An expedient synthesis of poly-substituted naphthalenes: consecutive Michael, intramolecular aldol, and decarboxylative Michael cascade of δ-ketonitriles

Article abstract of DOI:10.1016/j.tetlet.2010.01.062

An efficient synthetic method was developed for poly-substituted naphthalenes via the multi-step, one-pot domino reaction of δ-ketonitriles involving a sequential Michael addition, intramolecular aldol, lactonization, decarboxylative Michael addition, and elimination processes.

Full text of DOI:10.1016/j.tetlet.2010.01.062

Tetrahedron Letters 51 (2010) 1592–1595
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An expedient synthesis of poly-substituted naphthalenes: consecutive
Michael, intramolecular aldol, and decarboxylative Michael cascade
of d-ketonitriles
*
Sung Hwan Kim, Yu Mi Kim, Hyun Seung Lee, Jae Nyoung Kim
Department of Chemistry and Institute of Basic Science, Chonnam National University, Gwangju 500-757, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthetic method was developed for poly-substituted naphthalenes via the multi-step, one-
pot domino reaction of d-ketonitriles involving a sequential Michael addition, intramolecular aldol, lact-
onization, decarboxylative Michael addition, and elimination processes.
Received 14 December 2009
Revised 15 January 2010
Accepted 18 January 2010
Available online 25 January 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Poly-substituted naphthalenes
Michael addition
Decarboxylative Michael
Regioselective synthesis of naphthalenes has been and contin-
ues to be of great interest in organic synthesis.1,2 A new synthetic
procedure is still highly desired due to the abundance of the skel-
eton in many biologically important natural products. Recently, we
reported the synthesis of 1-arylisoquinoline derivatives via the in-
dium-mediated Barbier-type allylation of nitrile group of d-keto-
nitrile 1a (Scheme 1).3 The starting material 1a was easily
prepared by the SNAr reaction of 2-fluorobenzophenone with
methyl cyanoacetate.3 During the studies we thought that 1a could
be used for the synthesis of naphthalene 10a via the sequential Mi-
chael addition to methyl acrylate (2a), intramolecular aldol con-
densation, and elimination of HCN (vide infra, Scheme 2).
However, compound 10a was not formed in any trace amounts,
and the major product was compound 3a, unexpectedly.
Initially we carried out the reaction of 1a with 3.0 equiv of
methyl acrylate (2a) and obtained moderate yield of 3a (41%).4
However, the yield of 3a increased to 61%, as shown in Scheme
1, when we used 5.0 equiv of 2a.4,5 The mechanism for the forma-
tion of 3a could be proposed as shown in Scheme 2: (i) Michael
addition of 1a to 2a produced 4a, (ii) intramolecular aldol-type
cyclization to 5a, (iii) lactonization to tricyclic intermediate 6a,6
(iv) base-mediated decarboxylative Michael addition7,8 to methyl
acrylate via 7a to produce 8a, and (v) E2 elimination of HCN to give
naphthalene 3a. As shown in Scheme 1, compounds 4a (3%), 8a
(7%), and 9a (4%) were isolated together in low yields, and the re-
sults supported the proposed mechanism. Compound 9a might be
formed via the aerobic oxidation of 7a. We obtained 3a in 65% yield
under the same conditions (Cs2CO3, reflux) from 4a which was ob-
tained by the reaction of 1a and 2a under mild conditions (K2CO3,
50 °C),4 as shown in Scheme 3.
Encouraged by the results, we examined the reactions of 1a
with various Michael acceptors including ethyl acrylate (2b), phe-
nyl vinyl sulfone (2c), acrylonitrile (2d), and methyl vinyl ketone
(2e). When we used 2b and 2c, the corresponding naphthalenes
3b and 3c were obtained in moderate yields (entries 2 and 3 in
Table 1). However, the reactions with 2d and 2e showed the
formation of many intractable complex mixtures.9 The reactions
of other d-ketonitriles 1b–d and 2a afforded the corresponding
naphthalenes (3a, 3d, and 3e) in moderate yields (entries 4–6).
