Serendipitous synthesis of 2-amino-2,3-dihydrobenzofuran derivatives starting from Baylis-Hillman adducts

Article abstract of DOI:10.1016/j.tetlet.2006.03.167

Serendipitous synthesis of 2-amino-2,3-dihydrobenzofuran derivatives 4a-g was achieved starting from the Baylis-Hillman adducts. In the reaction sequence, intramolecular oxygen atom transfer from nitrogen atom to arene moiety was observed.

Full text of DOI:10.1016/j.tetlet.2006.03.167

Tetrahedron Letters 47 (2006) 3913–3917
Serendipitous synthesis of 2-amino-2,3-dihydrobenzofuran
derivatives starting from Baylis–Hillman adducts
a
b
a,
*
Ka Young Lee, Joobeom Seo and Jae Nyoung Kim
a
Department of Chemistry and Institute of Basic Science, Chonnam National University, Gwangju 500-757, Republic of Korea
b
Department of Chemistry and Research Institute of Natural Sciences, Gyeongsang National University,
Jinju 660-701, Republic of Korea
Received 22 February 2006; revised 22 March 2006; accepted 24 March 2006
Available online 21 April 2006
Abstract—Serendipitous synthesis of 2-amino-2,3-dihydrobenzofuran derivatives 4a–g was achieved starting from the Baylis–Hill-
man adducts. In the reaction sequence, intramolecular oxygen atom transfer from nitrogen atom to arene moiety was observed.
ꢀ
2006 Elsevier Ltd. All rights reserved.
3
The Baylis–Hillman reaction is a carbon–carbon bond-
forming reaction between activated vinyls and electro-
philes like aldehydes and imines with the aid of tertiary
carried out easily. During the studies on the chemical
2
,3
transformations of the Baylis–Hillman adducts,
we
introduced ethyl nitroacetate at the secondary position
of Baylis–Hillman adduct to prepare 3 (Scheme 1). We
thought that 3 could be used for the synthesis of naphthal-
ene derivative (Scheme 2), which might be produced by
the sequential intermolecular Friedel–Crafts reaction,
1
amine or phosphine. The Baylis–Hillman adducts have
versatile functionality and, as a result, the chemical
transformations using the Baylis–Hillman adducts have
1
–3
been investigated extensively by us and other groups.
6
intramolecular Friedel–Crafts type cyclization, and the
Cyclic a,a-disubstituted a-amino acids represent a unique
class of sterically constrained amino acids, which have
been used to modify the conformation and/or stability
following aromatization process.
The starting material 3a was synthesized as a diastereo-
meric mixture (syn/anti, 1:1) from the reaction of cinn-
amyl bromide derivative 2 and ethyl nitroacetate in the
presence of DABCO in aq THF in 75% yield as
4
of a biologically active peptide. In these respects, the
synthesis of highly sterically constrained amino acids
4
has been studied extensively. However, there have been
3
reported only a few examples of cyclic a-amino acid pre-
reported. With this compound 3a in our hands, we
cursors having heteroatom-containing substituent as one
of the a-substituents.
examined the reaction of 3a in benzene under a variety
5
of conditions. Among them the use of H SO /
2
4
CF COOH in benzene at 60–70 ꢁC gave 4a in 55%
3
Regioselective introduction of various nucleophiles at the
secondary position of the Baylis–Hillman adducts can be
isolated yield unexpectedly. The mechanism for the
formation of 4a could be proposed tentatively as follows
O N
COOEt
COOR1
2
1
. DABCO (2.0 equiv)
aq THF, rt, 20 min
OH
COOR1
Ar
COOR1
HBr
Ar
Ar
Br
2. ethyl nitroacetate (1.1 equiv)
rt, 48 h
1
2
3
Scheme 1.
Keywords: 2-Amino-2,3-dihydrobenzofurans; Baylis–Hillman adducts; Oxygen atom transfer; a-Amino acids.
*
Corresponding author. Tel.: +82 62 530 3381; fax: +82 62 530 3389; e-mail: kimjn@chonnam.ac.kr
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.03.167

3914
K. Y. Lee et al. / Tetrahedron Letters 47 (2006) 3913–3917
O N
COOEt
EtOOC
COOR1
2
benzene
EtOOC
Ar
3
Ar
Ar
Ph
COOR1
COOR1
Scheme 2.
