Palladium-catalyzed benzylic C-H benzylation via bis-benzylpalladium(II) complexes in water: An effective pathway for the direct construction of N-(1,2-diphenylethyl)anilines

Article abstract of DOI:10.1002/adsc.201401017

A strategy for the N-benzylation/benzylic C-H benzylation cascade of anilines by the π-benzylpalladium system using a water-soluble palladium(0)/sodium diphenylphosphinobenzene-3-sulfonate (TPPMS) catalyst and benzyl alcohol in water has been developed. This tandem process is devised as a novel and efficient synthetic route for N-(1,2-diphenylethyl)anilines. Benzylic C-H activation of a mono-N-benzylated intermediate with a π-benzylpalladium(II) complex affords a bis-π-benzylated palladium(II) intermediate. The nucleophilic η¹-σ-benzyl anion ligand attacks the electrophilic η³-π-benzyl ligand to give a dibenzylated product. The intermolecular competition between mono-N-benzylaniline and its monodeuterated form (monodeuterated at the benzylic group) with benzyl alcohol gave a KIE=4.6, suggesting that C-H bond cleavage was involved in the rate-determining step. Hammett studies on the rate constants of benzylation by various substituted anthranilic acids and mono-N-benzylanilines show a good correlation between the log(k_X/k_H) and the σ values of the respective substituents. From the slope, negative ρ values are obtained, suggesting that there is a build-up of positive charge in the transition state. The reaction of anilines with electron-donating and electron-withdrawing groups affords the corresponding N-(1,2-diphenylethyl)anilines in moderate to good yields (54-86%). Interestingly, the reaction of anthranilic acids proceeded smoothly to give only the corresponding dibenzylated products in good to excellent yields (70-87%). The carboxyl group of the anthranilic acids acts as a directing group in the benzylic C-H activation process.

Full text of DOI:10.1002/adsc.201401017

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DOI: 10.1002/adsc.201401017
À
Palladium-Catalyzed Benzylic C H Benzylation via Bis-Benzyl-
palladium(II) Complexes in Water: An Effective Pathway for the
Direct Construction of N-(1,2-Diphenylethyl)anilines
Hidemasa Hikawa,a,* Kyoko Izumi,a Yukari Ino,a Shoko Kikkawa,a
Yuusaku Yokoyama,a and Isao Azumayaa,*
a
Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan
Fax : (+81)-47-472-1595; phone: (+81)-47-472-1591
isao.azumaya @phar.toho-u.ac.jp; e-mail: hidemasa.hikawa@phar.toho-u.ac.jp
Received: October 26, 2014; Revised: December 21, 2014; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201401017.
Abstract: A strategy for the N-benzylation/benzylic ies on the rate constants of benzylation by various
À
C H benzylation cascade of anilines by the p-ben- substituted anthranilic acids and mono-N-benzylani-
zylpalladium system using a water-soluble palladi- lines show a good correlation between the log(kX/kH)
um(0)/sodium
diphenylphosphinobenzene-3-sulfo- and the s values of the respective substituents. From
nate (TPPMS) catalyst and benzyl alcohol in water the slope, negative 1 values are obtained, suggesting
has been developed. This tandem process is devised that there is a build-up of positive charge in the tran-
as a novel and efficient synthetic route for N-(1,2-di- sition state. The reaction of anilines with electron-
À
phenylethyl)anilines. Benzylic C H activation of donating and electron-withdrawing groups affords
a mono-N-benzylated intermediate with a p-benzyl- the corresponding N-(1,2-diphenylethyl)anilines in
palladium(II) complex affords a bis-p-benzylated moderate to good yields (54–86%). Interestingly, the
palladium(II) intermediate. The nucleophilic h1-s- reaction of anthranilic acids proceeded smoothly to
benzyl anion ligand attacks the electrophilic h3-p- give only the corresponding dibenzylated products in
benzyl ligand to give a dibenzylated product. The in- good to excellent yields (70–87%). The carboxyl
termolecular competition between mono-N-benzyl- group of the anthranilic acids acts as a directing
À
ACHTUNGTRENNUNGaniline and its monodeuterated form (monodeuterat- group in the benzylic C H activation process.
ed at the benzylic group) with benzyl alcohol gave
a KIE=4.6, suggesting that C H bond cleavage was Keywords: benzyl alcohol; benzylation; C H activa-
involved in the rate-determining step. Hammett stud- tion; palladium; water
À
À
Introduction
cially challenging to use because of their low reactivi-
ty towards Pd(0) compared with benzyl halides.
Palladium-catalyzed benzylation via a p-benzylpalla- Therefore, the development of a direct catalytic sub-
dium intermediate has been successfully developed stitution of benzylic alcohols, which affords the de-
for the formation of carbon-carbon and carbon-nitro- sired products along with water as the sole co-prod-
gen bonds.[1] Early studies on the generation of p-ben- uct, is highly essential in synthetic chemistry.[6]
zylpalladium complexes used benzyl halides[2] as elec-
The palladium-catalyzed allylation with allylic alco-
trophilic partners. Hartwig reported the thermal re- hols occurs in water (Tsuji–Trost reaction), since
3
À
ductive elimination to form a C(sp ) N bond in an water activates the hydroxy group of the allylic alco-
amine from a benzylpalladium amido complex.[2c] Re- hol to form the p-allyl palladium(II) complex
cently, benzyl esters,[3] carbonates,[4] and phosphates[5] (Scheme 1).[7] Shinokubo and Oshima performed the-
have been developed. Trost reported a palladium-cat- oretical calculations to elucidate the importance of
alyzed asymmetric benzylic alkylation of 3-aryloxin- hydration of the hydroxy group in allyl alcohol for
doles with benzylic methyl carbonates.[4a] Kuwano re- the smooth generation of the p-allylpalladium inter-
ported a benzylic amination using the DPEphos-palla- mediate. On the basis of this synthetic strategy, we
dium catalyst.[4k] In contrast, benzyl alcohols are espe- have developed a selective mono-N-allylation for
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Hidemasa Hikawa et al.
Scheme 1. Our strategy for benzylation using water-soluble
Pd catalysts in water.
Scheme 2. Formation of N-(1,2-diphenylethyl)anilines.
water-soluble free amino acids and anthranilic acids.[8] water has unusual chemical and physical properties
Therefore, we expected an analogous reaction for the such as strongly polar hydrogen bonds, and therefore
benzylation of benzyl alcohols due to their structural should play an important role in the development of
similarity to allylic alcohols.[9] As proof of the con- new and efficient reactions.[15]
cept, we began our studies of the benzylation with
benzyl alcohols 2 in water by choosing water-soluble
unprotected anthranilic acids as the substrates, and Results and Discussion
found that the p-benzylpalladium(II) complexes act
as the first water-soluble active catalysts for benzyl Effects of Catalysts and Solvents
[9g]
À
transfer and C H activation.
