Copper acetoacetonate [Cu(acac)2]/BINAP-promoted Csp 3-N bond formation via reductive coupling of N-tosylhydrazones with anilines

Article abstract of DOI:10.1002/adsc.201300466

We report the the copper(II) acetoacetonate [Cu(acac)₂]/BINAP- catalyzed synthesis of arylamines from N-tosylhydrazones and anilines. A fine tuning of the reaction conditions was required to accomplish the cross-coupling successfully, including the ligands effect and the addition of small amounts of water. The characteristic feature of this protocol is its functional group compatibility and its chemoselectivity when various aminophenol derivatives were used. Taking into consideration the interest for this copper-reductive coupling in which no stoichiometric metal hydride reagent is employed, this can be considered as an alternative to the conventional reductive amination.

Full text of DOI:10.1002/adsc.201300466

UPDATES
DOI: 10.1002/adsc.201300466
3
À
Copper Acetoacetonate [Cu
(acac)2]/BINAP-Promoted Csp N
Bond Formation via Reductive Coupling of N-Tosylhydrazones
with Anilines
Jessy Aziz,a Jean-Daniel Brion,a Abdallah Hamze,a,* and Mouad Alamia,*
a
Univ Paris-Sud, CNRS, BioCIS – UMR 8076, LabEx LERMIT, Laboratoire de Chimie Thꢀrapeutique, Facultꢀ de
Pharmacie, 5 rue J.-B. Clꢀment, F-92296 Chꢁtenay-Malabry, France
Fax : (+33)-1-4683-5828; phone: (+33)-1-4683-5498; e-mail: abdallah.hamze@u-psud.fr or mouad.alami@u-psud.fr
Received: May 28, 2013; Revised: June 25, 2013; Published online: August 9, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300466.
Abstract: We report the the copper(II) acetoaceto-
nate [Cu(acac)2]/BINAP-catalyzed synthesis of aryl-
with substrates containing reducible functional groups
(e.g., CN, NO2, C=C).[3] The use of sodium cyanobor-
ohydride as the reductant requires an excess of re-
agent (up to 5-fold)[4] and produces toxic cyanides as
by-products upon work-up.[5] The alternative sodium
triacetoxyborohydride has not been successful for aro-
matic and unsaturated carbonyl compounds.[6] Other
reported reductive amination reagents include BH3-
ACHTUNGTRENNUNG
amines from N-tosylhydrazones and anilines. A fine
tuning of the reaction conditions was required to
accomplish the cross-coupling successfully, including
the ligands effect and the addition of small amounts
of water. The characteristic feature of this protocol
is its functional group compatibility and its chemo-
selectivity when various aminophenol derivatives
were used. Taking into consideration the interest
for this copper-reductive coupling in which no stoi-
chiometric metal hydride reagent is employed, this
can be considered as an alternative to the conven-
tional reductive amination.
pyridine,[7]
Zn
A
NaBH4-NiCl2,[9]
NaBH3CN-TiCATHNUGTRNEUNG
(O-i-Pr)4,[10] Bu3SnH,[11] or Et3SiH-
TFA.[12] All these methods require stoichiometric or
excess of metal hydrides, therefore, the development
of alternative and general protocols for the prepara-
tion of a-branched arylamines that does not require
the use of metal hydrides, is highly desirable.[13]
3
N-Tosylhydrazones, easily prepared from aldehydes
or ketones, have emerged as a new type of cross-cou-
pling partner in organometallic chemistry.[14] They
have been extensively employed as a source for the
safe generation of diazo compounds and carbenes to
À
N
Keywords: carbenoid insertion; copper; Csp
bond formation; N-tosylhydrazones; synthetic
methods
Introduction
a-Branched arylamines are very important building
blocks for drug discovery. Figure 1 shows representa-
tive examples of bioactive molecules containing this
motif with various pharmacological properties.[1] It is
not surprising that numerous synthetic methodologies
to access such compounds have been explored in the
past decades.[2] The most common method to prepare
amines is the reduction of imino C=N bonds.[2a,e,h,i]
However, imines are not always easy to synthesize
and have limited stability. Tremendous efforts have
been devoted to the development of efficient reduc-
tive amination reactions. The choice of the reducing
agent is very critical to the success of the reaction and
the progress is far from satisfactory.[2a,c,d] Transition
metal-catalyzed hydrogenation may be incompatible Figure 1. Representative a-branched arylamines.
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Jessy Aziz et al.
UPDATES
Scheme 1. Reductive coupling of N-tosylhydrazones with amines.
merge with different types of transition metal-cata- metric metal hydride reagent is employed, herein, we
lyzed transformations. Elegant methods using N-tosyl- report a general protocol for the reductive coupling
À
hydrazones as a coupling partner in C C bond forma- of N-tosylhydrazones with anilines using a copper
tion include their reactions with aryl halides,[15] aryl salt/BINAP combination as
sulfonates,[16] alkynes,[17] azoles,[18] arylboronic acids,[19] system.
benzylic halides,[20] isocyanides,[21] etc.
a versatile catalytic
À
Recently, we described a copper-catalyzed C N
bond-forming reaction between N-tosylhydrazones Results and Discussion
1 and primary or secondary aliphatic amines, giving
rise to the reductive coupling products
(Scheme 1).[22]
3
In order to test the reactivity of hydrazones 1 and ani-
lines 2, an extensive screening of copper sources,
The mechanism proposed for this reaction compris- bases, solvents and ligands was carried for the cou-
es the following steps: (i) decomposition of the hydra- pling of hydrazone 1a with p-anisidine 2a (Table 1).[27]
zone 1 under basic and thermal conditions to form in A number of Cu(I) and Cu(II) salts were applied in
situ the diazo compound A; (ii) loss of nitrogen then this reductive coupling reaction, among them, Cu-
À
delivers the copper(I)-carbene complex B1; (iii) N H
ACHTUNGTERN(NUNG acac)2 gave the superior result. The screening was
insertion on the carbene center might take place to continued with respect to the solvent. Among several
produce copper ylide species C1; and (iv) a subsequent solvents tested (toluene, MeCN and THF), PhF re-
1,2-proton shift produces the reductive coupling prod- vealed to be the best solvent. When the coupling was
ucts 3.
achieved at 1208C in PhF the desired product 4a was
Although this reductive coupling proceeds very ef- obtained in a 40% isolated yield (Table 1, entry 2). In
ficiently with primary and secondary aliphatic amines, view of the finding that, in transition metal-catalyzed
À
to our disappointment, no reaction occurred between X H insertions, water can act as an efficient proton-
hydrazones and anilines. For instance, when reacting transport catalyst for the ylide 1,2-H shift process,[28]
1a with 2a under our previous optimized conditions,[22] we realized the coupling in the presence of H2O
the reductive coupling product 4a was not detected (25 equiv.) as a protic additive. Under these condi-
(Table 1, entry 1). Careful analysis by NMR showed tions, the yield of 4a was strikingly improved to 58%,
the presence of significant amounts of three by-prod- and formation of imine 6a was significantly dimin-
ucts: (i) the sulfone 5a,[23] (ii) imine 6a,[24] and (iii) ished (entry 3).[29] Then, we turned to a combination
ketone 7a. To promote the formation of 4a from ani- of the copper catalyst with different ligands. Although
lines, which are less nucleophilic than aliphatic diamino type ligands such as DMEDA, TMEDA, and
amines, we postulated that the use of effective ancil- 1,10-phenanthroline did not give any improvement on
lary ligands could be a prerequisite in order to control the yield of the desired product, however, we are de-
the coordination sphere of the copper catalyst.[25] The lighted to find that the use of phosphine ligands
electronic interaction between the copper and the markedly improved the yield of 4a. The best results
ligand should improve the reactivity and selectivity of were obtained with PPh3 and rac. BINAP offering 4a
À
the copper(I)-carbenoid B2 in the N H insertion re- in 78% and 85% isolated yields, respectively (en-
action.[26] A judicious choice of a copper-ligand tries 4 and 5). A control experiment, under metal-free
system to facilitate the formation of ylide C2 from B2 conditions,[30] shows that no product 4a was detected.
is thus required to fit into the narrow requirements of It should be noted that the coupling of hydrazone 1a
the process. Taking into consideration the interest of with p-anisidine 2a is not limited to a small scale
this copper-reductive coupling in which no stoichio- (0.57 mmol) as it could be conveniently performed on
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Copper Acetoacetonate [CuACTHNUTRGEN(UNG acac)2]/BINAP-Promoted Csp N Bond Formation via Reductive Coupling
Table 1. Preliminary experiments of reductive coupling of N-tosylhydrazone 1a with p-anisi-
dine 2a.[a]
[a]
Reaction conditions: N-tosylhydrazone 1a (1 equiv.), amine 2a (1.5 equiv.), CuACHTNUTGRNEUNG(acac)2
(10 mol%), Cs2CO3 (2.5 equiv.), solvent (2.5 mL) in a sealed tube at 1208C for 2 h.
