Expedient synthesis of highly substituted α-pyrones from Baylis-Hillman adducts and their conversion to poly-substituted aromatics

Article abstract of DOI:10.1016/j.tetlet.2009.06.124

An efficient synthetic protocol of fully substituted α-pyrones has been developed starting from the Baylis-Hillman adducts. Subsequent Diels-Alder reaction of the α-pyrones and DMAD produced poly-substituted aromatic compounds in high yields.

Full text of DOI:10.1016/j.tetlet.2009.06.124

Tetrahedron Letters 50 (2009) 5098–5101
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Tetrahedron Letters
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Expedient synthesis of highly substituted
a-pyrones from Baylis–Hillman
adducts and their conversion to poly-substituted aromatics
*
Eun Sun Kim, Ko Hoon Kim, Sung Hwan Kim, 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 protocol of fully substituted a-pyrones has been developed starting from the Bay-
Received 1 June 2009
Revised 16 June 2009
Accepted 19 June 2009
Available online 3 July 2009
lis–Hillman adducts. Subsequent Diels–Alder reaction of the
a-pyrones and DMAD produced poly-substi-
tuted aromatic compounds in high yields.
Ó 2009 Elsevier Ltd. All rights reserved.
Dedicated to the memory of the late
Professor Eung Kul Ryu whose vision,
passion in Organic, Medicinal Chemistry
was an inspiration for all
Keywords:
a-Pyrones
Baylis–Hillman adducts
Diels–Alder reaction
DMAD
DDQ
Recently, syntheses of a variety of acyclic and cyclic compounds
including various aromatic and heterocyclic compounds have been
carried out starting from the Baylis–Hillman adducts.1 Based on
the importance of poly-substituted aromatic compounds, the syn-
thesis of highly substituted benzenes and naphthalenes in a regio-
selective manner has been regarded as the most fruitful chemical
transformation in Baylis–Hillman chemistry.1
tions.2a,c,d,f Among the synthetic usefulness of
a-pyrones, Diels–Al-
der cycloaddition has been used as an efficient method to reach
highly substituted aromatic compounds.6
In these contexts, we decided to develop an efficient synthetic
method of highly substituted
a-pyrones 7 and their chemical
transformations including Diels–Alder reaction with DMAD
(dimethylacetylene dicarboxylate) to benzene derivatives 8 and
their oxidation with DDQ (1,2-dichloro-4,5-dicyanobenzoquinone)
to naphthalene derivatives 9 when R1-R2 is a cyclohexane moiety
(vide infra), as shown in Scheme 1. Our synthetic rationale of
a
-Pyrones have been used as important synthetic intermedi-
ates2–6 and are found in a wide variety of biologically interesting
natural substances.4 Thus, considerable efforts have been devoted
to the synthesis of
a
-pyrones2,5 and related compounds3 by
a-pyrone skeleton is a combination of the first introduction of a
numerous approaches involving transition metal-catalyzed reac-
suitable ketone derivative 2 at the secondary position of the Bay-
O
R1
R1
R1
R2
(2)
OH
COOMe
Br
R2
Ph
R2
Ph
R1
DABCO
R2
Ph
COOMe
COOMe
Ph
DMAD
COOMe
O
O
Ph
COOMe
O
1
B-H adduct
3
7
8
Scheme 1.
* 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 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.06.124

E. S. Kim et al. / Tetrahedron Letters 50 (2009) 5098–5101
5099
Table 1
Synthesis of starting materials 4a–h from 1 and 2a–h
R1
R1
1. DABCO (1.1 equiv)
CH3CN, rt, 30 min
LiOH (5.0 equiv)
aq THF, reflux, 24 h
R2
Ph
R2
Ph
O
COOH
O
1
COOMe
2. ketone 2 (1.2-3.0 equiv)
NaOH (1.2 equiv), rt, 24 h
4a-h (syn/anti mixture)
3a-h (syn/anti mixture)
Entry
Ketone 2a
3a–hb (%)
4a–hc (%)
1
2
3
4
5
6
7
8
Deoxybenzoin (2a)
Desoxyanisoin (2b)
Propiophenone (2c)
3a (78, 2:1)
3b (75, 2:1)
3c (62, 2:1)
3d (62, 3:2)
3e (60)
3f (54, 9:1)
3g (44, 2:1)
3h (45, 4:1)
4a (97)
4b (95)
4c (90)
4d (89)
4e (93)
4f (92)
4g (92)
4h (92)
a-Tetralone (2d)
Acetophenone (2e)
Cyclohexanone (2f)
4-Methlcyclohexanone (2g)
4-Phenylcyclohexanone (2h)
a
Ketone 2a–d (1.2 equiv) and ketone 2e–h (3.0 equiv) were used.