However, we could
not provide enough support for the benzylation path- First, the mixture of aniline (1a) and benzyl alcohol
way and the scopes of the substrates were limited. In (2a, 5 equiv.) in the presence of Pd(OAc)2 (5 mol%)
this paper, we describe new insights into the chemis- and sodium diphenylphosphinobenzene-3-sulfonate
À
try of the palladium-catalyzed benzylic C H activa- (TPPMS, 10 mol%) in water was heated at 1208C for
tion/benzylation pathway via bis-benzylpalladium(II) 16 h in a sealed tube. Dibenzylated product 4a was
complexes in water and the development of a tandem obtained in 54% yield along with mono-N-benzylated
process as a new synthetic route for N-(1,2-diphenyl- 3a in 10% yield and imine 5a in 19% yield (Table 1,
ACHTUNGTRENNUNGethyl)anilines. Palladium-catalyzed activation of car- entry 1). The use of benzyl chloride (5 equiv.) instead
bon-hydrogen bonds for coupling reactions is a prom- of benzyl alcohol 2a resulted in no reaction. With
ising strategy in organic synthesis,[10] and therefore the regard to the palladium catalyst, the use of PdCl2 re-
À
development of a p-benzylpalladium system for C H sulted in lower yield (entry 2). The use of zero-valent
activation should be particularly attractive.
palladium, Pd2(dba)3, gave the product 4a in 54%
It is worth noting that many interesting and impor- yield (entry 3). Since the benzylation did not proceed
tant reactions have been reported utilizing the benzy- in the absence of the palladium catalyst or phosphine
lation of imines,[11] hydroamination of alkynes/reduc- ligand (entries 4 and 5) or in the presence of only pal-
tion,[12] and reductive amination of ketones[13] for for- ladium catalysts (entries 6 and 7), an SN2-type reac-
mation of N-(1,2-diphenylethyl)anilines, which are tion mechanism was excluded in the formation of the
structural constituents of pharmacologically interest- dibenzylated 4a. Using organic solvents such as
ing compounds (Scheme 2).[14] However, oxidants are EtOH, DMSO, CPME, or toluene instead of H2O
required for preparation of aldehydes from alcohols, (entries 8–11) or using Pd(PPh3)4 instead of a water-
and stoichiometric zinc reagents are chemically unsta- soluble ligand (entries 12 and 13) resulted in no reac-
ble. In contrast, palladium-catalyzed direct substitu- tion or lower yield. Therefore, water must play an im-
tion of benzylic alcohols in a one-pot tandem ap- portant role in our catalytic system. When 2 equiv. of
proach in water could achieve reduced waste genera- benzyl alcohol 2a were used, the desired 4a was ob-
tion, use safer solvents and reaction conditions, and tained in only 19% yield (entry 14). The use of
increase energy efficiency, factors which assess the ef- 10 equiv. of 2a was slightly better to give 4a in 62%
ficiency of a chemical transformation. Additionally, yield (entry 15).
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Palladium-Catalyzed Benzylic C H Benzylation
Table 1. Effects of catalysts and solvents.[a]
Scheme 3. Pd-catalyzed benzylation of mono-N-benzylated
3a and 7a.
Entry
Pd catalysts
Solvent
Conv. [%][b]
mono-N-benzylated 7a converted to desired 8a more
smoothly compared with 3a. To confirm that mono-N-
benzylated 3a and 7a are the intermediates in our cat-
alytic system, we examined the benzylation of 3a and
7a instead of aniline 1a and anthranilic acid 6a
(Scheme 3). As expected, C-benzylation proceeded
smoothly to give dibenzylated products in good to ex-
cellent yields (4a, 69%; 8a, 90%).
3a
4a
5a
1
2
3
4
5
6
7
Pd(OAc)2/TPPMS
PdCl2/TPPMS
Pd2(dba)3/TPPMS
none
TPPMS
Pd(OAc)2
H2O
H2O
H2O
H2O
H2O
H2O
H2O
10
15
5
0
0
54
34
54
0
0
0
19
20
12
0[e]
0[e]
19
33
0[e]
10
Pd2(dba)3
0
8
9
Pd(OAc)2/TPPMS
Pd(OAc)2/TPPMS
Pd(OAc)2/TPPMS
Pd(OAc)2/TPPMS
Pd(PPh3)4
Pd(PPh3)4
Pd(OAc)2/TPPMS
Pd(OAc)2/TPPMS
EtOH
DMSO
CPME
toluene
toluene
H2O
no reaction
0
18
0
23
24
5
0
Effect of the Carboxyl Group
10
11
12
13
14[c]
15[d]
46
57
59
17
35
6
To determine the effect of the carboxyl group of an-
thranilic acid (6a), palladium-catalyzed benzylations
of aniline (1a), anthranilic acid (6a), and 4-aminoben-
zoic acid (6b) with 2a were carried out (Table 2).
While the reaction of aniline (1a) or 4-aminobenzoic
acid (6b) afforded the desired 4a or 9 in moderate
yields (entry 1, 54%; entry 2, 55%), anthranilic acid
(6a) resulted in an excellent yield (entry 3, 93%). Fur-
17
0[e]
14
7
21
0
19
62
H2O
H2O
[a]
Reaction conditions: aniline 1a (1 mmol), Pd catalysts
(5 mol%), TPPMS (10 mol%), benzyl alcohol 2a
(5 equiv.), solvent (4 mL), 1208C, 16 h under air in
a sealed tube.
The conversion was determined by H NMR analysis of
the crude product using para-nitroanisole as an internal
[b]
1
Table 2. Effect of the carboxyl group.[a]
standard.
[c]
[d]
[e]
Benzyl alcohol 2a (2 equiv.) was used.
Benzyl alcohol 2a (10 equiv.) was used.
Trace.
Reaction Progress
To gain further understanding of the reaction prog-
ress, the reactions of aniline (1a) or anthranilic acid
(6a) with benzyl alcohol (2a) were monitored (see
Figure S1 in the Supporting Information). After 2 h,
the reaction of aniline (1a) afforded mono-N-benzy-
lated 3a in 60% yield along with desired 4a in 18%
yield and imine 5a in 12% yield. Therefore, N-benzy-
lation of aniline 1a with 2a occurred quickly to form
mono 3a. The resulting N-benzylated 3a then slowly
Entry
R
Conversion [%]
di
mono
imine
1
2
3
H
10 (3a)
16 (7b)
7 (7a)
54 (4a)
55 (9)
93 (8a)
19 (5a)
23 (10)
trace
4-CO2H
2-CO2H
À
converted to desired 4a through benzylic C H benzy-
lation. In contrast, after 2 h, the reaction of anthranil-
ic acid (6a) proceeded smoothly to give dibenzylated
8a in 65% yield along with monobenzylated 7a in
only 15% yield. Furthermore, the reaction proceeded
almost completely in 5 h. These results suggested that
[a]
Reaction conditions:
1
or
6
(1 mmol), Pd(OAc)2
(5 mol%), TPPMS (10 mol%), benzyl alcohol 2a
(5 equiv.), H2O (4 mL), 1208C, 16 h in sealed tube. The
conversion was determined by H NMR analysis.