Ratio was determined by H NMR in the crude reaction mixture, see the Supporting In-
[b]
1
formation.
Yield of isolated product 4a.
Performing the reaction in the presence of CuACTHNUTRGEN(UNG acac)2 (5 mol%) and rac. BINAP
[c]
[d]
(5 mol%) led to 75% of 4a.
a 2 g scale for 1a (5.74 mmol), giving rise to an 80% tion must be noted, i.e., it can be carried out in the
yield of 4a. presence of a nitrile group (4e, 4k and 4l), and even
With the optimized reaction conditions in hand a hydroxy group (vide infra).
(Table 1, entries 4 and 5), the substrate scope was in-
Coupling of N-alkylanilines, constitutes a challeng-
vestigated (Table 2). Examples 4a–f demonstrate the ing issue, since they are an example of poor NH nu-
superiority of the bidentate ligand, rac. BINAP in cleophiles in metal-catalyzed cross-coupling. The
comparison to the monodentate PPh3, especially in problem is not the diminished NH acidity but rather
the case of electron-poor anilines (compounds 4d–f). the steric congestion around the nitrogen center. We
These observations highlight the ability of ligands to are pleased to find that under our optimized condi-
dictate the course of the catalytic reactions. Table 2 tions, satisfactory to good yields were obtained with
shows selected examples of anilines insertion products these secondary amines (compounds 4m–o).
(4a–y) which were obtained efficiently by using rac.
The present catalytic system was found to be equal-
BINAP ligand. The reaction is very general with re- ly successful in the coupling of heterocyclic anilines
spect to the structure of anilines and hydrazones. Re- or hydrazones (compounds 4p and 4q). The scope of
gardless of the electronic nature of the substituents the coupling reaction can be extended to N-tosylhy-
on the aniline or hydrazone partners (electron-with- drazones derived from benzophenones and benzyl ke-
drawing or electron-donating group), the reaction tones (compounds 4r–w). One can note a slight im-
proceeded with similar yields (compounds 4a–f and provement of the yield of compounds 4s–w with hy-
compounds 4k, 4l, 4q, 4u and 4v). The reaction does drazones derived from benzophenones in comparison
not display any dependence upon steric hindrance to those derived from acetophenones. To broaden the
either on the aniline or hydrazone moieties. ortho- scope of substrates, we further investigated this cou-
Anilines and sterically hindered hydrazones reacted pling reaction with tosylhydrazones derived from al-
completely and effectively in 2 h (compounds 4b and dehydes. We found that the reactions could also be
4i). The high functional group tolerance of the reac- carried out by the same copper/BINAP catalytic
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Table 2. Cu/BINAP-catalyzed reaction of N-tosylhydrazones with anilines.[a]
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Copper Acetoacetonate [CuACTHNUTRGEN(UNG acac)2]/BINAP-Promoted Csp N Bond Formation via Reductive Coupling
Table 2. (Continued)
[a]
Reaction conditions: N-tosylhydrazones 1 (1 equiv.), amines 2 (1.5 equiv.), CuACTHNUTRGNEUNG(acac)2 (10 mol%), rac. BINAP
(10 mol%), Cs2CO3 (2.5 equiv.), H2O (25 equiv.), PhF (2.5 mL) in a sealed tube at 1208C for 2 h.
Isolated yield of compounds 4 after column chromatography.
PPh3 was used as the ligand instead of BINAP.
Reaction was performed at 808C and K2CO3 was used as the base instead of Cs2CO3.
[b]
[c]
[d]
À
system, but the use of K2CO3 as the base in this case resulted in the O H bond insertion into the resulting
gives a better result compared with Cs2CO3; a- carbene.[30b] When Cu
(acac)2/rac. BINAP combination
branched arylamines (compounds 4x and y) were ob- as a catalytic system was applied, we observed high
À
tained in moderate yields. Unfortunately, when a tosyl- selectivity leading exclusively to C N bond forming
hydrazone derived from an aliphatic aldehyde was re- reaction; no C O products were detected by
À
acted with aniline, none of the desired product 4z was 1H NMR analysis of the crude reaction mixture. Sec-
detected.
ondary amines 4ai–4an were obtained in good isolat-
Although we have shown in our previous work that ed yields. Next, we examined the selectivity issue be-
aliphatic amines and azoles[22] reacted with tosylhy- tween aliphatic amine and N H azole. As expected,
drazones in the absence of ligand, we next investigat- the C N bond forming reaction took place exclusively
ed their reactivity under our novel protocol.
À
À
at the more nucleophilic and non-steric aliphatic
As depicted in Table 3, we demonstrated that the amine of 5-methoxytryptamine (compound 4am).
use of our new conditions led to a significant im- Then, we turned our attention to the reaction of a hy-
provement of the yield of the cross-coupling, this was drazone derived from benzophenone and an amino al-
proved with derivatives of the benzylamine-type, but cohol containing a chiral center [(S)-2-amino-3-phe-
also with other azoles[22,31] (compounds 4aa–4ah).
nylpropan-1-ol]. To our delight, we observed in this
À
To extend the scope of this protocol, we further in- case, a total regioselectivity in favor of the C N
vestigated the reaction selectivity issue between hy- bond-forming reaction, and the resulting amine prod-
drazones and anilines containing phenol or alcohol uct 4an was obtained with high yield and 98% ee;
À
À
group (C N versus C O bond forming reaction, therefore, no erosion of the chirality had occurred
Table 3). This study was anticipated to be a potential (Table 3).
challenge to overcome, since Barluenga and Valdes
Since this reaction is carried out in the presence of
group demonstrated that the base-promoted decom- BINAP as the ligand, this opens the way for an enan-
position of tosylhydrazones in the presence of phenols tioselective version of the coupling. Thus, we realized
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Jessy Aziz et al.
UPDATES
Table 3. Cu/BINAP catalyzed reaction of N-tosylhydrazones with various amines.[a]
[a]
Reactions conditions: N-tosylhydrazone 1 (1 equiv.), amine 2 (1.5 equiv.), CuACTHNUTRGNEUNG(acac)2 (10 mol%), rac.
BINAP (10 mol%) Cs2CO3 (2.5 equiv.), H2O (25 equiv.), PhF (2.5 mL) in a sealed tube at 1208C for
2 h.
[b]
[c]
[d]
Isolated yield of compounds 4 after column chromatography.
Reaction was performed without ligand in dioxane.
98% ee determined by HPLC on a chiral stationary phase type: Chiralcel Column OD.
the coupling between tosylhydrazone 1a and amine 2a
As sulfonylhydrazones could be simply prepared by
in the presence of (S)- and (R)-BINAP; unfortunate- mixing the related sulfonylhydrazides and the carbon-
ly, under our standard conditions, no control of the yl compounds, we investigated whether the reaction
enantioselectivity was observed. Other chiral biden- could be carried out in a one-pot fashion directly
date phosphines (JoSPOphos-type ligand) were also from carbonyl compounds 8, avoiding the isolation of
tested and a racemic mixture was always obtained.
the tosylhydrazone intermediates 1.
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À
Copper Acetoacetonate [CuACTHNUTRGEN(UNG acac)2]/BINAP-Promoted Csp N Bond Formation via Reductive Coupling
(compound 4ap). Good results were also obtained
with a-keto ester derivatives such as phenyl- or meth-
ylglyoxylate ethyl ester (compounds 4aq and 4ar). In
addition, the optimized conditions allow para-carbon-
yl-substituted aniline to react efficiently giving rise to
4as in a good 64% isolated yield.
