Novel domino elimination-rearrangement-addition reaction of N-alkoxy(arylmethyl)amines to N-alkyl arylamines

Article abstract of DOI:10.1055/s-2006-949642

A new domino reaction of N-alkoxy(arylmethyl)amines to N-alkyl arylamines, consisting of three types of reactions: elimination of alcohol, rearrangement of the aryl group, and addition of an organolithium or a magnesium reagent, has been developed for the first time. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-949642

LETTER
2219
Novel Domino Elimination–Rearrangement–Addition Reaction of
N-Alkoxy(arylmethyl)amines to N-Alkyl Arylamines
Domino
E
liminatio
k
n–Rearrang
i
e
ment–
k
A
ddition Re
a
o
ction of
N
-Alkoxy
M
(arylmethyl)amines iyata, Tatsuya Ishikawa, Masafumi Ueda, Takeaki Naito*
Kobe Pharmaceutical University, Motoyamakita, Higashinada, Kobe 658-8558, Japan
Fax +81(78)4417556; E-mail: taknaito@kobepharma-u.ac.jp
Received 13 June 2006
We now report the first example of domino elimination–
rearrangement–addition of alkoxy(arylmethyl)amines 1
using organolithium and organomagnesium reagents
(Scheme 1). This newly found domino reaction consists
of consecutive elimination–rearrangement–addition reac-
tion of alkoxy(arylmethyl)amines. The a-branched sec-
arylamines 2 readily prepared by this domino reaction are
widely found as a core structure in pharmaceuticals,
agrochemicals, and other important materials.9
Abstract: A new domino reaction of N-alkoxy(arylmethyl)amines
to N-alkyl arylamines, consisting of three types of reactions: elimi-
nation of alcohol, rearrangement of the aryl group, and addition of
an organolithium or a magnesium reagent, has been developed for
the first time.
Key words: domino reaction, N-alkoxyamine, Grignard reagent,
organolithium reagent, rearrangement
Domino processes consist of several bond-forming reac-
tions and allow highly efficient synthesis1 of complex
molecules starting from simple substrates because domi-
no reactions increase synthetic efficiency by decreasing
the number of laboratory operations required and the
quantities of chemicals and solvents used. We have now
developed a highly potential synthetic method for N-alkyl
arylamines via a route involving domino elimination–
rearrangement–alkylation of readily available alkoxy-
amines.
OR1
R3
HN
H
N
R3–M
R2
R2
M = Li, MgBr
2
1
1) elimination
2) rearrangement
M
R3
R2
addition
N
The alkoxyamines 1 have recently received much atten-
tion as a tin-free radical initiator2 and an important precur-
sor of amines, which are of fundamental interest in many
fields of chemistry. Generally, the alkoxyamines are
mainly prepared by alkylation of hydroxylamines,3 cy-
cloaddition of either nitroso compounds or nitrones to alk-
enes,4 and the addition of either nucleophiles or radicals to
oxime ethers.5 The alkoxyamines can be easily converted
to amines by either reductive or alkylative N–OC bond
cleavage. Furthermore, it is known that the reaction of
alkoxyamines with a reducing reagent such as Red-Al,
LiAlH4, and DIBAL-H gives rise to reductive rearrange-
ment which results in the formation of the secondary
amines.6,7 In contrast, little is known about the transfor-
mation of alkoxy(arylmethyl)amines to N-substituted
arylamines carrying a branched substituent by a domino
process including rearrangement and alkylation. As only
one related work, Yamamoto’s group has reported alkyla-
tive rearrangement of O-acylhydroxylamine carrying the
ethoxycarbonyl moiety, which acts as a good leaving
group, by the treatment with trialkylaluminums.8 Howev-
er, they had reported the reactions with only trialkylalumi-
num and not with more common and commercially
available organolithium and organomagnesium reagents.
