Simple and convenient method for the synthesis of 2-substituted glutaconaldehyde salts and 2-substituted glutaconaldehyde derivatives

Article abstract of DOI:10.1055/s-0029-1217105

Convenient and scalable syntheses of 2-substituted glutaconaldehyde salts were accomplished from the corresponding pyridinium salts. Glutaconaldehyde salts were additionally converted into aminopentadienal derivatives.

Full text of DOI:10.1055/s-0029-1217105

PAPER
103
Simple and Convenient Method for the Synthesis of 2-Substituted
Glutaconaldehyde Salts and 2-Substituted Glutaconaldehyde Derivatives
2
-Substituted G
u
lutaconaldeh
a
yde
D
eriva
n
tives Minh Nguyen, Sabrina Peixoto, Cécile Ouairy, Tung Dinh Nguyen, Michel Bénéchie, Christian Marazano†,*
Patrick Michel*
Centre de Recherche CNRS de Gif-sur-Yvette, Institut de Chimie des Substances Naturelles,
Avenue de la terrasse, 91198 Gif-sur-Yvette, France
Fax +33(1)69077247; E-mail: Patrick.Michel@icsn.cnrs-gif.fr
Received 30 July 2009; revised 24 August 2009
In memory of the late Dr. Christian Marazano who passed away on 12th November 2008
ly not adapted for convergent synthesis involving a highly
functionalized secondary amine. Another issue is also the
availability and the stability of the more reactive Zincke
aldehydes derived from primary amines due to their pro-
pensity to form a pyridinium salt (Scheme 2).5
Abstract: Convenient and scalable syntheses of 2-substituted
glutaconaldehyde salts were accomplished from the corresponding
pyridinium salts. Glutaconaldehyde salts were additionally convert-
ed into aminopentadienal derivatives.
Key words: Zincke aldehydes, aminopentadienal derivatives, pyri-
dinium salts, glutaconaldehyde
R
R
R
R2NH
Cl–
N
R
N+
Cl–
N
R
O
N+
A
We have proposed1 recently that the biosynthetic pathway
of manzamine alkaloids could involve substituted 5-ami-
nopenta-2,4-dienals, which could be formed by condensa-
tion of malonaldehyde with an aldehyde and subsequently
with an amine (Scheme 1).
R
RNH2
R
or
N
O
H
N+
N+
R
Cl–
Cl–
A
H
A = generic activating group
O
O
N
R2
R1
Scheme 2
O
– H2O
R2NH2
– H2O
R1
To overcome the above drawbacks, we investigated the
possibility to form aminopentadienals directly from
amine salts and glutaconaldehyde salts. Moreover, one
advantage of this strategy is that the starting materials are
water soluble whereas the final compound is soluble in the
organic phase. This should allow some unstable aldehydes
to be easily obtained with sufficient purity for the next
step through simple extraction.
R1
O
O
O
Scheme 1 Biogenetic scenario for the formation of aminopenta-
dienals
In order to test the chemical feasibility of this modifica-
tion of the Baldwin and Whitehead hypothesis,2 the syn-
thesis of aminopentadienals and one of their plausible
precursors, the glutaconaldehydes, was necessary.
The salts of glutaconaldehydes, first described by
Baumgarten6 in 1924, have been mostly used in the liter-
ature for intramolecular Diels–Alder7 reactions (after O-
acetylation) and for the synthesis of polyenic com-
pounds.8 Sodium or potassium salts of unsubstituted
glutaconaldehydes could be easily obtained by simple fil-
tration.9 However substituted glutaconaldehydes salts
were rarely made and the preparation involved a tedious
removal of a large quantity of water along with repeated
precipitation and filtration steps.10 Moreover, the reactiv-
ity was highly dependant of the method of preparation and
purification.
The ability of aminopentandienals to function both as
nucleophiles1 and electrophiles could allow for their use
as tailored reagents towards creating synthetic diversity.
The easiest way to obtain aminopentadienals (Zincke al-
dehydes) is to open appropriately activated pyridinium
salts as described over a century ago by Zincke and
König.3 Although examples appeared recently in the liter-
ature notably by Vanderwal and Marazano,4 the potential
of these compounds as versatile intermediates for natural
product synthesis remains largely unexploited. One limi-
tation for a more widespread use of Zincke aldehydes may
be their accessibility. Indeed, the use of two equivalents of
amine required to form the intermediate iminium is clear-
The new approach begins with the ring opening of 2,4-
dinitropyridinium salts 11b,11 using dimethylamine to af-
ford a mixture of (dimethylamino)pentadienals 2 and 3
(Table 1). 2,4-Dinitroaniline released during the reaction
is insoluble in water and is removed easily by simple fil-
tration before hydrolysis of the iminium salt. The relative-
ly modest yield of 2c can be explained by the solubility of
SYNTHESIS 2010, No. 1, pp 0103–0109
Advanced online publication: 06.11.2009
DOI: 10.1055/s-0029-1217105; Art ID: Z16009SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
0
9

104
T. M. Nguyen et al.
PAPER
this compound in water. In this particular case, the mini- substituent could be an alkyl group, a functionalized
mum amount of water should be used to remove the dini- chain, or a heteroatom. Moreover, the purification in-
troaniline. The mixture of 2e and 3e appears unstable, volves simple extraction or filtration allowing for the pro-
therefore it should be used directly in the next step. Ac- cess to be scalable.
cording to the literature, the reaction of 1e with dimethy-
Zincke aldehydes 5 derived from primary amines or sec-
ondary amines could be obtained easily by coupling gluta-
conaldehyde 4 with the corresponding amines (Table 2).
The reaction of one equivalent of alkylammonium trifluo-
roacetate salt (or 1 equivalent of the amine and 1 equiva-
lent trifluoroacetate) and a slight excess of 4 in
lamine affords only one compound 2e in 53% yield.12 We
observed that the experimental conditions used for hy-
drolysis of the intermediate iminium salt could change the
proportion of 2e/3e from 2:1 to 9:1. However, when the
ratio 2e/3e increases the overall yield of the reaction si-
multaneously decreases. This result could be due to the
dichloromethane afforded, after simple extraction, only
greater instability of 3e compared to 2e under the hydro-
one isomer 5, which could be used without further purifi-
cation. Indeed, unreacted starting materials or possible
lysis conditions.
byproducts like pyridinium salts will remain in the aque-
ous phase, whilst the product 5 will stay in the organic
phase. It was observed that the addition of one drop of wa-
ter to the solution accelerated the reaction.