The ratio of syn/anti is arbitrary and measured in 1H NMR.
Crude product (syn/anti mixture) and not characterized.
b
c
Table 2
Synthesis of
Table 2 (continued)
a
-pyrones 7a–h from 4a–h
Entry
5 (%)
7 (%)
R1
R1
DBU (0.5 equiv)
CH3CN, rt, 1 h
TFAA (2.0 equiv)
CH2Cl2, rt, 2 h
R2
Ph
R2
Ph
O
O
O
O
O
4a-h
6
O
O
Ph
O
Ph
O
Ph
O
7a-h
5a-h
7f (56)b
+ 6f (22)b
5f + 6f (70)a
Entry
5 (%)
7 (%)
Ph
Ph
Ph
Ph
Ph
O
O
O
O
O
1
2
3
7
8
Ph
O
O
Ph
O
Ph
O
Ph
O
7g (40)b
5a (91)
7a (87)
5g + 6g (84)a
+ 6g (22)b
OMe
OMe
Ph
Ph
Ph
Ph
Ph
O
O
O
MeO
MeO
b
O
O
7h (42)
Ph
5h + 6h (68)a
O
+ 6h (21)b
O
O
Ph
O
Ph
O
aInseparable mixture of 5f–h and 6f–h.
5b (88)
7b (74)
bSee Scheme 2.
Ph
Ph
lis–Hilman adduct via the DABCO salt concept7 and the following
cyclization to
-pyrone as reported previously.5
O
O
a
As summarized in Table 1, synthesis of starting materials d-keto
acids 4a–h was carried out by the following sequential processes:
(i) synthesis of cinnamyl bromide 1 from Baylis–Hillman adduct as
reported,8 (ii) introduction of various ketone derivatives 2a–h at
the secondary position of the Baylis–Hillman adduct via the DABCO
salt of 1 to form 3a–h,7,9 and (iii) hydrolysis of 3a–h with LiOH in
aqueous THF to make 4a–h.9 The d-keto esters 3a–h and d-keto
acids 4a–h were obtained as an inseparable syn/anti mixture and
we used them in the next cyclization without separation.
Ph
O
Ph
O
7c (78)
5c (83)
4
O
O
O
O
Ph
Ph
O
5d (90)
Ph
Ph
O
With d-keto acids 4a–h, we synthesized a-pyrones 7a–h via the
7d (74)
sequential lactonization of 4a–h with TFAA to methylene lactones
5a–h and the following DBU-catalyzed isomerization.9,10 The re-
sults are summarized in Table 2. The yields of methylene lactones
5a–e were good (83–91%) and the following DBU-catalyzed isom-
Ph
Ph
5
erization produced
a-pyrones 7a–e in good yields (74–87%) also.
O
O
However, exo-methylene compounds 6f–h were formed together
in appreciable amounts during the synthesis of 5f–h (entries
6–8) and the separation of 5f–h/6f–h was very difficult. However,
5e (85)
7e (85)

5100
E. S. Kim et al. / Tetrahedron Letters 50 (2009) 5098–5101
R
R
6
4a
TFAA, CH2Cl2
DBU (0.5 equiv)
O
O
H
4f-h
+
+
7f-h
6f-h
4
CH3CN, rt, 1 h
Ph
O
Ph
O
J = 12.9 Hz
R = H, Me, Ph
6f = 22% (single isomer)
6g = 22% (1:1 mixture)
6h = 21% (1:1 mixture)
7f = 56%
7g = 40%
7h = 42%
H
5f-h
H
J = 2.7 Hz
6f-h
5f + 6f = 70% (inseparable)
5g + 6g = 84% (inseparable)
5h + 6h = 68% (inseparable)
Scheme 2.
Ph
Ph
O
COOMe
R
R
COOMe
O
Ph
- CO2
p-xylene, 180 ºC
sealed tube, 25 h
+
O
R
COOMe
Ph
O
Ph
COOMe
COOMe
Ph
COOMe
7a (R = Ph)
7e (R = H)
8a (R = Ph, 98%)
8e (R = H, 94%)
Scheme 3.
