Synthesis of 1,3,4-Trisubstituted Benzenes from Morita-Baylis-Hillman Adducts of α-Bromocinnamaldehyde via [5+1] Annulation Strategy

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S. Y. Kim et al.
KOREAN CHEMICAL SOCIETY
Synthesis of 1,3,4-Trisubstituted Benzenes from Morita–Baylis–Hillman
Adducts of α-Bromocinnamaldehyde via [5+1] Annulation Strategy
*
Su Yeon Kim, Ko Hoon Kim, Jin Woo Lim, and Jae Nyoung Kim
Department of Chemistry and Institute of Basic Science, Chonnam National University, Gwangju 500-757,
Korea. *E-mail: kimjn@chonnam.ac.kr
Received May 7, 2015, Accepted August 11, 2015, Published online November 8, 2015
Keywords: Morita–Baylis–Hillman adducts, Trisubstituted benzenes, [5+1] Annulation,
Intramolecular 1,6-conjugate addition
The construction of suitably functionalized benzene ring in a
regioselective way is important in organic synthesis. The
Morita–Baylis–Hillman (MBH) adducts have been used as
useful starting materials for this purpose.1-6 There have been
reported numerous methods including [4+2] cycloaddition,2
6π-electrocyclization,3 [3+3] annulation,4 and consecutive
[3+1+2] annulation protocols.5 During our recent studies
using the MBH adducts of cinnamaldehydes,7 we reasoned
out that the synthesis of 1,3,4-trisubstituted benzenes 3 could
be realized by [5+1] annulation protocol8 from the acetates of
MBH adduct of α-bromocinnamaldehyde via a sequential
SN20 reaction of primary nitroalkane, an intramolecular 1,6-
conjugate addition,9 and eliminations of HBr and HNO2, as
shown in Scheme 1.
Thus, starting materials 1a-d were prepared from α-bromo-
cinnamaldehydes, as shown in Scheme 2. The MBH reaction
was carried out in the presence of 1,4-diazabicyclo[2.2.2]
octane (DABCO) to produce the corresponding MBH
adducts in good to moderate yields (45–83%), and the
following acetylation (Ac2O/DMAP) afforded 1a-d in good
yields (82–88%).10
The reaction of MBH acetate 1a and nitroethane (2a) in the
presence of Cs2CO3 (3.0 equiv) in DMF at room temperature
for 4 h afforded the desired product 3a in moderate yield
(45%) along with a small amount (5%) of unexpected phenol
4a, as shown in Scheme 3. The use of CH3CN or K2CO3
showed a similar result.11 The reaction mechanism for the for-
mation of 3a would be a sequential introduction of nitroethane
at the primary position of the MBH adduct by SN20 reaction to
afford I, and the following intramolecular 1,6-conjugate addi-
tion to produce II, and the final elimination of HBr and HNO2
to give 3a. For the formation of benzene ring, the MBH acetate
provided five carbons and nitroethane served one carbon. Dur-
ing the reaction intermediate II could be converted to IV by
SN2 reaction of the nitronate anion of nitroethane,12 and the
following Hass–Bender oxidation12 could afford V. A subse-
quent elimination of HNO2 and keto-enol tautomerization
would provide 4a as a minor product. However, another pos-
sibility involving sequential [2,3]-sigmatropic rearrangement
of allylic nitro intermediate and the following disproportion-
ation process13 cannot be ruled out completely at this stage.
Encouraged by the successful results, some representative
primary nitroalkanes 2b-i were examined under the same reac-
tion conditions, and the results are summarized in Table 1. The
reactions of 1a with 1-nitropropane (2b), 1-nitrobutane (2c),
1-nitropentane (2d), 1-nitrohexane (2e), ethyl nitroacetate
(2f), 2-phenylnitroethane (2g), 2-(2-thienyl)nitroethane (2h),
and methyl 4-nitrobutyrate (2i) showed similar results. The
corresponding benzene derivatives 3b-i were synthesized in
moderate yields (40–68%) along with phenol derivatives
4b-e (5–9%) as minor products in some cases. For the reac-
tions of 2f-i, the corresponding phenol derivatives were
observed on TLC at the right position; however, they could
not be separated in appreciable amount. The reaction of
MBH acetate 1b with 2b and 2f also provided 3j (44%) and
3k (71%), respectively. The reaction of acetyl derivative 1c
and 2f provided 3l (43%) in moderate yield.
