The regioselective α-alkylation of the benzophenone imine of glycinamide, alaninamide, and related derivatives

Article abstract of DOI:10.1139/V06-088

The benzophenone imine of glycinamide was alkylated using ion pair extraction (RX, 10% aq. NaOH, Bu₄NHSO₄ (1 equiv.), CH ₂Cl₂, rt) to give the α-monosubstituted products, which were then alkylated a second time

Full text of DOI:10.1139/V06-088

1301
The regioselective ␣-alkylation of the
benzophenone imine of glycinamide, alaninamide,
and related derivatives1
Martin J. O’Donnell, Jeremy D. Keeton, Vien Van Khau, and John C. Bollinger
Abstract: The benzophenone imine of glycinamide was alkylated using ion pair extraction (RX, 10% aq. NaOH,
Bu4NHSO4 (1 equiv.), CH2Cl2, rt) to give the α-monosubstituted products, which were then alkylated a second time
using stronger basic conditions (KO-t-Bu, THF, 0 °C, RX). Crystal structures of the Schiff bases of glycinamide, an α-
monosubstituted and an α,α-disubstituted product were reported.
Key words: benzophenone imines, Schiff bases, alkylation, ion pair extraction (IPE), phase-transfer catalysis (PTC),
anhydrous base, X-ray crystal structures.
Résumé : L’alkylation de la benzophénone imine du glycinamide par extraction par paire d’ions (RX, NaOH aqueux à
10%, Bu4HSO4 (1 équiv.), CH2Cl2, température ambiante) conduit à des produits α-monosubstitués qui sont alkylés une
deuxième fois dans des conditions plus basiques (KO-t-Bu, THF, 0 °C, RX). Les structures cristallines des bases de
Schiff du glycinamide, d’un produit α-monosubstitué et d’un produit α,α-disubstitué ont été déterminées.
Mots clés : imines de la benzophénone, bases de Schiff, alkylation, extraction par paire d’ions (EPI), catalyse par
transfert de phase (CTP), base anhydre, structures cristallines par diffraction des rayons X.
[Traduit par la Rédaction] O’Donnell et al. 1312
Introduction
amino acid ester (11)) and on-resin (1, R = Merrifield,
Wang, Rink, or Weinreb resin (l2)) monoalkylation of a ben-
zophenone-protected glycine residue in a peptide without ei-
ther N-alkylation or alkylation of a C-terminal glycine or
higher amino acid residue. Additionally, the on-resin
enantioselective syntheses of α-alkyl amino acids have been
achieved by both alkylation and Michael addition reactions
(13).
While monoalkylations of the aldimines of glycine esters
(ArCH=NCH2CO2R, 4a, Ar = 4-ClC6H4, R = Et; pKa
(DMSO) 18.8 (19) (refs. 2 and 3)) are possible (14), the sim-
ilar acidities of the unsubstituted (e.g., 4a) and monosub-
stituted (e.g., 5a) derivatives (2) can lead to overalkylation
and (or) racemization of products 5 by deprotonation–
reprotonation. In contrast, PTC alkylation of the aldimine of
a monoalkyl amino ester is generally the method of choice
to prepare α,α-dialkylated amino acid derivatives (Scheme 2)
(15). Similarly, the aldimine activating group has been used
for preparation of α-phenyl-α-alkyl amino acid derivatives
by phenylation of the α-alkyl derivatives (16) and the
regioselective solution (11) and on-resin (17) N-terminal α-
carbon alkylation of peptides containing an N-terminal non-
The development of new methods for the synthesis of un-
natural α-amino acids has been the focus of our research for
many years. The first general synthesis of α-amino acids by
phase-transfer catalysis (PTC) was reported in 1978 (1). On
treatment with base, the benzophenone imines of glycine
alkyl esters (1) function as glycine anion equivalents for re-
action with electrophiles to yield higher amino acid deriva-
tives 2 (Scheme 1, pKa experimental (calculated), refs. 2 and
3)) (4). A key tenet in this chemistry is the ability to achieve
selective monoalkylation of 1 to give 2 under mild (“nor-
mal”) PTC conditions, although a second alkylation to form
3 can be accomplished using stronger basic conditions (5).
The possibility of stopping the reaction at the monoalkyl-
ation stage is attributed to A1,3 strain in products 2 (6). The
lower acidity of the monoalkylation product 2 compared
with starting material 1 (2) has also been applied for the se-
lective monophenylation of 1 (7), in the catalytic enantio-
selective alkylation for the synthesis of monoalkyl products
without concomitant racemization under basic PTC condi-
tions (8–10), and in the regioselective solution (1, OR =
Received 6 February 2006. Accepted 31 March 2006. Published on the NRC Research Press Web site at http://canjchem.nrc.ca on
1 August 2006.
Dedicated to Dr. Alfred Bader for his contributions to humanity.
M.J. O’Donnell,2 J.D. Keeton, and V. Van Khau. Department of Chemistry and Chemical Biology, Indiana University – Purdue
University Indianapolis, 402 N. Blackford St., Indianapolis, IN 46202-3274, USA.
J.C. Bollinger. Department of Chemistry, Indiana University, Bloomington, IN 47405-4001, USA.
1This article is part of a Special Issue dedicated to Dr. Alfred Bader.
2Corresponding author (e-mail: odonnell@chem.iupui.edu).
Can. J. Chem. 84: 1301–1312 (2006)
doi:10.1139/V06-088
© 2006 NRC Canada

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Can. J. Chem. Vol. 84, 2006
Scheme 1. Selective monoalkylation of benzophenone imine glycinates.
O
O
R1X
R2X
PTC
Ph
N
Ph
N
Ph R1
2
No dialkylation
in " normal" PTC
OR
OR
PTC
Ph
1
[1a, R = Et;
pKa (DMSO) 18.7 (19)]
[2a, R1=Me, R = Et;
pKa (DMSO) 22.8 (21)]
O
R2X
Ph
N
OR
Stronger
Basic
Conditions
R1 R2
Ph
3
Scheme 2. Alkylation of a higher amino acid derivative by PTC.
glycine residue. A limitation of this methodology for the
preparation of α,α-dialkyl amino acids from their glycine
counterparts is the need to change activating groups from
ketimine (Ph2C=N-) (Scheme 1, 1 to 2) to aldimine
(ArCH=N-) (Scheme 2). As noted earlier (5), stronger base
may be used to prepare the α,α-dialkylated products
(Scheme 1, 2 to 3). Additionally, on-resin tandem alkyla-
tions of benzophenone imine protected glycinates have been
achieved by initial alkylation under PTC-like conditions fol-
lowed by introduction of a second group at the α-carbon us-
ing stronger base (18).
O
O
R2X
Ar
N
Ar
N
OR
OR
PTC
R1 R2
H
R1
H
5
[5a, Ar=4-ClC6H4, R1=Me, R=Et;
pKa (DMSO) 19.2 (21)]
6
Fig. 1. Calculated acidities (pKa in DMSO) using CAMEO for
The successful alkylation chemistry of the Schiff bases of
glycine alkyl esters (1) and higher amino acid esters (5)
prompted us to extend this methodology to the selective
α-carbon alkylations of amino amides as a route to α-
substituted and α,α-disubstituted amides (19). Reports of the
enantioselective synthesis of monosubstituted amino amides
by PTC have recently appeared (20).
the benzophenone imines of glycinamide and alaninamide.
O
O
24
26
Ph2C
N
Ph2C N
NH2
25
NH2
25
Me
10
11a
Enzymatic resolution of racemic α-substituted and α,α-
disubstituted amino acid amides has been developed by the
DSM group (21) for preparing these important compounds
and their associated α-amino acids in optically pure form
from the racemic or optically enriched products. One syn-
thetic route involves alkylation of 1b, hydrolysis of the
monoalkylated benzophenone imine of glycine methyl ester
(2, R = Me, R1 = alkyl), and conversion to the amide by
treatment with ammonia (21g). A route to the α,α-
disubstituted derivatives involved preparation of the aldimine
of a monosubstituted amino acid amide (7) followed by
alkylation under PTC conditions to give 8 (Scheme 3) (21c).
A more efficient route to the α,α-disubstituted derivatives
of amino acid amides would be to start with the benzophe-
none imine of glycinamide (10) (prepared from benzophe-
none imine (9) and glycinamide), carry out a selective
monoalkylation to (11), and then, without changing the
imine-protecting group, do a second alkylation to give 12. In
this paper we report the successful accomplishment of this
goal (Scheme 4).
O
O
24
26
PhCH
N
PhCH N
NH2
25
NH2
25
Me
13
7a
The predicted acidities of the α-protons in glycinamide
imines (10 or 13, α-CH pKa = 24) are only an order of mag-
nitude greater than the acidities of the NH protons on the
unsubstituted amides (10 or 13, NH pKa = 25). This small
effect is certainly not, by itself, sufficient to predict selective
α-monoalkylation over N-alkylation. Additionally, as in the
amino acid ester cases (2a), both the benzophenone imines
and aldimines were predicted to have the same acidities and
the monoalkyl derivatives were both predicted to be 102 less
acidic than their glycinamide counterparts. As in the ester
cases, the potential major acid-weakening effect in the ben-
zophenone imine of alaninamide (11a) was not predicted. If
this effect were taken into account, one would predict that
the α-proton in 11a would be even less acidic (higher pKa)
than those in 10. Thus, it would be expected that the second
alkylation of 10 would occur at nitrogen rather than at the α-
carbon. Even though these qualitative theoretical predictions
do not bode well for achieving the desired selective mono-
and di-alkylations in the amino acid amide imines, we pro-
ceeded with experimental studies of these alkylation reac-
tions.
Results and discussion
Prediction of the acidities of the benzophenone imines
of glycinamide and their monoalkylated derivatives
Although the experimental acidities of the imines of
glycinamide and their monoalkyl derivatives are not avail-
able, it was possible to use CAMEO to obtain qualitative
theoretical acidities (DMSO) of these compounds (Fig. 1).3
3 Previous alkylation and Michael addition studies of three active methylene derivatives (cyanoacetamide, acetoacetamide, and malonamide)
containing an unsubstituted amide and the predicted pKas (DMSO) of these compounds are summarized in the Supplementary material.
© 2006 NRC Canada

