde 4a resonance signals was observed
(Figure 1, top). Only traces (<5%) of a side product, pre-
sumable the imine 5, could be detected. Without irradia-
tion, only 6% of aldehyde 4a was formed, whereas no
reaction occurred when the solution was irradiated in the
absence of RFT.
The oxidation of amines by flavin in either its ground or
excited state, has been studied extensively to elucidate the
SYNTHESIS 2010, No. 10, pp 1712–1718
x
x.
x
x
.
2
0
1
0
Advanced online publication: 26.03.2010
DOI: 10.1055/s-0029-1218709; Art ID: Z01810SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Benzylamine Oxidation by Flavin Photocatalysis
1713
Secondary amine 3e was photooxidized to aldehyde 4c,
and branched benzylamine 3f was likewise oxidized to the
corresponding ketone, but benzylamine 3g, having a tert-
butyl group on the benzyl position, was converted into al-
dehyde 4a through elimination of the substituent. This ob-
servation allows, in analogy to the photooxidation of 1-(4-
methoxyphenyl)-2,2-dimethylpropan-1-ol,11 the discrimi-
nation between electron-transfer and hydrogen-abstrac-
tion mechanisms for the photooxidation of benzylamines.
Under the applied reaction conditions, we exclusively ob-
serve the electron-transfer pathway. Phenyl glycine meth-
yl ester (3h) was not converted under the reaction
conditions.
Compounds 3i and 3k were investigated for photooxida-
tion as examples of aliphatic, rather than benzylic amines.
Butylamine 3i was not oxidized to butyraldehyde 4i and
rapid bleaching of RFT was observed after four minutes
of irradiation. Butylamine was consumed when the irradi-
ation time was prolonged to 60 minutes and the catalyst
loading enhanced (100 mol% RFT), but no aldehyde for-
mation could be detected by 1H NMR analysis.
Aliphatic amine 3k, which bears an electron-rich aromatic
system, was photooxidized under the standard conditions
to give aldehyde 4a and a small amount of an unidentified
side-product. The RFT photocatalyst bleached rapidly
during the conversion of this substrate and addition of
more RFT (two times 10 mol%) was necessary to com-
plete the reaction.
Figure 1 Photooxidation of 3a (4·10–3 mmol) to 4a with RFT (10
mol%) in D2O (1 mL, 4% DMSO-d6). Top: Stack plot of H NMR
spectra of the aromatic region (perspective view of spectra is used; no
chemically induced shift of resonance signals was observed); bottom:
reaction kinetic as monitored by NMR analysis.
1
As an example of a cyclic secondary benzylamine, tet-
rahydroisoquinoline 6 was submitted to the standard pho-
tooxidation conditions. Compound 6 was oxidized to the
corresponding isoquinoline 7 in nearly quantitative yield;
oxidative ring opening was not observed.
No catalytic turnover was observed when the reaction was
conducted in the absence of air oxygen. These findings
confirm the proposed photocatalytic reaction mechanism.
The quantum yield of the photocatalytic oxidation of 3a
was determined to be 0.023 [2.3%; c = 0.01 mol/L in 1
mL of H2O and 1 mL of MeCN, 10 mol% of RFT, blue
light (440 nm) irradiation]. At low catalyst concentrations
(0.1 mol%) and prolonged reaction time (60 min), a min-
imal turnover number (TON) of 910 was determined.
Imine 5 was formed exclusively when the reaction was
performed in anhydrous acetonitrile. To demonstrate the
use of the photocatalytic oxidation on a preparative scale,
1 mmol of 3a was converted into 4a using 1 mol% of
RFT; under these conditions, aldehyde 4a was isolated in
77% yield.
Photocatalytic Cleavage of Benzyl Protecting Groups
Benzyl protecting groups are widely used in organic syn-
thesis for the protection of amines, carboxylic acids and
alcohols. For their cleavage, various conditions are used,
e.g., reduction, acetylation or oxidation, depending on the
electron density on the benzyl protecting group.12 Howev-
er, benzyl deprotection in the presence of other functional
groups that are easy to oxidize or reduce, can be difficult.
