Cobalt(II)/TPPMS-Catalyzed Dehydrative Nucleophilic Substitution of Alcohols in Water

Article abstract of DOI:10.1002/ejoc.201601501

A green and sustainable direct dehydrative amination of alcohols, catalyzed by cobalt(II)/TPPMS (sodium diphenylphosphinobenzene-3-sulfonate) in water, is described. Earth-abundant cobalt is used in form of Co(hfac)₂·xH₂O (hfac: hexa

Full text of DOI:10.1002/ejoc.201601501

DOI: 10.1002/ejoc.201601501
Communication
Dehydrative Substitution
Cobalt(II)/TPPMS-Catalyzed Dehydrative Nucleophilic
Substitution of Alcohols in Water
Hidemasa Hikawa,*[a] Yukiko Ijichi,[a] Shoko Kikkawa,[a] and Isao Azumaya*[a]
Abstract: A green and sustainable direct dehydrative amin- mild conditions without the need for a base or other additives
ation of alcohols, catalyzed by cobalt(II)/TPPMS (sodium diphen- and affords the corresponding benzylic and allylic anilines
ylphosphinobenzene-3-sulfonate) in water, is described. Earth- along with water as the only coproduct. Mechanistic studies
abundant cobalt is used in form of Co(hfac)2·xH2O (hfac: hexa- suggest that this system is driven by direct nucleophilic substi-
fluoroacetylacetone), which acts as a highly efficient Lewis tution of alcohols.
acidic catalyst. This simple atom-economical protocol features
Introduction
We have developed a dehydrative direct substitution of alco-
hols by using a water-soluble gold catalyst AuIII/TPPMS (sodium
diphenylphosphinobenzene-3-sulfonate) in water.[13] This
method affords unique reactivity and selectivity. The efficiency
for the activation of several sp3-C–O bonds is due to the oxo-
philic Lewis acidity of the gold(III) catalyst. However, the use of
expensive gold sources is a disadvantage in spite of the high
catalytic activity. Therefore, an alternative catalyst based on
earth-abundant first-row transition metals is highly desirable for
organic synthesis.
The alkylation of amines is one of the most useful transforma-
tions in organic synthesis since alkylamines are a valuable class
of compounds in pharmaceuticals, dyes, natural products, syn-
thetic intermediates, and materials. Conventional methods
for N-alkylation involve treating amines with alkylhalides
(Scheme 1A). However, these multistep and hazardous proc-
esses should be improved because of their low atom economy
and the stoichiometric production of waste. Therefore, the di-
rect use of alcohols through a dehydrative catalytic substitution
reaction with amines, which affords the desired products along
with water as the only coproduct, would be a more sustainable
strategy for C–N-bond formation because of certain advanta-
ges, such as being a salt-free and atom-economical process
(Scheme 1B). Recently, various Lewis acids (Au,[1] Zn,[2] Fe,[3]
Ag,[4] Ru,[5] In,[6] Re,[7] Yb,[8] Bi,[9] Al,[10] and Mo[11] ions) and
Brønsted acids[12] have been used as efficient catalysts for dehy-
drative nucleophilic substitution reactions of alcohols.
Green and sustainable chemistry based on cobalt-catalyzed
reactions continues to receive great attention (e.g., radical reac-
tions of alkylic halides,[14] C-H activation reactions,[15,16] direct
amination of alcohols by borrowing hydrogen methods,[17]
cross-coupling reactions,[18] hydration of terminal alkynes[19]).
While many elegant catalytic methods have been established
to date, direct dehydrative nucleophilic substitution of alcohols
is a challenging goal because of the low Lewis acidity of the
cobalt ion and thus, it remains an important objective of ongo-
ing research.[20] Our preliminary screening of catalysts revealed
that CoCl2·6H2O showed the same catalytic activity as
AuCl4Na·2H2O for dehydrative amination in water (Table 1, en-
try 1 vs. 2). Based on this result and our previous studies, we
hypothesize that cobalt(II)/TPPMS might be an efficient catalyst
in the nucleophilic substitution of alcohols in water. To the best
of our knowledge, a sustainable dehydrative amination based
on a cobalt salt as a Lewis acid has not been described before.
