On water reaction of deactivated anilines with 4-methoxy-3-buten-2-one, an effective butynone surrogate

Article abstract of DOI:10.1039/c6ob02402e

Poorly nucleophilic aromatic amines (nitroanilines, chloroanilines, etc.) react readily and selectively with trans-4-methoxy-3-buten-2-one, a convenient, effective and inexpensive surrogate for 3-butyn-2-one, to afford (Z)-enaminones. The efficiency of the reaction mostly lies in the use of water as a solvent, which enhances the reaction rate by a 45 to 200-fold factor with regard to other media.

Full text of DOI:10.1039/c6ob02402e

View Article Online
View Journal
Organic &
Biomolecular
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: M. JEBARI, K.
Pasturaud, B. PICARD, J. Maddaluno, F. REZGUI, I. CHATAIGNER and J. LEGROS, Org. Biomol. Chem.,
2016, DOI: 10.1039/C6OB02402E.
This is an Accepted Manuscript, which has been through the
Volume 14 Number
1 7 January 2016 Pages 1–372
Royal Society of Chemistry peer review process and has been
accepted for publication.
Organic &
Biomolecular
Chemistry
www.rsc.org/obc
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
ISSN 1477-0520
COMMUNICATION
Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
rsc.li/obc

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 1 of 3
View Article Online
DOI: 10.1039/C6OB02402E
Journal Name
COMMUNICATION
“On water” reaction of deactivated anilines with 4-methoxy-3-
buten-2-one, an effective butynone surrogate
Meriam Jebari,a,b Karine Pasturaud,a Baptiste Picard,a Jacques Maddaluno,a Farhat Rezgui,b
Isabelle Chataignera and Julien Legros*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Poorly
nucleophilic
aromatic
amines
(nitroanilines, and rather expensive substrate. In contrast, trans-4-
is ca. 20 times cheaper and it can be
chloroanilines,...) react readily and selectively with trans-4- methoxybutenone
1
methoxy-3-buten-2-one, a convenient, effective and inexpensive regarded as a butynone surrogate through formal vinylic
surrogate for 3-butyn-2-one, to afford (Z)-enaminones. The nucleophilic substitution (addition-elimination).§ While there
efficiency of the reaction mostly lies on the use of water as are some reports describing reaction between
1 and reactive
solvent, which enhances the reaction rate by a 45 to 200-fold anilines, the reaction scope is limited and yields are generally
modest.15–18 Herein we report that enaminones can be readily
obtained from and electron-poor anilines with the condition
factor with regard to other media.
1
The choice of the solvent in which a chemical reaction is
performed is often decisive for its outcome.1–3 Whereas it is
generally considered that homogeneous conditions are a
prominent point, the use of water with insoluble organic
reagents may trigger significant enhancement in reaction
rate.4–6 The beneficial impact of water has been exemplified in
several reactions, including the aza-Michael reaction of
aromatic amines with much simple acceptors, mostly vinyl
ketones and acrylate derivatives.7–10 Extending the range of
Michael acceptors to electron-poor acetylenic compounds
offers an attractive and shortened pathway for assembling the
potent enamine functionality.11,12 In this connection, the
addition of aromatic amines to 3-butyn-2-one has been
described.13,14 Thus, Whiting reported that the reaction
between simple aniline and the ynone was completed at room
temperature within 20 min in ethanol as solvent to afford the
corresponding (Z)-enaminone. This reaction was strongly
solvent dependent: only 67% conversion were observed after
16 h with water, and results were even worse in other
common organic solvents.14 This 1,4-addition in ethanol
proceeded well with electron-rich anilines but reaction times
skyrocketed with deactivated anilines: nitroaniline only
afforded low conversion into enaminone after several days.
Moreover butynone presents the drawbacks of being a volatile
of using water as solvent.
First, the effect of solvent (C = 1 M) was assessed by
measuring the rate constants of the reaction between 4-
methoxybutenone 1 (liquid) and a very weak Michael donor, 3-
nitroaniline 2a (solid) at 20 °C (Table 1).
