The reactions of the Betti base with 1,3-dicarbonyl compounds

Article abstract of DOI:10.3184/030823408X282686

Reaction of the Betti base 1-(α-aminobenzyl)-2-naphthol with 1,3-dicarbonyl compounds at room temperature in CH₃OH in the presence of p-toluenesulfonic acid leads to the corresponding enamino carbonyl products 3, in high yield and with high chemical purity. Among them, 3b was proven to be an enamine with cis-configuration by single crystal X-ray diffraction analysis.

Full text of DOI:10.3184/030823408X282686

JOURNAL OF CHEMICAL RESEARCH 2008
JANUARY, 3–5
RESEARCH PAPER
3
The reactions of the Betti base with 1,3-dicarbonyl compounds
Jian-Ming Wen, Cui-Pan Lin and Jing-Hua Li*
College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, 310032, China
Reaction of the Betti base 1-(a-aminobenzyl)-2-naphthol with 1,3-dicarbonyl compounds at room temperature in
CH3OH in the presence of p-toluenesulfonic acid leads to the corresponding enamino carbonyl products 3, in high
yield and with high chemical purity. Among them, 3b was proven to be an enamine with cis-configuration by single
crystal X-ray diffraction analysis.
Keywords: Betti base 1-(α-aminobenzyl)-2-naphthol, 1,3-dicarbonyl compounds, condensation, X-ray crystal structure
At the beginning of last century, Betti reported the synthesis
of 1-(α-aminobenzyl)-2-naphthol (Betti base),1-5 starting from
2-naphthol, benzaldehyde and ammonia. However, in spite of
the ready availability and low cost of this material, the early
publications were neglected. Only recently has there been an
increasing focus on the Betti base.6,7 The Betti base and its
derivatives have now been successfully applied in organic
synthesis.8-16 As chiral catalysts, cheap resolving agents or
optically active ligands. In spite of the two potentially reactive
functional groups in the Betti base, relatively few publications
have appeared in this field. To the best of our knowledge,
there are no reports on the reactions of the Betti base with
1,3-dicarbonyl compounds. Our present aim was to extend
the synthetic applicability of the Betti base in the preparation
of a new type of Betti base derivative. Herein, we report a
simple and convenient procedure for the condensation
of Betti base and 1,3-dicarbonyl compounds in the presence of
p-toluenesulfonic acid (p-TSA) in CH3OH at room temperature.
In our initial search for appropriate reaction conditions, we
examined the reaction of Betti base with methyl acetoacetate
(2a) as a model with a variety of catalysts in CH3OH at room
temperature (Scheme 1, Table 1). As shown in the Table 1,
(Table 1, entry 5) the best result was obtained when p-TSA
was used as the catalyst.
Table 1 Catalytic effect on the reaction of Betti base with
methyl acetoacetate
Entry
Catalyst
Time/h
Yield/%
1
2
3
4
5
H2SO4
12
12
12
12
6
80
74
82
84
88
H3PO4
CF3COOH
CH3SO3H
p-TSA
the best choice. The reactions of different 1,3-dicarbonyl
compounds with Betti base in CH3OH using p-TSA as a
catalyst at room temperature gave the corresponding products,
in many cases, in high yield (Table 2). However, no products
were produced when 2g or 2k was used as a substrate (entries
7 and 12, in Table 2).
Compounds 3 are assumed to be auxiliary-induced prochiral
enamine compounds which might yield the corresponding
chiral amino-alcohol after asymmetric hydrogenation.
However, they were inert when treated with reducing agents,
such as LiAlH4, NaBH4, Na/C2H5OH, Zn/AcOH, H2/Pd/C,
etc. This unusual phenomenon led us to determine the structure
of these compounds by X-ray crystallography.
Compound 3b (as a typical example of 3) was readily
obtained from Betti base by treatment with ethyl acetoacetate.