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Table 3. Scope of anilines 1 and benzyl alcohols 2.[a]
[a]
[b]
Reaction conditions: anilines 1 (1 mmol), Pd(OAc)2 (5 mol%), TPPMS (10 mol%), benzyl alcohols 2 (5 equiv.),
H2O (4 mL), 1208C, 16 h in sealed tube. Yield of isolated product.
Benzyl alcohol 2a (10 equiv.) was used. NMR yield.
thermore, the reaction of 3a was not enhanced by the phenoxy, and benzyl groups at the ortho position
addition of AcOH (1 equiv.), suggesting that the were tolerated in the benzylation (4o–r, 58–80%).
ortho substituted carboxyl group of 6a played an im- The reaction of N-(4-aminophenyl)acetamide with
portant role for benzylation.
electron-donating substituted benzyl alcohols 2 pro-
ceeded to give dibenzylated 4s–v in overall yields
ranging from 50–62%. In contrast, benzyl alcohol
with electron-withdrawing fluoro and nitro groups re-
sulted in no reaction. These results suggested that p-
Reaction Scope
Results for the reaction of several anilines 1 with benzylpalladium(II) cations play an important role in
benzyl alcohols 2 using Pd(OAc)2 and TPPMS are the N-benzylation step. The reaction of anthranilic
summarized in Table 3. The reaction of anilines acids 6 with benzyl alcohols 2 proceeded smoothly to
1 with electron-donating methyl and methoxy groups give dibenzylated products in yields ranging from 66–
proceeded to give dibenzylated 4b and 4c in moderate 87% along with no or trace amounts of mono-N-ben-
yields (4b, 58%; 4c, 54%). Anilines with electron- zylated products (see Figure S2 in the Supporting In-
withdrawing fluoro, cyano, ester, and benzoyl groups formation).[9g]
resulted in moderate to good yields (4d–h, 49–88%).
In contrast, the strong electron-withdrawing nitro
group resulted in no reaction. Surprisingly, a hydro- Hammett Studies
phobic aniline gave the dibenzylated product 4i in
84% yield (3-aminobiphenyl: clogP value of 2.8 vs. To demonstrate the electronic effect of benzylation,
aniline 1a: clogP value of 0.9). Furthermore, the reac- Hammett studies were conducted for the palladium-
tion of hydrophilic anilines with amide and cyclic catalyzed benzylation of substituted anthranilic acids
amino groups resulted in moderate to good yields 6 or mono-N-benzylanilines 3 with benzylic alcohol
(4j–n, 50–75%). Sterically demanding acetyl, phenyl, (2a). From these studies summarized in Figure 1, the
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Palladium-Catalyzed Benzylic C H Benzylation
Figure 1. Hammett plots for the rate constants of benzylation by various substituted anthranilic acids 6X (A) and mono-N-
benzylanilines 3X (B).
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Table 4. Benzylation of mono-N-benzylaniline 3a and imine
5a.
Entry
Substrate
(mmol)
2a
(mmol)
Conversion [%]
4a
3a
5a
1
3a (1)
5a (1)
3a (1)+5a (1)
3a (1)+BHT (1)
1
1
2
1
37
2
37
31
7
7
10
5
27
52
85
30
2
3[a]
4
Scheme 4. Mechanistic studies.
[a]
Conversion yield was calculated from 3a (1 mmol).
the benzylic C H activation reaction by 1H NMR
À
ratio of rate constants can be obtained. First, the rela- spectroscopy (Scheme 4B). Treatment of 3a with
tive rates of coupling of meta- or para-substituted an- Pd(OAc)2, TPPMS, and benzyl alcohol 2a in D2O for
thranilic acids (Me and F groups) with benzyl alcohol 2 h showed 24% deuterium incorporation at the ben-
(2a) were examined. Figure 1 shows a good correla- zylic position of 3a-d1. In contrast, in the absence of
tion (R2 =0.99) between the log(kX/kH) and the benzyl alcohol 2a, Pd(OAc)2, and TPPMS, deuterium
s values of the respective substituents that resulted in was not incorporated.
a negative 1 value of 2.17, suggesting that there is
a build-up of positive charge in the transition state.
Next, the relative rates of coupling of meta or para- Mechanistic Considerations
substituted mono-N-benzylanilines (OMe, Me, F, Ph,
and CO2Et groups) with benzyl alcohol (2a) were ex- On the basis of these results and our previous
amined. Figure 1 shows a good correlation (R2 =0.95) report,[6] we favor a catalytic system for the benzyla-
between the log(kX/kH) and the s values of the re- tion of anilines 1 with benzyl alcohols 2 in water as il-
spective substituents that resulted in a negative lustrated in Scheme 5. The mechanism for N-benzyla-
À
1 value of 2.75. Indeed, the reaction of mono-N-ben- tion/benzylic C H benzylation cascade proceeds as
zylanilines 3 with an electron-donating methoxy follows: (1) water-activated C O cleavage of benzyl
À
group proceeded smoothly (entry 1, 70% in Table 4), alcohol 2a to form mono-p-benzylpalladium(II) com-
while the reaction with electron-withdrawing fluoro, plex 11a, followed by nucleophilic substitution with
cyano, and benzoyl groups proceeded more slowly anilines 1; (2) the mono-p-benzylpalladium(II)-pro-
À
(entry 2, 67%; entry 3, 51%).
moted C H cleavage to furnish bis-p-benzylpalladi-
AHCTUNGTREGuNNUN m(II) intermediates I; (3) benzylic C-benzylation of
intermediates II or III with nucleophilic h1-s-benzyl
Kinetic Isotope Effects and D Incorporation
ligand and electrophilic h3-p-benzyl ligand.
Step 1: First, oxidative addition of benzyl alcohol
A KIE study was performed to gain further mechanis- 2a to water-soluble Pd(0)/TPPMS species affords the
À
tic details of benzylic C H activation. The intermolec- cationic mono-p-benzylpalladium(II) complex 11a.
ular competition between mono-N-benzylated 3a and This process should be favored by electron-donating
3a-d with benzyl alcohol 2a gave KIE=4.6 on the groups on intermediates 11, since these will stabilize
1
À
basis of H NMR analysis, suggesting that C H bond the positive charge on Pd(II). Indeed, the benzylation
cleavage was involved in the rate-determining step using 4-fluoro- and 4-nitrobenzyl alcohols 2 did not
(Scheme 4A). In contrast, benzylation of mono-N- proceed since the alcohols could not form cationic in-
benzylated 3a in water and in D2O afforded dibenzy- termediates (see Table 3). Next, the nucleophilic ani-
lated 4a in the same conversion yields, suggesting that line 1 attacks the electrophilically active p-benzylpal-
the hydrogen bond of water does not enhance the ladium(II) intermediate to afford the mono-N-benzy-
[16]
À
benzylic C H activation step. Next, we monitored lated product 3 and regenerate Pd(0).