DMAD (3.0 equiv)
xylene, 180 ºC, 24 h
DDQ (2.0 equiv)
ODCB, 140 ºC, 2 h
COOMe
COOMe
8d (94%)
COOMe
COOMe
7d
sealed tube
Ph
Ph
9d (93%)
Scheme 4.
R
R
DMAD (3.0 equiv)
xylene, 180 ºC, 24 h
DDQ (3.0 equiv)
ODCB, 140 ºC, 2 h
COOMe
COOMe
COOMe
COOMe
sealed tube
(for 7f-g)
R
Ph
Ph
O
8f: 96% (R = H)
8g: 96% (R = Me)
8h: 99% (R = Ph)
9f: 66% (R = H)
9g: 65% (R = Me)
9h: 68% (R = Ph)
Ph
O
7f-h
DMAD (3.0 equiv)
xylene, 180 ºC, 48 h
DDQ (3.0 equiv)
ODCB, 140 ºC, 2 h
O
no reaction
sealed tube
(for 7f)
Ph
10 (72%)
O
Scheme 5.
treatment of the mixture 5f/6f with DBU produced desired
a
-pyr-
the [4+2] cycloaddition and concomitant decarboxylation process
(Scheme 3).6 Compound 8e was synthesized from 7e in 94% simi-
larly. Diels–Alder reaction of 7d and DMAD also produced 8d
(94%), which was converted into phenanthrene derivative 9d via
oxidation with DDQ in o-dichlorobenzene (ODCB) in 93% (Scheme
4). Cyclohexane-fused compounds 7f–h were also converted into
naphthalene derivatives 9f–h, via the sequential Diels–Alder reac-
tion with DMAD to 8f–h (96–99%) and the following oxidation
with DDQ (Scheme 5). It is interesting to note that oxidation of
7f with DDQ produced compound 10, however, Diels–Alder reac-
tion of 10 and DMAD did not produce compound 9f at all, as de-
picted also in Scheme 5.
one 7f (56%). During the isomerization process, 6f (22%) was recov-
ered without change very fortunately as schematically explained in
Scheme 2. The situation was same for the mixtures 5g/6g and 5h/
6h. Compound 6f was obtained as a single isomer while 6g and 6h
were a diastereomeric mixture (1:1) due to the presence of the
substituent -R at 6-position.11 In 1H NMR spectrum of compound
6f, as an example, the proton at 4-position (d = 3.36 ppm) coupled
with the proton at 4a-position with a large coupling constant
(J = 12.9 Hz), which stated that the two protons are in trans-rela-
tionships, as shown in Scheme 2.
As a next trial, we examined the synthesis of fully substituted
aromatic compounds with the synthesized
a-pyrone derivatives
In summary, we developed an efficient synthetic protocol of
(Schemes 3–5). The reaction of 7a and DMAD in p-xylene in a
sealed tube afforded a fully substituted benzene 8a in 98% via
poly-substituted
a-pyrones including chromen-2-one. In addition,
we prepared various aromatic compounds including poly-substi-

E. S. Kim et al. / Tetrahedron Letters 50 (2009) 5098–5101
5101
and extracted with CH2Cl2 (50 mL). Drying with MgSO4 and removal of solvent
provided compound 4a as a white solid in a crude state, 691 mg (97%). To the
crude 4a (534 mg, 1.5 mmol) in CH2Cl2 (4 mL) was added TFAA (630 mg,
3.0 mmol) and stirred at room temperature (20–25 °C) for 2 h. After the usual
aqueous extractive workup and column chromatographic purification process
(hexanes/ether, 10:1) compound 5a was isolated as a white solid, 461 mg (91%).
Compound 5a (338 mg, 1.0 mmol) in CH3CN (3 mL) was treated with DBU (76 mg,
0.5 mmol) and stirred at room temperature (20–25 °C) for 1 h. After the usual
aqueous extractive workup and column chromatographic purification process
(hexanes/CH2Cl2/ether, 15:1:1) compound 7a was isolated as a white solid,
tuted benzenes, naphthalene, and phenanthrene from the prepared
-pyrones by using DDQ oxidation and/or Diels–Alder reaction
with DMAD.
a
Acknowledgments
This work was supported by the Korea Research Foundation
Grant funded by the Korean Government (MOEHRD, KRF-2008-
313-C00487). Spectroscopic data were obtained from the Korea Ba-
sic Science Institute, Gwangju branch.