The crystal was subjected to a single crystal X-ray diffraction
We then examined the reaction in other solvents, such as
CH2Cl2, THF, ether and toluene. We found that CH3OH was
Ph
NH2
OH
Ph
R1
O
O
CH3OH
R2
R3
+
R1
R3
N
H
Cat.
R2
OH
O
3
1
2
Scheme 1
Table 2 Condensations of Betti base with 1,3-dicarbonyl compounds at room temperature in the presence of p-TSA
Entry
Compound 2
R1
R2
R3
Time/h
Yield/%a
1
2
a
b
c
d
e
f
g
h
i
Me
H
OMe
OEt
6
3
88
95
Me
H
3
Me
H
H
Bn
OBu
OMe
OEt
6
92
4
Et
12
18
12
48
4
83
5
Me
82
6
CH2CH2CH2
CH2CH2CH2
OEt
91
7
Ph
Me
Me
Et
Ph
H
H
H
H
H
H
H
H
H
OEt
NDb
90
8
Me
9
Ph
6
88
10
12
13
14
j
k
l
Ph
72
48
2
71
Ph
NDb
95
Ph
m
Cyclohexyl
2
94
aIsolated yield.
bNo product was detected.
* Correspondent. E-mail: lijh571@163.com
PAPER: 07/4886

4
JOURNAL OF CHEMICAL RESEARCH 2008
analysis. The data collection was carried on a Rigaku
R-AXIS RAPID diffractometer at 298K. The X-ray structure
of compound 3b is shown in Fig. 1.17 In the structure of
compound 3b, The bond lengths of C(1)–N(2), N(2)–
C(18) and C(18)–C(19) are 1.4675(16) Å, 1.333(2) Å and
1.368(2) Å, respectively, and the bond angles of C(1)–N(2)–
C(18), C(18)–C(19)–C(20) are 126.54(10)°, 124.60(16)°,
respectively. The atoms N(2), C(18), C(19) are coplanar,
shown by the torsion angle N(2)–C(18)–C(19)–C(20) of –2.20
(2)° (Fig. 1 and Table 3). The structure of compound 3b can
be viewed as a conjugated system in which the electrons are
delocalised over the atoms N(2)–C(18)–C(19)–C(20)–O(32)
(Scheme 2). In the crystal structure, the amino, hydroxy and
carbonyl groups are involved in hydrogen bonding. Amino
atom N(2) acts as hydrogen-bond donor, via atom H(201),
to atom O(31) and O(32), forming intramolecular hydrogen
bonds. A centrosymmetric hydrogen-bond dimer centred at
(0, 1/2, 1/2) is formed by the intermolecular hydrogen bond
O(31)–H(301)…O(32)i [Symmetry code: (i) -x; -y + 1; -z + 1]
(Table 4 and Fig. 2). All of these probably make it difficult to
reduce the compound.
Fig. 1 Molecular structure of compound 3b.
Furthermore, the 1H NMR spectra of compound 3b
revealed that, in CDCl3 solution there was a set of weak
signals corresponding to 3b(B) besides the predominant
signals corresponding to 3b(A) (Scheme 3, the peak area ratio
is about 1:9). The spectra showed a broad singlet at δ 9.63
corresponding to HO group in naphthol, two singlets at δ 6.66,
δ 5.69 corresponding to CH of the enamine, which suggest the
presence of a chain tautomer 3b(B). However, in DMSO-d6
solution, compound 3b existed almost in the form of 3b(B).
The ring-chain tautomerism in other derivatives of Betti base
is a general feature.18-20 We concluded that in CDCl3 solution
Fig. 2 Partial packing diagram for compound 3b.
Table 3 Selected bond lengths (Å)
the compound 3b might exist in a ring-chain tautomeric
equilibrium between 3b(A) and 3b(B).
O(31)–C(11)
1.3624 (17)
O(33)-C(21)
1.429 (2)
In conclusion, we have developed a simple and convenient
method for the synthesis of a new type of Betti base derivatives
by treatment of the Betti base with 1,3-dicarbonyl compounds
in the presence of p-TSA as a catalyst.
