Catalytic Amination of β-(Hetero)arylethyl Ethers by Phosphazene Base t-Bu-P4

Article abstract of DOI:10.1021/acs.orglett.9b02309

We describe the catalytic amination of β-(hetero)arylethyl ethers with amines using the organic superbase t-Bu-P4 to obtain β-(hetero)arylethylamines. The reaction has a broad substrate scope and allows the transformations of electron-deficient and electron-neutral β-(hetero)arylethyl ethers with various amines including pyrrole, N-alkylaniline, diphenylamine, aniline, indole, and indoline derivatives. Mechanistic studies indicate a two-reaction pathway of MeOH elimination from the substrate to form a (hetero)arylalkene followed by the hydroamination of the alkene.

Full text of DOI:10.1021/acs.orglett.9b02309

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Catalytic Amination of β‑(Hetero)arylethyl Ethers by Phosphazene
Base t‑Bu-P4
Masanori Shigeno,* Ryutaro Nakamura, Kazutoshi Hayashi, Kanako Nozawa-Kumada,
and Yoshinori Kondo*
Department of Biophysical Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba, Sendai, 980-8578,
Japan
S
* Supporting Information
ABSTRACT: We describe the catalytic amination of β-
(hetero)arylethyl ethers with amines using the organic super-
base t-Bu-P4 to obtain β-(hetero)arylethylamines. The reaction
has a broad substrate scope and allows the transformations of
electron-deficient and electron-neutral β-(hetero)arylethyl
ethers with various amines including pyrrole, N-alkylaniline,
diphenylamine, aniline, indole, and indoline derivatives.
Mechanistic studies indicate a two-reaction pathway of
MeOH elimination from the substrate to form a (hetero)arylalkene followed by the hydroamination of the alkene.
arbon−nitrogen bond formations using readily and
Cwidely available amine nucleophiles are of great
importance for synthesizing functional molecules in pharma-
ceuticals, agrochemicals, and material sciences.1 Various
strategies available for C−N bond formation include
nucleophilic substitution of alkyl (pseudo)halides, transition-
metal-catalyzed cross-coupling, or SNAr reactions of aryl
(pseudo)halides, imine reduction, and the nucleophilic
addition of carbon-nucleophiles to imine derivatives.1,2 In
addition to these approaches, hydroamination of (hetero)aryl
alkenes in an anti-Markovnikov fashion has become a powerful
tool in organic chemistry, because the protocol allows a highly
atom-economic preparation of β-(hetero)arylethylamines, an
important scaffold in biologically active molecules (Figure
1a).3,4 The hydroamination of alkenes is catalyzed by transition
metals,5 rare earth metals,6 Brønsted bases,7,8 photocatalysts,9
Brønsted acids, and Lewis acids.10 Despite its wide applicability
in hydroaminations, however, the compatibility of the alkene
functional group in multistep transformations, used for the
synthesis of complex or highly functional molecules, is rather
low because of its relatively high reactivity under varied
reaction conditions.2a,11 In view of the challenge, the
development of a novel type of anti-Markovnikov hydro-
amination using a robust chemical functionality is highly
attractive and merits study.
We previously reported the substitution reactions of
methoxy groups in aryl and heteroaryl substrates by alcohol
and amine nucleophiles using the organic superbase t-Bu-P412
as a catalyst (Figure 1, (i)).13,14 In a related study, Bandar and
co-workers showed that the hydroalkoxylation of (hetero)aryl
alkenes with alcohols proceeds reversibly under t-Bu-P4
catalysis (Figure 1, (ii)).15 Building on our understating of
these processes, we report herein the facile catalytic synthesis
of β-(hetero)arylethylamines via exchange of the methoxy
Figure 1. β-(Hetero)arylethylamine formations based on anti-
Markovnikov addition and t-Bu-P4-catalyzed reactions underlying
this study.
Received: July 4, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02309
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Letter
group in β-(hetero)arylethyl ethers using t-Bu-P4 (Figure
1c).16 The reaction has a broad substrate scope. Electron-
deficient and neutral phenethyl ethers with various substituents
such as trifluoromethyl, cyano, halo, and methoxy groups can
be efficiently used in the developed amination reaction.