CF COOH (0.5 mL)
3
H N
2
O N
COOEt
COOMe
H SO (3.0 equiv)
COOEt
2
2
4
o
O
COOMe
benzene, 60-70 C, 3 h
Ph
3
a
4
a
+
H+
O
N
COOEt
COOMe
HN
OH
COOEt
HO
COOMe
Ph
O
(
I)
(V)
N
COOEt
COOMe
OH
H
O-transfer
to arene
from N-atom
Friedel-Crafts
H O, - H+
-
2
-
H+
,3-H shift
O
N
OH
N
OH2
HN
1
,3-H shift
COOEt
COOEt
COOMe
+
COOEt
COOMe
OH
+ H
1
OH
OH
COOMe
(II)
(III)
(IV)
Scheme 3.
Figure 1. ORTEP drawing of compound 4a.
Figure 2. ORTEP drawing of compound 4e.

K. Y. Lee et al. / Tetrahedron Letters 47 (2006) 3913–3917
3915
1
as shown in Scheme 3: (i) protonation at the nitro group
to give (I), (ii) intramolecular transfer of oxygen atom
from nitrogen to carbon of benzene moiety to afford
In the H NMR spectrum of 4a, broad singlet of –NH
2
appeared at 2.85 ppm and a singlet at 4.18 ppm corre-
sponding to the benzyl moiety of 4a. In the IR spec-
trum, two N–H stretching vibrations appeared at 3417
and 3332 cm . Mass spectra also showed the molecular
weight is m/z = 367. However, the assignment of the
structure of 4a was insufficient. Thus, we identified the
structure of 4a unequivocally by its X-ray crystal struc-
ture (Fig. 1). As shown in its X-ray structure, the geo-
metry of the double bond is Z-form. The benzene ring of
8
5
a,7
(
II),
(iii) successive 1,3-H shift to form the intermedi-
6
À1
ate (IV), (iv) intermolecular Friedel–Crafts type reac-
tion with benzene, and finally (v) formation of cyclic
aminal derivative 4a.5a Harada and co-workers reported
the synthesis of 1,3,3a,8-tetrahydro-2H-benzofuro[2,3-
b]pyrrol-2-ones, which were formed by the mechanism
9
5
a
very close to our proposed one.
a
Table 1. Synthesis of 2-amino-2,3-dihydrobenzofurans 4
b
Entry Substrate 3
Conditions
Product 4 (%)
H N
2
O N
COOEt
COOMe
COOEt
COOMe
2
Benzene
O
CF
SO
0–70 ꢁC, 3 h
3
COOH (0.5 mL)
1
Ph
H
2
4
(3.0 equiv)
6
4
a (55)
3
a
H N
2
COOEt
COOMe
O
2
3a
p-Xylene
CF COOH (0.5 mL)
SO (3.0 equiv)
0–40 ꢁC, 5 h
3
H
3
2
4
4b (51)
H N
2
COOEt
COOMe OMe
O
3
4
5
6
3a
1,4-Dimethoxybenzene (2.0 equiv)
CF COOH (0.5 mL), ClCH CH Cl
SO (3.0 equiv)
0–50 ꢁC, 4 h
3
2
2
H
4
2
4
4c (38)
MeO
O N
COOEt
COOEt
H N
2
2
COOEt
COOEt
O
Benzene
CF COOH (0.5 mL)
SO (3.0 equiv)
0–50 ꢁC, 5 h
Ph
3
H
2
4
4d (56)
3
b
4
H N
2
COOEt
COOEt
O
3b
p-Xylene
CF COOH (0.5 mL)
SO (3.0 equiv)
0–50 ꢁC, 4 h
3
H
2
4
4e (52)
4
H N
2
O N
2
COOEt
COOMe
COOEt
COOMe
O
Benzene
CF COOH (0.2 mL)
SO (1.0 equiv)
0–70 ꢁC, 20 h
3
H
2
4
4f (39)
3
c
6
H N
2
COOEt
COOMe
O N
2
COOEt
COOMe
O
7
Benzene
CF COOH (0.2 mL)
SO (1.0 equiv)
0–70 ꢁC, 24 h
3
Cl
H
6
2
4
4g (36)
3
d
Cl
a
The reaction was carried out with 1.0 mmol of 3.
Arene was used as solvent except for entry 3.
b

3916
K. Y. Lee et al. / Tetrahedron Letters 47 (2006) 3913–3917
benzyl group and the amino group were positioned in
opposite directions and this could be explained by the
proposed reaction mechanism.
1355; (c) Lee, M. J.; Park, D. Y.; Lee, K. Y.; Kim, J. N.