A
Scheme 1
We first investigated the domino reaction of N-meth-
oxy(phenylethyl)amine (3a) (Scheme 2, Table 1). Treat-
ment of phenethylamine 3a with two equivalents of n-
BuLi in Et2O at room temperature gave N-(1-methyl-
butyl)aniline (4a) in 39% yield.10 In order to improve the
yield of 4a, we next employed 3 equivalents of n-BuLi in
Et2O and obtained N-alkylaniline 4a in moderate yield
(entry 2). The reaction of 3a with PhLi gave 4b in 57%
yield (entry 3). Existence of either a p-methoxy group on
the benzene ring or a phenyl group at the R2 position in the
substrates promoted this domino reaction. The reaction of
3b with n-BuLi and PhLi gave the desired products 4c and
4d, respectively, in both 85% yields (entries 4 and 5). Fur-
thermore, upon treatment with n-BuLi and PhLi, N-meth-
oxydiphenyl methyl amine (3c) gave the desired products
4e and 4f both in high yields (entries 6 and 7). It is inter-
esting to note that all of the reactions proceeded quickly
and completed in only 15 minutes.12 Additionally, an aryl
group migrated selectively to give arylamines 4 and we
could not detect the product formed by migration of an
alkyl group. Corresponding N-cyclopenyl derivative of 3b
did not undergo the domino reaction under the same reac-
SYNLETT 2006, No. 14, pp 2219–2222
0
1
.0
9
.2
0
0
6
Advanced online publication: 24.08.2006
DOI: 10.1055/s-2006-949642; Art ID: U06706ST
© Georg Thieme Verlag Stuttgart · New York

2220
O. Miyata et al.
LETTER
Table 1 Reaction of N-Methoxybenzylamines 3 with RLi or RMgBr
Entry
Substrate
3a
R1
R2
R3–M (equiv)
n-BuLi (2)
n-BuLi (3)
PhLi (3)
Yield of 4 (%)
4a, 39
4a, 48
4b, 57
4c, 85
Yield of 5 (%)
1
2
H
Me
Me
Me
Me
Me
Ph
5a, –
5a, –
5a, –
5b, –
5b, –
5c, –
5c, –
5b, –
5c, 54
5c, 19
3a
H
3
3a
H
4
3b
MeO
MeO
H
n-BuLi (3)
PhLi (3)
5
3b
4d, 85
4e, 85
6
3c
n-BuLi (3)
PhLi (3)
7
3c
H
Ph
4f, 85
8
3b
MeO
H
Me
Ph
PhMgBr (3)
EtMgBr (3)
PhMgBr (3)
4d, 26
4g, 26
4f, –
9
3c
10
3c
H
Ph
Table 2 Domino Reaction of 6a,b
NHOMe
R2
H
N
N
R2
R2
R3–M
Entry
Substrate
R1
R2-M
n-BuLi
PhLi
Yield (%)
7a, 66
7b, 63
7c, 61
+
R3
Et2O, r.t.
15 min
R1
1
2
3
4
5
6a
6a
6a
6a
6b
Me
Me
Me
Me
Bn
R1
R1
3
4
5
Scheme 2
EtMgBr
PhMgBr
EtMgBr
7b, 65
7c, 66
tion conditions and was recovered completely. It suggests
that the secondary amino moiety in substrate is necessary
for this domino reaction.
We next examined the domino reaction with the Grignard
reagent, which is a weaker nucleophile than alkyl lithium.
When methoxyamine 3b was treated with PhMgBr, the
desired N-alkyl arylamine 4d and p-methoxyaniline were
obtained in 26% and 15% yields, respectively (entry 8).
The reaction of unsubstituted 3c with EtMgBr gave N-
alkyl arylamine 4g and imine 5c in 26% and 54% yields,
respectively, while the use of PhMgBr did not give N-sub-
stituted aniline 4f (entries 9 and 10). The fact that imine
5c was isolated in the domino reaction suggests strongly
that N-alkyl arylamine 4 would be formed through the
alkylation of 5. We attempted the domino reaction of 3a
with Me3Al and Et2Zn but the desired product was not ob-
tained.
To demonstrate the generality of the newly found domino
reaction of methoxyamines, we next investigated the
reaction of readily available cyclic alkoxyamines 6 and 8
with organolithium and magnesium reagents. The expect-
ed products of azepines 7 and 9 are known as the core
structure in pharmaceuticals due to their unique biological
activities.14
NHOMe
R
H
N
3 equiv R–M
15 min
S
Et2O, r.t.
S
6c
7d–h
Scheme 4
To the best of our knowledge, this reaction represents the
first example of N–OC bond cleavage of alkoxyamine
using Grignard reagents. It is known that upon treatment
with the Grignard reagent, O-tosyloximes undergo the N–
OC bond cleavage to afford amines.13
At first, the reactions of bicyclic alkoxyamines 6a,b with
organometallic compounds were examined (Scheme 3,
Table 2).