The formation of 3a from 1b and 2a (entry 4) supported again
the proposed mechanism in Scheme 2. It is interesting to note that
the reaction of 1e (entry 7) afforded 3a by following the mecha-
nism proposed in Scheme 4. Compound 1e has two acidic benzylic
protons and Michael addition occurred two times to produce 11,
which produced 3a via dehydrative cyclization and elimination
of HCN.
As a synthetic application of the synthesized naphthalene, we
examined the Friedel–Crafts reaction of 3a, as shown in Scheme
5. Hydrolysis of 3a (LiOH, aq THF) afforded the corresponding dia-
cid in 92%. Treatment of this crude diacid with H2SO4 (10 equiv) in
1,2-dichloroethane afforded fluorenone derivative 12 and peri-
naphthenone derivative 13.5,10 When the reaction stopped
after 6 h, compounds 12 and 13 were isolated in 80% and 5%,
* Corresponding author. Tel.: +82 62 530 3381; fax: +82 62 530 3389.
E-mail address: kimjn@chonnam.ac.kr (J.N. Kim).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.01.062

S. H. Kim et al. / Tetrahedron Letters 51 (2010) 1592–1595
1593
Ph
allylindium
N
Ref. 3
Ph
δ
COOMe
Ph
O
α
COOMe
COOMe
Ph
COOMe
CN
1a
COOMe
2a (5.0 equiv)
+ 4a (3%) + 8a (7%) + 9a (4%)
+
Cs2CO3, CH3CN
reflux, 20 h
COOMe
COOMe
10a (not formed)
3a (61%)
Scheme 1.
Ph
Ph OH
COOMe
- H2O
- HCN
Cs2CO3
O
10a
1a + 2a
COOMe
NC COOMe
NC COOMe
5a
4a
- MeOH
Ph
Ph
O
O
Ph
COOMe
COOMe
- HCN
base
COOMe
COOMe
2a
3a
- CO2
H
NC
NC
CN
6a
7a
8a
air oxidation
Ph
COOMe
9a
CN
Scheme 2.
K2CO3 (0.5 equiv)
2a (5.0 equiv)
4a
(69%)
3a
(65%)
1a
+
2a
CH3CN, 50 oC, 10 h
Cs2CO3 (2.0 equiv)
CH3CN, reflux, 24 h
(3.0 equiv)
Scheme 3.
respectively. When we run the reaction for longer time (30 h), the
amount of 13 increased to 60%. Compound 13 might be formed via
the air oxidation of 13’ which was formed by the Friedel–Crafts
reaction of 12. We could not detect the formation of 14 in the
reaction.
In summary, we disclosed an efficient synthesis of poly-substi-
tuted naphthalenes via the multi-step, one-pot domino reaction of
d-ketonitriles involving a sequential Michael addition, intramolec-
ular aldol, lactonization, decarboxylative Michael addition, and
elimination processes.
Ph
- H2O
- HCN
O
2a
3a (60%)
1e
(Entry 7)
COOMe
NC
COOMe
11
Scheme 4.

1594
S. H. Kim et al. / Tetrahedron Letters 51 (2010) 1592–1595
1. LiOH (10 equiv)
aq THF, rt, 6 h (92%)
O
O
O
O
O
3a
+
2. H2SO4 (10 equiv)
ClCH2CH2Cl, reflux, time
COOH
O
O
13
12
13'
14 (not formed)
after 6 h: 12 (80%), 13 (5%)
after 30 h: 12 (<5%), 13 (60%)
Scheme 5.
References and notes
Table 1
Synthesis of poly-substituted naphthalenesa
1. For our recent synthesis of naphthalene derivatives, see: (a) Lee, K. Y.; Kim, S.
C.; Kim, J. N. Tetrahedron Lett. 2006, 47, 977–980. and further references cited
therein; (b) Gowrisankar, S.; Kim, K. H.; Kim, J. N. Bull. Korean Chem. Soc. 2008,
29, 2537–2539; (c) Im, Y. J.; Lee, K. Y.; Kim, T. H.; Kim, J. N. Tetrahedron Lett.
