Original TDAE strategy using propargylic chloride: Rapid access to 1,4-diarylbut-3-ynol derivatives

Article abstract of DOI:10.3390/molecules18021540

We report herein the first synthesis of propargylic alcohols using an organic reducing agent. Diarylbutynol derivatives are formed in moderate to good yields under mild conditions from the reaction of 1-(3-chloroprop-1-ynyl)-4- nitrobenzene with various aromatic aldehydes using tetrakis(dimethylamino) ethylene (TDAE) as reductant.

Full text of DOI:10.3390/molecules18021540

Molecules 2013, 18, 1540-1548; doi:10.3390/molecules18021540
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Communication
Original TDAE Strategy Using Propargylic Chloride:
Rapid Access to 1,4-Diarylbut-3-ynol Derivatives
Manon Roche, Thierry Terme and Patrice Vanelle *
Laboratoire de Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, Institut de Chimie Radicalaire ICR,
UMR 7273, Aix-Marseille Univ, CNRS, 27 Boulevard Jean Moulin, 13385 Marseille Cedex 05, France
* Author to whom correspondence should be addressed; E-Mail: patrice.vanelle@univ-amu.fr;
Tel.: +33-491-835-573; Fax: +33-486-136-822.
Received: 12 November 2012; in revised form: 16 January 2013 / Accepted: 22 January 2013 /
Published: 25 January 2013
Abstract: We report herein the first synthesis of propargylic alcohols using an organic
reducing agent. Diarylbutynol derivatives are formed in moderate to good yields under
mild conditions from the reaction of 1-(3-chloroprop-1-ynyl)-4-nitrobenzene with various
aromatic aldehydes using tetrakis(dimethylamino)ethylene (TDAE) as reductant.
Keywords: TDAE; propargylic alcohol; organic reducing agent; aromatic aldehyde
1. Introduction
Propargylic alcohol derivatives have a major role to play in medicinal chemistry. They can act as
intermediates for many complex organic molecules with valuable biological activities [1,2], for
example efavirenz (Figure 1), an antiretroviral agent. Chalcone scaffolds (Figure 1), prepared from
propargylic alcohols such as diaryl butynols, have been already used in the design and synthesis of
molecules with anticancer activities. They are particularly important in the synthesis of novel
antitubulin agents [3–5].
Different methods can be used to obtain propargylic alcohols. The most commonly used method is
the addition of an acetylenic derivative to carbonyl compounds mediated by titanium, dialkyl zinc, etc. [2].
Tetrakis(dimethylamino)ethylene (TDAE) is an organic reducing agent [6,7] which reacts with
haloalkyl derivatives to generate an anion under mild conditions via two sequential transfers of one
electron. TDAE methodology has been widely explored in fluorine chemistry [8]. Since 2002, we have
been applying this methodology in the nitrobenzylic series with various electrophiles such as aromatic

Molecules 2013, 18
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aldehydes [9–12], ketones [9–12], α-ketoesters [13–15], diethyl ketomalonate [13–15], α-ketolactams [16],
-diketones [17,18] and sulfonimine derivatives [19]. In this way, we have developed a program to
explore the overall potential of TDAE-based chemistry in a medicinal setting [9,12,19–21]. To date,
there has been no example of a TDAE-initiated reaction on alkyne derivatives in order to synthesize
propargylic alcohols.
Figure 1. Example of molecules synthesized via propargylic alcohol derivatives.
O
F3C
Cl
R
NH
R'
N
O
H
Chalcone derivatives
Efavirenz (EFV)
In a recent work, we explored the concept of Long-Distance-SRN1 (LD-SRN1) on a propargylic
chloride derivative such as 1-(3-chloroprop-1-ynyl)-4-nitrobenzene [22]. This latter compound also
constitutes a potential substrate for the preparation of a propargylic anion using the TDAE strategy. In
continuation of our research program directed towards the development of original synthetic methods
in medicinal chemistry [23–28], we examined the use of TDAE methodology in the alkyne series. We
report herein the synthesis of diarylbutynol derivatives from the reaction of 1-(3-chloroprop-1-ynyl)-4-
nitrobenzene with various aromatic aldehydes in the presence of TDAE.
2. Results and Discussion
The synthesis of 1-(3-chloroprop-1-ynyl)-4-nitrobenzene (1) was inspired by Chinchilla’s work [29]
on Sonogashira reactions and was performed as previously described (Scheme 1) [22].
Scheme 1. Synthesis of chloride 1.
Cl
OH
Br
OH
i
ii
+
85 %
95 %
NO2
NO2
NO2
1
Reagents and Conditions: (i) Pd(PPh3)4 0.5%, Cul 1%, pyrrolidine 1.5 equiv., H2O/THF, 70 °C, 3 h;
(ii) SOCl2 3 equiv., CH2Cl2: 0 °C; 40 °C, 4 h.
In order to evaluate the reducibility of the substrate 1, we treated it under classical TDAE
conditions [9] but without electrophile. This reaction led to the reduction product 2 (Scheme 2) in 90%
yield, and confirmed the reducibility of 1 by TDAE.