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Palladium-Catalyzed Benzylic C H Benzylation
Scheme 5. Proposed mechanism.
À
Step 2: The mono-N-benzylated 3 coordinates with ate I (the KIE of 4.6 indicated that the C H cleavage
p-benzylpalladium(II) 11a to form cationic N-palla- might be involved in the turnover-limiting step). A
dated intermediate 12, which is favored by electron- positive charge of N-palladated complex 12 would in-
donating R groups that stabilize the positive charge. crease the acidity of the benzylic proton. White and
À
Indeed, Hammett studies show that there is a build- co-workers reported electrophilic allylic C H cleav-
up of positive charge in the transition state. Benzylic age of a-olefins using a palladium(II)/sulfoxide cata-
C H cleavage proceeds sequentially, followed by for- lyst to afford p-allylpalladium(II) intermediates.[17]
À
mation of stable bis-p-benzyl palladium(II) intermedi- Additionally, the high reactivity of anthranilic acids 8
compared with anilines 1 would be observed in
tandem benzylation, since the carboxyl group plays
À
important roles in the N-palladation and benzylic C
H activation (Scheme 7).
Step 3: The bis-benzyl palladium(II) intermediate is
in flux between three species; there is one bis-p-
benzyl species I and two combinations of h3-p-
benzyl-/h1-s-benzylpalladium (II and III). To form the
dibenzylated 4, there are two proposed mechanisms
involving the h3-p-benzyl/h1-s-benzyl intermediates II
or III (path A or B). Yamamoto and co-workers re-
ported that bis-p-allylpalladium complexes exhibit nu-
cleophilic reactivity, although it is widely accepted
that mono-(p-allyl)PdX-type complexes, where X is
an electron-withdrawing group such as Cl or OAc, ex-
Scheme 6. Different reactivity of mono- and bis-p-allylpalla-
dium complexes (A and B), and pincer complexes (C).
hibit electrophilic reactivity (Scheme 6A and B).[18]
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Scheme 7. Role of the carboxy group.
Scheme 8. The possible reaction pathways from imine 5 and
Pincer complexes are also employed in catalytic ally-
lations of electrophiles, since the allyl moiety is con-
strained to an h1-coordination state required for the
hydride palladium species.[21]
nucleophilic reactivity (Scheme 6C).[19] Therefore, we since hydrolysis of unstable imine 5 proceeds quickly
suggest that intermediates II and III with nucleophilic in water (see Table 4, entry 3).
h1-s-benzyl ligand and electrophilic h3-p-benzyl ligand
Finally, several control experiments were per-
À
are involved in the benzylic C H benzylation. In path formed to exclude the possibility of some reaction
A, intermediate II with electron-donating groups is pathways from imine 5 and the hydride palladium
generated to stabilize the d+ charge in p-benzyl species (Scheme 8 and Table 4). The reaction of imine
Pd(II), which makes the position more electrophilic 5a did not give the desired 4a, while mono-N-benzyl-
for direct intramolecular nucleophilic attack from the
ACHTUNGTRENaNUGN niline (3a) with benzyl alcohol (2a, 1 equiv.) afforded
s-benzyl anion ligand to afford dibenzylated 4. Addi- dibenzylated 4a in 37% yield (entries 1 and 2). Fur-
tionally, this d+ charge is stabilized by the nitrogen thermore, using a 1:1 mixture of mono-N-benzylani-
lone pair, and therefore mono-p-benzyl complex 11a line (3a) and imine 5a did not enhance the reaction
oxidizes the N-benzylated 3 via b-hydride elimination (entry 3). These results suggested that benzylated 3a
À
to the corresponding imines 5 along with the hydride should be the intermediate in the benzylic C H ben-
palladium species. Indeed, the reaction of mono-N- zylation process. Additionally, the carbon radical ad-
benzylaniline with an electron-donating methoxy dition to the imine via a single electron transfer pro-
group gave the imine in 25% yield, while the elec- cess did not proceed in our catalytic system, since the
tron-withdrawing cyano group resulted in trace reaction of 3a was not inhibited by the addition of
amounts of imine production (see Table 4). In path B, a radical scavenger (BHT) (entry 4).[22] Importantly,
the nucleophilic s-benzyl anion ligand attacks the our p-benzylpalladium system works on quite a differ-
electrophilic h3-p-benzyl ligand of intermediate III or ent mechanism from the hydrogen transfer methodol-
ion pair III’ to afford dibenzylated 4. This pathway ogy.
should be favored by electron-withdrawing groups on
intermediate III, since these will stabilize the negative
charge on the appropriate nucleophilic carbon. Conclusions
Chruma reported the palladium-catalyzed benzylation
of benzyl diphenylglycinate imines to the correspond- In summary, we have demonstrated a N-benzylation/
ing homobenzylic imines.[20]
benzylic C H activation strategy by the p-benzylpal-
À
With regard to the substituent effect on the ben- ladium system for the direct construction of N-(1,2-di-
zene ring, the reaction of mono-N-benzylanilines 3 phenylethyl)anilines. The domino reactions achieved
À
with electron-donating groups is favored in our cata- N-benzylation and benzylic C H benzylation in
3
À
lytic system (see Hammett studies and Table 4). How- water, which activates the sp C O bond, then stabil-
ever, anilines 1 with electron-donating methyl and izes the OHÀ by hydration for the smooth generation
methoxy groups resulted in moderate yields (see of the activated Pd(II) cation species. Furthermore,
Table 3). These results suggested that anilines 1 with the p-benzylpalladium system could be used not only
À
electron-donating groups react with benzaldehyde for benzylation, but also for C H activation. Notably,
13[21] to give stable imines 5. In contrast, electron-defi- the bis-benzylpalladium(II) complexes can undergo
cient imines with a cyano group could not be formed, innovative direct transformation reactions. We are
8
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FULL PAPERS
Palladium-Catalyzed Benzylic C H Benzylation
1H NMR (400 MHz, CDCl3): d=3.00 (dd, J=14.0, 8.4 Hz,
1H), 3.14 (dd, J=14.0, 5.6 Hz, 1H), 4.23 (d, J=3.6 Hz, 1H),
4.56 (ddd, J=8.0, 5.2, 5.2 Hz), 6.12 (ddd, J=11.6, 2.0 Hz,
1H), 6.23 (ddd, J=8.2, 0.8 Hz, 1H), 6.30 (ddd, J=17.2, 2.0,
1.2 Hz, 1H), 6.96 (ddd, J=14.8, 6.8, 6.8 Hz, 1H), 7.11 (d, J=
6.4 Hz, 2H), 7.2–7.37 (m, 8H); 13C NMR (100 MHz,
CDCl3): d=45.1, 59.3, 100.5 (d, J=25.8 Hz), 104.0 (d, J=
21.9 Hz), 109.5(d, J=1.9 Hz), 126.5, 126.9, 127.4, 128.7,
128.8, 129.3, 130.1 (d, J=9.5 Hz), 137.5, 142.9, 149.1 (d, J=
10.5 Hz), 163.9 (d, J=241.3 Hz); anal. calcd. for
C20H18FN·0.1H2O: C 81.94, H 6.26, N 4.78; found: C 82.45,
H 6.23, N 4.81; MS (EI): m/z (%)=291(M+, 2), 200 (100).
currently investigating the scope of various nucleo-
philes on the benzylation/C H activation cascade re-
action using p-benzylpalladium from benzyl alcohols
in aqueous media.