294 mg (87%).
A mixture of 7a (169 mg, 0.5 mmol) and DMAD (213 mg,
1.5 mmol) in p-xylene (1 mL) was heated to 180 °C in a sealed tube for 25 h.
After removal of solvent and column chromatographic purification process
(hexanes/CH2Cl2/ether, 15:1:1) compound 8a was isolated as a white solid,
214 mg (98%). Other compounds were synthesized analogously and
representative spectroscopic data of 7a, 7b, 7d, 7f, 6f, 8a, 8d, 9d, and 9h are as
follows. Known compounds, 7c,2a 7e,2a 8f,6a and 103a were identified by
comparison with the reported data.
References and notes
1. For the general review on Baylis–Hillman reaction, see: (a) Basavaiah, D.; Rao, A.
J.; Satyanarayana, T. Chem. Rev. 2003, 103, 811–891; (b) Singh, V.; Batra, S.
Tetrahedron 2008, 64, 4511–4574; (c) Declerck, V.; Martinez, J.; Lamaty, F. Chem.
Rev. 2009, 109, 1–48; (d) Ciganek, E.. In Organic Reactions; Paquette, L. A., Ed.; John
Wiley & Sons: New York, 1997; Vol. 51, pp 201–350; (e) Basavaiah, D.; Rao, P. D.;
Hyma, R. S. Tetrahedron 1996, 52, 8001–8062; (f) Drewes, S. E.; Roos, G. H. P.
Tetrahedron 1988, 44, 4653–4670; (g) Kim, J. N.; Lee, K. Y. Curr. Org. Chem. 2002, 6,
627–645; (h) Lee, K. Y.; Gowrisankar, S.; Kim, J. N. Bull. Korean Chem. Soc. 2005, 26,
1481–1490; (i) Langer, P. Angew. Chem., Int. Ed. 2000, 39, 3049–3052; (j) Krishna,
P. R.; Sachwani, R.; Reddy, P. S. Synlett 2008, 2897–2912.
Compound 7a: 87%; white solid, mp 176–178 °C; IR (KBr) 1712, 1540, 1489 cmÀ1
;
1H NMR (CDCl3, 300 MHz) d 1.98 (s, 3H), 6.81–6.92 (m, 4H), 6.98–7.08 (m, 3H),
7.12–7.29 (m, 8H); 13C NMR (CDCl3, 75 MHz) d 14.63, 119.37, 121.13, 127.05,
127.53, 127.81, 127.91, 128.00, 128.27, 129.14 (2C), 131.19, 132.73, 135.15,
136.57, 154.59, 154.61, 163.46; ESIMS m/z 339 (M++1). Anal. Calcd for C24H18O2:
C, 85.18; H, 5.36. Found: C, 85.01; H, 5.49.
Compound 7b: 74%; pale yellow solid, mp 202–204 °C; IR (KBr) 1705, 1606,
1504 cmÀ1 1H NMR (CDCl3, 300 MHz) d 1.95 (s, 3H), 3.69 (s, 3H), 3.75 (s, 3H),
;
6.55–6.60 (m, 2H), 6.67–6.75 (m, 4H), 6.87–6.91 (m, 2H), 7.14–7.26 (m, 5H); 13C
NMR (CDCl3, 75 MHz) d 14.57, 55.00, 55.17, 113.28, 113.56, 117.96, 120.13,
125.29, 127.41, 127.61, 127.93, 128.25, 130.62, 132.26, 136.89, 154.62, 155.19,
158.38, 160.02, 163.66; ESIMS m/z 399 (M++1). Anal. Calcd for C26H22O4: C, 78.37;
H, 5.57. Found: C, 78.62; H, 5.44.
2. For the synthesis of
a-pyrone derivatives, see: (a) Kuninobu, Y.; Kawata, A.;
Nishi, M.; Takata, H.; Takai, K. Chem. Commun. 2008, 6360–6362; (b) Yao, T.;
Larock, R. C. J. Org. Chem. 2003, 68, 5936–5942; (c) Larock, R. C.; Doty, M. J.; Han,
X. J. Org. Chem. 1999, 64, 8770–8779; (d) Larock, R. C.; Han, X.; Doty, M. J.
Tetrahedron Lett. 1998, 39, 5713–5716; (e) Bellina, F.; Biagetti, M.; Carpita, A.;
Rossi, R. Tetrahedron 2001, 57, 2857–2870; (f) Biagetti, M.; Bellina, F.; Carpita,
A.; Stabile, P.; Rossi, R. Tetrahedron 2002, 58, 5023–5038; (g) Zhu, X.-F.;
Schaffner, A.-P.; Li, R. C.; Kwon, O. Org. Lett. 2005, 7, 2977–2980; (h) Ma, S.; Yu,
S.; Yin, S. J. Org. Chem. 2003, 68, 8996–9002; (i) Ma, S.; Yin, S.; Li, L.; Tao, F. Org.