Table 1 Synthesis of 2-Subtituted Glutaconaldehyde Salts
Me
R
N
O
2
Me
R
N+
Cl–
1. Me2NH
2. NaOH
Me
KOH
KO
O
+
O2N
Table 2 Synthesis of 2-Substituted Aminopentadienal
THF–MeOH
R
R2R3NH, TFA
R2
4
KO
N
O
O
N
O
R3
R1
R1
3
CH2Cl2
NO2
Me
R
4
5
1
Entry Substrate R1
R2R3NHa
Product Yield (%)
Zincke salt
R
Ratio 2/3 Yield (%) Product Yield (%)
1
2
4a
4a
4b
4b
4b
4c
4d
4e
4f
H
BnNH2
Bn2NH
BnNH2
BuNH2
PMBNH2
BnNH2
5a
5b
5c
5d
5e
5f
98
1a
1b
1c
H
1:0
1:0
83
84
51
–
4a
4b
4c
4d
4e
4f
93
80
83
71b
65
69
H
97
Me
3
Me
79
(CH2)2OH 1:0
(CH2)10OH 5:1
4
Me
82
1da
1e
5
Me
82
OMe
Br
2:1
91
82
6
(CH2)2OH
70b
88
c
b
–
–
7
(CH2)10OH PMBNH2
5g
5h
5i
a The precursor of Zincke salt 1d was obtained in 3 steps from 3-me-
thylpicoline.
8
OMe
Br
PMBNH2
BnNH2
92
b Yield over two steps.
c 2f was obtained directly by bromination of 2a.13
9
63b
53b
10
4f
Br
PMBNH2
5j
To simplify the purification of 4 it was necessary to find a
suitable solvent or a mixture of solvents where potassium
hydroxide and the (dimethylamino)pentadienal are solu-
ble whilst the glutaconaldehyde salt formed precipitates
out of solution. Initial attempts with a mixture of tetrahy-
drofuran–water resulted in a biphasic system without any
precipitation. Finally a solvent system of tetrahydrofuran–
methanol or diethyl ether–methanol did indeed dissolve
potassium hydroxide and allowed for precipitation of the
glutaconaldehyde salt 4. Although the crude product ob-
tained directly by filtration of the reaction seems clean by
NMR, it is crucial to dissolve the solid in cold methanol
or ethanol and then filter the solution through Celite. Al-
though few insoluble materials were removed during the
process, it is not yet clearly understood why the reactivity
could be so different.14 Moreover, absence of water during
the reaction allows the formation of an anhydrous salt 4.
a PMB = 4-methoxybenzyl.
b Yield after column chromatography.
Some aminopentadienals 5 could be further purified by
column chromatography (Table 2, entry 6, 9, and 10), but
it is not really required and can increase the possible risk
of cyclization or decomposition of the compound. Sec-
ondary amines (Table 2, entry 2) could also react with 4.
Thus, this method, which uses only one equivalent of
amine, is a good alternative for the preparation of Zincke
aldehydes.
The same strategy could also be applied to obtain malon-
aldehyde salts (Scheme 3). Commercially available 3-
(dimethylamino)prop-2-enal (6) could be hydrolyzed to
the salt 7 under the same conditions described above for
the glutaconaldehyde salts. However, the reaction of 7
This procedure, thus, provides a convenient and reliable
access to 2-substituted glutaconaldehyde salts where the
Synthesis 2010, No. 1, 103–109 © Thieme Stuttgart · New York

PAPER
2-Substituted Glutaconaldehyde Derivatives
105
Celite. The filtrate was concentrated in vacuo to give 4a as a brown
solid; yield: 3.05 g (93%); mp >400 °C.
IR: 2786, 1595, 1516, 1370, 1186, 1021, 847, 649 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 5.11 (dd, J = 13.1, 9.2 Hz, 2 H,
2 CH), 7.05 (t, J = 13.1 Hz, 1 H, CH), 8.67 (d, J = 9.2 Hz, 2 H, 2
CH).
Bn
N
H
8a
BnNH2, TFA
KOH
O
+
Me
N
O
KO
O
84%
THF–MeOH
Me
6
Bn
7
93%
N
O
8b
H
13C NMR (75 MHz, DMSO-d6): d = 106.7, 160.3, 184.9.
MS (ESI–): m/z (%) = 97 ([M – K]–, 100).
Scheme 3
with benzylamine afforded a mixture of cis/trans-
enamine 8 in a 1:1 ratio.15
(2E,4E)-5-(Dimethylamino)-2-methylpenta-2,4-dienal (2b)
Me2NH (95 mL, 40 wt% in H2O, 357.1 mmol) was added to a stirred
soln of Zincke salt 1b (105.6 g, 357.1 mmol) in EtOH (300 mL) at
r.t. The mixture was stirred at reflux for 1 h, concentrated in vacuo,
and treated with cold H2O (200 mL). The yellow 2,4-dinitroaniline
was removed by filtration through Celite. The filtrate was washed
with Et2O (5 × 300 mL), basified with 5 M NaOH soln (200 mL),
and extracted with CH2Cl2 (5 × 400 mL). The organic layers were
combined, dried (MgSO4), filtered, and concentrated in vacuo to
give 2b as a red solid; yield: 42 g (84%); mp 73 °C.
In summary, we have described a convenient method for
the preparation of 2-substituted glutaconaldehyde salts
and 2-substituted aminopentadienals. These useful inter-
mediates should find application in a range of synthetic
programs. Further work is in progress in our laboratory to
investigate the enamine-like reactivity of these species.
IR: 2909, 1555, 1380, 1187, 957, 800 cm–1.
