Synthesis of novel β-aminocyclobutanecarboxylic acid derivatives by a solvent-free aza-Michael addition and subsequent ring closure

Article abstract of DOI:10.1039/c1ob05872j

Novel β-aminocyclobutanecarboxylic acid derivatives were prepared via a sequential solvent-free aza-Michael addition of benzophenone imine across 3-halopropylidenemalonates and base-induced ring closure. These highly substituted cyclobutanedicarboxylic acid derivatives were subjected to a reactivity study which demonstrated the tendency of these donor-acceptor substituted four-membered rings to be converted into their corresponding ring-opened products.

Full text of DOI:10.1039/c1ob05872j

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PAPER
Synthesis of novel b-aminocyclobutanecarboxylic acid derivatives by a
solvent-free aza–Michael addition and subsequent ring closure†‡
Tamara Meiresonne, Sven Mangelinckx§ and Norbert De Kimpe*
Received 1st June 2011, Accepted 13th July 2011
DOI: 10.1039/c1ob05872j
Novel b-aminocyclobutanecarboxylic acid derivatives were prepared via a sequential solvent-free
aza-Michael addition of benzophenone imine across 3-halopropylidenemalonates and base-induced
ring closure. These highly substituted cyclobutanedicarboxylic acid derivatives were subjected to a
reactivity study which demonstrated the tendency of these donor–acceptor substituted four-membered
rings to be converted into their corresponding ring-opened products.
Nevertheless, in recent years a lot of attention has been devoted
to the synthesis of this four-membered b-amino acid 1 and its
Introduction
The interest in cyclic b-amino acids has increased significantly in
the past decades,1–5 which is due to the ability of b-amino acids
to improve the metabolic stability of b-peptides in which they are
incorporated.6,7 Moreover, b-peptides represent an important class
of foldamers,8,9 as they can adopt various secondary structures
including helices, sheets and turns.7,10–12 More specifically, b-
peptides that contain or consist of b-aminocyclobutanecarboxylic
acid (b-ACBC 1) monomers show secondary structures both in
solution and in the solid state. The first cyclobutane-containing
dipeptide, which was synthesised by the group of Ortun˜o starting
from cis-b-ACBC 1a, shows a hairpin-like conformation in the
solid state, while a cis-cyclobutane-containing b-tetrapeptide and
hexa- and octamers of trans-b-ACBC 1b fold into 14- and 12-
helical conformations resulting from the formation of inter-
and intramolecular hydrogen bonds.13–15 Moreover, a b-peptide
composed of four cis-b-ACBC 1a residues has shown molecular
self-assembly to form nanosized fibrils and gels,16 and trans,trans-
and trans,cis-bis(cyclobutane)-b-dipeptides show a tendency to
assemble into nanoscale fibres.17,18
derivatives.
The most common way to synthesize b-ACBC deriva-
tives uses a [2 + 2] cycloaddition step.22–26 As such, the
group of Aitken recently developed a route to synthesize
the four enantiomers of b-aminocyclobutanecarboxylic acid
1, each in enantiomerically pure form.27,28 In previous re-
search, dialkyl 2-bromoethylidenemalonates and dialkyl 3-
chloropropylidenemalonates proved to be suitable substrates for
the Michael Induced Ring Closure (MIRC) reaction towards a
range of functionalised cyclopropanes and some cyclobutanes.29–32
b-Aminocyclobutanedicarboxylic acid derivatives are a poorly
studied class of donor–acceptor (DA) substituted cyclobutanes
which are prone to ring opening reactions.33,34 Therefore, in this
work, the use of 3-halopropylidenemalonate derivatives as sub-
strates for the synthesis of new b-aminocyclobutanedicarboxylic
acid derivatives via an aza-MIRC reaction was investigated.
Another reason for the enhanced interest in carbocyclic b-
amino acids is the biological activity of some of these con-
strained compounds, e.g. cis-2-aminocyclopentanecarboxylic acid
2 (cispentacin) which has shown antifungal activity against
various Candida strains.19,20 The in vitro antifungal activity of b-
aminocyclobutanecarboxylic acid 1 and 3- or 4-methylene-ACBC
against Candida strains is dramatically lower.19,21
Results and discussion
Commercially available 3-halopropanols 3 were transformed into
the corresponding aldehydes 4 using pyridinium chlorochromate
(PCC) as oxidizing agent.35 Subsequently, the Knoevenagel con-
densation of aldehydes 4 with malonates 5a–b and malononitrile
5c in the presence of titanium(IV) chloride and pyridine yielded 3-
halopropylidenemalonates 6a–d and -malononitrile 6e in 35–63%
yield.36 (Scheme 1)
Department of Sustainable Organic Chemistry and Technology, Faculty of
Bioscience Engineering, Ghent University, Coupure links 653, B-9000 Ghent,
Belgium. E-mail: norbert.dekimpe@UGent.be
† This article is part of an Organic & Biomolecular Chemistry web theme
issue on Foldamer Chemistry.