O’Donnell et al.
1303
Scheme 3. DSM route to α-alkyl amino amides and α,α-dialkyl amino amides.
O
O
O
1) R1X
R2X
Ph2C
N
PhCH
N
PhCH N
OMe
NH2
NH2
PTC
PTC
2) H3O+
3) NH3
4) PhCHO
R1 R2
R1
1b (R =Me)
8
7
Scheme 4. Selective mono- and di-alkylation of the benzophenone imine of glycinamide.
O
O
O
R1X
R2X
Ph2C
N
Ph2C N
Ph2C
N
NH2
NH2
NH2
Base
Base
R1 R2
R1
10
11
12
Scheme 5. Synthesis of the Schiff base of glycinamide (10) and
alaninamide (11a) by transimination.
Scheme 6. Alkylation of the benzophenone imine of glycinamide
(10) by ion pair extraction to form the α-monosubstituted deriva-
tives 11.
O
O
9
Ph2C NH ( )
O
H2N
Ph2C
N
O
R1X
NH2
NH2
Ph2C
N
Ph2C
N
•HCl
R1
R1
10% Aq. NaOH
Bu4NHSO4
CH2Cl2
NH2
NH2
R1
14
15
10 (R1= H) (70%, X-ray)
11a (R1=Me) (96%)
(R1=H)
(R1=Me)
rt, Overnight
10
11
O
O
Preparation and monoalkylation of the benzophenone
imine of glycinamide
Ph2C
N
Ph2C
N
NH2
NH2
The benzophenone imine of glycinamide (10) (22, 23)
was prepared from glycinamide hydrochloride 14 and benzo-
phenone imine by transimination following a protocol simi-
lar to that developed for preparation of the related imines of
glycine and monoalkyl amino acid esters (Scheme 5) (24).
Since glycinamide hydrochloride is relatively insoluble in
dichloromethane, the reaction was refluxed overnight in 1,2-
dichloroethane with triethylamine (1 equiv.). Removal of
solvent followed by recrystallization gave 10 (70%) as white
crystals. An X-ray crystal structure, which will be discussed
later, was obtained for 10.
Me
11a (84%)
11b
(75%)
(X-ray)
O
O
Ph2C
N
Ph2C
N
NH2
NH2
Et
Alkylations of the Schiff base of glycinamide 10 were ac-
complished by ion pair extraction (IPE) using representative
active (methyl, allyl, or benzyl) or less active (ethyl) halides,
10% aq. NaOH, and tetrabutylammonium hydrogen sulfate
(TBAH, 1.2 equiv.) in dichloromethane at room temperature
overnight (Scheme 6) (1a, 25). After work-up, the crude
products were purified by column chromatography (silica
gel was prewashed with 1% triethylamine because of the
acid lability of the imine). Notably, under these mild
alkylation conditions, the Cα-monoalkylated products (11a–
11d) were obtained in good yield (72%–84%). An X-ray
crystal structure, to be discussed later, was obtained of the α-
monoalkylated product 11b.
Cl
11d
(73%)
11c (72%)
reaction conditions (Scheme 7). In addition to the desired C-
monoalkylated product 12a, four other alkylation products
are possible in this reaction (16–19) (Fig. 2). The calculated
pKa values (CAMEO) of the α-CH and NH protons in these
products are given for reference (see Fig. 1 for predicted pKa
values of 10 and 11a).
The reactions were conveniently monitored by TLC
(Fig. 3). The optimized TLC system provides for separation
of the starting material (11a), the desired C-allylated target
(12a), the N-allylated product (16), the two possible
diallylated derivatives (17 and 18), and the triallylated com-
pound (19), as well as the hydrolysis product, benzophe-
none. Identities of the various spots were determined using
Alternatively, 11a was prepared in 96% yield by transi-
mination of alaninamide hydrochloride with benzophenone
imine (DMF, rt, overnight).
1
mass spectral analysis and H NMR.
Model study — Allylation of the benzophenone imine
of alaninamide
A model alkylation study for the proposed regioselective
Cα-alkylation of the Schiff base of alaninamide (11a) to pre-
pare the α,α-dialkylated product was conducted using allyl
bromide as the alkylating agent with a variety of bases and
Allylation of Schiff base 11a was studied using a variety
of bases and reaction conditions (Table 1). The alkylation
was first conducted using IPE conditions, however no reac-
tion was observed (Table 1, entry 1) (1a, 25). IPE conditions
using 50% aq. NaOH gave only trace amounts of desired
© 2006 NRC Canada

1304
Can. J. Chem. Vol. 84, 2006
Scheme 7. Model study for regioselective α-C alkylation of the
Schiff base of alaninamide (11a).
Fig. 3. TLC data for products from the allylation of the Schiff
base of alaninamide (11a).
O
O
Br
Ph2C
N
Ph2C
N
NH2
NH2
Base
Me
Me
11a
Solvent
Ph2C O
O
Ph2C N
Temp., Time
12a
NR2
R
O
Me
19
0.75
0.50
0.25
Ph2C N
Me
Fig. 2. Possible products from the alkylation of the Schiff base
of alaninamide (11a) with allyl bromide.
NHR
R
O
17
O
O
O
Ph2C N
Ph2C N
NHR
16
25
NH2
26
24
NH
24
Ph2C
N
Ph2C
N
Ph2C
N
Me
O
NH
Me
Me
Me
NR
2
Me
18
12a
16
17
O
Ph2C N
12a
NH2
Me
R
O
O
O
26
Ph2C
N
Ph2C
N
Ph2C N
N
N
NH2
Me
Me
Me
11a
18
19
product (12a) (Table 1, entry 2). Next, alkylation was per-
formed under nonaqueous conditions using the Schwesinger
base BTPP (tert-butylimino-tri(pyrrolidino)phosphorane,
0.9 equiv.) to again give only trace amounts of product.
BTPP is a relatively strong, organic soluble, nonionic base
used successfully for the α-alkylation of resin-bound Schiff
base derivatives of amino acids and peptides (26). From
these first experiments, it was apparent that stronger condi-
tions were needed to effect α-alkylation. Thus, alkylation
was next attempted using sodium ethoxide (in EtOH) in the
presence of catalytic TBAB in anhydrous acetonitrile
(Table 1, entry 4) (5). In this case, no reaction was observed
because of the insolubility of 11a in acetonitrile. In a second
set of reactions using the same reagents, the EtOH was first
removed from NaOEt and then acetonitrile was added, but
again the reaction was unsuccessful because of the insolubil-
ity of the starting Schiff base (Table 1, entry 4). LDA in
anhydr. THF gave only trace amounts of product (Table 1,
entry 5). The same conditions were applied using LiHMDS,
but again only trace amounts of desired product were ob-
served (Table 1, entry 6) (27). With KHMDS, the target α-
monoalkylated product (12a) was obtained in 24% yield
(Table 1, entry 7). The final and most effective base used
was KO-t-Bu (Table 1, entries 8–10) (27). When the reac-
tion was carried out at ambient temperature or –78 °C, 42%–
46% and 34%–48% yields, respectively, of 12a were ob-
tained (Table 1, entries 8 and 9). Optimal conditions were
obtained using Schiff base 11a (1 equiv.), KO-t-Bu
(1.2 equiv.), and allyl bromide (1.2 equiv.) in THF at 0 °C
for 3 h to give product 12a in 55%–61% yield (Table 1, en-
try 10). The addition of LiCl (5 equiv.), which has often
proven to be an effective additive in alkylation and other an-
ionic reactions (28), using the KO-t-Bu conditions at rt,
R= -CH2CH=CH2
Flash chromatography:
Hexanes/EtOAc/Et3N
75:25:1
0 °C, or –78 °C gave only trace amounts of product as did
other solvents (DMF or tert-butyl alcohol) with KO-t-Bu
(TLC, LC–MS, and H NMR).
1
The reaction conditions were studied further by using
0.9 equiv. of both allyl bromide and KO-t-Bu to understand
which of the various possible alkylations was occurring
and in what order. Hopefully, selective monoalkylation at the
α position to form 12a would occur first and further
alkylation would not be problematic when less than 1 equiv.
of base and alkylating reagent was used. If more than
1 equiv. of base and alkylating agent was used, selective Cα-
monoalkylation (12a) could occur followed by N-alkylation
(to 17), and possibly N,N-dialkylation (to 19).
The results from the model experiment showed that, even
when less than 1 equiv. of base and alkylating reagent were
used, the reaction gave mixtures of mono-, di-, and tri-
alkylation products (Fig. 2). From the earlier experimental
results (Table 1), in which the desired C-allylated product
was obtained in up to 61% yield, it is apparent that the pre-
dicted pKa values (Figs. 1 and 2) provide only a very qualita-
tive estimate of the various pKas.
Finally, the alkylation reaction of 11a with allyl bromide
was examined after 5 min by TLC to see if the product dis-
tribution was affected by time. At this time, all of the prod-
ucts shown in Fig. 3 were present.
© 2006 NRC Canada

