An aza-enolate alkylation strategy for the synthesis of α-alkyl-δ-amino esters and α-alkyl valerolactams

Article abstract of DOI:10.1055/s-2006-939726

Alkylation of the aza-enolate of valerolactim methyl ether with electrophiles affords α-alkyl lactims that may be hydrolysed under mild acidic conditions to afford their corresponding α-alkyl-δ-amino esters as their hydrochloride salts. Neutralisation of these salts with base results in smooth intramolecular cyclisation to afford their corresponding α-alkyl lactams in excellent yield. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-939726

LETTER
1347
An Aza-Enolate Alkylation Strategy for the Synthesis of a-Alkyl-d-amino
Esters and a-Alkyl Valerolactams
Synthesis of
a
i
e
d
-amino
E
s
r
ter
s
and
s
a
-Alkyl
V
alerol
J
actams . M. Taylor,a Steven D. Bull,*a Philip C. Andrewsb
a
Department of Chemistry, University of Bath, Bath, BA2 7AY, UK
Fax +44(1225)386231; E-mail: s.d.bull@bath.ac.uk
b
School of Chemistry, Monash University, P.O. Box 23, Clayton, Melbourne, Vic. 3800, Australia
Received 13 February 2006
N
OMe
N
OMe
R
(i) LDA, THF, –78 °C
(ii) RX, r.t.
Abstract: Alkylation of the aza-enolate of valerolactim methyl
ether with electrophiles affords a-alkyl lactims that may be hydro-
lysed under mild acidic conditions to afford their corresponding
a-alkyl-d-amino esters as their hydrochloride salts. Neutralisation
of these salts with base results in smooth intramolecular cyclisation
to afford their corresponding a-alkyl lactams in excellent yield.
1
2–4
Cl
O
O
R =
'
'
Key words: lactim ether, aza-enolate, alkylation, a-alkyl-d-amino
ester, a-alkyl lactams
2 (56%)
3 (60%)
4 (37%)
Scheme 1 Alkylation of the aza-enolate of valerolactim ether (1)
a-Alkyl-d-amino acid derivatives constitute an important
class of synthetic building blocks for the development of
medicinally active compounds,1 which have also been
employed as monomers for probing the conformation of
derived peptide isosteres.2 This type of d-amino acid may
also be used to prepare a-alkyl lactams that are useful for
the preparation of drug-like molecules.3 As part of studies
directed towards developing asymmetric methodology for
their syntheses, we required access to a series of racemic
a-alkyl-d-amino esters,4 as well as to their corresponding
a-alkyl valerolactams.5 Consequently, we now report on
the development of highly efficient aza-enolate alkylation
methodology that employs valerolactim methyl ether 1 as
a substrate for the preparation of both classes of com-
pound.
Similarly, treatment of valerolactim ether (1) with one
equivalent of n-BuLi in THF at –78 °C for one hour, be-
fore addition of three equivalents of benzyl bromide and
warming to room temperature resulted in recovered start-
ing material 1. We were surprised at the lack of reactivity
of valerolactim ether (1) under these conditions, since n-
BuLi is routinely used to deprotonate Schöllkopf’s bis-
lactim ether 8 in THF at –78 °C to afford a chiral aza-eno-
late 9 that reacts with electrophiles to afford trans-alkylat-
ed bis-lactim ethers 10 in high de.9 It is possible that the
increased reactivity of bis-lactim ether 8 under these
conditions is due to the presence of the lone-pair of elec-
trons of its N1 atom which can coordinate to the lithium
counterion of n-BuLi, thus facilitating kinetic deprotona-
tion at its C6 atom (Scheme 3).
A review of the literature revealed that Trost et al. had re-
ported that lithium aza-enolates of valerolactim ether (1)
could be alkylated with electrophiles to afford a-substi-
tuted lactim ethers 2–4 in moderate 37–60% yields
(Scheme 1).6 Lactim ether bonds are easily hydrolysed
using mild aqueous acid,7 and as a consequence we
reasoned that hydrolysis of a-alkyl lactim ethers 5 would
also afford a route to their corresponding a-alkyl-d-amino
methyl ester hydrochloride salts 6. Subsequent neutralisa-
tion of these hydrochloride salts with base would then
result in intramolecular cyclisation to give their corre-
sponding a-alkyl lactams 7 (Scheme 2).