‡ Electronic supplementary information (ESI) available. See DOI:
10.1039/c1ob05872j
§ Postdoctoral Fellow of the Research Foundation-Flanders (FWO).
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Scheme 1
Although the MIRC reaction of dimethyl (3-chloro-2,2-
dimethylpropylidene)malonate 6b with various nucleophiles (e.g.
methoxide, cyanide and tert-butylthiolate) yielded new b-
substituted cyclobutanedicarboxylates,31 treatment of malonate
6b with different nitrogen nucleophiles in order to obtain novel
b-ACBC derivatives was initially not successful. It appeared
that primary and secondary amines could not be used as
nucleophiles in this MIRC reaction. The Michael addition of
benzylamine, analogous to isopropylamine,31 across dimethyl 2-
(3-chloro-2,2-dimethylpropylidene)malonate 6b was followed by
a retro-Mannich type reaction that led to the formation of
N-(3-chloro-2,2-dimethylpropylidene)benzylamine and dimethyl
malonate 5a. Also the attempt to use a secondary amine, i.e.
pyrrolidine, as a nucleophile in the aza-MIRC reaction, was not
successful. In this case, a substitution of the leaving group by the
nucleophile was mainly observed, which was in analogy with the
outcome of the reaction of dialkyl 2-bromoethylidenemalonates
and secondary amines.37
the yield of the Michael addition of benzophenone imine across
alkylidenemalonate 6b to 67% and shortened the reaction time
(Table 1, Entry 2). The low solubility of adduct 7b in Et2O led
to a better conversion of the starting product 6b, disfavoring
the reverse retro-Michael reaction. 3-Bromoalkylidenemalonate
6a was treated with benzophenone imine under similar reaction
conditions to obtain pure b-amino ester 7a in 56% yield (Table 1,
Entry 3). Unfortunately, the Michael addition of benzophenone
imine leading to dimethyl malonates 7a and 7b proved to be poorly
reproducible under these conditions. Furthermore, the addition
of benzophenone imine across diethyl alkylidenemalonates 6c–d
appeared to be even more problematic, which is probably due to
the steric hindrance caused by the presence of the two geminal
ethyl esters on the double bond. When diethyl 2-(3-chloro-2,2-
dimethylpropylidene)malonate 6d was treated with 3 equiv of
benzophenone imine, only 66% conversion of the starting product
to the corresponding b-amino ester 7d could be observed after six
days of reaction (Table 1, Entry 4). In addition, the presence of
an excess of benzophenone imine in the crude reaction mixture
made isolation of the Michael adduct 7d very difficult to virtually
impossible.
Subsequently, sodium azide was evaluated as nitrogen nucleo-
phile. Sodium azide is
a
suitable nucleophile in the
synthesis of b-aminocyclopropanecarboxylic acid (b-ACC)
derivatives via the MIRC reaction starting from 2-bromoethyl-
idenemalonates.30,38 However, when dimethyl 2-(3-chloro-2,2-
dimethylpropylidene)malonate 6b was treated with sodium azide
under different reaction conditions in which the solvent (MeOH,
DMF, DMSO, acetone, tBuOH), temperature (r.t.–D) and time
were varied, no smooth conversion of the starting product to
the target cyclobutane derivative or Michael adduct could be
observed.
Therefore, other conditions for the Michael addition of ben-
zophenone imine across 3-halo alkylidenemalonates 6 had to be
explored. Neither altering the solvent (tBuOH–THF 4 : 1, Et2O,
THF, CH2Cl2, CH3CN) led to better results, nor did the use of
other bases (NaH, KOtBu) or addition of a Lewis acid (MgBr2).
The reaction was also conducted under microwave irradiation and
in a pressure vial, but again no good conversion of substrates 6 to
the corresponding acyclic b-amino esters 7 was observed.