Unless otherwise specified, materials were purchased from com-
mercial suppliers and used without further purification. CH2Cl2 was
distilled from P2O5. THF was distilled from Na/benzophenone ketyl
immediately before use. All other solvents were used as obtained
from commercial sources. Analytical TLC was performed on Merck
silica gel plates (60 F254) and visualized by UV fluorescence or
KMnO4. Flash column chromatography was carried out using
Merck silica gel (Geduran SI 60, 0.040–0.063 mm). Melting points
were measured on a Büchi melting point B-540 apparatus. IR spec-
tra were recorded on a Perkin-Elmer Spectrum-BX spectrophotom-
1H NMR (300 MHz, CDCl3): d = 1.77 (s, 3 H, CH3), 2.96 (s, 6 H, 2
CH3), 5.22 (t, J = 12.5 Hz, 1 H, CH), 6.76 (d, J = 12.5 Hz, 1 H, CH),
6.85 (d, J = 12.5 Hz, 1 H, CH), 9.18 (s, 1 H, CH).
13C NMR (75 MHz, CDCl3): d = 9.19, 41.2 (br s), 95.0, 126.1,
151.5, 153.7, 192.8.
HRMS (ESI+): m/z [M + H]+ calcd for C8H14NO: 140.1075; found:
140.1078.
1
(2E,4E)-5-Hydroxy-2-methylpenta-2,4-dienal Potassium Salt
(4b)
eter equipped with an ATR sampling accessory. H NMR spectra
were recorded at 300 MHz or 500 MHz on a Bruker Avance DPX-
300 instrument or Bruker AMX-500 instrument. 13C NMR spectra
were recorded at 75 MHz on a Bruker Avance DPX-300 instrument
referenced to the appropriate CHCl3 [d = 7.26 (1H), d = 77.16 (13C)],
MeOH [d = 3.31 (1H), d = 49.0 (13C)], or DMSO peak [d = 2.50 (1H),
d = 39.5 (13C)].
KOH (7.57 g, 85%, 114.9 mmol) was dissolved in MeOH (23 mL)
under argon. THF (160 mL) was added, followed by the addition of
2b (16 g, 115.0 mmol). The mixture was stirred at reflux for 6 h, the
slurry was cooled in an ice bath, and Et2O (500 mL) was added. The
brown solid was filtered and rinsed with CH2Cl2 (1 L). The crude
solid was dissolved EtOH (800 mL). The soln was cooled to –20 °C
and filtered through Celite. The filtrate was concentrated in vacuo
to give 4b as a yellow solid; yield: 14.02 g (80%); mp >400 °C.
(2E,4E)-5-(Dimethylamino)penta-2,4-dienal (2a)
Me2NH (50 mL, 40 wt% in H2O, 394.8 mmol) was added to a stirred
soln of Zincke salt 1a (50 g, 177.6 mmol) in EtOH (300 mL) at r.t.
The mixture was stirred at reflux for 90 min, concentrated in vacuo,
and treated with cold H2O (250 mL). The yellow 2,4-dinitroaniline
was removed by filtration through Celite. The filtrate was basified
with 5 M NaOH soln (100 mL) and extracted with CH2Cl2 (4 × 100
mL). The organic layers were combined, dried (MgSO4), filtered,
and concentrated in vacuo to give 2a as an orange-brown solid;
yield: 18.5 g (83%); mp 56 °C.
IR: 3164, 2974, 1502, 1342, 1712, 1604, 1502, 1342, 1263, 1203,
1190, 1000, 824 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.50 (s, 3 H, CH3), 5.10 (dd,
J = 12.7, 9.3 Hz, 1 H, CH), 6.92 (d, J = 12.7 Hz, 1 H, CH), 8.57 (s,
1 H, CH), 8.68 (d, J = 9.3 Hz, 1 H, CH).
13C NMR (75 MHz, DMSO-d6): d = 9.7, 103.9, 111.1, 158.9, 183.5,
183.6.
HRMS (ESI–): m/z [M – K]– calcd for C6H7O2: 111.0446; found:
IR: 2913, 1556, 1012, 973, 836 cm–1.
111.0437.
1H NMR (300 MHz, CDCl3): d = 2.88 (s, 6 H, CH3), 5.18 (dd,
J = 12.3, 11.5 Hz, 1 H, CH), 5.73 (dd, J = 14.3, 8.4 Hz, 1 H, CH),
6.73 (d, J = 12.3 Hz, 1 H, CH), 7.03 (dd, J = 14.3, 11.5 Hz, 1 H,
CH), 9.2 (d, J = 8.4 Hz, 1 H, CHO).
13C NMR (75 MHz, CDCl3): d = 40.7, 97.1, 119.5, 152.7, 156.8,
192.2.
1-(2,4-Dinitrophenyl)-3-(2-hydroxyethyl)pyridinium Chloride
(1c)
A soln of 1-chloro-2,4-dinitrobenzene (2.02 g, 10 mmol) and 3-(2-
hydroxyethyl)pyridine (1.2 g, 9.76 mmol) in acetone (20 mL) was
stirred at reflux for 16 h. The mixture was cooled to 0 °C and the
white slurry was filtered and rinsed with acetone to afford 1c as a
light brown solid; yield: 2.55 g (78%); mp 158 °C.
HRMS (ESI+): m/z [M + Na]+ calcd for C7H11NNaO: 148.0738;
found: 148.0738.
IR: 3216, 2947, 1609, 1538, 1340, 1053, 819, 735, 683 cm–1.
(2E,4E)-5-Hydroxypenta-2,4-dienal Potassium Salt (4a)9b
KOH (1.58 g, 85%, 24.0 mmol) was dissolved in MeOH (5 mL) un-
der argon. THF (45 mL) was added, followed by the addition of 2a
(3 g, 24.0 mmol). The mixture was stirred at reflux for 5 h, the slurry
was cooled in an ice bath, and Et2O (100 mL) was added. The brown
solid was filtered and rinsed with CH2Cl2 (200 mL). The crude solid
was dissolved in MeOH–EtOH (9:1, 300 mL) and filtered through
1H NMR (500 MHz, CD3OD): d = 3.21 (t, J = 5.5 Hz, 2 H, CH2),
3.97 (br t, J = 5.5 Hz, 2 H, CH2), 8.36 (dd, J = 9.0, 6.0 Hz, 1 H, CH),
8.38 (d, J = 9.0 Hz, 1 H, CH), 8.91 (dt, J = 9.0, 1.5 Hz, 1 H, CH),
8.95 (dd, J = 9.0, 3.0 Hz, 1 H, CH), 9.23 (dt, J = 6.0, 1.5 Hz, 1 H,
CH), 9.29 (d, J = 3.0 Hz, 1 H, CH), 9.30 (br s, 1 H, CH).
