Aerobic Oxidation of 4-Alkyl-N,N-dimethylbenzylamines Catalyzed by N-Hydroxyphthalimide: Protonation-Driven Control over Regioselectivity

Article abstract of DOI:10.1021/acs.joc.7b00563

A change in regioselectivity has been observed in the hydrogen atom transfer (HAT) reactions from 4-alkyl-N,N-dimethylbenzylamines (alkyl = ethyl, isopropyl, and benzyl) to the phthalimide N-oxyl radical (PINO) by effect of protonation. This result can be rationalized on the basis of an acid-induced deactivation of the C-H bonds α to nitrogen toward HAT to PINO as evidenced by the 10⁴-10⁷-fold decrease in the HAT rate constants in acetonitrile following addition of 0.1 M HClO₄. This acid-induced change in regioselectivity has been successfully applied for selective functionalization of the less activated benzylic C-H bonds para to the CH₂N(CH₃)₂ group in the aerobic oxidation of 4-alkyl-N,N-dimethylbenzylamines catalyzed by N-hydroxyphthalimide in acetic acid.

Full text of DOI:10.1021/acs.joc.7b00563

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Article
Aerobic Oxidation of 4-Alkyl-N,N-dimethylbenzylamines Catalyzed by N
Hydroxyphthalimide. Protonation Driven Control over Regioselectivity
Massimo Bietti, Osvaldo Lanzalunga, Andrea Lapi, Teo Martin,
Marco Mazzonna, Mariangela Polin, and Michela Salamone
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 08 May 2017
Downloaded from http://pubs.acs.org on May 9, 2017
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Aerobic Oxidation of 4ꢀAlkylꢀN,Nꢀ
dimethylbenzylamines Catalyzed by
NꢀHydroxyphthalimide.
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Protonation Driven Control over Regioselectivity
Massimo Bietti,b Osvaldo Lanzalunga,a,c* Andrea Lapi,a,c*
Teo Martin,a Marco Mazzonna,a Mariangela Polina and Michela Salamoneb
a
Dipartimento di Chimica, Sapienza Università di Roma and Istituto CNR di Metodologie
Chimiche (IMCꢀCNR), Sezione Meccanismi di Reazione, c/o Dipartimento di Chimica, Sapienza
Università di Roma, P.le A. Moro, 5 Iꢀ00185 Rome, Italy
b
Dipartimento di Scienze e Tecnologie Chimiche, Università "Tor Vergata", Via della Ricerca
Scientifica, 1 Iꢀ00133 Rome, Italy.
c CIRCC Interuniversity Consortium of Chemical Catalysis and Reactivity, Via Celso Ulpiani 27,
70126 Bari, Italy.
Email: osvaldo.lanzalunga@uniroma1.it; andrea.lapi@uniroma1.it
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if
required according to the journal that you are submitting your paper to)
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Abstract
:
A change in regioselectivity has been observed in the hydrogen atom transfer (HAT)
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reactions from 4ꢀalkylꢀN,Nꢀdimethylbenzylamines (alkyl = ethyl, isopropyl and benzyl) to the
phthalimide Nꢀoxyl radical (PINO) by effect of protonation. This result can be rationalized on the
basis of an acid induced deactivation of the C−H bonds α to nitrogen towards HAT to PINO as
evidenced by the 104ꢀ107 fold decrease in the HAT rate constants in acetonitrile following addition
of 0.1 M HClO4. This acid induced change in regioselectivity has been successfully applied for
selective functionalization of the less activated benzylic C−H bonds para to the CH2N(CH3)2 group
in the aerobic oxidation of 4ꢀalkylꢀN,Nꢀdimethylbenzylamines catalyzed by Nꢀhydroxyphthalimide
in acetic acid.
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Introduction
Since the pioneering studies by Ishii and coworkers, the aerobic oxidation of hydrocarbons
catalyzed by Nꢀhydroxyphthalimide (NHPI) has deserved an increasing attention.1 This particular
interest is associated to the mild reaction conditions, in terms of O2 pressure and temperature,
required in these oxidative processes. The key intermediate is represented by the phthalimide Nꢀ
oxyl radical (PINO), which can be formed by several different metal or nonmetal based activation
systems and O2 (Scheme 1, path a).1,2 Hydroperoxide oxidation products are then formed in a
catalytic cycle after hydrogen atom transfer (HAT) from the substrate (R−H) to PINO followed by
•
HAT from NHPI to the peroxyl radical (RO2 ) (Scheme 1, paths b and d, respectively).