Table 1 Solvent effect in the reaction between trans-4-methoxy-3-buten-2-one 1 and 3-
nitroaniline 2aa
Solvent
CH2Cl2
EtOH
Time (h)
Yield (%)b,c
k (M−1 h−1
0.13
)
24
24
2
76
55
19
83
31
86
96
98
0.05
TFE
0.21
0.26
24
2
HFIP
24
2
H2O
12.33
0.21
−
24
a
Reactions were performed with butenone 1 (0.5 mmol), aniline 2a (0.6 mmol)
and solvent (0.5 mL) under vigorous stirring (1400 rpm). b Measured by 1H NMR. c
Product 3a was obtained with a Z/E ratio of 98:02.
In CH2Cl2 the reaction afforded enaminone 3a in 76% yield
within 24 h (k = 0.13 M−1 h−1). Surprisingly, the use of EtOH led
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 2 of 3
View Article Online
DOI: 10.1039/C6OB02402E
COMMUNICATION
Journal Name
Table 2 On water reaction between 1 and anilines 2a-n.a
the rate constant to plummet (55% yield within 24 h, k = 0.05
M−1 h−1) while this solvent was by far the best to promote the
addition of aniline onto butynone.14 Highly polar protic
solvents such as trifluoroethanol (TFE), hexafluoroisopropanol
(HFIP) or water,1,19–21 have been previously shown to boost the
reaction between anilines and ethylenic Michael acceptors,7–
Entry Aniline
1
Temp
(°C)
20
Time
(h)
2
Product
Yield
(%)b,c
98
either by activating the electrophile9 and/or by
9,22
exacerbating the nucleophilicity of the amine.23 Accordingly,
3a
performing the reaction between
1 and 2a in TFE and HFIP
positively influenced the reaction rate (k = 0.21 and 0.26 M−1
h−1 respectively) but not as much as expected since the
conversion remained partial after 24 h. Switching to water
triggered an astonishing kinetics acceleration: the reaction
between these two reagents, both immiscible with water,
reached completion within only 2 h, the reaction rate being 45
times higher than in HFIP (k = 12.33 M−1 h−1 with water). The
same reaction was also assessed without solvent, and it
proceeded close to what observed in the fluorinated alcohols
(k = 0.21 M−1 h−1) and remained thus much slower than “on
water”. It is worth noting the enaminone was obtained as the
more stable Z,s-cis-isomer, a result fully consistent with that of
Whiting who observed that the 1H NMR NH signal in
enaminones recorded at 11.5 ppm for the Z-isomer (due to the
internal H-bonding with the carbonyl) was shifted at 7.1 ppm
for the E-isomer.14
2
3
60
60
1
2
3a
3b
96
77
2a
2b
2c
4
5
60
60
0.5
0.5
3c
98
94
3d
2d
2e
6
7
8
60
60
60
0.5
0.5
0.5
3e
3f
83
98
92
2f
The scope of this striking “on water” effect for the reaction
3g
between
1 and deactivated anilines was then evaluated with a
variety of aromatic amines bearing electron-withdrawing
substituents (Table 2). First, we found that the reaction time to
obtain 3a could be halved by warming the medium at 60 °C
time (2 h at 20 °C vs 1h at 60 °C; entries 1 and 2). Note that the
addition of poor nucleophiles such as 4-nitroaniline 2b or 4-
choroaniline 2f on butynone has been previously reported to
occur in relatively longer reaction times and poorer yields: 5
days for 3b (33% yield) and 6 h for 3f (92%).14 In our hands, 2b
was transformed in enaminone 3b (77%; entry 3) in only 2 h at
60 °C using water as “solvent”. Comparable and even better
results were obtained with the trifluoromethyl-containing
anilines that reacted with methoxybutenone, providing 3c-e in
84-93% yield after only 30 min (entries 4-6). Expectedly,
substituents exerting inductive electron-withdrawing effects
partly balanced by mesomeric electron-donating ones such as
the light halogen atoms (monochloro-, monofluoro-,
chlorofluoro- and difluoroanilines), led rapidly to enaminones
3f-l (84-94% yield within 0.5-4 h, entries 7-13). Finally,
relatively good nucleophiles such as aniline itself or p-anisidine
afforded the expected adducts (89 and 97% yield for 3m and
3n, respectively; entries 14 and 15) in short reaction times. It is
2g
2h
9
60
60
60
0.5
0.5
0.5
3h
3i
94
92
86
10
11
2i
3j
2j
12
13
20
20
4
2
3k
3l
84
87
2k
2l
14
15
60
20
0.5
1
3m
3n
89
97
2m
2n
a Reactions were performed with butenone 1 (0.5 mmol), aniline 2a-n (0.6 mmol)
worth mentioning that all the enaminones
3 obtained
b
and water (0.5 mL) at 20 or 60 °C under vigorous stirring (1400 rpm). Isolated
yield. c Products 3a-n were obtained with a Z/E ratio 98:02 to 100:0.
