Solvent-promoted and -controlled Aza-Michael reaction with aromatic amines

Article abstract of DOI:10.1021/jo9012699

(Chemical Equation Presented) 1,4-Addition of anilines onto Michael acceptors proceeds easily in specific polar protic solvents, without any promoting agent. According to the solvent and to the electrophile, the selectivity of the reaction can be finely tuned. With methyl acrylate as electrophile, only monoaddition takes place in water, while the diadduct is yielded in hexafluoroisopropyl alcohol (HFIP). The use of methyl vinyl ketone as a partner affords the monoadduct in water, the diadduct in trifluoroethanol (TFE), and the quinoline in HFIP.

Full text of DOI:10.1021/jo9012699

pubs.acs.org/joc
Solvent-Promoted and -Controlled Aza-Michael Reaction with Aromatic
Amines
ꢀ
Kavita De, Julien Legros,* Benoit Crousse,* and Daniele Bonnet-Delpon
ꢁ ꢁ
Laboratoire BioCIS-CNRS, Faculte de Pharmacie, Univ Paris Sud, rue JB Clement,
F-92296 Cha^tenay-Malabry, France
julien.legros@u-psud.fr; benoit.crousse@u-psud.fr
Received June 14, 2009
1,4-Addition of anilines onto Michael acceptors proceeds easily in specific polar protic solvents,
without any promoting agent. According to the solvent and to the electrophile, the selectivity of the
reaction can be finely tuned. With methyl acrylate as electrophile, only monoaddition takes place in
water, while the diadduct is yielded in hexafluoroisopropyl alcohol (HFIP). The use of methyl vinyl
ketone as a partner affords the monoadduct in water, the diadduct in trifluoroethanol (TFE), and the
quinoline in HFIP.
Introduction
is very sluggish and requires the assistance of powerful
promoters. However, it seems that the nucleophilicity of
aromatic amines is highly solvent dependent, as exemplified
by Mayr’s nucleophilic scale of amines, where aniline is
reportedtoreacttwotimesfasterinwaterthaninacetonitrile.2
As a comparison, this “unexpected high nucleophilicity” of
aniline in water is close to that of ethyl- and benzylamine.2
Following from this, the 1,4-addition between aromatic
amines and Michael acceptors proved to be highly challen-
ging3 until the recent breakthrough by the introduction of
aqueous media with promoting agents (e.g., metal catalyst,
surfactant).3b,e,i Still, examples are scarce, and most of the
methods provide only access to the monoaddition products.
We demonstrate herein that the highly polar protic solvents
water, trifluoroethanol (TFE), and hexafluoroisopropyl alco-
hol (HFIP) are able to promote the 1,4-addition of aromatic
amines onto Michael acceptors (methyl acrylate, methyl vinyl
ketone) and that the selectivity of the reaction is under
exclusive solvent control, affording thus monoadducts, di-
adducts, or even cyclialkylation products.
Anilines are poor nucleophiles with regard to aliphatic
amines;1 as a consequence, their addition onto electrophiles
*To whom correpondence should be addressed. Tel: þ33146835739. Fax:
þ33146835740.
(1) Lee, I.; Sung, D. D. In Chemistry of Anilines; Rappoport, Z., Ed.;
Wiley: Chichester, 2007; pp 537-581.
(2) Brotzel, F.; Chu, Y. C.; Mayr, H. J. Org. Chem. 2007, 72, 3679–3688.
(3) (a) Banushali, M. J.; Nandurkar, N. S.; Jagtap, S. R.; Bhanage, B. M.
Catal. Commun. 2008, 9, 1189–1195. (b) Chen, X.; She, J.; Shang, Z.; Wu, J.;
Zhang, P. Synthesis 2008, 24, 3931–3936. (c) Firouzabadi, H.; Iranpoor, N.;
Jafarpour, M.; Ghaderi, A. J. Mol. Catal. A: Chem. 2006, 252, 150–155. (d)
Fetterly, B. M.; Jana, N. K.; Verkade, J. G. Tetrahedron 2006, 62, 440–456.
(e) Surendra, K.; Krishnaveni, N. S.; Sridhar, R.; Rao, K. R. Tetrahedron
Lett. 2006, 47, 2125–2128. (f) Karodia, N.; Liu, X.; Ludley, P.; Pletsas, D.;
Stevenson, G. Tetrahedron 2006, 62, 11039–11043. (g) Yang, L.; Xu, L.-W.;
Zhou, W.; Li, L.; Xia, C.-G. Tetrahedron Lett. 2006, 47, 7723–7726. (h)
Duan, Z.; Xuan, X.; Li, T.; Yang, C.; Wu, Y. Tetrahedron Lett. 2006, 47,
5433–5436. (i) Firouzabadi, H.; Iranpoor, N.; Jafari, A. A. Adv. Synth. Catal.
2005, 347, 655–661. (j) Vicario, J.; Aparicio, D.; Palacios, F. J. Org. Chem.
2009, 74, 452–455. (k) Reboule, I.; Gil, R.; Collin, J. Eur. J. Org. Chem. 2008,
532–539. (l) Xu, L.-W.; Xia, C.-G. Eur. J. Org. Chem. 2005, 633–639. (m) Xu,
L.-W.; Xia, C.-G. Helv. Chim. Acta 2004, 87, 1522–1526. (n) Xu, L.-W.; Li,
J.-W.; Xia, C.-G.; Zhou, S.-L.; Hu, X.-X. Synlett 2003, 2425–2427.