Benzophenone imine has proven to be a suitable nucleo-
phile in the MIRC reaction starting from dialkyl 2-bromoalkyl-
idenemalonates leading to dialkyl 2-(diphenylmethylideneamino)
cyclopropane-1,1-dicarboxylates.29 Therefore, the reactivity of this
nitrogen nucleophile in the MIRC reaction towards dialkyl 2-
(diphenylmethylideneamino)cyclobutane-1,1-dicarboxylates was
investigated. To our satisfaction, when tert-butanol was used as
solvent, instead of more nucleophilic MeOH which gave rise to
side reactions, and in the presence of triethylamine as a base,
the Michael addition of benzophenone imine across malonate 6b
was observed, but the intramolecular substitution of the leaving
group in d-position which would lead to ring closure did not
occur. Thus, acyclic b-amino ester 7b was isolated in 57% yield
after recrystallization from Et2O (Table 1, Entry 1). The use of
the solvent mixture t-BuOH–Et2O in a ratio of 4 : 1 increased
After many attempts, it was found that the Michael addition
of benzophenone imine across alkylidenemalonates 6, using
Et3N as a base, could be achieved in the absence of a solvent
(neat conditions). Treatment of alkylidenemalonates 6a,b,d with
1.05 equiv benzophenone imine in the presence of triethylamine
at 60 ◦C for 4–48 h led to a full conversion to the corresponding
Michael adducts 7a,b,d, which were isolated in 67–79% yield after
recrystallization from Et2O (Table 1, Entries 5–7). The reaction
of diethyl 2-(3-bromo-2,2-dimethylpropylidene)malonate 6c and
benzophenone imine, however, gave rise to the formation of
an alternative product, more specifically diethyl 2-[2,2-dimethyl-
3-(diphenylmethylideneamino)propylidene]malonate 8b (Table 1,
Entry 8). The steric hindrance caused by the presence of the
two geminal ethyl esters hampered the Michael addition of the
nucleophile across the activated double bond, and in combination
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Table 1 Michael addition of benzophenone imine across alkylidenemalonates 6
Entry
Substrate
Reaction conditions
Compound (Yield)a
1
2
3
4
5
6
7
8
9
6b
6b
6a
6d
6a
6b
6d
6c
6c
tBuOH, D, 72 h
7b (57%)
7b (67%)
7a (56%)
7d (–)c
7a (79%)
7b (78%)
7d (67%)
8b (38%)
7c (76%)
tBuOH–Et2O 4 : 1, D, 55 h
tBuOH–Et2O 4 : 1, D, 24 h
tBuOH–Et2O 4 : 1, D, 6 db
neat, 60 ◦C, 4 h
neat, 60 ◦C, 24 h
neat, 60 ◦C, 48 h
neat, 60 ◦C, 20 h
neat, r.t., 119 h
a Isolated yield after recrystallization from Et2O. b Reaction was carried out with 3 equiv benzophenone imine and 3 equiv Et3N. c 66% conversion after 6
days, compound 7d was not isolated.
with the presence of a good leaving group (in this case bromide),
a direct substitution of the leaving group by the nucleophile
was more favorable. Detailed spectroscopic follow-up of the
reactions showed that this substitution reaction did not occur
when malonates 6a, 6b and 6d were used as substrates. The
reaction of malonate 6c and benzophenone imine proceeded more
selectively towards the Michael adduct 7c at room temperature,
but in this case a longer reaction time was required (Table 1,
Entry 9).
Scheme 2
and suffered from competitive retro-Michael addition giving rise
to alkylidenemalonate 6b (up to 50%). The presence of chloride as
leaving group and the sterically impeding geminal methyl groups
prevent a smooth cyclobutanation of diester 7b. Fortunately, the
addition of a catalytic amount of NaI to achieve an in situ exchange
of chloride by iodide, to the reaction of malonates 7b and 7d with
KOtBu in THF under reflux conditions, led to the desired clean
cyclization to b-ACBC derivatives 9a and 9b which were isolated
in 52–62% yield (Scheme 3).
The use of 2-(3-chloro-2,2-dimethylpropylidene)malononitrile
6e as substrate for the Michael addition of benzophenone imine
under similar neat reaction conditions, resulted in an intractable
mixture of reaction products in which the corresponding Michael
adduct could not be detected.
Nevertheless, in this manner, a very simple, practical and
more sustainable method for the Michael addition of ben-
zophenone imine across alkylidenemalonates 6a–d, without
the use of hazardous and volatile solvents, was developed.
In the very recent literature, other examples of solvent free
aza–Michael additions across unsaturated substrates have been
reported.39–41
In order to synthesize the target b-aminocyclobutanecarboxylic
acid derivatives 9a and 9b, the acyclic b-amino esters 7a–d were
treated with
a base to enable ring closure. Treatment
of 2-[3-bromo-2,2-dimethyl-1-(diphenylmethylideneamino)-
propyl]malonates 7a and 7c with 1.2 equiv of KOtBu in
THF for three hours at reflux temperature afforded b-amino-
cyclobutanecarboxylic acid derivatives 9a and 9b in good to
excellent yield (Scheme 2).
The cyclization of dimethyl 2-[3-chloro-2,2-dimethyl-1-
(diphenylmethylideneamino)propyl]malonate 7b to the corre-
sponding cyclobutane 9a was less straightforward. When KOtBu
in tert-butanol under reflux or KHMDS or LiHMDS in THF at
room temperature were used as basic conditions, the cyclization
of malonate 7b to cylobutane 9a was sluggish (0–66% conversion)
Scheme 3
In an attempt to synthesize the functionalized cyclobutanes 9a
and 9b in one step via the Michael Induced Ring Closure (MIRC)
reaction, malonates 6a–d were treated with benzophenone imine
in DMF at 55–65 ◦C in the presence of K2CO3 as a mild base
(Scheme 4). Under these conditions, the addition of benzophenone
imine to the activated substrates was followed by an intramolecular
substitution of the leaving group and cyclobutanes 9a,b could be
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Scheme 4
isolated, albeit in rather low yields after recrystallization from
MeOH.