Synthesis 2010, No. 1, 103–109 © Thieme Stuttgart · New York

106
T. M. Nguyen et al.
PAPER
13C NMR (75 MHz, CD3OD): d = 36.7, 61.7, 123.2, 128.8, 131.1,
13C NMR (75 MHz, CD3CN): d = 26.7, 29.4, 29.9, 30.0, 30.1, 30.2,
30.8, 33.1, 33.7, 62.4, 123.0, 128.9, 131.3, 132.9, 139.7, 144.4,
144.5, 145.4, 146.1, 149.7, 150.7.
132.7, 140.2, 143.3, 144.6, 144.8, 146.9, 150.7, 151.1.
HRMS (ESI+): m/z [M – Cl]+ calcd for C13H12N3O5: 290.0777;
found: 290.0776.
HRMS (ESI+): m/z [M – Cl]+ calcd for C21H28N3O5: 402.2029;
found: 402.2039.
(2E,4E)-5-(Dimethylamino)-2-(2-hydroxyethyl)penta-2,4-di-
enal (2c)
(2E,4E)-5-Hydroxy-2-(10-hydroxydecyl)penta-2,4-dienal
Potassium Salt (4d)
A 5.6 M soln of Me2NH in EtOH (14 mL, 78.4 mmol) was added to
a stirred soln of Zincke salt 1c (12 g, 36.9 mmol) in EtOH (300 mL)
at r.t. under argon. The mixture was stirred at reflux for 1 h, concen-
trated in vacuo, and treated with cold H2O (100 mL). The yellow
2,4-dinitroaniline was removed by filtration through Celite. The fil-
trate was washed with Et2O (3 × 50 mL), basified with 2.5 M NaOH
soln (25 mL), and extracted with CH2Cl2 (3 × 100 mL). The organic
layers were combined, dried (MgSO4), filtered, and concentrated in
vacuo to give 2c as a red solid; yield: 3.18 g (51%); mp 74 °C.
A 5.6 M Me2NH soln in EtOH (10 mL, 56 mmol) was added to a
stirred soln of Zincke salt 1d (14 g, 26.5 mmol) in EtOH (200 mL)
at r.t. under argon. The mixture was stirred at reflux for 1 h, concen-
trated in vacuo, and treated with cold H2O (600 mL). The yellow
2,4-dinitroaniline was removed by filtration through Celite. The fil-
trate was washed with Et2O (5 × 300 mL), basified with 2.5 M
NaOH soln (60 mL), and extracted with CH2Cl2 (3 × 300 mL). The
organic layers were combined, dried (MgSO4), filtered, and concen-
trated in vacuo to give a mixture of 2d and 3d (7.4 g). The crude res-
idue was used without further purification.
IR: 3225, 2953, 2901, 2833, 1631, 1537, 1342, 678 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.50 (t, J = 6.4 Hz, 2 H, CH2),
2.91 (s, 6 H, 2 CH3), 3.25 (br s, 1 H, OH), 3.58 (t, J = 6.4 Hz, 2 H,
CH2), 5.29 (t, J = 12.3 Hz, 1 H, CH), 6.79 (d, J = 12.3 Hz, 1 H, CH),
6.88 (d, J = 12.3 Hz, 1 H, CH), 9.05 (s, 1 H, CH).
13C NMR (75 MHz, CDCl3): d = 28.1, 40.9 (br s), 61.8, 94.6, 126.5,
153.0, 156.1, 193.1.
KOH (1.5 g, 85%, 22.7 mmol) was dissolved in MeOH (4.5 mL) un-
der argon. A soln of crude 2d and 3d in THF (41 mL) was added.
The mixture was stirred at reflux for 5 h then the slurry was cooled
in an ice bath and Et2O (200 mL) was added. The green solid was
filtered and rinsed with CH2Cl2 (100 mL). The crude solid was dis-
solved MeOH (20 mL). The soln was cooled to –30 °C, filtered
through Celite. The filtrate was concentrated in vacuo to give 4c as
a green solid; yield: 4.7 g (71%); mp 166–167 °C.
HRMS (ESI+): m/z [M + H]+ calcd for C9H16NO2: 170.1181; found:
170.1181.
IR: 3261, 2915, 2847, 1606, 1503, 1366, 1332, 1271, 1191, 1092
cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.22–1.48 (m, 16 H, 8 CH2),
2.02 (br s, 2 H, CH2), 3.35 (t, J = 6.3 Hz, 2 H, CH2), 5.11 (dd,
J = 12.8, 9.3 Hz, 1 H, CH), 6.81 (d, J = 12.8 Hz, 1 H, CH), 8.52 (s,
1 H, CH), 8.63 (d, J = 9.3 Hz, 1 H, CH).
13C NMR (75 MHz, DMSO-d6): d = 24.2, 25.5, 27.9, 28.9, 29.1,
29.4, 32.5, 60.6, 103.1, 116.9, 158.6, 183.3, 183.7.
HRMS (ESI+): m/z calcd for C15H26O3Na [M – K + H + Na]+:
277.1780; found: 277.1776.
(2E,4E)-5-Hydroxy-2-(2-hydroxyethyl)penta-2,4-dienal Potas-
sium Salt (4c)
KOH (545 mg, 85%, 8.27 mmol) was dissolved in MeOH (4 mL)
under argon. THF (25 mL) was added, followed by the addition of
2c (1.4 g, 8.28 mmol). The mixture was stirred at reflux for 5 h then
the slurry was cooled in an ice bath and Et2O (50 mL) was added.
The brown solid was filtered and rinsed with CH2Cl2 (100 mL). The
crude solid was dissolved EtOH (50 mL). The soln was cooled to
–30 °C and filtered through Celite. The filtrate was concentrated in
vacuo to give 4c as a light brown solid; yield: 1.25 g (83%); mp 250
°C (dec).
IR: 3251, 2904, 2799, 1503, 1327, 1196, 1164, 1031, 687 cm–1.