This result clearly demonstrates that this protocol is
À
chemoselective towards a carbenoid N H insertion
rather than the condensation of aniline with the
ketone group. Finally, we performed the coupling be-
tween an unsymmetrical benzophenone and (S)-2-
amino-3-phenylpropan-1-ol in order to examine the
À
diastereoselectivity at the new C N bond. However,
no enantiomeric control was observed using our stan-
dard conditions. In fact, product 4at was obtained in
an equimolar mixture of the two diastereomers.
A tentative rationale mechanism for the Cu/BINAP
catalysis in the reductive coupling of N-tosylhydra-
zones with anilines is depicted in Scheme 3.
Initially, N-tosylhydrazone 1 in basic media under-
goes thermal decomposition through the Bamford–
Stevens reaction to generate a diazo compound. This
latter would react with copper(I) species to give the
À
Cu(I) carbene complex I. Further copper carbene N
H insertion might proceed with attack of the nitrogen
atom on the electrophilic carbene to generate copper
species II. Ligand BINAP may preclude b-elimination
from copper ylide II to form hydride species III to-
gether with iminium intermediate, precursor of imine
6.[24] In addition, water can act as an efficient proton-
transport catalyst for the ylide 1,2-H shift process, as
was previously reported.[28]
Scheme 2. Examples of the one-pot procedure.
Conclusions
In conclusion, we have successfully developed the
We were pleased to successfully achieve this one- first copper/BINAP-catalyzed reductive coupling of
pot protocol, yields similar to those obtained from hy- N-tosylhydrazones with anilines for the rapid con-
drazones 1 were achieved (Scheme 2). A compound struction of a-branched arylamines. This catalytic
containing an allyl function was coupled successfully system performs well over a broad scope of sub-
3
À
Scheme 3. Proposed mechanism for the Cu/BINAP-promoted Csp N bond formation via reductive coupling of N-tosylhy-
drazones with anilines.
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Jessy Aziz et al.
UPDATES
(C), 129.2 (2CH), 117.6 (CH), 113.6 (2CH), 104.1 (2CH),
98.7 (CH), 55.4 (2OCH3), 54.1 (CH), 25.0 (CH3); HR-MS
(ESI): m/z=258.1493 (M+H)+, calculated for C16H20NO2:
258.1494.
strates, allowing the coupling to be chemoselective
and tolerates a variety of functional groups. This re-
ductive coupling reaction can be envisioned as a new
type of amination of carbonyl compounds through to-
sylhydrazones without the use of any metal hydride.
For the reasons above, and taking into consideration
the generality of the process, and the ready availabili-
ty of both types of coupling partners, we believe that
these reactions may be very useful in organic synthe-
sis.
N-[1-(3,5-Dimethoxyphenyl)ethyl]-4-fluoroaniline
(4d):
Flash chromatography on neutralized silica gel (cyclohex-
ane/ethyl acetate 90/10) afforded 4d as
a yellow oil;
yield:134 mg (0.49 mmol, 85%); M=275.32 gmolÀ1; Rf =
0.53 (cyclohexane/ethyle acetate 80/20); IR (film): n=2838,
1610, 1594, 1508, 1457, 1428, 1373, 1345, 1309, 1290, 1254,
1221, 1203, 1152, 1125, 1066, 1053, 1024, 908 cmÀ1; H NMR
1
(300 MHz, CDCl3): d=6.81 (t, J=8.8 Hz, 2H), 6.54 (d, J=
2.1 Hz, 2H), 6.45 (dd, J=8.8, 4.4 Hz, 2H), 6.35 (t, J=
2.1 Hz, 1H), 4.33 (q, J=6.7 Hz, 1H), 3.78 (s, 6H), 1.50 (d,
J=6.7 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=161.2 (2C),
Experimental Section
1
157.4–154.3 (C, JC,F =234.9 Hz), 148.1 (C), 143.7 (C), 115.7–
3
115.4 (2CH, 2JC,F =22.3 Hz), 114.3–114.2 (2CH, JC,F
=
General Procedure for Copper-Catalyzed Reductive
Coupling of N-Tosylhydrazones Derived from
Acetophenones or Benzophenones with Amines
7.6 Hz), 104.0 (2CH), 98.7 (CH), 55.4 (2OCH3), 54.5 (CH),
25.1 (CH3); 19F NMR (188 MHz, CDCl3): d=À128.3; HR-
MS (ESI): m/z=276.1402 (M+H)+, calculated for
C16H19FNO2: 276.1400.
The reactions were carried out in a sealed tube with N-tosyl-
hydrazone 1 (200 mg, 1.0 equiv.), CuACTHNUTRGNEN(UG acac)2 (10 mol%), rac-
4-[1-(3,5-Dimethoxyphenyl)ethylamino]benzonitrile (4e):
Flash chromatography on neutralized silica gel (cyclohex-
ane/ethyle acetat 90/10) afforded 4e as a colorless oil; yield:
127 mg (0.45 mmol, 78%); M=282.34 gmolÀ1; Rf =0.7 (cy-
clohexane/ethyl acetate 50/50); IR (film): n=3485, 3378,
3352, 3203, 2835, 2343, 2318, 2212, 2177, 2154, 2070, 2046,
BINAP (10 mol%), Cs2CO3 (2.5 equiv.), the amine
(1.5 equiv.) then 3 mL of fluorobenzene and 25 equiv. H2O
were successively added via syringe at room temperature.
The tube was sealed and put into a pre-heated oil bath at
1208C for 2 h. The crude reaction mixture was allowed to
cool to room temperature. EtOAc was added to the mixture,
which was filtered through celite. The solvents were evapo-
rated under reduced pressure and the crude residue was pu-
rified by flash chromatography on neutralized silica gel (2%
triethylamine). The chiral column used was Chiralcel OD-H
(DAIC, 4.6ꢃ250 mm). The solvent used was hexane/isopro-
panol (98:2) at a flow rate of 1 mLminÀ1 and the absorbance
monitored using a PDA detector at 240 nm.
1607, 1522, 1461, 1428, 1336, 1204, 1174, 1155, 1053 cmÀ1
;
1H NMR (300 MHz, CDCl3): d=7.34 (d, J=8.9 Hz, 2H),
6.54–6.40 (m, 4H), 6.35 (t, J=2.2 Hz, 1H), 4.54 (bs, 1H),
4.43 (q, J=6.7 Hz, 1H), 3.77 (s, 6H), 1.53 (d, J=6.7 Hz,
3H); 13C NMR (75 MHz, CDCl3): d=161.4 (2C), 150.3 (C),
146.6 (C), 133.7 (2CH), 120.5 (2C), 113.2 (2CH), 104.0
(2CH), 98.8 (CH), 55.5 (2OCH3), 53.6 (CH), 24.7 (CH3);
HR-MS (ESI): m/z=283.1441 (M+H)+, calculated for
C17H19N2O2: 283.1447.