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O
O
Catalyst activation
N O
N OH
O2
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O
PINO
O
NHPI
a
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O
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RH
ROOH
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N O
O
O
d
b
R
ROO
N OH
O
c
O2
Scheme 1. Catalytic cycle for the aerobic oxidation of hydrocarbons catalyzed by NHPI
HAT promoted by PINO plays a fundamental role in the catalytic cycle. Accordingly, a clear
dependence of the overall catalytic efficiency on the bond dissociation energy (BDE) differences
between the R−H and NO−H bonds was observed in HAT from alkylaromatics.3 Beside this
enthalpic factor, several studies showed that NHPI catalyzed aerobic oxidations are also
significantly influenced by polar effects due to the partial charge transfer from the substrate to
PINO in the HAT transition state (TS) as shown in Figure 1 for HAT from the benzylic CꢀH bond
of a generic alkylaromatic substrate to PINO.4
Figure 1. Partial charge transfer in the transition state for HAT
from benzylic CꢀH bonds to PINO
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Polar effects have been invoked to rationalize the high reactivity observed in HAT from electron
rich C−H bonds α to heteroatoms that are able to stabilize the partial positive charge that develops
on carbon in the HAT TS.4 On these basis, it was not surprising that, in aerobic oxidations
promoted by NHPI, tertiary amines are excellent substrates, in view of the presence of the electron
donating nitrogen atom. Accordingly, tertiary benzyl amines were shown to be efficiently oxidized
to the corresponding benzaldehydes by the NHPI/O2 system at room temperature and 1 atm of O2.5,6
It has been recently shown that in HAT from the αꢀC−H bonds of alkylamines to alkoxyl radicals
the addition of Lewis or Brønsted acids determines a significant decrease in reactivity.7 This effect
was attributed to acidꢀbase interactions that lead to an increase in the C−H BDE8 and destabilize the
HAT TS by increasing the extent of positive charge on the nitrogen center. In order to investigate
the deactivating effect of protonation on HAT from the α−C−H bonds of alkylamines to PINO, we
have explored kinetically the reactions of a series of tertiary amines with PINO in CH3CN, acetic
acid (AcOH) and in CH3CN containing 0.1 M HClO4.
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From a synthetic perspective the decrease in reactivity of an otherwise activated C−H bond by
protonation represents a useful tool to control the HAT regioselectivity, favoring the reaction of less
activated C−H bonds which are normally quite difficult to functionalize. This approach has been
successfully applied to the remote functionalization of amine substrates in metal based catalytic
systems,9 with potassium persulfate,10 and with methyl(trifluoromethyl)dioxirane.11 However no
metal free oxidation procedures using oxygen as terminal oxidant have been reported so far.
The acidꢀinduced change of regioselectivity in the HAT reactions promoted by PINO has been
analyzed by a kinetic and product study of the oxidation of tertiary 4ꢀalkylꢀN,Nꢀ
dimethylbenzylamines (Figure 2, 1-3). These substrates are characterized by the presence of
benzylic C−H bonds that are in a remote position from the nitrogen atom and were chosen to
investigate the possible competition of HAT from these positions and from the more activated
benzylic C−H bonds that are α to the heteroatom.
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Figure 2. 4ꢀAlkylꢀN,Nꢀdimethylbenzylamines investigated in this work.
Results and discussion
A kinetic study of the reactions of a series of tertiary amines, including 4ꢀXꢀN,Nꢀ
dimethylbenzylamines 1-3, to PINO was initially carried out in CH3CN, in the absence or in the
presence of HClO4 (0.1 M) and in AcOH, in order to quantitatively analyze the deactivating effect
of amine protonation on HAT from the C−H bonds that are α to nitrogen.
In MeCN HAT was in all cases too fast to be followed by conventional spectrophotometry,
therefore the reactions were kinetically investigated by the laser flash photolysis (LFP) technique,
where PINO was generated by HAT from NHPI to the cumyloxyl radical, which in turn was formed
by 355 nm LFP of dicumyl peroxide (Scheme 2).12
Scheme 2. Generation of PINO by laser flash photolysis
Under pseudo firstꢀorder conditions, using an excess of the amine substrate, the observed rate
constants (kobs) were measured following the decay of PINO at the absorption maximum (380
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nm).13 From the slope of the kobs vs [amine] plots, the second order rate constants for HAT (kH)
were determined (see Figures S17ꢀS25 in the Supporting Information). The kH values thus obtained
are collected in Table 1.
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Table 1. Second order rate constants (kH) for HAT from tertiary amines and alkylaromatics to PINO
in CH3CN, in CH3CN/HClO4 (0.1 M) and AcOH measured at T = 25 °C.
Substrate
kH (Mꢀ1sꢀ1)a
CH3CN
2.0 × 104
6.8 × 103
1.7 × 103
≤ 103
CH3CN/HClO4 (0.1 M)
AcOH
0.04
0.85
53
(CH3CH2)3N
(CH2=CHCH2)3N
(C6H5CH2)3N
DABCO
0.018
0.12
0.14
7.4 × 104
< 3×10ꢀ3
0.07
2.3 × 104
4.8 × 103
< 3×10ꢀ3
< 3×10ꢀ3
0.2
0.11
CH2N(CH3)2
9.2 × 103
9.4 × 103
6.4 × 103
1.9b
1.3
6.7
4.8
3.5b
2.7
18
17
5.4c
27c
CH2CH3
3.25d
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a
b
d
Average of at least three determinations. Error ± 5%. Ref. 14. c Ref. 15. In benzene + 10%
CH3CN, Ref. 3b.
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From the data reported in Table 1 it can be noted that in CH3CN, with the exclusion of 1,4ꢀ
diazabicyclo[2,2,2]ꢀoctane (DABCO), the kH values for HAT from the tertiary amines to PINO are
the highest so far determined in HAT from C−H bonds promoted by this shortꢀlived aminoxyl
radical,1c ranging from 1.7 × 103 to 7.4 × 104 Mꢀ1sꢀ1. These values are from 3 to 4 orders of
magnitude higher than those measured for the corresponding reactions of alkylbenzenes,3b,14,15,
a
result that is in full accordance with the aforementioned activating effect of an αꢀnitrogen atom. The
relevance of polar effects and the positive charge stabilization in the HAT TS is also in line with the
observed increase in kH with increasing the electron donating properties of the substituent in 4ꢀXꢀ
N,Nꢀdimethylbenzylamines [kH (Et) ~ kH (iPr) > kH (Bz) > kH (H)] as well indicated by the good
linear correlation obtained by plotting log(kH(X)/kH(H)) vs Hammett σ constants (ρ = ꢀ1.9, r2= 0.97,
see Figure S41 in the SI).
