Selective C-H Activation of Methoxy Groups in a Three-Component Photoreaction

Article abstract of DOI:10.1021/acs.joc.5b02373

Surprisingly, the photocatalytic activation of ethers by H-abstraction and addition of the generated radicals to iminium ions formed in situ from aldehydes and anilines predominantly yielded the products of methoxy activation for dimethoxymethane and 1,2-dimethoxyethane. Various anilines and aromatic as well as aliphatic aldehydes are suitable reaction partners for this three-component photoreaction (Porta-type process) which also provides a simple access to 1,2-aminoalcohols.

Full text of DOI:10.1021/acs.joc.5b02373

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Note
Selective C–H-Activation of Methoxy Groups
in a Three-Component Photoreaction
Günther Lahm, and Till Opatz
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02373 • Publication Date (Web): 17 Nov 2015
Downloaded from http://pubs.acs.org on November 24, 2015
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Selective C–H-Activation of Methoxy Groups in a
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Günther Lahm and Till Opatz*
Address: Institute of Organic Chemistry, University of Mainz, Duesbergweg 10–14, Dꢀ55128
Mainz, Germany
Email: opatz@uniꢀmainz.de
Table of Contents/ Abstract Graphic
O
O
n
TiO2, H2O,
R2
n = 1, 2
NH2 (NH ) S O ,
R1
N
O
H
4 2 2 8
R1
R2
h (350 nm), rt
O
n
OH
O
aq HCl
R2
R2
R1
(for n = 1)
R1
N
H
N
H
1,2-aminoalcohols
methoxy selectivity
Abstract
Surprisingly, the photocatalytic activation of ethers by Hꢀabstraction and addition of the
generated radicals to iminium ions formed in situ from aldehydes and anilines predominantly
yielded the products of methoxy activation for dimethoxymethane and 1,2ꢀdimethoxyethane.
Various anilines and aromatic as well as aliphatic aldehydes are suitable reaction partners for this
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threeꢀcomponent photoreaction (Portaꢀtype process) which also provides a simple access to 1,2ꢀ
aminoalcohols.
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Regioselectivity is an important goal in organic synthesis. In particular, manipulations of
unactivated C–H bonds are highly attractive elements for step economic syntheses and currently
1
ꢀ7
represent one of the most active research fields in organic chemistry. The growing demand for
waste and resources minimization calls for new and efficient processes utilizing abundantly
8
ꢀ15
available building blocks. Multicomponent reactions.
or modular oneꢀpot syntheses which
comprise a regioselective activation of an unactivated C–H bond may fulfil these criteria. Here,
we report a simple oneꢀpot procedure for the lightꢀinduced coupling reaction of
dimethoxymethane (DMM) or 1,2ꢀdimethoxyethane (DME) with anilines and aldehydes. The
products resulting from DMM can be easily transformed into 1,2ꢀaminoalcohols which are key
16
elements of a wide variety of bioactive compounds.
17
In the course of our work on protoberberine alkaloids we were in need of a facile synthesis of
18ꢀ21
αꢀaminoaldehydes. The photochemical version of the Portaꢀtype reaction
of anilines,
22
benzaldehydes and 1,3ꢀdioxolane reported by Shi appeared attractive as it provides Nꢀ[1,3ꢀ
dioxolanꢀ2ꢀyl(aryl)methyl]anilines, protected αꢀaminoaldehydes, in a single operation. When the
1,3ꢀdioxolane was replaced by DMM in the expectation to obtain the dimethyl acetal of an αꢀ
aminoaldehyde, the product of methoxy activation was surprisingly obtained as the major
regioisomer. The same unexpected observation was made for 1,2ꢀdimethoxyethane. In most
1
cases, the isomeric ratio determined by H NMR spectroscopy of the crude reaction mixtures was
higher than anticipated statistically (3:1 for DMM, 3:2 for DME). Remarkably, previous reports
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on the radical addition of DMM to Nꢀsulfonylimines (Scheme 1) or of DME to electron deficient
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nitrogen heterocycles all describe selectivity for the methylene position.
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Scheme 1. Radical addition of dimethoxymethane to imines.
Previous work
Tomioka, 2002
O
O
O
O
S
O
S
O
O
Me Zn
2
N
N
O
H
0° C
methylene selectivity
Shi, 2013
O
O
TiO /(NH ) S O
8
O
O
2
4 2
2
R2
CHO
NH2
h
(350 nm), rt
R1
R1
R2
N
H
methylene selectivity
O
This work
O
O
O
TiO /(NH ) S O
8
2
4 2
2
R2
O
R1
h (350 nm), rt
NH2
R1
N
R2
H
H
methoxy selectivity
The course of the reaction presumably involves Hꢀabstraction from the methoxy group of the
ether by the TiO photocatalyst or sulfate radicals generated by persulfate cleavage. The resulting
2
alkoxymethylene radicals are nucleophilic due to overlap of the SOMO with the lone pairs at
oxygen and preferably add to the electron deficient C=N bond of iminium ions formed in situ
2
5
from the aldehyde and the amine component (Scheme 2).
Scheme 2. Proposed reaction mechanism.
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While both TiO and UV irradiation turned out to be necessary, the persulfate additive could be
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omitted at the expense of the reaction rate. To explore the scope of the photochemical threeꢀ
component reaction, various amines and aldehydes were reacted with an aqueous solution of
DMM (1:1) containing TiO and (NH ) S O under UV irradiation (350 nm) in a sealed tube
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4 2
2
8
(argon) at room temperature (Table 1).
Table 1. Addition of DMM to imines formed in situ.
[a]
[d]
Entry
Αniline
Benzaldehyde
Product
Yield
Isomeric ratio
1
66%
72%
58%
4.5:1
2
3
4.5:1
5.9:1
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87%
12.5:1
4.2:1
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[b]
75%
NH2
[
b]
6
7
8
77%
71%
[c]
4.2:1
3.0:1
1
f
[b]
O
O
OH
NH2
N
H
1
g
OH
10
Cl
CHO
Cl
9
traces
[c]
2c
1
0
1
1
1
52%
[e]
2.8:1
2
[
a] Yields are those of products isolated by chromatography; [b] Minor regioisomeres could not be separated; [c]
Product could not be detected via NMR or ESIꢀMS; [d] Regioisomeric ratio of methoxyꢀ vs. methylene activation
determined by H NMR spectroscopy of the crude reaction mixture; [e] Complex mixture.
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The products of the methoxy activation could be obtained in moderate to high yields of 52–87%.