À
Experimental Section
General Procedure for the Synthesis of N-(1,2-
Diphenylethyl)anilines 4
A mixture of anilines 1 (1 mmol), palladium(II) acetate
(12 mg, 0.05 mmol), sodium diphenylphosphinobenzene-3-
sulfonate (TPPMS, 36 mg, 0.1 mmol) and benzyl alcohol 2
(5 mmol) in H2O (4 mL) was heated for 16 h in sealed tube.
After cooling, the reaction mixture was poured into water
and extracted with EtOAc. The organic layer was washed
with brine, dried over MgSO4 and concentrated under
vacuum. The residue was washed with hexanes, then puri-
fied by flash column chromatography (silica gel, hexanes/
EtOAc) to give desired product 4.
5-(1,2-Diphenylethylamino)-2-methylbenzonitrile
(4f):
Yield: 244 mg (78%); white solid; mp 119–1218C; IR
1
(KBr): n=3392, 2222 cmÀ1; H NMR (400 MHz, CDCl3): d=
2.31 (s, 3H), 2.99 (dd, J=14.0, 8.0 Hz, 1H), 3.14 (dd, J=
14.4, 5.6 Hz, 1H), 4.19 (d, J=3.2 Hz, 1H), 4.50–4.58 (m,
1H), 6.55 (dd, J=8.4, 2.0 Hz, 1H), 6.59 (d, J=2.4 Hz, 1H),
6.93 (d, J=8.4 Hz, 1H), 7.10 (d, J=6.8 Hz, 2H), 7.20–7.40
(m 8H), 7.17–7.38 (m, 10H); 13C NMR (100 MHz, CDCl3):
d=19.3, 45.1, 59.2, 112.8, 116.3, 118.5, 118.7, 126.4, 127.0,
127.5, 128.8, 128.9, 129.2, 130.4, 130.8, 137.3, 142.4, 145.3;
MS (EI): m/z (%)=312 (M+, 3), 221 (100); anal. calcd. for
C22H20N2: C 84.58, H 6.45, N 8.97; found: C 84.31, H 6.49, N
8.92.
N-(1,2-Diphenylethyl)aniline (4a):[12a] Yield: 189 mg
(69%); colorless oil; IR (KBr): n=3470 cmÀ1 1H NMR
;
(400 MHz, CDCl3): d=3.01 (dd, J=13.6, 8.4 Hz, 1H), 3.13
(dd, J=14.5, 6.0 Hz, 1H), 4.11 (brs, 1H), 4.58 (dd, J=8.5,
6.0 Hz, 1H), 6.46 (dd, J=7.6, 0.8 Hz, 2H), 6.62 (tt, J=4.8,
1.2 Hz, 1H), 7.05 (dd, J=7.2, 7.2 Hz, 2H), 7.12 (dd, J=6.8,
1.6 Hz, 2H), 7.15–7.38 (m, 8H); 13C NMR (100 MHz,
CDCl3): d=45.3, 59.3, 113.7, 117.6, 126.5, 126.8, 127.2, 128.7,
129.1, 129.3, 137.8, 143.5, 147.4; MS (EI): m/z (%)=273
(M+, 17.2), 182 (100).
Ethyl 3-[(1,2-diphenylethyl)amino]benzoate (4g): Yield:
304 mg (88%); white solid; mp 100–1038C; IR (KBr): n=
3395, 1695 cmÀ1 1H NMR (400 MHz, CDCl3): d=1.33 (t,
;
J=7.2 Hz, 3H), 3.03 (dd, J=14.0, 8.0 Hz, 1H), 3.15 (dd, J=
14.0, 5.6 Hz, 1H), 4.24–4.38 (m, 3H), 4.63 (dd, J=8.5,
6.0 Hz, 1H), 6.59 (ddd, J=8.2, 4.0, 0.8 Hz, 1H), 7.05–7.14
(m, 3H), 7.17–7.38 (m, 10H); 13C NMR (100 MHz, CDCl3):
d=14.4, 45.1, 59.2, 60.9, 114.8, 117.6, 118.6, 126.6, 126.9,
127.3, 128.7, 129.1, 129.3, 131.2, 137.5, 142.9, 147.2, 167.0;
MS (EI): m/z (%)=345 (M+, 1), 254 (100); anal. calcd. for
C24H26N2O·0.2H2O: C 79.15, H 6.76, N 4.01; found: C 79.04,
H 6.63, N 4.06.
N-(1,2-Diphenylethyl)-4-methylaniline (4b):[12b] Yield:
167 mg (58%); colorless oil; IR (KBr): n=3410 cmÀ1
;
1H NMR (400 MHz, CDCl3): d=2.16 (s, 3H), 2.99 (dd, J=
14.4, 8.4 Hz, 1H), 3.13 (dd, J=13.6, 5.6 Hz, 1H), 4.00 (brs,
1H), 4.55 (dd, J=8.4, 5.6 Hz, 1H), 6.37 (d, J=8.8 Hz, 2H),
6.85 (d, J=8.8 Hz, 2H), 7.13 (d, J=6.4 Hz, 2H), 7.18–7.39
(m, 8H); 13C NMR (100 MHz, CDCl3): d=20.3, 45.2, 59.4,
113.7, 126.4, 126.6, 126.7, 127.0, 128.5, 129.2, 129.5, 137.8,
143.6, 145.0; MS (EI): m/z (%)=287 (M+, 6.0), 196 (100).