O(32)–C(20)
O(33)–C(20)
1.235 (2)
1.350 (2)
N(2)–C(1)
1.4675 (16)
1.333 (2)
N(2)–C(18)
Table 4 Hydrogen-bond geometry (Å,°)
D–H…A
D–H
H…A
D…A
D–H…A
Experimental
O(31)–H(301)…O(32) i
N(2)–H(201)…O(31)
N(2)–H(201)…O(32)
0.93
0.89
0.89
1.80
2.25
2.11
2.7182 (15)
2.8182 (17)
2.7634 (13)
170
122
129
Melting points were determined on a Büchi B-540 melting apparatus
and are uncorrected. The NMR spectra were measured on a Bruker
Advance ׀׀׀ 500 or Varian Mercury Plus-400 instrument using DMSO-
d6 or CDCl3 as the solvent with TMS the as the internal standard.
IR spectra were recorded using KBr pellets on a Nicolet 6700 FI-IR
spectrophotometer. Mass spectra were measured with GCT Premier
CAB 075 or Thermo Finnigan LCQ-Advantage (EI). Compound 2j,
2l, 2m were prepared according to the literature.21-23
Symmetry code: (i) -x; -y + 1; -z + 1
O
N
H
O
H
General procedure
The 1,3-dicarbonyl compounds (1.5 mmol) and p-TSA (0.1 mmol)
were added to a solution of Betti base (1 mmol) in CH3OH (8 ml).
The mixture was stirred at room temperature for the time indicated
in Table 2, during which a crystalline product separated out.
The resulting mixture was concentrated in vacuo to about 3 ml, and
the crystalline product was collected by filtration and recrystallised
from CH3OH.
O
Scheme 2
H3C
OEt
H
N
CH3
O
OEt
NH
O
O
OH
3b(A)
3b(B)
Scheme 3
PAPER: 07/4886

JOURNAL OF CHEMICAL RESEARCH 2008
5
3a: Colourless crystals; m.p. 150–152°C; IR (KBr) cm-1: 3186,
2947, 1617, 1580, 1513, 1443, 1266, 1189, 815; H NMR (400 Hz,
4.23. Found: C, 79.88; H, 6.28; N, 4.31%.
1
3i: Colourless crystals; m.p. 202–204°C; IR (KBr) cm-1: 3416,
3060, 1618, 1533, 1515, 1342, 1282, 1092, 1068, 1030, 822, 806,
737, 718, 696; 1H NMR (400 Hz, DMSO-d6): δ 12.59–12.57 (ss, 1H),
10.35 (s, 1H), 7.86–7.23 (m, 16H), 6.94–6.92 (ss, 1H), 5.83 (s, 1H),
2.19 (s, 3H); MS m/z (%): 393 (M+, 1), 376 (2), 232 (37), 231 (100),
202 (23), 160 (24), 84 (11); Anal. Calcd for C27H23NO2: C, 82.42;
H, 5.89; N, 3.56. Found: C, 82.30; H, 5.97; N, 3.50%.
CDCl3 main form): δ 7.79–7.70 (m, 11H), 5.68–5.62 (ss, 1H), 3.71–
3.68 (ss, 3H), 3.39 (br, 1H), 2.99–2.77 (m, 2H), 1.63–1.60 (ss, 3H);
MS m/z (%): 347 (M+, 1), 274 (3), 231 (100), 115 (4), 84 (39); Anal.
Calcd for C22H21NO3: C, 76.06; H, 6.09; N, 4.03. Found: C, 76.18;
H, 5.98; N, 4.11%.