N-[1-(3,5-Dimethoxyphenyl)ethyl]-2-methoxyaniline (4b):
Flash chromatography on neutralized silica gel (cyclohex-
ane/ethyl acetate 90/10) afforded 4b as a yellow oil; yield:
135 mg (0.47 mmol, 82%); M=287.35 gmolÀ1; Rf =0.54 (cy-
clohexane/ethyl acetate 80/20); IR (film): n=2836, 1593,
1511, 1453, 1427, 1372, 1345, 1311, 1290, 1251, 1222, 1203,
N-[1-(3,5-Dimethoxyphenyl)ethyl]-4-(trifluoromethyl)ani-
line (4f): Flash chromatography on neutralized silica gel
(Ccyclohexane/ethyl acetate 90/10) afforded 4f as a white
solid; yield: 155 mg (0.48 mmol, 83%); M=325.33 gmolÀ1
;
1178, 1152, 1129, 1107, 1066, 1051, 1026, 926 cmÀ1; H NMR
1
mp 96–988C; Rf =0.56 (cyclohexane/ethyl acetate 70/30); IR
(film): n=3495, 3425, 3393, 3296, 1617, 1593, 1530, 1458,
1429, 1316, 1265, 1204, 1188, 1152, 1102, 1064, 1051, 1024,
(300 MHz, CDCl3): d=6.77 (ddd, J=15.1, 7.7, 1.5 Hz, 2H),
6.65 (td, J=7.7, 1.5 Hz, 1H), 6.59 (d, J=2.2 Hz, 2H), 6.43
(dd, J=7.7, 1.5 Hz, 1H), 6.37 (t, J=2.2 Hz, 1H), 4.68 (bs,
1H), 4.42 (q, J=6.7 Hz, 1H), 3.91 (s, 3H), 3.80 (s, 6H), 1.58
(d, J=6.7 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=161.2
(2C), 148.6 (C), 146.7 (C), 137.4 (C), 121.3 (CH), 116.6
(CH), 111.3 (CH), 109.4 (CH), 104.0 (2CH), 98.6 (CH), 55.5
(OCH3), 55.3 (2OCH3), 53.9 (CH), 25.1 (CH3); HR-MS
(ESI): m/z=288.1598 (M+H)+, calculated for C17H22NO3:
288.1600.
925 cmÀ1
;
1H NMR (300 MHz, CDCl3): d=7.33 (d, J=
8.6 Hz, 2H), 6.58–6.48 (m, 4H), 6.36 (t, J=2.2 Hz, 1H), 4.43
(q, J=6.7 Hz, 1H), 3.78 (s, 6H), 1.53 (d, J=6.7 Hz, 3H);
13C NMR (75 MHz, CDCl3): d=161.3 (2C), 149.6 (C), 147.2
(C), 130.5–126.9–123.3 (t, 1JC,F =270.41 Hz, C), 126.6 (q,
2
3JC,F =3.8 Hz, 2CH), 119.2–118.8 (d, JC,F =32.4 Hz, C), 112.7
(2CH), 104.00 (2CH), 98.7 (CH), 55.4 (2OCH3), 53.7 (CH),
24.8 (CH3); 19F NMR (188 MHz, CDCl3): d=À59.12; HR-
MS (ESI): m/z=326.1365 (M+H)+, calculated for
C17H19F3NO2: 326.1368.
N-[1-(3,5-Dimethoxyphenyl)ethyl]aniline (4c): Flash chro-
matography on neutralized silica gel (cyclohexane/ethyle
acetat 90/10) afforded 4c as a white solid; yield: 103 mg
(0.40 mmol, 70%); M=257.33 gmolÀ1; mp 97–998C; Rf =
0.47 (cyclohexane/ethyle acetate 80/20); IR (film): n=3408,
2962, 2836, 1596, 1505, 1459, 1428, 1373, 1346, 1320, 1289,
4-Methoxy-N-[1-(2,4,6-trimethoxyphenyl)ethyl]aniline
(4i): Flash chromatography on neutralized silica gel (cyclo-
hexane/ethyl acetate 90/10) afforded 4i as a yellow oil;
yield: 109 mg (0.34 mmol, 65%); M=317.38 gmolÀ1; Rf =
0.53 (cyclohexane/ethyl acetate 70/30); IR (film): n=2835,
1608, 1589, 1510, 1467, 1452, 1416, 1369, 1316, 1290, 1234,
1222, 1203, 1180, 1152, 1114, 1082, 1060, 1038, 1018, 951,
1257, 1203, 1153, 1065, 1052, 1023, 993, 925 cmÀ1; H NMR
1
(300 MHz, CDCl3): d=7.10 (t, J=7.9 Hz, 2H), 6.67 (t, J=
7.3 Hz, 1H), 6.54 (m, 4H), 6.34 (t, J=2.2 Hz, 1H), 4.40 (q,
J=6.7 Hz, 1H), 3.77 (s, 6H), 1.51 (d, J=6.7 Hz, 3H);
13C NMR (75 MHz, CDCl3): d=161.2 (2C), 148.2 (C), 147.3
909 cmÀ1
;
1H NMR (300 MHz, CDCl3): d= 6.69 (d, J=
9.1 Hz, 2H), 6.63 (d, J=9.1 Hz, 2H), 6.09 (s, 2H), 5.11 (q,
2424
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ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2013, 355, 2417 – 2429

3
À
Copper Acetoacetonate [CuACTHNUTRGEN(UNG acac)2]/BINAP-Promoted Csp N Bond Formation via Reductive Coupling
J=6.9 Hz, 1H), 3.84 (s, 6H), 3.76 (s, 3H), 3.70 (s, 3H), 1.49
(d, J=6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=159.8
(C), 158.9 (2C), 152.0 (C), 142.4 (C), 115.4 (2CH), 114.6
(2CH), 112.8 (C), 91.1 (2CH), 55.8 (2OCH3), 55.7 (OCH3),
55.3 (OCH3), 45.0 (CH), 20.7 (CH3); HR-MS (ESI): m/z=
318.1529 (M+H)+, calculated for C18H24NO4: 318.1527.
4-Methoxy-N-[1-(naphthalen-2-yl)ethyl]aniline (4j): Flash
chromatography on neutralized silica gel (cyclohexane/ethyl
acetate 95/5) afforded 4j as a yellow oil; yield: 131 mg
(0.47 mmol, 80%); M=277.36 gmolÀ1; Rf =0.69 (cyclohex-
ane/ethyl acetate 70/30); IR (film): n=3055, 2831, 1732,
1601, 1510, 1465, 1440, 1373, 1326, 1294, 1233, 1178, 1133,
6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=148.4 (C),
140.8 (C), 133.5 (C), 132.7 (C), 132.6 (C), 129.9 (2CH),
128.2 (CH), 128.1 (CH), 127.7 (CH), 126.2 (CH), 126.1
(CH), 125.8 (CH), 125.2 (CH), 113.9 (2CH), 57.3 (CH), 32.3
(CH3), 20.4 (CH3), 15.9 (CH3); HR-MS (ESI): m/z=
276.1739 (M+H)+, calculated for C20H22N: 276.1747.
1-[1-(3,5-Dimethoxyphenyl)ethyl]indoline (4o): Flash
chromatography on neutralized silica gel (cyclohexane/
ethyle acetat 90/10) afforded 4o as a colorless oil; yield:
122 mg (0.43 mmol, 75%); M=283.36 gmolÀ1; Rf =0.68 (cy-
clohexane/ethyl acetate 70/30); IR (film): n=3406, 3249,
3230, 3095, 2197, 2168, 2052, 1606, 1591, 1487, 1456, 1426,
1037 cmÀ1; H NMR (300 MHz, CDCl3): d=7.83 (dd, J=8.7,
1344, 1256, 1203, 1151, 1055, 1037, 924 cmÀ1 1H NMR
;
1
5.0 Hz, 4H), 7.62–7.39 (m, 3H), 6.70 (d, J=9.0 Hz, 2H),
6.54 (d, J=9.0 Hz, 2H), 4.59 (q, J=6.7 Hz, 1H), 3.69 (s,
3H), 1.59 (d, J=6.7 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d=153.1 (C), 141.8 (C), 139.7 (C), 133.6 (C), 133.0 (C),
128.6 (CH), 128.0 (CH), 127.8 (CH), 126.1 (CH), 125.7
(CH), 125.0 (CH), 124.7 (CH), 116.2 (2CH), 114.9 (2CH),
56.0 (CH), 55.8 (OCH3), 24.5 (CH3); HR-MS (ESI): m/z=
278.1546 (M+H)+, calculated for C19H20NO: 278.1545.