6260 J. Org. Chem. 2009, 74, 6260–6265
Published on Web 07/21/2009
DOI: 10.1021/jo9012699
r
2009 American Chemical Society

De et al.
JOCArticle
TABLE 1. Aza-Michael Reaction between Aniline and Methyl Acrylate
in Various Solventsa
impact on the reaction course with a lower conversion rate
(<80%) and a lower selectivity (1a/1b, 70:30; entry 5).
Unfortunately, this latter reaction could not be improved
with a lower amount of methyl acrylate (with 1 equiv:
80:20; entry 4). In contrast, with 3 equiv of the Michael
acceptor, the reaction performed in HFIP at reflux (58 °C)
afforded an excellent 95% conversion within 16 h (entry 7).
Moreover, in this solvent the reaction underwent a surpris-
ing complete switch of selectivity: the diaddition product
1b was obtained as almost a single product (96%; entry 6).
For comparison, the same reaction was performed
in refluxing dichloromethane (40 °C) and ethanol (78 °C;
entries 8 and 9, respectively). In these solvents, no reac-
tion occurred revealing the unique role of water and
fluoro alcohols in the promotion and the selectivity of the
reaction.
entry
solvent
water
water
methyl acrylate (equiv) T (°C) convb (%) 1a/1bc
1
2
3d
4
5
6
7
8
9
1.0
3.0
80
80
80
80
80
58
58
40
78
15
40
100
50
77
50
95
0
100:0
100:0
94:6
water/TFE 3.0
TFE
TFE
HFIP
HFIP
CH2Cl2
ethanol
1.0
3.0
1.0
3.0
1-3.0
1-3.0
80:20
71:29
37:63
4:96
Following the optimized reaction conditions reported in
Table 1, various aromatic amines were assessed with methyl
acrylate (3 equiv) in water, water/TFE, and HFIP under
heating (Table 2). In water, while with simple aniline the
reaction afforded 1a with only 34% yield after 16 h (entry 1),
the presence of electron-donating substituents (methyl,
methoxy) on the arene ring allowed the reaction to afford
the monoaddition products 2a and 3a in satisfying yields
(52% and 62%, respectively; entries 2 and 3). Conversely, the
presence of an electron-withdrawing group is detrimental, as
exemplified by the lack of reaction with 4-chloroaniline
as the substrate (entry 4). According to our preliminary
experiments, the addition of TFE to water proved to be
effective for the addition of simple aniline with 85% yield for
1a toward 34% without TFE (entries 1 and 5). However,
with 4-anisidine the conversion was complete but the reac-
tion yielded mixtures of mono- and disubstituted adducts
(entry 6), while with 4-chloroaniline only poor conversion
was obtained (entry 7). Conversely, switching to HFIP as
solvent gave excellent results to yield almost exclusively the
product stemming from a double addition, accompanied by
less than 5% of the monoaddition adduct. Yields of products
were good to excellent for aniline and the electron-rich
4-toluidine and 4-anisidine (75-95% yields; entries 8-10);
even 4-chloroaniline also reacted satisfyingly (66% yield,
entry 11). However, with 4-nitroaniline no product was
obtained (entry 12).
0
aReactions conditions: aromatic amine (1.5 mmol), Michael acceptor
(4.5 mmol) in solvent (1.5 mL). bConversion was measured by GC.
cRatio was determined by 1H NMR from the crude product. d2 equiv of
TFE (0.17 mL) was used.
Results
The monoaddition of aniline onto methyl acrylate has
been reported to proceed in water in the presence of tung-
stophosphoric acid3b or β-cyclodextrin,3e within 8-40 h at
room temperature. In this connection, our first experiments
were performed by reacting aniline and methyl acrylate in
neat water at 80 °C (Table 1). While with 1 equiv of the
electrophile only 15% conversion occurred after 16 h (entry
1), we were pleased to observe that with 3 equiv a reasonable
40% conversion took place to afford the β-amino monoester
1a as sole product (entry 2). Apart from water, the fluorous
alcohols TFE and HFIP have also been shown to be excellent
solvents for other nucleophilic reactions with anilines, as
exemplified by the opening of epoxides.4-6 Thus, the aza-
Michael addition was conducted again in water at 80 °C, but
with TFE as a cosolvent (entry 3); this resulted in a full
conversion of the starting material in 16 h, to yield 1a (94%),
along with traces of diaddition product 1b (6%). However,
the use of neat TFE as the reaction medium had a negative
The 1,4-addition of aromatic amines with methyl vinyl
ketone (MVK) as Michael acceptor has been previously
reported.3d-g As for methyl acrylate, most of the reports
describe the monoaddition onto the electrophile. However,
according to our observations described above, the solvent
could also influence the course of the reaction with this
partner (Table 3). Indeed, in water as the medium, the
reaction proceeded smoothly at room temperature within
short reaction times, less than 4 h for electron-rich arenes and
6 h for 4-chloroaniline, and all products were obtained in
good to high yields (65-83% yield, entries 1-7). Moreover,
the use of TFE also allowed a complete consumption of
starting materials at room temperature to lead exclusively to
the diaddition adducts, here also in good yields (70-80%;
entries 8-14). Furthermore, even with the poor nucleophile
4-nitroaniline, the reaction took place nicely in 24 h (70%
yield). Surprisingly, under the same conditions (with 3 equiv
of MVK at room temperature), the reaction performed
in HFIP also afforded the amino diketone 6b, albeit
ꢁ
ꢁ
(4) Das, U.; Crousse, B.; Kesavan, V.; Bonnet-Delpon, D.; Begue, J.-P. J.