For compounds 7–9, the minor regioisomer resulting from methylene activation could not be
removed by chromatography. 2ꢀAminophenol (1g) or 4ꢀ(dimethylamino)benzaldehyde (2d) were
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no suitable substrates for the three component reaction under identical conditions. In the case of
1
1
g (entry 8), no imine formation was detected under the reaction conditions ( H NMR) and
decomposition occurred presumably due to the tendency of the amine component to undergo oneꢀ
electron oxidation. For aldehyde 2c, steric hindrance might have led to a significant reduction of
the reaction rate. Compounds 1b and 2d formed the required imine but no radical addition took
place, possibly due an unfavourably high electron density (entry 10). While moderate to high
yields were obtained for the reaction of anilines, aliphatic amines failed to give the expected
products of radical addition. The lacking stabilization of the aminium radical cation B (Scheme 2)
resulting from C–C bond formation could account for this behavior. In extension of the scope
2
2
reported by Shi et al., aliphatic aldehydes can also be employed although the use of unbranched
representatives like pentanal resulted in complex mixtures (Table 1, entry 2f). The photochemical
three component Portaꢀtype reaction with DME is also efficient and provided the products of
methoxy activation in moderate to good yields of 38–64% under identical conditions. The results
are summarized in table 2.
Table 2. Addition of DME to in situ formed imines.
[a]
[b]
Entry
Αniline
Benzaldehyde
Product
Yield
Isomeric ratio
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61%
64%
43%
2.6:1
2.9:1
[c]
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O
O
N
H
1
7
4
5
52%
38%
2.4:1
[c]
[
a] Yields are those of products isolated by chromatography; [b] Regioisomeric ratio of methoxyꢀ vs. methylene
activation determined by H NMR spectroscopy of the crude reaction mixture taking into account all stereoisomers;
[c] Regioisomeric ratio could not be determined due to signal overlap in H NMR.
1
1
The reaction works for the same starting materials as used in combination with DMM. Compared
to the products of table 1, the regioisomeric ratios in table 2 are lower. This might be due to the
statistical effect combined with a smaller difference in accessibility in the Hꢀabstraction and
stability as well as reactivity for the two radical species formed from DME.
In case of the reaction with DMM, the methoxy activation provides a simple access to 1,2ꢀ
2
6ꢀ28
aminoalcohols which are e.g. an important compound class in medicinal chemistry.
In
29ꢀ38
comparison to many other methods for their synthesis,
hydroxymethylations of imines can be a simple and cheap alternative.
nucleophilic radical
1
8,39ꢀ42
In our case, the
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MOMꢀgroup can be removed from the addition products with aqueous HCl in THF at 60 °C. The
corresponding aminoalcohols 20a and 20b were obtained over two steps in yields of 48% and
42%, respectively (Scheme 3).
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Scheme 3. Preparation of 1,2ꢀaminoalcohols.
In summary, the photochemical Portaꢀtype addition of open chain ethers such as DME and DMM
to in situ formed imines was found to show a surprising selectivity for the C–H activation at the
methoxy group. The use of MTBE or anisole as alternative methoxyꢀfunctionalized ether
substrates only led to very low conversion under identical as judged by HPLC/MS instead.
Currently, we have no experimental evidence as to whether the observed regioselectivity for
DMM and DME is due to a preference of the photogenerated Hꢀabstracting species (vide supra)
for the sterically less hindered methoxy Hꢀatoms or to the reported instability of the
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3
dimethoxymethyl radical generated from DMM. However, no products resulting from methyl
radicals generated in the fragmentation of the dimethoxymethyl radical to methyl formate were
found. As the latter radical is more nucleophilic than its (methoxymethoxy)methyl isomer, the
rate of its reaction with electron deficient iminium ions should be higher. Preliminary calculations
at the UB3LYP/6ꢀ311G(2d,p) level of theory (data not shown) indicated the dimethoxymethyl
radical to be more stable by about 4.7 kcal/mol. An interconversion of the less stable, less
nucleophilic to the more stable, more nucleophilic radical by Hꢀabstraction from another
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molecule of DMM might explain why more electrophilic iminium species such as those derived
from 1c or 1d show higher selectivity for the products of methoxy activation. In the case of less
reactive iminium salts, longer radical lifetimes would favor this interconversion. This however
would require an as yet unseen preference for initial Hꢀabstraction at the methoxy group but
could explain the complementary behavior compared to known radical functionalizations of the
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same radical precursor. The reported threeꢀcomponent reaction is robust and uses only cheap
and readily available starting materials and reagents. Being one of the very rare cases of a C–H
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functionalization at methoxy groups,
it permits the synthesis of βꢀaminoethers in a single
operation with 100% atom economy and can be used to produce βꢀaminoalcohols in an additional
step.
Experimental Section
All reagents and solvents were obtained from commercial suppliers without further purification.
Anhydrous DME was distilled from potassium / benzophenone under argon. Melting points were
determined in open capillary tubes. NMR spectra were recorded with a 300 MHz spectrometer
1
13
1
13
(300 MHz H and 75.5 MHz C), a 400 MHz (400 MHz H and 100.6 MHz C) or with a 600
1
13
MHz spectrometer (600 MHz H and 151 MHz C) with digital architecture and equipped with 5
mm probes. The δ values are reported in parts per million (ppm) downfield from TMS and were
referenced to the residual solvent signal (CHCl , 7.26 ppm). Coupling constants J are given in
3
Hertz (Hz). IR spectra were recorded using a diamond ATR unit and are reported in terms of
–
1
frequency of absorption (ν, cm ). ESIꢀHRMS spectra were recorded on a QꢀTOF instrument
with a dual source and a suitable external calibrant. Preparative thinꢀlayer chromatography was
carried out on 2ꢀmm silica gel plates with fluorescence indicator. Substance bands were detected
by illumination with UV light (254 and 360 nm).
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General experimental procedure for the addition reactions:
TiO (20 mg, 0.25 mmol, 1.3 eq) and (NH ) S O (6.0 mg, 0.026 mmol, 0.13 eq) were dispersed
2
4 2
2
8
0
1
2
3
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8
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in a mixture of water (2.5 mL) and the respective ether (2.5 mL). After the addition of aldehyde
0.30 mmol, 1.5 eq) and amine (0.20 mmol), the reaction mixture was degassed by argon
(
bubbling for 1 min and stirred for 20 h under UVꢀA irradiation (400 W) at room temperature. The
mixture was filtered and the filter cake was washed with DCM (40 mL) and ethyl acetate (40
mL). The combined filtrates were concentrated in vacuo and the resulting crude product was
purified by chromatography unless otherwise noted.
N-[2-(Methoxymethoxy)-1-phenylethyl]aniline (3)
According to the general procedure, benzaldehyde (2a, 31.8 mg, 0.30 mmol 1.5 eq) was reacted
with aniline (1a, 18.6 mg, 0.20 mmol) and DMM (2.5 mL). After 20 h, purification by thinꢀlayer
chromatography (cyclohexane/AcOEt/NEt = 7.0/2.5/0.5) afforded the title compound (33.4 mg,
3
65%) as a colorless oil.