OAc
EWG
RCH2NO2 (2)
EWG
Ph
base (3.0 equuiv)
Ph
SN2'
Br
R
3
1
intramolecular 1,6-conjugate addition
Scheme 1. Synthetic rational of 1,3,4-trisubstituted benzene.
1. DABCO (10 mol%)
rt, 12 h
OAc
EWG
CHO
EWG
R1
R1
+
2. Ac2O (1.5 equiv)
DMAP (10 mol%)
CH2Cl2, rt, 2 h
Br
Br
1a-d
(1.5 equiv)
R1 = C6H5, 4-FC6H4
1a: R1 = C6H5, EWG = COOMe
1b: R1 = 4-FC6H4, EWG = COOMe
1c: R1 = C6H5, EWG = COMe
1d: R1 = C6H5, EWG = CN
However, the reaction of nitrile derivative 1d and 2b
afforded 3m in low yield (13%). As reported in many similar
cases,1,14 the SN20 reaction of a nucleophile to MBH acetate
produced a Z-form intermediate as a major as shown in
Scheme 4, and the following 1,6-conjugate addition could
EWG = COOMe, COMe, CN
Scheme 2. Preparation of starting materials.
Bull. Korean Chem. Soc. 2015, Vol. 36, 2932–2935
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OAc
Cs2CO3 (3.0 equiv)
DMF, rt, 4 h
COOMe HO
COOMe
COOMe
+
CH3CH2NO2
+
Ph
Ph
Ph
Br
1a
2a
Me
3a (45%)
Me
4a (5%)
COOMe
E
Br
COOMe
- HBr
Br
COOMe
Me
- AcOH
- HNO2
3a
Ph
Ph
Ph
Me NO2
III
Me NO2
I
II
NO2
O
N
O
H
H3C
N
O
COOMe
COOMe
H3C
O
O
- CH3CH=NOH
Hass-Bender
- HNO2
II
4a
SN2
Ph
Ph
Me NO2
Me NO2
V
IV
Scheme 3. One-pot synthesis of 3a and 4a.
Table 1. Synthesis of poly-substitutes benzenes.
2a: R2 = -CH3; 2b: R2 = -CH2CH3
EWG
OAc
HO
R1
EWG
2c: R2 = -(CH2)2CH3; 2d: R2 = -(CH2)3CH3
2e: R2 = -(CH2)4CH3; 2f: R2 = -COOEt
2g: R2 = -CH2Ph; 2h: R2 = -CH2-(2-thienyl)
2i: R2 = -CH2CH2COOCH3
Conditionsa
EWG
R2-CH2NO2
R1
+
+
R1
Br
R2
3a-m
R2
2a-i
4a-e (5-9%)b
1a-d
COOMe
COOMe
COOMe
COOMe
COOMe
COOMe
Ph
Ph
Ph
Ph
Ph
Ph
CH3
CH2(CH2)2CH3
CH2CH3
COOEt
CH2CH2CH3
CH2(CH2)3CH3
3d (40%)
(1a + 2d)
3f (68%)
(1a + 2f)
3e (42%)
(1a + 2e)
3a (45%)
(1a + 2a)
3b (45%)
(1a + 2b)
3c (51%)
(1a + 2c)
COOMe
COOMe
COOMe
Ar
COOMe
COOMe
COMe
CN
Ph
S
Ph
Ar
Ph
Ph
Ph
CH2CH3
COOEt
CH2CH2COOMe
CH2Ph
COOEt
CH2CH3
3k (71%)c
3l (43%)
(1c + 2f)
3m (13%)
(1d + 2b)
3j (44%)c
3h (60%)
(1a + 2h)
3i (55%)
(1a + 2i)
3g (62%)
(1a + 2g)
(1b + 2f)
(1b + 2b)
a Conditions: 1 (0.5 mmol), 2 (0.5 mmol), Cs2CO3 (3.0 equiv), DMF, rt, 4 h.
b The yield of phenols: 4a (5%), 4b (7%), 4c (9%), 4d (7%), 4e (7%).