3b: Colourless crystals; m.p. 162–164°C; IR (KBr) cm-1: 3294,
3064, 2978, 1635, 1588, 1518, 1437, 1355, 1261, 1183, 1104, 1053;
1H NMR (500 Hz, CDCl3 main form): δ 7.74–7.09 (m, 11H), 5.63–
5.61 (ss, 1H), 4.16 (q, 2H, J = 7 Hz), 3.37 (br, 1H), 2.94 (d, 1H,
J = 15 Hz), 2.79 (d, 1H, J = 15 Hz) 1.63–1.61 (ss, 3H), 1.24 (t, 3H,
3j: Pale yellow colour crystals; m.p. 194–195°C; IR (KBr) cm-1:
3424, 3061, 2973, 1590, 1572, 1531, 1514, 1432, 1343, 1278, 1183,
1059, 880, 691; 1H NMR (500 Hz, CDCl3): δ 13.02 (s, 1H), 9.69 (br,
1H), 8.11–6.84 (m, 16H), 6.79–6.78 (ss, 1H), 5.77 (s, 1H), 2.60 (q,
2H, J = 7.5 Hz), 1.30 (t, 3H, J = 7.5 Hz); MS m/z (%): 407 (M+, 1),
232 (39), 231 (100), 202 (22), 105 (13); Anal. Calcd for C28H25NO2:
C, 82.53; H, 6.18; N, 3.44. Found: C, 82.41; H, 6.27; N, 3.56%.
3l: Pale yellow colour crystals; m.p. 181–183°C; IR (KBr) cm-1:
3416, 3062, 1620, 1530, 1479, 1291, 1066, 1025, 890, 805, 741, 696;
1H NMR (400 Hz, DMSO-d6): δ 10.45 (s, 1H), 8.20 (br, 1H), 7.88–
7.19 (m, 17H), 6.69–6.66 (ss, 1H), 5.82–5.80 (ss, 1H); MS m/z (%):
379 (M+, 1), 232 (37), 231 (100), 202 (23), 105 (13), 77 (12); Anal.
Calcd for C26H21NO2: C, 82.30; H, 5.58; N, 3.69. Found: C, 82.43;
H, 5.46; N, 3.72%.
1
J = 7 Hz); H NMR (500 Hz, DMSO-d6): δ 10.31 (s, 1H), 10.08
(br, 1H), 8.08–7.20 (m, 11H), 6.81 (s, 1H), 4.48 (s, 1H), 4.01–4.00
(m, 2H), 2.05 (s, 1H), 1.16 (t, 3H, J = 6.8 Hz); 13C NMR (125 Hz,
DMSO-d6): δ 169.77, 161.53, 153.42, 143.42, 132.33, 130.04,
129.33, 128.74, 127.30, 126.96, 126.15, 123.00, 122.77, 119.51,
118.95, 82.75, 58.05, 52.54, 19.80, 15.05; MS m/z (%) 361 (M+, 1),
315 (13), 231 (100), 129 (5), 85 (8); Anal. Calcd for C23H23NO3:
C, 76.43; H, 6.41; N, 3.88. Found: C, 76.50; H, 6.34; N, 3.93%;
crystal data: (CCDC No. 601099). empirical formula C23H23NO3,
Mr = 361.44, crystal size 0.30 × 0.24 × 0.18 mm, crystal system
triclinic, space group P ī, Mo Kα radiation, a = 9.602(4) Å,
α = 100.775(19)°, b = 9.962(5) Å, β = 109.714(14)°, c = 10.899(5) Å,
γ = 93.722(18)°, V = 954.9(7) Å3, Z = 2, Dx = 1.257 g/cm3, θ = 3.1-
27.6°, μ = 0.08 mm-1, λ = 0.71075 Å, T = 298 (1) K, 9527 measured
reflections, 4346 independent reflections, 3124 reflections with I > 2σ
(I), –12 ≤ h ≤11, –12 ≤ k ≤12, –14 ≤ l ≤14, R = 0.0495.