4-[1-(4-Fluorophenylamino)ethyl]benzonitrile (4l): Flash
chromatography on neutralized silica gel (cyclohexane/ethyl
acetate 90/10) afforded 4l as a yellow oil; yield: 101 mg
(0.42 mmol, 66%); M=240.28 gmolÀ1; Rf =0.46 (cyclohex-
ane/ethyl acetate 70/30); IR (film): n=3456, 3436, 3413,
3373, 3082, 2228, 1609, 1505, 1315, 1257, 1221, 1206, 1142,
(300 MHz, CDCl3): d=7.14–7.00 (m, 2H), 6.67 (d, J=
7.3 Hz, 1H), 6.64 (d, J=2.1 Hz, 2H), 6.43 (m, 2H), 4.66 (q,
J=6.8 Hz, 1H), 3.81 (s, 6H), 3.41 (t, J=8.2 Hz, 2H), 2.99 (t,
J=8.2 Hz, 2H), 1.55 (d, J=6.8 Hz, 3H); 13C NMR (75 MHz,
CDCl3): d=161.0 (2C), 151.4 (C), 145.7 (C), 130.3 (C),
127.2 (CH), 124.4 (CH), 117.2 (CH), 107.5 (CH), 105.4
(2CH), 98.7 (CH), 55.4 (2OCH3), 55.0 (CH), 48.2 (CH2),
28.3 (CH2), 16.6 (CH3); HR-MS (ESI): m/z=284.1649 (M+
H)+, calculated for C18H22NO2: 284.1651.
N-[1-(3,5-Dimethoxyphenyl)ethyl]pyridin-2-amine
(4p):
Flash chromatography on neutralized silica gel (cyclohex-
ane/ethyl acetate 90/10) afforded 4p as a colorless oil; yield:
92 mg (0.36 mmol, 62%); M=258.32 gmolÀ1; Rf =0.21 (cy-
clohexane/ethyl acetate 70/30; IR (film): n=2836, 1593,
1571, 1528, 1504, 1455, 1427, 1373, 1325, 1290, 1245, 1203,
1
1018, 839, 818, 772 cmÀ1; H NMR (300 MHz, CDCl3): d=
1
7.61 (d, J=8.3 Hz, 2H), 7.47 (d, J=8.3 Hz, 2H), 6.80 (t, J=
8.8 Hz, 2H), 6.38 (m, 2H), 4.45 (q, J=6.8 Hz, 1H), 1.51 (d,
J=6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=157.64–
154.52 (C, 1JC,F =235.8 Hz), 150.9 (C), 143.0 (C), 132.7
1151, 1067, 1053, 1027, 987, 925 cmÀ1; H NMR (300 MHz,
CDCl3): d=8.06 (d, J=3.6 Hz, 1H), 7.32 (ddd, J=8.8, 7.3,
1.8 Hz, 1H), 6.54 (m, 3H), 6.33 (t, J=2.3 Hz, 1H), 6.21 (d,
J=8.4 Hz, 1H), 5.08 (d, J=5.8 Hz, 1H), 4.61 (p, J=6.8 Hz,
1H), 3.76 (s, 6H), 1.53 (d, J=6.8 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d=161.2 (2C), 158.1 (C), 148.1 (CH),
147.6 (C), 137.7 (CH), 113.2 (CH), 106.9 (CH), 104.0
(2CH), 98.9 (CH), 55.4 (2OCH3), 52.4 (CH), 24.5 (CH3);
HR-MS (ESI): m/z=259.1449 (M+H)+, calculated for
C15H19N2O2: 259.1447.
2
(2CH), 126.8 (2CH), 119.0 (C), 115.8 (2CH, JC,F =22.4 Hz),
114.3 (2CH, 3JC,F =7.2 Hz), 111.0 (C), 54.2 (CH), 25.0
(CH3); 19F NMR (188 MHz, CDCl3): d=À125.5; HR-MS
(ESI): m/z=241.1142 (M+H)+, calculated for C15H14FN2:
241.1141.
N,4-Dimethyl-N-(1-phenylethyl)aniline (4m): Flash chro-
matography on neutralized silica gel (cyclohexane/ethyl ace-
tate 95/5) afforded 4m as a yellow oil; yield: 91 mg
(0.40 mmol, yield 58%); M=225.33 gmolÀ1; Rf =0.47 (cyclo-
hexane/ethyl acetate 70/30); IR (film): n=3408, 3340, 3313,
3295, 3271, 3204, 3148, 2363, 2163, 2076, 2042, 2012, 1618,
4-Fluoro-N-[1-(pyridin-3-yl)ethyl]aniline (4q): Flash chro-
matography on neutralized silica gel (cyclohexane/ethyl ace-
tate 80/20) afforded 4q as a brown oil; yield: 102 mg
(0.47 mmol, 68%); M=216.25 gmolÀ1; Rf =0.08 (cyclohex-
ane/ethyle acetat 70/30); IR (film): n=3478, 3383, 3342,
1516, 1448, 1372, 1303, 1109, 1027, 908 cmÀ1
;
1H NMR
3230, 2489, 2278, 2235, 2203, 2152, 1928, 1509, 1212 cmÀ1
;
(300 MHz, CDCl3): d=7.34 (m, 5H), 7.08 (d, J=8.4 Hz,
2H), 6.79 (d, J=7.6 Hz, 2H), 5.07 (q, J=6.8 Hz, 1H), 2.66
(s, 3H), 2.28 (s, 3H), 1.54 (d, J=6.8 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d=148.4 (C), 143.1 (C), 129.8 (2CH),
128.5 (2CH), 127.1 (2CH), 127.0 (CH), 126.2 (C), 113.8
(2CH), 57.2 (CH), 32.2 (CH3), 20.4 (CH3), 16.3 (CH3); HR-
MS (ESI): m/z=226.1598 (M+H)+, calculated for C16H20N:
226.1596.
1H NMR (300 MHz, DMSO): d=(ppm) 8.57 (d, J=52.9 Hz,
2H), 7.78 (d, J=7.8 Hz, 1H), 7.37 (s, 1H), 6.83 (t, J=
9.0 Hz, 2H), 6.49 (dd, J=9.0, 4.6 Hz, 2H), 4.52 (q, J=
6.8 Hz, 1H), 1.43 (d, J=6.8 Hz, 3H); 13C NMR (75 MHz,
DMSO): d=155.8 (C), 152.8 (C), 147.7 (CH), 147.4 (CH),
2
144.2 (C), 133.9 (2CH), 115.1 (2CH, JC,F =22.0 Hz), 113.6
(2CH, 3JC,F =7.2 Hz), 50.2 (CH), 24.2 (CH3); 19F NMR
(188 MHz, CDCl3): d=À127.5; HR-MS (ESI): m/z=
217.1127 (M+H)+, calculated for C13H14FN2: 217.1136.
N-Benzhydryl-3,4,5-trimethoxyaniline (4t): Flash chroma-
tography on neutralized silica gel (cyclohexane/ethyle acetat
80/20) afforded 4t as a yellow solid (crystallized in a mixture
of diisopropyl ether/ethyle acetat); yield: 182 mg
(0.52 mmol, 91%); M=349.42 gmolÀ1; mp 142–1448C; Rf =
0.42 (cyclohexane/ethyle acetat 70/30); IR (film): n=3492,
3453, 3427, 3345, 3262, 3224, 3198, 3060, 2929, 2169, 1963,
1611, 1509, 1451, 1409, 1233, 1206, 1184, 1129, 1010,
N,4-Dimethyl-N-[1-(naphthalen-2-yl)ethyl]aniline
(4n):
Flash chromatography on neutralized silica gel (cyclohex-
ane/ethyl acetate 98/2) afforded 4n as a colorless oil; yield:
127 mg (0.46 mmol, 78%); M=275.39 gmolÀ1; Rf =0.77 (cy-
clohexane/ethyl acetate 70/30); IR (film): n=3473, 3417,
3386, 2219, 2092, 2036, 2012, 1736, 1679, 1616, 1515, 1368,
1
1237, 1180, 1108, 858 cmÀ1; H NMR (300 MHz, CDCl3): d=
7.88–7.80 (m, 2H), 7.78 (d, J=7.3 Hz, 2H), 7.54–7.42 (m,
3H), 7.10 (d, J=8.4 Hz, 2H), 6.86 (d, J=7.3 Hz, 2H), 5.22
(q, J=6.8 Hz, 1H), 2.69 (s, 3H), 2.30 (s, 3H), 1.65 (d, J=
912 cmÀ1 1H NMR (300 MHz, CDCl3): d=7.49–7.15 (m,
;
Adv. Synth. Catal. 2013, 355, 2417 – 2429
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2425

Jessy Aziz et al.