N-(1,2-Diphenylethyl)-4-methoxyaniline (4c):[12a] Yield:
[4-(1,2-Diphenylethylamino)phenyl]phenylmethanone
(4h): Yield: 185 mg (49%); white solid; mp 102–1058C; IR
1
(KBr): n=3343, 1692 cmÀ1; H NMR (400 MHz, DMSO-d6):
d=2.98 (dd, J=16.0, 8.0 Hz, 1H), 3.11 (dd, J=12.0, 8.0 Hz,
1H), 4.76 (dd, J=12.0, 8.0 Hz, 1H), 6.61 (d, J=12.0 Hz,
2H), 7.14–7.36 (m, 9H), 7.41 (d, J=8.0 Hz, 2H), 7.43–7.50
(m, 4H), 7.54 (d, J=8.0 Hz 2H), 7.60 (brs, 1H); 13C NMR
(100 MHz, CDCl3): d=47.7, 111.6, 126.6, 127.5, 127.7, 128.1,
128.9, 129.6, 131.4, 133.1, 138.3, 139.1, 151.9, 195.3; MS (EI):
m/z (%)=287 (M+, 100); HR-MS-EI: m/z= 377.1779 (M+),
calcd, for C27H23NO: 377.1780
164 mg (54%); brown oil; IR (KBr): n=3397 cmÀ1
;
1H NMR (400 MHz, CDCl3): d=2.99 (dd, J=14.0, 8.4 Hz
1H), 3.12 (dd, J=14.0, 5.6 Hz 1H), 3.90 (brs, 1H), 3.66 (s,
3H), 4.50 (dd, J=8.4, 5.6 Hz 1H), 6.41 (d, J=9.0 Hz 2H),
6.64 (d, J=9.0 Hz 2H), 7.13 (dd, J=8.4, 1.6 Hz 2H), 7.19–
7.35 (m, 8H); 13C NMR (100 MHz, CDCl3): d=45.6, 56.1,
60.4, 115.0, 115.3, 126.9, 127.1, 127.4, 128.9, 129.0, 129.6,
138.2, 141.9, 144.1, 152.4; MS (EI): m/z (%)=303 (M+, 5.6),
212 (100).
N-(1,2-Diphenylethyl)-[1,1’-biphenyl]-3-amine (4i): Yield:
294 mg (84%); colorless oil; IR (KBr): n=3414 cmÀ1
;
1H NMR (400 MHz, CDCl3): d=3.04 (dd, J=13.6, 8.0 Hz,
1H), 3.16 (dd, J=13.6, 5.2 Hz, 1H), 4.22 (brs, 1H), 4.64 (dd,
J=8.5, 6.0 Hz, 1H), 6.42 (dd, J=8.0, 1.6 Hz, 1H), 6.69 (t,
J=2.0 Hz, 1H), 6.83–6.88 (m, 1H), 7.10 (d, J=8.0 Hz, 1H),
7.14 (dd, J=8.4, 1.6 Hz, 2H), 7.19–7.44 (m, 13H); 13C NMR
(100 MHz, CDCl3): d=45.1, 59.3, 112.5, 112.6, 116.6, 137.6,
141.5, 142.0, 143.3, 147.5, 126.4, 126.7, 127.0, 127.1, 128.5,
128.6, 129.2, 129.4; MS (EI): m/z (%)=349 (M+, 17.5), 258
(100); HR-MS-EI: m/z=349.1832 (M+), calcd. for C26H23N:
349.1830.
N-(1,2-Diphenylethyl)-4-fluoroaniline
186 mg (64%); colorless oil; IR (KBr): n=3627 cmÀ1
(4d):[11c] Yield:
;
1H NMR (400 MHz, CDCl3): d=2.99 (dd, J=14.0, 8.4 Hz,
1H), 3.13 (dd, J=14.0, 5.6 Hz, 1H), 4.00 (brs, 1H), 4.51 (dd,
J=8.0, 5.6 Hz, 1H), 6.36 (ddd, J=9.2, 4.4, 2.4 Hz, 2H), 6.74
(ddd, J=8.8, 8.8, 2.4 Hz, 2H), 7.05–7.14 (m, 2H), 7.17–7.34
(m, 8H); 13C NMR (100 MHz, CDCl3): d=45.1, 59.9, 115.4
(d, J=22 Hz), 126.5, 126.8, 127.2, 128.6 (d, J=4.7 Hz), 129.2,
137.6, 143.1, 143.4, 155.9 (d, J=234.6 Hz); MS (EI): m/z
(%)=291 (M+, 4), 200 (100).
N-(1,2-Diphenylethyl)-3-fluoroaniline (4e): Yield: 227 mg
3-[(1,2-Diphenylethyl)amino]benzenesulfonamide
Yield: 264 mg (75%); white solid; mp 125–1298C; IR
(4j):
(78%); white solid; mp 60–638C; IR (KBr): n=3400 cmÀ1
;
Adv. Synth. Catal. 0000, 000, 0 – 0
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asc.wiley-vch.de
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FULL PAPERS
Hidemasa Hikawa et al.
1
(KBr): n=3254 cmÀ1; H NMR (400 MHz, CDCl3): d=3.01
12.0, 8.0 Hz, 1H), 4.87 (dd, J=8.0, 4.0 Hz, 1H), 6.51 (t, J=
4.0 Hz, 1H), 6.52 (d, J=8.0 Hz, 1H), 7.15–7.40 (m, 10H),
7.77 (d, J=8.0 Hz, 1H), 9.42 (d, J=8.0 Hz, 1H); 13C NMR
(100 MHz, DMSO-d6): d=27.9, 44.2, 57.5, 112.7, 114.3,
117.3, 126.3, 126.9, 128.1, 128.4, 129.3, 132.9, 134.7, 138.0,
143.1, 149.4, 200.9; MS (EI): m/z (%)=315 (M+, 1), 224
(100); HR-MS-EI: m/z=315.1625 (M+), calcd. for
C22H21NO: 315.1623.
(dd, J=14.0, 8.4 Hz, 1H), 3.16 (dd, J=14.0, 5.6 Hz, 1H),
4.44 (d, J=4.4 Hz, 1H), 4.59–4.70 (m, 3H), 6.56 (ddd, J=
7.2, 2.4, 2.4 Hz, 1H), 7.00 (d, J=2.0 Hz, 1H), 7.08–7.16 (m,
4H), 7.20–7.36 (m, 8H); 13C NMR (100 MHz, CDCl3): d=
45.0, 59.0, 111.1, 114.7, 117.1, 126.5, 127.0, 127.5, 128.8,
129.3, 130.0, 137.3, 142.4, 147.7; MS (EI): m/z (%)=352
(M+, 1), 261 (100); anal. calcd. for C20H20N2O2S·0.1H2O: C
67.81, H 5.75, N 7.91; found: C 67.57, H 5.73, N 7.91.
N-(1,2-Diphenylethyl)-[1,1’-biphenyl]-2-amine (4p): Yield:
248 mg (71%); white solid; mp 98–1028C; IR (KBr): n=
N-[4-(1,2-Diphenylethylamino)phenyl]acetamide
(4k):
1
Yield: 192 mg (58%); white solid; mp 134–1388C; IR
3406 cmÀ1; H NMR (400 MHz, DMSO-d6): d=2.83 (dd, J=
(KBr): n=3341, 1632 cmÀ1; H NMR (400 MHz, CDCl3): d=
12.0, 8.0 Hz, 1H), 3.02 (dd, J=16.0, 4.0 Hz, 1H), 4.60–4.70
(m, 2H), 6.33 (d, J=8.0 Hz, 1H), 6.58 (dd, J=8.0, 8.0 Hz,
1H), 6.77–7.00 (m, 2H), 7.07 (dd, J=8.0, 4.0 Hz, 2H), 7.10–
7.25 (m, 6H), 7.25–7.50 (m, 7H); 13C NMR (100 MHz,
CDCl3): d=45.6, 59.6, 111.7, 126.3, 126.7, 127.1, 127.2, 127.9,
128.5, 128.6, 128.7, 129.0, 129.2, 129.5, 130.0, 137.6, 139.4,
143.7, 144.2; MS (EI): m/z (%)=349 (M+, 3), 258 (100);
anal. calcd. for C26H23N: C 89.36, H 6.63, N 4.01; found: C
89.47, H 6.67, N 3.98.