Therefore, it was concluded that deprotonation of valero-
lactim ether (1) would require more forcing conditions for
aza-enolate formation to occur. However, we were aware
that Smith et al. had reported that treatment of valerolac-
tim ether (1) with alkyllithiums in diethyl ether at –24 °C
had resulted in an alternative reaction pathway involving
Li
N
OMe
base
N
OMe
R
N
OMe
RX
1
5
Initial attempts to employ Trost’s conditions to alkylate
the lithium aza-enolate of valerolactim ether (1)8 with
benzyl bromide proved unsuccessful, affording mainly
recovered starting material 1 with only trace amounts of
the desired a-benzyl valerolactim ether (5a, R = Bn).
aqueous
acid
O
H
N
O
R
ClH3N
OMe
base
R
7
6
SYNLETT 2006, No. 9, pp 1347–1350
Advanced online publication: 22.05.2006
DOI: 10.1055/s-2006-939726; Art ID: D04606ST
© Georg Thieme Verlag Stuttgart · New York
0
1.
0
6.
2
0
0
6
Scheme 2 Strategy for the synthesis of a-alkyl-d-amino esters 6 and
a-alkyl valerolactams 7

1348
P. J. M. Taylor et al.
LETTER
ularly noteworthy. This indicated to us that this class of
aza-enolate was non-basic, and as a consequence we
investigated whether the aza-enolates of a-alkyl lactim
ethers 5 could also be alkylated with electrophiles to af-
ford a,a-dialkyl lactim ethers. It was found that the best
yields obtained in these reactions occurred when the par-
ent a-alkyl valerolactim ether 5 was treated with a mixture
of 1.1 equivalents of t-BuLi and 1.1 equivalents of
KOt-Bu (Schlosser’s base) in THF at –78 °C, followed
by warming to 0 °C for 15 minutes, before recooling to
–78 °C and addition of an electrophile. Therefore, treat-
ment of a-isobutyl valerolactim ether 5g with t-BuLi/
KOt-Bu in THF under these conditions resulted in clean
formation of a,a-diisobutyl lactim ether (13) in 64% yield.
Identical conditions were also employed to prepare a-
methyl-a-benzyl lactim ether (14) via either methylation
of the aza-enolate of a-benzyl valerolactim ether (5a) in
70% yield, or via benzylation of the aza-enolate of a-
methyl valerolactim ether (5b) in 72% yield (Scheme 5).
n-BuLi,
THF, –78 °C
N
OMe
N
OMe
H
6
1
MeO
N
MeO
N
H
8
Li Bu
Li
N
N
OMe
RX
OMe
MeO
N
R
MeO
N
10
9
Scheme 3 Alkylation of the aza-enolate of bis-lactim ether 8
nucleophilic displacement of its methoxy substituent to
afford imines 11 and tertiary amines 12 as alternative
products (Scheme 4).10
We noted that nucleophilic addition of t-BuLi to valero-
lactim ether (1) under these conditions had afforded its
corresponding imine 11 (R = t-Bu) in a low 19% yield.
Therefore, it was decided to screen t-BuLi as a base in
THF to generate the aza-enolate of valerolactim ether (1),
since the use of this sterically demanding base should
minimize formation of any imine/amine by-products
arising from the competing nucleophilic displacement
pathway.
(i) t-BuLi, KOt-Bu,
THF, –78 °C
N
OMe
5g
5a
(ii) 0 °C
(iii) –78 °C, i-BuBr
i-Bu
i-Bu
13
(i) t-BuLi, KOt-Bu,
THF, –78 °C
(i) t-BuLi, KOt-Bu,
THF, –78 °C
N
OMe
Bn
5b
(ii) 0 °C
(iii) –78 °C, MeI
(ii) 0 °C
(iii) –78 °C, BnBr
Me
14
Scheme 5 Synthesis of a,a-dialkyl valerolactim ethers 13 and 14.