R = 0.60 (cyclohexane/AcOEt/Et N = 7.5/2.0/0.5). IR (ATR): 3397 (m, br), 2948 (s, sh), 2887
f
3
1
(
m), 1733 (m), 1603 (s), 1505 (s), 1109 (s), 1036 (s), 751 (s), 701 (s). H NMR, COSY (300
MHz, CDCl3): = 7.45–7.39 (m, 2H, Hꢀ2'', Hꢀ6''), 7.37–7.29 (m, 2H, Hꢀ3'', Hꢀ5''), 7.28–7.24 (m,
1H, Hꢀ4''), 7.13–7.05 (m, 2H, Hꢀ3, Hꢀ5), 6.66 (tt, J = 7.4, 1.3 Hz, 1H, Hꢀ4), 6.57–6.51 (m, 2H, Hꢀ
, Hꢀ6), 4.68 (d, J = 6.6 Hz, 1H, OCH O), 4.63 (d, J = 6.6 Hz, 1H, OCH O), 4.53 (dd, J = 8.0, 4.1
δ
2
2
2
Hz, 1H, Hꢀ1'), 3.86 (dd, J = 10.4, 4.1 Hz, 1H, H ꢀ2'), 3.66 (dd, J = 10.4, 8.0 Hz, 1H, H ꢀ2'), 3.32
a
b
13
(
s, 3H, OCH ). C NMR, HMBC, HSQC (75 MHz, CDCl ):
δ
= 147.7 (C1), 140.7 (C1''), 129.2
3
3
(C3, C5), 128.8 (C3'', C5''), 127.6, (C4''), 126.9 (C2'', C6''), 117.8 (C4), 113.9 (C2, C6), 96.8
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+
(
OCH O), 72.5 (C2'), 58.4 (C1'), 55.6 (OCH ). ESIꢀMS: m/z (%) = 258.1 (100) [M+H] . ESIꢀ
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+
HRMS: calcd for [C H NO ] : m/z = 258.1494, found: 258.1499.
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N-[2-(Methoxymethoxy)-1-phenylethyl]-4-methylaniline (4)
According to the general procedure, benzaldehyde (2a, 31.8 mg, 0.30 mmol 1.5 eq) was reacted
with pꢀtoluidine (1b, 21.4 mg, 0.20 mmol) and DMM (2.5 mL). After 20 h, purification by thinꢀ
layer chromatography (cyclohexane/AcOEt = 7/3) afforded the title compound (38.1 mg, 70%) as
a pale yellow oil.
R = 0.51 (cyclohexane/AcOEt = 7/3). IR (ATR): 3395 (w, br), 2884 (m, sh), 2825 (m), 1733 (w),
f
1
1
618 (m), 1520 (s), 1151 (m), 1108 (s), 1037 (s), 701 (m). H NMR, COSY (400 MHz, CDCl ):
δ
3
=
7.44–7.38 (m, 2H, Hꢀ2'', Hꢀ6''), 7.35–7.29 (m, 2H, Hꢀ3'', Hꢀ5''), 7.26–7.22 (m, 1H, Hꢀ4''), 6.92–
.87 (XX'ꢀpart of a AA'XX'ꢀsystem, 2H, Hꢀ3, Hꢀ5), 6.48–6.43 (AA'ꢀpart of a AA'XX'ꢀsystem,
2H, Hꢀ2, Hꢀ6), 4.67 (d, J = 6.6 Hz, 1H, OCH O), 4.62 (d, J = 6.6 Hz, 1H, OCH O), 4.51 (s, 1H,
6
2
2
NH), 4.50 (dd, J = 8.1, 4.1 Hz, 1H, Hꢀ1'), 3.84 (dd, J = 10.4, 4.1 Hz, 1H, H ꢀ2'), 3.64 (dd, J =
a
1
3
1
0.4, 8.1 Hz, 1H, H ꢀ2'), 3.31 (s, 3H, OCH ), 2.18 (s, 3H, CH ). C NMR, HMBC, HSQC (75
b 3 3
MHz, CDCl3):
δ = 145.3 (C1), 140.8 (C1''), 129.7 (2C, C3, C5), 128.7 (2C, C3'', C5''), 127.5
(
C4''), 127.0 (C4), 126.9 (2C, C2'', C6''), 114.1 (2C, C2, C6), 96.7 (OCH O), 72.6 (C2'), 58.6
2
+
(C1'), 55.6 (OCH ), 20.5 (CH ). ESIꢀMS: m/z (%) = 272.2 (100) [M+H] . ESIꢀHRMS: calcd for
3
3
+
[
C H NO ] : m/z = 272.1651, found: 272.1656.
17 22 2
4
-Bromo-N-[2-(methoxymethoxy)-1-phenylethyl]aniline (5)
According to the general procedure, benzaldehyde (2a, 31.8 mg, 0.30 mmol 1.5 eq) was reacted
with 4ꢀbromoaniline (1c, 34.4 mg, 0.20 mmol) and DMM (2.5 mL). After 20 h, purification by
thinꢀlayer chromatography (cyclohexane/AcOEt/NEt = 90/7/3) afforded the title compound
3
(38.9 mg, 58%) as a colorless amorphous solid.
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R = 0.40 (cyclohexane/AcOEt/Et N = 7.5/2.0/0.5). IR (ATR): 3395 (w, br), 2930 (m, sh), 2886
f
3
1
(
m), 1732 (w), 1594 (m), 1496 (s), 1107 (m), 1108 (s) 1036 (s) 702 (m). H NMR, COSY (300
MHz, CDCl3): = 7.41–7.26 (m, 5H, 5 × ArꢀH), 7.18–7.12 (XX'ꢀpart of a AA'XX'ꢀsystem, 2H,
δ
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Hꢀ3, Hꢀ5), 6.43–6.37 (AA'ꢀpart of a AA'XX'ꢀsystem, 2H, Hꢀ2, Hꢀ6), 4.68 (s, 1H, NH), 4.67 (d, J
= 6.6 Hz, 1H, OCH O), 4.62 (d, J = 6.6 Hz, 1H, OCH O), 4.48 (dd, J = 8.1, 4.0 Hz, 1H, Hꢀ1'),
2
2
3
.86 (dd, J = 10.4, 4.0 Hz, 1H, H ꢀ2'), 3.64 (dd, J = 10.4, 8.1 Hz, 1H, H ꢀ2'), 3.31 (s, 3H, OCH ).
a
b
3
1
3
C NMR, HMBC, HSQC (101 MHz, CDCl3):
δ = 146.5 (C1), 139.9 (C1''), 131.7 (2C, C3, C5),
128.7 (2C, C3'', C5''), 127.6 (C4''), 126.7 (2C, C2'', C6''), 115.4 (2C, C2, C3), 109.4 (C4), 96.7
+
(
OCH O), 72.4 (C2') 58.3 (C1') 55.7 (OCH ). ESIꢀMS: m/z (%) = 336.1 (100) [M+H] . ESIꢀ
2
3
8
18
1
+
HRMS: calcd for [C H BrNO Na] : m/z = 358.0419, found: 358.0421.