Heteroaryl groups such as pyridine and benzothiophene are
also compatible with the reaction conditions. Various amine
nucleophiles such as pyrrole, indoles, N-alkyl anilines,
diphenylamine, aniline, and indolines were successfully used
in the reaction. In comparison to the formally similar reactions
using β-(hetero)arylethyl (pseudo)halides as electrophiles, the
present system is beneficial in avoiding the formation of
stoichiometric inorganic salt wastes. Mechanistic studies were
carried out to probe the processes of the reaction. The reaction
mechanism involves the formation of a (hetero)aryl alkene
intermediate in situ by the elimination of methanol from the
substrate followed by hydroamination by an amine nucleo-
phile.
highlights the critical role of t-Bu-P4 in this reaction (Table
S1).18
With the optimized conditions in hand, we explored the
scope of various β-(hetero)arylethyl ethers under the reaction
conditions (Figure 2). Substrate 1b bearing an electron-
We began the evaluation of the amination reaction using
phenethyl ether 1a bearing a trifluoromethyl moiety as the test
substrate and pyrrole 2a as the nucleophile, in the presence of
catalyst t-Bu-P4 (Table 1). The reaction conducted at 40 °C
Table 1. Optimization of the Amination Conditions of 1a
a
and 2a
b
Entry
Deviation from standard conditions
3aa (%)
1
2
3
4
5
6
7
8
9
None
92
(9)
c
40 °C, without 3 Å MS
40 °C
61
60
44
43
84
40 °C, 4 Å MS instead of 3 Å MS
40 °C, 5 Å MS instead of 3 Å MS
10 mol % of t-Bu-P4
1,4-dioxane as solvent
toluene as solvent
c
(8)
d
Scale-up of the reaction
90
a
Standard conditions: 1a (0.20 mmol), 2a (0.40 mmol), t-Bu-P4
b
(0.04 mmol), 3 Å MS (70 mg), THF (0.3 mL), 60 °C, 12 h. Isolated
Figure 2. Scope of β-(hetero)arylethyl ethers 1 in catalytic amination
c
yields. The yields in parentheses were determined by 1H NMR
reaction.a,b a Reactions were conducted on a 0.2 mmol scale. b Isolated
d
spectroscopy with 1,1,2-trichloroethane as an internal standard. 1a
yields. Reaction was conducted in 1,4-dioxane at 130 °C. d Reaction
c
(1.0 mmol), 2a (2.0 mmol), t-Bu-P4 (0.20 mmol), 5 Å MS (350 mg),
THF (1.5 mL), 60 °C, 12 h.
was conducted in 1,4-dioxane at 110 °C. e Reaction was conducted for
f
24 h. Reaction was conducted at 90 °C.
withdrawing cyano group at the para-position afforded product
3ba in 83% yield. Halogen substituents (Cl and Br) are
compatible in the reaction and afforded products 3ca and 3da
in 87% and 88% yields, respectively. Substitutions at the ortho-
position of the phenyl ring with trifluoromethyl, cyano, fluoro,
and chloro groups furnished the desired products 3ea−3ha in
high yields of 90%, 95%, 73%, and 88%, respectively. The uses
of naphthalene (1i) and biphenyl (1j) derivatives also
delivered the amination products 3ia and 3ja in excellent
yields of 93% and 87%, respectively. The use of electronically
neutral phenyl substrate 1k resulted in the formation of the
corresponding product 3ka in 79% yield, while the methoxy
substitution in substrate 1l gave the product in 73% yield.
Electronically rich substrate 1m did not provide the product
3ma.19 Then, the reaction of α-substituted substrate 1n was
afforded the desired product 3aa, albeit in a low NMR yield of
9% (entry 2).17 The reactions were then carried out in the
presence of 3 Å molecular sieves to trap the methanol
generated in the reaction, which resulted in the formation of
3aa in a much improved yield of 61% (entries 3−5). We were
pleased to find an increase in the yield of 3aa to 92% with an
increase in the reaction temperature to 60 °C (entry 1). The
yield of the product decreased with the use of lower
equivalents of t-Bu-P4 (10 mol %, entry 6). The use of
dioxane as the reaction solvent afforded 3aa in a high yield of
84%, while toluene gave a lower yield of 8% (entries 7 and 8).
When scaling up the reaction to 1.0 mmol, a high yield of 90%
was obtained (entry 9). Use of other Brønsted bases was
completely ineffective for the formation of 3aa, which
B
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Letter
carried out, which resulted in the production of 3na in 67%
yield. The amination of 2,2-diphenylethy ether 1o also
proceeded to furnish the product 3oa in 57% yield. We next
evaluated the scope of heteroaryl substituents in this reaction.
4- and 2-Pyridyl-containing substrates 1p and 1q afforded the
products in 87% and 83% yields, respectively, while the use of
benzothiophene derivative 1r allowed amination in 87% yield.
