N-alkylation and [2,3]-sigmatropic rearrangement of N-allyl α-amino esters

Article abstract of DOI:10.1039/a705550a

N-Alkylation of N-allyl α-amino esters and [2,3]-Stevens rearrangement occur in one pot on warming in the solvent DMF, with the bases K₂CO₃ and DBU; this in situ formation of the quaternary ammonium salts and rearrange-ment of the su

Full text of DOI:10.1039/a705550a

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N-Alkylation and [2,3]-sigmatropic rearrangement of N-allyl
á-amino esters
Iain Coldham,*,a Mark L. Middletona and Philip L. Taylorb
a Department of Chemistry, University of Exeter, Stocker Road, Exeter, UK EX4 4QD
b ICI Paints, Wexham Road, Slough, Berkshire, UK SL2 5DS
H
NMe2
CO2Me
N-Alkylation of N-allyl á-amino esters and [2,3]-Stevens
rearrangement occur in one pot on warming in the solvent
DMF, with the bases K2CO3 and DBU; this in situ form-
ation of the quaternary ammonium salts and rearrange-
ment of the subsequent ylides gives N,N-dialkylated allyl
glycine derivatives.
2.2 equiv. MeI
R
N
CO2Me
R
1
2
Me Me
N
CO2Me
I–
+
As part of
a project investigating the [2,3]-aza-Wittig
rearrangement,1,2 we have discovered a simple and convenient
method for effecting the [2,3]-Stevens rearrangement. The [2,3]-
Stevens rearrangement of ammonium ylides (Scheme 1) is a
3
R′
R′′
R′
N
R′′X
R
N
CO2Me
CO2Me
DMF, K2CO3
DBU, 40 °C
NR2
R2 R2
2
R
R1
N
R3
4
5
R3
+
–
R1
NMe2
CO2Me
H
N
MeI
Scheme 1
CO2Me
CO2Me
DMF, K2CO3
DBU, 40 °C
useful carbon᎐carbon bond forming reaction in synthesis.3 The
rearrangement allows the formation of homoallylic amines
including ring-expanded or ring-contracted amines. The
ammonium ylides are commonly prepared by N-alkylation, fol-
lowed by isolation of the salt and its treatment with a strong
base (or fluoride ion desilylation).4 An alternative approach to
ylide formation using amine insertion into a carbene is cur-
rently proving popular.5 Despite the simplicity of the former
method, it suffers from the difficulties associated with the isol-
ation of the quaternary ammonium salt and the use of a strong
base (often KOBut or NaOH). We report in this communication
that these drawbacks can be avoided using a one pot alkylation–
rearrangement procedure.
50%
H
N
NMe2
CO2Me
MeI
DMF, K2
CO
DBU, 40 °C3
6
44% 88:12
Me2N
CO2Me
H
N
CO2Me
MeI
DMF, K2CO3
DBU, 40 °C
In an attempt to mono-methylate the secondary amine 1,
R = Me with methyl iodide in MeCN, K2CO3, the [2,3]-Stevens
rearrangement product 2, R = Me and the ammonium salt 3
were isolated (Scheme 2). The ammonium salt 3 could be con-
verted to the amine 2, R = Me under standard conditions for
the [2,3]-Stevens rearrangement (KOBut, THF, 40%). However,
we were intrigued by the possibility that both the N-alkylation
and the rearrangement could be carried out in one pot. On
changing the solvent for N-alkylation from MeCN to DMF, the
yield of the rearranged product 2, R = Me increased signifi-
cantly (Table 1, entry 2). Further improvement was obtained on
addition of the base 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)
and warming the mixture to 40 ЊC for 24 h. These conditions
avoid isolation of the quaternary ammonium salt and allow the
use of the simple N-allylated glycine methyl esters for the prep-
aration of C-allyl glycine derivatives (Table 1, entries 4–6).
N-Alkylation and [2,3]-sigmatropic rearrangement can be
carried out on secondary amines, such as 1, and tertiary amines,
such as 4. Yields of the [2,3]-Stevens products are normally in
the range 50–65% (Table 2). A mixture (inseparable by column
chromatography) of diastereomers is formed using amines 4,
R ≠ H. Although it was possible to prepare the N-benzyl-N-
methyl derivatives 5 (e.g. RЈ = Me, RЉ = Bn), attempted diben-
zylation and rearrangement of amine 1, R = Me (with excess
35% 50:50
Scheme 2
Table 1 [2,3]-Stevens rearrangement of secondary amines 1
Entry
R
Conditions
Yield 2 (%)
Ratio
1
2
3
4
5
6
Me
Me
Me
Me
H
MeCN, K2CO3, room temp.
DMF, K2CO3, room temp.
DMF, K2CO3, 40 ЊC
DMF, K2CO3, DBU, 40 ЊC
DMF, K2CO3, DBU, 40 ЊC
DMF, K2CO3, DBU, 40 ЊC
10
45
48
58
50
62
60:40
60:40
60:40
60:40
—
Ph
50:50
PhCH2Br) led only to the mono-benzylated amine 4, R = Me,
RЈ = Bn.
The combined N-alkylation-[2,3]-Stevens rearrangement
can be carried out successfully on a range of allylic amines, as
illustrated in Scheme 2. Diastereoselectivities were improved (to
88:12) using the cyclohexenylamine 6. We were disappointed,
however, that attempts to rearrange the amine 7, containing a
(Z)-alkene, were unsuccessful. Treatment of the amine 8,
derived from alanine or phenylglycine methyl ester, with methyl
J. Chem. Soc., Perkin Trans. 1, 1997
2951