(2E,4E)-5-Hydroxy-2-methoxypenta-2,4-dienal Potassium Salt
(4e)
1H NMR (300 MHz, DMSO-d6): d = 2.29 (t, J = 7.5 Hz, 2 H, CH2),
3.28 (t, J = 7.5 Hz, 2 H, CH2), 5.25 (dd, J = 13.0, 9.0 Hz, 1 H, CH),
6.94 (d, J = 13.0 Hz, 1 H, CH), 8.54 (s, 1 H, CH), 8.73 (d, J = 9.0
Hz, 1 H, CH).
13C NMR (75 MHz, DMSO-d6): d = 28.9, 60.2, 104.0, 113.2, 159.6,
184.0, 184.3.
A 5.6 M soln of Me2NH in EtOH (7 mL, 39.2 mmol) was added to
a stirred soln of Zincke salt 1e (4.90 g, 15.71 mmol) in EtOH (80
mL) at r.t. under argon. The mixture was stirred at reflux for 30 min,
concentrated in vacuo, and treated with cold H2O (80 mL). The yel-
low 2,4-dinitroaniline was removed by filtration through Celite.
The filtrate was basified with 1 M NaOH soln (80 mL) and extracted
with CH2Cl2 (4 × 100 mL). The organic layers were combined,
dried (MgSO4), filtered, and concentrated in vacuo to give a mixture
of 2e and 3e (2.22 g, 91%). The crude residue was used without fur-
ther purification.
HRMS (ESI–): m/z [M – K]– calcd for C7H9O3: 141.0552; found:
141.0550.
1-(2,4-Dinitrophenyl)-3-(10-hydroxydecyl)pyridinium Chlo-
ride (1d)
KOH (943 mg, 85%, 14.29 mmol) was dissolved in MeOH (3 mL)
under argon. A soln of crude 2e and 3e in THF (20 mL) was added.
The mixture was stirred at reflux for 3 h then the slurry was cooled
in an ice bath and Et2O (30 mL) was added. The brown solid was
filtered and rinsed with CH2Cl2 (50 mL). The crude solid was dis-
solved in EtOH (50 mL). The soln was cooled to –20 °C and filtered
through Celite. The filtrate was concentrated in vacuo to give 4e as
a beige solid; yield: 1.54 g (65%); mp 166 °C (dec).
A soln of 1-chloro-2,4-dinitrobenzene (12.5 g, 61.7 mmol) and 3-
(10-hydroxydecyl)pyridine16 (13.2 g, 56.1 mmol) in MeOH (20
mL) was stirred at reflux for 48 h under argon. H2O (60 mL) was
added. The aqueous phase was washed with CH2Cl2 (3 × 50 mL)
and concentrated in vacuo to give 1d as a sticky red foam; yield:
21.4 g (87%).
IR: 3340, 3013, 2923, 2852, 1611, 1538, 1341 cm–1.
IR: 2989–2755, 1491, 1256, 1126, 1029, 1000, 745 cm–1.
1H NMR (300 MHz, CD3CN): d = 1.27–1.42 (m, 14 H, 7 CH2),
1.70–1.76 (m, 2 H, CH2), 2.92 (t, J = 7.7 Hz, 2 H, CH2), 3.40 (t,
J = 7.7 Hz, 2 H, CH2), 3.42 (br s, 1 H, OH), 8.22 (dd, J = 8.1, 6.0
Hz, 1 H, CH), 8.31 (d, J = 8.7 Hz, 1 H, CH), 8.68 (d, J = 8.1 Hz, 1
H, CH), 8.83 (dd, J = 8.7, 2.5 Hz, 1 H, CH), 9.1 (d, J = 2.5 Hz, 1 H,
CH), 9.14 (d, J = 6.0 Hz, 1 H, CH), 9.24 (s, 1 H, CH).
1H NMR (300 MHz, CD3OD): d = 3.59 (s, 3 H, OCH3), 5.69 (dd,
J = 11.9, 11.9 Hz, 1 H, CH), 6.94 (d, J = 11.9 Hz, 1 H, CH), 8.20 (s,
1 H, CHO), 8.58 (d, J = 11.9 Hz, 1 H, CH).
13C NMR (75 MHz, CD3OD): d = 59.3, 105.9, 143.0, 154.1, 178.8,
186.3.
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HRMS (ESI–): m/z [M – K]– calcd for C6H7O3: 127.0395; found:
(2E,4E)-5-(Dibenzylamino)penta-2,4-dienal (5b)
127.0393.
Brown oil; yield: 86 mg (97%).
IR: 3027, 1657, 1565, 1130, 696 cm–1.
(2E,4E)-2-Bromo-5-(dimethylamino)penta-2,4-dienal (2f)13
Br2 (1.68 mL, 32.9 mmol) in CH2Cl2 (10 mL) was added to a stirred
soln of 2a (3.43 g, 27.4 mmol) in CH2Cl2 (60 mL) at –10 °C and un-
der argon. After 30 min at r.t., Et2O was added and the slurry was
filtered and rinsed with Et2O. The solid was dissolved in CH2Cl2
(100 mL) and the organic layer was washed with sat. aq NaHCO3
(100 mL) and brine (100 mL), dried (Na2SO4), filtered, and concen-
trated in vacuo. The residue was purified by flash chromatography
(CH2Cl2–MeOH, 9:1) to give 2f as a brown solid; yield: 4.61 (82%);
mp 96 °C.
1H NMR (300 MHz, CDCl3): d = 4.26 (s, 4 H, 2 CH2), 5.41 (dd,
J = 12.8, 11.6 Hz, 1 H, CH), 5.74 (dd, J = 14.6, 8.4 Hz, 1 H, CH),
7.00 (d, J = 12.8 Hz, 1 H, CH), 7.04–7.33 (m, 11 H, 10 HAr, CH),
9.23 (d, J = 8.4 Hz, 1 H, CHO).
13C NMR (75 MHz, CDCl3): d = 53.2, 98.3, 121.1, 127.0, 127.5,
128.1, 128.2, 128.5, 129.0, 135.7, 140.4, 151.8, 156.5, 192.5.
HRMS (ESI+): m/z [M + H]+ calcd for C19H20NO: 278.1545; found:
278.1547.
IR: 2907, 2802, 1607, 1538, 1385, 1216, 1128, 992, 806, 681 cm–1.