Org. Chem. 2000, 65, 6749–6751.
(5) For reviews on fluorous alcohols, see: (a) Shuklov, I. A.; Dubrovina,
N. V.; Borner, A. Synthesis 2007, 2925–2943. (b) Begue, J.-P.; Bonnet-
Delpon, D.; Crousse, B. Synlett 2004, 18–29. (c) Begue, J.-P.; Bonnet-Delpon,
D.; Crousse, B. In Handbook of Fluorous Chemistry; Gladysz, J. A., Curran, D.
P., Horvath, I. T., Eds.; Wiley-VCH: Weinheim, 2004; pp 341-350.
(6) For recent contributions on reactions in fluorous alcohols, see: (a)
Willot, M.; Chen, J. C.; Zhu, J. Synlett 2009, 577–580. (b) Ratnikov, M. O.;
Tumanov, V. V.; Smit, W. A. Angew. Chem., Int. Ed. 2008, 47, 9739–9742. (c)
€
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ꢁ
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ꢁ
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Fustero, S.; Roman, R.; Sanz-Cervera, J. F.; Simon-Fuentes, A.; Cunat, A.
C.; Villanova, S.; Murguıa, M. J. Org. Chem. 2008, 73, 3523–3529. (d) De, K.;
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Legros, J.; Crousse, B.; Bonnet-Delpon, D. Tetrahedron 2008, 64, 10497–
10500. (e) Westermaier, M.; Mayr, H. Chem.;Eur. J. 2008, 14, 1638–1647.
(f) Heydari, A.; Khaksar, S.; Tajbakhsh, M. Synthesis 2008, 3126–3130. (g)
Dohi, T.; Maruyama, A.; Minamitsuji, Y.; Takenaga, N.; Kita, Y. Chem.
Commun. 2007, 1224–1226. (h) Hata, K.; Hamamoto, H.; Shiozaki, Y.;
€
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N. V.; Shuklov, I. A.; Birkholz, M.-N.; Michalik, D.; Paciello, R.; Borner, A.
Adv. Synth. Catal. 2007, 349, 2183–2187. (j) Yagi, H.; Jerina, D. M. J. Org.
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Chem. 2007, 72, 9983–9990. (k) Jean, A.; Cantat, J.; Berard, D.; Bouchu, D.;
Canesi, S. Org. Lett. 2007, 9, 2553–2556. (l) Legros, J.; Crousse, B.;
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Ourevitch, M.; Bonnet-Delpon, D. Synlett 2006, 1899–1902. (m) Di Salvo,
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€
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De et al.
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TABLE 2. Aza-Michael Reaction of Aromatic Amines with Methyl
Acrylate in Water and HFIPa
the conjugate addition of the amine to MVK, followed by
cyclization and aromatization under air.7 The synthesis of
quinolines via a tandem aza-Michael reaction/cyclialkyla-
tion/oxidation process from aromatic amines and acrolein is
well-known as the Skraup-Doebner-von Miller reaction,
which takes place generally under harsh conditions (acidic
medium, strong heating).8 To our knowledge, there is only
one study involving methyl vinyl ketone as a partner for this
purpose: a reaction which proceeds with silica-supported
InCl3 under microwave irradiation.9 In this context, the
scope of the reaction between aniline and MVK in HFIP
was extended to other aromatic amines (entries 16-20). It
emerges that the process is quite general with electron-rich
anilines: 4-toluidine, 4-anisidine, 3-toluidine, 3-anisidine,
and 3,4-dimethoxy aniline also affording the corresponding
quinoline derivatives in satisfactory yields (50-60%). How-
ever, in the presence of an electron-withdrawing 4-nitro
group on the arene ring, monoaddition occurs but the
product did not undergo subsequent cyclization, and in-
stead, a second addition of the electrophile gave 17b (80%
yield; entry 21).
From a mechanistic standpoint, the solvent effect on the
reaction depicted herein is rather intriguing. Nevertheless,
one can notice that TFE and HFIP seem to share more
features with water than with ethanol, as the first three
solvents are able to promote the addition of aniline onto
methyl acrylate. Moreover, water, TFE, and HFIP are
highly polar and protogenic solvents, which could be key
factors.10 Indeed, it is commonly admitted that fluorous
alcohols can activate protophilic electrophiles through
hydrogen bonds (e.g., epoxides, esters, etc.).10b,11 Thus,
TFE and HFIP are both able to promote the first
1,4-addition of aniline onto a conjugated carbonyl com-
pound to yield the corresponding product. Knowing that
hydrogen bond donation ability of HFIP is much stronger
than that of TFE, it is not surprising that HFIP is able to
promote “further” transformation compared to TFE
(diaddition with methyl acrylate, cyclialkylation with
MVK). However, in the case of water the promotion of
the reaction cannot be attributed to hydrogen bond dona-
tion only. Indeed, the high nucleophilicity of aniline in
water, as described by Mayr, is based on the kinetics of
reactions between benzhydrylium ions and amines, which
does not take into account this effect. Thus, even if it is too
early at this stage to get a deeper insight on the solvent
effects, a reasonable hypothesis could be that water mainly
“activates” the nucleophile, while the fluoro alcohols act
more on the electrophile.
