Synthesis of β-Amino and β-Methoxy Ketones by Lewis Acids Promoted β-Substitution Reactions of βγ,-Unsaturated Ketones

Article abstract of DOI:10.1055/s-2003-42472

A reaction mixture of β,γ-unsaturated ketone and BF ₃·OEt₂ in CH₃OH was stirred at room temperature and β-methoxy ketone was produced in high yield. The β-amino ketone was obtained as the major product from a reaction mixture of β,γ-unsaturated ketone, AlCl₃ and Ts-NH₂ in CH₂Cl₂ at room temperature. This Lewis acid promoted β-substitution reaction mechanism was proposed as that the process occurred via in situ isomerization of β,γ-unsaturated ketone to α,β-unsaturated ketone followed by the 1,4-addition reaction.

Full text of DOI:10.1055/s-2003-42472

LETTER
2359
Synthesis of b-Amino and b-Methoxy Ketones by Lewis Acids Promoted
b-Substitution Reactions of b,g-Unsaturated Ketones
Synthesis of
b
-Am
d
ino and
b
-M
a
ethoxy Keto
m
nes
Shih-Yuan Lee,* Shu-Huei Wang, Yu-Ting Chang, Shu-Fang Chu
Department of Chemistry, Tamkang University, Tamsui, 251, Taiwan
Fax +886(2)26223830; E-mail: adamlee@mail.tku.edu.tw
Received 23 September 2003
tone, which is the synthetic precursor of a,b-unsaturated
ketone.12 Thus, we expected that the preparation of a,b-
unsaturated ketone may be achieved by the isomerization
of b,g-unsaturated ketone under mild acidic reaction con-
Abstract: A reaction mixture of b,g-unsaturated ketone and
BF3·OEt2 in CH3OH was stirred at room temperature and b-meth-
oxy ketone was produced in high yield. The b-amino ketone was ob-
tained as the major product from a reaction mixture of b,g-
unsaturated ketone, AlCl3 and Ts-NH2 in CH2Cl2 at room tempera- dition. A reaction mixture of 1-phenylpent-4-en-2-one
ture. This Lewis acid promoted b-substitution reaction mechanism
was proposed as that the process occurred via in situ isomerization
of b,g-unsaturated ketone to a,b-unsaturated ketone followed by the
1,4-addition reaction.
and Lewis acid (BF3·OEt2) in CH2Cl2 was refluxed for
two hours and only 40% yield of isomerized enone, 1-phe-
nyl-pent-3-en-2-one (I), was obtained (Scheme 1). When
the reaction mixture of 1-phenylpent-4-en-2-one and
BF3·OEt2 was stirred in CH3OH at room temperature for
two hours, 4-methoxy-1-phenylpentan-2-one was pro-
duced as the major product and isomerized enone I as the
minor product. The reaction rate for the formation of b-
alkoxy ketone decreased when the more sterically hin-
dered ethanol was introduced under the reaction condi-
tions. It should be noted that neither b-substitution
reaction nor isomerization reaction occurred in the ab-
sence of Lewis acid and more than 98% of b,g-unsaturated
ketone was recovered even if the reaction mixture was
stirred in MeOH at room temperature for 48 hours. Both
Lewis acid and alcohol are necessary for the formation of
b-alkoxy ketone.
Key words: b,g-unsaturated ketone, b-amino ketone, b-methoxy
ketone, a,b-unsaturated ketone, 1,4-addition reaction
b-Alkoxy and b-amino carbonyl compounds are poten-
tially biologically active molecules and important syn-
thetic intermediates in organic synthesis.1–4 Specific
formation of a new bond on the b-position to the carbonyl
functionality is typically produced by Aldol-type reac-
tion,5,6 organocopper addition reaction7,8 and 1,4-addition
reaction.9,10 Conjugate addition of organometallic reagent
to a,b-unsaturated ketone is the most direct and common-
ly used method for the preparation of b-substituted ke-
tone.11 Recently, our laboratory reported a simple and an
effective method for the synthesis of b,g-unsaturated ke-
The amount of Lewis acid used was investigated and
the results are shown in Scheme 2. The ratio of 0.7 to 1.0
0.2 M
OR
O
O
O
0.5 equiv BF3·OEt2,
+
PhCH2
PhCH2
+
PhCH2
CH3
CH3m
Solvent, r.t.
CH2Cl2, 2 h, reflux
I 40%
Unknowns
I 16%
I 20%
+
+
72% (R=Me)
75% (R=Et)
MeOH, 2 h
EtOH, 22 h
Scheme 1
O
O
O
OCH3
CH3
Lewis acid
+
PhCH2
CH3OH, r.t.
PhCH2
CH3
PhCH2
.
* 0.3 BF3 OEt2, CH3OH, 26 h
2%
+
+
+
+
17% + 59% S.M.
.
* 0.7 BF3 OEt2, CH3OH, 2 h
86%
89%
70%
10%
7%
.
* 1.0 BF3 OEt2, CH3OH, 2 h
.
6%
* 1.5 BF3 OEt2, CH3OH, 2 h
Scheme 2
SYNLETT 2003, No. 15, pp 2359–2363
0
1
.1
2
.2
0
0
3
Advanced online publication: 21.11.2003
DOI: 10.1055/s-2003-42472; Art ID: U20003ST
© Georg Thieme Verlag Stuttgart · New York