With DABCO, only an upper limit to the HAT rate constant could be given (kH ≤ 103 Mꢀ1sꢀ1). This
result is in accordance with previous kinetic studies on HAT from tertiary amines to alkoxyl
radicals16 and can be rationalized on the basis of the operation of stereoelectronic effects. With this
substrate the overlap between the nitrogen lone pair and the αꢀC−H bonds is reduced by the
geometrical restrictions imposed by the locked conformation, that reduce the activating effect
exerted by the nitrogen atom.
Stereoelectronic effects are also responsible for the relatively high kH value measured for
Nꢀmethylpyrrolidine (kH = 7.4 × 104 Mꢀ1sꢀ1). In this system optimal overlap between the αꢀCꢀH
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bonds and the nitrogen lone pair can be achieved resulting in a weakening of these bonds and a
more efficient stabilization of the radicals formed following HAT.17
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Kinetic studies were also carried out in AcOH and in CH3CN containing 0.1 M HClO4 (see
Figures S28ꢀS40 in the Supporting Information). In both cases the remarkable decrease in reactivity
observed as an effect of amine protonation allowed us to determine the HAT rate constants by UVꢀ
vis spectrophotometry generating PINO by oxidation of NHPI with lead(IV) tetraacetate.15,18 The kH
values were determined as described above for the LFP experiments. It is important to point out that
in the present study, for the first time, a combination of two techniques for kinetic analysis,
differing significantly in timeꢀresolution (LFP and UVꢀvis spectrophotometry) has been
successfully applied for the determination of HAT rate constants to a single oxygen centered radical
that span over than 7 orders of magnitude.
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With all the amines, as compared to the reactions carried out in MeCN, a greater than 3ꢀorder of
magnitude decrease in kH was observed after addition of 0.1 M HClO4. As an example, in the
reaction of PINO with triethylamine, a ∼ 106 fold decrease in kH was observed in the presence of
HClO4. In most cases the decrease in reactivity was such that the selfꢀdecay of PINO occurred in
competition with HAT and only an upper limit to the kH values could be given (< 3×10ꢀ3 Mꢀ1sꢀ1).
Thus, upon protonation, the activating electron releasing amino group is converted into an electron
withdrawing ammonium one, that strongly deactivates the αꢀC−H bonds towards HAT to PINO. In
contrast, with alkylbenzenes the addition of acid determines only a small increase in kH reasonably
due to the increased electrophilicity of PINO upon protonation of the carbonyl oxygen.14,19 Very
interestingly, a smaller decrease in kH by effect of HClO4 addition was observed for 4ꢀXꢀN,Nꢀ
dimethylbenzylamines 1-3 all having additional benzylic C−H bonds in a remote position to the N
atom.
Since AcOH is widely used as solvent in aerobic hydrocarbon oxidations catalyzed by
NHPI,1,15,18 the kinetic studies have been extended to this solvent. As reported in Table 1, also in
this case a remarkable decrease in reactivity, with respect to CH3CN, was observed. As compared to
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CH3CN/HClO4, a smaller extent of C−H deactivation was observed in AcOH, and accordingly in
this solvent kH values for all the amines investigated could be determined.20 Higher kH values were
again measured for substrates 1-3 containing remote benzylic C−H bonds with respect to the N
atom.
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The observation that higher kH values were measured for the amines bearing remote benzylic
C−H bonds in both neat AcOH and CH3CN/HClO4, suggests that in the reactions of 1-3 with PINO
a change in HAT regioselectivity may result following nitrogen protonation from the activated C−H
bonds αꢀto nitrogen to the remote benzylic ones. In accordance with this hypothesis is also the
observation that in the presence of HClO4 the kH values measured for 1-3 are comparable with those
measured previously for the corresponding reactions of alkylbenzenes.22
To test if the acidꢀinduced change in regioselectivity can be employed for the functionalization of
weakly activated benzylic C−H bonds in the aerobic oxidation of tertiary benzylamines, we have
investigated the oxidation of 4ꢀXꢀN,Nꢀdimethylbenzylamines 1-3 with NHPI (10 mol %), Co(OAc)2
as cocatalyst (1 mol %) and O2 (1 atm) in CH3CN and in AcOH according to the Ishii protocol (see
experimental section).18 In view of the previously discussed deactivation towards HAT of these
substrates in AcOH, it was necessary to raise the temperature from r.t. to 50 °C , reaction time from
5 h to 22 h and the reactant concentration in order to obtain a satisfactory substrate conversion in
AcOH with respect to CH3CN.23
In CH3CN, 4ꢀXꢀbenzaldehydes were formed in good yield as previously reported by Minisci et al.
(see Table 2 and Figure 3a),5 confirming that HAT occurs from the more activated benzylic position
that is αꢀ to nitrogen. In contrast, when the reaction was carried out in AcOH, product analysis
showed
the
formation
of
4ꢀ(dimethylaminomethyl)benzyl
alcohol
and/or
4ꢀ
(dimethylaminomethyl)phenyl ketone products (Table 2 and Figure 3b). The oxidation products
were all identified by comparison with authentic specimens (see Supporting Information).
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Figure 3. Products formed in the aerobic oxidation of 4ꢀXꢀN,Nꢀdimethylbenzylamines 1-3
catalyzed by NHPI (a) in CH3CN and (b) in AcOH.