(7) HFIP has already been shown to promote internal electrophilic
addition of aniline derivatives onto electron-poor ketones: Rodrigues, I.;
ꢁ
ꢁ
Bonnet-Delpon, D.; Begue, J.-P. J. Org. Chem. 2001, 66, 2098–2103.
(8) Name Reactions, 2nd ed.; Li, J. J., Ed.; Springer: Berlin, 2003; pp 117-
118 and 378-379.
aReaction conditions: aromatic amine (1.5 mmol), Michael accep-
tor (4.5 mmol) in water (1.5 mL; 80 °C) or HFIP (1.5 mL; 58 °C). bIn
HFIP, diaddition product was >95%. In water, only monoaddition
product was afforded. cIsolated yields of the major product. dNot
isolated.
(9) Ranu, B. C.; Hajra, A.; Jana, U. Tetrahedron Lett. 2000, 41, 531–533.
T
(10) (a) Polarity parameter EN for EtOH, 0.654; TFE, 0.898; HFIP,
1.068; H2O, 1.000. Reichardt, C. Chem. Rev. 1994, 94, 2319–2358. (b)
Hydrogen bond donation parameter AN for EtOH, 37.1; TFE, 53.8; HFIP,
66.7; H2O, 54.8. Eberson, L.; Hartshorn, M. P.; Persson, O.; Radner, F.
Chem. Commun. 1996, 2105–2112.
(11) For applications and studies on the hydrogen bond ability of
fluorous alcohols, see: (a) Vuluga, D.; Legros, J.; Crousse, B.; Bonnet-
accompanied by notable amounts of quinoline 18. Notably,
performing the same reaction at reflux in HFIP allowed us to
obtain 18 in 56% yield, without any traces of diadduct 6b
(entry 15). Clearly, the quinoline derivative 18 comes from
ꢁ
Delpon, D. Chem. Commun. 2008, 4954–4955. (b) Berrien, J.-F.; Ourevitch,
M.; Morgant, G.; Ghermani, N. E.; Crousse, B.; Bonnet-Delpon, D. J.
Fluorine Chem. 2007, 128, 839–843. (c) Berkessel, A.; Adrio, J. A.;
€
€
Huttenhain, D.; Neudorfl, J. M. J. Am. Chem. Soc. 2006, 128, 8421–8426.
6262 J. Org. Chem. Vol. 74, No. 16, 2009

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TABLE 3. Aza-Michael Reaction of Anilines with MVK in Water, TFE, or HFIPa
aReactions conditions: aromatic amine (1.5 mmol), Michael acceptor (2.3-4.5 mmol) in water (1.5 mL; 20 °C) or TFE (1.5 mL, 20 °C) or HFIP
(1.5 mL; 58 °C).
Conclusion
to afford mono- or diaddition products, or even quinolines, in
a one-pot fashion.12 Additional efforts involving the extension
of the methodology to other electrophiles and an in-depth
study for the solvent effect comprehension are underway.
In conclusion, the Michael addition of anilines onto elec-
tron-deficient olefins proceeds easily in water, trifluoroethanol
and hexafluoroisopropanol without any assisting agent. More-
over, according to the nature of the solvent and of the
electrophile, the selectivity of the reaction can be finely tuned
Experimental Section
General Procedure for the Aza-Michael Addition of Aromatic
Amines to Electron-Deficient Alkene in Water. A mixture
of aromatic amine (1.5 mmol) and alkene (methyl acrylate,
(12) Note that on a large scale the fluoro alcohol can be easily recovered
by simple distillation.
J. Org. Chem. Vol. 74, No. 16, 2009 6263

De et al.
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4.5 mmol; MVK, 2.3 mmol) in water (1.5 mL) was stirred at
room temperature under air. After completion of the reaction
(TLC monitoring), dichloromethane (30 mL) was added and
the reaction mixture was transferred into a separating funnel.
The organic layer was separated, and the aqueous layer
was extracted with dichloromethane (2ꢀ30 mL). The combined
organic layers were dried over anhyd MgSO4 and filtered,
and the solvent was evaporated under vacuum. The product
was isolated in pure form after column chromatography (cyclo-
hexane/AcOEt, 90:10).
General Procedure for the Aza-Michael Addition of Aromatic
Amines to MVK in TFE. A mixture of aromatic amine
(1.5 mmol) and MVK (4.5 mmol) in TFE (1.5 mL) was stirred
at room temperature under air. After completion of the reaction
(TLC monitoring), TFE was evaporated under vacuum and the
product was purified by column chromatography on silica gel
(cyclohexane/AcOEt 90:10).
General Procedure for the Aza-Michael Addition of Aromatic
Amines to Electron-Deficient Alkene in HFIP. A mixture of
aromatic amine (1.5 mmol) and alkene (4.5 mmol) in HFIP
(1.5 mL) was heated at reflux (60 °C) under stirring. After
completion of the reaction (TLC monitoring), HFIP was eva-
porated under vacuum and the product was purified by column
chromatography on silica gel (cyclohexane/AcOEt 90:10).
General Procedure for the One-Pot Synthesis of Quinolines in
HFIP. In a sealed tube, a solution of the aromatic amine
(1.5 mmol) and MVK (4.5 mmol) in HFIP (1.5 mL) was heated
at reflux (60 °C) under stirring. After completion of the reaction
(TLC monitoring), HFIP was evaporated under vacuum and the
product was purified by column chromatography on silica gel
(cyclohexane/AcOEt 50:50).