O’Donnell et al.
Table 1. α-Allylation of the benzophenone imine of alaninamide (11a) to form 12a (base study).
1305
Entry
Base
Solvent
Other
Temp. (°C)
Time (h)
12a (%)
1
2
3
10% Aq. NaOH
50% Aq. NaOH
BTPPb
CH2Cl2
CH2Cl2
CH2Cl2
TBAHa
TBAHa
—
TBABc
—
—
—
—
—
rt
rt
rt
18
18
18
No rxn.
Trace
Trace
4
5
6
7
8
9
10
NaOEt
LDA
CH3CN
THF
THF
THF
THF
THF
THF
—
—
3
3
3
3
No rxn.d
Trace
Trace
24
–78
–78
–78
rt
–78
0
LiHMDS
KHMDS
KO-t-Bu
KO-t-Bu
KO-t-Bu
42–46
34–48
55–61
3
3
—
aBu4NHSO4 (1 equiv.).
btert-Butylimino-tri(pyrrolidino)phosphorane.
cBu4NBr (cat.).
dStarting material insoluble.
materials (11b–11d) were prepared earlier by IPE from the
Schiff base of glycinamide (10, Scheme 6). These three
monoalkylated Schiff base glycinamides (11b–11d) were
then subjected to allylation and benzylation. In all cases, the
allylation of the benzophenone imines of these higher amino
amides did yield the desired products, although in low
yields. Allylation of Schiff base 11b gave 12i (21%), 11c
yielded 12j (25%), and 11d gave 12k (13%). For the synthe-
sis of Schiff base 12j, the addition of 4-chlorobenzyl bro-
mide to Schiff base 11b gave only a 10% yield of product.
This compared with the higher yield (25%) of the same
product (12j) obtained by allylation of the benzylated start-
ing material 11c.
Methylation of Schiff bases 11b and 10 gave a mixture of
products (TLC and LC–MS) and it was not possible to iso-
late the desired α-alkylated product, which was present only
in trace amounts, from the crude reaction mixture. Methyl-
ation of 11d gave the N-monoalkylated product (45%) and
methylation of 11c yielded less than 10% of product 12e,
compared with the 53% yield for the reverse order of
alkylation of the Schiff base alaninamide 11a using p-
chlorobenzyl bromide.
Alkylation of the Schiff base of monosubstituted amino
amides to give ␣,␣-disubstituted derivatives
Using the optimized results from the model alkylation
study described previously, several target molecules were
made by following the general procedure for alkylation of
the benzophenone imine of a monosubstituted amino amide.
Further alkylations included benzylation and alkylation with
less reactive alkyl halides as well as a Michael addition. The
model conditions used, unless otherwise noted, were as fol-
lows: KO-t-Bu (2.38 mmol) was added to the benzophenone
imine of a monosubstituted α-amino amide (1.98 mmol) dis-
solved in anhydr. THF at 0 °C and the reaction mixture was
stirred at 0 °C for 20 min. The alkylating agent (2.38 mmol)
was added and the reaction mixture was stirred at 0 °C for
an additional 3 h. After work-up, the crude product was
purified by flash chromatography using silica that was
prewashed with hexanes–EtOAc–triethylamine (75:25:1).
The product was then recrystallized from dichloromethane–
hexanes (1:15). Four monoalkylated starting materials (11a–
11d, Scheme 6) were used to prepare 10 new α,α-
disubstituted products (12a–12e and 12g–12k, Fig. 4).
The alkylation of 11a with allyl derivatives gave the high-
est yields for all alkylations studied (Fig. 4, products 12a–
12d). Alkylation of Schiff base 11a with allyl bromide, 4-
bromo-2-methyl-2-butene, 3-bromo-2-methylpropene, and
cinnamyl bromide, gave the respective Schiff bases (12a–
12d) in 36%–61% isolated yield. An X-ray crystal structure,
which will be discussed later, was obtained for dialkylated
product 12b.
Michael addition of the Schiff base of alaninamide
The Schiff base of alaninamide (11a) was reacted with the
Michael acceptor (tert-butyl acrylate) to give the Schiff base
20 (32%) (Scheme 8). Schiff base 11a (1.98 mmol) was dis-
solved in anhydr. THF, then tert-butyl acrylate (2.38 mmol)
was added, followed by KO-t-Bu (0.238 mmol), and the re-
action mixture was stirred at 0 °C for 3 h. This reaction was
optimal with 0.12 molar equiv. of KO-t-Bu rather than the
normal 1.2 equiv. in the case of alkylation. Attempted Mi-
chael addition with methyl acrylate did not give the desired
product as monitored by LC–MS, while use of acrylonitrile
gave the N,N-dialkylated product (1H NMR and LC–MS)
and only trace amounts of monoalkylated product (LC–MS).
The alkylation of Schiff base 11a using non-allylic halides
was examined next (Fig. 4, products 12e–12h). Alkylation
with 4-chlorobenzyl bromide gave the Schiff base 12e (53%)
while methylation gave a complex mixture of products,
likely owing to the reactivity and small size of the methyl
group. Alkylation of 11a with iodoethane gave 12g (24%)
while 1-iodo-2-methylpropane gave 12h (25%). Alkylation
with two α-haloesters, methyl bromoacetate, and tert-butyl
bromoacetate, did not give the desired α-alkylated products
X-ray crystal structures of the benzophenone imine of
amino amides
1
(LC–MS and H NMR).
Alkylation of the Schiff base of higher amino amides us-
ing the general procedure for the alkylation of 11a was also
studied (Fig. 4, products 12i–12k). The Schiff base starting
The X-ray crystal structures of the benzophenone imines
of the unsubstituted (10), a monosubstituted (11b), and a
disubstituted (12b) amino amide were obtained (Fig. 5). A
© 2006 NRC Canada