(2E,4E)-5-(Benzylamino)-2-methylpenta-2,4-dienal (5c)1a
1H NMR (300 MHz, CDCl3): d = 2.69 (br s, 3 H, CH3), 2.83 (br s, 3
H, CH3), 5.24 (dd, J = 12.5, 11.4 Hz, 1 H, CH), 6.74 (d, J = 12.5 Hz,
1 H, CH), 7.05 (d, J = 11.4 Hz, 1 H, CH), 8.69 (s, 1 H, CHO).
13C NMR (75 MHz, CDCl3): d = 37.2, 45.1, 97.1, 111.0, 153.3,
155.1, 183.2.
HRMS (ESI+): m/z [M + H]+ calcd for C7H1179BrNO: 204.0024;
found: 204.0018; calcd for C7H1181BrNO: 206.0004; found:
205.9998.
Orange solid; yield: 2.4 g (79%).
(2E,4E)-5-(Butylamino)-2-methylpenta-2,4-dienal (5d)4a
Red solid; yield: 2.5 g (82%).
(2E,4E)-5-(4-Methoxybenzylamino)-2-methylpenta-2,4-dienal
(5e)
Red solid; yield: 4.0 g (82%); mp 83–84 °C.
IR: 3220, 2958, 2831, 1548, 1511, 1173, 808 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.74 (s, 3 H, CH3), 3.81 (s, 3 H,
CH3), 4.25 (d, J = 5.3 Hz, 2 H, CH2), 5.26 (br s, 1 H, NH), 5.54 (t,
J = 12.1 Hz, 1 H, CH), 6.85 (d, J = 12.1 Hz, 1 H, CH), 6.90 (d,
J = 8.4 Hz, 2 H, CH2), 6.93 (dd, J = 12.1, 8.4 Hz, 1 H, CH), 7.23 (d,
J = 8.4 Hz, 2 H, CH2), 9.17 (s, 1 H, CH).
13C NMR (75 MHz, CDCl3): d = 9.17, 55.4, 96.3, 114.3, 127.2,
129.1, 129.3, 147.5, 153.7, 159.4, 193.1.
(2E,4E)-2-Bromo-5-hydroxypenta-2,4-dienal Potassium Salt
(4f)
KOH (2.84 g, 85%, 50.8 mmol) was dissolved in MeOH (10 mL)
under argon. THF (60 mL) was added, followed by the addition of
2f (10.38 g, 50.8 mmol). The mixture was stirred at reflux for 5 h
then cooled in an ice bath. The brown slurry was filtered and rinsed
with CH2Cl2 (100 mL). The crude solid was dissolved EtOH (1 L).
The soln was cooled to –20 °C and filtered through Celite. The fil-
trate was concentrated in vacuo to give 4f as a light brown solid;
yield: 7.53 g (69%); mp >400 °C.
HRMS (ESI+): m/z [M + Na]+ calcd for C14H17NNaO2: 254.1157;
found: 254.1169.
IR: 2797, 1618, 1503, 1353, 1129, 820 cm–1.
(2E,4E)-5-(Benzylamino)-2-(2-hydroxyethyl)penta-2,4-dienal
(5f)
The residue was purified by flash chromatography (CH2Cl2–
MeOH, 98:2) to give 5f as an orange solid; yield: 150 mg (70% from
4c); mp 107 °C.
1H NMR (300 MHz, CD3OD): d = 5.83 (dd, J = 12.6, 9.3 Hz, 1 H,
CH), 7.60 (d, J = 12.6 Hz, 1 H, CH), 8.48 (s, 1 H, CHO), 8.86 (d,
J = 9.3 Hz, 1 H, CH).
13C NMR (75 MHz, CD3OD): d = 102.4, 112.0, 159.9, 179.5, 189.7.
HRMS (ESI–): m/z [M – K]– calcd for C5H479BrO2: 174.9395;
found: 174.9387; calcd for C5H481BrO2: 176.9374; found:
176.9369.
IR: 3452, 3257, 3022, 2925, 2556, 2356, 1537, 1454, 1385, 1315,
1193, 1006, 819, 749, 701 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.54 (t, J = 6.5 Hz, 2 H, CH2),
2.79 (br s, 1 H, OH), 3.63 (t, J = 6.5 Hz, 2 H, CH2OH), 4.34 (d, J = 6
Hz, 2 H, CH2), 5.52 (br s, 1 H, NH), 5.62 (dd, J = 12.0, 12.0 Hz, 1
H, CH), 6.96 (d, J = 12.0 Hz, 1 H, CH), 6.99 (dd, J = 12.0, 9.0 Hz,
1 H, CH), 7.25–7.42 (m, 5 H, 5 HAr), 9.18 (s, 1 H, CHO).
13C NMR (75 MHz, CDCl3): d = 28.2, 49.0, 62.0, 96.2, 127.7,
127.9, 128.0, 129.0, 137.0, 149.3, 156.0, 193.9.
2-Substituted Aminopentadienals 5; General Procedure
Glutaconaldehyde 4 (2.1 mmol) was added to a stirred soln of alkyl-
ammonium trifluoroacetate salt (2 mmol) in CH2Cl2 (10 mL); H2O
(1 drop) was added. After 30 min, the mixture was quenched with
sat. aq NaHCO3 (25 mL). The aqueous phase was extracted with
CH2Cl2 (3 × 25 mL). The organic layers were combined, dried
(MgSO4), filtered, and concentrated in vacuo to give a 2-substituted
aminopentadienal.
HRMS (ESI+): m/z [M + Na]+ calcd for C14H17NNaO2: 254.1157;
found: 254.1156.
(E)-12-Hydroxy-2-[(E)-3-(4-methoxybenzylamino)prop-2-
enylidene]dodecanal (5g)
Red oil; yield: 4.62 g (88%).
(2E,4E)-5-(Benzylamino)penta-2,4-dienal (5a)
Red oil; yield: 186 mg (98%).
IR: 3253, 3026, 1556, 1139, 748, 698 cm–1.