The formation of corresponding phenols were observed in other entries; however, they were not isolated in appreciable amounts.
c Ar is 4-fluorophenyl.
not proceed. The minor E-isomer might produce 3m in low
Z
Br
NO2
yield.
CN Me
In summary, an efficient synthetic method of 1,3,4-
trisubstituted benzenesfromMorita–Baylis–Hillmanadducts
has been developed. The method involved a sequential nucle-
ophilic substitution (SN20) reaction, an intramolecular 1,6-
conjugate addition, and E2 elimination process.
Ph
Br
(major)
1d + 2b
E
CN
NO2
Me
3m (13%)
Ph
(minor)
Scheme 4. The reaction of nitrile derivative 1d.
Experimental
Typical procedure for the synthesis of 3a and 4a. To a stir-
red solution of 1a (170 mg, 0.5 mmol) and 2a (37 mg, 0.5
mmol) in DMF (3.0 mL) was added Cs2CO3 (489 mg, 1.5
mmol), and the reaction mixture was stirred at room
The starting materials 1a-d were prepared according to the
reported method,7,10 and the spectroscopic data are reported
in Supporting Information.
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temperature for 4 h. After the usual aqueous extractive workup
and column chromatographic purification process (hexanes/
EtOAc, 25:1), compound 3a (51 mg, 45%) was obtained as
colorless oil along with 4a (6 mg, 5%) as a white solid. Other
compounds were synthesized similarly, and the selected spec-
troscopic data of 3a-i, 4b, and 4c are as follows.
and 1.8 Hz, 1H), 8.48 (d, J = 1.8 Hz, 1H); 13C NMR
(CDCl3, 75 MHz) δ 13.63, 52.31, 61.20, 127.75, 128.11,
128.15, 129.03, 130.82, 130.95, 131.61, 131.85, 140.38,
146.63, 166.12, 167.92; ESIMS m/z 285 [M+H]+. Anal. Calcd
for C17H16O4: C, 71.82; H, 5.67. Found: C, 71.98; H, 5.43.
Compound 3g: 62%. Colorless oil; IR (film) 1723, 1435,
1
1291, 1250 cm−1; H NMR (CDCl3, 300 MHz) δ 3.85 (s,
Compound 3a: 45%. Colorless oil; IR (film) 1722, 1436,
1
1296 cm−1; H NMR (CDCl3, 300 MHz) δ 2.32 (s, 3H),
3H), 3.94 (s, 2H), 6.89 (d, J = 7.2 Hz, 2H), 7.05–7.21 (m,
5H), 7.25–7.35 (m, 4H), 7.88 (dd, J = 6.6 and 1.8 Hz, 1H),
7.90 (s, 1H); 13C NMR (CDCl3, 75 MHz) δ 38.88, 52.09,
125.93, 127.37, 127.42, 128.15, 128.30, 128.66, 128.93,
129.21, 130.34, 131.61, 138.55, 140.63, 140.79, 146.91,
167.02; ESIMS m/z 303 [M+H]+. Anal. Calcd for
C21H18O2: C, 83.42; H, 6.00. Found: C, 83.64; H, 6.15.
Compound 3h: 60%. Colorless oil; IR (film) 1723, 1436,
3.94 (s, 3H), 7.28–7.36 (m, 3H), 7.37–7.47 (m, 3H), 7.90
(d, J = 7.8 Hz, 1H), 7.97 (s, 1H); 13C NMR (CDCl3, 75
MHz) δ 20.41, 52.07, 126.95, 127.33, 128.19, 128.85,
129.88, 131.46, 135.62, 140.90, 146.53, 167.14, one carbon
was overlapped; ESIMS m/z 227 [M+H]+. Anal. Calcd for
C15H14O2: C, 79.62; H, 6.24. Found: C, 79.81; H, 6.13.
Compound 3b: 45%. Colorless oil; IR (film) 1723, 1436,
1
1291 cm−1; H NMR (CDCl3, 300 MHz) δ 1.14 (t, J = 7.5
1
1290, 1256 cm−1; H NMR (CDCl3, 300 MHz) δ 3.93 (s,
Hz, 3H), 2.66 (q, J = 7.5 Hz, 2H), 3.96 (s, 3H), 7.25–7.36
(m, 3H), 7.38–7.48 (m, 3H), 7.91 (d, J = 8.1 Hz, 1H), 8.02
(s, 1H); 13C NMR (CDCl3, 75 MHz) δ 15.44, 26.03, 52.08,
126.71, 127.25, 128.13, 128.82, 129.11, 129.83, 130.09,
140.93, 141.88, 146.27, 167.19; ESIMS m/z 241 [M+H]+.