To broaden the substrate scope in the present catalytic
amination, a variety of amine nucleophiles were tested with 1a
(Figure 3). N-Methylaniline 2b and its derivatives 2c−2f,
Having explored the scope of the amination reaction, we
conducted experiments to gain insights into the mechanism of
amination (Figure 4). Substrate 1i was subjected to the
Figure 4. Mechanistic studies. a The yield was determined by 1H
NMR spectroscopy with 1,1,2-trichloroethane as an internal standard.
reaction conditions in the absence of the amine nucleophile,
which resulted in the formation of the corresponding styrene
derivative 4i by the elimination of methanol.15 The reaction of
4i with 2a was carried out, which resulted in the formation of
the aminated product 3ia. The use of 4-(trifluoromethyl)-
benzyl methyl ether 5 in the reaction conditions afforded no
amination products, which eliminates the possibility of an SN2
reaction pathway. These reactions clearly indicate the
intermediacy of the alkene product.
Based on these results, we propose the mechanism described
in Figure 5, which involves two distinct processes by t-Bu-P4.
Figure 3. Scope of amines 2 in the catalytic amination reaction.a,b
a Reactions were conducted on a 0.2 mmol scale. b Isolated yields.
c Reaction was conducted at room temperature for 24 h. d Reaction
e
was conducted at 40 °C. Reaction was conducted in 1,4-dioxane at
f
130 °C. Reaction was conducted at 90 °C.
bearing a methyl, methoxy, chloro, and bromo groups on the
phenyl ring, formed the desired products in good yields of
71%, 71%, 76%, 79%, and 82%, respectively. N-Ethyl- and N-
benzylanilines 2g and 2h as well as diphenylaniline 2i
underwent the amination to afford the yields of 51%, 64%,
and 64%, respectively. Amination using aniline 2j also
proceeded in 58% yield. The use of indole 2k afforded the
corresponding product 3ak in 87% yield. Interestingly, the
reaction with 5-methoxytryptamine 2l proceeded chemo-
selectively at N−H of the indole moiety to afford 3al in 77%
yield. Indoline 2m and its derivatives 2n and 2o, bearing
methyl and bromo groups at the 5-position, coupled with 1a in
high yields, while 2-methylindoline 2p also gave the desired
product in 96% yield. Using 3,4-dihydro-2H-1,4-benzoxazine
2q as a substrate, the desired amination product 3aq was
obtained in 45% yield. When pyrrolidine 2r was employed, the
target product 3ar was furnished in 30% yield.
Figure 5. Proposed mechanism for catalytic amination.
Initially, the E2 elimination of MeOH occurs by the reaction of
substrate 1 with t-Bu-P4 to form aryl alkene 4 in a step that can
be regarded as the deprotection of the masked alkene.
Subsequent deprotonation of 2 occurs to form B, which
leads to the hydroamination on 4 to provide 3.
C
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(b) Rappoport, Z., Ed. The Chemistry of Anilines, Parts 1 and 2; John
Wiley & Sons: New York, 2007.
To further reveal the catalytic features of t-Bu-P4 in the
current system, the following experiment were conducted. A
catalytic amount of Brønsted bases other than t-Bu-P4 were
employed in the MeOH-elimination reaction from the
substrate 1i and the hydroamination of 2a on 4i (Tables S3
and S4). In both the investigations, the yields of the
corresponding products (4i in the former; 3ia in the latter)
were much lower than those obtained by using t-Bu-P4 (Figure
4).20,21 The results clearly displayed the validity of t-Bu-P4 as a
reactive catalyst in both the processes.
In summary, the amination reactions of β-(hetero)arylethyl
ethers with various amines under t-Bu-P4 catalysis were
reported. The optimized reaction conditions were applicable to
a wide range of β-(hetero)arylethyl ether substrates with varied
electronic properties and deliver excellent yields. The
mechanistic analysis indicated that the reaction proceeds
through two pathways, which includes the initial formation of
the (hetero)arylalkene by the elimination of MeOH followed
by its hydroamination with an amine.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02309.
Effects of organic or inorganic bases in the reaction of 1a
and 2a (Table S1); reactions of substrates containing a
leaving group other than methoxy group (Table S2);
effects of organic or inorganic bases in the MeOH-
elimination from 1i (Table S3); effects of organic or
inorganic bases in the hydroamination of 4i and 2a
(Table S4); preparations of 1a, 1n, 1o, 7, 8, and 9;
experimental procedures and spectra data for obtained
1
products; and H and 13C NMR spectra (PDF)
Castro, I. G.; Tillack, A.; Zapf, A.; Arlt, M.; Heinrich, T.; Bcţ tcher, H.;
Beller, M. Chem. - Eur. J. 2004, 10, 746. (d) Hartung, C. G.; Breindl,
C.; Tillack, A.; Beller, M. Tetrahedron 2000, 56, 5157. (e) Tzalis, D.;
Koradin, C.; Knochel, P. Tetrahedron Lett. 1999, 40, 6193.