2360
A. S.-Y. Lee et al.
LETTER
molar equivalents of Lewis acid to substrate afforded the All b,g-unsaturated ketones were transformed into their
highest yield of b-methoxy ketone. Interestingly, higher corresponding b-methoxy ketones in moderate to high
or lower ratios than this molar range led to a dramatic de- yields and a,b-unsaturated ketones also were generated
crease in the yield of b-methoxy ketone obtained. The under the reaction conditions. The b-methoxy ketones
BF3·OEt2 amount was determined to be in equal molar ra- were obtained in reasonable yields even if relatively acid-
tio to the substrate and it was introduced to provide the b- ic a-protons existed on b,g-unsaturated ketones (Table 1,
substitution reaction conditions. Other Lewis acids such entries 1–4, 7–10). b-Amino carbonyl compounds exhibit
as AlCl3, ZrCl4 and Me3SiOTf also can behave as promot- as an important structure in many natural products and a
ers for the b-substitution reactions of b,g-unsaturated ke- useful synthetic intermediate in organic synthesis.18–23 b-
tones. The experimental results showed that BF3·OEt2 is Amino ketone is typically produced by the addition reac-
the best choice of Lewis acid for the synthesis of b-meth- tion of nucleophilic amine to a,b-unsaturated ketone in
oxy ketone.
the absence of acidic a-protons. According to the results
b,g-unsaturated ketones were transformed into their corre-
sponding b-methoxy ketones by Lewis acid promoted b-
substitution reactions. This new Lewis acid promoted b-
substitution reaction may provide a useful method for the
synthesis of b-amino ketone under mild reaction condi-
tions. Thus, we expected and that the relatively acidic 4-
b-Methoxy of ketones are extensively observed in many
naturally occurring compounds and exhibit a wide range
of biological activities.13–17 A series of b,g-unsaturated
ketones was investigated under the typical reaction con-
ditions and the results are shown in Table 1.
Table 1 Synthesis of b-Methoxy Ketones
Entry
1
Substrate
Product
Time (h)
2
Yield (%)a
76 + 8b
OCH3
CH3m
O
O
nBu
nBu
O
OCH3
CH3m
O
2
3
4
2
1
3
58 + 13b
60
BrCH2CH2CH2
O
BrCH2CH2CH2
OCH3
O
CH3m
CH3m
50 + 12c
O
O
O
OCH3
OCH3
O
5
3
73 + 8b
CH3m
OCH3
CH3m
O
O
6
7
8
1.5
2
80 + 12b
89 + 7b
82 + 8b
MeO
MeO
CH3
OCH3
O
O
O
4
CH3
O
O
OCH3
CH3
9
4
8
77 + 7b
64 + 8b
O
OCH3
OCH3
CH3
S
S
MeO2C
O
O
10
MeO2C
a The yields were determined after chromatographic purification.
b The yield of isomerized enone after chromatographic purification.
c The yield of endo double bond isomer.
Synlett 2003, No. 15, 2359–2363 © Thieme Stuttgart · New York