Tetrahedron Lett. 2006, 47, 1833; (d) Park, D. Y.; Lee, M.
J.; Kim, T. H.; Kim, J. N. Tetrahedron Lett. 2005, 46, 8799;
(
e) Gowrisankar, S.; Lee, K. Y.; Kim, J. N. Tetrahedron
Lett. 2005, 46, 4859; (f) Lee, K. Y.; Gowrisankar, S.; Kim,
J. N. Tetrahedron Lett. 2005, 46, 5387; (g) Lee, C. G.; Lee,
K. Y.; Lee, S.; Kim, J. N. Tetrahedron 2005, 61, 1493.
. For the introduction of nucleophiles at the secondary
position of Baylis–Hillman adducts by using the DABCO
salt concept, see: (a) Kim, J. N.; Lee, H. J.; Lee, K. Y.;
Gong, J. H. Synlett 2000, 173; (b) Gong, J. H.; Kim, H.
R.; Ryu, E. K.; Kim, J. N. Bull. Korean Chem. Soc. 2002,
Without TFA the reaction showed more complex nature
although we could observe the formation of 4a in small
amounts on TLC. Actually, without TFA, dark and
3
4
sticky solution phase (H SO , most of the starting mate-
2
4
rial, and products were dissolved in this phase) was sep-
arated out from the upper benzene phase. Such phase
separation could make the reaction more complex.
When we used AcOH or formic acid instead of TFA,
we could obtain 4a although in low yields (20–25%) than
the standard conditions using TFA. From these obser-
vations we tentatively concluded that the use of TFA
improved the miscibility of the reaction mixtures and
make the reaction cleaner.
2
3, 789; (c) Kim, J. M.; Lee, K. Y.; Kim, J. N. Bull. Korean
Chem. Soc. 2004, 25, 328; (d) Chung, Y. M.; Gong, J. H.;
Kim, T. H.; Kim, J. N. Tetrahedron Lett. 2001, 42, 9023.
. For the synthesis and applications of unusual a-amino acid
derivatives, see: (a) Kotha, S. Acc. Chem. Res. 2003, 36, 342;
(
1
b) Mendel, D.; Ellman, J.; Schultz, P. G. J. Am. Chem. Soc.
993, 115, 4359; (c) Ellis, T. K.; Hochla, V. M.; Solo-
shonok, V. A. J. Org. Chem. 2003, 68, 4973; (d) Belokon, Y.
N.; Bespalova, N. B.; Churkina, T. D.; Cisarova, I.;
Ezernitskaya, M. G.; Harutyunyan, S. R.; Hrdina, R.;
Kagan, H. B.; Kocovsky, P.; Kochetkov, K. A.; Larionov,
O. V.; Lyssenko, K. A.; North, M.; Polasek, M.; Pere-
gudov, A. S.; Prisyazhnyuk, V. V.; Vyskocil, S. J. Am.
Chem. Soc. 2003, 125, 12860; (e) Jorgensen, M. R.; Olsen,
C. A.; Mellor, I. R.; Usherwood, P. N. R.; Witt, M.;
Franzyk, H.; Jaroszewski, J. W. J. Med. Chem. 2005, 48, 56.
. For the only example of cyclic a-oxyamino acid derivative,
see: (a) Harada, K.; Kaji, E.; Takahashi, K.; Zen, S. Chem.
Pharm. Bull. 1994, 42, 1562; (b) Kaji, E.; Takahashi, K.;
Kitazawa, M.; Zen, S. Chem. Pharm. Bull. 1987, 35, 3062;
(c) Ueda, S.; Naruto, S.; Yoshida, T.; Sawayama, T.; Uno,
H. J. Chem. Soc., Chem. Commun. 1985, 218; (d) Ueda, S.;
Naruto, S.; Yoshida, T.; Sawayama, T.; Uno, H. J. Chem.
Soc., Perkin Trans. 1 1988, 1013.
Encouraged by the results we examined the reaction of
starting materials 3a–d and arene nucleophiles including
benzene, p-xylene, and 1,4-dimethoxybenzene. We
obtained desired compounds 4b–g similarly, although
the yields were moderate (Table 1). The yields were
better when we used 1.0 equiv of H SO for the cases
2
4
of 3c and 3d. For 1,4-dimethoxybenzene (solid) we used
only 2.0 equiv of arene nucleophile for the facility of
separation. In order to make the structures of 4a–g more
clear we solved another X-ray crystal structure with 4e
5
6
8
,10
(
Fig. 2).