Upon reaction of malononitrile 6e in DMF at different tempera-
tures, a different reactivitytowards benzophenone imine compared
to malonates 6a–d was observed and a tetrahydropyridine was
isolated. Detailed information about this reaction and on the
thermal stability of functionalised cyclobutanes 9a–b in DMF can
be found in the ESI‡ (Section 1 and 2).
As second part of the reactivity study of the novel b-
aminocyclobutanecarboxylic acid derivatives 9, the reduction of
the imino function using NaCNBH3 in the presence of acetic
acid was carried out. Through this reduction, the donor–acceptor
substituted b-ACBC derivatives 11 are formed. The latter small-
membered rings are, unlike b-ACBC 1, not stable due to the
presence of the two geminal ester functions which exhibit a
strong electron-withdrawing effect. Accordingly, cyclobutanes 11
open via a push–pull mechanism towards imines 12, which
in turn are reduced to new d-amino esters 10 (70–90% yield)
(Scheme 5).42
Scheme 5
Michael addition of benzophenone imine, leads to instability of the
target cyclobutanes 9 under reducing and hydrolytic conditions.
Therefore, it was attempted to eliminate one of the ester func-
tions by a decarboxylation reaction under Krapcho conditions
(utilizing NaCl or LiBr in DMSO/H2O),43 but this was not
successful.
As a final part of the reactivity study, several attempts were
made to hydrolyze the ester functions of cyclobutanes 9 in
order to obtain the corresponding N-protected cyclic b-amino
acids. Unfortunately, none of the reaction conditions that were
tested (the use of aq. NaOH, NaOH in MeOH or LiOH·H2O)
led to the formation of the envisioned acids. Other methods
to transform these new b-amino esters 9 into the correspond-
ing b-amino acids are currently under investigation in our
lab.
The hydrolysis of the imino function of cyclobutane 9a, in
order to evaluate the possibility of forming the corresponding
b-amino acid eventually, led to the formation of an unstable b-
ACBC derivative 15, which was again prone to ring opening via a
push–pull mechanism due to the presence of the donor–acceptor
substituted cyclobutane ring. The crude reaction mixture, which
was not purified, contained aldehyde 13 and benzophenone 14 in
a 1 : 1 ratio (determined by analysis of the 1H NMR spectrum of
the crude reaction mixture) (Scheme 6).
Conclusion
In conclusion, a novel method to synthesize highly substituted
b-ACBC derivatives starting from 3-halopropylidenemalonates
was developed, using benzophenone imine in a solvent-free
aza–Michael addition followed by a base-induced ring clo-
sure. A reactivity study of these novel cyclobutanedicarboxy-
lates demonstrated the necessity of a suitable protecting group
on nitrogen to avoid ring opening of these small-membered
rings.
The presence of the two ester functions, which activate the
double bond of the starting compounds 6a–d, in order to enable the
Scheme 6
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is described here. In a flame-dried flask, triethylamine (2 mmol,
1.05 equiv) was added to a mixture of dimethyl 2-(3-bromo-2,2-
dimethylpropylidene)malonate 6a (1.9 mmol, 1 equiv) and ben-
zophenone imine (2 mmol, 1.05 equiv). This mixture was stirred at
60 ◦C under solvent-free conditions for four hours. Subsequently,
dry diethyl ether was added, the solution was filtered and the
filtrate was concentrated in vacuo. Pure dimethyl 2-[3-bromo-2,2-
dimethyl-1-(diphenylmethylideneamino)propyl]malonate 7a was
obtained after recrystallization from diethyl ether in 79% yield.
General methods
1H NMR spectra (300 MHz) and 13C NMR spectra (75 MHz)
were recorded on a Jeol Eclipse+ 300 NMR spectrometer. IR
spectra were recorded on a Perkin Elmer Spectrum BX FT-IR
spectrometer. Mass spectra were recorded on an Agilent 1100
Series Mass spectrometer using a direct inlet system (ES, 4000V).
Melting points were measured with a Bu¨chi B-540 apparatus.
Elemental analyses were measured with a Perkin–Elmer 2400
Elemental Analyzer.
Dimethyl 2-[3-bromo-2,2-dimethyl-1-(diphenylmethylideneamino)-
propyl]malonate 7a
Experimental section
Yield 79%. White crystals. Mp = 140.6–142.1 ◦C. 1H NMR
(CDCl3, 300 MHz): d 0.94 (3H, s); 1.05 (3H, s); 3.30 (1H, d,
J = 9.9 Hz); 3.42 (1H, d, J = 9.9 Hz); 3.52 (3H, s); 3.70 (3H, s);
4.02 (1H, d, J = 6.1 Hz); 4.36 (1H, d, J = 6.1 Hz); 7.27–7.60 (10H,
m). 13C NMR (CDCl3, 75 MHz): d 22.1; 23.4; 40.7; 44.2; 52.4;
52.7; 53.9; 66.0; 128.0; 128.1; 128.6; 128.7; 130.3; 135.5; 139.6;
168.4; 168.6; 169.5. IR (ATR, cm-1): nC = 1732; nC = 1626.