2002, 43, 4675–4678; (d) Gowrisankar, S.; Lee, H. S.; Kim, J. N. Tetrahedron Lett.
2007, 48, 3105–3108; (e) Im, Y. J.; Chung, Y. M.; Gong, J. H.; Kim, J. N. Bull.
Korean Chem. Soc. 2002, 23, 787–788.
Entry
Substrate 1
COPh
Substrate 2
Product (%)
COOMe
Ph
COOMe
CN
1
2a
1a
COOMe
2. For the synthesis of naphthalenes via a sequential Michael-aldol approach, see:
(a) Wildeman, J.; Borgen, P. C.; Pluim, H.; Rouwette, P. H. F. M.; Van Leusen, A.
M. Tetrahedron Lett. 1978, 19, 2213–2216; (b) Panasiewicz, M.; Zdrojewski, T.;
Chrulski, K.; Wojtasiewicz, A.; Jonczyk, A. ARKIVOC 2009, 98–110; For some
leading references to naphthalene synthesis, see: (c) Asao, N.; Takahashi, K.;
Lee, S.; Kasahara, T.; Yamamoto, Y. J. Am. Chem. Soc. 2002, 124, 12650–12651;
(d) Asao, N.; Nogami, T.; Lee, S.; Yamamoto, Y. J. Am. Chem. Soc. 2003, 125,
10921–10925; (e) Barluenga, J.; Vazquez-Villa, H.; Ballesteros, A.; Gonzalez, J.
M. Org. Lett. 2003, 5, 4121–4123; (f) Barluenga, J.; Vazquez-Villa, H.; Merino, I.;
Ballesteros, A.; Gonzalez, J. M. Chem. Eur. J. 2006, 12, 5790–5805; (g) Patil, N. T.;
Konala, A.; Singh, V.; Reddy, V. V. N. Eur. J. Org. Chem. 2009, 5178–5184; (h) Shi,
M.; Lu, J.-M. J. Org. Chem. 2006, 71, 1920–1923; (i) Jiang, X.; Kong, W.; Chen, J.;
Ma, S. Org. Biomol. Chem. 2008, 6, 3605–3610; (j) Dudnik, A. S.; Schwier, T.;
Gevorgyan, V. Tetrahedron 2009, 65, 1859–1870; (k) Balamurugan, R.; Gudla, V.
Org. Lett. 2009, 11, 3116–3119.
COOMe
COOEt
3a (61)
COOEt
Ph
2b
2
1a
COOEt
SO2Ph
3b (60)
SO2Ph
Ph
2cb
3
4
5
1a
SO2Ph
3c (69)
3a (57)
3. Kim, S. H.; Lee, H. S.; Kim, K. H.; Kim, J. N. Tetrahedron Lett. 2009, 50, 6476–
COPh
CN
6479.
4. When we used 3.0 equiv of methyl acrylate, the yield of 3a decreased to 41%
whereas the yield of 4a increased to 10%. When we used K2CO3 (2.0 equiv)
instead of Cs2CO3 in the reaction of 1a and 2a, product 3a was not formed at all,
instead compounds 4a (26%) and 8a (33%) were isolated. Compound 4a was
prepared as the major product (69%) under the influence of K2CO3 (0.5 equiv) at
50 °C (10 h).
