Catalytic asymmetric inverse-electron-demand (IED) [4+2] cycloaddition of salicylaldimines: Preparation of optically active 4-aminobenzopyran derivatives

Article abstract of DOI:10.1002/adsc.201000608

The catalytic asymmetric inverse-electron-demand (IED) [4+2] cycloaddition of various salicylaldehyde-derived N-arylimines with electron-rich alkenes in the presence of chiral BINOL-derived phosphoric acid catalysts has been studied with the aim of obtaining optically active 4-aminobenzopyran derivatives. Dienophiles such as 2,3-dihydro-2H-furan, benzyl N-vinylcarbamate and 2-vinylindole have been employed. Copyright

Full text of DOI:10.1002/adsc.201000608

FULL PAPERS
DOI: 10.1002/adsc.201000608
Catalytic Asymmetric Inverse-Electron-Demand (IED) [4+2]
Cycloaddition of Salicylaldimines: Preparation of Optically Active
4-Aminobenzopyran Derivatives
Luca Bernardi,a Mauro Comes-Franchini,a Mariafrancesca Fochi,a,* Virginia Leo,a
Andrea Mazzanti,a and Alfredo Riccia
a
Department of Organic Chemistry “A. Mangini”, University of Bologna, Viale Risorgimento 4, 40136 Bologna, Italy
Fax : (+39)-051-209-3654; phone: (+39)-051-209-3626; e-mail: mariafrancesca.fochi@unibo.it
Received: July 29, 2010; Published online: December 7, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000608.
Abstract: The catalytic asymmetric inverse-electron- benzyl N-vinylcarbamate and 2-vinylindole have
demand (IED) [4+2]cycloaddition of various salicy- been employed.
laldehyde-derived N-arylimines with electron-rich al-
kenes in the presence of chiral BINOL-derived phos-
phoric acid catalysts has been studied with the aim Keywords: asymmetric synthesis; cycloaddition; elec-
of obtaining optically active 4-aminobenzopyran de- tron-rich alkenes; fused-ring systems; organic cataly-
rivatives. Dienophiles such as 2,3-dihydro-2H-furan, sis
Introduction
ans in the presence of a chiral N-triflylphosphoramide
catalyst was reported.[6]
Nitrogen- and oxygen-containing heterocycles are
In this context, the development of new catalytic
prominent in nature and exhibit a wide range of inter- asymmetric methods for the preparation of the benzo-
esting biological properties. Among oxygen heterocy- pyran structure attracted our interest. Following our
cles, benzopyrans and their furan-fused analogues recent report on the asymmetric Povarov[7] reaction of
appear to be very appealing targets for synthetic pur- N-arylimines with 2- and 3-vinylindoles using chiral
poses due to the useful biological properties demon- BINOL-derived phosphoric acids[8,9] as catalyst, we
strated by their naturally occurring representatives[1,2] decided to examine the feasibility of an enantioselec-
as anti-hypertensive and anti-ischaemic drugs.[3]
tive inverse-electron-demand (IED) [4+2]cycloaddi-
4-Aminobenzopyrans and their derivatives have re- tion of o-hydroxybenzaldimines 1 with electron-rich
ceived considerable attention in the last decade as alkenes. In particular, besides the evident synthetic
they can be used as modulators of potassium channels utility of this reaction, we were intrigued by the possi-
influencing the activity of the heart and blood pres- ble competing pathways expected in the reactions of
sure.[4] As a result of the significance of the 4-amino- these imines with electron-rich dienophiles, leading to
benzopyran framework, their synthesis has attracted two distinct products. Besides the already mentioned
considerable attention;[5] angularly trans-fused pyra- cycloaddition giving benzofurans (Scheme 1, route a),
nobenzopyrans have been obtained by [4+2]cycload- N-arylimines 1 can indeed undergo a [4+2] IED aza-
dition of o-quinonemethides using p-toluenesulfonic Diels–Alder cycloaddition at their N-arylimine
acid as catalyst,[5a] whereas cis-fused furano- and pyra- moiety (Povarov reaction) (Scheme 1, route b).