1
2.08 (s, 3H), 3.00 (dd, J=14.0, 8.4 Hz, 1H), 3.13 (dd, J=
14.0, 5.6 Hz), 4.15 (brs, 1H), 4.55 (dd, J=8.4, 5.6 Hz, 1H),
6.40 (d, J=6.8 Hz, 2H), 6.92 (brs, 1H), 7.08–7.14 (m, 4H),
7.19–7.33 (m, 8H); 13C NMR (100 MHz, CDCl3): d=24.3,
45.2, 59.4, 113.9, 122.3, 126.5, 126.8, 127.2, 128.1, 128.6,
129.2, 137.6, 143.3, 144.6, 168.1; MS (EI): m/z (%)=330
(M+, 3.9), 239 (100); anal. calcd. for C15H14N2: C 79.97, H
6.71, N 8.48; found: C 80.14, H 6.63, N 8.40.
4-(1,2-Diphenylethylamino)benzamide (4l): Yield: 180 mg
(57%); pale yellow solid; mp 62–668C; IR (KBr): n=3329,
N-(1,2-Diphenylethyl)-2-phenoxyaniline
(4q):
Yield:
274 mg (75%); white solid; mp 104–1068C; 1H NMR
(400 MHz, CDCl3): d=2.94 (dd, J=13.6, 8.4 Hz, 1H), 3.05
(dd, J=14.0, 6.0 Hz, 1H), 4.55 (q, J=7.2 Hz, 1H), 4.71 (brs,
1H), 6.41 (d, J=7.6 Hz, 1H), 6.54 (dd, J=8.0, 8.0 Hz, 1H),
6.78 (d, J=8.0 Hz, 1H), 6.82 (dd, J=8.0, 8.0 Hz, 1H), 6.89
(dd, J=8.0, 0.8 Hz, 2H), 6.95–7.20 (m, 2H), 7.06 (dd, J=7.2,
7.2 Hz, 1H), 7.11–7.17 (m, 3H), 7.18–7.35 (m, 7H);
13C NMR (100 MHz, CDCl3): d=45.4, 59.3, 112.9, 117.0,
117.3, 119.6, 122.7, 124.9, 126.5, 126.7, 127.2, 128.5, 128.7,
129.3, 129.8, 137.6, 139.7, 143.0, 143.4, 157.8; MS (EI): m/z
(%)=365 (M+, 3), 274 (100); anal. calcd. for
C26H23NO·0.2H2O: C 85.61, H 6.39, N 3.80; found: C 84.65,
H 6.30, N 3.84.
1649 cmÀ1 1H NMR (400 MHz, CDCl3): d=3.04 (dd, J=
;
14.8 Hz 1H), 3.17 (dd, J=14.6 Hz 1H), 4.51 (brd, J=4.8 Hz
1H), 4.66 (ddd, J=8.4, 5.2, 5.2 Hz 1H), 6.44 (d, J=6.8 Hz
2H), 7.08–7.12 (m, 2H), 7.21–7.35 (m, 8H), 7.53 (d, J=
6.8 Hz 2H); 13C NMR (100 MHz, CDCl3): d=44.9, 58.7,
112.7, 126.4, 127.0, 127.4, 128.7, 129.0, 129.1, 137.1, 142.4,
150.2, 169.1; MS (EI): m/z (%)=316 (M+, 1.4), 225 (100);
HR-MS-EI: m/z=316.1575 (M+), calcd. for C21H20N2O:
316.1576.
N-(1,2-Diphenylethyl)-4-morpholinoaniline (4m): Yield:
179 mg (50%); pale brown solid; mp 90–948C; IR (KBr):
1
n=3362 cmÀ1; H NMR (400 MHz, CDCl3): d=2.93 (d, J=
4.8 Hz, 2H), 2.94 (d, J=4.8 Hz, 2H), 2.99 (dd, J=14.0,
8.0 Hz, 1H), 3.12 (dd, J=14.0, 5.6 Hz, 1H), 3.79 (d, J=
4.8 Hz, 2H), 3.80 (d, J=4.8 Hz, 2H), 3.92 (brs, 1H), 4.52
(dd, J=8.4, 5.6 Hz, 1H), 6.42 (d, J=8.8 Hz, 2H), 6.70 (d,
J=8.8 Hz, 2H), 7.12 (d, J=7.2 Hz, 2H), 7.18–7.38 (m, 8H);
13C NMR (100 MHz, CDCl3): d=45.2, 51.2, 59.8, 67.0, 114.6,
118.1, 126.5, 126.7, 127.0, 128.5, 129.2, 137.8, 142.0, 143.7;
anal. calcd. for C24H26N2O: C 80.41, H 7.31, N 7.81; found:
C 80.29, H 7.25, N 7.78; MS (EI): m/z (%)=358 (M+, 19.4),
267 (100).
2-Benzyl-N-1,2-diphenylethylaniline (4r): Yield: 211 mg
(58%); white solid; mp 68–708C; IR (KBr): n=3415 cmÀ1
;
1H NMR (400 MHz, CDCl3): d=2.80 (dd, J=14.4, 8.4 Hz,
1H), 2.98 (dd, J=13.6, 5.6 Hz, 1H), 3.76 (d, J=16.0 Hz,
1H), 3.85 (d, J=16.0 Hz, 1H), 4.02 (brs, 1H), 4.56 (dd, J=
8.0, 6.0 Hz, 1H), 6.34 (d, J=7.6 Hz, 1H), 6.61 (dd, J=7.6,
1.2 Hz, 1H), 6.92–7.03 (m, 6H), 7.10–7.30 (m, 11H);
13C NMR (100 MHz, CDCl3): d=38.4, 45.4, 58.8, 112.1,
117.1, 126.4, 126.6, 126.7, 127.0, 127.7, 128.5, 128.6, 128.7,
128.8, 129.3, 130.7, 137.7, 139.4, 143.4, 145.0; MS (EI): m/z
(%)=363 (M+, 3), 272 (100); HR-MS-EI: m/z=363.1988
(M+), calcd. for C27H25N 363.1978.