3m: Pale yellow colour crystals; m.p. 190–192°C; IR (KBr) cm-1:
3423, 3061, 2934, 1629, 1513, 1435, 1318, 1281, 1160, 1086, 983,
877, 813, 742, 697; 1H NMR (400 Hz, DMSO-d6 main form):
δ 11.38–11.33 (dd, 1H, J1 = 10.4 Hz, J2 = 12.4 Hz), 10.25 (s, 1H),
7.85–7.15 (m, 11H), 6.53–6.51 (ss,1H), 3.62–3.58 (m, 1H), 2.36–
2.06 (m, 4H), 1.77–1.54 (m, 4H); MS m/z (%): 357 (M+,1), 232 (37),
231 (100), 202 (23), 144 (7); Anal. Calcd for C24H23NO2: C, 80.64;
H, 6.49; N, 3.92. Found: C, 80.71; H, 6.43; N, 3. 87%.
3c: Colourless crystals; m.p. 150–152°C; IR (KBr) cm-1: 3279,
2961, 2863, 1630, 1589, 1515, 1262, 1181, 1113, 1056, 1012, 815;
1H NMR (500 Hz, CDCl3 main form): δ 7.73–7.06 (m, 11H), 5.68–
5.61 (ss, 1H), 4.13–4.08 (m, 2H), 3.34 (br, 1H), 2.95–2.77 (m, 2H),
1.64–1.54 (m, 5H), 1.40–1.32 (m, 2H), 0.88 (t, 3H, J = 7 Hz); MS
m/z (%) 389 (M+, 2), 232 (38), 231 (100), 202 (22), 105 (13), 91
(26), 84 (20); Anal. Calcd for C25H27NO3: C, 77.09; H, 6.99; N, 3.60.
Found: C, 76.98; H, 6.84; N, 3.49%.
Received 15 October 2007; accepted 14 January 2008
Paper 07/4886
doi: 10.3184/030823408X282686
References
3d: Colourless crystals; m.p. 144–146°C; IR (KBr) cm-1: 3423,
3325, 2990, 2852, 1620, 1600, 1394, 1120, 1054; 1H NMR (400 Hz,
CDCl3 main form): δ 7.72–7.08 (m, 11H), 5.69–5.56 (ss, 1H), 3.70–
3.67 (ss, 3H), 3.48 (br, 1H), 2.94–2.70 (m, 2H), 1.98–1.87 (m, 2H),
0.98 (t, 3H, J = 8 Hz); MS m/z (%):361 (M+, 1), 315 (4), 238 (61),
231 (100), 115 (3); Anal. Calcd for C23H23NO3: C, 76.43; H, 6.41; N,
3.88. Found: C, 76.32; H, 6.25; N, 3.92%.
1
2
3
4
5
6
M. Betti, Gazz. Chim. Ital., 1900, 30, 310.
M. Betti, Gazz. Chim. Ital., 1901, 31, 377.
M. Betti, Gazz. Chim. Ital., 1901, 31, 170.
M. Betti and C. Speroni, Gazz. Chim. Ital., 1901, 31, 191.
M. Betti, Org. Synth., 1929, 9, 60.
C. Cardellicchio, G. Ciccarella, F. Naso, E. Schingaro and F. Scordari,
Tetrahedron: Asymm., 1998, 9, 3667.
7
C. Cardellicchio, G. Ciccarella, F. Naso, F. Perna and P. Tortorella,
Tetrahedron, 1999, 55, 14685.
3e: Colourless crystals; m.p. 126–128°C; IR (KBr) cm-1: 3423,
1
3328, 2981, 1724, 1621, 1453, 1392, 1244, 1167, 1101, 1051; H
8
9
I. Szatmári and F. Fülöp, Curr. Organic Synth., 2004, 1, 155.
G. Palmieri, Tetrahedron: Asymm., 2000, 11, 3361.
NMR (400 Hz, CDCl3 mian form): δ 7.81–7.69 (m, 2H), 7.33–6.93
(m, 14H), 5.70–5.68 (ss, 1H), 4.21–3.97 (m, 2H), 3.42–3.34 (m, 1H),
3.22–2.99 (m, 2H), 2.39 (s, 1H), 1.72–1.59 (ss, 3H), 1.23–0.97 (m,
3H); MS m/z (%): 451 (M+, 24), 360 (15), 314 (8), 231 (100), 219
(48), 202 (63), 144 (47); Anal. Calcd for C30H29NO3: C, 79.80; H,
6.47; N, 3.10. Found: C, 79.95; H, 6.53; N, 3.21%.