Molecules 2013, 18
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Scheme 2. TDAE-initiated reactivity of chloride 1.
Cl
CH3
TDAE 1.1 equiv.
1) -20 °C, 1 h
2) rt, 2 h
NO2
NO2
2
1
We therefore proceeded to explore whether of a propargylic anion could be formed using TDAE
with nucleophilic addition to a carbonyl derivative as electrophile. The first attempt was made under
classical TDAE conditions [9]. The reaction of the 1-(3-chloroprop-1-ynyl)-4-nitrobenzene (1) with
three equiv. of p-chlorobenzaldehyde (3a) in the presence of 1.1 equiv. of TDAE at −20 °C for 1 h
(stage 1) followed by 2 h at rt (stage 2) yielded diarylbutynol 4a in 40% yield (Entry 1, Table 1).
Aromatic aldehydes were chosen as electrophiles based on our previous TDAE studies (more reactive
electrophiles for the TDAE strategy) and with the view to obtaining chalcone precursors. In order to
optimize this reaction, we changed some parameters (solvent, amount of aldehyde, solvent volume,
temperature during stage 1 or stage 2 and reaction time of stage 2), as shown in Table 1 and Scheme 3.
During this study, the formation of an oxirane derivative 5a was observed as by-product when we used
10 or 20 mL of DMF (Entries 4 and 7).
Scheme 3. TDAE-initiated reactivity of chloride 1 and p-chlorobenzaldehyde 3a.
Cl
Cl
O
Cl
OH
O
H
TDAE
+
+
N2, Solvent
1) 1 h at T1
2) x h at T2
NO2
NO2
NO2
Cl
3a
1
5a
4a
Modification of certain parameters (solvent, aldehyde amount and reaction time) did not lead to any
increase in yield of 4a. Reducing the temperature of stage 1 (−20 °C to −50 °C; Entry 8) did not
change diarylbutynol yields, but did improve the treatment of the reaction. Recently, we showed that
the temperature of stage 2 affects TDAE reactivity in the o-nitrobenzylic series [30]. Thus, in Entry 9
the reaction was stirred under 60 °C for 2 h in stage 2 and diarylbutynol 4a was obtained in 65% yield.
As observed in benzylic [9,13], heterocyclic [14] and quinonic [12] series, the formation of this
product may be explained by an ionic addition of carbanion, formed by action of TDAE with
1-(3-chloroprop-1-ynyl)-4-nitrobenzene, on the carbonyl group of the benzaldehyde.

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Table 1. Reactivity of 1-(3-chloroprop-1-ynyl)-4-nitrobenzene 1 with p-chlorobenzaldehyde 3a.
(%) Yield c
Equiv. of
Time of reaction
d
e
Entry a
Solvent
T1
T2
3a
3
3
3
3
1
4
3
3
3
3
3
3
3
(stage 2)
2 h
1
-
4a
40
-
5a
1
2 b
3
DMF, 4 mL
THF, 4 mL
−20 °C
−20 °C
rt
rt
rt
rt
rt
rt
rt
rt
-
2 h
-
-
MeCN, 4 mL −20 °C
2 h
85
-
-
-
4
DMF, 4 mL
DMF, 4 mL
DMF, 4 mL
−20 °C
−20 °C
−20 °C
6 h
6
traces
5
2 h
-
12
20
38
45
65
25
30
38
25
-
-
6
2 h
-
7
DMF, 10 mL −20 °C
DMF, 4 mL −50 °C
2 h
-
20
-
8
2 h
-
9
DMF, 4 mL −50 °C
DMF, 10 mL −50 °C
DMF, 20 mL −20 °C
DMF, 20 mL −50 °C
DMF, 20 mL −50 °C
2 h
2 h
60 °C
-
-
10
11
12
rt
rt
rt
rt
-
35
traces
25
25
2 h
-
2 h
-
13
6 h
-
a
All reactions were performed using strictly anhydrous solvent, with 1 equiv. (0.5 mmol) of chloride 1,
1.1 equiv. of TDAE and 1 h for stage 1; b Only degradation products were observed; c All yields refer to the
d
chromatographically isolated products and are relative to chloride 1;
T1: Temperature stage 1;
e T2: Temperature stage 2.
Otherwise, the reaction led to oxirane 5a as by-product in entries 4 and 7. Using the TDAE
methodology, the formation of oxirane derivatives with gem-dihalomethyl derivatives has already been
described [11], but not with monohalogenated compounds. To elucidate the pathway for the formation
of this product, certain parameters were modified (Table 1, Entries 10–13). In these assays, the best
yield (35%) of product 5a was obtained for Entry 10, in the presence of 1.1 equiv. of TDAE at −50 °C
for 1 h (stage 1) followed by 2 h at rt (stage 2), in 10 mL of extra-dry DMF. The reaction with the
highest volume of DMF (Entry 12) did not lead to an increased yield of product 5a. All this suggests
the formation of oxirane 5a in dilute solutions by an intramolecular rearrangement via the
propargylic/allenic equilibrium (Scheme 4). 1H-NMR spectral studies identify oxirane as cis-isomer by
their coupling constant. Two distinct doublets appeared in the region at 3.97–4.25 ppm with a coupling
constant J = 3.8 Hz, in agreement with the literature [31,32].
Scheme 4. Hypothetical pathway for the formation of oxirane derivative.
Cl
O
CH2
Cl
O
Cl
O
H
O
H
H
C
+
Cl
3a
NO2
NO2
NO2
NO2
5a
In order to generalize and to confirm this new and original methodology of synthesizing
diarylbutynol derivatives, we extended this study to other aromatic aldehydes using an optimized

