Synthesis of β-amino esters by regioselective amination of allyl bromides with aryl and alkyl amines

Article abstract of DOI:10.1055/s-2005-871934

One of the two possible regioisomers can be exclusively formed by combining a suitable solvent and a specific amount of triethylamine as a base during the amination of allyl bromide 5. The S_N2′ product 7 was produced using dichloromethane as a

Full text of DOI:10.1055/s-2005-871934

LETTER
2035
Synthesis of b-Amino Esters by Regioselective Amination of Allyl Bromides
with Aryl and Alkyl Amines
Synthesis of
b
-Am
u
inoEsters ng-Yang Chen,a Laxmikant N. Patkar,b Shau-Hua Ueng,b Chun-Cheng Lin,*b,c Adam Shih-Yuan Lee*a
a
b
c
Department of Chemistry, Tamkang University, Tamsui, Taiwan
Institute of Chemistry and Genomic Research Center, Academia Sinica, Taipei, Taiwan
Department of Applied Chemistry, National Chiao Tung University, Hsinchu, Taiwan
Fax +88(62)26223830; E-mail: adamlee@mail.tku.edu.tw
Received 1 June 2005
SN2' product
NHR
SN2 product
Abstract: One of the two possible regioisomers can be exclusively
formed by combining a suitable solvent and a specific amount of tri-
ethylamine as a base during the amination of allyl bromide 5. The
SN2¢ product 7 was produced using dichloromethane as a solvent
and triethylamine (7 equiv) as base; SN2 product 6 was predomi-
nantly generated in hexane with 0.5 equivalents of triethylamine.
Furthermore, a new reaction condition for the efficient cyclization
of 7 to yield a-methylene b-lactam 8 using Sn[N(TMS)2]2 as a
reagent, is disclosed.
OH
E
RNH2
E
NHR
E
R
R
+
R
E
solvent
R
Br
1
2
3
4
E = electron-withdrawing group e.g. –COR, –COOR, –CN, –SO2Ph
R = –Ar, COOR, P(=O)(OEt)2
Scheme 1
Key words: b-amino ester, amination, regioselectivity, a-methyl-
ene b-lactam, allyl bromide
basicity of the nitrogen nucleophile, on the polarity of the
solvent used in the reaction, and on the substituent at C-2
position of the allyl bromide 2. The addition of amine to
the allyl bromide 2 with ester substituent at the C-2 posi-
tion has been reported to yield a mixture of 3 and 4.2b,12a
The thermodynamically more stable product 3 was pro-
duced by the SN2 replacement of the bromide with amine,
and the kinetic product 4 was formed by either N-allylic
rearrangement or the SN2¢ replacement of allyl bromide
with amine.10–13 In this work the polarity of the solvent,
the basicity of the nucleophilic amines and amount of base
strongly affected the regioselective addition of allylic
bromides with arylamines.
b-Amino acid is a non-proteinogenic amino acid and an
important moiety in many biologically active com-
pounds.1 It is an important precursor in the synthesis of b-
lactams.2 b-Lactams themselves are important antibiotics
and clinically important molecules,3 so numerous synthet-
ic methods have been developed to construct b-amino
acids and b-lactam skeletons. For instance, the Mannich
reaction,4 Michael addition (nitrogen nucleophiles),5
base-catalyzed ring-opening of b-lactams,6 epoxide ring-
opening by nitrogen nucleophiles,7 aziridine ring-
opening8 and Sharpless aminohydroxylation9 are some of
the methods used to synthesize b-amino acids. Despite the
impressive range of synthetic methods, newer and simpler
methods by which chemists can control the regio- and ste-
reoselectivity of the synthesis of b-amino esters are highly
desirable. Scheme 1 presents one such simple method in
which a nitrogen nucleophile attacks allyl bromide inter-
mediate 2, obtained from Baylis–Hillman adduct 1, to
yield SN2 b-amino acid 3 and SN2¢ product 4 (for
E = COOR, Scheme 1).2b However, the nucleophilic
attack by nitrogen at the allyl bromide a,b-unsaturated
system commonly leads to the formation of a mixture of
SN2 and SN2¢ products.2b,10–12 This work reports the
regioselective amination of allyl bromo a,b-unsaturated
compounds by controlling the solvent and the base.
As shown in Table 1, the reaction time was shortened
from four days to under 12 hours, and the regioselectivity
was improved from that of two regioisomers in a ratio of
1:1 to that of an exclusive product 7 using excess base (7
equiv, entries 1–4). When the reaction procedure was
modified by initially stirring triethylamine and allyl-
bromide 5 for 30 minutes and then adding the arylamines
(entries 2–4), 7a was formed exclusively with very little
change in yields over a range of reaction times. The use of
aryl amines as nucleophiles caused only a very slight
change in the yield (entries 5–10). Notably, alkyl amines
(allylamine, n-butylamine, morpholine and diethylamine)
failed to give any clean isolable products under the same
reaction conditions.14 Entries 5–12 (Table 1) show the
effect of the substituent at the C-3 position of allyl
bromide and arylamines.15 Good yields of exclusively
formed 7b–i were obtained in these cases, indicating that
the regioselectivity of the addition reactions of allylic
bromides with arylamines was only weakly affected by
the substituents at the C-3 position of allyl bromide and
arylamines, except in the case of entry 12.
In earlier investigations of the amination of allyl bromides
2 (Scheme 1), where the substituents at the C-2 positions
were nitrile,10 sulfonyl,11 ketone12 or ester,2b,12a,13 the
product formation depended on the steric bulk and
SYNLETT 2005, No. 13, pp 2035–2038
1
9
.0
8
.2
0
0
5
Advanced online publication: 07.07.2005
DOI: 10.1055/s-2005-871934; Art ID: U17105ST
© Georg Thieme Verlag Stuttgart · New York