Lett. 2002, 4, 505–507.
Compound 7d: 74%; yellow solid, mp 172–174 °C; IR (KBr) 1697, 1629,
1530 cmÀ1 1H NMR (CDCl3, 300 MHz) d 1.92 (s, 3H), 2.31 (t, J = 7.8 Hz, 2H),
;
2.78 (t, J = 7.8 Hz, 2H), 7.12–7.18 (m, 3H), 7.25–7.34 (m, 2H), 7.39–7.51 (m, 3H),
7.88–7.91 (m, 1H); 13C NMR (CDCl3, 75 MHz) d 14.50, 23.39, 27.49, 112.64,
120.98, 123.04, 127.04, 127.47, 127.56, 128.24, 128.37, 128.77, 129.65, 136.14,
136.69, 151.64, 153.90, 163.40; ESIMS m/z 289 (M++1). Anal. Calcd for C20H16O2:
C, 83.31; H, 5.59. Found: C, 83.24; H, 5.76.
3. For the synthesis of coumarin and isocoumarin derivatives, see: (a) Park, K. H.;
Jung, I. G.; Chung, Y. K. Synlett 2004, 2541–2544; (b) Kadnikov, D. V.; Larock, R.
C. J. Org. Chem. 2003, 68, 9423–9432; (c) Kadnikov, D. V.; Larock, R. C. Org. Lett.
2000, 2, 3643–3646.
Compound 7f: 56%;colorless oil; IR (film) 1712, 1642, 1558 cmÀ1;1H NMR (CDCl3,
300 MHz) d 1.56–1.64 (m, 2H), 1.66–1.80 (m, 2H), 1.82 (s, 3H), 1.93–1.97 (m, 2H),
2.55–2.59 (m, 2H), 7.06–7.10 (m, 2H), 7.35–7.47 (m, 3H); 13C NMR (CDCl3,
75 MHz) d 13.95, 21.68, 22.29, 25.18, 27.47, 112.50, 119.58, 127.29, 127.96,
128.60, 136.37, 154.50, 156.07, 164.19; ESIMS m/z 241 (M++1).
4. For the synthesis and biological activities of
a-pyrone moiety-containing
substances, see: (a) Oh, D.-C.; Gontang, E. A.; Kauffman, C. A.; Jensen, P. R.;
Fenical, W. J. Nat. Prod. 2008, 71, 570–575; (b) Trisuwan, K.; Rukachaisirikul, V.;
Sukpondma, Y.; Preedanon, S.; Phongpaichit, S.; Rungjindamai, N.; Sakayaroj, J. J.
Nat. Prod. 2008, 71, 1323–1326; (c) Aly, A. H.; Edrada-Ebel, R.; Wray, V.; Muller,
W. E. G.; Kozytska, S.; Hentschel, U.; Proksch, P.; Ebel, R. Phytochemistry 2008, 69,
1716–1725; (d) Cutignano, A.; Fontana, A.; Renzulli, L.; Cimino, G. J. Nat. Prod.
2003, 66, 1399–1401; (e) Sata, N.; Abinsay, H.; Yoshida, W. Y.; Horgen, F. D.;
Sitachitta, N.; Kelly, M.; Scheuer, P. J. J. Nat. Prod. 2005, 68, 1400–1403.
Compound 6f: 22%; colorless oil; IR (film) 1739, 1680, 1237, 1166 cmÀ1 1H NMR
;
(CDCl3, 300 MHz) d 1.10–1.26 (m, 1H), 1.34–1.49 (m, 1H), 1.53–1.71 (m, 2H),
2.03–2.16 (m, 2H), 2.67–2.77 (m, 1H), 3.36 (dt, J = 12.9 and 2.7 Hz, 1H), 5.13 (dd,
J = 2.7 and 1.2 Hz, 1H), 5.49–5.52 (m, 1H), 6.56 (dd, J = 2.7 and 1.2 Hz, 1H), 7.13–
7.17 (m, 2H), 7.28–7.41 (m, 3H); 13C NMR (CDCl3, 75 MHz) d 20.96, 23.41, 28.31,
37.79, 50.22, 107.33, 127.53, 128.76, 128.94, 130.19, 138.74, 138.78, 150.03,
162.73; ESIMS m/z 241 (M++1).