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Can. J. Chem. Vol. 84, 2006
Fig. 4. Alkylation of the benzophenone imines of monosubstituted amino amides (11) with KO-t-Bu to form the α,α-disubstituted
products 12.
O
O
1. KOtBu, THF
oC, 20 min
2. R2X, 0 ºC, 3h
Ph2C
N
Ph2C
N
NH2
NH2
0
R1
R2
R1
11
12
O
O
O
O
O
O
Ph2C
N
Ph2C
N
Ph2C
N
Ph2C
N
Ph2C
N
Ph2C
NH2
N
NH2
NH2
NH2
NH2
NH2
Me
Me
Me
Me
Me
Me
Me
Cl
12d
(58%)
12a (61%)
12c (52%)
12b (36%)
(X-Ray)
12e (53%)
12f (Mult. Prod.)
O
O
O
O
O
Ph2C
N
Ph2C
N
Ph2C
N
Ph2C
N
Me
Ph2C
N
NH2
NH2
NH2
NH2
NH2
Et
Et
Me
Cl
12j (25%)
12i
12g (24%)
12h (25%)
(21%)
12k (13%)
(Allylation Last)
12j (10%)
(Benzylation Last)
comparison, in the unsubstituted Schiff base esters
(Ph2C=NCH2CO2Et, 1a, Σ = 71°; Ph2C=NCH2CO2-t-Bu, 1c,
Σ = 86° (4)) and in the α-benzyl or α-phenyl substituted
Schiff base esters (Ph2C=NCH(CH2C6H4-4-Cl)CO2-t-Bu, 2c,
Σ = 97° (4); Ph2C=NCH(Ph)CO2Et, 2d, Σ = 82° (7)). The X-
ray structure of an α,α-disubstituted Schiff base ester in this
series was not determined.
Scheme 8. Michael addition of the benzophenone imine of
alaninamide with tert-butyl acrylate.
O
O
1.
CO2tBu
Ph2C
N
Ph2C
N
NH2
NH2
THF, 0 °C
2. KOtBu, 0 °C, 3 h
Me
Me
CO2tBu
The bond lengths to the quaternary α-carbon in the
disubstituted Schiff base amide (12b) relative to the other
two compounds in the series are also of interest. Three of
the four bonds to the α-carbon are the longest in the series:
the Cα—Nimine bond(1.477 Å), the Cα—Me bond (1.536 Å),
and the Cα-CCO bond (1.555 Å), which is a result of the
steric congestion about the quaternary α-carbon in 12b.
11a
20 (32%)
summary of the crystallographic data is given in Table 2.4 In
addition to confirming the structures of these products, sev-
eral other points are of interest in this series of compounds.
The cis-phenyl group (Phc) on the imine is considerably
farther out of planarity with the imine double bond than is
the trans-phenyl group (Pht). This is due to A1,3 strain (6) in
the mono- and di-substituted derivatives, where the effect is
more pronounced than in the unsubstituted case. Interest-
ingly, the sum of these two values (Σ) increases in going
from 10 (Σ = 88°) to 11b (Σ = 92°) to 12b (Σ = 99°). As a
Experimental
General
Unless otherwise noted, all manipulations were carried
out under an inert atmosphere (argon) in glassware dried
4 Supplementary data for this article are available on the journal Web site (http://canjchem.nrc.ca) or may be purchased from the Depository
of Unpublished Data, Document Delivery, CISTI, National Research Council Canada, Ottawa, ON K1A 0R6, Canada. DUD 5057. For more
information on obtaining material refer to http://cisti-icist.nrc-cnrc.gc.ca/irm/unpub_e.shtml. CCDC 296438, 296439, and 296437 (com-
pounds 10, 11b, and 12b, respectively) contain the crystallographic data for this manuscript. These data can be obtained, free of charge, via
http://www.ccdc.cam.ac.uk/conts/retrieving.html (Or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax +44 1223 336033; or deposit@ccdc.cam.ac.uk).
© 2006 NRC Canada

O’Donnell et al.
1307
Fig. 5. Crystal structures of representative unsubstituted, α-monosubstituted, and α,α-disubstituted amino amide derivatives.
with a heat gun. THF was freshly distilled before use from
sodium benzophenone ketyl. Sure SealTM bottles of potas-
sium tert-butoxide (1.0 mol/L in THF and 1.0 mol/L in tert-
butyl alcohol), sodium ethoxide (21 wt% in denatured ethyl
alcohol), lithium diisopropylamine (2.0 mol/L in heptane–
THF–ethylbenzene), potassium bis(trimethylsilyl)amide
(0.5 mol/L in toluene), lithium bis(trimethylsilyl)amide
(1.0 mol/L in THF), and all solvents other than THF were
purchased from the Sigma-Aldrich Chemical Co.
Nuclear magnetic resonance (NMR) spectra were re-
corded on a 300 MHz Varian Gemini spectrometer. Infrared
(IR) spectra were obtained neat in thin films on NaCl plates
(oils) using a Matteson Genesis FT-IR. Elemental analyses
were performed by Midwest Microlabs, Indianapolis, Indi-
ana. High-resolution mass spectrometry was run in the FAB
mode at Indiana University. Melting points were determined
in open-end capillaries using a Thomas-Hoover Unimelt
melting apparatus and are uncorrected. Thin layer chroma-
tography (TLC) was performed on silica gel 60 F254 alumi-
num sheets with UV visualization. Column chromatography
was performed using silica gel (60 Å, 40–63 µm standard
grade gel) with the solvent systems described in the individ-
ual procedures. Liquid chromatography – mass spectrometry
Preparation of the benzophenone imines of glycinamide
and alaninamide by transimination
2-[(Diphenylmethylene)amino]acetamide (10)
Glycinamide hydrochloride (14, 5.00 g, 45.2 mmol) and
1,2-dichloroethane (60 mL) were added to a dried 250 mL
three-necked round-bottomed flask equipped with a reflux
condenser,
a magnetic stirrer, and an argon source.
Diphenylketimine (7.6 mL, 45.2 mmol), triethylamine
(6.93 mL, 49.7 mmol), and 1,2-dichloroethane (20 mL) were
added by syringe to a separate dry 50 mL round-bottomed
flask equipped with an argon source. The mixture was
stirred for 5 min and was added slowly by cannula under ar-
gon to the reaction flask. The mixture was refluxed under ar-
gon overnight, cooled, filtered, and the solvent was removed
under reduced pressure to give a light yellow solid.
Recrystallization from hexanes–EtOAc (2:3 by volume) gave
10 as white crystals (7.55 g, 70%); mp 160–163 °C (lit value
1
(22) mp 162 to 163 °C). IR (cm–1): 1681, 3442. H NMR δ:
3.96 (s, 2H, CH2), 5.55–5.75 (br s, 2H, NH2), 7.10–7.70 (m,
10H, aromatic). 13C NMR (CDCl3) δ: 58.2, 128.9, 129.8,
130.0, 130.1, 130.5, 130.6, 132.3, 137.6, 140.4, 156.7,
172.0, 175.1.
(LC–MS) was performed on
a Waters 2795 liquid
chromatograph, a Waters 996 photodiode array, a Sedex 75
light scatterer, and a Waters Micromass ZQ mass spectrome-
ter. The mobile-phase solvent was 90% H2O – 5% ACN –
5% – 0.2% formic acid buffer at approximately pH 3.0.
X-ray crystallography was performed at the Molecular
Structure Center at Indiana University. X-ray diffraction data
were collected using a Bruker diffractometer with SMART
6000 CCD detector. Structures were solved via the SHELXTL
program suite (29). Further structure determination details
are available in CIF form in the Supplementary material.4
( )-2-[(Diphenylmethylene)amino]propanamide (11a)
( )-Alaninamide hydrochloride (15, 1.00 g, 8.03 mmol)
followed by anhydr. DMF (50 mL) were added to a dried
250 mL round-bottomed flask equipped with a magnetic stir-
rer. The solution was stirred at room temperature under ar-
gon for 30 min or until the solid was completely dissolved.
Benzophenone imine (1.45 g, 8.03 mmol) was added
dropwise via syringe to the alaninamide solution under ar-
gon at room temperature. The reaction mixture was stirred at
room temperature under argon overnight. The solution was
© 2006 NRC Canada

1308
Can. J. Chem. Vol. 84, 2006
Table 2. Crystallographic data.
Crystal
10
11b
12b
Emperical formula
C15H14N2O
C18H18N2O
C21H24N2O
Formula mass
238.28
278.34
320.42
Colour, habit
Crystal dimensions (mm)
Crystal system
Space group
Multifaceted, colourless
0.5×0.5×0.25
Monoclinic
C2/c
Plate, colourless
0.5×0.3×0.08
Triclinic
Colourless, block
0.26×0.18×0.14
Triclinic
P-1
P-1
Z
8
6
4
a (Å)
b (Å)
c (Å)
α (°)
β (°)
γ (°)
26.640(6)
5.9821(14)
18.643(4)
90.00
118.543(5)
90.00
11.1428(3)
12.9776(3)
16.5402(4)
92.3530(10)
99.9610(10)
101.0850(10)
–15 ≤ h ≤ 15,
8.9409(7)
11.6696(8)
17.8861(13)
102.943(2)
95.127(2)
97.676(2)
–12 ≤ h ≤ 12,
Collection ranges
–31 ≤ h ≤ 27,
–7 ≤ k ≤ 7,
–18 ≤ k ≤ 18,
–16 ≤ k ≤ 16,
–20 ≤ l ≤ 22
120(2)
2609.8(10)
1.213
–23 ≤ l ≤ 23
120(2)
2304.97(10)
1.203
25 ≤ l ≤ 25
117(2)
1788.7(2)
1.190
Temperature (K)
Volume (Å3)
Dcalcd (Mg m–3)
Radiation (Å)
MoKα (λ = 0.710 73)
MoKα (λ = 0.710 73)
MoKα (λ = 0.710 73)
Absorption coeff (µ, mm–1)
Absorption correction
F(000)
0.078
0.075
0.073
Semiempirical
1008
Semiempirical
888
Numerical
688
θ range for data (°)
Observed reflections
Independent reflections
Data/restraints/parameters
Maximum shift/error
GOF on F2
2.44–29.97
7106
2302
2302/0/219
0.003
0.995
2.07–30.01
42 952
13 452
13452/0/815
0.002
1.462
3.50–29.86
38 005
7930
7930/0/625
0.001
1.553
Final R indices [I > 2σ(I)]
R1 = 0.0698, wR2 = 0.1749
R1 = 0.0461, wR2 = 0.0960
R1 = 0.0457, wR2 = 0.1007
R indices (all data)
R1 = 0.1109, wR2 = 0.2293
R1 = 0.0739, wR2 = 0.1038
R1 = 0.0648, wR2 = 0.0963
Absolute structure parameter
Extinction coefficient
Largest diff peak and hole (e Å–3)
NA
NA
NA
NA
NA
NA
0.368 and –0.395
0.352 and –0.227
0.432 and –0.215
quenched with H2O (100 mL), Et2O (100 mL) was added,
the layers were separated, and the aqueous layer was ex-
tracted with Et2O (3 × 75 mL). The combined organic layers
were washed with H2O (3 × 100 mL) and brine (50 mL),
dried over MgSO4, filtered, and the solvent was removed
under reduced pressure. The solid was washed with hexanes
(5 × 20 mL) to give 11a as a white solid (1.94 g, 96%).
Recrystallization from CH2Cl2–hexanes (1:15) gave the
product as a fine white powder (see the following analytical
data).
solution was stirred for 3 min and then the system was
placed under argon. The alkylating agent (4.2 mmol) was
added dropwise via syringe and the reaction mixture was
stirred at room temperature under argon overnight. The reac-
tion mixture was transferred to a separatory funnel and dis-
tilled water (10 mL) and dichloromethane (10 mL) were
added. The layers were separated and the aqueous layer was
extracted with dichloromethane (3 × 5 mL). The organic
layer was washed with distilled water (3 × 10 mL), dried
over MgSO4, filtered, and the solvent was removed under
reduced pressure to give the crude product. The product was
purified by flash column chromatography (SiO2, first
washed with hexanes–EtOAc–Et3N (90:10:1)) using EtOAc–
hexanes (50:50) to EtOAc–hexanes (85:15) gave the purified
products 11.
General procedure for the alkylation of the
benzophenone imine of glycinamide (10) by IPE to
form the ␣-monosubstituted products 11
Aqueous NaOH (10%, 2.52 mmol) followed by
tetrabutylammonium hydrogen sulfate (1.03 mmol) were
added to a dried 25 mL round-bottomed flask equipped with
a magnetic stirrer and the reaction mixture was stirred for
5 min. The benzophenone imine of glycinamide (10,
0.84 mmol) was dissolved in dichloromethane (1.5 mL) and
then added dropwise via syringe to the reaction mixture. The
( )-2-[(Diphenylmethylene)amino]propanamide (11a)
The general procedure described in the previous section
using 10% aq. NaOH (0.9 g, 2.52 mmol), tetrabutyl-
ammonium hydrogen sulfate (0.351 g, 1.03 mmol), 10
(0.200 g, 0.84 mmol) in dichloromethane (1.5 mL), and
© 2006 NRC Canada