2036
H.-Y. Chen et al.
LETTER
Table 1 Amination of Allyl Bromide 5 in CH2Cl2
Ar2HN
Ar1
O
O
O
Ar2NH2 (2 equiv), Et3N
Ar1
Ar1
OMe
OMe
NHAr2
6a–6i
SN2 product
OMe
+
CH2Cl2
Br
5
7a–7i
SN2' product
Entry
Ar1
Ar2
Et3N (equiv)
Time (h)
Yield (%)
Ratio 6:7
1:1
Product
1
2
Ph
Ph
–
7
7
7
7
7
7
7
7
7
96
3
61
91
93
94
86
90
89
95
87
91
6a:7a
7a
Ph
Ph
0:1a
3
Ph
Ph
6
0:1a
7a
4
Ph
Ph
12
6
0:1a
7a
5
Ph
p-MeOPh
2,4-Me2Ph
p-MeOPh
Ph
0:1a
7b
7c
6
Ph
6
0:1a
7
m-BrPh
m-BrPh
6
0:1a
7d
7e
8
6
0:1a
9
p-MeOPh
Ph
6
0:1a
7f
10
Ph
24
0:1a
7g
11
12
Ph
Ph
7
7
24
24
81
20
0:1a
0:1a
7h
7i
S
O
a Reaction was performed by stirring 5 with Et3N for 30 min and adding the amine, whereas in other entries all the reactants were added together
and stirred for the indicated time.
Based on the facts reported herein and other reports,12,13
a
ing the reaction solvent to hexane. Initially, when allyl
speculative reaction mechanism, presented in Scheme 2, bromide 5 and aniline were stirred together in hexane at
is proposed to explain the exclusive formation of 7. Allyl room temperature for five days (entry 1, Table 2), a mix-
bromide 5 initially reacts with the added base triethyl- ture of products 6a and 7a in a 2:1 ratio was obtained with
amine to yield ammonium salt, which then undergoes a 66% yield. When triethylamine (0.3 equiv of 5) was add-
SN2¢ attack at the C-3 carbon by amine nucleophile to pro- ed as a base, the reaction time was shortened to 10 hours
duce an intermediate with the release of bromotriethyl- and the regioselectivity markedly improved with a five-
amine salt. The abstraction of a proton from nitrogen on fold increase in the product yield (entry 2). Further in-
the intermediate by the base yields 7, which is known to creasing the amount of base (0.5 equiv) further increased
be able to rearrange to 6 in the presence of ammonium regioselectivity (entry 3), which then decreased as the
halide or a base.12
amount of base was increased to one equivalent or seven
equivalents. (entries 4 and 5). Thus, 0.5 equivalents of tri-
ethylamine were used in the following reactions. Entries
6–10 show the effect of the substituent at the C-3 position
Non-polar solvent promoted SN2 substitution in ester-sub-
stituted allyl bromide 2.12a Therefore, an attempt was
made to change the reaction product from 7 to 6 by chang-
Ar2NH2
..
Et3N
Ar2
Ar2
H
β
NH
CO2Me
Br
CO2Me
N
Et3N
Ar1
Ar1
H
CO2Me
CO2Me
Ar1
excess
Ar1
NEt3
Br
7aꢀ7i
5
ammonium salt
Scheme 2
Synlett 2005, No. 13, 2035–2038 © Thieme Stuttgart · New York