Dialkyl 2-(3-halo-2,2-dimethylpropylidene)malonates 6 were pre-
pared following a literature procedure.31,36
Dimethyl 2-(3-bromo-2,2-dimethylpropylidene)malonate 6a
1
Yield 58%. Clear oil. Rf 0.28 (petroleum ether–EtOAc 6 : 1). H
NMR (CDCl3, 300 MHz): d 1.26 (6H, s); 3.37 (2H, s); 3.79 (3H,
s); 3.84 (3H, s); 6.92 (1H, s). 13C NMR (CDCl3, 75 MHz): d
25.2; 38.4; 44.0; 52.5; 52.7; 127.3; 151.1; 164.3; 166.8. IR (ATR,
cm-1): nC = 1730; nC = 1646. MS (ES, pos. mode): m/z (%):
O
N
MS (ES, pos. mode): m/z (%): 460/62 (M+H+, 100). Anal. Calcd
for C23H26BrNO4: C 60.01, H 5.69, N 3.04. Found: C 59.83, H
5.58, N 3.27.
O
C
279/81 (M+H+, 100). HRMS (ESI) calcd for C10H15BrO4 279.0232
(M+H+), found 279.0223.
Dimethyl 2-[3-chloro-2,2-dimethyl-1-(diphenylmethylideneamino)-
propyl]malonate 7b
Diethyl 2-(3-bromo-2,2-dimethylpropylidene)malonate 6c
Yield 78%. White crystals. Mp = 127.3–128.4 ◦C. 1H NMR
(CDCl3, 300 MHz): d 0.92 (3H, s); 1.04 (3H, s); 3.35 (1H, d,
J = 11.0 Hz); 3.47 (1H, d, J = 11.0 Hz); 3.53 (3H, s); 3.70 (3H, s);
4.04 (1H, d, J = 6.1 Hz); 4.34 (1H, d, J = 6.1 Hz); 7.28–7.60 (10H,
m). 13C NMR (CDCl3, 75 MHz): d 21.0; 22.3; 41.3; 52.4; 52.7;
53.3; 53.7; 65.9; 128.0; 128.1; 128.6; 128.7; 130.3; 135.6; 139.7;
168.4; 168.6; 169.4. IR (ATR, cm-1): nC = 1733; nC = 1657.
Yield 56%. Clear oil. Rf 0.18 (petroleum ether–EtOAc 20 : 1). 1H
NMR (CDCl3, 300 MHz): d 1.27 (6H, s); 1.29 (3H, t, J = 7.2
Hz); 1.34 (3H, t, J = 7.2 Hz); 3.39 (2H, s); 4.24 (2H, q, J = 7.2
Hz); 4.31 (2H, q, J = 7.2 Hz); 6.88 (1H, s). 13C NMR (CDCl3,
75 MHz): d 14.0; 14.1; 25.4; 38.4; 44.1; 61.6; 61.7; 128.1; 150.3;
163.9; 166.4. IR (ATR, cm-1): nC = 1726; nC = 1647. MS (ES,
O
C
O
N
pos. mode): m/z (%) = 307/09 (M+H+, 100). HRMS (ESI) calcd
MS (ES, pos. mode): m/z (%): 416/18 (M+H+, 100). Anal. Calcd
for C23H26ClNO4: C 66.42, H 6.30, N 3.37. Found: C 66.43, H
6.60, N 3.32.
for C12H19BrO4 307.0545 (M+H+), found 307.0554.
Diethyl 2-(3-chloro-2,2-dimethylpropylidene)malonate 6d
Yield 63%. Clear oil. Rf 0.20 (petroleum ether–EtOAc 10 : 1). 1H
NMR (CDCl3, 300 MHz): d 1.24 (6H, s); 1.29 (3H, t, J = 7.2 Hz);
1.35 (3H, t, J = 7.2 Hz); 3.48 (2H, s); 4.24 (2H, q, J = 7.2 Hz); 4.31
(2H, q, J = 7.2 Hz); 6.90 (1H, s). 13C NMR (CDCl3, 75 MHz): d
14.0; 14.1; 24.5; 39.1; 54.4; 61.6; 61.7; 128.3; 150.1; 163.9; 166.5.
