Synthesis of functionalized chromans by PnBu3- catalyzed reactions of salicylaldimines and salicylaldehydes with allenic ester

Article abstract of DOI:10.1021/ol102461c

PⁿBu₃-catalyzed cyclization reactions of salicylaldimines and salicylaldehydes with ethyl 2,3-butadienoate gave the corresponding functionalized chromans in moderate to good yields in THF under mild conditions. The new reaction provi

Full text of DOI:10.1021/ol102461c

ORGANIC
LETTERS
2010
Vol. 12, No. 24
5664-5667
Synthesis of Functionalized Chromans
by PnBu3-Catalyzed Reactions of
Salicylaldimines and Salicylaldehydes
with Allenic Ester
Yin-Wei Sun,† Xiao-Yang Guan,‡ and Min Shi*,†,‡
Key Laboratory for AdVanced Materials and Institute of Fine Chemicals, School of
Chemistry & Molecular Engineering, East China UniVersity of Science and
Technology, 130 Mei Long Road, Shanghai 200237 China, and State Key Laboratory
of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences, 354 Fenglin Road, Shanghai, China, 200032
mshi@mail.sioc.ac.cn
Received October 11, 2010
ABSTRACT
PnBu3-catalyzed cyclization reactions of salicylaldimines and salicylaldehydes with ethyl 2,3-butadienoate gave the corresponding functionalized
chromans in moderate to good yields in THF under mild conditions. The new reaction provides a new method for the synthesis of biologically
active chroman products.
2H-1-Chromenes or chromans are important classes of oxygen-
ated heterocycles that have attracted much synthetic interest
because of the biological activity of naturally occurring repre-
sentatives.1,2 The synthesis of 2H-1-chromenes or chromans
via the cyclization of suitably elaborated phenyl ethers
commonly suffers from a lack of regioselectivity control at
the key cyclization step. Recently, the reactions of salicyclic
aldehydes with various conjugated olefins, such as acrylate
derivatives and R,ꢀ-unsaturated ketones, to give different
substituted chromenes or chromans have been reported.3
Moreover, the reactions of salicylaldehydes or salicylaldi-
mines with allenic ketones or esters4-6 have also been
disclosed thus far. For example, Huang and co-workers
recently have found phosphine-catalyzed interesting domino
reactions of salicyl N-thiophosphinyl imines with electron-
deficient allenes, affording cis-2,3-dihydrobenzofurans or
chroman derivatives in good yields under mild conditions
(Scheme 1).7
† East China University of Science and Technology.
‡ Chinese Academy of Sciences.
(1) (a) Schweizer, E. E.; Meeder-Nycz, O. In Chromenes, Chromanes,
Chromones; Ellis, G. P., Ed.; Wiley-Interscience: New York, 1977; pp
11-139. (b) Bowers, W. S.; Ohta, T.; Cleere, J. S.; Marsella, P. A. Science
During our ongoing investigation on the phosphine- or
nitrogen-containing Lewis base-catalyzed domino cyclization
of salicylaldehydes or salicylaldimines with electron-deficient
1976, 193, 542
.
(2) Hepworth, J. ComprehensiVe Heterocyclic Chemistry; Katrizky,
A. R., Rees, C. W., Eds.; Pergamon: Oxford, 1984; Vol. 3, pp 737-883.
10.1021/ol102461c  2010 American Chemical Society
Published on Web 11/11/2010