The treatment of 1-alkoxyaminotetraline 6a with n-BuLi
and PhLi in Et2O gave the 2-butyl- and 2-phenylbenzaze-
pines 7a and 7b in 66 and 63% yields, respectively (en-
tries 1 and 2). Similarly, the reaction of 6a with Grignard
reagents proceeded smoothly to give 7c and 7b (entries 3
and 4). When the cyclic alkoxyamine 6b bearing a benzyl-
oxy group was used as a substrate, the yield of benz-
azepine 7c was similar to that shown in entry 3 (entry 5).
NHOR1
R2
H
3 equiv R2–M
N
15 min
MeO
MeO
Et2O, r.t.
6a,b
7a–c
Scheme 3
Synlett 2006, No. 14, 2219–2222 © Thieme Stuttgart · New York

LETTER
Domino Elimination–Rearrangement–Addition Reaction of N-Alkoxy(arylmethyl)amines
Table 4 Domino Reaction of 8
2221
Table 3 Domino Reaction of 6c
Entry
Substrate R-M (equiv)
Yield of 9 Yield 10
Entry
R-M
Yield (%)
7d, 81
7e, 79
7f, 91
(%)
(%)
1
2
3
4
5
6
n-BuLi
1
2
3
4
5
6
7
8
9
8a
8a
8a
8a
8a
8b
8b
8b
8b
EtMgBr (3)
9a, 69
9a, 89
9b, 92
9c, 94
9d, 87
9e, 84
9f, 86
9g, 82
9h, 81
10a, 23
10a, –
10a, –
10a, –
10a, –
10b, –
10b, –
10b, –
10b, –
PhLi
EtMgBe (4)
EtMgBr
PhMgBr
AllylMgBr
VinylMgBr
PhMgBr (4)
7e, 90
7g, 87
7h, 75
Allyl MgBr (4)
Vinyl MgBr (4)
EtMgBr (4)
PhMgBr (4)
In the case of 4-methoxyaminobenzothiopyran (6c), 1,5-
benzothiazepines 7d–h bearing alkyl and phenyl groups
were obtained in better yields (Scheme 4, entries 1–4 in
Table 3). Furthermore, the allyl- and vinyl magnesium
bromides were also effective for this domino reaction
(entries 5 and 6).
Allyl MgBr (4)
Vinyl MgBr (4)
We next investigated the domino reaction of tricyclic
alkoxyamines 8 with Grignard reagents (Scheme 5,
Table 4).
R3
M
OR1
H
N
OR1
HN
R3–M
1) elimination
2) rearrangement
When three equivalents of EtMgBr was used in the reac-
tion of 8a, ethylated dibenzo[b,f][1,4]thiazepine 9a was
obtained in addition to a minor product of diben-
zo[b,f][1,4]thiazepine 10a (entry 1). However, reaction of
8a with four equivalents of EtMgBr proceeded smoothly
to give 9a in 89% yield as the sole product (entry 2). As
shown in Table 4, the desired products 9b–d were ob-
tained in high yield in the reaction of 8a with various types
of Grignard reagents (entries 3–5). Under the same reac-
tion conditions, dibenzopyran 8b gave dibenz[b,f][1,4]ox-
azepines 9e–h in more than 80% yield (entries 6–9).
R2
R2
1
B
M
R3
R3
R2
H
N
N
R2
addition
2
C
Scheme 6
R
NHOBn
HN
Possibility of the nitrenoid11 would not be excluded as an
R–M
intermediate in conversion of B to C.15
Et2O, r.t.
X
X
In conclusion, we have shown for the first time that the
domino elimination–rearrangement–addition reaction of
N-alkoxy(arylmethyl)amines proceeds smoothly in the
presence of organometal reagent to give the N-substituted
arylamines. Furthermore, we have succeeded in the syn-
thesis of cyclic compounds carrying an azepine ring wide-
ly found in biologically active compounds.
9a–h
8a: X = S
8b: X = O
+
N
X
10a,b
Scheme 5
Acknowledgment
We propose a possible reaction pathway for the formation
of N-alkyl arylamine 2 as shown in Scheme 6. At first, N-
alkoxy(arylmethyl)amine 1 would be chelated with orga-
nolithium or Grignard reagent to generate the intermedi-
ate B which is converted to the imine C via a-elimination
of both proton on the nitrogen atom of the oxime ether and
the alkoxide anion and subsequent rearrangement of a
phenyl group to nitrogen atom. Finally, the addition of
organolithium and magnesium reagents to the imine C
proceeds smoothly to give N-alkyl arylamines 2.