Table 2. Products and Yields observed in the aerobic oxidation of 4ꢀXꢀN,Nꢀdimethylbenzylamines
(1-3) catalyzed by NHPI in CH3CNa and in AcOH.b
Substrate
Solvent Convers.
Products (Yields%)c
R'
C
R
CH2N(CH3)2
H
1 R=CH3, R’=H
2 R=R’=CH3
CH3CN
AcOH
99
70
80
ꢀ
ꢀ
ꢀ
25
41
CH3CN
AcOH
75
52
55
ꢀ
ꢀ
ꢀ
ꢀ
45
3 R=C6H5, R’=H
CH3CN
AcOH
81
51
67
ꢀ
ꢀ
ꢀ
9.7
37
a
Reaction conditions: Amine (0.2 M), NHPI (2 × 10ꢀ2 M), Co(AcO)2 (2 × 10ꢀ3 M) in MeCN (1
mL) under O2 (1 atm) at room temperature for 5 h (3h for 3).
b Reaction conditions: Amine (0.7 M), NHPI (7 × 10ꢀ2 M), Co(AcO)2 (7 × 10ꢀ3 M) in AcOH (1
mL) under O2 (1 atm), T=50 °C for 22 h.
c Determined by GCꢀMS and 1H NMR analysis and referred to the initial amount of substrate.
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In AcOH the reaction products are formed following HAT from the benzylic C−H bonds in the
para position with respect to the (CH3)2NH+CH2ꢀ group to PINO. A plausible mechanism
describing the formation of the oxidation products is reported in Scheme 3.
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H
H
N
N
O
a
.
N-O
+
-NHPI
.
O
C R
R'
H C R
R'
H
H
H
N
N
N
O2
x
2
O2
b
+
c
.
OO C R
R'
HO C R
R'
R
O
ox
d
Scheme 3. Mechanism of products formation in the oxidation of 1-3 (X = Et, iꢀPr, Bn) with the
NHPI/Co(OAc)2/O2 system in AcOH.
Thus, in line with the kinetic predictions and in particular with the significantly higher kH values
measured in AcOH for 4ꢀalkylꢀN,Nꢀdimethylbenzylamines 1-3 bearing remote benzylic C−H bonds
(kH between 2.7 and 19 Mꢀ1sꢀ1) as compared to the unsubstituted N,Nꢀdimethylbenzylamine (kH =
0.11 Mꢀ1sꢀ1), a change in HAT regioselectivity from the activated C−H bonds αꢀto nitrogen to the
less activated benzylic C−H bonds has been accomplished in the NHPI catalyzed aerobic oxidation
of 1-3 by changing the solvent from CH3CN to AcOH. This method represents a suitable way to
control the HAT regioselectivity in the oxidative functionalization of amine substrates with a great
advantage with respect to the previously reported methodologies9ꢀ11 represented by the use of the
most environmentally benign oxidant (O2).
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Conclusions
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In conclusion, in this study we have reported the first example of an acid induced change of
regioselectivity in the HATꢀbased C−H bond functionalization of tertiary amines promoted by
aminoxyl radicals. Formation of different products in the aerobic oxidation of a series of 4ꢀalkylꢀ
N,Nꢀdimethylbenzylamines catalyzed by NHPI are observed in CH3CN and AcOH, showing that
acidꢀbase interactions can represent a powerful tool to modulate siteꢀselectivity. The application of
these concepts to the selective C−H bond functionalization of more challenging target molecules
containing amine functionalities is currently under investigation in our laboratories.
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Experimental Section
Instrumentation
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H NMR and C NMR spectra were recorded on a 300MHz spectrometer. GCꢀMS analyses were
performed on a gas chromatograph equipped with a methylsilicone capillary column (30 m x I.D. =
0.25 mm x df = 0.25 ꢁm) coupled with a mass selective detector. UVꢀvis measurements were
performed on a diode array spectrophotometer. Laser flash photolysis experiments were carried out
with a laser kinetic spectrometer providing 8 ns pulses, using the third armonic (355 nm) of a
Nd:YAG laser.
Materials
Acetonitrile (HPLC grade), acetic acid, Nꢀhydroxyphthalimide, Co(AcO)2 (H2O)4, Pb(AcO)4 and
HClO4 were commercially available and used as received. N,NꢀDimethylbenzylamine,
triallylamine, tribenzylamine, DABCO, Nꢀmethylpyrrolidine and triethylamine were commercially
available at their highest purity and used as received. 4ꢀEthylꢀN,NꢀDimethylbenzylamine (1), 4ꢀ
isopropylꢀN,Nꢀdimethylbenzylamine (2), 4ꢀbenzylꢀN,Nꢀdimethylbenzylamine (3) and Nꢀmethylꢀ4ꢀ
methylpiperidine were prepared following procedures reported in the literature.
4ꢀEthylꢀN,NꢀDimethylbenzylamine (1). The compound was prepared according to a procedure
reported in the literature24 modified as follows. A mixture containing 4ꢀethylbenzaldehyde (4.1 g,
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31 mmol), dimethylamine hydrochloride (5.0 g, 62 mmol), triethylamine (6.1 g, 60 mmol) and
titanium isopropoxide (18 mL, 60 mmol) in absolute ethanol (50 mL) was stirred at room
temperature for 18 h, then NaBH4 (1.7 g, 45 mmol) was added. The mixture was stirred at 25 °C for
6 h and then treated with 2 M ammonia solution (50 mL). The slurry thus obtained was centrifuged
to eliminate the solid precipitate. The solution was extracted with CH2Cl2 (three aliquots, 100 mL
each). The collected organic phases were concentrated to ca. 50 mL by rotary evaporator and then
extracted with 2 M HCl (three aliquots, 30 mL each). The aqueous phases were basified by adding
10 % NaOH and then extracted with CH2Cl2 (four aliquots, 100 mL each) carefully maintaining a
basic pH in the aqueous phase. The collected organic phases were dried over anhydrous Na2SO4
and, after solvent removal, the clear liquid obtained was filtered over silica gel using ethyl acetate
as the eluent. After solvent removal, pure 4ꢀethylꢀN,Nꢀdimethylbenzylamine (1). was obtained as a
clear liquid (2.6 g, 16 mmol, 53 %).