One option to circumvent these problems is the use of
photochemical methods for removing benzyl protecting
groups.12
We investigated the use of the flavin-mediated photooxi-
dation of benzylamines described above, to remove ben-
zyl protecting groups under mild conditions to extend the
scope of photocleavage methods.
The optimized reaction conditions were then applied to
the photocatalytic conversion of a variety of benzyl-
amines; the results are summarised in Table 1.
The conversion rate of primary benzylamines depends on
the electronic character of the arene: Benzene rings bear-
ing electron-donating substituents lead to fast and com-
plete conversion, while electron-poor arenes decelerate
the photooxidation. This is in accordance with previous
observations on flavin-mediated photooxidation of benzyl
alcohols.4
Several benzyl-protected compounds were submitted to
flavin-mediated photodeprotection on an analytical scale
[c = 0.01 mol/L; 10 mol% of RFT in MeCN (0.5 mL) and
H2O (0.5 mL); LED irradiation]. Each sample was irradi-
ated by two LEDs (440 nm, 3 W) under stirring in capped
sample vials for the time given in Table 2.
Synthesis 2010, No. 10, 1712–1718 © Thieme Stuttgart · New York

1714
R. Lechner, B. König
PAPER
Table 1 Photocatalytic Oxidation of Benzylaminesa
Table 1 Photocatalytic Oxidation of Benzylaminesa (continued)
R2
R2
RFT (10 mol%)
air, D2O–DMSO-d6
(24:1), LED 440 nm
RFT (10 mol%)
air, D2O–DMSO-d6
(24:1), LED 440 nm
R1
R1
N
N
H
O
O
X
H
X
X
X
10 min
10 min
Z
Z
Z
Z
4
3
4
3
Amine
Product
Conversion
(%)b
Amine
Product
Conversion
(%)b
96
6c
MeO
MeO
NH
N
97k
NH2
0d
O
MeO
MeO
31e
91f
77g
MeO
MeO
6
7
3a
4a
a Reaction conditions: amine (4·10–3 mmol) in D2O (1 mL, 4%
DMSO-d6), RFT (10 mol%), Irradiation for 10 min at 440 nm (LED).
b Determined by 1H NMR analysis.
OMe
c Without irradiation.
d Without catalyst.
NH2
e RFT 0.1 mol%, reaction time 60 min.
f RFT 30 mol%, 20% DMSO-d6, deoxygenated solution.
g Isolated yield, amine (1 mmol), RFT (1 mol%), reaction time 2 h.
h Amine (0.1 mmol), anhydrous MeCN (1 mL).
i Reaction time 4 min.
95h
MeO
N
3a
OMe
j RFT 30 mol%, reaction time 15 min.
k 24% DMSO-d6.
5
NH2
O
79
16
50
90
As expected from the results for the benzylamine oxida-
tions, the unsubstituted benzyl protecting group (Bzl) was
cleaved slower from primary amines than the 4-methoxy-
benzyl (Mob) group: The Mob protecting group was
cleaved within 15 minutes giving only amines 10 and 13,
aldehyde 4a and RFT, as indicated by HPLC (entries 1–
3). Protected prolines 14 and 16 (entries 4 and 5) gave
complex product mixtures upon photocatalytic flavin ox-
idation. In these cases, the deprotected secondary amine
may act as an electron donor for the flavin, yielding un-
wanted amine oxidation side-products. The allylic double
bond was not affected by flavin-mediated photodeprotec-
tion of allyl-amine 17 (entry 6), which was deprotected
without any detectable side-products within 15 minutes.
At pH 3 (adjusted by 0.1 N HCl), Mob-protected nitro-
aniline 19 (entry 7) was deprotected in a clean reaction,
whereas a complex product mixture was obtained in a
H2O–MeCN mixture. This might be the result of over-
oxidation of the product of the deprotection reaction,
aniline (20), as in the case of secondary amines.