exhibited the (Z)-s-cis geometry.
In these conditions, secondary anilines proved likewise to
behave as potent nucleophiles (Scheme 1). N-Methylaniline
Several explanations have been proposed for the “on
water” effect. In particular, the activation of the substrate
through H-bonding at oil-water interface has been evoked,24–27
as well as the protonation due to strong adsorption of
hydroxide ions at water surface.28–31 These theories have been
(
2o) and its less nucleophilic 4-chloro analog (2p) reacted with
methoxybutenone 1 in 1 h at 60 °C (97% and 83% yield,
respectively for 3o and 3p). In this case, the products obtained
exhibited exclusively the E-configuration, probably due to the
absence of any stabilizing H-bonding.14
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 3 of 3
View Article Online
DOI: 10.1039/C6OB02402E
Journal Name
COMMUNICATION
8
K. De, J. Legros, B. Crousse and D. Bonnet-Delpon, J. Org.
Chem., 2009, 74, 6260–6265.
C. B. W. Phippen, J. K. Beattie and C. S. P. McErlean, Chem.
supported by several evidences. Therefore, it could be
supposed that water activates the methoxybutenone
1 by one
9
of these means. However, this phenomenon alone cannot be
considered since the acidity and H-bonding donation ability of
water (α1 = 1.54) is comprised between that of TFE (α1 = 1.36)
and HFIP (α1 = 1.86), the fluorinated alcohols being much less
effective than water.21 Another explanation could be the local
pressure exerted on organic molecules “on” water,32,33 since
pressure has been shown to have a highly beneficial impact on
aza-Michael reactions.10,22
Commun., 2010, 46, 8234–8236.
10 M. Uddin, K. Nakano, Y. Ichikawa and H. Kotsuki, Synlett,
2008, 2008, 1402–1406.
11 A.-Z. A. Elassar and A. A. El-Khair, Tetrahedron, 2003, 59
8463–8480.
,
12 I. O. Edafiogho, S. B. Kombian, K. V. V. Ananthalakshmi, N. N.
Salama, N. D. Eddington, T. L. Wilson, M. S. Alexander, P. L.
Jackson, C. D. Hanson and K. r. Scott, J. Pharm. Sci., 2007, 96
2509–2531.
,
13 I.-H. Um, E.-J. Lee and J.-S. Min, Tetrahedron, 2001, 57
9585–9589.
,
14 D. R. Chisholm, R. Valentine, E. Pohl and A. Whiting, J. Org.
Chem., 2016, 81, 7557–7565.
15 P. R. Girling, A. S. Batsanov, H. C. Shen and A. Whiting, Chem.
Commun., 2012, 48, 4893–4895.
16 K. C. Nicolaou, H. Zhang, J. S. Chen, J. J. Crawford and L.
Pasunoori, Angew. Chem. Int. Ed., 2007, 46, 4704–4707.
17 J. D. Crowley, A. J. Goshe, I. M. Steele and B. Bosnich, Chem.
– Eur. J., 2004, 10, 1944–1955.
Scheme 1 Synthesis of (E)-enaminones 3o-p.
18 C. P. Roll, A. G. Martin, H. Görls, G. Leibeling, D. Guillon, B.
Donnio and W. Weigand, J. Mater. Chem., 2004, 14, 1722–1730.