Molecules 2013, 18
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protocol. The reaction of 1-(3-chloroprop-1-ynyl)-4-nitrobenzene 1 with electrophiles 3a–g in the
presence of TDAE, under the conditions of Entry 9 (Table 1), led to the corresponding diarylbutynol
derivatives 4a–g in moderate to good yields (30% to 65%) as shown in Table 2 and Scheme 5.
Scheme 5. Extension of the reactivity of chloride 1 with various benzaldehydes 3a–g.
R
Cl
OH
O
H
R
TDAE
+
1) -50 °C, 1 h
2) 60 ° C, 2 h
DMF
NO2
NO2
1
3a-g
4a-g
Table 2. Reaction of chloride 1 with various aromatic aldehydes a.
Aromatic aldehyde
R
(%) Yield b
4-Chlorobenzaldehyde
4-Cl
4a
4b
4c
4d
4e
4f
65
57
34 c
traces
51
4-Nitrobenzaldehyde
4-NO2
4-Fluorobenzaldehyde
4-F
4-Tolualdehyde
4-CH3
4-Trifluoromethylbenzaldehyde
2-Nitro-4,5-dimethoxybenzaldehyde
4-CF3
2-NO2-4,5-(OCH3)2
H
32
30 d
Benzaldehyde
4g
a
All reactions are performed using 3 equiv. of aromatic aldehyde 3a–g, 1 equiv. (0.5 mmol) of chloride 1,
1.1 equiv. of TDAE in 4 mL of strictly anhydrous DMF, stirred at −50 °C for 1 h and then warmed at 60 °C for
b
2 h;
All yields refer to the chromatographically isolated products and are relative to chloride 1;
c We observed the formation of reduction product 2 in 25% yield; d We observed the formation of reduction
product 2 in 20% yield.
As already described in the nitrobenzylic [9,10] or quinonic [12] series, aromatic aldehydes with an
electron withdrawing group are more reactive than aromatic aldehydes substituted by an electron-
donor group such as methyl (compound 3d). The formation of the reduction product 2, isolated as by-
product with 4-tolualdehyde (3d) or benzaldehyde (3g), has already been detected in our previous
studies when the substrate is more reducible and the electrophile is less reactive [15,33,34].
3. Experimental
3.1. General
Elemental analysis or mass spectrometry were performed by the Spectropole Centre, Aix Marseille
1
13
University (Marseille, France) The H- and C-NMR spectra were determined on a Bruker AC 200
spectrometer operating at 200 and 50 MHz, respectively. The 1H-NMR chemical shifts are reported as
parts per million downfield from tetramethylsilane (Me4Si), the 13C chemical shifts were referenced to
the solvent peaks [CDCl3: 76.9 ppm and (CD3)2CO: 206.3 ppm and 29.8 ppm]. Absorptions are