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1H NMR (CDCl3, 300 MHz) δ: 1.21ꢀ1.26 (t, 3H), 2.26 (s, 6H), 2.60ꢀ2.68 (q, 2H), 3.43 (s, 2H), 7.15ꢀ
7.26 (m, 4H).
13C NMR (CDCl3, 75 MHz) δ: 15.6, 28.5, 45.3, 64.1, 127.7, 129.0, 136.0, 142.9.
EIꢀMS (70 eV) m/z (relative intensity): 163 (M+, 100), 162 (89), 119 (78), 91 (40), 58 (80).
HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C11H18N 164.1439; Found 164.1436.
Both 1H and 13C NMR data were in agreement with those reported in the literature.9d
4ꢀIsopropylꢀN,Nꢀdimethylbenzylamine (2). The compound was prepared according to a
procedure reported in the literature9d modified as follows. A 25 mL round bottom flask containing
4ꢀisopropylbenzylamine (1.49 g, 10 mmol) was cooled to 0 °C (ice/water bath) and then formic acid
(1.9 mL, 50 mmol) was slowly added. After addition of formaldehyde (36 wt %, 1.8 mL, 22 mmol),
the mixture was refluxed for 16 h. After cooling to room temperature, aqueous HCl (2M, 5 mL) was
added and the solvent removed by rotary evaporation. The resulting material was dissolved in H2O
(5 mL), basified with aqueous NaOH (20 % w/v) and extracted with diethyl ether (3 × 10 mL). The
combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated. After
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chromatographic purification (basic alumina, CHCl3) pure 4ꢀisopropylꢀN,Nꢀdimethylbenzylamine
(2) was obtained as a pale yellow liquid (1.24 g, 7.0 mmol, 70 %).
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1H NMR (CDCl3, 300 MHz) δ: 1.25 (d, 6H), 2.24 (s, 6H), 2.90 (septet, 1H), 3.40 (s, 2H), 7.17ꢀ7.25
(m, 4H).
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13C NMR (CDCl3, 75 MHz) δ: 25.0, 34.8, 46.4, 65.1, 127.3, 130.1, 137.1, 148.7.
EIꢀMS (70 eV) m/z (relative intensity): 177 (M+, 100), 176 (89), 134 (24), 133 (65), 117 (23), 105
(21), 91 (26), 58 (74).
All the spectral data were in agreement with those reported in the literature.25
4ꢀBenzylꢀN,Nꢀdimethylbenzylamine (3). The title compound was prepared by reduction of N,Nꢀ
dimethylꢀ4ꢀbenzyl benzamide prepared according a literature procedure26 modified as follows. tꢀ
Butylhydroperoxide (70 % in H2O, 3.6 mL, 25.7 mmol) was added over 5 min in a 100 mL round
bottom flask containing 4ꢀbenzyl benzoic acid27 (3.63 g, 17.1 mmol) and Cu(II) triflate28 (0.62 g,
1.71 mmol) in DMF (34 mL). The mixture was then stirred at 100 °C for 20 h. After cooling to
room temperature H2O, (100 mL) was added and the mixture extracted with ethyl acetate (4 × 80
mL). The combined organic extracts were washed with saturated NaHCO3 (2 × 100 mL), water
(100 mL) and brine (100 mL). After solvent removal by rotary evaporator the dark liquid obtained
was dissolved in hot EtOH. Hot water was then added until precipitation of a dark compound that
was filtered off. The cooled clear solution thus obtained was extracted with CH2Cl2 (4 × 50 mL).
The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated
yielding N,Nꢀdimethylꢀ4ꢀbenzyl benzamide as a viscous pale yellow oil (2.48 g, 10.4 mmol, 61 %)
enough pure to be used in the next step without further purification. [1H NMR (CDCl3, 300 MHz) δ:
2.99 (s, 3H), 3.11 (s, 3H), 4.00 (s, 2H), 7.2ꢀ7.4 (m, 9H). EIꢀMS (70 eV) m/z (relative intensity): 239
(M+, 29), 238 (38), 195 (100), 165 (28), 152 (18)]. The amide thus obtained (2.38 g, 9.97 mmol)
was dissolved in dry THF (10 mL) and slowly added in a three necks 50 mL round bottom flask
cooled at 0 °C (ice/water bath) containing 1M LiAlH4 in THF (11 mL, 11 mmol) under N2
atmosphere. The solution was then refluxed under N2 atmosphere for 7 h. After cooling to 0 °C,
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NaOH (300 mg) in H2O (8 ml) was slowly added. The mixture was then diluted in H2O (80 mL)
and extracted with diethyl ether (4 × 80 mL). The combined organic extracts were washed with
water (100 mL) and brine (100 mL) and dried over anhydrous Na2SO4. After filtration, solvent
evaporation and chromatographic purification (basic alumina, CHCl3), pure 4ꢀbenzylꢀN,Nꢀ
dimethylbenzylamine (3) was obtained as a clear liquid (1.39 g, 6.18 mmol, 62 %).
1H NMR (CDCl3, 300 MHz) δ: 2.25 (s, 6H), 3.41 (s, 2H), 3.99 (s, 2H), 7.1ꢀ7.3 (m, 9 H).
13C NMR (CDCl3, 75 MHz) δ: 41.8, 45.6, 64.3, 126.2, 128.6, 129.0, 129.1, 129.4, 136.8, 140.1,
141.4.
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EIꢀMS (70 eV) m/z (relative intensity): 225 (M+, 100), 224 (74), 181 (45), 166 (24), 165 (40), 91
(22), 58 (55).
HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C16H20N 226.1596; Found 226.1598.
Nꢀmethylꢀ4ꢀmethylpiperidine. The compound was prepared according to a procedure reported in the
literature29 modified as follows. Zn powder (10.4 g, 65 mmol) was slowly added in a round bottom
flask containing a stirred solution of 4ꢀmethylpiperidine (9.6 mL, 81 mmol) and aq. Formaldehyde
(37 %, 8.9 mL, 120 mmol) in glacial acetic acid (18 mL) at 0 °C (ice/water bath). The mixture was
stirred at room temperature for 2.5 h after which aqueous ammonia (30 %, 160 mL) was added and
the reaction mixture was extracted with diethyl ether (4 × 80 mL). The combined organic extracts
were dried over anhydrous Na2SO4, filtered and the solvent removed by rotary evaporator. After
distillation, pure Nꢀmethylꢀ4ꢀmethylpiperidine was obtained as a colorless oil (2.1 g, 18.7 mmol, 23
%).
1H NMR (CDCl3, 300 MHz) δ: 2.80 (d, J = 11.8 Hz, 2H), 2.25 (s, 3H), 1.90 (t, J = 11.4 Hz, 2H),
1.61 (d, J = 10.7 Hz, 2H), 1.29ꢀ1.21 (m, 3H), 0.91 (d, J = 5.9 Hz, 3H).
13C NMR (CDCl3, 75 MHz) δ: 21.8, 30.1, 34.3, 46.4, 55.9.
EIꢀMS (70 eV) m/z (relative intensity): 113 (M+, 38), 112 (100), 98 (7), 70 (20), 58 (7).
13C NMR spectrum was in agreement with that reported in the literature.30
Product Characterization.
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4ꢀEthylbenzaldehyde, 4ꢀisopropylbenzaldehyde and 4ꢀbenzylbenzaldehyde obtained in the NHPI
promoted oxidation of 1ꢀ3 in MeCN were characterized by comparison with commercial samples.
The oxidation products obtained in AcOH were compared with that obtained as follows.
1ꢀ[4ꢀ(dimethylaminomethyl)phenyl]ꢀethanone: An O2 saturated solution of 4ꢀethylꢀN,Nꢀ
dimethylbenzylamine (500 mg, 3.1 mmol), Nꢀhydroxyphthalimide (51 mg, 0.32 mmol) and
Co(AcO)2 (5.4 mg, 0.02 mmol) in AcOH (4 mL) was stirred in a Schlenk tube for 30 h at 50 °C
under O2 atmosphere. After solvent removal by rotary evaporator, 100 mL of 30 % NaOH were
added and then extracted with of Et2O (4×20mL). The collected organic fractions were washed with
brine, dried over anhydrous Na2SO4 and the solvent removed by rotary evaporator. GCꢀMS analysis
of the crude residue showed the presence of 1ꢀ[4ꢀ(dimethylaminomethyl)phenyl]ꢀethanone (ca. 30
%) and 1ꢀ[4ꢀ(dimethylaminomethyl)phenyl]ꢀethanol (ca. 8 %). Basic alumina chromatography
(hexane/ethyl acetate 9:1) afforded 1ꢀ[4ꢀ(dimethylaminomethyl)phenyl]ꢀethanone as a clear liquid
(160 mg, 25 %). Both 1H NMR and 13C NMR analyses were in agreement with those reported in the
literature.31
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1H NMR (CDCl3, 300 MHz) δ: 2.25 (s, 6H), 2.59 (s, 3H), 3.47 (s, 2H), 7.39ꢀ7.42 (m, 2H), 7.90ꢀ7.93
(m, 2H).
13C NMR (CDCl3, 75 MHz) δ: 26.5, 45.4, 63.9, 128.3, 129.0, 136.0, 144.5, 197.8.
EIꢀMS (70 eV) m/z (relative intensity): 177 (M+, 70), 176 (46), 133 (21), 105 (19), 90 (14), 89 (14),
58 (100).
1ꢀ[4ꢀ(dimethylaminomethyl)phenyl]ꢀethanol: Attempts to isolate 1ꢀ[4ꢀ(dimethylaminomethyl)ꢀ
phenyl]ꢀethanol from the reaction mixture obtained in the aerobic oxidation of 4ꢀethylꢀN,Nꢀ
dimethylbenzylamine catalyzed by NHPI in AcOH, as described above, were unsuccessful, thus it
was synthesized by reduction of 1ꢀ[4ꢀ(dimethylaminomethyl)phenyl]ꢀethanone with NaBH4 in
EtOH. NaBH4 (17 mg, 0.45 mmol) was added to a stirred solution of 1ꢀ[4ꢀ
(dimethylaminomethyl)phenyl]ꢀethanone (53 mg, 0.3 mmol) in absolute EtOH (5 mL) and allowed
to react for 24 h at room temperature. After solvent removal by rotary evaporator, the residue was
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diluted in CH2Cl2 (25 mL), washed with three portions (25 mL each) of water, dried over anhydrous
Na2SO4 and the solvent removed. The residue was purified by preparative TLC (silica gel, ethyl
acetate) affording 1ꢀ[4ꢀ(dimethylaminomethyl)phenyl]ꢀethanol (48 mg, 89 %).