2a
2a
COOEt
COPh
1b
F
Ph
F
COOMe
5. Typical procedure for the synthesis of compound 3a: A stirred mixture of 1a
(279 mg, 1.0 mmol),3 2a (430 mg, 5.0 mmol), and Cs2CO3 (652 mg, 2.0 mmol) in
acetonitrile (2.0 mL) was heated to reflux for 20 h. After the usual aqueous
workup and column chromatographic purification process (hexanes/CH2Cl2/
EtOAc, 10:1:1), we obtained 3a (212 mg, 61%), 4a (11 mg, 3%), 8a (26 mg, 7%),
and 9a (11 mg, 4%). Other compounds were prepared similarly and the selected
spectroscopic data of 3a, 4a, 8a, 9a, 3c, 12, and 13 are as follows:
CN
COOMe
1c
COOMe
COOMe
3d (63)
COAr
CN
Ar
Compound 3a: 61%; colorless oil; IR (film) 1736, 1730, 1433, 1220 cmÀ1 1H
;
6c
2a
2a
NMR (CDCl3, 300 MHz) d 2.83 (t, J = 7.8 Hz, 2H), 3.49 (t, J = 7.8 Hz, 2H), 3.60 (s,
3H), 3.74 (s, 3H), 7.25–7.30 (m, 2H), 7.39–7.50 (m, 4H), 7.57–7.64 (m, 2H), 7.80
(s, 1H), 8.09 (d, J = 8.4 Hz, 1H); 13C NMR (CDCl3, 75 MHz) d 28.08, 34.75, 51.77,
51.90, 123.30, 125.25, 126.23, 127.26, 127.62, 127.63, 127.83, 128.81, 129.65,
132.96, 133.04, 136.29, 139.01, 140.50, 168.62, 173.23; ESIMS m/z 371
(M++Na). Anal. Calcd for C22H20O4: C, 75.84; H, 5.79. Found: C, 75.66; H, 5.92.
1d
1e
COOMe
COOMe
3e (61)
3a (60)
COPh
CN
Compound 4a: 3%; colorless oil; IR (film) 2243, 1744, 1736, 1366, 1229 cmÀ1
;
7
1H NMR (CDCl3, 300 MHz) d 2.45–2.93 (m, 4H), 3.65 (s, 3H), 3.66 (s, 3H), 7.44–
7.50 (m, 4H), 7.58–7.65 (m, 2H), 7.75–7.83 (m, 3H); 13C NMR (CDCl3, 75 MHz) d
30.28, 32.18, 51.78, 51.89, 53.75, 118.15, 128.09, 128.42, 128.88, 130.47,
131.23, 131.38, 133.44, 133.91, 136.93, 136.97, 167.41, 172.01, 197.28; ESIMS
m/z 388 (M++Na).
a
Conditions: 1 (1.0 mmol), 2 (5.0 equiv), Cs2CO3 (2.0 equiv, CH3CN, reflux, 20 h
(8 h for entry 3).
b
Compound 8a: 7%; white solid, mp 125–126 °C; IR (KBr) 2224, 1730, 1705,
3.0 equiv of 2c.
Ar is 4-methoxyphenyl.
1221 cmÀ1 1H NMR (CDCl3, 300 MHz) d 2.16–2.26 (m, 1H), 2.36–2.47 (m, 2H),
;
c
2.57–2.67 (m, 1H), 3.18 (d, J = 16.5 Hz, 1H), 3.25 (d, J = 16.5 Hz, 1H), 3.52 (s, 3H),
3.61 (s, 3H), 6.85 (dd, J = 7.5 and 1.2 Hz, 1H), 7.13–7.16 (m, 2H), 7.23 (td, J = 7.5
and 1.2 Hz, 1H), 7.35–7.45 (m, 4H), 7.61 (ddd, J = 7.5, 1.2, and 0.6 Hz, 1H); 13C
NMR (CDCl3, 75 MHz) d 30.19, 31.42, 34.40, 41.01, 51.74, 51.86, 121.85, 122.16,
126.33, 127.80, 128.13, 128.56, 128.74, 129.60, 129.87, 133.20, 133.28, 137.68,
145.46, 167.51, 172.23; ESIMS m/z 398 (M++Na).