RLi, Et2O,
–24 °C
H
N
N
OMe
N
R
R
R
+
A brief investigation applying these mixed base condi-
tions to other lactim ether substrates of different ring sizes
was then carried out.8 Alkylation of the aza-enolate of
seven-membered caprolactim ether (15) with allyl bro-
mide or benzyl bromide successfully afforded a-allyl ca-
prolactim ether (17a) and a-benzyl caprolactim ether
(17b) in 72% and 78% yields, respectively. However, at-
tempts to alkylate the aza-enolate of five-membered buty-
rolactim ether (16) with allyl bromide using these mixed
base conditions were unsuccessful, affording a complex
mixture of products that could not be characterised. Treat-
ment of butyrolactim ether (16) with n-BuLi as an alterna-
tive base under otherwise identical conditions also
afforded a complex mixture of products. However, repeat-
ed chromatographic purification of this mixture enabled
one of the major reaction products to be isolated in 12%
yield which was shown to be 5-(hept-1-en-4-yl)-3,4-dihy-
dro-2H-pyrrole (18, Figure 1). Therefore, it is proposed
that 18 is formed by nucleophilic displacement of the
methoxy substituent of 16 by n-butyl anion to afford an
intermediate imine 19 that is then deprotonated by excess
n-BuLi to afford a lithiated enamine anion that reacts with
allyl bromide. In support of this proposed mechanism it
was found that treatment of butyrolactim ether (16) with
one equivalent of n-BuLi in THF at 0 °C in the absence of
any electrophile resulted in formation of 5-butyl-3,4-di-
hydro-2H-pyrrole (19) in 67% yield (Figure 1).
1
11
12
R = Me, n-Pr, n-Bu, t-Bu or Ph
Scheme 4 Alternative pathway for nucleophilic addition of alkyl-
lithiums to valerolactim ether (1).
After a series of optimisation reactions it was found that
treatment of valerolactim ether (1) with one equivalent of
t-BuLi in THF at –78 °C, followed by warming to 0 °C for
15 minutes, recooling to –78 °C before addition of three
equivalents of benzyl bromide resulted in clean formation
of a-benzyl-valerolactim ether (5a, R = Bn) that was eas-
ily purified by Kugelrohr distillation in vacuo in 87%
yield (Table 1).11 These conditions were then employed to
alkylate the aza-enolate of valerolactim ether (1) with six
further electrophiles to afford a series of a-alkyl valero-
lactim ethers 5b–g in 63–83% yield after purification by
Kugelrohr distillation in vacuo (Table 1).12 It was subse-
quently found that n-BuLi could be used as an alternative
base to t-BuLi in these aza-enolate reactions, affording the
same series of a-alkyl lactims 5a–g in essentially identical
yields.
The good yields obtained for alkylation of the lithium aza-
enolate of valerolactim ether (1) using a sterically hin-
dered electrophile such as isopropyl iodide that could
undergo a competing E2 elimination reaction were partic-
Synlett 2006, No. 9, 1347–1350 © Thieme Stuttgart · New York

LETTER
Synthesis of a-Alkyl-d-amino Esters and a-Alkyl Valerolactams
1349
50:50 biphasic mixture of CHCl3 and 0.1 M HCl(aq) re-
sulted in a series of clean hydrolysis reactions. Simple
removal of solvents in vacuo gave the corresponding a-
alkyl-w-amino esters 6a–g as their hydrochloride salts in
81–97% yields with no further purification steps neces-
sary (Table 1).14
OMe
R
N
N
N
n-Bu
OMe
2
N
n()
3
19
15 n = 3
16 n = 1
17a R = allyl
17b R = Bn
18
Attempts to hydrolyse a,a-diisobutyl valerolactim ether
(13) under these conditions was unsuccessful, instead af-
fording the corresponding a,a-diisobutyl valerolactam
(20) in 93% yield. It is likely that an alternative hydrolysis
mechanism is operating in this case due to the presence of
its sterically hindered quaternary C3 atom preventing nu-
cleophilic attack of water at its C2 atom.15 Therefore, pro-
tonation of the nitrogen atom of 13 is followed by AAl2-
type nucleophilic attack of a chloride nucleophile at its
methoxy substituent, thus resulting in direct formation of
the amide functionality of a,a-diisobutyl valerolactam
(20, Scheme 6).