1H NMR (CDCl3, 300 MHz) δ: 1.50 (d, 3H), 2.30 (s, 6H), 3.52 (s, 2H), 4.91 (q, 1H), 7.30ꢀ7.37 (m,
4H).
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13C NMR (CDCl3, 75 MHz) δ: 25.1, 45.2, 64.0, 70.1, 125.3, 129.2, 132.3, 144.7.
EIꢀMS (70 eV) m/z (relative intensity): 179 (M+, 94), 178 (72), 134 (20), 117 (19), 91 (31), 58
(100).
HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C11H18NO 180.1388; Found 180.1391.
2ꢀ(4ꢀdimethylaminomethylꢀphenyl)ꢀpropanꢀ2ꢀol. The title compound was isolated by
chromatography (basic alumina, CHCl3) from the reaction mixture obtained for the NHPI mediated
oxidation of 2 in AcOH. Pure 2ꢀ(4ꢀdimethylaminomethylꢀphenyl)ꢀpropanꢀ2ꢀol (41 mg) was
obtained as a clear liquid.
1H NMR (CDCl3, 300 MHz) δ: 1.56 (s, 6H), 2.20 (s, 6H), 3.40 (s, 2H), 7.25 (m, 2H), 7.43 (m, 2H)
13C NMR (CDCl3, 75 MHz) δ: 31.8, 45.4, 64.0, 72.3, 124.5, 129.1, 136.9, 148.2
EIꢀMS (70 eV) m/z (relative intensity): 193 (M+, 100), 192 (74), 177 (24), 176 (18), 175 (29), 174
(24), 134 (24), 131 (34), 91 (20), 58 (100)
HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C12H20NO 194.1545; Found 194.1548.
(4ꢀdimethylaminomethylꢀphenyl)ꢀphenylꢀmethanol. This compound was found as side product in
the synthesis of 3 (see experimental section), maybe derived from the LiAlH4 reduction of N,Nꢀ
dimethylꢀ4ꢀbenzoyloxy benzamide impurity present in the N,Nꢀdimethylꢀ4ꢀbenzyl benzamide used.
Pure (4ꢀdimethylaminomethylꢀphenyl)ꢀphenylꢀmethanol (70 mg) was then isolated during
chromatography purification of 3.
1H NMR (CDCl3, 300 MHz) δ: 2.20 (s, 6H), 3.38 (s, 2H), 5.81 (s, 1H), 7.24ꢀ7.37 (m. 9 H)
13C NMR (CDCl3, 75 MHz) δ: 44.5, 63.3, 75.8, 126.65, 126.72, 127.5, 128.5, 129.8, 136.0, 143.8,
144.4
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EIꢀMS (70 eV) m/z (relative intensity): 241 (M+, 100), 240 (65), 134 (20), 105 (56), 77 (21), 58 (90)
HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C16H20NO 242.1545; Found 242.1542.
4ꢀdimethylamminomethylꢀbenzophenone. The title compound was obtained by Jones oxidation of
(4ꢀdimethylaminomethylꢀphenyl)ꢀphenylꢀmethanol following a literature procedure32 modified as
follows: 120 ꢁL of 8 N Jones reagent dissolved in acetone (1.5 mL) were added over 20 min in a 5
mL round bottom flask containing a magnetically stirred solution of (4ꢀdimethylaminomethylꢀ
phenyl)ꢀphenylꢀmethanol (50 mg, 0.207 mmol) in acetone (1 mL) cooled to 0 °C (ice/water bath).
2ꢀPropanol was then added dropwise until the solution turned to deep green. Saturated aqueous
K2CO3 (6 mL) was then added and the solution extracted with CH2Cl2 (4 × 20 mL). The combined
organic extracts were then washed with water (50 mL) and brine (50 mL) and dried over anhydrous
Na2SO4. After solvent removal by rotary evaporator, pure 4ꢀdimethylamminomethylꢀbenzophenone
(41 mg, 0.172 mmol, 83 %) was obtained as a white solid.
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1H NMR (CDCl3, 300 MHz) δ: 2.26 (s, 6H), 3.49 (s, 2H), 7.41ꢀ7.49 (m, 4H), 7.54ꢀ7.58 (m, 1H),
7.56ꢀ7.80 (m, 4H)
13C NMR (CDCl3, 75 MHz) δ: 45.6, 64.1, 128.4, 128.9, 130.1, 130.3, 132.4, 136.5, 137.8, 144.1,
196.6
EIꢀMS (70 eV) m/z (relative intensity): 239 (M+, 100), 238 (55), 167 (23), 165 (19), 105 (17), 77
(18), 58 (98)
HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C16H18NO 240.1388; Found 240.1389.
Aerobic oxidations of 1-3 catalyzed by NHPI/Co(OAc)2.