Acknowledgments
Compound 9a: 4%; white solid, mp 147–149 °C; IR (KBr) 2241, 1726, 1437,
1250 cmÀ1 1H NMR (CDCl3, 300 MHz) d 3.65 (s, 3H), 7.26–7.29 (m, 2H), 7.48–
;
This research was supported by Basic Science Research Program
through the National Research Foundation of Korea (NRF) funded
by the Ministry of Education, Science and Technology (2009-
0070633). Spectroscopic data was obtained from the Korea Basic
Science Institute, Gwangju branch.
7.59 (m, 4H), 7.65–7.69 (m, 1H), 7.75–7.80 (m, 1H), 8.31–8.34 (m, 1H), 8.40 (s,
1H); 13C NMR (CDCl3, 75 MHz) d 52.40, 110.20, 117.16, 125.25, 127.51, 128.11,
128.12, 128.15, 128.79, 129.03, 130.03, 132.44, 132.65, 133.31, 137.41, 146.85,
166.67; ESIMS m/z 310 (M++Na).
Compound 3c: 69%; white solid, mp 176–177 °C; IR (KBr) 1447, 1306,
1146 cmÀ1 1H NMR (CDCl3, 300 MHz) d 3.56–3.76 (m, 4H), 6.82–6.85 (m,
;

S. H. Kim et al. / Tetrahedron Letters 51 (2010) 1592–1595
2H), 7.18–7.44 (m, 10H), 7.53–7.75 (m, 4H), 8.00–8.06 (m, 3H), 8.29 (s, 1H); 13
1595
C
8. The mechanism involving retro-Dields–Alder reaction of tricyclic compound 6a
to form the dihydronaphthalene derivative 7a with loss of CO2 could be ruled
out. Similar cyclo-reversions have been reported to occur at high temperature
(250–570 °C) under flash vacuum pyrolysis conditions, see: (a) Holland, J. M.;
Jones, D. W. J. Chem. Soc. (C) 1970, 536–540; (b) Spangler, R. J.; Beckmann, B. G.;
Kim, J. H. J. Org. Chem. 1977, 42, 2989–2996.
9. In the reaction of 1a and 2e, we isolated low yields of 4-(3-acetyl-4-
phenylnaphthalen-1-yl)butan-2-one (3f, 18%) and 3-acetyl-4-phenyl
naphthalene-1-carbonitrile (9f, 5%).
NMR (CDCl3, 75 MHz) d 26.18, 56.21, 122.87, 123.48, 127.07, 127.43, 127.51,
127.84, 128.10, 128.39, 128.84, 129.28, 129.48, 131.01, 132.50, 133.20, 134.02,
134.03, 134.18, 134.43, 136.52, 138.74, 140.89, 141.19; ESIMS m/z 535
(M++Na). Anal. Calcd for C30H24O4S2: C, 70.29; H, 4.72 Found: C, 70.51; H, 4.94.
Compound 12: 80%; orange solid, mp 234–235 °C; IR (KBr) 3447, 1709,
1209 cmÀ1
;
1H NMR (DMSO-d6, 300 MHz) d 2.69 (t, J = 7.5 Hz, 2H), 3.34 (t,
J = 7.5 H, 2H), 7.36–7.41 (m, 1H), 7.56 (s, 1H), 7.60–7.65 (m, 2H), 7.73–7.76 (m,
2H), 8.17–8.20 (m, 1H), 8.26 (d, J = 7.5 Hz, 1H), 8.66–8.70 (m, 1H), 12.20 (br s,
1H); 13C NMR (DMSO-d6 + CDCl3, 75 MHz) d 28.18, 34.45, 119.45, 122.96,
123.67, 124.91, 125.40, 127.18, 128.26, 128.27, 129.04, 131.01, 134.14, 134.30,
135.78, 138.91, 141.40, 144.76, 174.44, 194.36; ESIMS m/z 325 (M++Na). Anal.
Calcd for C20H14O3: C, 79.46; H, 4.67. Found: C, 79.17; H, 4.97.
