Synthesis of β-amino arylketones through the addition of ArLi derivatives to β-aminoesters

Article abstract of DOI:10.1016/S0040-4039(01)00358-6

2-Lithiumthiophene and 2-lithiumpyridine were allowed to react with N-substituted β-aminoesters. Only β-amino arylketones were obtained from N-BOC, N-H derivatives, while arylenoates were formed (retro-conjugate addition) from those substrates bearing N-Bn, N-H substituents, despite the aryllithium used. When the nitrogen is disubstituted (BOC and Bn), the product distribution depended on the nucleophile, leading to tertiary alcohols for 2-lithiumthiophene or ketones for 2-lithiumpyridine. Tertiary alcohols were also formed when PhLi was used as a nucleophile.

Full text of DOI:10.1016/S0040-4039(01)00358-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3525–3527
Synthesis of b-amino arylketones through the addition of ArLi
derivatives to b-aminoesters
Paulo G. Lima,a,b Lucia C. Sequeirab and Paulo R. R. Costaa,*
aLaborato´rio de Qu´ımica Bioorgaˆnica (LQB), Nu´cleo de Pesquisas de Produtos Naturais, Centro de Cieˆncias da Sau´de, bloco H,
Ilha da Cidade Universita´ria, Universidade Federal do Rio de Janeiro (UFRJ), 21941-590 Rio de Janeiro, Brazil
bInstituto de Qu´ımica, Universidade Federal do Rio de Janeiro (UFRJ), 21941-590 Rio de Janeiro, Brazil
Received 25 October 2000; revised 26 February 2001; accepted 1 March 2001
Abstract—2-Lithiumthiophene and 2-lithiumpyridine were allowed to react with N-substituted b-aminoesters. Only b-amino
arylketones were obtained from N-BOC, N-H derivatives, while arylenoates were formed (retro-conjugate addition) from those
substrates bearing N-Bn, N-H substituents, despite the aryllithium used. When the nitrogen is disubstituted (BOC and Bn), the
product distribution depended on the nucleophile, leading to tertiary alcohols for 2-lithiumthiophene or ketones for 2-lithi-
umpyridine. Tertiary alcohols were also formed when PhLi was used as a nucleophile. © 2001 Elsevier Science Ltd. All rights
reserved.
While carboxylic acids1 and amides2 react with organo-
lithium compounds to give preferentially ketones, ter-
tiary alcohols are usually obtained when esters are used
as substrates,3 due to the decomposition of the tetra-
hedral lithium alkoxide intermediate, followed by the
reaction of the resulting ketone, which is more reactive
than the corresponding ester, with another equivalent
of the nucleophile before the work-up (Scheme 1, path-
way A). However, the presence of polar groups at the
a-position can stabilize the alcoxide intermediate by an
inductive effect or formation of five membered chelated
species (Scheme 1, X=O or N, n=1), leading preferen-
tially to ketones (pathway B).4 On the other hand, we
did not find examples in the literature for this type of
stabilization involving b-aminoesters as substrates
(Scheme 1, X=N, n=2).5
In this letter we disclose the results obtained for the
reactions of 2-lithiumthiophene (5a)6 and 2-lithi-
umpyridine (5b)6 with b-aminoesters 3a,b, 4a,b and
5a,b.
These b-aminoesters were prepared from methyl acry-
late (1a) or chiral enoate 1b7, as shown in Scheme 2.
Conjugate addition of benzylamine to 1a and 1b led,
respectively, to adducts 2a and syn-2b in excellent
yields. Compound syn-2b (85% de, crude)8 could be
obtained in an optically pure form, after chromatogra-
Li
Li
O
X
O
O
X
X
R1Li
R1Li
RO
RO
RO
R1
R1
pathway A
pathway B
alcoxide stabilized
by chelation
alcoxide not stabilized
spontaneous decomposition
work-up
O
O
X
X
X
R1
R1Li
HO
work-up
R1
R1
R1
Scheme 1. Possible reaction pathway for the addition of R1Li to a- and b-substituted esters.
* Corresponding author. Tel.: (21)5235938; fax: (21)2702683; e-mail: lqb@nppn.ufrj.br
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00358-6