corresponding functionalized chromans in moderate to good
yields under mild conditions.
Scheme 1. Phosphine-Catalyzed Domino Reaction of Salicyl
N-Thiophosphinyl Imines with Electron-Deficient Allenes
Initially, we examined the reactions of salicylaldimine 1a (0.1
mmol, 1.0 equiv) with ethyl 2,3-butadienoate (0.2 mmol, 2.0
equiv) catalyzed by various phosphine Lewis bases (20 mol
%) in tetrahydrofuran (THF) (1.5 mL) at 20 °C (room
temperature) in the presence of phenol (20 mol %) as an
additive. The results are summarized in Table 1. Using PnBu3,
Table 1. Screening of Catalysts and Solvents for the Reaction
yields
(%)b
time
solvent (h)
2a
(E:Z)
olefins as well as allenic ketones or esters, we found that
the nucleophilicity and electronic property of the employed
phosphine- or nitrogen-containing Lewis base can signifi-
cantly affect the reaction outcomes. Herein, we wish to report
the cyclization reactions of salicylaldimines and salicylal-
dehydes with allenic ester catalyzed by PnBu3 to give the
entrya catalyst
additive
1
PnBu3
PMe3
PPhMe2 phenol
PPh2Me phenol
phenol
phenol
THF
THF
THF
THF
THF
THF
THF
12
12
12
12
12
57 (3:1)
52 (4:1)
46 (5:1)
18
2c
3
4
5d
6
PnBu3
PnBu3
PnBu3
PnBu3
PnBu3
PnBu3
PnBu3
PnBu3
PnBu3
PnBu3
PnBu3
PnBu3
PnBu3
PnBu3
PnBu3
phenol
phenol
45 (2:1)
2.5 56 (3:1)
12
12
12
12
7
4-nitrophenol
1,3,5-trihydroxybenzene THF
4-tert-butylphenol
2-naphthol
4-tert-butylphenol
4-tert-butylphenol
4-tert-butylphenol
4-tert-butylphenol
4-tert-butylphenol
none
50 (2:1)
55 (5:1)
58 (4:1)
44 (4:1)
11
8
9
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THF
THF
10
11
12
13
14
15
16e
17f
18f
19g
toluene 12
Et2O 12
CH2Cl2 48
MeCN 48
DMSO 12
14
NR
NR
complex
79 (2:1)
86 (3:1)
67 (2:1)
87 (3:1)
THF
THF
THF
THF
12
12
12
12
none
4-tert-butylphenol
none
a The reaction was carried out on a 0.1 mmol scale in solvents (1.5
mL), and the ratio of 1/allene is 1:2. b Isolated yields. c PMe3 is a 1.0 mol/L
solvent in THF. d At 60 °C. e 2.5 mL of THF was used. f 5.0 mL of THF
was used. g 7.5 mL of THF was used.
(4) For reactions of allenoates with N-tosylated imines: (a) Xu, Z.; Lu,
X. Tetrahedron Lett. 1997, 38, 3461–3464. (b) Xu, Z.; Lu, X. J. Org. Chem.
1998, 63, 5031–5041. (c) Lu, X.; Zhang, C.; Xu, Z. Acc. Chem. Res. 2001,
34, 535–544. (d) Zhu, X.-F.; Lan, J.; Kwon, O. J. Am. Chem. Soc. 2003,
125, 4716–4717. (e) Zhao, G.-L.; Huang, J.-W.; Shi, M. Org. Lett. 2003,
5, 4737–4739. (f) Zhu, X.-F.; Henry, C. E.; Kwon, O. J. Am. Chem. Soc.
2007, 129, 6722–6723. (g) Moreno-Clavijo, E.; Carmona, A. T.; Reissig,
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4778–4781. (h) Zhu, X.-F.; Henry, C. E.; Kwon, O. Tetrahedron 2005, 61,
6276–6282. (i) Zhao, G.-L.; Shi, M. J. Org. Chem. 2005, 70, 9975–9984.
(5) For reactions of allenoates with aldehydes catalyzed by phosphine
Lewis base: (a) Zhu, X.-F.; Henry, C. E.; Wang, J.; Dudding, T.; Kwon,
O. Org. Lett. 2005, 7, 1387–1390. (b) Zhu, X.-F.; Schaffner, A.-P.; Li,
R. C.; Kwon, O. Org. Lett. 2005, 7, 2977–2980. (c) Castellano, S.; Fiji,
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2009, 7, 1272–1275. (i) Xu, S.; Zhou, L.; Zeng, S.; Ma, R.; Wang, Z.; He,
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4369.
PMe3, PPhMe2, and PPh2Me as the Lewis base promoters, it
was found that the corresponding chroman derivative 2a was
formed in 18-57% yields as E- and Z-isomeric mixtures after
12 h, and PnBu3 is the best catalyst in this reaction (Table 1,
(6) For reactions of allenic esters and ketones with salicyl N-tosylimines
or aldehydes: (a) Shi, Y.-L.; Shi, M. Org. Lett. 2005, 7, 3057–3060. (b)
Zhao, G.-L.; Shi, M. Org. Biomol. Chem. 2005, 3, 3686–3694. (c) Zhao,
G.-L.; Shi, Y.-L.; Shi, M. Org. Lett. 2005, 7, 4527–4530. (d) Dai, L.-Z.;
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967–972.
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(b) Meng, X.; Huang, Y.; Zhao, H.; Xie, P.; Ma, J.; Chen, R. Org. Lett.
2009, 11, 991–994.
(8) The crystal data of E-4c have been deposited in CCDC with number
792029. Empirical Formula: C13H13BrO4; Formula Weight: 313.14; Crystal
Color, Habit: colorless; Crystal Dimensions: 0.402 × 0.357 × 0.313 mm;
Crystal System: Triclinic; Lattice Type: Primitive; Lattice Parameters: a )
6.9575(10) Å, b ) 8.3542(12) Å, c ) 11.9845(17) Å, R ) 74.696(3)°, ꢀ
) 75.421(2)°, γ ) 74.571(3)°, V ) 635.22(16) Å3; Space group: P-1; Z )
2; Dcalc ) 1.637 g/cm3; F000 ) 316; Diffractometer: Rigaku AFC7R;
Residuals: R; Rw: 0.0582, 0.1410.
Org. Lett., Vol. 12, No. 24, 2010
5665