In CH3CN: The amine (0.2 mmol, 32.6 mg for 1, 35,4 mg for 2 and 45.0 mg for 3) and NHPI
(3.3 mg, 0.02 mmol) were added in a Schlenk tube containing a solution of Co(OAc)2 (0.5 mg,
0.002 mmol) in CH3CN (1 mL). After O2 bubbling (10 min), the mixture was stirred at room
temperature for 5 h (3 h for 3) under an O2 atmosphere obtained by connecting the Schlenk tube to a
O2 filled latex balloon. An internal standard (4ꢀmethoxybenzophenone) was then added and, after
addition of saturated sodium carbonate (10 mL), the mixture was extracted with 3 aliquots of ethyl
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acetate (20 mL each). The collected organic phases were then washed with brine and dried over
anhydrous Na2SO4. After solvent removal by rotary evaporator, the mixture was analyzed by GCꢀ
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MS and H NMR that showed the presence of the corresponding 4ꢀalkylbenzaldehydes (identified
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by comparison with authentic specimen) as the main product, (80 %, 55 %, 67 % for 1, 2 and 3
respectively; yields referred to the initial amount of substrate). No products were formed in blank
experiments carried out in the absence of the NHPI catalyst.
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In AcOH: The amine (0.7 mmol, 114 mg for 1, 124 mg for 2 and 158 mg for 3) and NHPI (11.4
mg, 0.07 mmol) were added in a Schlenk tube containing a solution of Co(OAc)2 (1.7 mg, 0.007
mmol) in AcOH (1 mL). After O2 bubbling (10 min), the mixture was stirred at 50 °C for 22 h
under an O2 atmosphere obtained by connecting the Schlenk tube to a O2 filled latex balloon. An
internal standard (4ꢀmethoxybenzophenone) was then added and the AcOH partially removed by
rotary evaporator (up to ca 0.1 mL). After addition of saturated sodium carbonate (10 mL), the
mixture was extracted with 3 aliquots of ethyl acetate (20 mL each). The collected organic phases
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were then washed with brine and dried over anhydrous Na2SO4. GCꢀMS and H NMR analyses of
the reaction mixture that showed the exclusive presence of unreacted amine accompanied by the
oxidation products (identified by comparison with the authentic samples, see SI for details) listed
below with the relative yields referred to the initial amount of substrate:
N,NꢀDimethylꢀ4ꢀethylꢀbenzylamine (1). 1ꢀ[4ꢀ(dimethylaminomethyl)phenyl]ꢀethanone (41 %) and
1ꢀ[4ꢀ(dimethylaminomethyl)phenyl]ꢀethanol (25 %).
N,Nꢀdimethylꢀ4ꢀisopropylꢀbenzylamine (2). 2ꢀ(4ꢀdimethylaminomethylꢀphenyl)ꢀpropanꢀ2ꢀol (45 %).
N,Nꢀdimethylꢀ4ꢀbenzylꢀbenzylamine (3). (4ꢀdimethylaminomethylꢀphenyl)ꢀphenylꢀmethanol (9.7 %)
and 4ꢀdimethylamminomethylꢀbenzophenone (37 %).
No products were formed in blank experiments carried out in the absence of the NHPI catalyst.
Laser Flash Photolysis Studies. LFP experiments were carried out with a laser kinetic
spectrometer, equipped with a Qꢀswitched Nd:YAG laser, delivering 8 ns pulses at 355 nm. The
laser energy was adjusted to < 3 mJ/pulse by the use of the appropriate filter. A 3 mL quartz cell (10
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mm × 10 mm) was used in all experiments. Argon saturated CH3CN solutions containing dicumyl
peroxide (1 M), NHPI (5.5ꢀ10.5 mM) and the amine (0.4 to 4 mM) were employed. All of the
experiments were carried out at T = 25 ± 0.5 °C under magnetic stirring. Experiments in the
absence of the amine showed that the PINO absorption intensity was significantly stable and its
decay negligible in the milliseconds scale. The observed pseudo firstꢀorder rate constants (kobs) were
measured following the decay of the PINO radical absorption band at 380 nm. They were obtained
by averaging 3−5 individual values and were reproducible to within 5%. Secondꢀorder rate
constants (kH) for the reactions of the PINO radical with the amines were obtained from the slopes
of the kobs versus [substrate] plots.
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Spectrophotometric Kinetic Studies with tertiary amines. PINO was generated by the oxidation
of NHPI (2 mM) with Pb(OAc)4 (0.25 mM) in AcOH or in CH3CN containing 0.1M HClO4 at 25
°C. A solution of the substrate was added into the PINO solution in the cuvette (substrate
concentration in the range 4ꢀ25 mM for CH3CN/HClO4 and 5ꢀ125 mM for AcOH) and the
absorbance change was monitored at 380 nm. For all the substrates investigated each kinetic trace
obeyed a firstꢀorder kinetic. Secondꢀorder rate constants were obtained from the slopes of plots of
the observed rate constants kobs vs substrate concentration.
Acknowledgements. Thanks are due to the Ministero dell’Istruzione, dell’Università e della
Ricerca (MIUR) for financial support and to the CIRCC, Interuniversity Consortium of Chemical
Catalysis and Reactivity.
Supporting Information Available: 1H and 13C NMR spectra of synthesized amines and oxidation
products, dependence of kobs for the decay of PINO on the concentration of tertiary amines,
Hammett plot for HAT from 4ꢀXꢀN,Nꢀdimethylbenzylamines to PINO in CH3CN. This material is
available free of charge via the Internet at http://pubs.acs.org.
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(20) In view of the much higher HAT reactivity of the αꢀC−H bonds in the amine than in the
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same solvent (3.5 Mꢀ1sꢀ1) (ref. 14). The lower kH value determined for 1 can be attributed to the EW
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effect of the (CH3)2NH+CH2ꢀ group.
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(23) Reactions carried out in CH3CN at r.t. for the same time used for the reactions in AcOH led
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