LETTER
Synthesis of b-Amino Esters
2037
of allyl bromide and arylamines. In all of the examples, bases such as ethyl magnesium bromide, n-butyllithium,
product 6 was the major product. Notably, naphthalenyl- potassium tert-butoxide, lithium hydroxide and potassium
substituted allyl bromide had the best regioselectivity (en- hydroxide, which were reported earlier to have been used
try 8, 6l:7l >99:1), and other substituents on allyl bromide in such cyclizations, failed to cyclize 7 to b-lactam (en-
afforded less regioselectivity than that of phenyl substitu- tries 1–5). Thus, another reagent, Sn[N(TMS)2]2, which
ents. Other aryl and allyl amines such as para-methoxy- has been previously used in the cyclization of b-ami-
aniline and allylamine, also displayed SN2 favored noesters,2a was examined. The reaction solvent and tem-
selectivity (entries 11 and 12). However, when more basic perature importantly affected the cyclization of 7a, as
alkyl amines such as n-butylamine, diethylamine and shown in entries 6–11. The optimal cyclization conditions
morpholine were used, the trend was reversed, and regio- were found to involve 1.5 equivalents of Sn[N(TMS)2]2 in
isomer 7 was formed as the dominant product (entries 13– toluene under reflux.
15).
In conclusion, reaction conditions are disclosed in which
The ability to access b-aminoesters 7 exclusively was ex- one of two possible regioisomeric reaction products can
ploited and its cyclization to a-methylene b-lactam 8 be obtained using a properly chosen solvent and base.
(Table 3), which is a valuable precursor in the synthesis of Moreover, Sn[N(TMS)2]2 was found to be a good reagent
substituted b-lactams, was investigated.16 Conventional in the cyclization of product 7 to b-lactam.
Table 2 Amination of Allyl Bromide 5 in Hexane
R1R2N
Ar3
O
O
O
R1R2NH2 (2 equiv), Et3N
hexane
Ar3
OMe
Ar3
OMe
OMe
+
NR1R2
Br
5
7j–7s
SN2' product
6j–6s
SN2 product
Entry
Ar3
Ph
Ph
Ph
Ph
Ph
R1R2NH
PhNH2
PhNH2
PhNH2
PhNH2
PhNH2
Et3N (equiv)
Time (h)
Yield (%)
Ratioa 6:7
2:1
Product
6a:7a
6a:7a
6a:7a
6a:7a
6a:7a
6j:7j
1
2
3
4
5
6
7
8
–
120
10
10
10
10
10
10
10
66
89
93
91
87
88
80
77
0.3
0.5
1
10:1
30:1
17:1
7
6:1
p-MeOPh
m-BrPh
PhNH2
PhNH2
PhNH2
0.5
0.5
0.5
19:1
16:1
6k:7k
6l:7l
>99:1
9
PhNH2
PhNH2
0.5
0.5
10
10
82
71
24:1
16:1
6m:7m
6n:7n
S
10
O
11
12
13
14
15
Ph
p-MeOPhNH2 0.5
10
10
10
10
10
75
89
99
92
90
6:1
4:1
1:2
1:3
1:3
6o:7o
6p:7p
6q:7q
6r:7r
6s:7s
Ph
Ph
Ph
Ph
allylamine
n-BuNH2
Et2NH
0.5
0.5
0.5
0.5
morpholine
a The ratios of 6:7 were determined after chromatographic purification.
Synlett 2005, No. 13, 2035–2038 © Thieme Stuttgart · New York

2038
H.-Y. Chen et al.
LETTER
Table 3 Cyclization of b-Aminoesters 7 to a-Methylene
b-Lactam 8
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1
2
EtMgBr (2.0 equiv), THF, 0 °C to r.t., 2 d
n.r.
n-BuLi (1.2 equiv), THF, 0 °C to r.t., 2 d
n.r.
3
t-BuOK (1.5 equiv), THF, 0 °C to r.t., 30 min
LiOH (2.0 equiv), H2O–dioxane, reflux, 1.5 h
KOH (2.0 equiv), MeOH, r.t., 2 d
mess
mess
mess
n.r.
4
5
6
Sn[N(TMS)2]2 (1.2 equiv), THF, r.t., 48 h
Sn[N(TMS)2]2 (1.2 equiv), THF, reflux, 48 h
Sn[N(TMS)2]2 (2.0 equiv), THF, reflux, 96 h
Sn[N(TMS)2]2 (1.5 equiv), toluene, reflux, 6 h
Sn[N(TMS)2]2 (2.5 equiv), toluene, reflux, 6 h
7
5%a
29%b
83%
83%
8
9
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10
a Starting material (80%) was recovered.
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Synthesis of b-Aminoester 7 (SN2¢ Product)
To a solution of compound 5 (1.0 mmol) in 5 mL CH2Cl2 was added
Et3N (1 mL) and the reaction mixture was stirred at r.t. for 30 min.
Aniline (2.0 mmol) was added at r.t. when the solution became a
suspension. After the reaction was complete (monitored by TLC),
aq HCl (2 M, 10 mL) was added. The mixture was extracted with
Et2O (3 ꢁ 20 mL) and the organic layer was washed with brine (40
mL), dried (MgSO4), filtered and concentrated.
Synthesis of b-Aminoester 6 (SN2 Product)
To a solution of compound 5 (1.0 mmol) in 5 mL hexane was added
Et3N (0.5 mmol) and aniline (2.0 mmol) at r.t. The reaction mixture
was stirred at r.t. for 10 h and then H2O (10 mL) was added. The
mixture was extracted with Et2O (3 ꢁ 20 mL) and the organic layer
was dried with MgSO4, filtered and concentrated. Purification was
achieved by silica gel flash chromatograph and eluted with EtOAc–
hexane.
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with ester substituent at C-2 position, 38% yield was
afforded.
Acknowledgment
We thank Tamkang University, Academia Sinica and National
Science Council in Taiwan for their financial support.
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Synlett 2005, No. 13, 2035–2038 © Thieme Stuttgart · New York