Figure 1
Therefore, it is clear that the nucleophilic displacement
pathway previously reported by Smith et al. operates
when butyrolactim ether (16) is treated with n-BuLi in
THF. This is in direct contrast to the aza-enolate chemis-
try observed when valerolactim ether (1) or caprolactim
ether (15) are treated with n-BuLi in THF under the same
conditions.13 In considering the mechanism of these reac-
tions, it is proposed that both reaction pathways are initi-
ated by coordination of the lithium counterion of the
alkyllithium to the lone-pair of the nitrogen atom of the
lactim ether. In the case of six- and seven-membered
lactim ethers 1 and 15, lithium aggregates are formed that
contain n-butyl anions with the correct orientation to
deprotonate their acidic C3 protons, thus affording aza-
enolate intermediates. Conversely, treatment of butyro-
lactim ether (15) with n-BuLi results in a lithium aggre-
gate which contains n-butyl anions that are incorrectly
positioned for deprotonation to occur, and as a conse-
quence competing nucleophilic attack of the n-butyl anion
at the C2-sp2 atom occurs to afford imine 19.
H
N
Me
O
H
N
Cl
Cl
O
HCl
13
MeCl
20
Scheme 6 Proposed AAl2-like mechanism for the hydrolysis of a,a-
diisobutylvalerolactim ether (13).
Finally, it was found that neutralisation of the hydro-
chloride salts of a-alkyl-w-amino esters 6a–g with potas-
sium carbonate in a mixture of methanol–water (85:15)
resulted in clean cyclisation to afford their corresponding
a-alkyl valerolactams 7a–g in 88–97% yield, with no
further purification steps necessary (Table 1).16
A range of solvents were then screened to identify condi-
tions that would enable hydrolysis of the lactim ether
bonds of a-alkyl valerolactim ethers 5a–g to afford their
corresponding a-alkyl-w-amino esters 6a–g hydro-
chloride salts in good yield. Therefore, it was found that
rapid stirring of a-alkyl valerolactim ethers 5a–g in a
Table 1 Yields for Formation of a-Alkyl Valerolactim Ethers 5a–g, a-Alkyl-d-amino Esters 6a–g and a-Alkyl Lactams 7a–g12
0.1 M HCl(aq)
CHCl3
O
K2CO3(aq)
MeOH
H
N
N
OMe
N
OMe
R
(i) t-BuLi, THF, –78 °C
O
R
ClH3N
OMe
(ii) 0 °C
(iii) RX
R
1
5a–g
6a–g
7a–g
Entry
R
a-Alkyl valerolac- Yield (%)
tim ethers 5a–ga
a-Alkyl-d-amino Yield (%)
esters 6a–g
a-Alkyl valerolac- Yield (%)
tams 7a–g
1
2
3
4
5
6
7
Bn
5a
5b
5c
5d
5e
5f
87
63
66
78
68
64
83
6a
6b
6c
6d
6e
6f
92
95
90
97
81
91
94
7a
7b
7c
7d
7e
7f
91
94
97
93
91
88
89
Me
Allyl
Propargyl
Et
i-Pr
i-Bu
5g
6g
7g
a Yields are for pure compounds isolated after purification by bulb to bulb distillation in vacuo using a Kugelrohr apparatus.
Synlett 2006, No. 9, 1347–1350 © Thieme Stuttgart · New York

1350
P. J. M. Taylor et al.
LETTER
to 0 °C for 15 min, recooled to –78 °C, an electrophile (3
equiv) added dropwise and the reaction was allowed to warm
to r.t. overnight. The reaction was quenched with H2O (pH
>8), extracted with Et2O (3ꢀ), dried (MgSO4), and
concentrated in vacuo before Kugelrohr distillation in vacuo
to afford a-alkyl lactim ethers 5.