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νmax(neat)/cmϪ1 1730 (C᎐O) and 1645 (C᎐C); δ (400 MHz,
Table 2 [2,3]-Stevens rearrangement of tertiary amines 4
᎐
᎐
H
CDCl3) 0.96 (3H, d, J 7, Mea), 1.05 (3H, d, J 7, Meb), 2.30 (12H,
Entry
R
RЈ
RЉX
Yield 5(%)
Ratio
a
b
s, NMe2 and NMe2 ), 2.50–2.69 (2H, m, CHaCH3 and
CHbCH3), 2.89 (1H, d, J 10, CHCO2Mea), 2.97 (1H, d, J 10,
CHCO2Meb), 3.64 (3H, s, CO2Mea), 3.70 (3H, s, CO2Meb),
1
2
3
4
5
6
H
Me
H
Me
H
Me
Me
Me
Me
Me
CH2Ph
CH2Ph
MeI
MeI
PhCH2Br
PhCH2Br
MeI
48
53
52
65
51
63
—
60:40
—
60:40
—
60:40
a
b
4.90–5.12 (4H, m, CH᎐CH and CH᎐CH ), 5.66 (1H, ddd,
᎐
᎐
2
2
a
J 17, 10 and 7, CH᎐CH ), 5.78 (1H, ddd, J 17, 10 and 7,
CH᎐CH ); δ (100 MHz, CDCl ) 16.92, 17.57, 37.42, 37.70,
᎐
2
b
᎐
2
C
3
MeI
41.12, 41.48, 50.41, 50.65, 72.52, 72.72, 114.36, 115.50, 140.21,
140.95, 171.40, 171.47 (Found Mϩ 171.1260. C9H17NO2
requires M, 171.1259); m/z 171 (Mϩ, 2.3%), 116 (M Ϫ C4H7,
25), 112 (M Ϫ CO2Me, 20), 57 (100).
H
N
CO2Me
Acknowledgements
7
We thank the EPSRC and ICI Paints for a Studentship
(M. L. M.) through the industrial CASE scheme.
H
N
NMe2
MeI
CO2Me
CO2Me
References
DMF, K2CO3
DBU, 80 °C
R
R
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9
8
R = Me 42%
R = Ph 47%
2 For other examples of the aza-Wittig rearrangement, see Y. Murata
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NMe2
CO2Me
10
iodide, under the conditions described above, gave the quater-
nary ammonium salt, but none of the amino ester 9. Increasing
the temperature of the reaction to 80 ЊC, however, resulted in
the formation of the desired α,α-disubstituted amino ester 9
(42–47%).
Hydrogenation of allyl glycine 2, R = Me gives the diastere-
omeric N,N-dimethyl isoleucine methyl esters 10, which were
compared with an authentic sample of anti-10, prepared from
-isoleucine. This confirmed that the major isomer from
rearrangement of the amine (E)-1, R = Me, has the anti stereo-
chemistry, which is in line with expectations, based on related
[2,3]-Stevens rearrangements.3
Experimental
N-Alkylation and rearrangement of the amine 1, R ؍ Me
Methyl iodide (0.1 cm3, 1.4 mmol) was added to the amine 1,
R = Me (100 mg, 0.7 mmol) and K2CO3 (0.19 g, 1.4 mmol) in
dry DMF (0.5 cm3) under argon. After 20 min, the mixture was
warmed to 40 ЊC and DBU (0.23 cm3, 1.4 mmol) was added.
After 24 h, the mixture was poured into saturated NaHCO3 (5
cm3) and extracted with CHCl3 (3 × 5 cm3). The organic layer
was washed with brine (2 × 5 cm3), dried (Na2SO4) and purified
by column chromatography on silica gel, eluting with light pet-
roleum (bp 40–60 ЊC)–EtOAc (5:1) to give the amine 2, R = Me
(69 mg, 58%), as a mixture of diastereomers a and b (60:40);
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Tetrahedron Lett., 1996, 37, 2165.
Paper 7/05550A
Received 31st July 1997
Accepted 20th August 1997
2952
J. Chem. Soc., Perkin Trans. 1, 1997