LETTER
Synthesis of b-Amino and b-Methoxy Ketones
2361
toluenesulfonamide (Ts-NH2, pKa = 16)24,25 may possibly pent-3-en-2-one (I) and BF3·OEt2 in MeOH was stirred at
react as a nuclephile rather than a base under this Lewis room temperature for 2 hours yielding 80% of b-methoxy
acid promoted b-substitution reaction conditions and in- ketone while 9% of the starting material was recovered
vestigated this reaction. A reaction mixture of 1-phenyl- (Scheme 4). The reaction mixture of 1-phenylpent-3-en-
pent-4-en-2-one, BF3·OEt2, and Ts-NH2 in CH2Cl2 was 2-one (I), Ts-NH2 and AlCl3 in CH2Cl2 was stirred at
stirred at room temperature for 20 hours and a very low room temperature for 96 hours and 65% of b-amino ke-
yield (<3%) of the expected product was formed with tone A and 10% b-chloro ketone C were obtained. It is in-
many undetermined side products. The 47% yield of the teresting to note that a higher yield of b-amino ketone or
expected b-amino ketone A and 28% of 1-phenylpent-3- b-methoxy ketone was obtained by reaction with b,g-un-
en-2-one (I) were obtained when the amount of BF3·OEt2 saturated ketone instead of a,b-unsaturated ketone under
was decreased to 0.5 molar equivalents with respect to the this Lewis acid promoted b-substitution reaction condi-
substrate (Scheme 3). Other Lewis acids such as AlCl3, tions. The b-substitution reaction did not occur when the
ZrCl4 and Me3SiOTf were also investigated and AlCl3 carbon-carbon double bond isomerization process of b,g-
proved to be the best choice for b-amination reaction of unsaturated ketone was inhibited. When a reaction mix-
b,g-unsaturated ketone. The yield of b-amino ketone A ture of 1-phenyl-pent-4-en-2-one and BF3·OEt2 in THF
was improved dramatically to 79% when 1.5 equivalents was refluxed for 14 hours only 21% of 1-phenyl-pent-3-
of Ts-NH2 were introduced. It should be noted that the en-2-one (I) and 66% of starting material were obtained.
yield of b-amino ketone decreased when more than 0.5 These results showed that the isomerization rate is much
equivalents of the amine were introduced. The best b-am- faster in MeOH than in THF. Thus, we believed that the
ination reaction conditions were determined to be 0.5 formation of b-substituted ketone proceeded firstly by the
equivalents of AlCl3 and 1.5 equivalents of Ts-NH2 to 1 in situ isomerization of b,g-unsaturated ketone to a,b-un-
equivalent of substrate in CH2Cl2 solvent. Other more ba- saturated ketone followed by the 1,4-addition reaction.
sic amines such as n-Bu-NH2, Ph-NH2, pyrrolidine and
In conclusion, this Lewis acid promoted b-substitution re-
Et2NH were investigated and none of the expected b-ami-
action of b,g-unsaturated ketone provides a simple and
no ketones were produced. Only low yields of a,b-unsat-
highly efficient method for synthesis of b-amino and b-
urated ketone and some unidentified side products were
alkoxy ketones. The C–N and C–O bonds are selectively
obtained under these reaction conditions.
formed on the b-position to the carbonyl group even if
A series of b,g-unsaturated ketones was investigated un- the acidic a-protons exist. The extension of this reaction
der the typical reaction conditions and the results are to differently b-substituted b,g-unsaturated ketones and
shown in Table 2. All b,g-unsaturated ketones were trans- a,b-unsatured ketones using this Lewis acid promoted b-
formed into their corresponding b-amino ketones as the substitution reactions is underway.
major product and b-chloro ketones and a,b-unsaturated
ketones as the minor products. The b-amino ketones were
obtained in moderate to high yields even if relatively acid-
ic a-protons exist on b,g-unsaturated ketones (Table 2, en-
tries 1–4, 7–9).
Typical Procedure for the Synthesis of b-Methoxy Ketone
A reaction mixture of b,g-unsaturated ketone (1.0 mmol) and
BF3·OEt2 (1.0 mmol) in anhyd CH3OH (5 mL) was stirred at r.t. Af-
ter the reaction was completed (monitored by TLC), the organic sol-
vent was removed directly under reduced pressure. Further
purification was achieved by flash chromatography with EtOAc/
hexane as eluant.
The mechanism for Lewis acid promoted formation of b-
amino ketone and b-methoxy ketone from b,g-unsaturated
ketone was investigated. A reaction mixture of 1-phenyl-
O
O
O HNTs
O
Cl
L.A., Ts-NH2
Solvent
+
+
PhCH2
PhCH2
PhCH2
PhCH2
C
A
I
* 1.0 BF3·OEt2, 1.0 Ts-NH2, CH2Cl2, r.t., 20 h
* 0.5 BF3·OEt2, 1.0 Ts-NH2, CH2Cl2, r.t., 96 h
A (<3%) + Unknowns
A (47%) + I (28%)
A (57%) + I (5%) + C (22%)
A (46%) + C (9%)
* 0.5 AlCl3, 1.0 Ts-NH2, CH2Cl2, r.t., 96 h
* 0.5 ZrCl4, 1.0 Ts-NH2,CH2Cl2, r.t., 96 h
* 0.5 Me3SiOTf, 1.0 Ts-NH2, CH2Cl2, r.t., 96 h
A (28%)
* 0.7 AlCl3, 1.0 Ts-NH2, CH2Cl2, r.t., 96 h
* 0.5 AlCl3, 1.5 Ts-NH2, CH2Cl2, r.t., 96 h
* 0.5 AlCl3, 2.0 Ts-NH2, CH2Cl2, r.t., 96 h
* 0.5 ZrCl4, 1.5 Ts-NH2, CH2Cl2, r.t., 96 h
A (55%) + I (6%) + C (14%)
A (79%) + I (4%) + C (12%)
A (60%) + I (3%) + C (16%)
A (57%) + I (4%) + C (8%)
Scheme 3
Synlett 2003, No. 15, 2359–2363 © Thieme Stuttgart · New York