We herein present the first example of a cobalt(II)/TPPMS-
catalyzed direct amination of alcohols as an atom-economic
process in water, which provides the corresponding benzylic
and allylic anilines along with water in good to excellent yields.
Furthermore, we can extend this catalytic system to the dehy-
drative Friedel–Crafts alkylation of N-alkylanthranilic acids.
Mechanistic studies reveal that the reaction proceeds by direct
nucleophilic substitution of alcohols. Therefore, this method
should provide a mechanistic alternative to the borrowing
hydrogen methodology.
Scheme 1. N-Alkylation of amines with alcohols.
[a] Faculty of Pharmaceutical Sciences, Toho University,
2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan
E-mail: hidemasa.hikawa@phar.toho-u.ac.jp
isao.azumaya@phar.toho-u.ac.jp
http://www.toho-u.ac.jp/phar/labo/yakusei.html
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201601501.
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Communication
Results and Discussion
substituted anthranilic acids 1 were tolerated well to produce
the corresponding products 3b–l in moderate to excellent
yields. The scope of alcohols 2 was examined next with
4-bromoanthranilic acid (1a) as the coupling partner. The use
of benzhydryl alcohols with electron-donating methoxy and
methyl groups, or electron-withdrawing fluoro and chloro
groups, resulted in excellent yields (4a–e). Furthermore, α-
methylbenzyl alcohol, 4-methoxybenzyl alcohol, and allylic al-
cohols reacted to give the corresponding N-benzylic and allylic
products 4f–i. The reaction system could be applied to other
nucleophiles such as aminobenzoic acids and electron-deficient
anilines to afford N-benzylic anilines 5a–h in moderate to excel-
lent yields. In contrast, electron-sufficient anilines such as
anisidine and toluidine did not react.
Initially, water-soluble 5-bromoanthranilic acid (1a) and benz-
hydrol (2a) were chosen as model compounds to optimize the
reaction conditions. When using AuCl4Na·H2O/TPPMS as cata-
lyst, the desired N-benzylated product 3a was obtained select-
ively in 53 % yield (Table 1, entry 1). To our surprise,
CoCl2·6H2O/TPPMS catalyst showed the same high catalytic ac-
tivity as Lewis acidic AuCl4Na·2H2O/TPPMS for N-benzylation of
1a (entry 2). Control experiments using HCl suggested that the
CoII catalyst was essential for the amination to proceed (entry
3). No reaction occurred when using PPh3 or other water-solu-
ble phosphine ligands such as 4-(diphenylphosphino)benzoic
acid or [4-(dimethylamino)phenyl]diphenylphosphine instead of
TPPMS (entries 4 and 5). Other salts based on CuII, FeII, IrIII, InII,
or RuIII were less effective than CoII (entries 6–10).
Co(hfac)2·xH2O (hfac: hexafluoroacetylacetone) provided the
best result among the cobalt salts screened (92 %, entry 16).
Replacing water with organic solvents such as EtOH, DMF, 1,4-
dioxane, or toluene resulted in no reaction (entries 19–23).