10 C. Cimarelli, G. Palmieri and E. Volpini, Tetrahedron: Asymm., 2002, 13,
2417.
11 D. X.Liu, L.C. Zhang, Q. Wang, C.S. Da, Z.Q. Xin, R. Wang,
M.C.K. Choi and A.S.C. Chan, Org. Lett., 2001, 3, 2733.
12 J. Lu, X.N. Xu, S.Z. Wang, C.D. Wang, Y.Y. Hu and H.W. Hu, J. Chem.
Soc., Perkin Trans., 2002, 1, 2900.
13 Y. Wang, X. Li and K. Ding, Tetrahedron: Asymm., 2002, 13, 1291.
14 J.X. Ji, L.Q. Qiu, C.W. Yip and A.S.C. Chan, J. Org. Chem., 2003, 68,
1589.
15 M. Periasamy, M.N. Reddy and S. Anwar, Tetrahedron: Asymm., 2004,
15, 1809.
16 X.Y. Wang and Y.M. Dong, J. Org. Chem., 2005, 70, 1897.
17 J.H. Li and C.P. Lin, Acta. Cryst E., 2006, 62, o942; CCDC No. 601099.
18 H.E. Smith and N.E. Cooper, J. Org. Chem., 1970, 35, 2212
19 I. Szatmári, T.A. Martinek, L. Lázár and F. Fülöp, Tetrahedron, 2003, 59,
2877.
20 I. Szatmári, T.A. Martinek, L. Lázár, A. Koch, E. Kleinpeter, K. Neuvonen
and F. Fülöp, J. Org. Chem., 2004, 69, 3645
21 B.R. Davis and M.G. Hinds, Aust. J. Chem., 1992, 45, 865.
22 O. Sezer and O. Anac, Helv. Chim. Acta., 1994, 77, 2323.
23 D.A. May, Jr. and T.D. Lash, J. Org. Chem., 1992, 57, 4820.
3f: Colourless crystals; m.p. 168–169°C; IR (KBr) cm-1: 3325,
2968, 1641, 1580, 1516, 1273, 1163, 1089, 812, 744; 1H NMR
(500 Hz, DMSO-d6): δ 10.27 (s, 1H), 9.10 (br, 1H), 8.11–7.18
(m, 11H), 6.61 (s, 1H), 4.05 (t, 2H, J = 7 Hz), 2.80–2.37 (m, 4H),
1.78–1.70 (m, 2H), 1.17 (t, 3H, J = 7 Hz); MS m/z (%): 387 (M+,2),
232 (36), 231 (100), 202 (24), 155 (17), 110 (16); Anal. Calcd for
C25H25NO3: C, 77.49; H, 6.50; N, 3.61. Found: C, 77.54; H, 6.41;
N, 3.75%.
3h: Colourless crystals; m.p. 198–200°C; IR (KBr) cm-1: 3423,
3058, 2599, 1595, 1547, 1440, 1322, 1249, 1099, 1025, 976, 816,
1
751, 694; H NMR (400 Hz, CDCl3): δ 12.33 (s, 1H), 9.77 (s, 1H),
8.04–7.15 (m, 11H), 6.73–6.72 (ss, 1H), 5.02 (s, 1H), 2.10 (s, 3H),
1.99 (s, 3H); MS m/z (%): 331 (M+, 5), 314 (3), 232 (46), 231 (100),
202 (20), 84 (5); Anal. Calcd for C22H21NO2: C, 79.73; H, 6.39; N,
PAPER: 07/4886