1
6
2
4-{[2-(Methoxymethoxy)-1-phenylethyl]amino}benzoic acid (6)
According to the general procedure, benzaldehyde (2a, 31.8 mg, 0.30 mmol 1.5 eq) was reacted
with 4ꢀaminobenzoic acid (1d, 27.4 mg, 0.20 mmol) and DMM (2.5 mL). After 20 h the reaction
mixture was filtered and washed with DCM (40 mL) and methanol (40 mL). The filtrate was
concentrated in vacuo and the resulting crude product filtered through a short plug of silica to
afford the title compound (52.4 mg, 87%) as a colorless amorphous solid.
R = 0.57 (AcOEt). IR (ATR): 3363 (w, br), 2940 (w, sh), 2886 (w), 1671 (m), 1604 (s), 1284
f
1
(
m), 1175 (m), 1034 (m), 702 (w). H NMR, COSY (400 MHz, CDCl ):
δ
= 7.86–7.80 (AA'ꢀpart
3
of a AA'XX'ꢀsystem, 2H, Hꢀ2, Hꢀ6), 7.40–7.31 (m, 4H, ArꢀH), 7.30–7.25 (m, 1H, Hꢀ4''), 6.55–
6.47 (XX'ꢀpart of a AA'XX'ꢀsystem, 2H, Hꢀ3, Hꢀ5), 5.18 (s, 1H, NH), 4.68 (d, J = 6.6 Hz, 1H,
OCH O), 4.63 (d, J = 6.6 Hz, 1H, OCH O), 4.62 (m, 1H, Hꢀ1') 3.90 (dd, J = 10.5, 4.0 Hz, 1H,
2
2
1
3
H ꢀ2'), 3.71 (dd, J = 10.5, 7.6 Hz, 1H, H ꢀ2'), 3.31 (s, 3H, OCH ). C NMR, HMBC, HSQC (101
a
b
3
MHz, CDCl3):
δ
= 171.6 (COOH), 151.9 (C4), 139.6 (C1''), 132.2 (2C, C2, C6), 128.9 (2C, C3'',
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C5''), 127.9 (C4''), 126.8 (2C, C2'', C6''), 117.9 (C1), 112.7 (2C, C3, C5), 96.9 (OCH O), 72.4
2
+
(
C2'), 57.8 (C1'), 55.7 (OCH ). ESIꢀMS: m/z (%) = 302.1 (100) [M+H] . ESIꢀHRMS: calcd for
3
6
7
8
9
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1
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6
+
[C H NO Na] : m/z = 324. 1212, found: 324.1222.
1
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-Methoxy-N-[2-(methoxymethoxy)-1-phenylethyl]aniline (7)
According to the general procedure, benzaldehyde (2a, 31.8 mg, 0.30 mmol 1.5 eq) was reacted
with 4ꢀmethoxyaniline (1e, 24.6 mg, 0.20 mmol) and DMM (2.5 mL). After 20 h, purification by
thinꢀlayer chromatography (cyclohexane/AcOEt/NEt = 90/7/3) afforded the title compound
3
(
42.8 mg, 75%) as a yellow oil. The minor regioisomer Nꢀ(2,2ꢀdimethoxyꢀ1ꢀphenylethyl)ꢀ4ꢀ
methoxyaniline could not be separated (isomeric ratio 4.3:1)
1
R = 0.37(cyclohexane/AcOEt/Et N = 7.5/2.0/0.5). H NMR, COSY (400 MHz, CDCl ):
δ =
f
3
3
7
.45–7.39 (m, 2H, Hꢀ2'', Hꢀ6''), 7.36–7.29 (m, 2H, Hꢀ3'', Hꢀ5''), 7.28–7.24 (m, 1H, Hꢀ4''), 6.77–
6.66 (BB'ꢀpart of a AA'BB'ꢀsystem, 2H, Hꢀ3, Hꢀ5), 6.52–6.47 (AA'ꢀpart of a AA'BB'ꢀsystem, 2H,
Hꢀ2, Hꢀ6), 4.68 (d, J = 6.6 Hz, 1H, OCH O), 4.63 (d, J = 6.6 Hz, 1H, OCH O), 4.46 (dd, J = 8.3,
2
2
4
.0 Hz, 1H, Hꢀ1'), 3.83 (dd, J = 10.3, 4.0 Hz, 1H, H ꢀ2'), 3.69 (s, 3H, OCH ), 3.63 (dd, J = 10.3,
a 3
13
8.3 Hz, 1H, H ꢀ2'), 3.32 (s, 3H, CH OCH ). C NMR, HMBC, HSQC (75 MHz, CDCl ):
δ =
b
2
3
3
1
52.3 (C4), 141.8 (C1), 140.8 (C1''), 128.8 (2C, C3'', C5''), 127.9 (C4''), 127.0 (2C, C2'', C6''),
115.2 (2C, C2, C6), 114.8 (2C, C3, C5), 96.8 (OCH O), 72.6 (C2'), 59.2 (C1'), 55.8 (OCH ), 55.6
2
3
+
+
(
CH OCH ). ESIꢀMS: m/z (%) = 288.1 (100) [M+H] . ESIꢀHRMS: calcd for [C H NO Na] :
2 3 17 21 3
m/z = 310.1419, found: 310.1415.
N-[2-(Methoxymethoxy)-1-phenylethyl]-2,4,6-trimethylaniline (8)
According to the general procedure, benzaldehyde (2a, 31.8 mg, 0.30 mmol 1.5 eq) was reacted
with 2,4,6ꢀtrimethylaniline (1f, 27.0 mg, 0.20 mmol) and DMM (2.5 mL). After 20 h, purification
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by thinꢀlayer chromatography (cyclohexane/AcOEt/NEt = 90/7/3) afforded the title compound
3
(46.0 mg, 77%) as a yellow oil. The minor regioisomer Nꢀ(2,2ꢀdimethoxyꢀ1ꢀphenylethyl)ꢀ2,4,6ꢀ
trimethylaniline could not be separated (isomeric ratio 4.6:1).
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1
R = 0.44 (cyclohexane/AcOEt/NEt = 90/7/3). H NMR, COSY (300 MHz, CDCl ):
δ = 7.40–
f
3
3
7.23 (m, 5H, ArꢀH), 6.77 (s, 2H, Hꢀ3, Hꢀ5), 4.59 (s, 2H, OCH O), 4.30 (pseudoꢀt, J = 4.9 Hz, 1H,
2
Hꢀ1'), 3.9–3.81 (m, 2H, H ꢀ2', H ꢀ2'), 3.20 (s, 3H, OCH ), 2.20 (s, 3H, C4ꢀCH ), 2.15 (s, 6H, C2ꢀ
a
b
3
3
13
CH C6ꢀCH ). C NMR, HMBC, HSQC (75 MHz, CDCl ):
δ
= 142.4 (C1), 142.2 (C2''), 129.6
3,
3
3
(
2C, C3, C5), 128.4 (2C, C3'', C5''), 127.2 (C4''), 127.2 (2C, C2'', C6''), 96.8 (OCH O), 70.8
2
(
C2'), 61.4 (C1'), 55.5 (OCH ), 20.7 (C4ꢀCH3), 18.9 (2C, C2ꢀCH , C6ꢀCH ). Three quaternary
3
3
3
+
carbons could not be dedicated out of the mixture. ESIꢀMS: m/z (%) = 300.1 (100) [M+H] . ESIꢀ
+
HRMS: calcd for [C H NONa] : m/z = 322.1783, found: 322.1787.