(300 MHz, CDCl3) δ 2.57 (t, J=6.9 Hz, 4H), 3.57 (t, J = 7.2 Hz,
4H), 3.70 (s, 6H), 3.79 (s, 3H), 6.77 (d, J=9.3 Hz, 2H), 6.87 (d, J=
9.3 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 32.4, 48.1, 51.6, 55.6,
114.9, 116.4, 141.4, 152.7, 172.6. Anal. Calcd for C15H21NO5: C,
61.00; H, 7.17; N, 4.74. Found: C, 60.98; H, 7.46; N, 4.90.
Methyl 3-[(2-methoxycarbonylethyl)-4-chlorophenylamino]pro-
panoate (4b): yellow oil, 265 mg, 66% yield; 1H NMR (300 MHz,
CDCl3) δ 2.56 (t, J=7.2 Hz, 4H), 3.62 (t, J=7.2 Hz, 4H), 3.67 (s,
6H), 6.61 (d, J=9.0 Hz, 2H), 7.16 (d, J=9.0 Hz, 2H); 13C NMR
(75 MHz, CDCl3) δ 32.1, 47.0, 51.8, 113.8, 122.0, 129.2, 145.3,
172.3. Anal. Calcd for C14H18NClO4: C, 56.10; H, 6.05; N, 4.67.
Found: C, 56.22; H, 5.88; N, 5.24.
Methyl 3-(N-methyl-N-phenylamino)propanoate (5): yellow
oil, 280 mg, 96% yield; 1H NMR (300 MHz, CDCl3) δ 2.64 (t,
J = 7.2 Hz, 2H), 3.0 (s, 3H), 3.73, (s, 3H), 3.74 (t, J = 7.2 Hz,
2H), 6.76-6.81 (m, 3H), 7.30-7.33 (m, 2H); 13C NMR
(75 MHz, CDCl3) δ 31.6, 38.3, 48.7, 51.8, 112.6, 116.9, 129.3,
148.6, 172.8. Anal. Calcd for C11H15NO2: C, 63.37; H, 7.82; N,
7.25. Found: C, 68.19; H, 7.82; N, 7.29.
4-Phenylaminobutan-2-one (6a): white solid, 198 mg, 80%
1
yield; mp 38 °C; H NMR (300 MHz, CDCl3) δ 2.17 (s, 3H),
2.75 (t, J= 6.1 Hz, 2H), 3.42 (t, J= 6.1 Hz, 2H), 3.99 (bs, 1H),
6.62 (d, J= 8.6 Hz, 2H), 6.72 (t, J= 7.3 Hz, 1H), 7.12- 7.21 (m,
2H); 13C NMR (75 MHz, CDCl3) δ 30.3, 38.4, 42.6, 113.0, 117.6,
129.3, 147.7, 208.1. Anal. Calcd for C10H13NO: C, 73.59; H,
8.03; N, 8.58. Found: C, 73.46; H, 7.92; N, 8.50.
4-(2-Methylphenylamino)butan-2-one (7a): brown oil, 186 mg,
70% yield; 1H NMR (300 MHz, CDCl3) δ 2.15 (s, 3H), 2.19 (s,
3H), 2.80 (t, J = 6.0 Hz, 2H), 3.49 (t, J=6.0 Hz, 2H), 3.92 (bs,
1H), 6.64-6.73 (m, 2H), 7.07-7.19 (m, 2H); 13C NMR (75 MHz,
CDCl3) δ 17.5, 30.3, 38.4, 42.6, 109.7, 117.2, 122.6, 127.1, 130.3,
145.7, 208.3. Anal. Calcd for C11H15NO: C, 74.54; H, 8.53; N,
7.90. Found: C, 74.51; H, 8.31; N, 8.12.
4-(3-Methylphenylamino)butan-2-one (8a): orange oil, 192 mg,
72% yield; 1H NMR (300 MHz, CDCl3) δ 2.17 (s, 3H), 2.30 (s,
3H), 2.74 (t, J=6.3 Hz, 2H), 3.42 (t, J=6.3 Hz, 2H), 3.93 (bs, 1H),
6.42-6.45 (m, 2H), 6.56 (d, J=7.5 Hz, 1H), 7.08 (t, J=7.7 Hz
1H); 13C NMR (75 MHz, CDCl3) δ 21.6, 30.3, 38.4, 42.7, 110.2,
113.8, 118.6, 129.2, 139.1, 147.8, 208.1. Anal. Calcd for C11H15-
NO: C, 74.54; H, 8.53; N, 7.90. Found: C, 74.97; H, 8.51; N, 7.83.
4-(4-Methylphenylamino)butan-2-one (9a). yellow solid, 200 mg,
80%; mp 37 °C; 1H NMR (300 MHz, CDCl3) δ 2.16 (s, 3H), 2.25
(s, 3H), 2.73 (t, J = 6.3 Hz, 2H), 3.40 (t, J=6.3 Hz, 2H), 3.81 (bs,
1H), 6.54 (d, J=8.1 Hz, 2H), 7.00 (d, J=8.1 Hz, 2H); 13C NMR
(75 MHz, CDCl3) δ20.3, 30.3, 38.8, 42.6, 113.3, 127.0, 129.8, 145.4,
208.1. Anal. Calcd for C11H15NO: C, 74.54; H, 8.53; N, 7.90.
Found: C, 74.49; H, 8.41; N, 7.92.