We acknowledge Grants-in Aid for Scientific Research (B) (T.N.)
and Scientific Research (C) (O.M.) from the Japan Society for the
Promotion of Science, and Scientific Research on Priority Areas
(A) (T.N.) from the Ministry of Education, Culture, Sports, and
Technology. Our thanks are also directed to the Science Research
Promotion Fund of the Japan Private School Promotion Foundation
for a research grant.
Synlett 2006, No. 14, 2219–2222 © Thieme Stuttgart · New York

2222
O. Miyata et al.
LETTER
(10) N-Butyl-1-phenylethylamine was also obtained in 11% yield
as a minor product. This product would be formed by
substitution of the methoxy group with an n-butyl group. P.
Beak11 and co-workers reported nucleophilic displacement
of alkoxide by the alkyl group at the nitrogen atom in the
alkoxyamines.
(11) (a) Beak, P.; Basha, A.; Kokko, B.; Loo, D. J. Am. Chem.
Soc. 1986, 108, 6016. (b) Beak, P.; Basu, K. C.; Lee, J. J. J.
Org. Chem. 1999, 64, 5218. (c) Beak, P.; Basha, A.; Kokko,
B. J. Am. Chem. Soc. 1984, 106, 1511. (d) Boche, G.;
Wagner, H.-U. J. Chem. Soc., Chem. Commun. 1984, 1591.
(e) Dembech, P.; Seconi, G.; Ricci, A. Chem. Eur. J. 2000,
6, 1281. (f) Greck, C.; Genêt, J. P. Synlett 1997, 741.
(12) Typical Procedure for Domino Elimination–
Rearrangement–Addition Reaction of 4,N-Dimethoxy-a-
methyl Benzenemethanamine(3b) with n-BuLi (entry 4
in Table 1).
To a stirred solution of 3b (45 mg, 0.25 mmol) in Et2O (1.7
mL) was added n-BuLi (1.6 mol/L in n-hexane; 0.47 mL,
0.75 mmol) under a nitrogen atmosphere at r.t. After being
stirred at the same temperature for 15 min, the reaction
mixture was diluted with H2O at 0 °C and extracted with
CHCl3. The organic phase was dried over MgSO4 and
concentrated under reduced pressure. Purification of the
residue by PTLC (n-hexane–EtOAc, 6: 1) afforded 4c (44
mg, 85%) as a pale yellow oil. IR: nmax = 3393 cm–1. 1H
NMR (200 MHz): d = 6.77 (2 H, br d, J = 9.0 Hz), 6.55 (2 H,
br d, J = 9.0 Hz), 3.74 (3 H, s), 3.36 (1 H, sext, J = 6.0 Hz),
1.60–1.27 (6 H, m), 1.14 (3 H, d, J = 6.0 Hz), 0.90 (3 H, t,
J = 6.0 Hz). 13C NMR (50 MHz): d = 152.2, 144.0, 115.3,
114.9, 55.7, 50.0, 36.6, 28.3, 22.7, 20.5, 14.0. HRMS: m/z
calcd for C13H21NO [M+]: 207.1624; found: 207.1626.
(13) Hattori, K.; Maruoka, K.; Yamamoto, H. Tetrahedron Lett.
1982, 23, 3395.
(14) le Count, D. J. Comprehensive Heterocyclic Chemistry, Vol.
9; Katritzky, A. R.; Rees, C. W.; Scriven, E. F.; Newcome,
G. R., Eds.; Elsevier: Oxford, 1996, Chap. 9.01, 1–43.
(15) Yamamoto8 group has employed O-ethoxycarbonyl-N-
benzyl-N-cycloalkylhydroxylamines as substrates, which
have no hydrogen atom on a nitrogen atom. Substrates of our
newly found reaction need the secondary amino moiety.
Thus reaction pathway of our domino reaction using
organolithium and organomagnesium reagents would be
completely different from Yamamoto’s reaction.8
References and Notes
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Synlett 2006, No. 14, 2219–2222 © Thieme Stuttgart · New York