Table 2. Scope of amines 1 and alcohols 2.[a]
Table 1. Effects of catalysts and solvents.[a]
Entry
Catalyst
Solvent
t [h]
Conv. [%][b]
1
2
3
4
5
AuCl4Na·H2O
CoCl2·6H2O
HCl
CoBr2(PPh3)2
CoCl2·6H2O[e]
CuCl2
H2O
H2O
H2O
H2O
H2O
1
1
16
16
1
53
52 (74)[c]
0
0
0
17
[d]
6
H2O
1
7
FeCl2
H2O
1
22
8
9
IrCl3·xH2O
InCl2
H2O
H2O
1
1
30
23
10
11
12
13
14
15
16
17
18
19
20
21
22
23
RuCl3
CoBr2
CoI2·xH2O
CoO
Co(OAc)2
Co(acac)2·2H2O
Co(hfac)2·xH2O
Co(acac)3
[Cp*2Co]PF6
Co(hfac)2·xH2O
Co(hfac)2·xH2O
Co(hfac)2·xH2O
Co(hfac)2·xH2O
Co(hfac)2·xH2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
1
30
65
80
trace
34
57
92
41
trace
0
16
16
16
16
16
16
16
16
16
16
16
16
16
H2O
EtOH
DMF
0
0
0
1,4-dioxane
toluene
DMF/H2O[f]
[a] Reaction conditions: 1 (1 mmol), Co(hfac)2·xH2O (5 mol-%), TPPMS
(10 mol-%), 2 (1.2 mmol), H2O (4 mL), 120 °C, 16 h in a sealed tube. Yield of
isolated product. [b] Cinnamyl alcohol (2 equiv.) was used. [c] 2-Methyl-3-
buten-2-ol (3 equiv.) was used. [d] 48 h.
trace
[a] Reaction conditions: 1a (1 mmol), catalysts (5 mol-%), TPPMS (10 mol-%),
2a (1.2 mmol), solvent (4 mL), 80 °C, 1 or 16 h under air. [b] The conversion
was determined by 1H NMR analysis of the crude product with p-nitroanisole
as internal standard. [c] 16 h. [d] Without TPPMS. [e] With other water-soluble
phosphine ligands such as 4-(diphenylphosphino)benzoic acid or [4-(dimeth-
ylamino)phenyl]diphenylphosphine instead of TPPMS. [f] 1:1.
To demonstrate the electronic effect of substituents on the
rates of the C–O-bond cleavage and C–N-bond formation reac-
tions, Hammett studies were conducted for the cobalt(II)/
TPPMS-catalyzed amination (see the Supporting Information).
With the optimized conditions in hand, we examined the First, the relative rates of coupling of 5-substituted anthranilic
substrate scope of the dehydrative amination (Table 2). Both acids 1 (R1 = OMe, Me, F, Br, and I) with benzhydrol (2a) were
electron-donating (OMe, Me, and NHAc) and electron-with- examined (Hammett study I). Figure S1 shows a good correla-
drawing groups (F, Cl, I, NO2, and CF3) on the benzene ring of tion (R2 = 0.95) between the log (kX/kH) and the σ value of the
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Communication
respective substituents that resulted in a negative ρ value of benzyl-α,α-d2 alcohol (2c-d2) and 3-methylbenzyl alcohol (2d)
1.54. Next, the relative rates of the reaction between 5-bromo- was conducted (Scheme 3C). If dehydrative amination proceeds
anthranilic acid (1a) and para-substituted benzhydryl alcohols through the borrowing hydrogen pathway, H/D scrambling
2 (R2 = Me, F, and Cl) were examined (Hammett study II). Figure products should be formed by reductive amination of the in
S2 also shows good correlation (R2 = 0.94) between the situ generated aldehyde with amines 1 by a cobalt(II)–hydride
log (kX/kH) and the σ+ value of the respective substituents that (H/D) species. However, these scrambling compounds were not
resulted in a negative ρ value of 2.58. The results of the Ham- obtained.
mett studies indicate a build-up of positive charge in the transi-
tion state.
Based on these results and previous reports, the following
mechanism can be suggested (Scheme 2). The cobalt(II)/TPPMS
catalyst ligates with anthranilic acids 1 and benzhydryl alcohols
2 to form complex A. The Lewis acidic cobalt(II)/TPPMS cation
species activates the sp3-C–O bond of alcohol 2 for the smooth
generation of benzylic cation B. A negative ρ value in the reac-
tion of para-substituted benzhydryl alcohols 2 with 1a clearly
shows the formation of a positive charge on the benzylic posi-
tion in the transition state (see Hammett study II in the Sup-
porting Information). Next, the nucleophilic amine ligand C at-
tacks the electrophilic benzyl cation B to afford the correspond-
ing N-benzylated product 3 along with water as the only co-
product.