19 C. Reichardt, Chem. Rev., 1994, 94, 2319–2358.
20 D. Vuluga, J. Legros, B. Crousse, A. M. Z. Slawin, C. Laurence,
P. Nicolet and D. Bonnet-Delpon, J. Org. Chem., 2011, 76, 1126–
1133.
21 C. Laurence, J. Legros, A. Chantzis, A. Planchat and D.
Jacquemin, J. Phys. Chem. B, 2015, 119, 3174–3184.
22 A. Fedotova, B. Crousse, I. Chataigner, J. Maddaluno, A. Y.
Rulev and J. Legros, J. Org. Chem., 2015, 80, 10375–10379.
In conclusion, 4-methoxy-3-buten-2-one is
a handy,
effective and affordable surrogate of butynone for the
synthesis of enaminones from anilines. Running the reaction
“on water” exerts a dramatic effect on reaction rates, allowing
the addition of deactivated aromatic amines (nitro-, chloro-,
fluoroanilines) within at most a few hours. The effect is even
more striking with nitroanilines that react under these
conditions in 2 h while several days were usually required.
These results could be of interest in organocatalysed
transformations where the formation of transient enamines is
often involved.
23 F. Brotzel, Y. C. Chu and H. Mayr, J. Org. Chem., 2007, 72
3679–3688.
24 Y. Jung and R. A. Marcus, J. Am. Chem. Soc., 2007, 129
,
,
5492–5502.
25 A. Manna and A. Kumar, J. Phys. Chem. A, 2013, 117, 2446–
2454.
26 K. Karhan, R. Z. Khaliullin and T. D. Kühne, J. Chem. Phys.,
2014, 141, 22D528.
27 D. Guo, D. Zhu, X. Zhou and B. Zheng, Langmuir, 2015, 31
13759–13763.
28 J. K. Beattie, A. M. Djerdjev and G. G. Warr, Faraday Discuss.,
2008, 141, 31–39.
Acknowledgements
Financial support from Labex SynOrg (ANR-11-LABX-0029),
Normandie University, Rouen University, CNRS, INSA Rouen,
and Région Normandie (CRUNCh network) is acknowledged.
Meriam Jebari from “Laboratoire LR99ES14, Tunisia”, is
grateful for a travel fellowship.
,
29 A. Gray-Weale and J. K. Beattie, Phys. Chem. Chem. Phys.,
2009, 11, 10994–11005.
30 J. K. Beattie, C. S. P. McErlean and C. B. W. Phippen, Chem. -
Eur. J., 2010, 16, 8972–8974.
Notes and references
31 P. Creux, J. Lachaise, A. Graciaa, J. K. Beattie and A. M.
Djerdjev, J. Phys. Chem. B, 2009, 113, 14146–14150.
32 M. R. J. Dack, Chem. Soc. Rev., 1975, 4, 211–229.
‡ Electronic Supplementary Information (ESI) available: kinetics,
experimental details and analytical data.
§ For example Sigma-Aldrich provides 3-butyn-2-one for 88 €/g
and 4-methoxy-3-buten-2-one for 4 €/g.
33 Y. Marcus, Chem. Rev., 2013, 113, 6536–6551.
1
Y. Marcus, The properties of solvents, Wiley, Chichesterꢀ;
New York, 1998.
E. Buncel, R. A. Stairs and H. Wilson, The role of the solvent in
2
chemical reactions, Oxford University Press, Oxford; New York,
2003.
3
C. Reichardt and T. Welton, Solvents and solvent effects in
organic chemistry, Wiley-VCH, Weinheim, 2010.
S. Narayan, J. Muldoon, M. G. Finn, V. V. Fokin, H. C. Kolb
and K. B. Sharpless, Angew. Chem. Int. Ed., 2005, 44, 3275–3279.
4
5
6
T. Sela and A. Vigalok, Org. Lett., 2014, 16, 1964–1967.
K. Itami, T. Nokami and J. Yoshida, Angew. Chem. Int. Ed.,
2001, 40, 1074–1076.
H. Firouzabadi, N. Iranpoor and A.ꢀA. Jafari, Adv. Synth.
Catal., 2005, 347, 655–661.
7
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins