One-pot pyrrolidine-catalyzed synthesis of benzopyrans, benzothiopyranes, and dihydroquinolidines

Article abstract of DOI:10.2533/chimia.2007.219

A simple catalytic racemic synthesis of benzopyranes, benzothiopyranes and 1,2-dihydroquinolines is presented. The organocatalytic domino reactions between 2-heteroatom substituted aldehyde derivatives and α,β-unsaturated aldehydes or α,β-unsaturated cycl

Full text of DOI:10.2533/chimia.2007.219

ORGANOCATALYSIS
219
doi:10.2533/chimia.2007.219
CHIMIA 2007, 61, No. 5
Chimia 61 (2007) 219–223
© Schweizerische Chemische Gesellschaft
ISSN 0009–4293
One-Pot Pyrrolidine-Catalyzed Synthesis
of Benzopyrans, Benzothiopyranes, and
Dihydroquinolidines
Ismail Ibrahem, Henrik Sundén, Ramon Rios, Gui-Ling Zhao, and Armando Córdova*
Abstract: A simple catalytic racemic synthesis of benzopyranes, benzothiopyranes and 1,2-dihydroquinolines is
presented. The organocatalytic domino reactions between 2-heteroatom substituted aldehyde derivatives and
α,β-unsaturated aldehydes or α,β-unsaturated cyclic ketones proceed with excellent chemoselectivity to give the
corresponding products in good to high yields.
O
O
O
N
H
R1
H
R1
R2
XH
X
R2
X= NH, S, O
high chemoselectivity
up to 91% yield
Keywords: Asymmetric synthesis · Organocatalytic domino reactions · Pyrrolidine
Introduction
4
R
O
O
3
O
H O
R
O
Heterocycles are of immense importance
in the design and discovery of new com-
pounds for pharmaceutical applications.[1]
Benzopyranes,[2] benzothiopyranes[3] and
dihydroquinolines[4] are valuable com-
pounds that have attracted much attention
from a broad area of science, including me-
dicinal chemistry, physical chemistry, syn-
thetic organic chemistry and natural prod-
uct chemistry due to their biological activi-
ties, distinctive structures and the potential
N
H
-H O
2
1
H
1
R
1
R
R
( 1)
2
XH
2
R
3
2
X
R
R
X
R
3
R
X=NH, O, S
Scheme 1.
an elegant route to tetrahydroxanthenones
and chromenes based on the 1,4-diazabicy-
clo[2.2.2]octane (DABCO) mediated reac-
tion between salicylic aldehyde derivatives
and α,β-unsaturated ketones and aldehydes,
hydrothioxanthenone derivatives based on
this concept.[10] Encouraged by the research
on organocatalytic domino reactions, we
envisioned a simple catalytic route to the
synthesis of different heterocycles by or-
for further transformations. Thus, several
methods have been developed for the syn-
thesis of this type of heterocycle.[5] In this
context, Bräse and co-workers described
respectively. This reaction proceeds via a
ganocatalytic domino reactions between
Baylis-Hillman reaction pathway.[6] More
recently, Shi and co-workers reported a new
approach to the synthesis of tetrahydroxan-
thenones using N-tosylimines as substrates
and dimethylphenylphosphine as the cata-
lyst.[7]
2-heteroatom substituted benzaldehydes 1
and enals 2 or cyclic enones 3 via iminium
and enamine activation (Scheme 1).
Herein, we present the one-pot pyrro-
lidine-catalyzed synthesis of chromenes,
thiochromenes,
1,2-dihydroquinolines,
Recently, organocatalytic asymmetric
transformations that involve catalytic dom-
ino or cascade reactions via enamine and
iminium intermediates were reported.[8,9]
However, to the best of our knowledge,
there are no reports on the synthesis of ra-
cemic chromene, thiochromene, dihydro-
quinoline, tetrahydroxanthenone and tetra-
tetrahydroxanthenones and tetrahydrothio-
xanthenones in good to excellent yields.
*Correspondence: Prof. Dr. A. Córdova
Department of Organic Chemistry
Arrhenius Laboratory
Stockholm University
SE-106 91 Stockholm
Sweden
Fax: +64 8 154 908
E-Mail: acordova1a@netscape.net
Results and Discussion
In an initial screen, we found that pyr-
rolidine catalyzed the reaction between

ORGANOCATALYSIS
220
CHIMIA 2007, 61, No. 5
Table 1. Direct organocatalytic domino oxo-Michael/aldol condensation
between hydroxybenzaldehydes 1 and α,β-unsaturated aldehydes 2a
Table 2. Direct organocatalytic domino thia-Michael/aldol condensation
between 2-mercaptobenzaldehyde 1c and α,β-unsaturated aldehydes 2a
R 1
R 1
pyrrolidine (35 mol%)
pyrrolidine (35 mol%)
benzoic acid (35 mol%)
R 2
R 3
CHO
R 5
R 2
R 3
CHO
OH
CHO
benzoic acid (35 mol%)
CHO
R
CHO
SH
CHO
+
+
R 5
DMSO, rt, 3h
DMSO, rt, 3h
O
S
R
R 4
R 4
1c
2
5
1
2
4
Yieldb
86%
Yieldb
60%
ꢀꢁꢂ unsaturated aldehyde
Product
Product
Entry
Aldehyde
Entry
Salicylic Aldehyde
enal
CHO
CHO
CHO
SH
CHO
CHO
CHO
1
1
S
O
OH
2a
2a
5a
4a
1c
1c
1a
CHO
Naph
CHO
Naph
CHO
CHO
2
86%
2
1a
34%
S
5b
O
4b
2b
2b
CHO
CHO
CHO
CHO
3
4
1c
1c
82%
48%
3
4
1a
1a
70%
42%
S
O
Cl
Cl
2c
2c
2d
2a
2b
Cl
Cl
5c
4c
CHO
CO2Et
CHO
CHO
CHO
CHO
EtO2C
EtO2C
2d
S
O
CO2Et
5d
4d
CHO
MeO
MeO
CHO
MeO
CHO
OH
S
5
6
5
6
73%
69%
73%
68%
NC
1c
1c
O
2e
5e
CN
1b
1b
4e
CHO
n-Bu
CHO
Naph
CHO
n-Bu
S
2f
O
5f
4f
MeO
CHO
CHO
CHO
7
8
1b
1b
2c
2d
75%
49%
O
4g
7
1c
64%
S
5g
2g
O2N
Cl
NO2
MeO
CHO
O
CO2Et
4h
aExperimental conditions: A mixture of 1 (0.3 mmol), 2 (0.25 mmol),
benzoic acid (35 mol%) and pyrrolidine (35 mol%) in 1 ml of DMSO was
stirred at room temperature. bIsolated yield of pure compound 4.
aExperimental conditions: A mixture of 1c (0.3 mmol), 2 (0.25 mmol),
benzoic acid (35 mol%) and pyrrolidine (35 mol%) in 1 ml of DMSO was
stirred at room temperature. bIsolated yield of pure compound 5.
2-hydroxybenzaldehyde 1a (0.30 mmol)
and cinnamic aldehyde 2a (0.25 mmol) with
high chemoselectivity in different solvents
to give the corresponding chromene 4a in
high yields. For instance thiochromene 5b
was assembled in 86% yield.
a highly chemoselective catalyst for this
domino aza-Michael/aldol condensation
reaction.
Next, we explored the scope of the pyr-
rolidine-catalyzed domino reaction using
Encouraged by the reports of the Hama-
da group,[5v–w] we next investigated the
good yields. To our delight, we found that
domino reaction between 2-aminobenzal-
the best results were obtained in DMSO
with pyrrolidine as the catalyst (35 mol%)
and benzoic acid (35 mol%) as the additive
at room temperature. Under these condi-
tions, pyrrolidine catalyzed the formation
dehydes derivatives and α,β-unsaturated al-
α,β-unsaturated ketones as the substrates.
dehydes (Table 3). This is a more challeng-
We first investigated the reaction between
ing reaction, since competing imine forma-
tion could possibly occur (Scheme 2).
Happily, the reactions proceeded
2-mercaptobenzaldehyde 1c and 2-cyclo-
hexene-1-one 3a. After screening several
reaction conditions, we found that the best
results were obtained when pyrrolidine (20
mol%) was used as the catalyst and benzoic
of the corresponding chromene 4a in 60% smoothly and the corresponding racemic
yield. Encouraged by this result, we decid-
ed to investigate the catalytic domino oxo-
Michael/aldol reaction between 1a and dif-
1,2-dihydroquinolines 6 were assembled
in 56–79 % yield. Thus, pyrrolidine was
acid (20 mol%) was used as an additive in
ferent α,β-unsaturated aldehydes (Table 1).
The reactions were highly chemoselec-
O
tive and gave the corresponding chromene-
H
3-carbaldehydes 4a–4h in moderate to high
yields. We next investigated the domino
reaction between 2-mercaptobenzaldehyde
1c and α,β-unsaturated aldehydes 2 vide in-
O
O
+
N
N
R1
H
N
H
H
H
H
O
NH2
H
(2)
R1
Not
NH2
R1
Enal
R
fra (Table 2).
R
H2 N
Nucleophile only
The reactions were more efficient com-
II
I
pared to the domino reactions with 2-hy-
droxybenzaldehyde and furnished the cor-
responding thiochromenes derivatives 5 in
R1
Scheme 2.

ORGANOCATALYSIS
221
CHIMIA 2007, 61, No. 5
Table 3. Direct organocatalytic domino aza-Michael/aldol condensation
between 2-aminobenzaldehydes 1 and α,β-unsaturated aldehydes 2a
Table 4. Direct organocatalytic domino thio-Michael/aldol condensation
between 2-mercaptobenzaldehyde 1 and α,β-unsaturated ketones 3a
pyrrolidine (35 mol%)
O
CHO
R
CHO
NH2
CHO
pyrrolidine (20 mol%)
O
benzoic acid (35 mol%)
CHO
benzoic acid (20 mol%)
+
R 1
R 1
DMSO, rt, 3h
N
H
+
R
R 1
R 1
CHCl3, rt, 14h
S
R 2
SH
R 2
1c
1
2
6
1c
3
7
Product
Entry
Aldehyde
Yieldb
79%
ꢀꢁꢂ unsaturated aldehyde
Product
Entry
Aldehyde
Yieldb
83%
ꢀꢁꢂ unsaturated Ketone
CHO
O
O
CHO
CHO
CHO
SH
1
2
N
1
H
NH2
Cl
2c
6a
S
Cl
7a
1d
3a
1c
1c
CHO
CHO
O
O
CHO
1d
67%
60%
65%
2
3
59%
82%
91%
N
H
O2N
2g
2e
6b
S
NO2
3b
7b
7c
O
CHO
O
3
4
1d
N
1c
H
3c
NC
CN
CHO
S
S
6c
O
O
MeO
MeO
MeO
MeO
CHO
NH2
CHO
EtO2C
2d
N
H
CO2Et
CHO
1c
4
7d
3d
6d
11de
MeO
MeO
CHO
aExperimental conditions: A mixture of 1 (0.3 mmol), 3 (0.25 mmol),
benzoic acid (20 mol%) and pyrrolidine (20 mol%) in 1 ml of CHCI3 was
stirred at room temperature. bIsolated yield of pure compound 7.
N
H
5
6
56%
78%
NC
1d
1e
2e
6e
CN
CHO
CHO
NH2
F
N
CO2Et
2d
F
H
6f
11fe
Table 5. Direct organocatalytic domino oxo-Michael/aldol condensation
between 2-hydroxybenzaldehydes 1 and α,β-unsaturated ketones 3a
aExperimental conditions: A mixture of 1 (0.3 mmol), 2 (0.25 mmol),
benzoic acid (35 mol%) and pyrrolidine (35 mol%) in 1 ml of DMSO was
stirred at room temperature. bIsolated yield of pure compound 6.
O
pyrrolidine (20 mol%)
benzoic acid (20 mol%)
O
CHO
OH
R 1
R 1
+
O
R 2
R 1
Toluene, rt, 14h
R 1
R 2
1
1c
3
chloroform. Thus, we chose this reaction
Yieldb
Product
Entry
Aldehyde
ꢀꢁꢂ unsaturated Ketone
condition for the reaction between alde-
O
hyde 1c and different α,β-unsaturated cyclic
O
CHO
ketones 3 (Table 4).
1
59%
The reactions gave the corresponding
OH
O
1a
thioxanthenones derivatives 7 in 59–91%
yield. For example, the reaction between
aldehyde 1c and 2-pentenone gave the cor-
responding thioxanthenone 7c in 82% yield
8a
3b
O
MeO
MeO
CHO
OH
2
3b
65%
O
1b
8b
(entry 3). The reaction can also be employed
O
O
MeO
to gain access to thioxanthenones with a
60%
3
1b
tertiary thio-center such as 7d (entry 4).
We next optimized the reaction between
salicylic aldehyde 1a and 2-cyclohexenone
3b.After extensive screening, we found that
we were able to furnish the corresponding
tetrahydroxanthenone 8a in good yield by
using pyrrolidine (20 mol%) as the catalyst
and benzoic acid (20 mol%) as the addi-
tive in toluene. We next investigated the
pyrrolidine-catalyzed reaction for a set of
different 2-hydroxy-benzaldehyde deriva-
tives 1 and α,β-unsaturated cyclohexenones
O
8c
3a
3a
O
CHO
OH
4
83%
O
1g
1f
8d
O
O
CHO
OH
5
3a
3b
85%
62%
O
O
1g
1h
8e
8f
6
11gf
3 (Table 5).
The organocatalytic domino reactions
furnished the corresponding tetrahydro-
O
CHO
3a
7
78%
OH
1h
O
F
xanthenones 8a–8g in 59–85% yields.
For example, the fluoro-substituted tetra-
hydroxanthenone 8g was synthesized in
78% yield (entry 7).
We propose the following mechanism
for the pyrrolidine-catalyzed domino reac-
1i
F
8g
aExperimental conditions: A mixture of 1 (0.3 mmol), 3 (0.25 mmol),
benzoic acid (20 mol%) and pyrrolidine (20 mol%) in 1 ml of CHCI3 was
stirred at room temperature. bIsolated yield of pure compound 8.

ORGANOCATALYSIS
222
CHIMIA 2007, 61, No. 5
tions. The direct organocatalytic domino
hetero-Michael/aldol condensation reac-
O
N
tion starts with iminium activation of the
α,β-unsaturated aldehyde or ketone by the
pyrrolidine. Next, a nucleophilic conjugate
attack on the β-carbon of the enal or enone
by the heteroatom of the benzaldehyde 1 re-
sults in an enamine intermediate (Scheme
N
+
2
-H
R
CHO
2
R
1
X
R
XH
1
R
+
H
3). The in situ generated enamine interme-
H O
2
O
diate will next perform an intramolecular
six-exo trig aldol addition, followed by hy-
drolysis of the resulting iminium intermedi-
ate to give the aldol product. Next, elimina-
tion of water gives the corresponding het-
2
R
X= NH, S, O
1
R
H O
2
O
H N
2
R
N
1
rocyclic product. This is further supported
H
X
R
by the fact that the aldol intermediate was
observed when the reaction was monitored
by NMR analyses of the crude reaction
O
O
H O
2
2
R
R
mixture. The reactivity of the reaction is in
1
1
X
R
X
R
accordance with the nucleophilicity of the
in coming hetero-Michael nucleophile i.e.
thiol > aniline > phenol.
H O
2
In summary, we report a simple one-
pot organocatalytic domino hetero-Mi-
chael/aldol reaction. Pyrrolidine catalyzed
the domino reactions between 2-hydroxy-,
2-mercapto- or 2-aminobenzaldehyde de-
rivatives and α,β-unsaturated aldehydes or
ketones with high chemoselectivity and
furnished the corresponding heterocyclic
derivatives in good to high yields. Further
application of this methodology in total
synthesis and mechanistic studies are on-
going in our laboratory.[10]
Scheme 3. A plausible reaction pathway for the organocatalytic hetero-
Michael/aldol reaction
13
Typical experimental procedure for the
reaction between 2-hydroxybenzaldehydes
derivatives 1 and α,β-unsaturated ketones 3:
CNMR (75 MHz, CDCl ): δ =53.6,
3
113.4, 117.4, 117.8, 126.1, 128.0, 128.7,
130.1, 133.38, 133.40, 143.2, 144.3,
To a round bottom flask, pyrrolidine (0.05
145.6, 190.4.
7a: 1 HNMR(400MHz, CDCl ):δ=7.52(d,
mmol, 0.20 equiv.), benzoic acid (0.05
mmol, 0.20 equiv.) and 1 ml of toluene
were added sequentially. Next, the 2-hy-
droxy benzaldehyde derivative (0.3 mmol,
3
J =2.1Hz, 1H), 7.40–7.10 (m, 3H), 4.27
(ddd, J =2.4Hz, J’=5.7Hz, J’’ =11.1Hz,
1H), 2.70–2.60 (m, 1H), 2.50–2.40 (m,
1H), 2.30–1.80 (m, 5H). CNMR (100
MHz, CDCl ): δ =197.2, 135.5, 135.4,
13
1.2 equiv.) 1 and α,β-unsaturated ketone 3
(0.25 mmol, 1 equiv.) were added sequen-
3
Experimental
tially. The reaction was stirred at room tem-
131.7, 131.4, 130.5, 130.1, 126.6, 126.0,
perature for two days. Next the crude reac-
tion mixture was purified by column chro-
reaction between 2-hetero substituted benz- matography (pentane:AcOEt mixtures) to
39.2, 38.3, 28.4, 20.9.
1
Typical experimental procedure for the
8c: HNMR (400 MHz, CDCl ): δ =7.39 (d,
3
J =2.4Hz, 1H), 6.82 (d, J =1.6Hz, 1H),
6.74 (t, J=2.0Hz, 1H), 4.92 (m, 1H), 3.76
aldehydes and α,β-unsaturated aldehydes: afford the final compound.
Pyrrolidine (0.0875 mmol, 0.35 equiv.),
The analytical data of some representa-
(s,3H),2.62–2.35(m,2H),2.12–1.94(m,
2H), 1.76–1.62 (m, 2H). 13CNMR (100
benzoic acid (0.0875 mmol, 0.35 equiv.) tive products are given below:
and 1 ml of DMSO were added to a round
4d: 1 HNMR (300 MHz, CDCl ): δ =1.18
MHz, CDCl ): δ =197.7, 154.7, 150.2,
3
3
bottom flask. Next, the 2-heterosubstituted
benzaldehyde 1 (0.3 mmol, 1.2 equiv.) and
α,β-unsaturated aldehyde 2 (0.25 mmol, 1
(t, J =6.9 Hz, 3H), 4.12 (dq, J =6.9, 2.1
131.8, 131.3, 122.8, 118.4, 116.9, 113.7,
74.8, 56.0, 39.1, 29.8, 18.2. HRMS(ESI):
Hz, 2H), 5.81 (s, 1H), 6.96–7.04 (m, 2H),
7.24 (dd, J =7.2, 1.8 Hz, 1H), 7.32–7.37
(m, 2H), 9.63 (s, 1H). 13CNMR (75
+
calcd. for [M+Na] (C H O )requires
14 14 3
equiv.) were added sequentially. The reac-
m/z 253.0835, found 253.0823.
MHz, CDCl ): δ =14.0, 61.9, 70.5,
117.1, 119.7,3 122.6, 129.8, 130.0, 133.9,
140.8, 155.0, 168.7, 188.9. MALDI-
tion was stirred at room temperature for 3
h. Next the crude reaction mixture was puri-
fied by column chromatography (Pentane:
AcOEt mixtures) to afford the final com-
pound.
Acknowledgements
We gratefully acknowledge the Swedish
+
TOFMS: 255.0634; C H O (M+Na :
13 12 4
National Research Council and Carl-Trygger
Foundation for financial support.
calcd 255.0633).
Typical experimental procedure for the
5a: 1 HNMR (400 MHz, CDCl ): δ =9.66 (s,
3
Received: March 23, 2007
reaction between 2-mercaptobenzaldehyde
1c and α,β-unsaturated ketones 3: In a round
bottom flask, pyrrolidine (0.05 mmol, 0.20
equiv.), benzoic acid (0.05 mmol, 0.20
1H), 7.46 (s, 1H), 7.386 (d, 1H, J =7Hz),
7.27-7.16 (m, 8H), 5.22 (s, 1H). 13
C
[1] a) E. A. Couladourous, A. T. Strongilos,
Angew. Chem., Int. Ed. 2002, 41, 3677;
NMR (100 MHz, CDCl ): δ =191.07,
3
145.05, 141.62, 134.37, 134.04, 131.70,
b) Z. Gan, P. T. Reddy, S. Quevillon, S.
130.95, 129.83, 128.59, 127.77, 127.54,
equiv.) were added in 1 ml of CHCl3. Then
Couve-Bonnaire, P. Arya, Angew. Chem.,
Int. Ed. 2005, 44, 1366; c) ‘Comprehen-
sive Heterocyclic Chemistry’, Eds. A. R.
Katrizky, C. W. Rees, Pergamon, Oxford,
126.44, 125.80, 38.29. HRMS (ESI):
2-mercaptobenzaldehyde (0.3 mmol, 1.2
equiv.) 1c and α,β-unsaturated ketone 3
(0.25 mmol, 1 equiv.) were added sequen-
calcd. for (C H OS+H) =253.0682.
16 12
found 253.0677.
6a: 1 HNMR (300 MHz, CDCl ): δ =4.54
tially. The reaction was stirred at room tem-
3
1984, Vol.3, pp 737–883.
(s, 1H), 5.68 (d, J =1.9 Hz, 1H), 6.47 (d,
J =7.9, 0.8 Hz, 1H), 6.66 (dt, J =7.9, 0.8
Hz, 1H), 7.12–7.18 (m, 2H), 7.22–7.30
(m, 4H), 7.36–7.41 (m, 2H), 9.49 (s, 1H).
perature over 14 h. Next the crude reaction
mixture was purified by column chroma-
tography (pentane:AcOEt mixtures) to af-
ford the final compound.
[2] a) V. K. Dua, V. P. Ojha, R. Roy, B. C. Jo-
shi, N. Valecha, C. U. Devi, M. C. Bhat-
nagar, V. P. Sharma, S. K. Subbarao, J.

ORGANOCATALYSIS
223
CHIMIA 2007, 61, No. 5
Ethnopharmacol. 2004, 95, 247; b) H.
Statzger, B. Schmidt, C. Root, W. Zinth,
S. Murai, J. Org. Chem. 2000, 65, 4913.
Via multiple bond activation-electrophilic
J. Am. Chem. Soc. 2005, 127, 15710; e) Y.
Yamamoto, N. Momiyama, H.Yamamoto,
B. Fierz, F. Krieger, T. Kiefhaber, P. Gilch,
substitution: i) U. Koch-Pomeranz, H. -
J. Hansen, H. Schmid, Helv. Chim. Acta
J. Am. Chem. Soc. 2004, 126, 5962; f) D.
B. Ramachary, N. S. Chowdari, C. F. Bar-
J. Phys. Vhem. A 2004, 108, 10072; c)
M. Itoigowa, C. Ito, H. Tokuda, F. Enjo,
1973, 56, 2981; j) B. M. Trost, F. D. Tos-
bas III, Angew. Chem., Int. Ed. 2003, 42,
H. Nishinno, H. Furukawa, Cancer Lett.
2004, 214, 165; d) M. Goez, B. H. M.
Hussein, PhysChemChemPhys 2004, 6,
5490; e) S. Milseni, M. Fagnoni, A. Albi-
ni, J. Org. Chem. 2005, 70, 603; f) K. C.
Nicolau, J. A. Pferfferkorn, A. J. Roecker,
G. Q. Cao, S. Barluenga, H. J. Mitchell, J.
Am. Chem. Soc. 2000, 122, 9939; g) K. C.
Nicolau, J. A. Pferfferkorn, S. Barluenga,
H. J. Mitchell, A. J. Roecker, G. Q. Cao, J.
Am. Chem. Soc. 2000, 122, 9968.
te, J. Am. Chem. Soc. 1996, 118, 6305; k)
4233; g) H. Sundén, I. Ibrahem, L. Eriks-
R. C. Larock, M. J. Dotty, Q. Tian, J. M.
son, A. Córdova, Angew. Chem., Int. Ed.
2005, 44, 4877; h) D. Enders, M. R. M.
Hüttl, C. Grondal, G. Raabe, Nature 2006,
441, 861.
A. Ballesteros, E. Rubio, J. M. Gonzalez, [9] For an excellent review on domino reac-
Chem. Commun. 2005, 2008; m) S. A. tions see: L. F. Tietze, Chem. Rev. 1996,
Zenner, J. Org. Chem. 1997, 62, 7536. By
cyclization of aryl propargylic ethers: l) J.
Barluenga, M. Trincado, M. Marco-Arias,
Worlikar, T. Kersharwani, T. Yao, R. C.
96, 115.
Larock, J. Org. Chem. 2007, 72, 1347. [10] Inspired by this research, we and others
For selected examples of recent methods
have developed asymmetric methods for
for synthesis of benzothiochromenes: n)
the synthesis of heterocycles based on
[3] a) J. S. Carter, B. Devadas, J. J. Talley, D.
J.-F. Bonfanti, D. Craig, Tetrahedron Lett. the concept presented in this paper: a) For
L. Brown, M. J. Graneto, D. J. Rogier Jr.,
S. R. Nagarajan, C. E. Hanau, S. J. Hart-
mann, C. L. Ludwid, S. Metz, D. E. Korte,
2005, 46, 3719; o) P. T. Kaye, S. Afr. J. asymmetric chromene synthesis see: a) H.
Sci. 2004, 100, 545; p) P. T. Kaye, X. W. Sundén, I. Ibrahem, G.-L. Zhao, L. Eriks-
Nocanda, Synthesis 2001, 2389; q) A. Ar- son, A. Córdova, Chem. Eur. J. 2007, 13,
S. R. Bertenshaw, M. G. Obukowicz, PCT
574. Other examples in the literature: b) T.
noldi, M. Carughi, Synthesis 1998, 155; r)
Int. Appl. 2000, WO 2000023433A1; b) J.
S. Carter, M. G. Obukowicz, B. Devadas,
K. Kobayashi, H. Konishi, T. Kitamura, O. Govender, L. Hojabri, F. M. Moghaddam,
Morikawa, R. Nakahashi, J. Chem. Soc., P. I.Arvidsson, Tetrahedron Asymm. 2006,
J. J. Talley, D. L. Brown, M. J. Graneto,
Perkin Trans. 1 1999, 1547; s) G. V. Nen-
ajdenko, A. V. Sanin, A. V. Churakov, J.
A. K. Howard, E. S. G. Balenkova, Hete-
17, 1763; c) H. Li, J. Wang, T. E-Nunu,
L. Zu, W. Jiang, S. Wei, W. Wang, Chem.
Commun. 2007, 507. For asymmetric thi-
ochromene synthesis see: d) R. Rios, H.
Sundén, I. Ibrahem, G.-L. Zhao, L. Eriks-
son, A. Córdova, Tetrahedron Lett. 2006,
47, 8547; e) W. Wang, H. Li, J. Wang, L.
Zu, J. Am. Chem. Soc. 2006, 128, 10354.
For 1,2-dihydroquinolidine synthesis see:
S. R. Bertenshaw, D. J. Rogier Jr., S. R.
Nagarajan, C. E. Hanau, S. J. Hartmann,
Int. Appl.
1998, WO 9847890 A1; c) B. P. Chekal,
E. Freund, C. M. Grill, E. Huthmann, M.
C. L. Ludwig, S. Metz, PCT
rocycl. Compd. 1999, 35, 549. For selected
examples of recent methods for synthesis
of dihydroquinolidines: t) M. Takamura,
Juza, V. Leshchinskaya, M. T. Maloney,
K. Funabashi, M. Kanai, M. Shibasaki, J.
Am. Chem. Soc. 2000, 122, 6327; u) M.
L. M. Miller Jr., Y. Wang, M. Zeng, US
Patent Appl. A1 20060020022, January
26th 2006; d) J. F. Geissler, J. L. Roesel,
Takamura, K. Funabashi, M. Kanai, M.
Shibasaki, J. Am. Chem. Soc. 2001, 123, f) H. Sundén, R. Rios, I. Ibrahem, G.-L.
T. Meyer, U. P. Trinks, P. Traxler, N. B.
6801; v) K. Makino, O. Hara, Y. Takigu- Zhao, L. Eriksson, A. Córdova, Adv. Syn-
Lydon, Cancer Res. 1992, 52, 4492; e)
A. Bargagna, M. Longobardi, E. Maria-
ni, P. Schenone, C. Losasso, G. Esposito,
C. Falzarano, E. Marmo, Farmaco 1990,
45, 405; f) A. Arnoldi, A. Bonsignori, P.
Melloni, L. Merlini, M. L. Quadri, A. C.
Rossi, M. Valsecchi, J. Med. Chem. 1990,
33, 2865.
chi, T. Katano, Y. Asakawa, K. Hatano, th. Cat. 2007, 349, 827; g) H. Li, J. Wang,
H. Xie, L. Zou, W. Jiang, E. N. Duesler,
Y. Hamada, Tetrahedron Lett. 2003, 44,
8925; w) O. Hara, K. Sugimoti, K. Maki-
no, Y. Hamada, Synlett 2004, 1625.