3b
4b
NH2
O
HOOC
HOOC
3c
4c
NH2
O
N
N
3d
4d
N
O
H
MeO
MeO
3e
4e
O
NH2
44
95
3f
4f
t-Bu
NH2
O
MeO
MeO
4a
The Mob-protected carboxylic acid 21 (entry 8) was part-
ly deprotected under the applied conditions, whereas no
conversion was obtained for the Bzl-protected acid 23
(entry 9).
3g
COOMe
NH2
COOMe
O
0
The protected alcohols 25 and 27 behaved similarly: Only
the Mob group was partly cleaved under photocatalytic
oxidation conditions (entry 10) within 15 minutes, where-
as the Bzl-protecting group showed no reactivity at all.
Mob-protected phenol 29 was deprotected (aldehyde 4a
was detected), but phenol 30 was immediately further ox-
idized to unidentified products under the photooxidative
conditions.
4h
4i
3h
3i
0i
NH2
O
NH2
O
89j
MeO
MeO
4a
3k
Synthesis 2010, No. 10, 1712–1718 © Thieme Stuttgart · New York

PAPER
Benzylamine Oxidation by Flavin Photocatalysis
1715
The carboxybenzoyl (Cbz) protected amines in com- 3. The presence of RFT and blue light irradiation is there-
pounds 31 and 33 were not affected under the reaction fore essential for the benzyl photodeprotection.
conditions (entries 13 and 14), which should allow the se-
lective deprotection of benzyl-protected amines in the
presence of a Cbz-protected amine.
Compounds 11 and 25 were photodeprotected on a 1
mmol scale (entries 2 and 10). For ease of purification,
only 1 mol% of RFT was used as photocatalyst and the re-
Sodium dibenzyl phosphonate 35 (entry 16) did not react actions were performed under acidic conditions (pH 3 ad-
under the applied reaction conditions. The solvent mixture justed with 0.1 N HCl)13 in 250 mL Erlenmeyer flasks
of water and acetonitrile used for the deprotection reaction under irradiation with 12 LEDs (3 W each).14 The hydro-
is of importance because no deprotection of the com- chloride salt of phenylalanine methyl ester was isolated by
pounds shown in entries 2, 8 and 10 was observed using extraction and crystallization in 90% yield after 60 min-
acetonitrile without addition of water. No reactions were utes irradiation of compound 11. The deprotected alcohol
observed when solutions of compounds 11 and 25 were ir- 26 was isolated in 65% yield via column chromatography
radiated in the absence of RFT or when the samples were after 60 minutes of irradiation. All analytical data, includ-
stirred in the dark in the presence of 10 mol% RFT at pH ing optical rotation of phenylalanine methyl ester hydro-
Table 2 Photocatalytic Deprotection of Benzyl Compoundsa
Entry Benzyl-protected
compound
Product
Conversion Time Entry Starting material
Product
Conversion Time
(%)b
(min)
(%)b
(min)
COOMe
Ph
COOMe
COOBzl
NHBoc
COOH
NHBoc
Ph
Ph
Ph
1
81
60
9
10
11
0
30
NH
NH2
Bzl
23
24
10
9
COOMe
COOMe
Ph
Ph
OMob
NHBoc
Ph
Ph
OH
NHBoc
91
45
2
15
15
30
30
90c
65c
NH
NH2
Mob
11
25
Ph
27
26
Ph
28
10
COOMe
COOMe
NH2
OBzl
NHBoc
OH
NHBoc
3
99
0
NH
Mob
13
15
12
OMob
OH
product
COOMe
4
15
15
12
13
0d
30
60
COOMe
N
mixtured
N
H
Mob
29
30
14
HO
HO
product
COOMe
COOMe
NH2
5
0
N
COOBzl
COOMe
mixtured
COOBzl
N
H
N
N
H
Bzl
Cbz
15
18
16
17
32
31
COOMe
NH2
HO
NHMob
HO
6
7
99
15
30
14
15
0
0
60
NHCbz
33
34
O
NHMob
NH2
O
P
O–
98e
240
P
BzlO
OBzl
Na+
BzlO
OH
O2N
O2N
OH
36a
19
20
35
O
COOMob
NHBoc
COOH
NHBoc
Ph
Ph
P
8
9
30
HO
OH
OH
21
22
36b
a Reaction conditions: substrate (0.01 mmol) in H2O (0.5 mL) and MeCN (0.5 mL), RFT (10 mol%), irradiation at 440 nm with two LEDs
(3 W each) for the time indicated.
b Calculated from crude HPLC data of reaction mixtures.
c Isolated yield. Substrate (1.0 mmol), RFT (1 mol%), pH 3 adjusted with 0.1 N HCl, reaction time 60 min.
d Starting material was consumed.
e pH 3 adjusted with 0.1 N HCl.