Methyl 3-(phenylamino)propanoate (1a):3a white solid, 90 mg,
34% yield; mp 38 °C; 1H NMR (300 MHz, CDCl3) δ 2.47 (t, J=
6.3 Hz, 2H), 3.30 (t, J=6.3 Hz, 2H), 3.55 (s, 3H), 3.88 (bs, 1H),
6.46-6.49 (d, J= 8.6 Hz, 2H), 6.55-6.60 (t, J=7.3 Hz, 1H),
7.01-7.07 (m, 2H); 13C NMR (75 MHz, CDCl3) 33.7, 39.4, 51.8,
113.0, 117.7, 129.3, 147.6, 172.8. Anal. Calcd for C10H13NO2: C,
67.02; H, 7.31; N, 7.82. Found: C, 66.54; H, 7.26; N, 7.65.
Methyl 3-(4-methylphenylamino)propanoate (2a):3a white solid,
150 mg, 52% yield; mp 60 °C; 1H NMR (300 MHz, CDCl3) δ 2.26
(s, 3H), 2.63 (t, J=6.4 Hz, 2H), 3.45 (t, J=6.4 Hz, 2H), 3.71 (s, 3H),
3.89 (bs, 1H), 6.57 (d, J=8.5, 2H), 7.01 (d, J=8.7 Hz, 2H); 13
C
NMR (75 MHz, CDCl3) 20.4, 33.7, 39.8, 51.7, 113.3, 127.0, 129.8,
145.3, 172.9. Anal. Calcd for C11H15NO2: C, 68.37; H, 7.82; N,
7.25. Found: C, 68.32; H, 7.49; N, 7.08.
Methyl 3-(4-methoxyphenylamino)propanoate (3a): yellow oil,
275 mg, 62% yield; 1H NMR (300 MHz, CDCl3) δ 2.61 (t, J=6.4
Hz, 2H), 3.4 (t, J=6.4 Hz, 2H), 3.69 (s, 3H), 3.74 (s, 3H), 6.61 (d,
J = 8.9, 2H), 6.77 (d, J = 8.9 Hz, 2H); 13C NMR (75 MHz,
CDCl3) 33.7, 40.5, 51.7, 55.8, 114.6, 114.9, 141.7, 152.4, 172.9.
Anal. Calcd for C11H15NO3: C, 63.14; H, 7.23; N, 6.69. Found:
C, 62.82; H, 7.03; N, 6.53.
Methyl 3-[(2-methoxycarbonylethyl)phenylamino]propanoate
(1b): yellow oil, 199 mg, 75% yield; 1H NMR (300 MHz, CDCl3)
δ 2.65 (t, J=7.2 Hz, 4H), 3.71 (t, J=7.2 Hz, 4H), 3.73 (s, 6H),
6.74-6.80 (m, 3H), 7.26-7.32(m, 2H); 13C NMR (75 MHz,
CDCl3) δ 32.3, 47.0, 51.8, 112.6, 117.1, 129.5, 146.7, 172.5. Anal.
Calcd for C14H19NO4: C, 63.38; H, 7.22; N, 5.28. Found: C,
63.37; H, 7.11; N, 5.31.
Methyl 3-[(2-methoxycarbonylethyl)-4-methylphenylamino]pro-
panoate (2b): orange oil, 335 mg, 80% yield; 1H NMR (300
MHz, CDCl3) δ 2.15 (s, 3H), 2.47 (t, J=6.9 Hz, 4H), 3.52 (t, J=
6.9 Hz, 4H), 3.57 (s, 6H), 6.55 (d, J=8.7 Hz, 2H), 6.95 (d, J=
8.1 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 20.0, 32.1, 47.0, 51.4,
113.2, 126.4,29.8, 144.5, 172.4. Anal. Calcd for C15H21NO4: C,
64.50; H, 7.58; N, 5.01. Found: C, 64.56; H, 7.41; N, 5.06.
Methyl 3-[(2-methoxycarbonylethyl)-4-methoxyphenylamino]pro-
panoate (3b): orange solid, 420 mg, 95% yield; mp 36 °C; 1H NMR
4-(3-Methoxyphenylamino)butan-2-one (10a): orange oil,
1
188 mg, 65% yield; H NMR (300 MHz, CDCl3) δ 2.15 (s,
3H), 2.73 (t, J=6.1 Hz, 2H), 3.39 (t, J=6.0 Hz, 2H), 3.76 (s,
3H), 4.02 (bs, 1H), 6.15 (t, J=2.4 Hz 1H), 6.22 (dd, J=2.4,
8.1 Hz, 1H), 6.28 (dd, J=2.4, 8.1 Hz, 1H), 7.07 (t, J=8.1 Hz,
1H); 13C NMR (75 MHz, CDCl3) δ 30.3, 38.3, 42.6, 55.1, 99.0,
102.7, 106.1, 130.1, 149.1, 160.9, 208.1. Anal. Calcd for C11-
H15NO2: C, 68.37; H, 7.82; N, 7.25. Found: C, 68.48; H, 7.70;
N, 7.23.
4-(4-Methoxyphenylamino)butan-2-one (11a): orange oil, 230
mg, 80% yield; 1H NMR (300 MHz, CDCl3) δ 2.13 (s, 3H), 2.69
(t, J=6.1 Hz, 2H), 3.33 (t, J=6.0 Hz, 2H), 3.71 (bs, 1H), 3.72 (s,
3H), 6.56 (d, J=8.7 Hz, 2H), 6.76 (d, J=8.7 Hz, 2H); 13C NMR
(75 MHz, CDCl3) δ 30.3, 39.5, 42.7, 55.7, 114.6 (2C), 114.9 (2C)
141.9, 152.3, 208.2. Anal. Calcd for C11H15NO: C, 68.37; H,
7.82; N, 7.25. Found: C, 68.30; H, 7.60; N, 7.35.