Anal. Calcd for C16H16O2: C, 79.97; H, 6.71. Found: C,
80.14; H, 6.97.
3H), 4.14 (s, 2H), 6.58–6.61 (m, 1H), 6.87 (dd, J = 5.1 and
3.3 Hz, 1H), 7.11 (dd, J = 5.1 and 1.2 Hz, 1H), 7.26–7.31
(m, 2H), 7.32–7.44 (m, 4H), 7.97 (dd, J = 8.1 and 1.8 Hz,
1H), 8.05 (d, J = 1.8 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ
33.32, 52.13, 123.88, 125.17, 126.69, 127.56, 127.72,
128.22, 128.90, 129.33, 130.40, 131.29, 137.96, 140.27,
143.83, 146.49, 166.91; ESIMS m/z 309 [M+H]+. Anal. Calcd
for C19H16O2S: C, 74.00; H, 5.23. Found: C, 74.07; H, 5.36.
Compound 3i: 55%. Colorless oil; IR (film) 1723, 1436,
Compound 3c: 51%. Colorless oil; IR (film) 1723, 1436,
1
1294 cm−1; H NMR (CDCl3, 300 MHz) δ 0.82 (t, J = 7.2
1
1294, 1249 cm−1; H NMR (CDCl3, 300 MHz) δ 2.45 (t, J
Hz, 3H), 1.46–1.60 (m, 2H), 2.60 (t, J = 7.5 Hz, 2H), 3.94
(s, 3H), 7.24–7.33 (m, 3H), 7.36–7.50 (m, 3H), 7.90 (d, J
= 7.5 Hz, 1H), 7.99 (s, 1H); 13C NMR (CDCl3, 75 MHz) δ
13.89, 24.27, 34.91, 52.03, 126.70, 127.21, 128.10, 128.86,
128.96, 130.14, 130.46, 140.39, 141.04, 146.52, 167.19;
ESIMS m/z 255 [M+H]+. Anal. Calcd for C17H18O2: C,
80.28; H, 7.13. Found: C, 80.10; H, 7.31.
= 7.5 Hz, 2H), 2.98 (t, J = 7.5 Hz, 2H), 3.60 (s, 3H), 3.93 (s,
3H), 7.26–7.32 (m, 3H), 7.34–7.47 (m, 3H), 7.92 (dd, J =
8.1 and 1.8 Hz, 1H), 7.98 (d, J = 1.8 Hz, 1H); 13C NMR
(CDCl3, 75 MHz) δ 28.12, 34.84, 51.57, 52.11, 127.41,
127.53, 128.35, 128.69, 129.25, 130.20, 130.40, 138.14,
140.42, 146.61, 166.91, 172.91; ESIMS m/z 299 [M+H]+.
Anal. Calcd for C18H18O4: C, 72.47; H, 6.08. Found: C,
72.35; H, 6.30.
Compound 3d: 40%. Colorless oil; IR (film) 1724, 1436,
1
1291, 1247 cm−1; H NMR (CDCl3, 300 MHz) δ 0.78 (t, J
= 7.2 Hz, 3H), 1.14–1.27 (m, 2H), 1.40–1.52 (m, 2H), 2.60
(t, J = 7.8 Hz, 2H), 3.93 (s, 3H), 7.23–7.30 (m, 3H),
7.32–7.44 (m, 3H), 7.87 (dd, J = 8.1 and 1.5 Hz, 1H), 7.97
(d, J = 1.5 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 13.75,
22.41, 32.53, 33.37, 52.05, 126.65, 127.21, 128.09, 128.87,
128.94, 130.12, 130.46, 140.64, 140.99, 146.46, 167.21;
ESIMS m/z 269 [M+H]+. Anal. Calcd for C18H20O2: C,
80.56; H, 7.51. Found: C, 80.59; H, 7.82.