O’Donnell et al.
1309
iodomethane (0.593 g, 4.2 mmol) gave solid product 11a
137.4, 140.9, 171.0, 177.6. Anal. calcd. for C17H18N2O: C
76.66, H 6.81, N 10.52; found: C 76.94, H 6.84, N 10.55.
1
(177 mg, 84%); mp 120–123 °C. IR (cm–1): 1651, 3451. H
NMR δ: 1.35 (d, 3H, J = 7.4 Hz, CH3), 4.00 (q, 1H, J =
6.9 Hz, CH), 5.30–5.45 (br s, 2H, NH2), 7.00–7.70 (m, 10H,
aromatic). 13C NMR (CDCl3) δ: 22.3, 63.0, 128.9, 129.8,
130.1, 130.3, 130.4, 130.5, 132.2, 137.2, 140.7, 170.5,
178.5. Anal. calcd. for C16H16N2O: C 76.17, H 6.39, N
11.10; found: C 76.36, H 6.50, N 11.14.
General procedure for the alkylation of the
benzophenone imines of ␣-monosubstituted amino
amides (11) using KO-t-Bu to form the ␣,␣-
disubstituted products 12
The benzophenone imine of a monosubstituted α-amino
amide (11, 1.98 mmol) and anhydr. THF (5 mL) were added
at room temperature to a dried 15 mL round-bottomed flask
containing a magnetic stirrer and an argon source. The solu-
tion was cooled to 0 °C and KO-t-Bu (1.0 mol/L in THF,
2.38 mmol) was added dropwise via syringe. The reaction
mixture was stirred at 0 °C for 20 min. The alkylating agent
(2.38 mmol) was added dropwise via syringe to the reaction
mixture at 0 °C and the solution was stirred for 3 h. The re-
action mixture was quenched with satd. NH4Cl (5 mL), H2O
(10 mL), and CH2Cl2 (15 mL) were added. The layers were
separated, the organic layer was washed with H2O (2 ×
10 mL), and the aqueous layer was extracted with CH2Cl2
(3 × 15 mL). The combined organic layers were washed
with brine (10 mL), dried over MgSO4, filtered, and the sol-
vent was removed under reduced pressure. The product was
purified by flash column chromatography (silica was washed
with hexanes–EtOAc–Et3N, 75:25:1) to give, in most cases,
a solid product. Recrystallization from CH2Cl2–hexanes
(1:15) gave the purified products 12.
( )-2-[(Diphenylmethylene)amino]-4-pentenamide (11b)
The general procedure described previously using 10% aq.
NaOH (11.65 g, 31.5 mmol), tetrabutylammonium hydrogen
sulfate (4.38 g, 12.9 mmol), 10 (2.50 g, 10.5 mmol) in di-
chloromethane (20 mL), and allyl bromide (5.07 g,
42.0 mmol) gave a glassy oil, which was purified by flash
column chromatography (SiO2, first washed with hexanes–
EtOAc–Et3N (90:10:1)) using EtOAc–hexanes (50:50) to
EtOAc–hexanes (85:15) to give 11b as a white solid (2.20 g,
1
75%); mp 78–80 °C. IR (cm–1): 1686, 3448. H NMR δ:
2.54 (t, 2H, J = 6.6 Hz, CH2), 4.07 (t, 1H, J = 5.9 Hz, CH),
5.04 (m, 2H, CH2), 5.44 (br s, 1H, NH), 5.68 (m, 1H, CH),
6.82 (br s, 1H, NH), 7.10–7.66 (m, 10H, aromatic). 13C
NMR (CDCl3) δ: 39.8, 65.9, 117.7, 127.8, 128.2, 128.6,
128.7, 128.9, 130.6, 134.0, 135.7, 139.3, 169.8, 175.3. Anal.
calcd. for C18H18N2O: C 77.67, H 6.52, N 10.06; found: C
77.36, H 6.52, N 10.00.
( )-2-[(Diphenylmethylene)amino]-3-(4-chlorophenyl)pro-
panamide (11c)
( )-2-[(Diphenylmethylene)amino]-2-methyl-4-
The general procedure described previously using 10% aq.
NaOH (11.6 g, 31.5 mmol), tetrabutylammonium hydrogen
sulfate (4.38 g, 12.9 mmol), 10 (2.50 g, 10.5 mmol) in di-
chloromethane (22 mL), and 4-chlorobenzyl bromide
(2.65 g, 12.9 mmol) gave a white solid, which was purified
by flash column chromatography (SiO2, first washed with
hexanes–EtOAc–Et3N (90:10:1)) using EtOAc–hexanes
(50:50) to EtOAc–hexanes (85:15) to give the alkylated
product 11c as a white solid (2.74 g, 72%); mp 181 to
pentenamide (12a) and by-products (16–19)
The general procedure described in the previous section
using 11a (0.500 g, 1.98 mmol) and allyl bromide (0.287 g,
2.38 mmol) gave product 12a as a white solid (0.35 g, 61%);
mp 127–129 °C. Rf 0.39 (hexanes–EtOAc, 7:3). IR (cm–1):
1682, 3438. 1H NMR δ: 1.23 (s, 3H, CH3), 2.25 (dd, 1H, J =
6.3, 14.3 Hz, CH), 2.69 (dd, 1H, J = 7.4, 14.7 Hz, CH), 5.05
(m, 2H, CH2), 5.56 (bs, 1H, NH), 5.71–5.82 (m, 1H, CH),
7.12–7.52 (m, 10H, aromatic). 13C NMR (CDCl3) δ: 24.7,
43.9, 67.8, 117.6, 127.9, 128.0, 128.1, 128.6, 130.3, 133.6,
138.3, 166.9, 179.1. Anal. calcd. for C19H20N2O: C 78.05, H
6.89, N 9.58; found: C 77.94, H 6.93, N 9.62.
1
182 °C. IR (cm–1): 1681, 3441. H NMR δ: 3.01 (dd, 1H,
J = 9.6, 13.2 Hz, CH), 3.15 (dd, 1H, J = 3.3, 12.9 Hz, CH),
4.17 (q, 1H, J = 4.2 Hz, CH), 5.38 (br s, 1H, NH), 6.55 (d,
2H, J = 6.6 Hz, CH), 6.73 (br s, 1H, NH), 6.94–7.59 (m,
14H, aromatic). 13C NMR (CDCl3) δ: 42.4, 69.1, 128.9,
129.8, 130.1, 130.2, 132.3, 132.9, 133.9, 136.8, 137.8,
140.7, 171.9, 176.5. HRMS m/z calcd. for C22H20N2OCl:
363.1186 (M + Na+); found: 363.1252.
Selected analytical data for the by-products
N-Allylated product 16: Rf 0.62 (hexanes–EtOAc, 7:3).
1
Selected H NMR signals: 1.30 (d, 3H, CH3), 4.00 (q, 1H,
CH), 5.0–6.0 (m, 3H, vinyl of one allyl). LC–MS: 293.
Cα,N-Diallylated product 17: Rf 0.71 (hexanes–EtOAc, 7:3).
1
( )-2-[(Diphenylmethylene)amino]butanamide (11d)
Selected H NMR signals: 1.23 (s, 3H, CH3), 5.0–6.0 (m, 6
H, vinyls of two allyls). LC–MS: 333. N,N-Diallylated prod-
uct 18: Rf 0.52 (hexanes–EtOAc, 7:3). Selected H NMR
signals: 1.30 (d, 3H, CH3), 4.00 (q, 1H, CH), 5.0–6.0 (m,
6H, vinyls of two allyls). LC–MS: 333. Cα,N,N-Triallylated
product 19: Rf 0.77 (hexanes–EtOAc, 7:3). Selected 1H
NMR signals: 1.23 (s, 3H, CH3), 5.0–6.0 (m, 9H, vinyls of
three allyls). LC–MS: 373.
The general procedure described previously using 10% aq.
NaOH (11.6 g, 31.5 mmol), tetrabutylammonium hydrogen
sulfate (4.38 g, 12.9 mmol), 10 (2.50 g, 10.5 mmol) in di-
chloromethane (25 mL), and iodoethane (2.01 g, 12.9 mmol)
gave a light yellow solid, which was purified by flash col-
umn chromatography (SiO2, first washed with hexanes–
EtOAc–Et3N (90:10:1)) using EtOAc–hexanes (50:50) to
EtOAc–hexanes (85:15) to give 11d as a white solid (2.05 g,
73%); mp 116 to 117 °C. IR (cm–1): 1686, 3451. 1H NMR δ:
0.88 (t, 3H, J = 7.4 Hz, CH3), 1.78–1.85 (m, 2H, CH2), 3.93
(q, 1H, J = 3.9 Hz, CH), 5.41 (br s, 1H, NH), 6.80 (br s, 1H,
NH), 7.10–7.68 (m, 10H, aromatic). 13C NMR (CDCl3) δ:
11.7, 30.3, 68.8, 129.3, 129.8, 130.2, 130.3, 130.4, 132.2,
1
( )-2-[(Diphenylmethylene)amino]-2,5-dimethyl-4-
hexenamide (12b)
The general procedure described previously using 11a
(0.500 g, 1.98 mmol) and 4-bromo-2-methyl-2-butene
(0.355 g, 2.38 mmol) gave product 12b as a white solid
© 2006 NRC Canada