Scheme 2. Proposed mechanism.
Scheme 3. Control experiments.
Notably, water is essential for achieving dehydrative amin-
ation with our catalytic system. Theoretical calculations by
Shinokubo and Oshima have elucidated the importance of hy-
dration of the hydroxy group for the smooth generation of π-
allylpalladium species.[21] Thus, water would activate the sp3-C–
O bond by forming a hydrogen bond with the hydroxyl group
of the alcohol in intermediate A. Furthermore, the hydrophobic
effect “on water” would also accelerate the dehydrative amin-
ation in our catalytic system. Indeed, no reaction occurred when
using DMF/H2O (1:1) as solvent (see Table 1, entry 23).[22] Since
water molecules have unusual chemical and physical properties
compared with organic solvents, water should play an impor-
tant role in the development of new and efficient reactions.
Several control experiments were performed to exclude the
possibility of other reaction pathways such as a radical pathway
based on single electron transfer (SET)[14] or a borrowing
hydrogen pathway.[17] First, radical clock experiments using α-
cyclopropylbenzyl alcohol (2b) were conducted to observe the
rapid isomerization of the cyclopropylmethyl radical to the allyl-
methyl radical, which is well-known in free-radical chemistry
(Scheme 3A). As expected, 4j was obtained in 95 % yield via
the cyclopropylmethyl cation but not the ring-opened product
4k. Furthermore, in the presence of the radical scavenger BHT
(dibutylhydroxytoluene), dehydrative amination proceeded in
47 % yield (Scheme 3B). Next, a crossover experiment using
We also examined the scalability of our catalytic system. N-
Benzylation of 5-bromoanthranilic acid (1a) with benzhydrol
(2a) could be performed on gram scale (see the Supporting
Information). After 10 min, a white suspension formed in water,
which slowly turned into an insoluble gum-like substance of
a yellowish-brown color. After 16 h, the reaction mixture was
extracted with EtOAc, then crude 3a could be purified simply
by recrystallization from hexanes and EtOAc to give the desired
product 3a in 80 % isolated yield.
Finally, when using N-alkylanthranilic acids as nucleophiles,
C-benzylated 8a–b were obtained in good yields with the
amino group left intact (Scheme 4).[23] To the best of our knowl-
edge, this is the first example of a cobalt-catalyzed dehydrative
Friedel–Crafts alkylation in water.
Scheme 4. Dehydrative Friedel–Crafts alkylation of N-alkylanthranilic acids.
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Conclusion
In conclusion, we have reported the first example of a sustaina-
ble and environmentally benign procedure for direct dehydra-
tive amination of benzylic and allylic alcohols by using a co-
balt(II)/TPPMS catalyst in water. This catalytic system is applica-
ble for the direct modification of unprotected anthranilic acids
and electron-deficient anilines in moderate to excellent yields
and could be utilized for the synthesis of active pharmaceuti-
cals. We are currently investigating the scope of various nucleo-
philes and applications.
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Acknowledgments
This work was supported by Japan Society for the Promotion
of Science (JSPS), Grants-in-Aid for Scientific Research (KAK-
ENHI) Grant Number 16K08179.
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Keywords: Cobalt · Amination · Water · Dehydration ·
Benzylation · Nucleophilic substitution
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Received: November 25, 2016
Published Online: ■
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Dehydrative Substitution
H. Hikawa,* Y. Ijichi, S. Kikkawa,
I. Azumaya* ......................................... 1–5
Cobalt(II)/TPPMS-Catalyzed Dehy-
drative Nucleophilic Substitution of
Alcohols in Water
A green and sustainable direct de- phenylphosphinobenzene-3-sulfonate)
hydrative amination of alcohols, cata- in water, is described.
lyzed by cobalt(II)/TPPMS (sodium di-
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