entries 1-4). Raising the reaction temperature did not facilitate
the formation of 2a, and the reaction could in fact complete
within 2.5 h if using PnBu3 as the catalyst under otherwise
identical conditions (Table 1, entries 5 and 6). Other phenolic
compounds such as 4-nitrophenol, 1,3,5-trihydroxyphenol,
4-tert-butylphenol, and 2-naphthol also facilitated the formation
of 2a under the standard conditions, affording 2a in 44-58%
yields (Table 1, entries 7-10). The solvent effects have also
been examined in the presence of PnBu3 (20 mol %) and 4-tert-
butylphenol (20 mol %) (Table 1, entries 11-15). We found
that THF is the solvent of choice for this reaction, and other
solvents such as toluene, Et2O, CH2Cl2, MeCN, and DMSO
did not favor the formation of 2a. During our further examina-
tion of the reaction conditions, we found that when the reaction
was carried out in diluted THF solution 2a could be obtained
in higher yields even in the absence of phenolic additives (Table
1, entries 16-19). The best reaction conditions were found that
when 0.1 mmol (1.0 equiv) of 1a and 0.2 mmol (2.0 equiv) of
ethyl 2,3-butadienoate were employed and the reaction was
carried out at 20 °C (room temperature) in THF (7.5 mL),
affording the product 2a in 87% yield as E- and Z-isomeric
mixtures (3:1) within 12 h (Table 1, entry 19).
Scheme 2
.
Using Isopropyl or tert-Butyl 2,3-Butadienoates in
the Reaction
Their structures were determined by H and 13C NMR
spectroscopic data and MS and HRMS analyses. The major
isomers of 2 have been identified as E-configuration on the
basis of their 1H NMR spectroscopic data with its analogue
E-4c, which has been unambiguously determined as E-
configuration by X-ray diffraction. The ORTEP drawing of
E-4c is shown in Figure 1, and its CIF data are presented in
the Supporting Information.1
1
Next, we examined the substrate scope of this reaction
using a variety of salicylaldimines 1 with ethyl 2,3-
butadienoate under these optimized conditions. The results
are shown in Table 2. The corresponding cyclization products
Table 2. Scope of the Reaction in the Presence of PnBu3
Figure 1. X-ray crystal structure of E-4c.
The reactions of salicylic aldehydes 3 with ethyl 2,3-
butadienoate were also examined under the standard condi-
tions. The results are summarized in Table 3. The corre-
Table 3. Scope of the Reaction Using Salicylic Aldehydes as
the Substrates
a The reaction was carried out on a 0.3 mmol scale in THF (22.5 mL),
and the ratio of 1/allene is 1:2. b Isolated yields.
2 were obtained in moderate to good yields as E- and
Z-isomers at room temperature (Table 2, entries 1-5). These
two isomers can be easily separated via silica gel chroma-
tography (Supporting Information). For the starting materials
1 having an electron-withdrawing group on the aromatic ring,
the corresponding adducts 2d and 2e were obtained in lower
yields, which is presumably due to the electronic effects.
To improve the stereoselectivity of the product, isopropyl
or tert-butyl 2,3-butadienoates were employed in this reaction
under these optimized conditions. However, the yields of
the corresponding products 2g and 2h declined remarkably
along with similar E/Z ratios (Scheme 2).
entrya
R
yield (%)b
1
2
3
4
5
6
7
8
H
4a, 84
4b, 85
4c, 45
4d, 55
4e, 15
4f, 95
4g, 23
4h, 73
3-Me
5-Br
5-Cl
3,5-Br2
3-MeO
4-MeO
5-MeO
a The reaction was carried out on a 0.3 mmol scale in THF (22.5 mL),
and the ratio of the 3/allene is 1:2. b Isolated yields.
5666
Org. Lett., Vol. 12, No. 24, 2010