(f) Hamana, H.; Iwasaki, F.; Nagashima, H.; Hattori, K.; Hagiwara,
T.; Narita, T. Bull. Chem. Soc. Jpn. 1992, 65, 1109. For a review, see:
(g) Seayad, J.; Tillack, A.; Hartung, C. G.; Beller, M. Adv. Synth. Catal.
2002, 344, 795.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: mshigeno@m.tohoku.ac.jp.
*E-mail: ykondo@m.tohoku.ac.jp.
ORCID
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Int. Ed. 2014, 53, 6198. (b) Nguyen, T. M.; Nicewicz, D. A. J. Am.
Chem. Soc. 2013, 135, 9588.
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2016, 57, 1150. (b) Abou-Shehada, S.; Teasdale, M. C.; Bull, S. D.;
Wade, C. E.; Williams, J. M. J. ChemSusChem 2015, 8, 1083.
(c) Bhanushali, M. J.; Nandurkar, N. S.; Bhor, M. D.; Bhanage, B. M.
Catal. Commun. 2008, 9, 425.
(11) Hartwig, J. F. Organotransition Metal Chemistry. From Bonding
to Catalysis; University Science Books: Sausalito, CA, 2010.
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M.; Boele, J.; Fritz, H.; Putzas, D.; Rotter, H. W.; Bordwell, F. G.;
Satish, A. V.; Ji, G.-Z.; Peters, E.-M.; Peters, K.; von Schnering, H. G.;
Walz, L. Liebigs Ann. 1996, 1996, 1055.
(13) (a) Shigeno, M.; Hayashi, K.; Nozawa-Kumada, K.; Kondo, Y.
Chem. - Eur. J. 2019, 25, 6077. (b) Shigeno, M.; Hayashi, K.; Nozawa-
Kumada, K.; Kondo, Y. Org. Lett. 2019, 21, 5505. For our related t-
Bu-P4 catalyzed reactions, see: (c) Araki, Y.; Kobayashi, K.;
Yonemoto, M.; Kondo, Y. Org. Biomol. Chem. 2011, 9, 78. (d) Hirono,
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Masanori Shigeno: 0000-0002-9640-8283
Kanako Nozawa-Kumada: 0000-0001-8054-5323
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by JSPS KAKENHI Grant
Number 19H03346 (Y.K.), JSPS KAKENHI Grant Number
17K15419 (M.S.), JSPS KAKENHI Grant Number 19K06967
(M.S.), Grand for Basic Science Research Projects from The
Sumitomo Foundation (M.S.), Yamaguchi Educational and
Scholarship Foundation (M.S.), NIPPON SHOKUBAI Award
in Synthetic Organic Chemistry, Japan (M.S.), and also the
Platform Project for Supporting Drug Discovery and Life
Science Research funded by Japan Agency for Medical
Research and Development (AMED) (M.S., K.N.K., and Y.K.).
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(17) Even when the reaction time was prolonged to 72 h, 3aa was
formed in a low NMR yield of 17% (results not shown).
(18) Substrates having a leaving group other than methoxy group
were also tested (Table S2). Reaction of the substrate bearing an
ethoxy group took place in 65% yield. The substrate having a (tert-
butyldimethylsilyl)oxy group afforded 3aa in an NMR yield of 7%,
while those containing acetate or benzoate groups did not.
(19) In the reaction of 1m, 4-methoxystyrene was formed in 4%
yield with recovery of 1m (96%). When 4-methoxystyrene was
subjected to the reaction conditions, 3ma was obtained in 12% yield
with its recovery (80%). Thus, in the amination of 1m, neither MeOH
elimination nor hydroamination, noted in Figure 5, efficiently occurs.
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used for the MeOH-elimination from β-arylethyl ethers; see:
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(c) Deagostino, A.; Prandi, C.; Venturello, P. Tetrahedron 1996, 52,
1433.
(21) Recently, Bandar and co-workers reported that KO-t-Bu
catalyzes the reversible addition of MeOH on (hetero)arylalkene in
DMSO as t-Bu-P4; see ref 15c.
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