nobenzopyrans have been obtained by [4+2]cycliza-
Herein we present our efforts and results in the
tion of o-hydroxybenzaldimines with 3,4-dihydro-2H- asymmetric organocatalytic synthesis of 4-aminoben-
pyran and 2,3-dihydro-2H-furan employing several zopyran derivatives of type 5–7 using electron-rich al-
Brønsted acids and Lewis acids as catalyst.[5b–g] kenes such as 2,3-dihydro-2H-furan 2 (DHF), benzyl
During the preparation of this work, the first example N-vinylcarbamate 3 and 2-vinylindole 4 (Scheme 2).
of a direct access to optically pure 4-aminobenzopyr-
Adv. Synth. Catal. 2010, 352, 3399 – 3406
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Luca Bernardi et al.
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Scheme 1. Possible cycloaddition pathways.
Scheme 2. IED [4+2]cycloaddition of o-hydroxybenzaldimines 1 with electron-rich alkenes 2–4. Cbz=benzyloxycarbonyl.
Results and Discussion
was obtained as a single diastereosomer with an enan-
tiomeric ratio (er) of 83:17 (Table 1 entry 9).
An initial evaluation of the proposed cycloaddition
The relative configuration of compound 5a was de-
reaction was performed with N-phenylsalicylaldimine termined to be cis-cis (i.e., 3aR*,4S*,9aS*) by NMR
1a and DHF 2 at room temperature. Envisaging the NOE analysis. The absolute configuration was then
activation of imines by H-bond interactions with a assigned by means of time-dependent density func-
chiral catalytic system, we unsurprisingly found that tional theory (TD-DFT) calculations of the electronic
BINOL-derived phosphoric acids 8 (Figure 1) were circular dichroism (ECD) spectra.[11]
the most competent catalytic systems for this asym-
metric cycloaddition.
Electronic excitation energies and rotational
strengths for the simulations have been calculated at
A thorough screening of catalyst structures and re- the BH&HLYP/6-311++GACTHUNRTGNEUNG(2d,p)//B3LYP/6-31G(d)
action conditions was then undertaken (see Table 1 level on the two most stable conformations (see the
and the Supporting Information). Optimised condi- Supporting Information for more details). As shown
tions derived from this screening entailed the use of in Figure 2, the spectrum calculated assuming the
8f[10] as catalyst (10 mol%), and toluene as the solvent 3aR,4S,9aS absolute configuration matches well the
(Table 1, entries 1–6, and 12–14). The introduction of experimental ECD.
5ꢁ molecular sieves (MS) was found to be critical to
As previously mentioned, the first example of enan-
achieve useful selectivities (Table 1, entries 7–11). tioselective domino Mannich-ketalisation reaction of
Using this set of conditions cis-fused benzopyran 5a o-hydroxybenzaldimines with electron-rich alkenes in
the presence of a chiral N-triflylphosphoramide cata-
lyst for a direct access to optically pure 4-aminoben-
zopyrans was reported.[6] This reaction proceeded
with excellent results both with DHF 2, and with 3,4-
dihydro-2H-pyran (DHP) leading to 3a,4-trans-3a,9a-
cis-4-aminobenzopyrans.
The selective formation of the 3a,4-cis-3a,9a-cis de-
rivative 5 thus showed the full diastereocomplemen-
tarity of our approach based on simple (S)-BINOL-
Figure 1. (S)-BINOL-derived phosphoric acids.
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Catalytic Asymmetric Inverse-Electron-Demand (IED) [4+2]Cycloaddition of Salicylaldimines
Table 1. Evaluation of phosphoric acid catalyst architecture
AHCTUNGTREGbNNUN enzaldimines with various N-aryl residues 1a–g. The
obtained results are summarised in Table 2 (entries 1–
6).
and reaction conditions.[a]
Table 2. Scope of the Brønsted acid-catalysed cycloaddition
with DHF 2 toward benzopyran derivatives 5.[a]
Entry
8
Solvent Additive Yield [%][b] dr[c] er[d]
1
2
3
4
5
6
7
8
a
b
c
d
e
f
f
f
f
f
f
f
f
f
toluene none
toluene none
toluene none
toluene none
toluene none
toluene none
toluene MS 3ꢁ
toluene MS 4ꢁ
toluene MS 5ꢁ
toluene CaCO3
toluene Py
82
–
52
–
10:1
–
30:1 64:36
–
–
0
–
–
–
–
58
88
82
88
65
23
27
15
80
15:1 67:33
Entry
1
R1
R2
5 Yield [%][b] dr[c] er[d]
[e]
–
–
–
–
68:32
70:30
83:17f)
69:31
[e]
[e]
[e]
1[e]
2
3
4
5
6
7
8
b
c
d
e
f
g
h
i
4-OMe
4-Me
4-Cl
4-Br
4-NO2
2-Me
H
H
H
H
H
H
H
b 55
c 55
d 60
e 42
f 35
18:1 88:12[f]
9
55:1 95:5
[g]
10
11
12
13
14
–
82:18
45.1 71:29
40:1 77:23
35:1 55:45
30:1 72:28
50:1 81:19
THF
DCE
MS 5ꢁ
MS 5ꢁ
8:1
–
–
70:30
–
78:22
–
g <5
[g]
TBME MS 5ꢁ
4-OMe h 38
3-OMe i <5
H
–
[a]
Reaction conditions: 1a, 2 (1.5 equiv.), 8 (10 mol%),
0.3M.
9
10
j
k
H
H
5-Br
5-NO2 k 60
j 25
15:1 89:11
45:1 58:42
[b]
[c]
Yield of isolated product after chromatography.
1
[a]
Determined by H NMR spectroscopy on the crude ma-
Reaction conditions: 1, 2 (1.5 equiv.), 8f (10 mol%),
0.3M.
terial.
[d]
[e]
[f]
[b]
[c]
Determined by HPLC analysis.
Yield of isolated product after chromatography.
1
Only one diastereoisomer detected.
The same reaction performed at À208C for 3 days gave
the product in 83% yield and 84.5:15.5 er.
Determined by H NMR spectroscopy on the crude ma-
terial.
[d]
[e]
[f]
Determined by HPLC analysis.
Reaction time: 48 h.
The reaction performed at À208C for 3 days gave 5b in
36% yield with er 90:10.
[g]
Only one diastereoisomer detected.
In general moderate to good enantiomeric ratios
and very good diastereoselectivity values were ob-
tained irrespective of the N-aryl group used (R1 on
the N-aromatic ring), whereas the yields obtained
were rather low (Table 2, entries 1–5). The highest
enantiomeric ratios (er 95:5; er 88:12 Table 2, en-
tries 1 and 2) were obtained with N-p-tolyl and N-p-
methoxyphenylaldimines 1c and 1b. No reaction was
observed when the substituent R1 was at the 2-posi-
tion (imine 1g, Table 2, entry 6).
Figure 2. Experimental (black) and TD-DFT calculated
ECD spectra (grey) of 5a. The experimental spectrum was
obtained in acetonitrile (1·10À4 M). Molecular CD (De) are
expressed in LmolÀ1 cmÀ1. The simulated spectrum was red-
shifted by 7 nm in order to match the experimental trace.
Different substituents (R2) can also be positioned
into the aromatic ring of the parent salicylaldehyde
(Table 2, entries 7–10). The desired 4-aminobenzopyr-
an derivatives 5g–k were obtained with contrasting re-
sults in terms of yields, ranging from an acceptable
phosphoric acids, with respect to the chiral N-triflyl- 60% yield for imine 1k, to a lack of reactivity for
phosphoramide-catalysed reaction.
imine 1i.
Then we set up to investigate the possibility of
Subsequently, the scope of the reaction was inspect-
ed by using first differently substituted o-hydroxy- using different kinds of dienophiles.
Adv. Synth. Catal. 2010, 352, 3399 – 3406
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Scheme 3. IED [4+2]cycloaddition of 1a with benzyl N-vinylcarbamate 3.