1H NMR (300 MHz, CDCl3): d = 4.31 (br s, 2 H, CH2), 5.39 (br s, 1
H, NH), 5.49 (dd, J = 12.8, 11.6 Hz, 1 H, CH), 5.82 (dd, J = 14.4,
8.4 Hz, 1 H, CH), 6.95 (dd, J = 12.8, 8.4 Hz, 1 H, CH), 7.10 (dd,
J = 14.4, 11.6 Hz, 1 H, CH), 7.20–7.49 (m, 5 H, 5 HAr), 9.29 (d,
J = 8.4 Hz, 1 H, CHO).
13C NMR (75 MHz, CDCl3): d = 48.7, 98.6, 120.7, 127.1, 127.2,
128.8, 137.1, 149.3, 157.2, 192.7.
IR: 3294, 2921, 2850, 1607, 1564, 1555, 1509, 1440, 1244, 1170,
1084, 1170, 1083, 1032, 811 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.25 (m, 14 H, 7 CH2), 1.53 (m, 2
H, CH2), 2.22 (t, J = 7.5 Hz, 2 H, CH2), 3.59 (t, J = 6.4 Hz, 2 H,
CH2), 3.77 (br s, 1 H, OH), 3.78 (s, 3 H, OCH3), 4.24 (br s, 2 H,
CH2N), 5.53 (t, J = 12.2 Hz, 1 H, CH), 5.57 (br s, 1 H, NH), 6.78 (d,
J = 12.2 Hz, 1 H, CH), 6.86–6.70 (m, 3 H, 3 CH), 7.21 (d, J = 8.5
Hz, 2 H, 2 CH), 9.10 (s, 1 H, CH).
HRMS (ESI+): m/z [M + H]+ calcd for C12H14NO: 188.1075; found:
188.1082.
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T. M. Nguyen et al.
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13C NMR (75 MHz, CDCl3): d = 24.0, 25.8, 28.6, 29.4, 29.5, 29.6,
29.7, 32.8, 55.3, 62.8, 96.2, 113.9, 114.2, 128.3, 128.9, 129.3,
131.9, 147.8, 154.0, 159.2, 192.9.
HRMS (ESI+): m/z [M + Na]+ calcd for C23H35NNaO3: 396.2515;
found: 396.2516.
(E)-3-(Benzylamino)pent-2-enal (8)
Malonaldehyde salt 7 (104 mg, 0.94 mmol) was added to a stirred
soln of TFA (72 mL, 0.93 mmol) and BnNH2 (100 mL, 0.92 mmol)
in CH2Cl2 (5 mL); H2O (1 drop) was added. After 30 min, the mix-
ture was quenched with sat. aq NaHCO3 (15 mL). The aqueous
phase was extracted with CH2Cl2 (3 × 15 mL). The organic layers
were combined, dried (MgSO4), filtered, and concentrated in vacuo
to give 8 as an orange oil; yield: 125 mg (84%).
(2Z,4E)-2-Methoxy-5-(4-methoxybenzylamino)penta-2,4-di-
enal (5h)
Dark red oil; yield: 339 mg (92%).
IR: 3212, 3022, 2769, 1583, 1168 cm–1.
IR: 3285, 2932, 2834, 1555, 1509, 1440, 1243, 1142, 1029, 813,
748 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.94–4.04 (br s, 2 HA, CH2), 4.11
(d, J = 6.0 Hz, 2 HB, CH2), 4.75 (dd, J = 7.0, 2.1 Hz, 1 HA, CH), 5.07
(dd, J = 13.1, 8.1 Hz, 1 HB, CH), 5.43–5.72 (br s, 1 HB, NH), 6.54
(ddd, J = 12.9, 7.0, 3.0 Hz, 1 HA, CH), 6.92–7.12 (m, 5 HA, 6 HB, 10
HAr, CH), 8.81–8.84 (m, 1 HB, CH), 8.85 (dd, J = 3.0, 2.1 Hz, 1 HA,
CH), 9.74–10.07 (m, 1 HA, NH).
13C NMR (75 MHz, CDCl3): d = 53.4, 95.2, 127.2, 127.9, 128.2,
128.9, 129.0, 137.3, 154.4, 188.5.
MS (EI, 70 eV): m/z (%) = 161 ([M]+, 47), 91 (100).
1H NMR (300 MHz, CDCl3): d = 3.69 (s, 3 H, OCH3), 3.77 (s, 3 H,
OCH3), 4.21 (s, 2 H, CH2), 5.64 (dd, J = 12.4, 12.4 Hz, 1 H, CH),
5.80 (s, 1 H, NH), 6.44 (d, J = 12.4 Hz, 1 H, CH), 6.86 (d, J = 7.7
Hz, 2 H, HAr), 6.92 (d, J = 12.4 Hz, 1 H, CH), 7.12 (d, J = 7.7 Hz, 2
H, HAr), 8.86 (s, 1 H, CHO).
13C NMR (75 MHz, CDCl3): d = 47.9, 55.3, 59.3, 93.4, 113.9,
114.1, 128.9, 142.9, 147.4, 147.6, 159.1, 185.4.
HRMS (ESI+): m/z [M + H]+ calcd for C14H18NO3: 248.1287; found:
248.1278.
References
(2Z,4E)-5-(Benzylamino)-2-bromopenta-2,4-dienal (5i)17
The residue was purified by flash chromatography (CH2Cl2–
MeOH, 100:0 then 97.5:2.5) to give 5i as an orange solid; yield: 261
mg (63%, from 4f); mp 155 °C.
(1) (a) Wypych, J.-C.; Nguyen, T. M.; Nuhant, P.; Bénéchie, M.;
Marazano, C. Angew. Chem. Int. Ed. 2008, 47, 5418.
(b) Kaiser, A.; Billot, X.; Gateau-Olesker, A.; Marazano, C.;
Das, B. C. J. Am. Chem. Soc. 1998, 120, 8026.
(2) (a) Baldwin, J. E.; Claridge, T. D. W.; Culshaw, A. J.;
Heupel, F. A.; Lee, V.; Spring, D. R.; Whitehead, R. C.
Chem. Eur. J. 1999, 5, 3154. (b) Baldwin, J. E.; Whitehead,
R. C. Tetrahedron Lett. 1992, 33, 2059.
(3) (a) Zincke, T. Justus Liebigs Ann. Chem. 1903, 330, 361.
(b) Zincke, T.; Heuser, G.; Möller, W. Justus Liebigs Ann.