Molecules 2013, 18
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reported with the following notations: s, singlet, d, doublet, t, triplet, q, quartet, m, a more complex
multiplet or overlapping multiplets. The following absorbents were used for column chromatography:
silica gel 60 (Merck, particle size 0.0063–0.200, 70–230 mesh ASTM). TLC was performed on
5 cm × 10 cm aluminium plates coated with silica gel 60 F-254 (Merck) with an appropriate eluent.
3.2. General Procedure for TDAE Reaction with Aromatic Aldehydes
All materials were dried for one day at 120 °C. Into a two-necked flask equipped with a silica-gel
drying tube and a nitrogen inlet, was added, under nitrogen at –50 °C, an anhydrous DMF solution (4 mL)
of 1 (0.1 g, 0.51 mmol) and aldehyde 3a–g (1.53 mmol, 3 equiv.). The solution was stirred and
maintained at this temperature for 30 min and then the TDAE (0.127 mL, 0.55 mmol, 1.1 equiv.) was
added dropwise (via a syringe). A green color immediately developed. The solution was vigorously
stirred at −50 °C for 1 h and then warmed at 60 °C for 2 h. After this time TLC analysis
(dichloromethane) clearly showed that 1 was totally consumed. The brown turbid solution was
hydrolyzed with H2O (5 mL). The aqueous solution was extracted with dichloromethane (3  10 mL),
the combined organic layers washed with brine (3 × 10 mL) and dried over MgSO4. Evaporation of the
solvent left the crude product as a viscous orange liquid. Purification by silica gel chromatography
(eluent dichloromethane) gave the corresponding diarylbutynols 4a–g.
1
1-(4-Chlorophenyl)-4-(4-nitrophenyl)but-3-yn-1-ol (4a). A yellow oil (98 mg, 65%). H-NMR
(CDCl3):  8.16 (2H, d, J = 8.8 Hz), 7.50 (2H, d, J = 8.8 Hz), 7.37 (4H, s), 4.98 (1H, t, J = 6.2 Hz),
13
2.90 (2H, d, J = 6.2 Hz). C-NMR (CDCl3): δ 146.9 (C), 140.9 (C), 133.9 (C), 132.4 (2CH), 130.1
(C), 128.7 (2CH), 127.2 (2CH), 123.5 (2CH), 91.6 (C), 81.7 (C), 71.8 (CH), 30.5 (CH2). HRMS calcd.
for C16H12ClNO3: [M+H]+ = 302.0578, found: [M+H]+ = 302.0577.
1
1,4-Bis(4-nitrophenyl)but-3-yn-1-ol (4b). A yellow solid (90 mg, 57%). H-NMR [(CD3)2CO]:  8.25
(2H, d, J = 8.6 Hz), 8.19 (2H, d, J = 8.6 Hz), 7.83 (2H, d, J = 8.6 Hz), 7.59 (2H, d, J = 8.6 Hz), 5.19
13
(1H, m), 2.97 (2H, d, J = 5.5 Hz). C-NMR [(CD3)2CO]: δ 152.5 (C), 148.3 (C), 147.9 (C), 133.2
(2CH), 131.3 (C), 128.1 (2CH), 124.4 (2CH), 124.0 (2CH), 93.2 (C), 82.0 (C), 71.7 (CH), 30.6 (CH2).
HRMS calcd. for C16H12N2O5: [M+Na]+ = 335.0638, found: [M+Na]+ = 335.0638.
1
1-(4-Fluorophenyl)-4-(4-nitrophenyl)but-3-yn-1-ol (4c). A yellow oil (50 mg, 34%). H-NMR
(CDCl3):  8.15 (2H, d, J = 8.8 Hz), 7.5 (2H, d, J = 8.8 Hz), 7.40 (2H, m), 7.08 (2H, m), 4.98 (1H, t,
13
J = 6.3 Hz), 2.90 (2H, d, J = 6.3 Hz). C-NMR (CDCl3): δ 162.3 (1C, d, J = 246.6 Hz), 147.0 (C),
138.2 (C), 132.4 (2CH), 130.2 (C), 127.6 (2CH, d, J = 8.4 Hz), 123.6 (2CH), 115.4 (2CH, d, J = 21.6 Hz),
91.6 (C), 81.7 (C), 71.9 (CH), 30.6 (CH2). HRMS calcd. for C16H12FNO3: [M+Na]+ = 308.0693,
found: [M+Na]+ = 308.0692.
1
4-(4-Nitrophenyl)-1-p-tolylbut-3-yn-1-ol (4d). Traces. H-NMR (CDCl3):  8.29 (2H, d, J = 8.8 Hz),
7.40 (2H, m), 7.10 (4H, m), 7.08 (2H, m), 4.98 (1H, m), 2.41 (3H, s).
4-(4-Nitrophenyl)-1-[4-(trifluoromethyl)phenyl]but-3-yn-1-ol (4e). A yellow oil (87 mg, 51%).
1H-NMR (CDCl3):  8.17 (2H, d, J = 8.8 Hz), 7.60 (4H, m), 7.50 (2H, d, J = 8.8 Hz), 5.06 (1H, m),
2.93 (2H, d, J = 6.3 Hz), 2.42 (1H, bs, OH). 13C-NMR (CDCl3): δ 147.0 (C), 146.3 (C), 132.4 (2CH),