1310
Can. J. Chem. Vol. 84, 2006
1
(0.226 g, 36%); mp 127–129 °C. IR (cm–1): 1638, 3442. H
NMR δ: 1.21 (s, 3H, CH3), 1.50 (s, 3H, CH3), 1.67 (s, 3H,
CH3), 2.12 (dd, 1H, J = 5.9, 14.7 Hz, CH), 2.70 (dd, 1H, J =
7.3, 15.5 Hz, CH), 5.09 (m, 1H, CH), 5.59 (br s, 1H, NH),
7.18–7.53 (m, 10H, aromatic), 7.96 (br s, 1H, NH). 13C
NMR (CDCl3) δ: 18.0, 24.5, 25.9, 38.6, 67.8, 119.2, 127.9,
128.1, 128.4, 130.2, 134.1, 138.4, 141.2, 179.6. Anal. calcd.
for C21H24N2O: C 78.71, H 7.55, N 8.74; found: C 78.51, H
7.59, N 8.74.
(m, 1H, CH), 6.20 (br s, 1H, NH), 7.20–7.53 (m, 10H, aro-
matic), 8.14 (br s, 1H, NH). 13C NMR (CDCl3) δ: 10.7, 26.7,
33.9, 69.9, 129.3, 129.6, 129.7, 130.1, 131.8, 140.1, 142.8,
167.9, 181.7. Anal. calcd. for C18H20N2O: C 77.11, H 7.19,
N 9.99; found: C 76.83, H 7.28, N 9.82.
( )-2-[(Diphenylmethylene)amino]-2,4-dimethylpentan-
amide (12h)
The general procedure described previously using 11a
(0.500 g, 1.98 mmol) and 1-iodo-2-methylpropane (0.437 g,
2.38 mmol) gave product 12h as a white solid (0.150 g,
( )-2-[(Diphenylmethylene)amino]-2,4-dimethyl-4-
pentenamide (12c)
1
25%); mp 136–138 °C. IR (cm–1): 1700, 3061. H NMR δ:
0.86 (d, 3H, J = 6.6 Hz, CH3), 0.93 (d, 3H, J = 6.6 Hz,
CH3), 1.16 (s, 3H, CH3), 1.42 (dd, 1H, J = 5.1, 14.0 Hz,
CH), 1.80 (m, 1H, CH), 1.97 (dd, 1H, J = 8.1, 14.0 Hz, CH),
5.57 (br s, 1H, NH), 7.19–7.53 (m, 10H, aromatic), 8.19
(br s, 1H, NH). 13C NMR (CDCl3) δ: 24.2, 25.8, 26.9, 28.4,
49.6, 68.9, 129.0, 129.6, 129.7, 129.8, 130.1, 130.2, 131.8,
140.1, 142.8, 167.8, 182.2. HRMS m/z calcd. for
C20H25N2O: 309.1889 (M + Na+); found: 309.1961.
The general procedure described previously using 11a
(0.500 g, 1.98 mmol) and 3-bromo-2-methylpropene
(0.320 g, 2.38 mmol) gave product 12c as a white solid
(0.314 g, 52%); mp 122 to 123 °C. IR (cm–1): 1686, 3443.
1H NMR δ: 1.28 (s, 3H, CH3), 1.61 (s, 3H, CH3), 1.96 (d,
1H, J = 16.2 Hz, CH), 2.80 (d, 1H, J = 16.2 Hz, CH), 4.76
(d, 2H, J = 26.5 Hz, CH2), 5.56 (br s, 1H, NH), 7.21–7.52
(m, 10H, aromatic), 8.13 (br s, 1H, NH). 13C NMR (CDCl3)
δ: 25.7, 28.5, 47.5, 68.8, 114.7, 129.3, 129.5, 129.6, 129.8,
130.1, 131.8, 139.9, 142.8, 143.2, 167.7, 181.3. HRMS m/z
calcd. for C20H23N2O: 307.1732 for (M + Na+); found:
307.1797.
2-[(Diphenylmethylene)amino]-2-(2-propenyl)-4-
pentenamide (12i)
The general procedure described previously using 11b
(0.500 g, 1.79 mmol) and allyl bromide (0.266 g,
2.16 mmol) gave the product 12i as a solid (0.119 g, 21%);
( )-2-[(Diphenylmethylene)amino]-2-methyl-(5E)-phenyl-
4-pentenamide (12d)
1
mp 138–140 °C. IR (cm–1): 1691, 3435. H NMR δ: 2.23
(dd, 2H, J = 6.3, 14.3 Hz, CH2), 2.67 (dd, 2H, J = 7.4,
13.2 Hz, CH2), 5.05 (m, 4H, CH2), 5.73 (m, 2H, CH), 7.26–
7.48 (m, 10H, aromatic), 8.72 (br s, 1H, NH). 13C NMR
(CDCl3) δ: 43.6, 72.7, 119.3, 128.9, 129.7, 129.8, 130.5,
131.9, 134.7, 139.9, 142.8, 168.7, 179.4. Anal. calcd. for
C21H22N2O: C 79.21, H 6.96, N 8.80; found: C 79.34, H
7.01, N 8.80.
The general procedure described previously using 11a
(0.500 g, 1.98 mmol) and cinnamyl bromide (0.466 g,
2.38 mmol) gave product 12d as a white solid (0.423 g,
58%); mp 149 to 150 °C. IR (cm–1): 1686, 3442. 1H NMR δ:
1.26 (s, 3H, CH3), 2.40 (dd, 1H, J = 7.0, 13.6 Hz, CH), 2.84
(dd, 1H, J = 7.4, 14.0 Hz, CH), 5.55 (br s, 1H, NH), 6.15
(m, 1H, CH), 6.39 (d, 1H, J = 14.6 Hz, CH), 7.16–7.53 (m,
15H, aromatic), 7.94 (br s, 1H, NH). 13C NMR (CDCl3) δ:
26.4, 44.8, 69.8, 126.9, 127.8, 128.7, 129.5, 129.7, 129.8,
130.0, 130.3, 131.9, 134.4, 139.2, 140.0, 142.7, 168.7,
180.6. Anal. calcd. for C25H24N2O: C 81.49, H 6.57, N 7.60;
found: C 81.29, H 6.61, N 7.63.
( )-2-(4-Chlorobenzyl)-2-[(diphenylmethylene)amino]-4-
pentenamide (12j) by allylation
The general procedure described previously using 11c
(0.500 g, 1.38 mmol) and allyl bromide (0.196 g,
1.65 mmol) gave product 12j as a solid (0.139 g, 25%); mp
1
143 to 144 °C. IR (cm–1): 1686, 2360, 3442. H NMR δ:
( )-2-[(Diphenylmethylene)amino]-2-(4-chlorophenyl)pro-
panamide (12e)
2.27 (dd, 1H, J = 5.9, 14.7 Hz, CH), 2.71 (dd, 1H, J = 7.4,
14.7 Hz, CH), 2.89 (d, 1H, J = 14.0 Hz, CH), 3.23 (d, 1H,
J = 14.7 Hz, CH), 5.05 (d, 2H, J = 12.5 Hz, CH2), 5.53 (br s,
1H, NH), 5.72 (m, 1H, CH), 7.09–7.49 (m, 14H, aromatic),
7.93 (br s, 1H, NH). 13C NMR (CDCl3) δ: 43.3, 45.3, 72.8,
119.7, 128.9, 129.7, 129.8, 129.9, 130.6, 132.1, 132.6,
133.8, 134.4, 137.2, 139.8, 142.6, 168.7, 178.7. HRMS m/z
calcd. for C25H24N2OCl: 403.1499 (M + Na+); found:
403.1595.
The general procedure described previously using 11a
(0.500 g, 1.98 mmol) and 4-chlorobenzyl bromide (0.490 g,
2.38 mmol) in anhydr. THF (1 mL) gave product 12e as a
white solid (0.392 g, 53%); mp 147–149 °C. IR (cm–1):
1
1686, 3444. H NMR δ: 1.14 (s, 3H, CH3), 2.87 (d, 1H, J =
14.0 Hz, CH), 3.25 (d, 1H, J = 13.2 Hz, CH), 5.39 (bs, 1H,
NH), 7.05–7.50 (m, 14H, Ar). 13C NMR (CDCl3) δ: 26.4,
44.8, 69.8, 126.9, 127.8, 128.7, 129.5, 129.7, 129.8, 130.0,
131.9, 134.4, 139.2, 140.0, 142.7, 168.7, 180.6. Anal. calcd.
for C23H21ClN2O: C 73.30, H 5.62, Cl 9.41, N 7.43; found:
C 73.06, H 5.62, Cl 9.52, N 7.43.
( )-2-(4-Chlorobenzyl)-2-[(diphenylmethylene)amino]-4-
pentenamide (12j) by benzylation
The general procedure described previously using 11b
(0.250 g, 0.90 mmol) and 4-chlorobenzyl bromide (0.222 g,
1.08 mmol) in THF (1 mL) gave product 12j as a solid
(0.036 g, 10%). See previous analytical data.
( )-2-[(Diphenylmethylene)amino]-2-methylbutanamide
(12g)
The general procedure described previously using 11a
(0.500 g, 1.98 mmol) and iodoethane (0.371 g, 2.38 mmol)
gave of product 12g as a white solid (0.129 g, 24%); mp 137
( )-2-[(Diphenylmethylene)amino]-2-ethyl-4-pentenamide
(12k)
The general procedure described previously using 11d
(0.500 g, 1.87 mmol) and allyl bromide (0.273 g,
1
to 138 °C. IR (cm–1): 1680, 3436. H NMR δ: 0.87 (t, 3H,
J = 7.6 Hz, CH3), 1.22 (s, 3H, CH3), 1.45 (m, 1H, CH), 1.96
© 2006 NRC Canada