2362
A. S.-Y. Lee et al.
LETTER
Table 2 Synthesis of b-Amino Ketones
Entry
1
Substrate
O
Product
Time (h)
78
Yielda
NHTs
CH3m
O
68% (0%, 4%)b
51% (0%, 17%)b
34% (0%, 20%)b
nBu
nBu
O
NHTs
CH3m
O
2
3
4
61
48
50
BrCH2CH2CH2
O
BrCH2CH2CH2
NHTs
O
CH3m
CH3m
39% (4%, 11%)b
40% (6%, 23%)b
O
O
O
NHTs
NHTs
O
5
50
CH3
NHTs
CH3m
O
O
6
7
8
96
96
96
69% (0%, 7%)b
79% (4%, 12%)b
66% (0%, 14%)b
MeO
MeO
CH3
NHTs
O
O
O
CH3
O
O
NHTs
CH3m
9
50
57% (4%, 19%)b
O
NHTs
S
S
a Yields were determined after chromatographic purification.
b Yields of a,b-unsaturated ketone and b-chloroketone.
O
OCH3
O
1.0 equiv BF3·OEt2,
PhCH2
O
CH3
PhCH2
80% + 9% S.M.
CH3OH, r.t., 2 h
CH3
O
HNTs
CH3
AlCl3, Ts-NH2,
O
Cl
+
PhCH2
CH2Cl2, r.t., 96 h
CH3
PhCH2
PhCH2
CH3
I
A 65%
+ C 10% + (8% S.M.)m
1.0 equiv BF3·OEt2,
O
OCH3
CH3
O
PhCH2
PhCH2
CH3OH, r.t., 48 h
90% recovery of S.M.
Scheme 4
Typical Procedure for the Synthesis of b-Amino Ketone
The reaction mixture of b,g-unsaturated ketone (1.0 mmol), AlCl3
(0.5 mmol) and Ts-NH2 (1.5 mmol) in anhyd CH2Cl2 (5 mL) was
stirred at r.t. After the reaction was completed (monitored by TLC),
the organic solvent was removed directly under reduced pressure.
Further purification was achieved by flash chromatography with
EtOAc/hexane as eluant.
Acknowledgment
We thank the National Science Council in Taiwan (NSC 91-2113-
M-032-004) and Tamkang University for financial support.
Synlett 2003, No. 15, 2359–2363 © Thieme Stuttgart · New York

LETTER
Synthesis of b-Amino and b-Methoxy Ketones
2363
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Synlett 2003, No. 15, 2359–2363 © Thieme Stuttgart · New York