Molecules 2013, 18
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130.3 (1C, q, J = 32.3 Hz), 129.9 (C), 126.1 (2CH), 127.5 (2CH, q, J = 3.6 Hz), 124.0 (C, q, J = 272.3 Hz),
123.6 (2CH), 91.2 (C), 81.9 (C), 71.9 (CH), 30.5 (CH2). HRMS calcd. for C17H12F3NO3:
[M+Na]+ = 358.0661, found: [M+Na]+ = 358.0661.
1-(4,5-Dimethoxy-2-nitrophenyl)-4-(4-nitrophenyl)but-3-yn-1-ol (4f). A brown oil (60 mg, 32%).
1H-NMR (CDCl3):  8.15 (2H, d, J = 8.8 Hz), 7.62 (1H, s), 7.51 (2H, d, J = 8.8 Hz), 7.40 (1H, s), 5.76
(1H, dd, J = 6.9 and 4.3 Hz), 3.96 (6H, s), 3.15 (1H, dd, J = 16.9 and 4.3 Hz), 3.05 (1H, dd, J = 16.9
and 6.9 Hz). 13C-NMR (CDCl3): δ 153.7 (C), 148.2 (C), 146.9 (C), 139.7 (C), 133.4 (C), 132.4 (2CH),
130.2 (C), 123.6 (2CH), 109.2 (CH), 107.8 (CH), 91.7 (C), 81.8 (C), 67.7 (CH), 56.4 (2OCH3), 29.7
(CH2). HRMS calcd. for C18H16N2O7: [M+Na]+ = 395.0850, found: [M+Na]+ = 395.0849.
1
4-(4-Nitrophenyl)-1-phenylbut-3-yn-1-ol (4g). A yellow oil (41 mg, 30%). H-NMR (CDCl3):  8.15
(2H, d, J = 8.8 Hz), 7.50 (2H, d, J = 8.8 Hz), 7.40 (5H, m), 5.00 (1H, t, J = 6.3 Hz), 2.92 (2H, d,
13
J = 6.3 Hz). C-NMR (CDCl3): δ 146.9 (C), 142.5 (C), 132.4 (2CH), 130.3 (C), 128.6 (2CH), 128.2
(CH), 125.8 (2CH), 123.5 (2CH), 92.2 (C), 81.5 (C), 72.6 (CH), 30.5 (CH2). HRMS calcd. for
C16H13NO3: [M+NH4]+ = 285.1234, found: [M+NH4]+ = 285.1238.
Compound 5a was isolated in 35% yield according to the general procedure cited above, but using
10 mL of DMF as solvent, rt for stage 2 (Table 1, Entry 10) and purification by silica gel
chromatography (dichloromethane/petroleum ether 7/3).
2-(4-Chlorophenyl)-3-[(4-nitrophenyl)ethynyl]oxirane (cis isomer) (5a). A yellow oil (57 mg, 35%).
1H-NMR (CDCl3):  8.14 (2H, d, J = 8.8 Hz), 7.40 (2H, d, J = 8.8 Hz), 7.39 (4H, s), 4.24 (1H, d,
J = 3.8 Hz), 3.98 (1H, d, J = 3.8 Hz). 13C-NMR (CDCl3): δ 134.6 (C), 132.6 (2CH), 132.5 (C), 128.5
(C), 128.2 (4CH), 123.6 (2CH), 88.6 (C), 84.1 (C), 58.7 (CH), 48.4 (CH). C–NO2 was not observed
under these experimental conditions. HRMS calcd. for C16H10ClNO3: [M+NH4]+ = 317.0687, found:
[M+NH4]+ = 317.0687.
4. Conclusions
This study is the first to report on the use of the TDAE methodology in an alkyne series. The
reaction of 1-(3-chloroprop-1-ynyl)-4-nitrobenzene (1) with aromatic aldehydes led to the
corresponding alcohols 4a–g in moderate to good yields. We present here the first example of the
formation of a propargylic carbanion via the TDAE methodology. This is an original and mild method
to synthesize diarylbutynol derivatives as chalcone precursors with potential for pharmacological use
as anticancer agents.
Acknowledgments
This work was supported by the Centre National de la Recherche Scientifique. We express our
thanks to Vincent Remusat for recording the 1H and 13C-NMR spectra.
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