Synthesis 2010, No. 10, 1712–1718 © Thieme Stuttgart · New York

1716
R. Lechner, B. König
PAPER
Benzylamine Photooxidation on 1 mmol Scale; Typical Proce-
dure
chloride and alcohol 26, were consistent with the
analytical data of authentic samples.
4-Methoxybenzylamine (3a; 1.0 mmol) and RFT (0.01 mmol) were
dissolved in MeCN–H2O (4 mL/96 mL). The mixture was irradiated
at 440 nm with 12 LEDs (3 W each) in a 250-mL Erlenmeyer flask,
open to air, for 2 h. The pH was adjusted to 1 by addition of 1 N HCl
and the product was extracted into Et2O. The organic layer was
dried over MgSO4, concentrated and the residue was taken up in PE
and filtered. Concentration of the filtrate gave aldehyde 4a as a co-
lourless oil (105 mg, 0.77 mmol, 77%).
In conclusion, photocatalytic oxidation of benzylamines
to their corresponding aldehydes under mild conditions
without over-oxidation has been accomplished using RFT
as photocatalyst. The use of LEDs emitting in the visible
region at 440 nm as light source for RFT excitation avoids
undesired non-sensitized photo processes. Oxygen is em-
ployed as the terminal oxidant and H2O2 and NH3 appear
as sole side-products of the oxidation of primary benzyl-
amines. The protocol is limited to benzylic amines bear-
ing an electron-rich arene group.
Benzylamine Photodeprotection Reaction on an Analytical
Scale; General Procedure
A reaction mixture containing the benzyl-protected compound
(0.01 mmol) and RFT (10 mol%) in MeCN (0.5 mL) and H2O (0.5
mL) was irradiated at 440 nm with two LEDs (3 W each) in a
capped sample vial under air. When anaerobic or anhydrous condi-
tions were used for comparison, the reaction mixtures were irradiat-
ed under inert atmosphere in sample vials capped with septa or vials
mounted with CaCl2-filled syringes. Degassing of solutions was
achieved by three freeze-pump-thaw cycles.
Furthermore, we have developed a photocatalytic proto-
col for Mob group deprotection of primary amines and al-
cohols. Double bonds, benzyl-protected esters and
alcohols are tolerated under the applied conditions. Mob
esters react much slower and Cbz-protected amines and
benzyl phosphate esters are inert under the photodeprotec-
tion conditions. The deprotection of protected secondary
amines is not applicable, presumable due to the oxidation
of the electron-rich secondary amines by excited RFT.
Photodeprotection Reaction on 1 mmol Scale; General Proce-
dure
A reaction mixture containing the benzyl-protected amine (1.0
mmol) and RFT (1 mol%) in MeCN (50 mL) and H2O (50 mL) at
pH 3 (adjusted by 0.1 N HCl), was irradiated at 440 nm with 12
LEDs (3 W each) in a 250 mL Erlenmeyer flask open to air. The
conversion was monitored by TLC until completion of the reaction.
MeCN was removed in vaccuo and the residue was washed with
Et2O. Concentration of the aqueous layer by lyophilization gave the
crude product, which was crystallized from acetone–Et2O in the
case of the hydrochloride salt of phenylalanine methyl ester, or pu-
rified over silica (PE–EtOAc) in the case of compound 26.
The reported procedures are easy to perform and robust on
a laboratory scale. The photocatalyst and the light sources
are readily available and the application limits of the pro-
cess are well defined, which facilitate their use in organic
synthesis.