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N-[1-(2,4-Dimethoxyphenyl)-2-(methoxymethoxy)ethyl]-4-methylaniline (9)
According to the general procedure, 2,4ꢀdimethoxybenzaldehyde (2b, 49.9 mg, 0.30 mmol 1.5
eq) was reacted with pꢀtoluidine (1b, 21.4 mg, 0.20 mmol) and DMM (2.5 mL). After 20 h,
purification by thinꢀlayer chromatography (cyclohexane/AcOEt/NEt = 80/15/5) afforded the title
3
compound (47.0 mg, 71%) as a yellow oil. The minor regioisomer Nꢀ[1ꢀ(2,4ꢀdimethoxyphenyl)ꢀ
2,2ꢀdimethoxyethyl]ꢀ4ꢀmethylaniline could not be separated (isomeric ratio 3.5:1).
1
R = 0.35 (cyclohexane/AcOEt/Et N = 7.5/2.0/0.5). H NMR, COSY (400 MHz, CDCl ):
δ =
f
3
3
7
.29–7.24 (m, 1H, Hꢀ6''), 6.89–6.86 (XX'ꢀpart of a AA'XX'ꢀsystem, 2H, Hꢀ3, Hꢀ5), 6.48–6.46 (m,
1H, Hꢀ3''), 6.46–6.42 (AA'ꢀpart of a AA'XX'ꢀsystem, 2H, Hꢀ2, Hꢀ6), 6.42–6.48 (m, 1H, Hꢀ5''),
.83 (dd, J = 7.3, 3.9 Hz, 1H, Hꢀ1'), 4.66 (d, J = 6.5 Hz, 1H, OCH O), 4.60 (d, J = 6.5 Hz, 1H,
4
2
OCH O), 3.89–3.85 (m, 4H, ArꢀOCH , H ꢀ2'), 3.77 (s, 3H, ArꢀOCH ), 3.60 (dd, J = 10.2, 7.3 Hz,
2
3
a
3
1
3
1
H, H ꢀ2'), 3.32 (s, 3H, CH OCH ), 2.18 (s, 3H, C4ꢀCH ). C NMR, HMBC, HSQC (101 MHz,
b 2 3 3
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CDCl3):
δ
= 160.1 (CH OC ), 157.9 (CH OC ), 145.4 (C1), 129.6 (2C, C3, C5), 128.5 (C6''),
3
q
3
q
126.6 (C4) 120.5 (C1''), 113.9 (2C, C2, C6), 104.3 (C5''), 98.7 (C3''), 96.7 (OCH O), 70.9 (C2'),
6
7
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5
5
5
5
6
2
5
1
5.5 (CH OCH ), 55.5 (OCH ), 55.4 (OCH ), 52.4 (C1'), 20.5 (C4ꢀCH ). Three carbons at 145.4,
2
3
3
3
3
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2
3
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26.6, 120.6 were dedicated out of the HMBC spectrum. ESIꢀMS: m/z (%) = 332.0 (100)
+
+
[M+H] . ESIꢀHRMS: calcd for [C H NO Na] : m/z = 354.1681, found: 354.1690.
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N-[1-Cyclohexyl-2-(methoxymethoxy)ethyl]-4-methylaniline (13)
According to the general procedure, cyclohexanecarbaldehyde (2e, 33.7 mg, 0.30 mmol 1.5 eq)
was reacted with pꢀtoluidine (1b, 21.4 mg, 0.20 mmol) and DMM (2.5 mL). After 20 h reaction
time, the crude product was isolated as described and purified by HPLC (ACE 5 C18ꢀPFP, 150 x
30 mm, isocratic: water/acetonitrile for 2 min (90/10), 30 mL/min, then gradient 15 min → 100%
acetonitrile 30 mL/min, 17.8 min) to afforded the title compound (28.85 mg, 52%) as a colorless
oil.
R = 0.50 (cyclohexane/AcOEt/Et N = 7.5/2.0/0.5). IR (ATR): 3400 (w, br), 2923 (s), 2852 (m),
f
3
1
1681 (m), 1520 (s), 1146 (m), 1112 (m), 1045 (s), 807 (m). H NMR, COSY (400 MHz, CDCl ):
3
δ
= 6.99–6.92 (XX'ꢀpart of a AA'XX'ꢀsystem, 2H, Hꢀ3, Hꢀ5), 6.56–6.50 (AA'ꢀpart of a AA'XX'ꢀ
system, 2H, Hꢀ2, Hꢀ6), 4.61 (d, J = 6.5 Hz, 1H, OCH O), 4.59 (d, J = 6.5 Hz, 1H, OCH O), 3.65–
2
2
3.56 (m, 2H, H ꢀ2', H ꢀ2'), 3.34 (s, 3H, OCH ), 3.31–3.25 (m, 1H, Hꢀ1'), 2.22 (s, 3H, C4ꢀCH ),
a
b
3
3
1.95–1.87 (m, 1H, CH ), 1.81–1.70 (m, 3H, CH ), 1.70–1.59 (m, 2H, CH ), 1.31–0.97 (m, 5H,
2
2
2
1
3
CH ). C NMR, HMBC, HSQC (75 MHz, CDCl ):
δ
= 146.0 (C1), 129.9 (2C, C3, C5) 126.2
2
3
(C4), 113.5 (2C, C2, C6), 96.9 (OCH O), 67.5 (C2'), 58.1 (C1'), 55.5 (OCH ), 39.9 (C1''), 30.0,
2
3
+
2
9.5, 26.7, 26.6, 26.6 (5 × CH ), 20.5 (C4ꢀCH ). ESIꢀMS: m/z (%) = 278.2 (100) [M+H] . ESIꢀ
2 3
+
HRMS: calcd for [C H NO Na] : m/z = 300.1939, found: 300.1947.
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N-[2-(2-Methoxyethoxy)-1-phenylethyl]aniline (15)
According to the general procedure, benzaldehyde (2a, 31.8 mg, 0.30 mmol 1.5 eq) was reacted
with aniline (1a, 18.6 mg, 0.20 mmol) and DME (2.5 mL). After 20 h, the reaction mixture was
filtered and washed with DCM (40 mL) and ethyl acetate (40 mL). After 20 h, purification by
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flashꢀchromatography (cyclohexane/AcOEt/NEt = 90/7/3) afforded the title compound (33.1 mg,
3
61%) as a colorless oil.