3526
P. G. Lima et al. / Tetrahedron Letters 42 (2001) 3525–3527
R1
a
O
O
b
Bn = CH2Ph; BOC = CO2t-Bu
O
a, R1 = H; b, R1 =
O
1a,b
R1
Bn
O
R1
O
R1
O
c
O
N
O
O
NH
N
BOC
Bn
BOC
H
3a,b
2a,b
4a,b
Scheme 2. Preparation of b-aminodiesters 2–4 from enoates 1a,b. (a) 3 equiv. BnNH2 neat, −40°C, 2a (12 h, 100%), 2b (3 days,
90%); (b) (Boc)2O/MeOH, 100% for 3a,b; (c) H2 (1 atm), MeOH; (Boc)2O/MeOH, 100% for 4a,b.
phy. Reaction of 2a,b with (BOC)2O led to 3a,b, while
hydrogenolysis of 2a,b followed by in situ reaction with
(BOC)2O, furnished 4a,b.9
was used as a nucleophile. In contrast, ketones 7a,b
were obtained from the reaction of 3a,b with 5b.
In the next sequence, the reaction of 2a,b with 5a,b was
investigated (Scheme 4). In all cases neither ketones nor
tertiary alcohols were formed and the reaction pathway
The reactions involving 3a,b as substrates are shown in
Scheme 3. Tertiary alcohols 6a,b were formed when 5a
S
S
1-ArLi 5a,b
THF
R1
Bn
O
R1
Bn
R1
Bn
N
OH
-780C
O
BOC
O
BOC
N
N
N
or
BOC
2-AcOH
3
6a,b
7a,b
Li
5a =
O
S
Li
5b =
= H; b, R1 =
N
For 3, 6 and 7: a, R1
O
3a
6a, 70%
3b
6b, 30%
3a
7a, 61%
3b
7b, 88%
Scheme 3. Reaction of b-aminodiesters 2a,b with phenyllithium derivatives 5a–c.
O
R1
Bn
O
O
a
N
Ar
a
N
9, Ar =
O
N
Bn
O
~20%
51-68%
H
O
S
10, Ar =
8
2a,b
9 or 10
Scheme 4. Addition of 5a,b to enoates 2a,b. (a) ArLi, THF, −78°C, 30 min; AcOH, THF.
S
1- ArLi
R1
Ar
11, Ar =
12, Ar =
13, Ar =
R1
O
a, R = H
THF
-780C
N
O
N
O
N
BOC
H
O
BOC
H
b, R =
O
2- AcOH, THF
4a,b
11, 12 or 13
4
11 (a, 45%; b, 40%)
4
12 (a, 61%; b, 58%)
4
13 (a, 76%; b, 80%)
*contamined with ~10% of the corresponding
tertiary alcohols
S
5b,
5c,
Li
N
Li
5a,
Li
Scheme 5. Preparation of b-aminoketones 11–13 from enoates 4a,b.

P. G. Lima et al. / Tetrahedron Letters 42 (2001) 3525–3527
3527
O
O
O
O
a, R = H
b, R =
O
O
O
R1
Ar
R1
Ar
R1
R1
Bn
S
N
Li
N
O
N
OLi
BOC
N
N
Bn
16
Li
BOC
O
Li
Bn
15
BOC
17
14
Figure 1. Possible tetrahedral lithium alcoxide intermediates in the additon of 5 to 2, 3 and 4.
Acknowledgements
was shown to be dependent on the structure of the
substrate. While 2a led to the b-lactam 8, despite the
ArLi used, arylenoates 9 and 10 were obtained from 2b.
This work was supported by grant from PRONEX
(No. 41.96.0888.00). P.R.R.C and P.G.L. are recipients
of CNPq fellowships.
In the last set of experiments 4a,b were used as sub-
strates and ArLi 5a–c as nucleophiles (Scheme 5). In all
cases, despite the nature of both the b-aminoester and
aryllithium employed, b-aminoarylketones were prefer-
entially formed (11a,b, 12a,b and 13a,b).
References
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Since tertiary alcohols (6a,b) were exclusively formed in
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its decomposition in the reaction medium. However,
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