4-(4-Chlorophenylamino)butan-2-one (12a): white solid, 230
mg, 77%; mp 71 °C; 1H NMR (300 MHz, CDCl3) δ 2.15 (s, 3H),
2.71 (t, J=6.0 Hz, 2H), 3.36 (t, J=6.0 Hz, 2H), 4.02 (s, 3H), 6.51
(d, J=9.0 Hz, 2H), 7.10(d, J=9.0 Hz, 2H); 13C NMR (75 MHz,
CDCl3) δ 30.3, 38.5, 42.4, 114.1, 122.1, 129.1, 146.3, 208.0. Anal.
6264 J. Org. Chem. Vol. 74, No. 16, 2009

De et al.
JOCArticle
Calcd for C10H12NClO: C, 60.76; H, 6.12; N, 7.09. Found: C,
60.85; H, 5.78; N, 6.85.
(75 MHz, CDCl3) 18.7, 121.9, 123.9, 126.3, 128.3, 129.2, 130.0,
144.4, 148.0, 150.2; ESI m/z (rel int) 144 [M þ H]þ (100). Anal.
Calcd for C10H9N: C, 83.88; H, 6.34; N, 9.78. Found: C, 83.50;
H, 6.28; N, 9.89.
4,6-Dimethylquinoline (15): yellow oil, 125 mg, 53% yield;
1H NMR (300 MHz, CDCl3) δ 2.59 (s, 3H), 2.69 (s, 3H), 7.16
(dd, J=4.3 Hz, 1H), 7.52 (dd, J=1.7, 8.5 Hz, 1H), 7.72 (m, 1H),
7.99 (d, J=8.6 Hz, 1H), 8.69 (d, J=4.2 Hz); 13C NMR (75 MHz,
CDCl3) δ 18.6, 21.8, 121.8, 122.7, 128.2, 129.6, 131.3, 136.0,
143.5, 146.4, 149.2; ESI m/z (rel int) 158 [M þ H]þ(100). Anal.
Calcd for C11H11N: C, 84.04; H, 7.05; N, 8.91. Found: C, 83.70;
H, 6.98; N, 8.96.
4-[(3-Oxobutyl)phenylamino]butan-2-one (6b): yellow oil, 290
mg, 80% yield; 1H NMR (300 MHz, CDCl3) δ 2.07 (s, 6H), 2.63
(t, J=6.0 Hz, 4H), 3.50 (t, J=6.0 Hz, 4H), 6.58 (d, J=8.1 Hz,
2H), 6.64 (t, J = 7.3 Hz, 1H) 7.12-7.18 (m, 2H); 13C NMR
(75 MHz, CDCl3) δ 30.5, 41.2, 45.8, 112.7, 116.9, 129.5, 147.0,
207.7. Anal. Calcd for C14H19NO2: C, 72.07; H, 8.21; N, 6.00.
Found: C, 71.93; H, 8.27; N, 5.90.
4-[(3-Oxobutyl)-2-methylphenylamino]butan-2-one (7b): orange
oil, 286 mg, 75%; 1H NMR (300 MHz, CDCl3) δ 2.06 (s, 6H), 2.22
(s, 3H), 2.51 (t, J=6.0 Hz, 4H), 3.23 (t, J=6.0 Hz, 4H), 7.0-7.19
(m, 4H); 13C NMR (75 MHz, CDCl3) δ 18.0, 30.3, 41.3, 48.8,
122.5, 124.3, 126.4, 131.2, 135.5, 148.2, 208.0. Anal. Calcd for C15-
H21NO2: C, 72.84; H, 8.56; N, 6.00. Found: C, 72.72; H, 8.48; N,
6.11.
4-[(3-Oxobutyl)-3-methylphenylamino]butan-2-one (8b): yellow
oil, 295 mg, 77%; 1H NMR (300 MHz, CDCl3) δ 2.15 (s, 6H), 2.31
(s, 3H), 2.71 (t, J=6.0 Hz, 4H), 3.57 (t, J=6.0 Hz, 4H), 6.44-6.51
(m, 2H), 6.56 (d, J=7.3 Hz, 1H), 7.12 (t, J=7.3 Hz, 1H); 13C NMR
(75 MHz, CDCl3) δ21.9, 30.5, 41.2, 45.7, 110.0, 113.5, 117.9, 129.3,
139.2, 147.1, 207.8. Anal. Calcd for C15H21NO2: C, 72.84; H, 8.56;
N, 5.66. Found: C, 72.71; H, 8.57; N, 5.82.
4-[(3-Oxobutyl)-4-methylphenylamino]butan-2-one (9b): yellow
oil, 305 mg, 80%; 1H NMR (300 MHz, CDCl3) δ 2.14 (s, 6H), 2.25
(s, 3H), 2.69 (t, J=6.0 Hz, 4H), 3.54 (t, J=6.0 Hz, 4H), 6.61 (d, J=
9.0 Hz, 2H), 7.05 (d, J=9.0 Hz, 2H); 13C NMR (75 MHz, CDCl3)
δ 20.2, 30.6, 41.1, 46.1, 113.5, 126.5, 130.0, 145.0, 208.0. Anal.
Calcd for C15H21NO2: C, 72.84; H, 8.56; N, 5.66. Found: C, 73.05;
H, 8.70; N, 5.93.