Compound 4b: 7%. White solid, m.p. 94–96 ꢀC; IR (KBr)
3429, 1721, 1310, 1232 cm−1; 1H NMR (CDCl3, 300 MHz) δ
1.07 (t, J = 7.5 Hz, 3H), 2.43 (q, J = 7.5 Hz, 2H), 3.94 (s, 3H),
4.83 (br s, 1H), 7.28 (d, J = 1.5 Hz, 1H), 7.31 (d, J = 1.5 Hz,
1H), 7.44–7.62 (m, 5H); 13C NMR (CDCl3, 75 MHz) δ
15.24, 26.50, 52.15, 113.68, 121.59, 128.62, 129.49,
129.93, 130.56, 132.26, 134.19, 143.69, 152.84, 166.99;
ESIMS m/z 257 [M+H]+. Anal. Calcd for C16H16O3: C,
74.98; H, 6.29. Found: C, 75.11; H, 6.50.
Compound 4c: 9%. White solid, m.p. 102–103 ꢀC; IR (KBr)
3428, 1722, 1321, 1229 cm−1; 1H NMR (CDCl3, 300 MHz) δ
0.77(t, J = 7.2 Hz, 3H), 1.37–1.54(m, 2H), 2.37(t, J = 7.5 Hz,
2H), 3.92 (s, 3H), 4.83 (br s, 1H), 7.26 (s, 1H), 7.28 (s, 1H),
7.39–7.62 (m, 5H); 13C NMR (CDCl3, 75 MHz) δ 13.89,
24.05, 35.29, 52.15, 113.62, 122.26, 128.58, 129.43,
129.97, 130.33, 132.52, 134.22, 142.16, 152.87, 167.00;
ESIMS m/z 271 [M+H]+. Anal. Calcd for C17H18O3: C,
75.53; H, 6.71. Found: C, 75.29; H, 6.94.
Compound 3e: 42%. Colorless oil; IR (film) 1724, 1436,
1
1291 cm−1; H NMR (CDCl3, 300 MHz) δ 0.80 (t, J = 6.9
Hz, 3H), 1.10–1.30 (m, 4H), 1.41–1.54 (m, 2H), 2.61 (t, J
= 7.8 Hz, 2H), 3.94 (s, 3H), 7.25–7.32 (m, 3H), 7.34–7.46
(m, 3H), 7.89 (dd, J = 7.8 and 1.8 Hz, 1H), 7.98 (d, J = 1.8
Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 13.88, 22.26,
30.85, 31.53, 32.82, 52.05, 126.66, 127.22, 128.10, 128.86,
128.98, 130.12, 130.46, 140.70, 141.02, 146.47, 167.21;
ESIMS m/z 283 [M+H]+. Anal. Calcd for C19H22O2: C,
80.82; H, 7.85. Found: C, 80.68; H, 7.96.
Compound 3f: 68%. Colorless oil; IR (film) 1727, 1437,
1
1306, 1248 cm−1; H NMR (CDCl3, 300 MHz) δ 1.03 (t, J
Acknowledgments. This research was supported by Basic
Science Research Program through the National Research
Foundation of Korea (NRF) funded by the Ministry of
= 7.2 Hz, 3H), 3.96 (s, 3H), 4.12 (q, J = 7.2 Hz, 2H),
7.30–7.34 (m, 2H), 7.37–7.48 (m, 4H), 8.17 (dd, J = 8.1
Bull. Korean Chem. Soc. 2015, Vol. 36, 2932–2935
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Education, Science and Technology (2014R1A1A2053606).
Spectroscopic data were obtained from the Korea Basic
Science Institute, Gwangju branch.
SupportingInformation. Additionalsupportinginformation
is available in the online version of this article.
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2476; (b) J. W. Lim, K. H. Kim, S. H. Kim, J. N. Kim, Tetrahe-
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J. N. Kim, Tetrahedron Lett. 2013, 54, 2595.