In conclusion, we have shown that alkylation of the lithi-
um aza-enolate of valerolactim methyl ether with electro-
philes affords a-alkyl lactims that may be hydrolysed
under mild acid conditions to afford their corresponding
a-alkyl-d-amino esters as their hydrochloride salts.
Neutralisation of these salts with base affords their free
amines, which undergo smooth intramolecular cyclisation
to afford their corresponding a-alkyl lactams in excellent
yield.
(12) All new compounds were fully characterised. Selected data
for new compounds follows.
3,4,5,6-Tetrahydro-2-methoxy-3-(prop-2-ynyl)pyridine
(5d). 1H NMR (300 MHz, CDCl3): d = 1.39–1.55 (1 H, br m,
H5A), 1.56–1.76 (2 H, br m, H4A and H5B), 1.83–1.88 (1 H,
m, H4B), 1.92 (1 H, t, J = 2.6 Hz, C≡CH), 2.34 (2 H, m,
CHAHBC≡CH and H3), 2.52 (1 H, app ddd, J = 12.6 Hz, 7.4
Hz, 2.6 Hz, CHAHBC≡CH), 3.36–3.45 (2 H, m, 2 ꢀ H6),
3.54, (3 H, s, OMe). 13C NMR (100 MHz, CDCl3): d = 21.7,
22.0, 26.2, 35.9, 47.4, 52.5, 70.2, 82.1, 163.2. HRMS (EI):
m/z calcd [MH]+: 152.1070; found: 152.1070.
Methyl 5-Amino-2-methylpentanoate Hydrochloride
(6b): 1H NMR (300 MHz, CD3OD): d = 1.07 (3 H, d, J = 7.0
Hz, CHCH3), 1.30–1.68 (4 H, br m, 2 ꢀ CH2), 2.41 (1 H, app
hept, J = 7.0 Hz, CHCH3), 2.80 (2 H, t, J = 6.8 Hz, CH2NH2),
3.56 (3 H, s, OCH3). 13C NMR (100 MHz, CD3OD):
d = 17.9, 26.7, 31.8, 40.5, 41.0, 52.6, 178.6. HRMS (EI):
m/z calcd [MH]+: 146.1176; found: 146.1172.
Acknowledgment
We thank the EPSRC (PJMT), Royal Society (SDB) and CELL-
TECH (CASE award to PJMT) for funding, the Royal Society of
Chemistry for an International Travel Award (PCA) and the Mass
Spectrometry Service at Swansea, University of Wales for their
assistance.
References and Notes
(1) (a) Li, Z.-H.; Bulychev, A.; Kotra, L. P.; Massova, I.;
Mobashery, S. J. Am. Chem. Soc. 1998, 120, 13003.
(b) Seebach, D.; Schaeffer, L.; Brenner, M.; Hoyer, D.
Angew. Chem. Int. Ed. 2003, 42, 776.
(2) Langenhan, J. M.; Gellman, S. H. J. Org. Chem. 2003, 68,
6440.
(3) (a) Meissner, R. S.; Perkins, J. J.; Duong, L. T.; Hartman, G.
D.; Hoffman, W. F.; Huff, J. R.; Ihle, N. C.; Leu, C.-T.;
Nagy, R. M.; Naylor-Olsen, A.; Rodan, G. A.; Rodan, S. B.;
Whitman, D. B.; Wesolowski, G. A.; Duggan, M. E. Bioorg.
Med. Chem. Lett. 2002, 12, 25. (b) Ting, P. C.; Lee, J. F.;
Anthes, J. C.; Shih, N.-Y. Bioorg. Med. Chem. Lett. 2001,
11, 491.
(4) (a) Orwig, K. S.; Dix, A. T. Tetrahedron Lett. 2005, 46,
7007. (b) Appleby, I.; Boulton, L. T.; Cobley, C. J.; Hill, C.;
Hughes, M. L.; De Koning, P. D.; Lennon, I. C.; Praquin, C.;
Ramsden, J. A.; Samuel, H. J.; Willis, N. Org. Lett. 2005, 7,
1931.