Tetraacetyl riboflavin,10 N-propyl-4-methoxybenzylamine (3e),15
2-(4-methoxyphenyl)ethanamine (3k),16 Bzl-Phe-OMe (9), Mob-
Phe-OMe (11), Mob-Ala-OMe (12),17 Mob-Pro-OMe (14),18 Bzl-
Pro-OMe (16),19 Boc-Phe-OMob (21),20 Boc-Phe-OBzl (23),21 tert-
butyl 1-(benzyloxy)-3-phenylpropan-2-ylcarbamate (27),22 and
Cbz-(OH)-Pro-OBzl (31),23 were prepared as previously reported.
All other chemicals were purchased from commercial suppliers and
used as received. Anhydrous DMF was purchased from Fluka. TLC
was performed on silica gel 60 F254 aluminium sheets (Merck),
with detection under 254 nm or 333 nm UV light. Flash column
chromatography was carried out on silica gel (0.035–0.070 mm, 60
Å), obtained from Acros. NMR spectra were recorded with a Bruker
spectrometer operating at 300 MHz (1H NMR) or 75 MHz (13C
NMR) with TMS as the external standard. Electron-impact (EI) and
chemical ionization (CI) mass spectra were recorded with a Finni-
gan TSQ 710 spectrometer. Electrospray ionization (ES) mass spec-
tra were recorded with a ThermoQuest Finnigan MAT 9595
spectrometer. IR spectra were recorded with a Biorad Spectrometer
Excalibur FTS 3000. Optical rotation was recorded with a Perkin–
Elmer 241 Polarimeter. Melting points were determined with a
Lambda Photometrics OptiMelt MPA 100. Luxeon high power roy-
al blue LEDs [3 W, irradiation maximum 440 nm (+/– 10 nm)] were
used as light sources. Petroleum ether (PE), where used, had a boil-
ing range of 60–80 °C.
1-(4-Methoxyphenyl)-2,2-dimethylpropan-1-one24
Anisole (2.16 g, 20 mmol) and pivaloyl chloride (1.21 g, 10 mmol)
were dissolved in toluene (6 mL) and AlCl3 (1.33 g, 20 mmol) was
added. The mixture was stirred at 70 °C for 20 min, cooled and 1 N
HCl was added. The product was extracted into PE (3 × 10 mL), the
organic layer was washed with sat. NaHCO3 (30 mL) and dried over
MgSO4. Removal of the solvent and Kugelrohr distillation (160 °C/
0.99 mbar) gave the title compound.
Yield: 1.56 g (81%); colourless oil.
1H NMR (300 MHz, CDCl3): d = 7.85 (d, J = 9.06 Hz, 2 H, ArH),
6.90 (d, J = 9.06 Hz, 2 H, ArH), 3.85 (s, 3 H, CH3), 1.37 (s, 9 H,
CH3).
13C NMR (75 MHz, CDCl3): d = 206.3 (q, 1 × C), 162.0 (q, 1 × C),
131.0 (+, 2 × C), 130.1 (q, 1 × C), 113.2 (+, 2 × C), 55.4 (+, 1 × C),
43.9 (q, 1 × C), 28.4 (+, 3 × C).
MS (EI): m/z (%) = 192.1 (4) [M]+, 135.0 (100).
1-(4-Methoxyphenyl)-2,2-dimethylpropan-1-amine (3g)
1-(4-Methoxyphenyl)-2,2-dimethylpropan-1-one (580 mg, 3.0
mmol) was dissolved in formamide (6 mL) and formic acid (3 mL)
and the mixture was heated at reflux for 2 h. H2O (20 mL) and Et2O
(20 mL) were added, and the organic layer was separated and
washed with brine (30 mL), dried over MgSO4 and the solvent was
removed. The residue was dissolved in 1 N HCl (15 mL) and the
mixture was heated at reflux for 1 h. The mixture was diluted with
H2O (50 mL) and a pH >10 was set by the addition of solid NaOH.
The product was extracted into Et2O (3 × 15 mL), the organic layer
was dried over MgSO4 and the solvent was removed to yield the title
compound that solidified upon cooling.