Compound 3f: 18%; colorless oil; IR (KBr) 1719, 1711, 1686, 1678, 1366,
1356 cmÀ1 1H NMR (CDCl3, 300 MHz) d 1.91 (s, 3H), 2.22 (s, 3H), 2.96 (t,
;
J = 7.8 Hz, 2H), 3.42 (t, J = 7.8 Hz, 2H), 7.34–7.37 (m, 2H), 7.42–7.52 (m, 5H),
7.57–7.62 (m, 1H), 7.72 (d, J = 8.4 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H); 13C NMR
(CDCl3, 75 MHz) d 26.54, 30.06, 30.70, 44.06, 123.49, 124.04, 126.40, 127.39,
128.15, 128.27, 128.52, 130.70, 132.42, 132.75, 137.17, 137.28, 137.70, 138.38,
204.92, 207.54; ESIMS m/z 339 (M++Na).
Compound 13: 5%; reddish solid, mp 282–284 °C (decomp.); IR (KBr) 1713,
1632, 1570, 1215 cmÀ1 1H NMR (DMSO-d6 + CDCl3, 300 MHz)
; d 6.71 (d,
J = 9.6 Hz, 1H), 7.40–7.45 (m, 1H), 7.61 (td, J = 7.8 and 1.2 Hz, 1H), 7.71–7.77
(m, 2H), 7.90 (dd, J = 8.4 and 7.5 Hz, 1H), 7.91 (s, 1H), 8.08 (d, J = 7.8 Hz, 1H),
8.68 (dd, J = 7.2 and 1.2 Hz, 1H), 8.86 (dd, J = 8.4 and 1.2 Hz, 1H); 13C NMR
(DMSO-d6 + CDCl3, 75 MHz) d 123.82, 124.15, 124.50, 127.53, 128.15, 128.37,
128.50, 129.83, 130.17, 131.19, 131.49, 131.72, 132.29, 133.99, 134.76, 141.53,
143.31, 145.86, 184.69, 192.54; ESIMS m/z 305 (M++Na). Anal. Calcd for
C20H10O2: C, 85.09; H, 3.57. Found: C, 84.76; H, 3.89.
Compound 9f: 5%; white solid, mp 137–138 °C; IR (KBr) 2222, 1684 cmÀ1 1H
;
NMR (CDCl3, 300 MHz) d 1.92 (s, 3H), 7.34–7.38 (m, 2H), 7.54–7.62 (m, 4H),
7.75–7.80 (m, 2H), 8.13 (s, 1H), 8.31–8.34 (m, 1H); 13C NMR (CDCl3, 75 MHz) d
30.39, 110.47, 117.18, 125.38, 128.21, 128.32, 128.86, 129.09, 129.77, 130.13,
131.34, 131.96, 133.05, 136.76, 137.30, 143.48, 202.29; ESIMS m/z 294
(M++Na).
6. For the formation of a similar tricyclic intermediate by lactonization, see: Kim,
S. C.; Lee, K. Y.; Lee, H. S.; Kim, J. N. Tetrahedron 2008, 64, 103–109.
7. For the similar decarboxylative Michael addition, see: (a) Patil, N. T.; Huo, Z.;
Yamamoto, Y. J. Org. Chem. 2006, 71, 6991–6995; (b) Wang, C.; Tunge, J. A. Org.
Lett. 2005, 7, 2137–2139; (c) Okada, K.; Okamoto, K.; Morita, N.; Okubo, K.;
Oda, M. J. Am. Chem. Soc. 1991, 113, 9401–9402.
10. For the synthesis and biological activities of similar fluorenone and
perinaphthenone derivatives, see: (a) Zhang, X.; Larock, R. C. Org. Lett. 2005,
7, 3973–3976; (b) Waldo, J. P.; Zhang, X.; Shi, F.; Larock, R. C. J. Org. Chem. 2008,
73, 6679–6685. and further references cited therein; (c) Zhao, S.; Freeman, J. P.;
Szmuszkovicz, J. J. Org. Chem. 1992, 57, 4051–4053.