Thieme Chemistry Journal Awardees - Where are they now? Microwave-assisted rhodium-catalyzed decarbonylation of functionalized 3-formyl-2H-chromenes: A sequence for functionalized chromenes like deoxycordiachromene

Article abstract of DOI:10.1055/s-0029-1217179

3-Formyl-2H-chromenes which are readily accessible through an oxa-Michael reaction of salicylaldehydes and α,β-unsaturated aldehydes undergo a smooth decarbonylation reaction upon treatment with rhodium catalysts. With our method, a great variety of funct

Full text of DOI:10.1055/s-0029-1217179

LETTER
1383
Thieme Chemistry Journal Awardees – Where Are They Now?
Microwave-Assisted Rhodium-Catalyzed Decarbonylation of Functionalized
3-Formyl-2H-chromenes: A Sequence for Functionalized Chromenes like
Deoxycordiachromene
D
ecarbonylation of Fun
a
ctionalize
d
n
3-Formyl-
2
u
H
-chromene
e
s
l C. Bröhmer,a,b Nicole Volz,a,b Stefan Bräse*a,b
a
b
Received 30 September 2008
Abstract: 3-Formyl-2H-chromenes which are readily accessible
through an oxa-Michael reaction of salicylaldehydes and a,b-unsat-
urated aldehydes undergo a smooth decarbonylation reaction upon
treatment with rhodium catalysts. With our method, a great variety
of functionalized chromenes is accessible in a two-step sequence
from salicylaldehydes.
Key words: domino oxa-Michael–aldol reaction, decarbonylation,
benzopyran, rhodium-catalysis, natural products
Chromenes (benzopyrans) form an important class of nat-
ural products widespread in higher plants, many of them
showing biological activity (Figure 1).1
Stefan Bräse was born in Kiel, Germany in 1967. After he studied in
Göttingen (Germany), Bangor (UK), and Marseille (France), he recei-
ved his PhD in 1995, after working with Armin de Meijere in Göttin-
gen. After post-doctoral appointments at Uppsala University in
Sweden (Jan E. Bäckvall) and The Scripps Research Institute, La Jol-
la, USA (K. C. Nicolaou), he began his independent research career
at the RWTH Aachen, Germany, in 1997 (associated to Dieter
Enders). In 2001, he finished his Habilitation and moved to the Uni-
versity of Bonn as Professor for Organic Chemistry. Since 2003, he is
full professor at the University of Karlsruhe, Germany. He is recipient
of, among other awards, the OrChem award of the GDCh and the Li-
lly award. His research interests include methods in drug discovery
(including drug delivery), combinatorial chemistry towards the syn-
thesis of biologically active compounds, total synthesis of natural pro-
ducts, and nanotechnology.
MeO
N
N
R2
OH OMe
N
N
R1
O
O
O
O
rubustic acid
protein kinase inhibitor
potassium channel activator
OH
O
Me
MeO
O
Me
H
OH
OH
MeO
MeO
O
HO
O
Chromenes are also intermediates in the synthesis of
many natural products including cannabinoids, anthocya-
nides, and flavones. Simple hydrogenation of the double
bond makes accessible a further substance class, the chro-
manes.
HO
O
O
tephrosine
anti-tumor agent
O
Me
mallotochromene
HIV-1 reverse transcriptase inhibitor
In principle, chromenes are accessible for example via
reaction of propargyl alcohols and ether,2 Claisen and oth-
er rearrangements,3 and ring-closing-metathesis reac-
tions.4 In particular, the condensation of a,b-unsaturated
aldehydes with resorcylates provides a straightforward
access to chromenes.5 However, differently substituted
chromenes cannot be synthesized using this route. We6
and others7 have shown that salicylaldehydes and a,b-
unsaturated aldehydes provide 3-formyl-2H-chromenes
in good to excellent yields. Recently, also asymmetric ap-
proaches were published.8
Me
Me
O
HO
HO
O
O
O
cordiachromene
O
inophyllum B
Figure 1 Selected natural products containing a chromene motif
Herein we report the first synthesis of chromenes from 3-
formyl-2H-chromenes using a rhodium-catalyzed decar-
bonylation reaction (Scheme 1).
SYNLETT 2009, No. 9, pp 1383–1386
Advanced online publication: 13.05.2009
DOI: 10.1055/s-0029-1217179; Art ID: S09808ST
x
x.
x
x.
2
0
0
9
© Georg Thieme Verlag Stuttgart · New York

1384
M. C. Bröhmer et al.
LETTER
The rhodium-catalyzed decarbonylation reaction has been
extensively studied for aromatic and aliphatic com-
pounds,9 whereas formylalkenes are less frequent being
explored (e.g. cinnamal aldehyde).9d To our knowledge,
this reaction has not been explored for formylchromenes.
no restriction in X
asymmetric variant known
CHO
R1
R2
X
X
CHO
OH
CHO
R2
R1
2
As a model system, we synthesized formylchromene 3a
(Table 1, entry 1) by base-catalyzed condensation of sali-
cylaldehyde and citral (54% yield). Catalytic deformyla-
tion of the aldehyde 3a with RhCl3 and dppp in refluxing
diglyme yielded deoxycordiachromene 4a in 59% yield,
which was reported before, albeit via a longer sequence.10
O
1
3
+ "CO"
– CO Rh0
CHO
R2
X
X
H
Then we investigated the scope of the reaction sequence,
starting with different substituted salicylaldehydes 1 and
a,b-unsaturated aldehydes 2 (Scheme 2). Decarbonyla-
tion of the formylchromenes 3 under the standard condi-
tions gave the corresponding chromenes 4 in good yields
(Table 1).11,12
R1
R2
R1
OH
O
4
X = mostly 4-OH or 2-OH required
asymmetric variant unknown
Scheme 1 Strategies for the synthesis of chromenes based on a,b-
Table 1 Rhodium-Catalyzed Decarbonylation of Aldehydesa
Entry
1
Aldehyde 3
Product 4
Yield (%)
59
O
O
O
4a
4b
3a
O
O
2
3
52
34
O
O
O
3b
O
OH
OH
4c
3c
O
4
5
52
34
O
O
3d
4d
4e
O
O
O
O
O
3e
6
32
O
OMe
OMe
4f
3f
Synlett 2009, No. 9, 1383–1386 © Thieme Stuttgart · New York

LETTER
Decarbonylation of Functionalized 3-Formyl-2H-chromenes
1385
Table 1 Rhodium-Catalyzed Decarbonylation of Aldehydesa (continued)
Entry
7
Aldehyde 3
Product 4
Yield (%)
39
O
O
O
4g
3g
O
O
O
MeO
MeO
8
9
72
50
O
O
4h
3h
O
Br
O
O
OMe
OMe
4i
3i
O
I
I
b
10
11
–
O
O
4j
3j
O
Br
Br
12c
O
O
4k
3k
a Conditions: RhCl3·xH2O (5 mol%), dppp (10 mol%), diglyme, reflux (oil bath), 16 h.
b Starting material 3i (100%) was recovered.
c Dehalogenated product was isolated in 9% yield.
This reaction is compatible with double bonds, hydroxy, However, when using enantiopure formylchromene 3g,
methoxy, and ester groups, but not with halides. In the synthesized according to reference 8b, the deformylated
case of aldehyde 3i a dehalogenation was observed. Alde- product 4g was isolated as a racemate. The racemization
hyde 3j could not be converted at all. However, the start- took place upon heating in diglyme, regardless of the pres-
ing material was recovered quantitatively. As a positive ence of catalyst, and was complete within six hours. The
result, we were able to isolate halogenated chromene 4k, same racemization occurred under microwave conditions.
albeit in poor yield.
We suppose an electrocyclic ring-opening–ring-closing
Due to the moderate yields and the problem of dehaloge-
nation, we investigated alternative reaction conditions.
O
O
1) senecialdehyde (30%)
2) RhCl3⋅xH2O, dppp (72%)
MeO
3) LiAlH4 (62%)
HO
By using microwave irradiation, we could increase the
yield of the reaction significantly (Table 2). Furthermore
dehalogenation of 4k was avoided (Table 2, entry 8).
OH
O
1
eulatachromene (5)
The reduction of chromene 4h gave eulatachromene (5), a
natural product isolated from the Italian Eutypa culture
(Scheme 3).13
Scheme 3 Synthesis of eulatachromene (5): rhodium-catalyzed de-
carbonylation as a key step
R1
R1
O
R1
RhCl3⋅xH2O (5 mol%)
R2
R3
CHO
OH
CHO
R6
R2
R3
R2
R3
Na2CO3 (0.5 equiv)
dppp (10 mol%)
+
R6
R5
R6
R5
dioxane–H2O (3:1)
55 °C, 3 d
diglyme
reflux, 16 h
R5
O
O
R4
R4
R4
see text
32–72%
1
2
3
4
Scheme 2 Rhodium-catalyzed decarbonylation reactions of 3-formyl-2H-chromenes 3
Synlett 2009, No. 9, 1383–1386 © Thieme Stuttgart · New York

1386
M. C. Bröhmer et al.
LETTER
Miyamoto, O.; Sato, K. J. Org. Chem. 1987, 52, 5495.
Table 2 Optimization of the Reaction Conditions
(c) Nicolaou, K. C.; Pfefferkorn, J. A.; Cao, G.-Q. Angew.
Chem. Int. Ed. 2000, 39, 734. (d) Larock, R. C.; Wei, L.;
Hightower, T. R. Synlett 1998, 522.
Entry
Product 4 Conditionsa Time
Yield (%)
1
2
4e
4e
4e
4e
4a
4a
4k
4k
4g
4g
A
B
B
B
A
B
A
B
C
D
16 h
34
29
40
60
59
61
12
64
–
(4) Chang, S.; Grubbs, R. H. J. Org. Chem. 1998, 63, 864.
(5) El Sohly, M. A.; Boeren, E. G.; Turner, C. E. J. Heterocycl.
Chem. 1978, 15, 699.
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Synth. Catal. 2005, 347, 555. (b) Lesch, B.; Toräng, J.;
Nieger, M.; Bräse, S. Synthesis 2005, 1888.
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Kowalski, T. J.; Lee, W. H.; White, D. H.; Kimble, E. F.
J. Med. Chem. 1993, 36, 3580. (b) Kaye, P. T.; Nocanda,
X. W. J. Chem. Soc., Perkin Trans. 1 2002, 1331.
(c) Ibrahem, I.; Sundén, H.; Rios, R.; Zhao, G.-L.; Córdova,
A. CHIMIA 2007, 61, 219.
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Arvidsson, P. I. Tetrahedron: Asymmetry 2006, 17, 1763.
(b) Sundén, H.; Ibrahem, I.; Zhao, G.-L.; Eriksson, L.;
Córdova, A. Chem. Eur. J. 2007, 13, 574. (c) Zu, L.; Wang,
J.; Li, H.; Xie, H.; Jiang, W.; Wang, W. J. Am. Chem. Soc.
2007, 129, 1036.
(9) (a) Ohno, K.; Tsuji, J. J. Am. Chem. Soc. 1968, 90, 99.
(b) Doughty, D. H.; Pignolet, L. H. J. Am. Chem. Soc. 1978,
100, 7083. (c) Beck, C. M.; Rathmill, S. E.; Park, Y. J.;
Chen, J.; Crabtree, R. H.; Liable-Sands, L. M.; Rheingold,
A. L. Organometallics 1999, 18, 5311. (d) Kreis, M.;
Palmelund, A.; Bunch, L.; Madsen, R. Adv. Synth. Catal.
2006, 348, 2148. (e) Taarning, E.; Madsen, R. Chem. Eur. J.
2008, 14, 5638. (f) Use in total synthesis: Takahashi, T.;
Naito, Y.; Tsuji, J. J. Am. Chem. Soc. 1981, 103, 5261. (g)
Asymmetric variant: Fessard, T.; Andrews, S. P.;
Motoyoshi, H.; Carreira, E. M. Angew. Chem. Int. Ed. 2007,
46, 9331. (h) For a review, see: Necas, D.; Kotora, M. Curr.
Org. Chem. 2007, 11, 1566.
30 min
50 min
2 × 40 min
16 h
3
4
5
6
2 × 40 min
16 h
7
8
30 min
4 d
9
10
60 min
–
a Conditions A: RhCl3⋅xH2O (5 mol%), dppp (10 mol%), diglyme, re-
flux (oil bath). Conditions B: RhCl3×xH2O (5 mol%), dppp (10
mol%), diglyme, microwave irradiation (200 °C, 200 W). Conditions
C: [IrCl(cod)]2 (2.5 mol%), Ph3P (5 mol%), THF, reflux (oil bath).
Conditions D: [IrCl(cod)]2 (2.5 mol%), Ph3P (5 mol%), THF, MW
irradiation (100 °C, 200 W).
O
O
O
Δ
O
Me
O
O
Me
(R)-3g
rac-3g
(10) (a) Yus, M.; Foubelo, F.; Ferrández, J. V. Eur. J. Org. Chem.
2001, 2809. (b) Asymmetric variants: Bouzbouz, S.;
Goujon, J.-Y.; Deplanne, J.; Kirschleger, B. Eur. J. Org.
Chem. 2000, 3223.