Photooxidation of Benzyl Amines on an Analytical Scale; Gen-
eral Procedure
Reaction mixtures of the amine (4·10–3 mmol) and RFT (10 mol%)
in D2O (1 mL) containing 4% DMSO-d6 were irradiated by one
LED (3 W; 440 nm) in capped sample vials. The course of the reac-
tion was monitored by 1H NMR analysis.
Synthesis 2010, No. 10, 1712–1718 © Thieme Stuttgart · New York

PAPER
Benzylamine Oxidation by Flavin Photocatalysis
1717
Yield: 480 mg (83%); pale-yellow oil; mp 44–45 °C; Rf = 0.2
(CHCl3–MeOH, 9:1).
tion was quenched with sat. NH4Cl (20 mL) and H2O (20 mL) was
added. The product was extracted into Et2O (3 × 15 mL), and the or-
ganic layer was washed with brine (20 mL), dried over MgSO4 and
concentrated. Purification over silica (PE–EtOAc) gave the title
compound.
IR (ATR): 3374, 3011, 2957, 2867, 1612, 1584, 1515, 1247, 1192,
1032, 818 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.21 (d, J = 8.78 Hz, 2 H, ArH),
6.83 (d, J = 8.78 Hz, 2 H, ArH), 3.80 (s, 3 H, CH3), 3.67 (s, 1 H,
CH), 1.74 (br s, 2 H, NH2), 0.89 (s, 9 H, CH3).
13C NMR (75 MHz, CDCl3): d = 158.4 (q, 1 × C), 135.7 (q, 1 × C),
129.2 (+, 2 × C), 112.9 (+, 2 × C), 64.7 (+, 1 × C), 55.2 (+, 1 × C),
35.1 (q, 1 × C), 26.8 (+, 1 × C), 26.5 (+, 1 × C), 26.4 (+, 1 × C).
Yield: 1.44 g (3.86 mmol, 64%); colourless solid.
1H NMR (300 MHz, CDCl3): d = 7.27 (d, J = 8.51 Hz, 2 H, ArH),
7.25–7.15 (m, 5 H, ArH), 6.90 (d, J = 8.51 Hz, 2 H, ArH), 4.93–
4.87 (m, 1 H), 4.48 (d, J = 11.52 Hz, 1 H, CH2), 4.39 (d,
J = 11.52 Hz, 1 H, CH2), 3.93 (br s, 1 H), 3.82 (s, 3 H, CH3), 3.40–
3.31 (m, 2 H, CH2), 2.94–2.80 (m, 2 H, CH2), 1.42 (s, 9 H, CH3).
MS (CI, NH3): m/z (%) = 194.2 (17) [M + H]+, 177.1 (100).
13C NMR (75 MHz, CDCl3): d = 159.3 (q, 1 × C), 155.4 (q, 1 × C),
138.3 (q, 1 × C), 130.2 (q, 1 × C), 129.5 (+, 2 × C), 129.5 (+, 2 × C),
128.4 (+, 2 × C), 126.3 (+, 2 × C), 79.3 (q, 1 × C), 72.9 (–, 1 × C),
69.7 (–, 1 × C), 55.3 (+, 1 × C), 51.7 (+, 1 × C), 37.9 (–, 1 × C), 28.4
(+, 3 × C).
N-(4-Methoxybenzyl)prop-2-en-1-amine (17)25
Allylamine (428 mg, 7.5 mmol) and 4-methoxybenzaldehyde (4a;
1.36 g, 10 mmol) were dissolved in EtOH (15 mL) and the solution
was stirred at r.t. for 18 h. NaBH4 (709 mg, 18.7 mmol) was added
and the mixture was stirred until gas evolution had ceased. H3PO4
(0.5 N, 10 mL) was added and the mixture was further stirred until
gas evolution had ceased. The product was extracted into CH2Cl2
(3 × 10 mL), dried over MgSO4 and the solvent was removed. The
residue was purified by Kugelrohr distillation (125 °C/0.12 mbar)
to yield the title compound.