Compound 8a: 98%; white solid, mp 159–162 °C; IR (KBr) 1736, 1219 cmÀ1 1H
;
5. For the synthesis of
a-pyrones and their derivatives from Baylis–Hillman
adducts, see: (a) Kim, S. J.; Lee, H. S.; Kim, J. N. Tetrahedron Lett. 2007, 48, 1069–
1072; (b) Kim, S. C.; Lee, H. S.; Kim, J. N. Bull. Korean Chem. Soc. 2007, 28, 147–
150; (c) Singh, V.; Madapa, S.; Batra, S. Synth. Commun. 2008, 38, 2113–2124; d
Zhong, W.; Su, W.; Zhao, Y. Faming Zhuanli Shenqing Gongkai Shuomingshu
2007, CN 10069825 (Chem. Abstr. 2008, 148, 121588).
NMR (CDCl3, 300 MHz) d 2.18 (s, 3H), 3.46 (s, 3H), 3.91 (s, 3H), 6.65–6.71 (m, 2H),
6.79–6.87 (m, 3H), 6.92–7.19 (m, 10H); 13C NMR (CDCl3, 75 MHz) d 18.28, 52.09,
52.56, 125.83, 126.58, 126.62, 126.69, 127.17, 127.71, 129.69, 129.84, 130.57,
131.41, 132.03, 133.94, 137.77, 138.63, 138.71, 139.38, 143.33, 144.46, 168.82,
168.97; ESIMS m/z 437 (M++1). Anal. Calcd for C29H24O4: C, 79.80; H, 5.54. Found:
C, 79.97; H, 5.78.
6. For the synthesis of poly-substituted aromatic compounds from a-pyrones by
Compound 8d: 94%; white solid, mp 174–175 °C; IR (KBr) 1736, 1221 cmÀ1 1H
;
Diels–Alder reaction, see: (a) Kuninobu, Y.; Takata, H.; Kawata, A.; Takai, K. Org.
Lett. 2008, 10, 3133–3135; (b) Kuninobu, Y.; Kawata, A.; Nishi, M.; Takata, H.;
Takai, K. Chem. Commun. 2008, 6360–6362; (c) Tolmachova, N. A.; Gerus, I. I.;
Vdovenko, S. I.; Essers, M.; Frohlich, R.; Haufe, G. Eur. J. Org. Chem. 2006, 4704–
4709; (d) Cho, C.-G.; Kim, Y.-W.; Lim, Y.-K.; Park, J.-S.; Lee, H.; Koo, S. J. Org.
Chem. 2002, 67, 290–293; (e) Komiyama, T.; Takaguchi, Y.; Tsuboi, S. Synth.
Commun. 2007, 37, 533–536; (f) Afarinkia, K.; Vinader, V.; Nelson, T. D.; Posner,
G. H. Tetrahedron 1992, 48, 9111–9171. and further references cited therein.
7. For the regioselective introduction of nucleophiles at the secondary positions of
Baylis–Hillman adducts by using the DABCO salt concept, see: (a) Kim, J. N.;
Kim, J. M.; Lee, K. Y.; Gowrisankar, S. Bull. Korean Chem. Soc. 2004, 25, 1733–
1736; (b) Gowrisankar, S.; Lee, H. S.; Kim, J. M.; Kim, J. N. Tetrahedron Lett. 2008,
49, 1670–1673.
8. The cinnamyl bromides were prepared by treatment of the Baylis–Hillman
alcohols with aqueous HBr according to the literature procedure, see: (a)
Buchholz, R.; Hoffmann, H. M. R. Helv. Chim. Acta 1991, 74, 1213–1220; (b)
Ameer, F.; Drewes, S. E.; Emslie, N. D.; Kaye, P. T.; Mann, R. L. J. Chem. Soc.,
Perkin Trans. 1 1983, 2293–2295.