The reaction of N-phenylsalicylaldimine 1a with ucts 6a and 9a, which could be easily separated by
benzyl N-vinylcarbamate 3[12,13] was tested in the pres- chromatography on silica gel.
ence of the different BINOL-derived phosphoric
The scope of the reaction was next examined espe-
acids 8a–f (Scheme 3). In contrast with what was pre- cially focused at investigating the effect of the differ-
viously observed with DHF 2, dienophile 3 reacted ent substituents at the N-aryl moiety on the ratio be-
with imine 1a via two different competing pathways. tween the two possible products. The obtained results
A mixture of the benzopyran 6a and the 1,2,3,4-tetra- are reported in Table 3. As expected electron-donat-
hydroquinoline 9a, deriving from the [4+2] IED aza- ing substituents on the N-aryl group (Table 3, entry 2)
Diels–Alder reaction (Povarov reaction) with the N- favoured the formation of the Povarov product 9
arylimine moiety, was in fact obtained in most cases. whereas electron-withdrawing substituents (Table 3,
Ratios between these two products were strongly de- entry 6) led to the prevalent or even exclusive forma-
pendent on catalyst structure (See Supporting Infor- tion of the 4-aminobenzopyran derivative 6.
mation). After a thorough screening of catalysts and
Next we evaluated the possibility of using 2-vinylin-
reaction conditions, catalyst 8d[14] in p-xylene was dole 4[15] as electron-rich dienophile which would
judged as a good compromise between selectivity and allow the introduction of the indole moiety, a very
reactivity, affording the benzopyran derivative 6a in common structure in natural and bioactive mole-
45% yield as a mixture of two diastereoisomers (12:1) cules.[16] In the presence of phosphoric acid catalysts
beside the tetrahydroquinoline 9a in 46% yield 8, 2-vinylindole 4 reacted selectively with N-aryl-
(Scheme 2). Enantioselectivity was good in both prod-
ACHTUNGTRENiNUGN mines, affording exclusively the corresponding benzo-
Table 3. Scope of the Brønsted acid-catalysed cycloaddition with enecarbamate 3.
Entry[a]
1
R1
R2
6
Yield [%][b]
dr[c]
er[d]
9
Yield [%][b]
er[d]
1
2
3
4
5
6
7
8
a
b
c
d
e
f
H
H
H
H
H
H
H
4-OMe
5-Br
a
b
c
d
e
f
45
15
22
59
60
70
27
41
12:1
7:1
4.5:1
9:1
7:1
3:1
95:5
89:11
95:5
95:5
95:5
90:10
98:2
92:8
a
b
c
d
e
f
46
74
62
39
38
–
98.5:1.5
95:5
95:5
96:4
96:4
–
4-OMe
4-Me
4-Cl
4-Br
4-NO2
H
h
j
h
j
1.5:1
3:1
g
h
37
39
93:7
93:7
H
[a]
Reaction conditions: 1, 3 (1.5 equiv.), 8d (10 mol%), p-xylene 0.2M, 6h.
[b]
[c]
[d]
Yield of isolated product after chromatography.
1
Determined by H NMR spectroscopy on the crude material.
Determined by HPLC analysis.
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Adv. Synth. Catal. 2010, 352, 3399 – 3406

Catalytic Asymmetric Inverse-Electron-Demand (IED) [4+2]Cycloaddition of Salicylaldimines
Table 4. Brønsted acid-catalysed IED [4+2]cycloaddition
cycloaddition with 4 toward benzopyran derivatives 7.[a]
plementarity of our approach with respect to the
recent one published by Rueping and Lin. When
benzyl N-vinylcarbamate 3 was used as the dieno-
phile, the reaction afforded both the benzopyran de-
rivatives 6 and the tetrahydroquinolines 9. Enantiose-
lectivity was good in both products and the regiose-
lectivity of the cycloaddition reaction could be direct-
ed versus one of the two products by varying the sub-
stituent on the aromatic rings.