UPDATES
10H), 5.80 (s, 2H), 5.45 (s, 1H), 4.18 (bs, 1H), 3.74 (s, 3H),
3.66 (s, 6H); 13C NMR (75 MHz, CDCl3): d=153.9 (3C),
143.0 (3C), 128.9 (4CH), 127.6 (2CH), 127.5 (4CH), 91.5
(2CH), 64.0 (CH), 61.2 (OCH3), 55.9 (2OCH3); HR-MS
(ESI): m/z=350.1752 (M+H)+, calculated for C22H24NO3:
350.1756.
127.8 (CH), 126.1 (CH), 125.6 (CH), 125.4 (CH), 125.0
(CH), 58.7 (CH), 47.7 (CH2), 32.4 (CH2), 24.32 (CH3), 20.62
(CH2), 14.11 (CH3); HR-MS (ESI): m/z=228.1738 (M+
H)+, calculated for C16H22N: 228.1747.
1-(3,5-Dimethoxyphenyl)-N-(4-methoxybenzyl)ethana-
mine (4ab): Flash chromatography on neutralized silica gel
(cyclohexane/ethyl acetate 90/10) afforded 4ab as a yellow
N-Benzhydryl-4-fluoroaniline (4u): Flash chromatography
on neutralized silica gel (cyclohexane/ethyl acetate 95/5) af-
forded 4u as a yellow oil; yield: 130 mg (0.47 mmol, 82%);
M=277.34 gmolÀ1; Rf =0.78 (cyclohexane/ethyle acetat 70/
30); IR (film): n=3028, 1506, 1451, 1399, 1345, 1309, 1264,
oil; yield: 129 mg (0.43 mmol, 75%); M=301.38 gmolÀ1
;
Rf =0.13 (cyclohexane/ethyl acetate 70/30); IR (film): n=
3112, 2836, 1610, 1594, 1512, 1457, 1427, 1346, 1290, 1244,
1203, 1151, 1117, 1055, 1033, 926, 908 cmÀ1
;
1H NMR
1220, 1156, 1111, 1090, 1064, 1028, 908 cmÀ1
;
1H NMR
(300 MHz, CDCl3): d=7.22 (d, J=8.6 Hz, 2H), 6.86 (d, J=
8.6 Hz, 2H), 6.56 (d, J=2.2 Hz, 2H), 6.38 (t, J=2.2 Hz,
1H), 3.81 (s, 6H), 3.79 (s, 3H), 3.72–3.48 (m, 3H), 1.36 (d,
J=6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=161.1 (2C),
158.7 (C), 148.5 (C), 132.8 (C), 129.4 (2CH), 113.9 (2CH),
104.7 (2CH), 98.9 (CH), 57.8 (CH), 55.4 (2OCH3), 55.4
(OCH3), 51.1 (CH2), 24.5 (CH3); HR-MS (ESI): m/z=
302.1757 (M+H)+, calculated for C18H24NO3: 302.1756.
1-(3,5-Dimethoxyphenyl)-N-(4-fluorobenzyl)ethanamine
(4ad): Flash chromatography on neutralized silica gel (cyclo-
hexane/ethyl acetate 90/10) afforded 4ad as a yellow oil;
yield: 100 mg (0.34 mmol, 60%); M=289.34 gmolÀ1; Rf =
0.13 (cyclohexane/ethyl acetate 70/30); IR (film): n=2962,
2836, 1976, 1609, 1594, 1509, 1457, 1428, 1345, 1292, 1221,
(300 MHz, CDCl3): d=7.45–7.14 (m, 10H), 6.79 (t, J=
8.7 Hz, 2H), 6.45 (dd, J=8.7, 4.4 Hz, 2H), 5.41 (s, 1H), 4.12
(s, 1H); 13C NMR (75 MHz, CDCl3): d=157.7–154.5 (C,
1JC,F =235.5 Hz), 143.7 (C), 142.8 (2C), 128.9 (4CH), 127.6
(2CH), 127.5 (4CH), 115.8–115.5 (2CH, 2JC,F =22.2 Hz),
114.6 (2CH), 63.8 (CH); 19F NMR (188 MHz, CDCl3): d=
À128.0; HR-MS (ESI): m/z=278.1344 (M+H)+, calculated
for C19H17FN: 278.1345.
N-[Bis(4-fluorophenyl)methyl]-4-methoxyaniline
(4v):
Flash chromatography on neutralized silica gel (cyclohex-
ane/ethyl acetate 95/5) afforded 4v as a yellow oil; yield:
121 mg (0.37 mmol, 72%); M=325.35 gmolÀ1; Rf =0.77 (cy-
clohexane/ethyle acetat 70/30); IR (film): n=3481, 3465,
3442, 3423, 3330, 3215, 3173, 3058, 3034, 2358, 2158, 2136,
1203, 1152, 1122, 1054, 907 cmÀ1
;
1H NMR (300 MHz,
2038, 2005, 1601, 1506, 1243, 1223, 1156, 1037, 842 cmÀ1
;
CDCl3): d=7.24 (dd, J=8.8, 5.3 Hz, 2H), 6.97 (t, J=8.8 Hz,
2H), 6.51 (d, J=2.3 Hz, 2H), 6.36 (t, J=2.3 Hz, 1H), 3.79
(s, 6H), 3.72 (q, J=13.1, 6.6 Hz, 1H), 3.59 (q, J=13.1 Hz,
2H), 1.34 (d, J=6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d=163.6–160.4 (C, 1JC,F =244 Hz), 161.1 (2C), 148.3 (C),
136.4 (C, 4JC,F =2.7 Hz), 129.8 (2CH, 3JC,F =7.9 Hz), 115.2
1H NMR (300 MHz, CDCl3): d=7.31 (m, 4H), 7.01 (t, J=
8.5 Hz, 4H), 6.73 (d, J=8.6 Hz, 2H), 6.50 (d, J=8.6 Hz,
2H), 5.39 (s, 1H), 3.72 (s, 3H); 13C NMR (75 MHz, CDCl3):
d=162.2 (2C, J=235.0 Hz), 156.4 (C), 152.7 (C), 138.8
(2C), 129.1 (4CH, J=8.0 Hz), 122.8 (2CH), 115.8 (4CH,
J=21.4 Hz), 114.1 (2CH), 62.7 (CH), 55.9 (OCH3);
19F NMR (188 MHz, CDCl3): d=À113.2; HR-MS (ESI): m/
z=326.1328 (M+H)+, calculated for C20H18F2NO: 326.1325.
N-[4-(Benzhydrylamino)phenyl]-N-methylacetamide
2
(2CH, JC,F =21.2 Hz), 104.7 (2CH), 98.9 (CH), 57.9 (CH),
55.4 (2OCH3), 51.0 (CH2), 24.5 (CH3); 19F NMR (188 MHz,
CDCl3): d=À116.5; HR-MS (ESI): m/z=290.1554 (M+
H)+, calculated for C17H21NO2F: 290.1556.
(4w): Flash chromatography on neutralized silica gel (cyclo-
hexane/ethyle acetat 90/10) afforded 4w as a yellow solid
(crystallized in a mixture of diisopropyl ether/ethyl acetate);
yield: 149 mg (0.45 mmol, 79%); M=330.42 gmolÀ1; mp
152–1548C; Rf =0.19 (cyclohexane/ethyl acetate 70/30); IR
(film): n=3487, 3460, 3405, 3389, 3296, 3190, 3147, 2510,
2194, 1997, 1973, 1657, 1637, 1517, 1449, 1420, 1381, 1319,
5-[1-(3,5-Dimethoxyphenyl)ethylamino]-2-methoxyphenol
(4ai): Flash chromatography on neutralized silica gel (cyclo-
hexane/ethyl acetate 90/10) afforded 4ai as a red oil; yield:
125 mg (0.41 mmol, 72%); M=303.35 gmolÀ1; Rf =0.26 (cy-
clohexane/ethyl acetate 70/30); IR (film): n=3402, 3104,
1593, 1511, 1455, 1427, 1345, 1203, 1151, 1065, 1052, 1023,
980 cmÀ1
;
1H NMR (300 MHz, CDCl3): d=6.63 (d, J=
1
1278, 1177, 1142, 975 cmÀ1; H NMR (300 MHz, CDCl3): d=
8.6 Hz, 1H), 6.54 (d, J=2.0 Hz, 2H), 6.33 (d, J=2.0 Hz,
1H), 6.28 (d, J=2.4 Hz, 1H), 6.08 (dd, J=8.6, 2.4 Hz, 1H),
4.32 (q, J=6.7 Hz, 1H), 3.77 (s, 9H), 1.51 (d, J=6.7 Hz,
3H); 13C NMR (75 MHz, CDCl3): d=161.2 (2C), 152.8 (C),
147.5 (C), 146.5 (C), 139.9 (C), 112.4 (CH), 105.7 (CH),
104.3 (2CH), 102.2 (CH), 99.0 (CH), 56.9 (CH), 55.4
(3OCH3), 24.6 (CH3); HR-MS (ESI): m/z=304.1535 (M+
H)+, calculated for C17H22NO4: 304.1543.