R = 0.30 (cyclohexane/AcOEt/Et N = 7.0/2.5/0.5). IR (ATR): 3390 (w, br), 3025 (w), 2924 (m,
f
3
1
sh), 1733 (w), 1601 (s), 1504 (s), 1104 (s, sh), 751 (s), 701 (s, sh). H NMR, COSY (300 MHz,
CDCl3): = 7.44–7.39 (m, 2H, Hꢀ2'', Hꢀ6''), 7.36–7.29 (m, 2H, Hꢀ3'', Hꢀ5''), 7.28–7.24 (m, 1H,
δ
Hꢀ4''), 7.11–7.03 (m, 2H, Hꢀ3, Hꢀ5), 6.66 (tt, J = 7.3, 1.1 Hz, 1H, Hꢀ4), 6.55–6.59 (m, 2H, Hꢀ2,
Hꢀ6), 4.53 (dd, J = 9.0, 4.0 Hz, 1H, Hꢀ1'), 3.75 (dd, J = 10.3, 4.0 Hz, 1H, H ꢀ2' ), 3.68 (pseudoꢀt,
a
J = 4.5 Hz, 1H, H ꢀ1'''), 3.65–3.61 (m, 1H, H ꢀ1'''), 3.60–3.52 (m, 3H, CH ), 3.39 (s, 3H, OCH ).
a
b
2
3
1
3
C NMR, HMBC, HSQC (75 MHz, CDCl3):
δ = 147.9 (C1), 140.8 (C1''), 129.1 (2C, C3, C5),
128.8 (2C, C3'', C5''), 127.5 (C4''), 126.9 (2C, C2'', C6''), 117.7 (C4), 114.1 (2C, C2, C6), 75.9
+
(
C2'), 72.0 (C2'''), 70.3 (C1'''), 59.2 (OCH ), 58.2 (C1'). ESIꢀMS: m/z (%) = 272.1 (100) [M+H] .
3
+
ESIꢀHRMS: calcd for [C H NO Na] : m/z = 294.1470 found: 294.1470.
1
7
21
2
N-[2-(2-Methoxyethoxy)-1-phenylethyl]-4-methylaniline (16)
According to the general procedure, benzaldehyde (2a, 31.8 mg, 0.30 mmol 1.5 eq) was reacted
with pꢀtoluidine (1b, 21.4 mg, 0.20 mmol) and DME (2.5 mL). After 20 h, purification by
chromatography (cyclohexane/AcOEt/NEt = 90/7/3) afforded the title compound (36.5 mg,
3
64%) as a pale yellow oil.
R = 0.30 (cyclohexane/AcOEt/Et N = 7.5/2.0/0.5). IR (ATR): 3383 (w, br), 2919 (m, sh), 1618
f
3
1
(m), 1520 (s), 1453 (m), 1106 (s, sh), 809 (m), 702 (m). H NMR, COSY (400 MHz, CDCl ):
δ
=
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7.44–7.39 (m, 2H, Hꢀ2'', Hꢀ6''), 7.35–7.29 (m, 2H, Hꢀ3'', Hꢀ5''), 7.27–7.22 (m, 1H, Hꢀ4''), 6.91–
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
6
.85 (XX'ꢀpart of a AA'XX'ꢀsystem, 2H, Hꢀ3, Hꢀ5), 6.47–6.41 (AA'ꢀpart of a AA'XX'ꢀsystem,
2H, Hꢀ2, Hꢀ6), 4.50 (dd, J = 9.1, 4.0 Hz, 1H, Hꢀ1'), 3.73 (dd, J = 10.3, 4.0 Hz, 1H, H ꢀ2'), 3.71–
a
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
.66 (m, 1H, H ꢀ1'''), 3.64–3.59 (m, 1H, H ꢀ1'''), 3.59–3.57 (m, 1H, H ꢀ2'), 3.56–3.52 (m, 2H, H ꢀ
a b b a
13
2
''', H ꢀ2'''), 3.39 (s, 3H, OCH ), 2.18 (s, 3H, C4ꢀCH ). C NMR, HMBC, HSQC (101 MHz,
b
3
3
CDCl3):
δ = 145.5 (C1), 140.8 (C1''), 129.4 (2C, C3, C5), 128.6 (2C, C3'', C5''), 127.3 (C4''),
1
26.8 (2C, C2'', C6''), 126.7 (C4), 114.1 (2C, C2, C6), 75.8 (C2'), 71.8 (C2'''), 70.1 (C1'''), 59.1
+
(OCH ), 58.3 (C1'), 20.4 (C4ꢀCH ). ESIꢀMS: m/z (%) = 286.1 (100) [M+H] . ESIꢀHRMS: calcd
3
3
+
for [C H NO Na] : m/z = 308.1626, found: 308.1637.
18
23
2
N-[2-(2-Methoxyethoxy)-1-phenylethyl]-2,4,6-trimethylaniline (17)
According to the general procedure, benzaldehyde (2a, 31.8 mg, 0.30 mmol 1.5 eq) was reacted
with 2,4,6ꢀtrimethylaniline (1f, 27.0 mg, 0.20 mmol) and DME (2.5 mL). After 20 h, purification
by chromatography (cyclohexane/AcOEt/NEt = 90/7/3) afforded the title compound (26.9 mg,
3
43%) as a yellow oil.
R = 0.40 (cyclohexane/AcOEt/Et N = 7.5/2.0/0.5). IR (ATR): 3383 (w, br), 2922 (s, sh), 2873
f
3
1
(
s), 1734 (m), 1485 (s), 1453 (s), 1109 (s, sh), 734 (m) 700 (s). H NMR, COSY (300 MHz,
CDCl3): = 7.39–7.33 (m, 2H, Hꢀ2'', Hꢀ6''), 7.33–7.27 (m, 2H, Hꢀ3'', Hꢀ5''), 7.27–7.21 (m, 1H,
Hꢀ4''), 6.75 (s, 2H, Hꢀ3, Hꢀ5), 4.27 (t, J = 5.0 Hz, 1H, Hꢀ1'), 3.79 (d, J = 5.0 Hz, 2H, Hꢀ2'), 3.60–
δ
3
5
3
.55 (m, 2H, Hꢀ1'''), 3.52–3.46 (m, 2H, Hꢀ2'''), 3.32 (s, 3H, OCH ), 2.19 (s, 3H, C4ꢀCH ), 2.14
3
3
1
3
(s, 6H, C2ꢀCH , C6ꢀCH ). C NMR, HMBC, HSQC (75 MHz, CDCl ):
δ
= 142.3 (2C, C1, C1'),
3
3
3
1
30.8 (C4), 129.6 (2C, C3, C5), 129.5 (2C, C2, C6), 128.3 (2C, C3'', C5''), 127.3 (2C, C2'', C6''),
27.2 (C4''), 74.7 (C2'), 72.0 (C2'''), 70.7 (C1'''), 61.5 (C1'), 59.1 (OCH ), 20.7 (C4ꢀCH ), 18.9
1
3
3
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3
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4
5
5
5
5
5
5
5
5
5
5
6
+
(
2C, C2ꢀCH C6ꢀCH ) ESIꢀMS: m/z (%) = 314.2 (100) [M+H] . ESIꢀHRMS: calcd for
3
,
3 .