zwitterionic intermediate A or another resonance-stabilized
zwitterionic intermediate B, which undergoes the nucleo-
philic attack with salicylaldimine 1 or salicylaldehyde 3 to
give the corresponding intermediate C. Subsequent proton
transferring produces intermediate D. The cyclization of the
resulting intermediate D affords the intermediate E, which
is followed by elimination of PnBu3 to produce chroman
derivative 2 or 4 and regenerates PnBu3 promoter.
Scheme 3
.
Plausible Mechanism for the Formation of
Functionalized Chromans
In this paper, we have presented a fairly efficient, PnBu3-
catalyzed reaction of salicylaldimines and salicylaldehydes
with allenic ester, which provides an easy access to the
synthesis of the corresponding functionalized chroman
derivatives under mild reaction conditions in moderate
to good yields as well as good geometric selectivities for
salicylaldehydes. The diluted reaction condition is crucial
to produce 2 or 4 in higher yield, presumably due to that
it can avoid the further alteration of the reaction product
in the presence of PnBu3 and ethyl 2,3-butadienoate.
Efforts are in progress to elucidate the mechanistic details
of this reaction and to disclose its scope and limitations.
Acknowledgment. We thank the Shanghai Municipal
Committee of Science and Technology (08dj1400100-2),
National Basic Research Program of China (973)-
2009CB825300, and the National Natural Science Founda-
tion of China for financial support (20872162, 20672127,
20732008, 20821002, and 20702013).
sponding adducts 4 were formed in moderate to good yields
as E-configuration exclusively on the basis of spectroscopic
data (Table 3, entries 1-8). In some cases, such as the
salicylic aldehydes 3e and 3g, the corresponding products
4e and 4g were obtained in lower yields, presumably due to
the electronic properties of these substituents on the aromatic
rings (Table 3, entries 5 and 7).
The mechanism of this unprecedented reaction has not
been unequivocally established, but a plausible explanation
is proposed in Scheme 3.4-7 Initially the Lewis base
promoter PnBu3 acts as a nucleophilic trigger, producing the
1
Supporting Information Available: 13C and H NMR
spectroscopic and analytic data for compounds 2 and 4 and
the ORTEP drawing of E-4c. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL102461C
Org. Lett., Vol. 12, No. 24, 2010
5667