Entry
1
R1
R2
7 Yield [%][b]) dr[c]
er[d]
Experimental Section
1
2
3
4
a
b
e
j
H
H
H
H
a 60
b 35
e 30
14:1
>98:2 83:17
2:1
3:1
88:12
General Procedure for the Organocatalytic
[4+2]Cycloaddition Reaction of Aldimines 1a–k
with 2,3-Dihydro-2H-furan 2
4-OMe
4-Br
H
90:10
75:25
5-Br j 56
[a]
To a flame-dried Schlenk tube equipped with a magnetic
stirring bar, 5ꢁ powder molecular sieves (100 mg) were
added under a nitrogen atmosphere. The molecular sieves
were then thermally activated under vacuum for 10 min and
then allowed to cool to room temperature. The aldimine 1
(0.10 mmol) was then added under a nitrogen atmosphere,
followed by anhydrous toluene (330 mL, 0.3M), the catalyst
8f (8.6 mg, 0.010 mmol) and 2,3-dihydro-2H-furan 2 (15 mL,
0.15 mmol). The mixture was then stirred at room tempera-
ture under nitrogen atmosphere. After 18 h, the reaction
mixture was filtered through a plug of silica gel, and the
plug washed with EtOAc (2ꢂ). After concentration of the
Reaction conditions: 1, 4 (1.2 equiv.), 8e (10 mol%),
0.3M.
[b]
[c]
Yield of isolated product after chromatography.
1
Determined by H NMR spectroscopy on the crude ma-
terial.
[d]
Determined by HPLC analysis.
pyran derivatives 7 as the IED-aza-Diels–Alder-type
products could never be detected.
The usual screening of the catalyst structures and
reaction conditions was then undertaken and the opti-
mised conditions resulted in the use of 8e as the cata-
lyst beside 5ꢁ molecular sieves (MS) as additive in
THF at 458C (see Supporting Information). This set
of conditions allowed the preparation of 7a in 60%
yield as a mixture of two diastereoisomers (14:1) and
88:12 er (Table 4, entry 1).
The scope of the reaction was then briefly evaluat-
ed using some N-arylimines 1 and the obtained results
are detailed in Table 4. Moderate to good enantiomer-
ic ratios and rather low yields were obtained irrespec-
tive of the N-aryl group used (R1 on the N-aromatic
ring) (Table 4, entries 2 and 3) and the substituents
(R2) positioned in the aromatic ring of the parent sali-
cylaldehyde (Table 4, entry 1).
1
solvents, the residue was analysed by H NMR spectroscopy
to determine the diastereomeric ratio of the cycloadducts.
Finally, the residue was purified by chromatography on
silica gel (n-hexane/EtOAc mixtures) obtaining as the first
Rf fraction the non-converted starting imine, as the second
Rf fraction the minor diastereoisomer (if present) and as the
third Rf fraction the major diastereoisomer.
N-Phenyl-3,3a,4,9a-tetrahydro-2H-furoACHTNUTRGNEUNG[2,3-b]chromen-4-
amine (5a): N-Phenylsalicylaldimine 1a (19.7 mg) was react-
1
ed following the general procedure. H NMR of the crude
mixture showed the presence of a single diastereoisomer.