Chem. 1904, 333, 296. (c) König, W. J. Prakt. Chem. 1904,
69, 105.
IR: 3184, 3001, 1590, 1504, 1450, 1111, 692 cm–1.
1H NMR (300 MHz, CDCl3): d = 4.35–4.44 (m, 2 H, CH2), 5.16 (br
s, 1 H, NH), 5.85 (dd, J = 12.5, 11.5 Hz, 1 H, CH), 7.06–7.16 (m, 1
H, CH), 7.22–7.45 (m, 6 H, 5 HAr, CH), 9.06 (s, 1 H, CHO).
HRMS (ESI+): m/z [M + H]+ calcd for C12H1379BrNO: 266.0181;
found: 266.0178; calcd for C12H1381BrNO: 268.0156; found:
268.0160.
(4) (a) Jakubowicz, K.; Ben Abdeljelil, K.; Herdemann, M.;
Martin, M.-T.; Gateau-Olesker, A.; Al Maourabit, A.;
Marazano, C.; Das, B. C. J. Org. Chem. 1999, 64, 7381.
(b) Kearney, A. M.; Vanderwal, C. D. Angew. Chem. Int. Ed.
2006, 45, 7803. (c) Martin, D. B. C.; Vanderwal, C. D.
J. Am. Chem. Soc. 2009, 131, 3472.
(2Z,4E)-2-Bromo-5-(4-methoxybenzylamino)penta-2,4-dienal
(5j)
The residue was purified by flash chromatography (CH2Cl2–
MeOH, 100:0 then 97.5:2.5) to give 5j as an orange oil; yield: 315
mg (53%, from 4f).
(5) Genisson, Y.; Marazano, C.; Mehmandoust, M.; Gnecco, D.;
IR: 3223, 3026, 1592, 1501, 1115, 810, 685 cm–1.
Das, B. C. Synlett 1992, 431.
1H NMR (300 MHz, CDCl3): d = 3.79 (s, 3 H, OCH3), 4.34 (d,
J = 6.9 Hz, 2 H, CH2), 5.71–5.91 (m, 1 H, CH), 6.83–6.98 (m, 3 H,
2 HAr, CH), 7.15–7.40 (m, 4 H, 2 HAr, CH, NH), 8.85 (s, 1 H, CHO).
13C NMR (75 MHz, CDCl3): d = 47.3, 55.3, 97.5, 111.7, 114.2,
128.2, 129.1, 152.1, 154.5, 159.1, 184.0.
(6) Baumgarten, P. Ber. Dtsch. Chem. Ges. 1924, 57, 1622.
(7) (a) Jorgensen, T.; Nielsen, H. C.; Malhotra, N.; Becher, J.;
Begtrup, M. J. Heterocycl. Chem. 1992, 29, 1841.
(b) Berthon, L.; Tahri, A.; Uguen, D. Tetrahedron Lett.
1994, 35, 3937.
(8) (a) Soullez, D.; Plé, G.; Duhamel, L. J. Chem. Soc., Perkin
Trans. 1 1997, 1639. (b) Vicart, N.; Castet-Caillabet, D.;
Ramondenc, Y.; Plé, G.; Duhamel, L. Synlett 1998, 411.
(c) Lipshutz, B. H.; Ullman, B.; Lindsley, C.; Pecchi, S.;
Buzard, D. J.; Dickson, D. J. Org. Chem. 1998, 63, 6092.
(9) (a) Malhotra, S. S.; Whiting, M. C. J. Chem. Soc. 1960,
3812. (b) Becher, J. Org. Synth. 1979, 59, 79.
HRMS (ESI+): m/z [M + H]+ calcd for C13H1579BrNO: 296.0286;
found: 296.0281; calcd for C13H1581BrNO: 298.0266; found:
298.0262.
(E)-3-Hydroxypent-2-enal Potassium Salt (7)
KOH (8.46 g, 85%, 128.4 mmol) was dissolved in MeOH (30 mL)
under argon. THF (180 mL) was added, followed by the addition of
3-(dimethylamino)pent-2-enal (6, 15 g, 151.3 mmol). The mixture
was stirred at reflux for 5 h then the slurry was cooled in an ice bath
and Et2O (100 mL) was added. The brown solid was filtered and
rinsed with CH2Cl2 (200 mL). The crude solid was dissolved in
MeOH (300 mL) and filtered through Celite. The filtrate was con-
centrated in vacuo to give 7 as an orange solid; yield: 13.24 g (93%);
mp 280 °C (dec).
(10) Wypych, J.-C.; Nguyen, T. M.; Bénéchie, M.; Marazano, C.
J. Org. Chem. 2008, 73, 1169.
(11) (a) Gnecco, D.; Juarez, J.; Galindo, A.; Marazano, C.;
Enriquez, R. G. Synth. Commun. 1999, 29, 281. (b) Eda,
M.; Kurth, M. J.; Nantz, M. H. J. Org. Chem. 2000, 65, 5131.
(12) Mäding, P.; Steinbach, J.; Johannsen, B. J. Labelled
Compds. Radiopharm. 1997, XXXIX, 585.
(13) Stämpfli, U.; Neuenschwander, M. Helv. Chim. Acta 1983,
IR: 3366, 2768, 1712, 1555, 1348, 1262, 1167, 1020, 818 cm–1.
66, 1427.
(14) The yield of a reaction between 4 and an amine could change
from trace to quantitative.
1H NMR (300 MHz, CD3OD): d = 5.25 (t, J = 10.0 Hz, 1 H, CH),
8.63 (d, J = 10.0 Hz, 2 H, 2 CH).
13C NMR (75 MHz, CD3OD): d = 110.2, 192.2.
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2-Substituted Glutaconaldehyde Derivatives
109
(15) Nair, V.; Vietti, D. E.; Cooper, C. S. J. Am. Chem. Soc. 1981,
(17) 5i is not sufficiently soluble in CDCl3 to record a 13
C
103, 3030.
spectrum and decomposition was observed when other
solvents were used.
(16) Grube, A.; Timm, C.; Köck, M. Eur. J. Org. Chem. 2006,
1285.
Synthesis 2010, No. 1, 103–109 © Thieme Stuttgart · New York