Based on the X-ray data of 4e it was clear
that the arene moiety at the benzylic site of 4a–g was
derived from the external nucleophile, arene solvent.
In summary, we disclosed the first synthesis of unusual
amino acid esters, 2-amino-2,3-dihydrobenzofuran deriv-
atives, starting from the Baylis–Hillman adducts. In the
reaction, unusual oxygen atom transfer process was the
key step. Further studies on the reaction mechanism
and synthetic applications are actively underway.
. The reactions of nitro compounds including ethyl nitroac-
etate under strongly acidic conditions, see: (a) Ohwada, T.;
Yamagata, N.; Shudo, K. J. Am. Chem. Soc. 1991, 113,
1
364; (b) Coustard, J.-M.; Jacquesy, J.-C.; Violeau, B.
Tetrahedron Lett. 1991, 32, 3075; (c) Coustard, J.-M.;
Jacquesy, J.-C.; Violeau, B. Tetrahedron Lett. 1992, 33,
8
085; (d) Sartori, G.; Bigi, F.; Maggi, R.; Tomasini, F.
Tetrahedron Lett. 1994, 35, 2393; (e) Berrier, C.; Brahmi, R.;
Carreyre, H.; Coustard, J.-M.; Jacquesy, J.-C. Tetrahedron
Lett. 1989, 30, 5763; (f) Ohta, T.; Shudo, K.; Okamoto, T.
Tetrahedron Lett. 1984, 25, 325; (g) Miyake, S.; Sasaki, A.;
Ohta, T.; Shudo, K. Tetrahedron Lett. 1985, 26, 5815.
. For the examples of oxygen atom transfer, see: (a)
Nakamura, S.; Uchiyama, M.; Ohwada, T. J. Am. Chem.
Soc. 2003, 125, 5282; (b) Collado, D.; Perez-Inestrosa, E.;
Suau, R. J. Org. Chem. 2003, 68, 3574; (c) Li, X.;
Incarvito, C. D.; Vogel, T.; Crabtree, R. H. Organomet-
allics 2005, 24, 3066; (d) Terrier, F.; Beaufour, M.; Halle,
J.-C.; Cherton, J.-C.; Buncel, E. Tetrahedron Lett. 2001,
Acknowledgments
This work was supported by the Korea Research Foun-
dation Grant funded by the Korean Government
MOEHRD, KRF-2005-041-C00248). Spectroscopic
data was obtained from the Basic Science Institute,
Gwangju branch.
7
(
References and notes
4
2, 4499; (e) Kaplan, L. A.; Angres, I. A.; Shipp, K. G. J.
1
. General review article of B–H reaction, (a) Basavaiah, D.;
Rao, A. J.; Satyanarayana, T. Chem. Rev. 2003, 103, 811;
Org. Chem. 1977, 42, 1262; (f) Madhusudanan, K. P.;
Bajpai, L. K.; Bhaduri, A. P. Rapid Commun. Mass
Spectrom. 1997, 11, 1263; (g) Wakamatsu, K.; Kouda, M.;
Shimaoka, K.; Yamada, H. Tetrahedron Lett. 2004, 45,
6395; (h) Tovrog, B. S.; Mares, F.; Diamond, S. E. J. Am.
Chem. Soc. 1980, 102, 6616; (i) Topiwala, U. P.; Whiting,
D. A. J. Chem. Soc., Chem. Commun. 1994, 2443.
(
b) Ciganek, E. In Organic Reactions; Paquette, L. A., Ed.;
John Wiley & Sons: New York, 1997; Vol. 51, pp 201–350;
c) Basavaiah, D.; Rao, P. D.; Hyma, R. S. Tetrahedron
996, 52, 8001; (d) Kim, J. N.; Lee, K. Y. Curr. Org.
(
1
Chem. 2002, 6, 627; (e) Lee, K. Y.; Gowrisankar, S.; Kim,
J. N. Bull. Korean Chem. Soc. 2005, 26, 1481, and further
references cited therein.
8. Spectroscopic data of 4a and 4e are as follows.
Compound 4a: 55%; white solid, mp 120–121 ꢁC; IR
À1
1
2
. For our recent chemical transformations of Baylis–Hillman
adducts, see: (a) Lee, K. Y.; Kim, S. C.; Kim, J. N.