4-[4-(1,2-Diphenylethylamino)phenyl]morpholin-3-one
(4n): Yield: 197 mg (53%); white solid; mp 143–1478C; IR
1
(KBr): n=3390, 1677 cmÀ1; H NMR (400 MHz, CDCl3): d=
N-4-[1,2-Bis(4-methoxyphenyl)ethylamino]phenylaceta-
mide (4s): Yield: 219 mg (56%); white solid; mp 130–
2.97 (dd, J=14.0, 8.8 Hz, 1H), 3.13 (dd, J=14.0, 5.6 Hz,
1H), 3.58 (dd, J=4.4, 1.2 Hz, 1H), 3.60 (dd, J=4.4, 1.2 Hz,
1H), 3.93 (d, J=4.8 Hz, 1H), 3.94 (d, J=4.8 Hz, 1H), 4.20
(d, J=3.2 Hz, 1H), 4.26 (s, 2H), 4.54 (quin, J=4.0 Hz, 1H),
6.44 (d, J=8.8 Hz, 2H), 6.94 (d, J=8.8 Hz, 2H), 7.12 (dd,
J=8.4, 1.6 Hz, 2H), 7.20–7.34 (m, 8H); 13C NMR (100 MHz,
CDCl3): d=45.3, 50.2, 59.4, 64.3, 68.6, 114.0, 126.5, 126.6,
126.9, 127.3, 128.7, 128.8, 129.2, 131.2, 137.6, 143.3, 146.5,
166.9; MS (EI): m/z (%)=372 (M+, 5), 281 (100); anal.
calcd. for C24H24N2O2: C 77.39, H 6.50, N 7.52; found: C
77.40, H 6.52, N 7.44.
1
1338C; IR (KBr): n=3320, 1650 cmÀ1; H NMR (400 MHz,
CDCl3): d=2.09 (s, 3H), 2.92 (dd, J=14.4, 8.0 Hz, 1H), 3.03
(dd, J=14.4, 6.0 Hz, 1H), 3.79 (d, J=1.6 Hz, 6H), 4.45 (dd,
J=8.0, 6.0 Hz, 1H), 6.40 (d, J=8.8 Hz, 2H), 6.77–6.89 (m,
4H), 6.70 (d, J=8.4 Hz, 2H), 7.11 (d, J=8.8 Hz, 2H), 7.12
(d, J=8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3): d=24.3,
44.3, 55.2, 58.9, 113.8, 113.9, 122.2, 127.5, 128.0, 129.6, 130.2,
135.3, 144.6, 158.3, 158.5, 168.0; MS (EI): m/z (%)=390
(M+, 1), 269 (100); anal. calcd. for C24H26N2O3: C 73.82, H
6.71, N 7.17; found: C 73.57, H 6.65, N 7.15.
1-[2-(1,2-Diphenylethylamino)phenyl]ethan-1-one
Yield: 252 mg (80%); yellow solid; mp 90–948C; IR (KBr):
n=3295, 1700 cmÀ1 1H NMR (400 MHz, DMSO-d6): d=
2.53 (s, 3H), 3.01 (dd, J=12.0, 8.0 Hz, 1H), 3.10 (dd, J=
(4o):
N-4-(1,2-Di-para-tolylethyl)aminophenylacetamide (4t):
Yield: 222 mg (62%); white solid; mp 116–1208C; IR
1
;
(KBr): n=3277, 1615 cmÀ1; H NMR (400 MHz, CDCl3): d=
2.08 (s, 3H), 2.31 (s, 3H), 2.32 (s, 3H), 2.92 (dd, J=14.0,
10
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Palladium-Catalyzed Benzylic C H Benzylation
8.4 Hz, 1H), 3.09 (dd, J=14.0, 5.2 Hz, 1H), 4.05 (brs, 1H),
4.49 (dd, J=8.4, 5.6 Hz, 1H), 6.39 (d, J=8.8 Hz, 2H), 6.87
(brs, 1H), 7.01 (d, J=8.0 Hz, 2H), 7.06–7.14 (m, 6H), 7.20
(d, J=8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3): d=21.1,
24.2, 44.7, 59.1, 113.8, 122.2, 126.3, 127.9, 129.0, 129.2, 129.3,
134.6, 136.2, 136.6, 140.4, 144.7, 168.0; MS (EI): m/z (%)=
358 (M+, 3), 253 (100); anal. calcd. for C24H26N2O: C 80.41,
H 7.31, N 7.81; found: C 80.18, H 7.25, N 7.85.
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N-[4-(1,2-Di-meta-tolylethylamino)phenyl]acetamide
(4u): Yield: 215 mg (60%); white solid; mp 122–1248C; IR
1
(KBr): n=3231, 1640 cmÀ1; H NMR (400 MHz, CDCl3): d=
2.08 (s, 3H), 2.31 (s, 3H), 2.33 (s, 3H), 2.88 (dd, J=14.0,
8.8 Hz, 1H), 3.09 (dd, J=14.4, 5.6 Hz, 1H), 4.05 (brs, 1H),
4.48 (dd, J=8.8, 5.2 Hz, 1H), 6.39 (d, J=8.8 Hz, 2H), 6.80–
6.98 (m, 3H), 7.02–7.22 (m, 7H); 13C NMR (100 MHz,
CDCl3): d=21.5, 21.6, 24.3, 45.3, 59.5, 113.9, 122.3, 123.5,
126.2, 127.1, 127.6, 127.8, 127.9, 128.1, 128.5, 130.0, 137.8,
138.3, 143.6, 144.8, 168.2; MS (EI): m/z (%)=358 (M+, 5),
253 (100); anal. calcd. for C24H26N2O: C 80.41, H 7.31, N
7.81; found: C 80.37, H 7.31, N 7.77.
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1667 cmÀ1 1H NMR (400 MHz, CDCl3): d=0.97 (t, J=
;
7.6 Hz, 6H), 1.48 (sext, J=7.6 Hz, 4H), 1.75 (quin, J=
6.4 Hz, 4H), 2.09 (s, 3H), 2.89 (dd, J=14.4, 8.0 Hz, 1H),
3.02 (dd, J=13.6, 5.6 Hz, 1H), 3.93 (t, J=6.4 Hz, 4H), 4.04
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J=8.8 Hz, 2H), 7.11 (d, J=9.2 Hz, 2H), 7.18 (d, J=8.4 Hz,
2H); 13C NMR (100 MHz, CDCl3): d=14.0, 19.4, 24.2, 31.5,
44.3, 59.0, 67.8, 113.9, 114.6, 122.3, 127.6, 128.3, 129.6, 130.3,
135.2, 144.7, 158.0, 158.2, 168.5; MS (EI): m/z (%)=474
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Acknowledgements
This work was supported by JSPS KAKENHI Grant
Number 25460026.
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À
Palladium-Catalyzed Benzylic C H Benzylation via Bis-
Benzylpalladium(II) Complexes in Water: An Effective
Pathway for the Direct Construction of N-(1,2-
Diphenylethyl)anilines
13
Adv. Synth. Catal. 2015, 357, 1 – 13
Hidemasa Hikawa,* Kyoko Izumi, Yukari Ino,
Shoko Kikkawa, Yuusaku Yokoyama, Isao Azumaya*
Adv. Synth. Catal. 0000, 000, 0 – 0
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ÞÞ
These are not the final page numbers!