7.43–7.23 (m, 10H), 6.90 (d, J=8.6 Hz, 2H), 6.54 (d, J=
8.6 Hz, 2H), 5.49 (s, 1H), 3.18 (s, 3H), 1.83 (s, 3H);
13C NMR (75 MHz, CDCl3): d=171.4 (C), 146.7 (C), 142.5
(2C), 135.0 (C), 129.0 (4CH), 127.9 (2CH), 127.7 (2CH),
127.5 (4CH), 114.2 (2CH), 63.4 (CH), 37.4 (CH3), 22.5
(CH3); HR-MS (ESI): m/z=331.1808, (M+H)+, calculated
for C22H23N2O: 331.1810.
N-[1-(Naphthalen-2-yl)ethyl]butan-1-amine (4aa): Flash
chromatography on neutralized silica gel (cyclohexane/ethyl
acetate 80/20) afforded 4aa as a colorless oil; yield: 110 mg
(0.48 mmol, 82%); M=227.34 gmolÀ1; Rf =0.18 (cyclohex-
ane/ethyle acetate 70/30); IR (film): n=3393, 3253, 2959,
2927, 2017, 1968, 1947, 1730, 1602, 1509, 1381, 1183, 1127,
2-{4-[(1-{3,5-dimethoxyphenyl}ethyl)amino]phenyl}ethanol
(4aj): Flash chromatography on neutralized silica gel (cyclo-
hexane/ethyl acetate 80/20) afforded 4aj as a yellow oil;
yield: 125 mg (0.41 mmol, 72%); M=301.38 gmolÀ1; Rf =
0.22 (cyclohexane/ethyl acetate 70/30); IR (film): n=3425,
3242, 2355, 2218, 2203, 2166, 2151, 2088, 2069, 2009, 1609,
1077 cmÀ1
;
1H NMR (300 MHz, CDCl3): d=7.82 (m, 3H),
1593, 1517, 1427, 1257, 1203, 1151, 1065 cmÀ1 1H NMR
;
7.75 (s, 1H), 7.56–7.39 (m, 3H), 3.96 (q, J=6.6 Hz, 1H),
2.64–2.37 (m, 2H), 1.48 (m, 4H), 1.30 (dd, J=15.0, 7.7 Hz,
3H), 0.87 (t, J=7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d=142 (C), 133.6 (C), 133.0 (C), 128.4 (CH), 127.9 (CH),
(300 MHz, CDCl3): d=6.95 (d, J=8.5 Hz, 2H), 6.55 (d, J=
2.3 Hz, 2H), 6.50 (d, J=8.5 Hz, 2H), 6.34 (t, J=2.3 Hz,
1H), 4.37 (q, J=6.7 Hz, 1H), 3.86–3.63 (m, 8H), 2.71 (t, J=
6.6 Hz, 2H), 1.50 (d, J=6.7 Hz, 3H); 13C NMR (75 MHz,
2426
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3
À
Copper Acetoacetonate [CuACTHNUTRGEN(UNG acac)2]/BINAP-Promoted Csp N Bond Formation via Reductive Coupling
CDCl3): d=161.2 (2C), 148.2 (C), 145.9 (C), 129.8 (2CH),
127.0 (C), 113.8 (2CH), 104.1 (2CH), 98.6 (CH), 63.9 (CH2),
55.4 (2OCH3), 54.2 (CH), 38.3 (CH2), 24.9 (CH3); HR-MS
(ESI): m/z=302.1743 (M+H)+, calculated for C18H24NO3:
302.1751.
MS (ESI): m/z=318.1860 (M+H)+, calculated for
C22H24NO: 318.1858.
General Procedure for Copper-Catalyzed Reductive
Coupling of N-Tosylhydrazones Derived from
Benzaldehydes with Amines
5-(Benzhydrylamino)-2-methoxyphenol (4ak): Flash chro-
matography on neutralized silica gel (cyclohexane/ethyl ace-
tate 90/10) afforded 4ak as
a red oil; yield: 161 mg
The reactions were carried out in a sealed tube with N-tosyl-
hydrazone (200 mg, 1.0 equiv.), CuACTHNUTRGNENUG(acac)2 (10 mol%), race-
(0.53 mmol, 92%); M=305.37 gmolÀ1; Rf =0.5 (cyclohexane/
ethyl acetate 70/30); IR (film): n=3424, 3261, 2211, 1594,
1512, 1451, 1350, 1291, 1244, 1204, 1153, 1066, 1028,
mic BINAP (10 mol%), K2CO3 (2.5 equiv.), the amine
(1.5 equiv.) then 3 mL of fluorobenzene and 25 equiv. H2O
were successively added via syringe at room temperature.
The tube was sealed and put into a pre-heated oil bath at
808C for 2 h. The crude reaction mixture was allowed to
cool to room temperature. EtOAc was added to the mixture,
which was filtered through celite. The solvents were evapo-
rated under reduced pressure and the crude residue was pu-
rified by flash chromatography on neutralized silica gel (2%
triethylamine).
961 cmÀ1 1H NMR (300 MHz, CDCl3): d=7.27 (m, 10H),
;
6.62 (d, J=8.6 Hz, 1H), 6.22 (d, J=2.5 Hz, 1H), 6.00 (dd,
J=8.6, 2.5 Hz, 1H), 5.50 (bs, 1H), 5.40 (s, 1H), 3.74 (s, 3H);
13C NMR (75 MHz, CDCl3): d=146.6 (C), 143.2 (2C), 142.8
(C), 139.4 (C), 128.8 (4CH), 127.6 (4CH), 127.4 (2CH),
112.4 (CH), 104.7 (CH), 101.5 (CH), 63.8 (CH), 56.9
(OCH3); HR-MS (ESI): m/z=306.1496 (M+H)+, calculated
for C20H20NO2: 306.1494.
N-(3,5-Dimethoxybenzyl)-4-methoxyaniline (4x): Flash
chromatography on neutralized silica gel (cyclohexane/ethyl
acetate 90/10) afforded 4x as a yellow oil; yield: 90 mg
(0.33 mmol, 55%); M=273.33 gmolÀ1; Rf =0.55 (cyclohex-
ane/ethyl acetate 70/30); IR (film): n=3476, 3443, 3334,
3277, 3261, 3202, 3099, 3000, 2600, 2315, 2186, 2169, 2124,
2094, 2038, 2007, 1983, 1596, 1512, 1429, 1234, 1204, 1155,
4-(Benzhydrylamino)phenol (4al): Flash chromatography
on neutralized silica gel (cyclohexane/ethyl acetate 80/20)
afforded 4al as a yellow oil; yield: 134 mg (0.49 mmol,
85%); M=275.34 gmolÀ1; Rf =0.54 (cyclohexane/ethyl ace-
tate 70/30); IR (film): n=3197, 2341, 2235, 2150, 2013, 1598,
1511, 1491, 1451, 1416, 1343, 1304, 1234, 1119, 1028 cmÀ1
;
1H NMR (400 MHz, DMSO): d=8.37 (bs, 1H), 7.40 (d, J=
7.3 Hz, 4H), 7.29 (t, J=7.6 Hz, 4H), 7.19 (t, J=7.3 Hz, 2H),
6.48 (dd, J=18.5, 8.8 Hz, 4H), 5.76 (bs, 1H), 5.49 (s, 1H);
13C NMR (75 MHz, CDCl3): d=147.8 (C), 143.3 (2C), 141.9
(C), 128.8 (4CH), 127.5 (4CH), 127.4 (2CH), 116.2 (2CH),
114.9 (2CH), 64.0 (CH); HRMS (ESI): m/z=276.1385 (M+
H)+, calculated for C19H18NO: 276.1388.