IR (ATR, cm-1): nC = 1726; nC = 1647. MS (ES, pos. mode):
Diethyl 2-[3-bromo-2,2-dimethyl-1-(diphenylmethylideneamino)-
propyl]malonate 7c
Prepared at room temper◦ature instead of 60 ◦C. Yield 76%. White
crystals. Mp = 96.9–97.4 C. 1H NMR (CDCl3, 300 MHz): d 0.93
(3H, s); 1.04 (3H, t, J = 7.2 Hz); 1.05 (3H, s); 1.23 (3H, t, J = 7.2
Hz); 3.31 (1H, d, J = 9.9 Hz); 3.43 (1H, d, J = 10.5 Hz); 3.88–4.04
(2H, m); 3.98 (1H, d, J = 6.6 Hz); 4.16 (2H, q, J = 7.2 Hz); 4.38 (1H,
d, J = 6.6 Hz); 7.26–7.60 (10H, m). 13C NMR (CDCl3, 75 MHz): d
13.9; 14.0; 22.0; 23.4; 40.8; 44.3; 54.3; 61.4; 61.6; 65.9; 127.9; 128.1;
128.6; 128.76; 128.82; 130.2; 135.6; 139.7; 167.9; 168.2; 169.3. IR
(ATR, cm-1): nC O = 1727; nC N = 1626. MS (ES, pos. mode): m/z
(%): 488/90 (M+H+, 100). Anal. Calcd for C25H30BrNO4: C 61.48,
H 6.19, N 2.87. Found: C 61.39, H 6.06, N 2.88.
O
C
m/z (%): 263/65 (M+H+, 100). HRMS (ESI) calcd for C12H19ClO4
263.1050 (M+H+), found 263.1044.
2-(3-Chloro-2,2-dimethylpropylidene)malononitrile 6e
1
Yield 35%. Clear oil. Rf 0.19 (petroleum ether–EtOAc 9 : 1). H
NMR (CDCl3, 300 MHz): d 1.46 (6H, s); 3.54 (2H, s); 7.29 (1H,
s). 13C NMR (CDCl3, 75 MHz): d 24.6; 41.8; 53.0; 89.6; 110.8;
112.6; 172.7. IR (ATR, cm-1): nCN = 2236; nC = 1607. MS (ES,
C
neg. mode): m/z (%): 194/96 (39), 185/87 (33), 149 (100).
Diethyl 2-[3-chloro-2,2-dimethyl-1-(diphenylmethylideneamino)-
propyl]malonate 7d
Synthesis of dialkyl 2-[3-halo-2,2-dimethyl-1-
(diphenylmethylideneamino)propyl]-malonates 7
Yield 67%. White crystals. Mp = 83.9–84.1 ◦C. 1H NMR (CDCl3,
300 MHz): d 0.91 (3H, s); 1.04 (3H, t, J = 6.9 Hz); 1.04 (3H, s);
1.23 (3H, t, J = 6.9 Hz); 3.36 (1H, d, J = 11.1 Hz); 3.47 (1H, d, J =
11.0 Hz); 3.94 (2H, q, J = 7.0 Hz); 3.99 (1H, d, J = 6.0 Hz); 4.16
As a representative example, the synthesis of dimethyl 2-[3-bromo-
2,2-dimethyl-1-(diphenylmethylideneamino)propyl]malonate 7a
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(2H, q, J = 6.8 Hz); 4.36 (1H, d, J = 6.6 Hz); 7.26–7.59 (10H, m).
13C NMR (CDCl3, 75 MHz): d 13.9; 14.0; 21.0; 22.3; 41.4; 53.4;
54.2; 61.4; 61.6; 65.8; 127.9; 128.0; 128.6; 128.77; 128.85; 130.2;
(1H, s); 7.15–7.64 (10H, m). 13C NMR (CDCl3, 75 MHz): d 23.8;
29.5; 37.0; 38.0; 52.4; 52.5; 53.7; 67.7; 128.0; 128.1; 128.3; 128.47;
128.51; 130.1; 136.5; 139.4; 167.9; 170.3; 172.1. IR (ATR, cm-1):
nC = 1725; nC = 1628. MS (ES, pos. mode): m/z (%): 380
135.6; 139.8; 168.0; 168.2; 169.3. IR (ATR, cm-1): nC = 1723;
O
O
N
nC N = 1627. MS (ES, pos. mode): m/z (%): 444/46 (M+H+, 100).
Anal. Calcd for C25H30ClNO4: C 67.63, H 6.81, N 3.15. Found: C
67.59, H 6.85, N 3.17.