Scheme 4 Proposed mechanism of the racemization of 3g
mechanism (Scheme 4). Similar racemizations were
reported for a series of 2-aryl-2-methyl-2H-chromenes.14
Attempts to decrease the reaction temperature and/or us-
ing other catalysts15 in order to prevent this racemization
reaction were unfruitful, yet (Table 2, entries 9 and 10).
(11) Typical Procedure for the Rh-Catalyzed Deformylation
of 3-Formyl-2H-chromenes
Formylchromene 3a (390 mmol), RhCl3·xH2O (19.5 mmol, 5
mol%), and dppp (39.0 mmol, 10 mol%) in diglyme (2 mL)
were refluxed under argon for 16 h. After cooling, pentane
(10 mL) was added, and the mixture was washed with H2O
(5 × 5 mL). The organic layer was dried over Na2SO4 and
evaporated. The crude product was purified by column
chromatography on SiO2.
In summary, we present the first metal-catalyzed decarbo-
nylation reaction of 3-formylchromenes and its applica-
tion in the synthesis of the natural product
eulatachromene. The application towards the synthesis of
more complex chromenes is under investigation.
(12) Selected Data
Compound 4a: 1H NMR (400 MHz, CDCl3): d = 1.40 (s, 3
H), 1.58 (s, 3 H), 1.60–1.79 (m, 2 H), 1.67 (s, 3 H), 2.12 (mc,
2 H), 5.11 (tt, J = 7.2, 1.4 Hz, 1 H), 5.56 (d, Jcis = 9.8 Hz, 1
H), 6.36 (d, Jcis = 9.8 Hz, 1 H), 6.77 (d, J = 8.0 Hz, 1 H), 6.82
(ddd, J = 7.6, 7.4, 1.2 Hz, 1 H), 6.96 (dd, J = 7.6, 1.6 Hz, 1
H), 7.09 (ddd, J = 8.0, 7.4, 1.6 Hz, 1 H). 13C NMR (100
MHz, CDCl3): d = 17.6, 22.7, 25.7, 26.5, 41.3, 78.4, 116.1,
120.5, 121.1, 122.8, 124.1, 126.3, 129.0, 129.6, 131.7,
153.2. MS–FAB: m/z (%) = 229.2 (11) [M+ + H], 228.2 (18)
[M+], 145.1 (100) [M+ – C6H11], 136.1 (10). HRMS: m/z
calcd for C16H20O: 228.1514. Found: 228.1510. Anal. Calcd
for C16H20O: C, 84.16; H, 8.83. Found: C, 84.14; H, 8.69.
(13) Smith, L. R.; Mahoney, N.; Molyneux, R. J. J. Nat. Prod.
2003, 66, 169.
Acknowledgment
Financial support has been provided by the DFG (Bonn) and the
University of Karlsruhe (TH). We thank Prof. Karola Rück-Braun
for helpful discussions.
References and Notes
(1) Shi, Y.; Shi, M. Org. Biomol. Chem. 2007, 1499; and
references cited therein.
(2) (a) Iwai, I.; Ide, J. Chem. Pharm. Bull. 1963, 11, 1042.
(b) Babu, K. S.; Raju, B. C.; Praveen, B.; Kishore, K. H.;
Murty, U. S.; Rao, J. M. Heterocycl. Commun. 2003, 9, 519.
(3) (a) Kahn, P. H.; Cossy, J. Tetrahedron Lett. 1999, 40, 8113.
(b) Inoue, S.; Ikeda, H.; Sato, S.; Horie, K.; Ota, T.;
(14) Harié, G.; Samat, A.; Guglielmetti, R.; Van Parys, I.;
Saeyens, W.; De Keukeleire, D.; Lorenz, K.; Mannschreck,
A. Helv. Chim. Acta 1997, 80, 1122.
(15) Iwai, T.; Fujihara, T.; Tsuji, Y. Chem. Commun. 2008, 6215.
Synlett 2009, No. 9, 1383–1386 © Thieme Stuttgart · New York

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