The title compound was obtained as white solid after chro-
matography on silica gel (n-hexane/EtOAc 90:10); yield:
88%. The er of the product was determined by HPLC using
a Chiralcel OJ-H column (n-hexane/i-PrOH 80:20, flow-rate
0.75 mLminÀ1):
tmin =33.9 min, tmaj =38.3 min, er 83:17;
1H NMR (400 MHz, CDCl3): d=7.37 (d, J=7.5 Hz, 1H),
7.30–7.17 (m, 3H), 7.01–6.90 (m, 2H), 6.83–6.71 (m, 3H),
5.90 (d, 1H, J=5.6 Hz), 4.99 (bs, 1H), 3.99–3.90 (m, 1H),
3.90–3.81 (m, 1H), 3.18–3.06 (m, 1H), 1.93 (m, 1H), 1.63
(m, 1H); 13C NMR (100 MHz, CDCl3): d=152.9, 147.0,
129.6, 128.8, 126.2, 124.6, 121.9, 118.4, 117.2, 113.4, 102.4,
68.0, 48.8, 43.3, 23.9; ESI-MS: m/z=290 [M+ +Na]. The rel-
Conclusions
In summary, we have presented a catalytic asymmet-
ric synthesis of 4-aminobenzopyran derivatives
through an inverse-electron-demand (IED) [4+2]cy-
cloaddition of salicylaldimines with electron-rich al-
kenes. When 2,3-dihydro-2H-furan 2 and 2-vinylin-
dole 4 were used as the dienophiles the reaction af-
forded exclusively the 4-aminobenzopyran derivatives
in moderate to good yields and enantiomeric excesses.
Interestingly, the selective formation of the 3a,4-cis-
ative configuration was determined to be cis (9a-3a)/cisACHTUNGTRENNUNG(3a-
4) by nOe experiments.
General Procedure for the Organocatalytic
[4+2]Cycloaddition Reaction of Aldimines 1a–j with
Benzyl N-Vinylcarbamate 3
To a screw-topped test tube equipped with a magnetic stir-
3a,9a-cis derivative 5 showed the full diastereocom- ring bar, the aldimine 1 (0.10 mmol) was added under a ni-
Adv. Synth. Catal. 2010, 352, 3399 – 3406
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Luca Bernardi et al.
FULL PAPERS
trogen atmosphere, followed by anhydrous p-xylene
(500 mL), the catalyst 8d (5.9 mg, 0.010 mmol) and benzyl N-
vinylcarbamate 3 (22 mg, 0.12 mmol). The mixture was then
stirred at the room temperature. After 6 h, the reaction mix-
ture was filtered through a plug of silica gel, and the plug
washed with EtOAc (2ꢂ). After concentration of the sol-
98.5:1.5; 1H NMR (400 MHz, CDCl3): d=8.71 (bs, OH),
7.42–7.29 (m, 6H), 7.25–7.05 (m, 3H), 6.69–6.73 (m, 3H),
6.72 (d, J=8.3 Hz, 1H) 5.31–5.19 (m, 1H), 5.17 (s, 2H), 4.94
(d, J=9.5 Hz, 1H), 4.60 (dd, J=12.2 and 2.3 Hz, 1H), 4.31
(bs, NH), 2.49 (ddd, J=12.8, 6.2 and 2.6 Hz, 1H), 2.23 (dd,
J1 =J2 =12.0 Hz, 1H); 1H NMR (600 MHz, CD3CN): d=
8.31 (s, 1H), 7.39 (bd, 4H), 7.36–7.32 (m, 1H), 7.26 (d, J=
7.6 Hz, 1H), 7.17 (m, 2H), 7.07 (t, J=7.7 Hz, 1H), 6.87(dt,
J=7.5, 1.0 Hz, 1H), 6.83 (dd, J=8.0 and 0.9 Hz, 1H), 6.77 (t,
J=7.5 Hz, 1H), 6.71 (d, J=8.2 Hz, 1H), 5.86 (d, J=9.4 Hz,
1H)5.11 (dd J1 =J2 =12.1 Hz, 2H), 5.08 (m, 1H), 4.96 (bs,
1H), 4.72 (d, J=11.4 Hz, 1H); 2.26 (dd, J=12.0 and 5.5 Hz,
1H); 2.08 (dd, J1 =J2 =11.7 Hz, 1H); 13C NMR (150 MHz,
CD3CN): d=156.8, 155.7, 144.6, 137.7, 128.8, 128.7, 128.3,
128.15, 128.11, 127.9, 127.8, 127.3, 123.9, 120.2, 119.3, 116.44,
116.39, 66.3, 53.9, 48.1, 35.9; ESI-MS: m/z=397 [M+ +Na].
1
vents, the residue was analysed by H NMR spectroscopy to
determine the diastereoselectivity. Finally, the residue was
purified by chromatography on silica gel (n-hexane/EtOAc
mixtures).