O’Donnell et al.
1311
Mrozack, and T.A. Cripe. J. Am. Chem. Soc. 110, 8520
(1988); (b) F.G. Bordwell. Acc. Chem. Res. 21, 456 (1988).
2.25 mmol) gave the product 12k as a solid (0.075 g, 13%);
1
mp 136 to 137 °C. IR (cm–1): 1679, 3447. H NMR δ: 0.85
(t, 3H, J = 7.4 Hz, CH3), 1.43 (m, 1H, CH), 1.94 (m, 1H,
CH), 2.20 (dd, 1H, J = 6.6, 14.7 Hz, CH), 2.64 (dd, 1H, J =
7.4, 14.7 Hz, CH), 5.03 (m, 2H, CH2), 5.74 (m, 2H, CH2),
7.24–7.49 (m, 10H, aromatic), 8.33 (br s, 1H, NH). 13C
NMR (CDCl3) δ: 1.6, 10.3, 32.3, 44.1, 44.2, 119.0, 128.6,
129.6, 129.7, 129.8, 129.9, 130.3, 131.6, 131.8, 133.9,
135.0, 168.2, 187.5. Anal. calcd. for C20H22N2O: C 78.40, H
7.24, N 9.14; found: C 78.28, H 7.26, N 9.13.
3. (a) Computer-assisted mechanistic evaluation of organic reac-
tions (CAMEO): A.J. Gushurst and W.L. Jorgensen. J. Org.
Chem. 51, 3513 (1986); (b) For a recent paper on first-
principle predictions of absolute pKas of organic acids in
DMSO, see: Y. Fu, L. Liu, R.-Q. Li, R. Liu, and Q.-X. Guo. J.
Am. Chem. Soc. 126, 814 (2004).
4. M.J. O’Donnell, I.A. Esikova, A. Mi, D.F. Shullenberger, and
S. Wu. In Phase-transfer catalysis: Mechanisms and syntheses.
Edited by M.E. Halpern. American Chemical Society, Wash-
ington, D.C. 1997. Chap. 10. pp 124–135.
Michael addition of the benzophenone imine of
alaninamide
5. A. López, M. Moreno-Mañas, R. Pleixats, A. Roglans J.
Ezquerra, and C.Pedregal. Tetrahedron, 52, 8365 (1996).
6. R.W. Hoffmann. Chem. Rev. 89, 1841 (1989).
1,1-Dimethylethyl ( )-5-amino-4-[(diphenylmethylene)amino]-
4-methyl-5-oxopentanoate (20)
7. M.J. O’Donnell, W.D. Bennett, W.N. Jacobsen, and Y.-a. Ma.
Tetrahedron Lett. 30, 3909 (1989).
2-[(Diphenylmethylene)amino]propanamide (11a, 0.500 g,
1.98 mmol) and anhydr. THF (5 mL) were added at room
temperature to a dried 15 mL round-bottomed flask contain-
ing a magnetic stirrer and an argon source. The solution was
cooled to 0 °C and tert-butyl acrylate (0.305 g, 2.38 mmol)
followed by KO-t-Bu (1.0 mol/L in THF, 0.238 mL,
0.238 mmol) were added dropwise via syringe. The reaction
mixture was stirred at 0 °C for 3 h. The reaction mixture
was quenched with satd. NH4Cl (5 mL), H2O (10 mL), and
CH2Cl2 (15 mL) were added. The layers were separated, the
organic layer was washed with H2O (2 × 10 mL), and the
aqueous layer was extracted with CH2Cl2 (3 × 15 mL). The
combined organic layers were washed with brine (10 mL),
dried over MgSO4, filtered, and the solvent was removed un-
der reduced pressure. The product was purified by flash col-
umn chromatography (silica was washed with hexanes–
EtOAc–Et3N, 75:25:1) to give product 20 as a white solid
(0.242 g, 32%). Recrystallization from CH2Cl2–hexanes
(1:15) gave the purified product; mp 161 to 162 °C. IR (cm–1):
8. Early development of enantioselective PTC alkylations of the
benzophenone imine of glycine tert-butyl ester with Cinchona-
derived quaternary ammonium salts: (a) M.J. O’Donnell, W.D.
Bennett, and S. Wu. J. Am. Chem. Soc. 111, 2353 (1989);
(b) M.J. O’Donnell, S. Wu, and J.C. Huffman. Tetrahedron,
50, 4507 (1994); (c) E.J. Corey, F. Xu, and M.C. Noe. J. Am.
Chem. Soc. 119, 12414 (1997); (d) B. Lygo and P.G. Wain-
wright. Tetrahedron Lett. 38, 8595 (1997).
9. Reviews from the author’s laboratory. Asymmetric PTC reac-
tions: (a) M.J. O’Donnell. In Catalytic asymmetric synthesis.
Edited by I. Ojima. VCH, New York. 1993. Chap. 8. pp. 389–
411; (b) M.J. O’Donnell. In Catalytic asymmetric synthesis.
2nd Ed. Edited by I. Ojima. Wiley-VCH, New York. 2000.
Chap. 10. pp. 727–755; (c) Preparation of optically active α-
amino acids from the benzophenone imine of glycine deriva-
tives: M.J. O’Donnell. Aldrichimica Acta, 34, 3 (2001);
(d) Enantioselective synthesis of α-amino acids by PTC with
achiral Schiff base esters: M.J. O’Donnell. Acc. Chem. Res.
37, 506 (2004).
10. Selected reviews or lead references for enantioselective PTC
reactions of the benzophenone imine of glycine alkyl esters for
the preparation of optically active α-amino acids: (a) C.
Nájera. Synlett, 1388 (2002); (b) B. Lygo and B.I. Andrews.
Acc. Chem. Res. 37, 518 (2004); (c) Y. Fukuta, T. Ohshima, V.
Gnanadesikan, T. Shibuguchi, T. Nemoto, T. Kisugi, T. Okino,
and M. Shibasaki. Proc. Nat. Acad. Sci. U.S.A. 101, 5433
(2004); (d) M.-S. Yoo, B.-S. Jeong, J.-H. Lee, H.-g. Park, and
S.-s. Jew. Org. Lett. 7, 1129 (2005); (e) K. Maruoka. Pure
Appl. Chem. 77, 1285 (2005).
1
1686, 3438. H NMR δ: 1.20 (s, 3H, CH3), 1.38 (s, 9H, tert-
butyl), 1.77–1.81 (m, 2H, CH2), 6.10 (br s, 1H, NH), 7.22–
7.52 (m, 10H, aromatic), 8.03 (br s, 1H, NH). 13C NMR
(CDCl3) δ: 24.3, 24.9, 28.0, 30.5, 31.1, 33.1, 34.7, 62.1,
66.8, 125.8, 125.9, 127.7, 128.1, 128.2, 128.4, 128.5, 128.6,
130.4, 138.1, 140.9, 145.3, 146.0, 167.3, 172.2, 172.7,
179.4, 179.8. HRMS m/z calcd. for C23H29N2O3: 381.2100
(M + Na+); found: 381.2187.
11. M.J. O’Donnell, T.P. Burkholder, V.V. Khau, R.W. Roeske,
Acknowledgements
and Z. Tian. Pol. J. Chem. 68, 2477 (1994).
12. (a) M.J. O’Donnell, C. Zhou, and W.L. Scott. J. Am. Chem.
Soc. 118, 6070 (1996); (b) M.J. O’Donnell, C.W. Lugar, R.S.
Pottorf, C. Zhou, W.L. Scott, and C.L. Cwi. Tetrahedron Lett.
38, 7163 (1997); (c) W.L. Scott, F. Delgado, K. Lobb, R.S.
Pottorf, and M.J. O’Donnell. Tetrahedron Lett. 42, 2073
(2001); (d) M.J. O’Donnell, M.D. Drew, R.S. Pottorf, and
W.L. Scott. J. Comb. Chem. 2, 172 (2000).
We thank the National Institutes of Health (R01
GM028193) and Eli Lilly and Company for financial sup-
port of this work. We acknowledge helpful discussions with
H.E. Schoemaker, Q.B. Broxterman, and B. Kaptein of DSM
Research (Geleen, The Netherlands). A generous gift of ( )-
alaninamide hydrochloride from DSM Research is gratefully
acknowledged.
13. M.J. O’Donnell, F. Delgado, and R.S. Pottorf. Tetrahedron, 55,
6347 (1999).
14. L. Ghosez, J.-P. Antoine, E. Deffense, M. Navarro, V. Libert,
M.J. O’Donnell, W.A. Bruder, K. Willey, and K.
Wojciechowski. Tetrahedron Lett. 23, 4255 (1982).
15. M.J. O’Donnell, B. LeClef, D.B. Rusterholz, L. Ghosez, J.-P.
Antoine, and M. Navarro. Tetrahedron Lett. 23, 4259 (1982).
16. M.J. O’Donnell, W.D. Bennett, W.N. Jacobsen, and Y.-a. Ma.
Tetrahedron Lett. 30, 3913 (1989).
References
1. (a) M.J. O’Donnell, J.M. Boniece, and S.E. Earp. Tetrahedron
Lett. 2641 (1978); (b) M.J. O’Donnell and T.M. Eckrich. Tet-
rahedron Lett. 4625 (1978).
2. (a) M.J. O’Donnell, W.D. Bennett, W.A. Bruder, W.N.
Jacobsen, K. Knuth, B. LeClef, R.L. Polt, F.G. Bordwell, S.R.
© 2006 NRC Canada