MS (ESI): m/z (%) = 372.0 (100) [M + H]+.
1-Methoxy-4-(phenoxymethyl)benzene (29)28
4-Methoxybenzyl chloride (320 mg, 2.05 mmol) was added to a
mixture of phenol (565 mg, 6.0 mmol) and K2CO3 (1000 mg) in an-
hydrous acetone (10 mL) under nitrogen. The mixture was heated at
reflux for 18 h, cooled and filtered. After removing the solvent, the
crude product was purified over silica to yield the title compound.
Colourless oil.
1H NMR (300 MHz, CDCl3): d = 7.25 (d, J = 8.76 Hz, 2 H, ArH),
6.88 (d, J = 8.76 Hz, 2 H, ArH), 5.98–5.86 (m, 1 H, CH), 5.22–5.15
(m, 1 H, CH2), 5.13–5.08 (m, 1 H, CH2), 3.79 (s, 3 H, CH3), 3.73 (s,
2 H, CH2), 3.27 (d, J = 6.03 Hz, 2 H, CH2), 1.44 (br s, 1 H, NH).
13C NMR (75 MHz, CDCl3): d = 158.6 (q, 1 × C), 136.9 (+, 1 × C),
132.4 (q, 1 × C), 129.4 (+, 2 × C), 116 (–, 1 × C), 113.8 (+, 2 × C),
55.3 (+, 1 × C), 52.7 (–, 1 × C), 51.7 (–, 1 × C).
Yield: 360 mg (1.98 mmol, 82%); colourless solid.
1H NMR (300 MHz, CDCl3): d = 7.38 (d, J = 8.78 Hz, 2 H, ArH),
7.33–7.27 (m, 2 H, ArH), 7.00–6.97 (m, 3 H, ArH), 6.93 (d,
J = 8.78 Hz, 2 H, ArH), 5.00 (s, 2 H, CH2), 3.83 (s, 3 H, CH3).
13C NMR (75 MHz, CDCl3): d = 159.5 (q, 1 × C), 158.9 (q, 1 × C),
129.5 (+, 2 × C), 129.3 (+, 2 × C), 129.1 (q, 1 × C), 120.9 (+, 1 × C),
114.9 (+, 2 × C), 114.0 (+, 2 × C), 69.7 (–, 1 × C), 55.3 (+, 1 × C).
MS (CI, NH3): m/z (%) = 178.1 (100) [M + H]+.
MS (EI): m/z (%) = 214.1 (2) [M]+, 121.1 (100).
N-(4-Methoxybenzyl)-4-nitrobenzenamine (19)26
4-Nitroaniline (1.04 g, 7.5 mmol) and 4-methoxybenzaldehyde (4a;
1.02 g, 7.5 mmol) were dissolved in MeOH (15 mL) and the solu-
tion was stirred at r.t. for 18 h. NaBH4 (709 mg, 18.75 mmol) was
added and the mixture was stirred until gas evolution had ceased.
H2O (30 mL) was added to the mixture and the product was extract-
ed into EtOAc (3 × 10 mL). The organic layer was washed with 1 N
HCl (20 mL), sat. NaHCO3 (20 mL), dried over MgSO4 and the sol-
vent was removed. Purification over silica (CHCl3) gave the title
compound.
Acknowledgment
We thank the Deutsche Forschungsgemeinschaft (GRK 1626), the
Fonds der Chemischen Industrie and the University of Regensburg
for support of our research.
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tert-Butyl 1-(4-Methoxybenzyloxy)-3-phenylpropan-2-ylcar-
bamate (25)27
Boc-phenylalaninol (1.5 g, 6.0 mmol) was dissolved in anhydrous
DMF (12 mL) under a nitrogen atmosphere. The solution was
cooled to 0 °C and NaH (60%, 552 mg, 13.8 mmol) was added por-
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Synthesis 2010, No. 10, 1712–1718 © Thieme Stuttgart · New York

1718
R. Lechner, B. König
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Synthesis 2010, No. 10, 1712–1718 © Thieme Stuttgart · New York