+
[
C H NO ] : m/z =314.2120, found: 314.2119.
2
0
28
2
0
1
2
3
4
5
6
7
8
9
0
1
2
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4
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9
0
4
-{[2-(2-Methoxyethoxy)-1-phenylethyl]amino}benzoic acid (18)
According to the general procedure, benzaldehyde (2a, 31.8 mg, 0.30 mmol 1.5 eq) was reacted
with 4ꢀaminobenzoic acid (1d, 27.4 mg, 0.20 mmol) and DME (2.5 mL). After 20 h, the reaction
mixture was filtered and the filter cake was washed with DCM (40 mL) and methanol (40 mL).
The combined filtrates were concentrated in vacuo and the resulting crude product purified by
HPLC (ACE 5 C18ꢀPFP, 150 x 30 mm, isocratic: water/acetonitrile (60/40), 30 mL/min, 9.3 min)
to afforded the title compound (32.8 mg, 52%) as a colorless amorphous solid.
R = 0.52 (AcOEt). IR (ATR): 3344 (w, br), 2891 (w, br), 1671 (m), 1604 (s), 1528 (m), 1420
f
1
1
(m), 1283 (m), 1102 (m, sh). H NMR, COSY (600 MHz, CDCl ):
δ
= H NMR 7.80 (d, J = 8.4
3
Hz, 2H, Hꢀ2, Hꢀ6), 7.38–7.35 (m, 2H, Hꢀ2'', Hꢀ6''), 7.35–7.31 (m, 2H, Hꢀ3'', Hꢀ5''), 7.29–7.25 (m,
H, Hꢀ4''), 6.48 (d, J = 8.4 Hz, 2H, Hꢀ3, Hꢀ5), 5.31 (br s, 1H, NH), 4.61 (dd, J = 8.1, 3.4 Hz, 1H,
Hꢀ1'), 3.80 (dd, J = 10.4, 3.4 Hz, 1H, H ꢀ2'), 3.72–3.67 (m, 1H, H ꢀ1''') 3.65–3.59 (m, 2H, H ꢀ2',
1
a
a
b
1
3
H ꢀ1'''), 3.59–3.53 (m, 2H, H ꢀ2''', H ꢀ2'''), 3.40 (s, 3H, OCH ). C NMR, HMBC, HSQC (151
b
a
b
3
MHz, CDCl3):
δ = 171.5 (COOH), 152.2 (C4), 139.7 (C1''), 132.2 (2C, C2, C6), 129.0 (2C, C3'',
C5''), 127.9 (C4''), 126.7 (2C, C2'', C6''), 118.0 (C1), 112.9 (2C, C3, C5), 75.5 (C2'), 72.0 (C2'''),
7
0.5 (C1'''), 59.2 (OCH ), 57.7(C1'). Two carbons at 171.5, 118.0 were dedicated out of the
3
+
HMBC spectrum. ESIꢀMS: m/z (%) = 316.1 (100) [M+H] . ESIꢀHRMS: calcd for
+
[C H NO Na] : m/z = 338.1368, found: 338.1376.
1
8
21
4
N-[1-Cyclohexyl-2-(2-methoxyethoxy)ethyl]-4-methylaniline (19)
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According to the general procedure, cyclohexanecarbaldehyde (2e, 33.7 mg, 0.30 mmol 1.5 eq)
was reacted with pꢀtoluidine (1b, 21.4 mg, 0.20 mmol) and DME (2.5 mL). After 20 h,
purification by thinꢀlayer chromatography (cyclohexane/AcOEt/NEt = 7.5/2.0/0.5) afforded the
3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
title compound (22.1 mg, 38%) as a colorless oil.
R = 0.45 (cyclohexane/AcOEt/Et N = 7.5/2.0/0.5). IR (ATR): 3385 (w, br), 2923 (s), 2853 (m),
f
3
1
1
618 (m), 1520 (s), 1449 (m) 1251 (m), 1119 (m, sh), 807 (m). H NMR, COSY (300 MHz,
CDCl3): = 6.98–6.91 (XX'ꢀpart of a AA'XX'ꢀsystem, 2H, Hꢀ3, Hꢀ5,), 6.56–6.50 (AA'ꢀpart of a
AA'XX'ꢀsystem, 2H, Hꢀ2, Hꢀ6), 3.60–3.53 (m, 3H, CH ), 3.53–3.47 (m, 3H, CH ), 3.37 (s, 3H,
δ
2
2
OCH ), 3.27 (pseudoꢀq, J = 4.9 Hz, 1H, Hꢀ1'), 2.22 (s, 3H, C4ꢀCH ), 1.92–1.82 (m, 1H, CH ),
3
3
2
13
1
.81–1.69 (m, 3H, CH ), 1.69–1.58 (m, 2H, CH ), 1.32–0.93 (m, 5H, CH ). C NMR, HMBC,
2 2 2
HSQC (101 MHz, CDCl3):
δ = 146.2 (C1), 129.9 (2C, C3, C5), 126.1 (C4), 113.5 (2C, C2, C6),
7
2.1 (C2''), 70.9 (C2'), 70.7 (C1''), 59.2 (OCH ), 58.1 (C1'), 39.8 (C1'''), 29.9, 29.4, 26.7, 26.6,
3
+
26.6 (5 x CH ), 20.5 (C4ꢀCH ). ESIꢀMS: m/z (%) = 292.2 (100) [M+H] . ESIꢀHRMS: calcd for
2
3
+
[
C H NO Na] : m/z = 314.2096, found: 314.2100.
18 29 2
2-[(4-Methylphenyl)amino]-2-phenylethanol (20a)
TiO (20 mg, 0.25 mmol, 1.3 eq), and (NH ) S O (6 mg) were dispersed in a mixture of water
2
4 2
2
8
(2.5 mL) and DMM (2.5 mL). After the addition of benzaldehyde (2a, 31.8 mg, 0.30 mmol 1.5
eq) and pꢀtoluidine (1b, 21.4 mg, 0.20 mmol), the reaction mixture was degassed with argon for 1
min and stirred for 20 h under UVꢀA (400 W) at room temperature. Then it was filtered and the
filter cake was washed with DCM (40 mL) and ethyl acetate (40 mL). The combined filtrates
were concentrated in vacuo and the resulting residue dissolved in DCM (40 mL) and filtered
again. After the removal of DCM, the residue was dissolved in THF (0.2 mL). To the resulting
mixture were added water (0.5 mL) and 1M HCl (4 mL) and the mixture was stirred at 60 °C for
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2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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4
4
4
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5
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5
5
5
6
1
2 h. After cooling to room temperature, water (10 mL) was added and the solution was made
alkaline by addition of 1N NaOH prior to extraction with DCM (3 x 20 mL). The combined
organic layers were dried over Na SO and concentrated in vacuo. The residue was purified by
2
4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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6
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8
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flash column chromatography (cyclohexane/AcOEt = 4/1) to afforded the title compound (21.8
mg, 48%) as a yellow oil).