1312
Can. J. Chem. Vol. 84, 2006
17. W.L. Scott, C. Zhou, Z. Fang, and M.J. O’Donnell. Tetrahe-
dron Lett. 38, 3695 (1997).
18. D.L. Griffith, M.J. O’Donnell, R.S. Pottorf, W.L. Scott, and
and H. Hiemstra. Org. Lett. 1, 717 (1999); (h) F.P.J.T. Rutjes,
J.J.N. Veerman, W.J.N. Meester, H. Hiemstra, and H.E.
Schoemaker. Eur. J. Org. Chem. 1127 (1999); (i) B. Kaptein,
Q.B. Broxterman, H.E. Schoemaker, F.P.J.T. Rutjes, J.J.N.
Veerman, J. Kamphuis, C. Peggion, F. Formaggio, and C.
Toniolo. Tetrahedron, 57, 6567 (2001).
J.A. Porco, Jr. Tetrahedron Lett. 38, 8821 (1997).
19. Taken in part from: (a) J.D. Keeton. M.S. thesis, Purdue Uni-
versity, Indianapolis, Indiana. 2002; (b) V. Van Khau. M.S.
thesis, Purdue University, Indianapolis, Indiana. 1988.
20. (a) S. Kumar and U. Ramachandran. Tetrahedron: Asymmetry,
14, 2539 (2003); (b) T. Ooi, D. Sakai, M. Takeuchi, E.
Tayama, and K. Maruoka. Angew. Chem. Int. Ed. 42, 5868
(2003); (c) S. Kumar and U. Ramachandran. Tetrahedron Lett.
46, 19 (2005); (d) T. Ooi, M. Takeuchi, D. Kato, Y, Uematsu,
E. Tayama, D. Sakai, and K. Maruoka. J. Am. Chem. Soc.
127, 5073 (2005).
21. (a) Review: H.E. Schoemaker, W.H.J. Boesten, B. Kaptein,
E.C. Roos, Q.B. Broxterman, W.J.J. van den Tweel, and J.
Kamphuis. Acta. Chem. Scand. 50, 225 (1996); (b) Review:
H.E. Schoemaker, W.H.J. Boesten, Q.B. Broxterman, E.C.
Roos, B. Kaptein, W.J.J. van den Tweel, J. Kamphuis, E.M.
Meijer, and F.P.J.T. Rutjes. Chimia, 51, 308 (1997); (c) B.
Kaptein, W.H.J. Boesten, Q.B. Broxterman, H.E. Schoemaker,
and J. Kamphuis. Tetrahedron Lett. 33, 6007 (1992); (d) B.
Kaptein, H.M. Moody, Q.B. Broxterman, and J. Kamphuis. J.
Chem. Soc. Perkin Trans. 1, 1495 (1994); (e) F.P.J.T. Rutjes
and H.E. Schoemaker. Tetrahedron Lett. 38, 677 (1997); (f) J.
Van Betsbrugge, D. Tourwé, B. Kaptein, H. Kierkels, and R.
Broxterman. Tetrahedron, 53, 9233 (1997); (g) F.P.J.T. Rutjes,
K.C.M.F. Tjen, L.B. Wolf, W.F.J. Karstens, H.E. Schoemaker,
22. E.C. Taylor, N.F. Haley, and R.J. Clemens. J. Am. Chem. Soc.
103, 7743 (1981).
23. Amination (7 mol/L NH3, MeOH) of the benzophenone imine
of glycine methyl ester (1b) gave 10, see: D.J. Hyett, D. Mink,
Q.B. Broxterman, B. Kaptein, and H.J.M. Zeegers. PCT Int.
Appl. 078702, 2004; Chem. Abstr. CAN 141:243830, AN
2004:756676.
24. For the use of transimination for the preparation of the benzo-
phenone Schiff bases of amino esters, see: M.J. O’Donnell and
R.L. Polt. J. Org. Chem. 47, 2663 (1982).
25. A. Brändström. Preparative ion pair extraction. Apotekarsocieteten/
Hässle, Läkemedel, Sweden. 1974.
26. M.J. O’Donnell, F. Delgado, C. Hostettler, and R. Schwesinger.
Tetrahedron Lett. 39, 8775 (1998).
27. G. Guillena, B. Mancheño, C. Nájera, J. Ezquerra, and C.
Pedregal. Tetrahedron, 54, 9447 (1998).
28. G. Guillena and C. Nájera. Tetrahedron: Asymmetry, 9, 3935
(1998).
29. Bruker Analytical X-ray Systems. SHELXTL. Version 6.12
[computer program]. Bruker Analytical X-ray Systems, Madi-
son, Wisconsin. 2001.
© 2006 NRC Canada