(5) (a) Yue, T.-Y.; Nugent, W. A. J. Am. Chem. Soc. 2002, 124,
13692. (b) Suh, Y.-G.; Kim, S.-A.; Jung, J.-K.; Shin, D.-Y.;
Min, K.-H.; Koo, B.-A.; Kim, H.-S. Angew. Chem. Int. Ed.
1999, 38, 3545. (c) Enders, D.; Groebner, R.; Raabe, G.;
Runsink, J. Synthesis 1996, 941.
(6) Trost, B. M.; Kunz, R. A. J. Org. Chem. 1974, 39, 2475.
(7) Menezes, R.; Smith, M. B. Synth. Commun. 1988, 18, 1625.
(8) Lactim ethers 1, 15 and 16 were prepared using a protocol
previously employed to prepare bis-lactim ether 8, see: Bull,
S. D.; Davies, S. G.; Moss, W. O. Tetrahedron: Asymmetry
1998, 9, 321.
3-Benzylpiperidin-2-one (7a): 1H NMR (300 MHz,
CDCl3): d = 1.32–1.46 (1 H, br m, H4A), 1.51–1.81 (3 H, br
m, H4B and 2 ꢀ H5), 2.48 (1 H, tdd, J = 10.0, 5.5, 3.8 Hz, H3),
2.61 (1 H, dd, J = 13.4, 10.0 Hz, CHAHBPh), 3.17–3.25 (2 H,
m, 2 ꢀ H6), 3.34 (1 H, dd, J = 13.4, 3.6 Hz, CHAHBPh), 5.76
(1 H, br s, NH), 7.10–7.27 (5 H, br m, Ar-H). 13C NMR (100
MHz, CDCl3): d = 18.5, 22.1, 30.3, 37.5, 48.8, 127.9, 130.0,
130.8, 141.3, 179.3. HRMS (EI): m/z calcd [MH]+:
190.1229; found: 190.1226.
(13) Numerous attempts to alkylate the aza-enolate of eight-
membered enantholactim methyl ether using a range of
bases and conditions with benzyl bromide as an electrophile
were unsuccessful, returning unreacted starting material in
good yield.
(14) Representative Experimental Procedure.
An a-alkyl lactim ether 5 (0.125 mmol) was dissolved in
CHCl3 (1.5 mL) and then 0.1 M aq HCl (1.5 mL) added. The
resultant biphasic solution was stirred rapidly overnight,
before solvents were removed in vacuo to afford a d-amino-
a-alkyl methyl ester hydrochloride salt 6.
(15) An alternative mechanism involving hydrolysis of 13 to its
corresponding a,a-dialkyl-w-amino ester hydrochloride,
followed by in situ ring closure to afford 20 was discounted
because a,a-dialkyl-w-amino ester hydrochloride salts are
known to be stable under acidic conditions, see: Maligres, P.
E.; Chartrain, M. M.; Upadhyay, V.; Cohen, D.; Reamer, R.
A.; Askin, D.; Volante, R. P.; Reider, P. J. J. Org. Chem.
1998, 63, 9548.
(16) Representative Experimental Procedure.
A d-amino-a-alkyl methyl ester hydrochloride salt 6 (0.018
mmol) was dissolved in MeOH (0.6 mL) and then added to
a solution of K2CO3(aq) (0.2 mL) before stirring for 24 h. The
resulting solution was neutralised to pH 7.0, extracted with
EtOAc, dried (MgSO4) and the solvent was removed in
vacuo to afford the desired a-alkyl lactam 7.
(9) Schöllkopf, U.; Hartwig, W.; Pospischil, K. H.; Kehne, H.
Synthesis 1981, 966.
(10) Zezza, C. A.; Smith, M. B.; Ross, B. A.; Arhin, A.; Cronin,
P. L. E. J. Org. Chem. 1984, 49, 4397.
(11) Representative Experimental Procedure.
A solution of t-BuLi in hexane (1.1 equiv) was added to a
stirred solution of lactim ether 1 (1 equiv, 2.0 mmol) in THF
(10 mL) at –78 °C under nitrogen. The reaction was warmed
Synlett 2006, No. 9, 1347–1350 © Thieme Stuttgart · New York