9. Typical procedure for the synthesis of 3a, 4a, 7a, and 8a: A mixture of cinnamyl
bromide 1 (765 mg, 3.0 mmol) and DABCO (370 mg, 3.3 mmol) in CH3CN (5 mL)
was stirred for 30 min at room temperature (20–25 °C). To the reaction mixture
deoxybenzoin (2a, 706 mg, 3.6 mmol) and NaOH (144 mg, 3.6 mmol) were
added and stirred further for 24 h at room temperature (20–25 °C). After the
usual aqueous extractive workup and column chromatographic purification
process (hexanes/CH2Cl2/ether, 15:1:1) compound 3a was isolated as a white
solid, 866 mg (78%, syn/anti mixture). Compound 3a (740 mg, 2.0 mmol) was
dissolved in aqueous THF (H2O/THF, 1:1, 5 mL) and LiOH (420 mg, 10 mmol) was
added and the reaction mixture was heated to reflux for 24 h. After cooling to
room temperature, the reaction mixture was acidified with dilute HCl solution
NMR (CDCl3, 300 MHz) d 2.07 (s, 3H), 2.38–2.42 (m, 2H), 2.64–2.69 (m, 2H), 3.76
(s, 3H), 3.91 (s, 3H), 7.07–7.14 (m, 2H), 7.17–7.25 (m, 3H), 7.33–7.49 (m, 4H); 13C
NMR (CDCl3, 75 MHz) d 17.90, 27.71, 28.85, 52.46, 52.53, 126.38, 126.63, 127.37,
127.50, 127.83, 128.53, 128.76, 128.79, 131.71, 131.87, 132.98, 133.15, 138.48,
139.64, 140.23, 143.12, 169.34, 170.53; ESIMS m/z 387 (M++1). Anal. Calcd for
C25H22O4: C, 77.70; H, 5.74. Found: C, 77.89; H, 5.48.
Compound 9d: 93%; white solid, mp 67–69 °C; IR (KBr) 1736, 1282 cmÀ1 1H NMR
;
(CDCl3, 300 MHz) d 2.21 (s, 3H), 3.97 (s, 3H), 3.98 (s, 3H), 7.20–7.25 (m, 3H), 7.43–
7.61 (m, 6H), 7.80–7.84 (m, 1H), 8.19–8.23 (m, 1H); 13C NMR (CDCl3, 75 MHz) d
18.06, 52.73, 52.92, 124.64, 125.58, 125.77, 126.27, 127.06, 127.60, 128.45,
128.57, 128.68, 128.72, 128.92, 129.74, 130.74, 132.27, 132.43, 132.70, 139.05,
142.27, 169.58, 171.47; ESIMS m/z 385 (M++1). Anal. Calcd for C25H20O4: C, 78.11;
H, 5.24. Found: C, 78.05; H, 5.49.
Compound 9h: 68%; colorless oil; IR (film) 1732, 1212 cmÀ1 1H NMR (CDCl3,
;
300 MHz) d 2.22 (s, 3H), 3.96 (s, 3H), 4.04 (s, 3H), 7.24–7.56 (m, 11H), 7.77 (dd,
J = 8.7 and 1.8 Hz, 1H), 8.27 (d, J = 8.7 Hz, 1H); 13C NMR (CDCl3, 75 MHz) d 18.39,
52.58, 52.76, 124.58, 126.23, 126.49, 127.30, 127.35, 127.64, 127.71, 128.71,
128.81 (2C), 129.74, 130.16, 132.22, 133.83, 138.70, 139.88, 140.45, 142.87,
168.22, 169.25; ESIMS m/z 411 (M++1). Anal. Calcd for C27H22O4: C, 79.01; H, 5.40.
Found: C, 79.33; H, 5.74.
10. For DBU-mediated isomerization, see: (a) Kim, K. H.; Lee, H. S.; Kim, J. N.
Tetrahedron Lett. 2009, 50, 1249–1251; (b) Kim, S. C.; Lee, H. S.; Lee, Y. J.; Kim, J.
N. Tetrahedron Lett. 2006, 47, 5681–5685; (c) Lee, M. J.; Lee, K. Y.; Gowrisankar,
S.; Kim, J. N. Tetrahedron Lett. 2006, 47, 1355–1358.
11. It is interesting to note that the phenyl group at 4-position of 7g and 7h showed
the presence of six carbon peaks in their 13C NMR spectrum, presumably due to
an asymmetry effect provided by the substituent at 6-position (–CH3 or phenyl).
The situation is same for the phenyl group of compounds 8g and 8h.