4. For synthesis of poly-substituted benzenes from MBH adducts
via [3+3] annulation protocol, see:(a) D. Y. Park, K. Y. Lee,
J. N. Kim, Tetrahedron Lett. 2007, 48, 1633; (b) D. Y. Park,
S. J. Kim, T. H. Kim, J. N. Kim, Tetrahedron Lett. 2006, 47,
6315; (c) J. W. Lim, S. H. Kim, J. Yu, J. N. Kim, Bull. Korean
Chem. Soc. 2013, 34, 3503; (d) D. Y. Park, K. Y. Lee,
S. Gowrisankar, J. N. Kim, Bull. Korean Chem. Soc. 2008,
29, 701.
5. For synthesis of poly-substituted benzenes from MBH adducts
via [3+1+2] annulation protocol, see:(a) M. J. Lee, K. Y. Lee,
S. Gowrisankar, J. N. Kim, Tetrahedron Lett. 2006, 47, 1355;
(b) D. Y. Park, S. Gowrisankar, J. N. Kim, Tetrahedron Lett.
2006, 47, 6641; (c) S. C. Kim, H. S. Lee, Y. J. Lee, J. N. Kim, Tet-
rahedron Lett. 2006, 47, 5681;(d)S. C. Kim, K. Y. Lee, H. S. Lee,
J. N. Kim, Tetrahedron 2008, 64, 103; (e) M. J. Lee, K. Y. Lee,
D. Y. Park, J. N. Kim, Tetrahedron 2006, 62, 3128.
6. For other routes of poly-substituted benzene derivatives
from MBH adducts, see:(a) C. R. Reddy, U. Dilipkumar,
M. D. Reddy, Org. Lett. 2014, 16, 3792; (b) P.-Y. Chen,
H.-M. Chen, L.-Y. Chen, J.-Y. Tzeng, J.-C. Tsai, P.-C. Chi,
S.-R. Li, E.-C. Wang, Tetrahedron 2007, 63, 2824.
7. For synthetic applications of MBH adducts of cinnamaldehydes,
see:(a) K. H. Kim, S. H. Kim, S. Park, J. N. Kim, Tetrahedron
2011, 67, 3328; (b) K. H. Kim, S. Lee, J. Lee, M. J. Go,
J. N. Kim, Tetrahedron Lett. 2013, 54, 5739; (c) B. M. Trost,
10. For synthetic details of starting materials, see supporting infor-
mation. The synthesisof MBHacetate of(Z)-2-bromohex-2-enal
was examined; however, the MBH reaction with methyl acrylate
failed.
11. Many conditions were examined in order to increase the yield of
3a; however, the yield was not increased due to the formations of
many side products including a rearranged primary acetate of 1a
and a trace amount of unreactive Z-form SN20 intermediate.
12. (a) H. B. Hass, M. L. Bender, J. Am. Chem. Soc. 1949, 71, 1767;
(b) T. A. Klein, J. M. Schkeryantz, Tetrahedron Lett. 2005, 46,
4535; (c) P. G. Gildner, A. A. S. Gietter, D. Cui, D. A. Watson,
J. Am. Chem. Soc. 2012, 134, 9942; (d) B. M. Trost,
J. Richardson, K. Yong, J. Am. Chem. Soc. 2006, 128, 2540.
13. For the [2,3]-sigmatropic rearrangement of allylic nitro com-
pounds and a following disproportionation process, see:
(a) E. Dumez, J. Rodriguez, J.-P. Dulcere, Chem. Commun.
1999, 2009; (b) C. Alameda-Angulo, B. Quiclet-Sire,
E. Schmidt, S. Z. Zard, Org. Lett. 2005, 7, 3489;
(c) S. Z. Zard, Helv. Chim. Acta. 2012, 95, 1730;
(d) J. Boivin, L. E. Kaim, J. Kervagoret, S. Z. Zard, J. Chem.
Soc. Chem. Commun. 1989, 1006.
14. For the selective formation of Z-isomer in SN2’ reaction of MBH
adduct of acrylonitrile, see:(a) M. Nayak, S. Batra, Eur. J. Org.
Chem. 2009, 3505; (b) J. S. Yadav, M. K. Gupta, S. K. Pandey,
B. V. S. Reddy, A. V. S. Sarma, Tetrahedron Lett. 2005, 46,
2761; (c) Y. J. Im, J. E. Na, J. N. Kim, Bull. Korean Chem.
Soc. 2003, 24, 511.
Bull. Korean Chem. Soc. 2015, Vol. 36, 2932–2935
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de 2935