6-Methoxy-4-methylquinoline (16):13 brown oil, 130 mg, 50%
yield; 1H NMR (300 MHz, CDCl3) δ 2.63 (s, 3H), 3.93 (s, 3H),
7.15-7.18 (m, 2H), 7.35 (dd, J =2.7, 9 Hz, 1H), 8.0 (d, J =
9.3 Hz, 1H), 8.61 (d, J=4.2 Hz); 13C NMR (75 MHz, CDCl3)
δ 18.8, 55.5, 101.9, 121.4, 122.1, 129.2, 131.4, 142.7, 144.0, 147.6,
157.6; ESI m/z (rel int) 174 [M þ H]þ (100).
6,7-Dimethoxy-4-methylquinoline (17):14 orange solid, 171 mg,
56% yield; mp 108 °C (lit.14 mp 112.5 °C); 1H NMR (400 MHz,
CDCl3) δ 2.62 (s, 3H), 4.02 (s, 6H), 7.08 (s, 1H), 7.12 (s, 1H), 7.32
(s, 1H), 8.48 (d, J=4.5 Hz, 1H); 13C NMR (75 MHz, CDCl3)
δ 18.8, 55.9, 56.0, 101.4, 108.4, 120.4, 123.4, 142.2, 145.0, 147.9,
149.3, 152.0; ESI m/z (rel int) 204 [M þ H]þ (100).
4,7-Dimethylquinoline (18):15 orange oil, 118 mg, 50% yield;
1H NMR (300 MHz, CDCl3) δ 2.54 (s, 3H), 2.64 (s, 3H), 7.14 (d,
J=4.5 Hz, 1H), 7.38 (dd, J=1.3, 8.6 Hz, 1H), 7.87 (m, 2H), 8.71
(d, J=4.3 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 18.6, 21.7,
121.1, 123.5, 126.3, 128.5, 128.8, 139.3, 144.1, 148.1, 150.0; ESI
m/z (rel int) 158 [M þ H]þ (100).
4-[(3-Oxobutyl)-4-chlorophenylamino]butan-2-one (12b): white
solid, 300 mg, 74% yield; mp 60 °C; 1H NMR (300 MHz, CDCl3)
δ 2.14 (s, 6H), 2.68 (t, J=6.0 Hz, 4H), 3.54 (t, J=6.0 Hz, 4H), 6.56
(d, J=9 Hz, 2H), 7.15 (d, J=9 Hz, 2H); 13C NMR (75 MHz,
CDCl3) δ 30.6, 40.9, 45.8, 113.8, 121.7, 129.2, 145.6, 207.5. Anal.
Calcd for C14H18NClO2: C, 62.80; H, 6.78; N, 5.23. Found: C,
62.68; H, 6.76; N, 5.22.
7-Methoxy-4-methylquinoline (19): orange oil, 161 mg, 62%
yield; 1H NMR (300 MHz, CDCl3) δ 2.62 (s, 3H), 3.92 (s, 3H),
7.05 (d, J=4.5 Hz, 1H), 7.18 (dd, J=2.7, 9.0 Hz, 1H), 7.40 (d, J=
2.4 Hz,1H), 7.84 (d, J=9.3 Hz,1H), 8.65 (d, J=4.5 Hz, 1H); 13
C
NMR (75 MHz, CDCl3) δ 18.6, 55.4, 107.8, 119.2, 120.0, 123.3,
125.0, 144.2, 150.0, 150.4, 160.3; ESI m/z (rel int) 174 [M þ
H]þ(100).
4-[(3-Oxobutyl)-4-nitrophenylamino]butan-2-one (13b): yellow
solid, 293 mg, 70% yield; mp 165 °C; 1H NMR (300 MHz,
CDCl3) δ 2.19 (s, 6H), 2.77 (t, J=6.9 Hz, 4H), 3.71 (t, J=6.9 Hz,
4H), 6.56 (d, J=9.6 Hz, 2H), 8.10 (d, J=9.3 Hz, 2H); 13C NMR
(75 MHz, CDCl3) δ 30.5, 40.8, 45.6, 110.4, 126.4, 137.3, 151.6,
206.6. Anal. Calcd for C14H18N2O4: C, 60.42; H, 6.52; N, 10.07.
Found: C, 60.36; H, 6.57; N, 10.07.
Acknowledgment. Central Glass Co. Ltd. is gratefully
acknowledged for kindly providing HFIP. K.D. thanks the
Indo-French program CEFIPRA/IFCPAR for financial
support.
4-Methylquinoline (14): yellow oil, 120 mg, 56% yield; 1H
NMR (300 MHz, CDCl3) δ 2.73 (s, 3H), 7.25 (d, J=4.3 Hz, 1H),
7.59 (t, J =8.2 Hz, 1H), 7.74 (t, J=8.2, 1H), 8.02 (d, J=9.0 Hz,
1H), 8.14 (d, J=9.0 Hz, 1H), 8.80 (d, J=4.2 Hz, 1H); 13C NMR
Supporting Information Available: 1H and 13C NMR spec-
tra for all compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
(14) Roberts, D.; Joule, J. A.; Bros, M. A.; Alvarez, M. J. Org. Chem.
1997, 62, 568–577.
(15) Osborne, A. G. Tetrahedron 1983, 39, 2831–2841.
(13) Theeraladanon, C.; Arisawa, M.; Nishida, A.; Nakagawa, M. Tetra-
hedron 2004, 60, 3017–3035.
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