(M+H+, 100). Anal. Calcd for C23H25NO4: C 72.80, H 6.64, N
3.69. Found: C 72.49, H 6.24, N 3.72.
Diethyl 3,3-dimethyl-2-(diphenylmethylideneamino)cyclobutane-
1,1-dicarboxylate 9b
Synthesis of diethyl 2-[2,2-dimethyl-3-(diphenylmethy-
lideneamino)propylidene]malonate 8b
◦
1
Yield 75%. White crystals. Mp 57.9–59.7 C. H NMR (CDCl3,
300 MHz): d 0.84 (3H, s); 1.10 (3H, t, J = 7.2 Hz); 1.12 (3H, s);
1.20 (3H, t, J = 7.2 Hz); 1.86 (1H, dd, J = 12.8 Hz, 1.4 Hz); 2.92
(1H, d, J = 12.8 Hz); 4.04–4.27 (4H, m); 4.42 (1H, s); 7.15–7.65
(10H, m). 13C NMR (CDCl3, 75 MHz): d 14.0; 14.2; 23.9; 29.4;
36.9; 38.1; 53.7; 61.1; 61.2; 67.7; 127.9; 128.1; 128.3; 128.4; 128.6;
In a flame-dried flask, triethylamine (1.7 mmol, 1.05 equiv)
was added to
a
mixture of diethyl 2-(3-bromo-2,2-
dimethylpropylidene)malonate 6c (1.6 mmol, 1 equiv) and
benzophenone imine (1.7 mmol, 1.05 equiv). The reaction
mixture was stirred at 60 ◦C under solvent-free conditions for 20
h. Subsequently, dry diethyl ether was added, the solution was
filtered and the solvent was removed in vacuo. Pure diethyl 2-[2,2-
dimethyl-3-(diphenylmethylideneamino)propylidene]malonate 8b
was obtained after recrystallization from diethyl ether in a yield
of 38%.
130.0; 136.6; 139.5; 167.7; 169.8; 171.6. IR (ATR, cm-1): nC
=
O
1726; nC = 1661. MS (ES, pos. mode): m/z (%): 408 (M+H+,
N
100). Anal. Calcd for C25H29NO4: C 73.68, H 7.17, N 3.44. Found:
C 73.58, H 7.33, N 3.35.
Synthesis of dialkyl 2-[2,2-dimethyl-3-(diphenylmethylamino)-
propyl]malonates 10
Diethyl 2-[2,2-dimethyl-3-(diphenylmethylideneamino)-
propylidene]malonate 8b
The synthesis of dimethyl 2-[2,2-dimethyl-3-(diphenylmethyl-
amino)propyl]malonate 10a is described as a representative ex-
ample. To a solution of cyclobutane 9a (0.37 mmol, 1 equiv) in
MeOH (4 mL), NaCNBH3 (0.92 mmol, 2.5 equiv) and acetic
acid (0.44 mmol, 1.2 equiv) were added. The reaction mixture
was stirred at room temperature for 17 h, poured into 0.5 N
NaOH (10 mL) and extracted with CH2Cl2 (3 ¥ 5 mL). Subse-
quently, the combined organic fractions were dried over MgSO4.
Removal of the drying agent through filtration and evaporation
of the solvent in vacuo afforded dimethyl 2-[2,2-dimethyl-3-
(diphenylmethylamino)propyl]malonate 10a which was purified
by column chromatography on silica gel (petroleum ether–EtOAc
1 : 1).
◦
1
Yield 38%. White crystals. Mp 75.6–77.0 C. H NMR (CDCl3,
300 MHz): d 1.18 (6H, s); 1.28 (3H, t, J = 7.2 Hz); 1.31 (3H, t, J =
7.2 Hz); 3.31 (2H, s); 4.22 (2H, q, J = 7.2 Hz); 4.24 (2H, q, J = 7.2
Hz); 7.07 (1H, s); 7.11–7.15 (2H, m); 7.29–7.50 (6H, m); 7.61–7.65
(2H, m). 13C NMR (75 MHz, CDCl3): d 14.0; 14.1; 24.7; 39.4;
61.26; 61.35; 64.2; 126.4; 127.8; 128.0; 128.4; 128.5; 128.6; 130.0;
136.8; 139.8; 153.7; 164.5; 167.0; 168.7. IR (ATR, cm-1): nC
=
O
1725; nC = 1646, nC = 1626.). MS (ES, pos. mode): m/z (%):
C
N
408 (M+H+, 100). Anal. Calcd for C25H29NO4: C 73.68, H 7.17, N
3.44. Found: C 73.28, H 7.17, N 3.41.
Synthesis of dialkyl 3,3-dimethyl-2-(diphenylmethylideneamino)-
cyclobutane-1,1-dicarboxylates 9
Dimethyl 2-[2,2-dimethyl-3-(diphenylmethylamino)propyl]-
malonate 10a
As a representative example, the synthesis of dimethyl 3,3-
dimethyl-2-(diphenylmethylideneamino)cyclobutane-1,1-dicar-
boxylate 9a is described. To a solution of dimethyl 2-[3-bromo-2,2-
dimethyl-1-(diphenylmethylideneamino)propyl]malonate 7a (0.9
mmol, 1 equiv) in dry THF (10 mL), 1.2 equiv KOtBu (1.08
mmol) was added. After stirring the reaction mixture at reflux
temperature for three hours, an aqueous saturated solution of
ammonium chloride (10 mL) was added and this mixture was
extracted with EtOAc (3 ¥ 10 mL). The combined organic
layers were dried over MgSO4. The drying agent was removed
by filtration and the filtrate was concentrated in vacuo. Af-
ter recrystallization from MeOH, pure dimethyl 3,3-dimethyl-
2-(diphenylmethylideneamino)cyclobutane-1,1-dicarboxylate 9a
was obtained as white crystals in a yield of 94%.