Tetrahedron Lett. 2006, 47, 977; (b) Lee, M. J.; Lee, K. Y.;
Gowrisankar, S.; Kim, J. N. Tetrahedron Lett. 2006, 47,
(KBr) 3417, 3332, 1751, 1716, 1200 cm
;
H NMR
(CDCl , 300 MHz) d 1.24 (t, J = 7.2 Hz, 3H), 2.85 (br s,
3
2H), 3.63 (s, 3H), 4.06–4.15 (m, 1H), 4.18 (s, 2H), 4.31–
4.42 (m, 1H), 6.08–6.87 (m, 2H), 7.18–7.30 (m, 6H), 7.38

K. Y. Lee et al. / Tetrahedron Letters 47 (2006) 3913–3917
3917
1
3
(
d, J = 7.8 Hz, 1H); C NMR (CDCl
3
, 75 MHz) d 14.16,
9. Crystal data of compound 4a: solvent of crystal growth
5
(hexanes/CH Cl , 95:5); empirical formula C21H21NO ,
3
3
1
1
(
(
5.74, 51.79, 62.06, 98.50, 111.09, 121.61, 124.14, 125.79,
26.28, 126.72, 128.08, 128.86, 132.48, 137.17, 145.26,
61.29, 167.46, 169.48; Mass (70 eV) m/z (rel intensity) 77
2
2
Fw = 367.39, crystal dimensions 0.30 · 0.20 · 0.10 mm , tri-
˚
˚
clinic, space group P-1, a = 9.0560(5) A, b = 10.2779(6) A,
˚
49), 91 (100), 234 (97), 262 (63), 276 (38), 294 (80), 350
c = 11.1313(7) A, a = 78.6020(10)ꢁ, b = 66.5910(10)ꢁ, c =
79.6730(10)ꢁ, V = 926.17(9) A , Z = 2, Dcalcd = 1.317 mg/m .
+
+
+
˚
3
3
M À17, 3), no M ; ESIMS 368 (M +H). Anal. Calcd
˚
for C H NO : C, 68.65; H, 5.76; N, 3.81. Found: C,
F
= 388, Mo Ka (k = 0.71073 A), R = 0.0522, wR =
000 1 2
2
1
21
5
6
8.72; H, 5.83; N, 3.70. Compound 4e: 52%; white solid,
0.1217 (I > 2r(I)). We omitted hydrogen atoms for clarity
(Fig. 1). The X-ray data has been deposited in CCDC with
number 295991.
mp 175–176 ꢁC; IR (KBr) 3421, 3336, 1751, 1712,
À1
1
1
200 cm
;
H NMR (CDCl , 300 MHz) d 1.18 (t,
3
J = 7.2 Hz, 3H), 1.26 (t, J = 7.2 Hz, 3H), 2.21 (s, 3H),
10. Crystal data of compound 4e: solvent of crystal growth
2
3
.34 (s, 3H), 2.88 (br s, 2H), 3.98 (d, J = 16.2 Hz, 1H),
.95–4.07 (m, 1H), 4.08 (d, J = 16.2 Hz, 1H), 4.14–4.26
(hexanes/CH Cl , 95:5); empirical formula C24H27NO ,
2 2 5
3
Fw = 409.47, crystal dimensions 0.30 · 0.20 · 0.20 mm ,
1
3
˚
(
m, 2H), 4.28–4.41 (m, 1H), 6.78–7.28 (m, 7H); C NMR
CDCl , 75 MHz) d 13.74, 14.06, 19.20, 21.13, 33.70,
0.87, 61.78, 98.21, 110.72, 121.33, 124.11, 125.55, 126.66,
monoclinic, space group P2(1)/c, a = 12.0151(9) A, b =
˚
˚
(
3
11.4533(8) A, c = 15.4885(11) A, a = 90ꢁ, b = 98.4690(10)ꢁ,
˚
3
3
6
1
1
c = 90ꢁ, V = 2108.2(3) A , Z = 4, Dcalcd = 1.290 mg/m .
˚
27.10, 127.40, 130.03, 131.97, 133.25, 135.10, 135.36,
F000 = 872,
Mo Ka
(k = 0.71073 A),
1
R = 0.0613,
+
44.35, 160.98, 167.50, 168.75; ESIMS 410 (M +H).
wR = 0.1413 (I > 2r(I)). We omitted hydrogen atoms for
2
Anal. Calcd for C24
H27NO
5
: C, 70.40; H, 6.65; N, 3.42.
clarity (Fig. 2). The X-ray data has been deposited in CCDC
Found: C, 70.49; H, 6.71; N, 3.39.
with number 295992.