W. Wang, Org. Lett. 2006, in press. For
tetrahydrothioxanthenone synthesis see:
h) R. Rios, H. Sundén, I. Ibrahem, G.-
L. Zhao, A. Córdova, Tetrahedron Lett.
2006, 47, 8679. For tetrahydroxantheno-
ne synthesis see: i) R. Rios, H. Sundén, I.
Ibrahem, G.-L. Zhao, A. Córdova, Tetra-
hedron Lett. 2007, 48, 2181.
[6] a) B. Lesch, S. Bräse, Angew. Chem., Int.
Ed. 2004, 43, 115; b) C. F. Nising, U.
K. Ohnemüller, A. Friedrich, B. Lesch,
J. Steiner, H. Schnöckel, M. Nieger, S.
Bräse, Chem. Eur. J. 2006, 12, 3647; c)
B. Lesch, S. Vanderheyden, S. Bräse, Adv.
Synth. Catal. 2005, 347, 555; d) U. K.
[4] a) S. W. Elmore, M. J. Coghlan, D. D.
Anderson, J. K. Pratt, B. E. Green, A. X.
Wang, M. A. Staschko, C. W. Lin, C. M.
Tyree, J. N. Miner, P. B. Jacobson, D. M.
Ohnemüller, C. F. Nising, M. Nieger, S.
Wilcox, B. C. Lane, J. Med. Chem. 2001,
Bräse, Eur. J. Org. Chem. 2006, 1535. For
44, 4481; b) P. D. Leeson, T. W. Carling,
other examples see: a) P. T. Kaye, M. A.
Musa, X. W. Nocada, R. S. Robinson, Org.
G. Stevenson, T. Chan, R. Baker, A. C.
K. W. Moore, A. M. Moseley, J. D. Smith,
Biom. Chem. 2003, 1, 1133; b) P. T. Kaye,
S. Afr. J. Sciences 2004, 100, 545; c) P. T.
Kaye, M. A. Musa, Synthesis 2002, 2701;
d)Y. Satoh, J. L. Stanton, A. J. Hutchison,
Foster, S. Grimwood, J. A. Kemp, G. R.
Marschall, K. Hoogsteen, J. Med. Chem.
1992, 35, 1954.
[5] For selected examples of recent methods
for synthesis of chromenes see: a) I. Ya-
vari, A. Ramazani, Synth. Commun. 1997,
27, 1385; b) S. Chang, R. H. Grubbs, J.
Org. Chem. 1998, 63, 864; c) S. W. Youn,
J. I. Eom, Org. Lett. 2005, 7, 3355; d) G.
Lu, H. C. Malinakova, J. Org. Chem. 2004,
69, 4701; e) F. Kakiuchi, M. Yamauchi,
N. Chantani, S. Murai, Chem Lett 1996,
A. H. Libby, T. J. Kowalski, W. H. Lee,
D. H. White, E. F. Kimble, J. Med. Chem.
1993, 36, 3580; e) G. -L. Zhao, Y. -L. Shi,
M. Dhi, Org. Lett. 2005, 7, 4527 and refe-
rences therein; f) G. -L. Zhao, J. -W. Hu-
ang, M. Shi, Org. Lett. 2003, 5, 4737.
[7] Y.-L. Shi, M. Shi, Synlett 2005, 2623.
[8] a) N. Halland, P. S. Aburell, K. A. Jør-
gensen, Angew. Chem., Int. Ed. 2004, 43,
25, 111; f) R. K. Thalji, K. A. Ahrendt, R.
1272; b)Y. Huang, A. M. Walji, C. H. Lar-
G. Bergman, J. A. Ellman, J. Am. Chem.
Soc. 2001, 123, 9692; g) P. S. Bararn, E.
J. Corey, J. Am. Chem. Soc. 2002, 124,
7904. Via arene metallation-Heck type re-
sen, D. W. C. MacMillan, J. Am. Chem.
Soc. 2005, 127, 15051; c) J. W. Yang, M.
T. Hechavarria Fonseca, B. List, J. Am.
Chem. Soc. 2005, 127, 15036; d) M. Mari-
action: h) N. Chatani, H. Inoue, T. Ikeda,
go, T. Schulte, J. Franén, K. A. Jørgensen,