Yield 70%. Viscous oil. Rf 0.17 (petroleum ether–EtOAc 10 : 1).
1H NMR (CDCl3, 300 MHz): d 0.88 (6H, s); 1.54 (1H, br s); 2.03
(2H, d, J = 6.6 Hz); 2.31 (2H, s); 3.46 (1H, t, J = 6.3 Hz); 3.68 (6H,
s); 4.70 (1H, s); 7.16–7.40 (10H, m). 13C NMR (CDCl3, 75 MHz):
d 25.4 (CH3); 34.1 (C); 38.2 (CH2); 47.9 (CH); 52.6 (CH3); 58.2
(CH2); 68.1 (CH); 126.9 (CH); 127.3 (CH); 128.4 (CH); 144.4 (C);
170.7 (C). IR (ATR, cm-1): nC = 1733. MS (ES, pos. mode):
O
m/z (%): 384 (M+H+, 100). HRMS (ESI) calcd for C23H29NO4
384.2175 (M+H+), found 384.2157.
Diethyl 2-[2,2-dimethyl-3-(diphenylmethylamino)propyl]malonate
10b
Yield 90%. Viscous oil. Rf 0.28 (petroleum ether–EtOAc 9 : 1). 1H
NMR (CDCl3, 300 MHz): d 0.89 (6H, s); 1.22 (6H, t, J = 7.2 Hz);
1.57 (1H, br s); 2.03 (2H, d, J = 6.1 Hz); 2.31 (2H, s); 3.41 (1H,
t, J = 6.3 Hz); 4.13 (2H, qxd, J = 10.7, 7.2 Hz); 4.15 (2H, qxd,
J = 11.0, 7.2 Hz); 4.71 (1H, s); 7.15–7.41 (10H, m). 13C NMR
(CDCl3, 75 MHz): d 14.0 (CH3); 25.5 (CH3); 34.1 (C); 38.0 (CH2);
Dimethyl 3,3-dimethyl-2-(diphenylmethylideneamino)cyclobutane-
1,1-dicarboxylate 9a
Yield 94%. White crystals. Mp 123.4–124.2 ◦C. 1H NMR (CDCl3,
300 MHz): d 0.82 (3H, s); 1.11 (3H, s); 1.86 (1H, d, J = 12.7
Hz); 2.91 (1H, d, J = 12.6 Hz); 3.67 (3H, s); 3.72 (3H, s); 4.43
7090 | Org. Biomol. Chem., 2011, 9, 7085–7091
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48.3 (CH); 58.1 (CH2); 61.4 (CH2); 68.1 (CH); 126.9 (CH); 127.2
17 E. Torres, E. Gorrea, E. Da Silva, P. Nolis, V. Branchadell and R. M.
Ortun˜o, Org. Lett., 2009, 11, 2301–2304.
18 E. Gorrea, P. Nolis, E. Torres, E. Da Silva, D. B. Amabilino, V.
Branchadell and R. M. Ortun˜o, Chem.–Eur. J., 2011, 17, 4588–4597.
19 A. Kuhl, M. G. Hahn, M. Dumic and J. Mittendorf, Amino Acids, 2005,
29, 89–100.
20 T. Oki, M. Hirano, K. Tomatsu, K. Numata and H. Mamei, J.
Antibiotics, 1989, 42, 1756–1762.
21 J. Mittendorf, F. Kunisch, M. Matzke, H. C. Militzer, A. Schmidt and
W. Scho¨nfeld, Bioorg. Med. Chem. Lett., 2003, 13, 433–436.
22 D. J. Aitken, D. Gauzy and E. Pereira, Tetrahedron Lett., 2002, 43,
6177–6179.
(CH); 128.4 (CH); 144.4 (C); 170.3 (C). IR (ATR, cm-1): nC
=
O
1748; nC = 1729. MS (ES, pos. mode): m/z (%): 412 (M+H+,
O
100). HRMS (ESI) calcd for C25H33NO4 412.2488 (M+H+), found
412.2473.
Acknowledgements
The authors are indebted to Ghent University (GOA) and the
Fund for Scientific Research-Flanders (FWO-Vlaanderen) for
financial support.
23 C. Gauzy, C. Pereira, S. Faure and D. J. Aitken, Tetrahedron Lett., 2004,
45, 7095–7097.
24 C. Gauzy, B. Saby, E. Pereira, S. Faure and D. J. Aitken, Synlett, 2006,
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