1064, 1032 cmÀ1 1H NMR (300 MHz, CDCl3): d=6.76 (s,
;
4H), 6.55 (s, 2H), 6.36 (s, 1H), 4.22 (s, 2H), 3.77 (s, 6H),
3.74 (s, 3H); 13C NMR (75 MHz, CDCl3): d=161.1 (2C),
154.0 (C), 140.2 (C), 139.3 (C), 116.5 (2CH), 115.0 (2CH),
106.1 (2CH), 99.8 (CH), 55.9 (OCH3), 55.5 (2OCH3), 51.0
(CH2); HR-MS (ESI): m/z=274.1438 (M+H)+, calculated
for C16H20NO3: 274.1443.
N-Benzhydryl-2-(5-methoxy-1H-indol-3-yl)ethanamine
(4am): Flash chromatography on neutralized silica gel (cy-
clohexane/ethyl acetate 80/20) afforded 4am as a brown oil;
yield: 157 mg (0.44 mmol, 77%); M=356.46 gmolÀ1; Rf =
0.26 (cyclohexane/ethyl acetate 70/30); IR (film): n=2163,
1624, 1584, 1485, 1453, 1437, 1293, 1265, 1214, 1171, 1071,
N-Benzyl-4-methoxyaniline (4y): Flash chromatography
on neutralized silica gel (cyclohexane/ethyl acetate 90/10)
afforded 4y as a yellow oil; yield: 78 mg (0.37 mmol, 50%);
M=213.28 gmolÀ1; Rf =0.68 (cyclohexane/ethyl acetate 70/
30); IR (film): n=3471, 3431, 3351, 3334, 3313, 3215, 3174,
3053, 2181, 2122, 2061, 2016, 1512, 1233, 1036, 903 cmÀ1
;
1
1029, 923, 834, 794, 734, 698, 641 cmÀ1; H NMR (400 MHz,
1H NMR (300 MHz, CDCl3): d=7.43–7.24 (m, 5H), 6.80 (d,
J=9.0 Hz, 2H), 6.62 (d, J=9.0 Hz, 2H), 4.30 (s, 2H), 3.76
(s, 3H); 13C NMR (75 MHz, CDCl3): d=152.35 (C), 142.60
(C), 139.84 (C), 128.72 (2CH), 127.67 (2CH), 127.29 (CH),
115.07 (2CH), 114.25 (2CH), 55.94 (OCH3), 49.39 (CH2);
HR-MS (ESI): m/z=214.1227 (M+H)+, calculated for
C14H16NO: 214.1232.
CDCl3): d=8.03 (bs, 1H), 7.42 (d, J=7.3 Hz, 4H), 7.32 (t,
J=7.3 Hz, 4H), 7.22 (dd, J=15.8, 8.2 Hz, 3H), 7.05 (d, J=
2.4 Hz, 1H), 6.96–6.78 (m, 2H), 4.91 (s, 1H), 3.86 (s, 3H),
3.00 (dd, J=12.3, 5.3 Hz, 4H), 1.84 (s, 1H); 13C NMR
(101 MHz, CDCl3): d=153.9 (C), 144.3 (2C), 131.6 (C),
128.5 (4CH), 127.9 (C), 127.4 (4CH), 127.0 (2CH), 122.9
(CH), 113.8 (C), 112.3 (CH), 112.0 (CH), 100.8 (CH), 67.4
(CH), 56.0 (OCH3), 48.1 (CH2), 26.0 (CH2); HR-MS (ESI):
m/z=357.1960 (M+H)+, calculated for C24H25N2O:
357.1961.
General Procedure for the One-Pot Copper-
Catalyzed Reductive Coupling of N-Tosylhydrazones
with Amines
(R)-2-(Benzhydrylamino)-3-phenylpropan-1-ol
(4an):
Flash chromatography on neutralized silica gel (cyclohex-
ane/ethyl acetate 90/10) afforded 4an as a yellow oil; yield:
152 mg (0.48 mmol, 84%); M=317.42 gmolÀ1; Rf =0.44 (cy-
clohexane/ethyl acetate 70/30); IR (film): n=3270, 3228,
The reactions were carried out in a sealed tube with the car-
bonyl compound (100 mg), tosylhydrazide (1 equiv.) and
2 mL PhF. The vessel was sealed with a septum and put in
a heated oil bath at 808C until completion (1–2 h). Then,
3180, 3148, 3088, 2326, 2235, 1493, 1452, 1086, 1047 cmÀ1
;
CuACHTNURGTENUNG(acac)2 (10 mol%), rac-BINAP (10 mol%), Cs2CO3
1H NMR (300 MHz, CDCl3): d=7.54–6.77 (m, 15H), 4.91 (s,
1H), 3.57 (dd, J=10.8, 3.4 Hz, 1H), 3.32 (dd, J=10.8,
4.6 Hz, 1H), 2.96–2.63 (m, 3H); 13C NMR (75 MHz,
CDCl3): d=143.6 (2C), 138.6 (C), 129.4 (2CH), 128.6
(6CH), 127.5 (2CH), 127.3 (2CH), 127.2 (2CH), 126.5
(CH), 64.2 (CH), 63.1 (CH2), 57.6 (CH), 38.4 (CH2); HR-
(2.5 equiv.), the amine (1.5 equiv.) and 25 equiv. H2O were
successively added to the resulting reaction mixture. Again,
the vessel was sealed with a septum and placed into a pre-
heated oil bath at 1208C for 2 h. The crude reaction mixture
was allowed to cool to room temperature. EtOAc was
added to the mixture, which was filtered through celite. The
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Jessy Aziz et al.
UPDATES
solvents were evaporated under reduced pressure and the References
crude residue was purified by flash chromatography on neu-
tralized silica gel (2% triethylamine).
N-{1-[3,5-Bis(allyloxy)phenyl]ethyl}-4-methoxyaniline
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(300 MHz, CDCl3): d=6.70 (d, J=8.9 Hz, 2H), 6.56 (d, J=
2.2 Hz, 2H), 6.47 (d, J=8.9 Hz, 2H), 6.36 (t, J=2.2 Hz,
1H), 6.03 (m, 2H), 5.53–5.18 (m, 4H), 4.49 (dt, J=5.3,
1.3 Hz, 4H), 4.31 (q, J=6.7 Hz, 1H), 3.70 (s, 3H), 1.47 (d,
J=6.7 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=160.1 (2C),
152.1 (C), 148.5 (C), 141.8 (C), 133.4 (2CH), 117.8 (2CH2),
114.9 (2CH), 114.7 (2CH), 105.1 (2CH), 100.1 (CH), 69.0
(2CH2), 55.9 (CH), 54.7 (OCH3), 25.1 (CH3); HR-MS (ESI):
m/z=340.1910 (M+H)+, calculated for C21H26NO3:
340.1913.
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1
1988, 1938, 1596, 1521, 1272, 1180 cmÀ1; H NMR (300 MHz,
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6.54 (d, J=8.8 Hz, 2H), 5.62 (d, J=4.6 Hz, 1H), 4.79 (d, J=
4.6 Hz, 1H), 2.46 (s, 3H); 13C NMR (75 MHz, CDCl3): d=
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127.8 (2CH), 127.5 (4CH), 127.3 (C), 112.5 (2CH), 62.5
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Acknowledgements
The CNRS is gratefully acknowledged for financial support
of this research. Our laboratory BioCIS UMR 8076 is
a member of the Laboratory of Excellence LERMIT sup-
ported by a grant from ANR (ANR-10-LABX-33). We thank
the Lebanese University for the award of a research fellow-
ship to J. A.
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