R = 0.21 (cyclohexane/AcOEt/Et N = 7.0/2.5/0.5). IR (ATR): 3388 (s, br), 3025 (m), 2920 (m),
f
3
1
2
868 (m), 1616 (m), 1517 (s), 1302 (m), 1068 (m), 808 (s), 701 (m). H NMR, COSY (400 MHz,
CDCl3): = 7.39–7.32 (m, 4H, ArꢀH), 7.30–7.24 (m, 1H, Hꢀ1'), 6.96–6.90 (XX'ꢀpart of a
AA'XX'ꢀsystem, 2H, Hꢀ3'', Hꢀ5''), 6.54–6.49 (AA'ꢀpart of a AA'XX'ꢀsystem, 2H, Hꢀ2'', Hꢀ6''),
.49 (dd, J = 7.2, 4.2 Hz, 1H, Hꢀ2), 3.93 (dd, J = 11.1, 4.2 Hz, 1H, H ꢀ1), 3.73 (dd, J = 11.1, 7.2
δ
4
a
1
3
Hz, 1H, H ꢀ1), 2.21 (s, 3H, C4''ꢀCH ). C NMR, HMBC, HSQC (101 MHz, CDCl ):
δ
= 145.0
b
3
3
(C1''), 140.4 (C1'), 129.8 (2C, C3'', C5''), 128.9 (2C, C3', C5'), 127.7 (C4'), 127.3 (C4''), 126.8
(2C, C2', C6'), 114.2 (2C, C2'', C6''), 67.5 (C1), 60.3 (C2), 20.5 (C4''ꢀCH ). ESIꢀMS: m/z (%) =
3
+
2
28.1 (100) [M+H] .
3
7
The spectroscopic data are in accordance with the literature.
2-Phenyl-2-(phenylamino)ethanol (20b)
TiO (20 mg, 0.25 mmol, 1.3 eq), and (NH ) S O (6 mg) were dispersed in a mixture of water
2
4 2
2
8
(2.5 mL) and DMM (2.5 mL). After the addition of benzaldehyde (2a, 31.8 mg, 0.30 mmol 1.5
eq) and aniline (1a, 18.6 mg, 0.20 mmol), the reaction mixture was degassed with argon for 1
min and stirred for 20 h under UVꢀA (400 W) at room temperature. Then it was filtered and
washed with DCM (40 mL) and ethyl acetate (40 mL). The filtrate was concentrated in vacuo and
the resulting residue dissolved in DCM (40 mL) and filtered again. After the removal of DCM the
residue was dissolved in THF (0.2 mL). To the resulting mixture were added water (0.5 mL) and
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M HCl (4 mL) and the mixture was stirred at 60 °C for 12 h. After cooling to room temperature,
water (10 mL) was added and the solution was made alkaline by addition of 1N NaOH prior to
extraction with DCM (3 x 20 mL). The combined organic layers were dried over Na SO and
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
concentrated in vacuo. The residue was purified by flash column chromatography
cyclohexane/AcOEt = 8/2) to afforded the title compound (17.9 mg, 42%) as a yellow oil).
R = 0.19 (cyclohexane/AcOEt/Et N = 7.0/2.5/0.5). IR (ATR): 3520 (m, sh), 3396 (s, br), 1601
(
f
3
1
(
s), 1503 (s), 1316 (m), 1066 (m), 1028 (m), 750 (s), 649 (s). H NMR, COSY (300 MHz,
CDCl3): = 7.41–7.31 (m, 4H, Hꢀ2'', Hꢀ3'', Hꢀ5'', Hꢀ6''), 7.31–7.24 (m, 1H, Hꢀ4''), 7.15–7.06 (m,
H, Hꢀ3', Hꢀ5'), 6.68 (tt, J = 7.4, 1.0 Hz, 1H, Hꢀ4'), 6.61–6.54 (m, 2H, Hꢀ2', Hꢀ6'), 4.52 (dd, J =
.9, 4.2 Hz, 1H, Hꢀ2), 3.96 (dd, J = 11.1, 4.2 Hz, 1H, H ꢀ1), 3.77 (dd, J = 11.1, 6.9 Hz, 1H, H ꢀ1).
δ
2
6
a
b
1
3
C NMR, HMBC, HSQC (75 MHz, CDCl3):
δ 147.2 (C1'), 140.1 (C1''), 129.3 (2C, C3', C5'),
1
29.0 (2C, C3'', C5''), 127.8 (C4''), 126.9 (2C, C2'', C6''), 118.1 (C4'), 114.1 (2C, C2', C6'), 67.5
+
(C1), 60.1 (C2). ESIꢀMS: m/z (%) = 214.0 (100) [M+H] .
37
The spectroscopic data are in accordance with the literature.
Acknowledgements
We thank Stefan Pusch (Mainz) for the DFT calculations, Dr. J. C. Liermann (Mainz) for NMR
spectroscopy and Dr. N. Hanold (Mainz) for mass spectrometry.
Supporting Information
Oneꢀ and twoꢀdimensional NMR spectra of all compounds. This material is available free of
charge via the Internet at http://pubs.acs.org
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Kuhl, N.; Hopkinson, M. N.; WencelꢀDelord, J.; Glorius, F. Angew. Chem. Int. Ed. 2012,
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Satoh, T.; Miura, M. Chem. – Eur. J. 2010, 16, 11212ꢀ11222.
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Andreatta, J. R.; McKeown, B. A.; Gunnoe, T. B. J. Organomet. Chem. 2011, 696, 305ꢀ
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Foley, N. A.; Lee, J. P.; Ke, Z.; Gunnoe, T. B.; Cundari, T. R. Acc. Chem. Res. 2009, 42,
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Godula, K.; Sames, D. Science 2006, 312, 67ꢀ72.
(
Jazzar, R.; Hitce, J.; Renaudat, A.; SofackꢀKreutzer, J.; Baudoin, O. Chem. – Eur. J. 2010,
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Ramachary, D. B.; Jain, S. Org. Biomol. Chem. 2011, 9, 1277ꢀ1300.
Pellissier, H. Chem. Rev. 2013, 113, 442ꢀ524.
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(10) Brauch, S.; Gabriel, L.; Westermann, B. Chem. Commun. 2010, 46, 3387ꢀ3389.
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R. S.; Solhy, A. ACS Sustainable Chem. Eng. 2013, 1, 1154ꢀ1159.
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