2-(N-Carbobenzyloxy)amino-4-(phenylamino)chromane
(6a) and 4-(N-carbobenzyloxy)amino-2-(2-hydroxyphenyl)-
1,2,3,4-tetrahydroquinoline (9a): N-Phenylsalicylaldimine 1a
(19.7 mg) was reacted following the general procedure.
1H NMR of the crude mixture showed the presence 6a as a
mixture of two diastereoisomers in a 12:1 ratio and 9a as a
single diastereoisomer. Chromatography on silica gel (n-
hexane/EtOAc 90:10) afforded 6a in 45% yield as a mixture
of two diastereoisomers as the first Rf fraction and 9a in
46% yield as the second Rf fraction.
1
Full assignments of H and 13C NMR signals of 9a were
obtained by HSQC and HMBC bi-dimensional sequences in
CDCl3 as the solvent., and NOE spectra were acquired in
order to establish the relative stereochemistry. The relative
stereochemistry was found to be cis.
6a: The er of the major diastereoisomer was determined
by HPLC using a Chiralcel OD column (n-hexane/i-PrOH
80:20, flow-rate 1.0 mLminÀ1):
tmaj =81.73 min, tmin =
31.15 min, er 95:5; 1H NMR (400 MHz, CDCl3): d=7.42–
7.20 (m, 9H), 6.94 (m, 2H) 6.78 (t, J=7.0 Hz, 1H), 6.67 (d,
J=8.1 Hz, 2H), 5.74 (bt, J=10.7 Hz, 1H), 5.54 (bd, J=
10.2 Hz, 1H), 5.16 (b dd, J1 =J2 =11.8 Hz, 2H), 4.69 (bs,
1H), 3.99 (bs, 1H), 2.41 (dt, J=13.3 and 2.3 Hz, 1H), 1.99
(ddd, J=12.0, 9.3, 4.3 Hz, 1H); 1H NMR (600 MHz,
CD3CN): d=7.38 (m, 3H), 7.34 (m, 1H), 7.31 (dd, J=7.7
and 1.7 Hz, 1H), 7.22 (dt, 1H), 7.18 (m, 2H), 6.94 (dt, J=
7.4 and 1.1 Hz, 1H) 6.88 (bs, 1H), 6.83 (d, J=8.2 Hz, 1H),
6.72 (d, J=7.9 Hz, 2H), 6.68 (t, J=7.8 Hz, 2H), 5.65 (dt, J=
10.1 and 2.1 Hz, 1H), 5.12 (bs, 2H), 4.75 (bs, 1H), 2.25 (bd,
J=13.6 Hz, 1H), 2.07 (m, 1H); 13C NMR (100 MHz,
CD3CN): d=153.9, 147.1, 137.1, 130.5, 129.5, 129.4, 129.1,
128.7, 128.30, 122.5, 121.1, 117.4, 116.9, 113.0, 76.4, 66.7,
47.2, 32.1; ESI-MS: m/z=397 [M+ +Na].
General Procedure for the Organocatalytic
[4+2]Cycloaddition Reaction of Aldimines 1a, b, e, j
with 2-Vinylindole 4
To a flame-dried Schlenk tube equipped with a magnetic
stirring bar, 5ꢁ powder molecular sieves (100 mg) were
added under a nitrogen atmosphere. The molecular sieves
were then thermally activated under vacuum for 10 min and
then allowed to cool to room temperature. The aldimine 1
(0.10 mmol) was added under a nitrogen atmosphere, fol-
lowed by anhydrous THF (330 mL), the catalyst 8e (7.5 mg,
0.010 mmol) and 2-vinylindole 4 (17.2 mg, 0.12 mmol). The
mixture was then stirred at 458C under a nitrogen atmos-
phere. After 24 h, the reaction mixture was filtered through
a plug of silica gel, and the plug washed with EtOAc (2ꢂ).
After concentration of the solvents, the residue was ana-
1
6a’: The er of the minor diastereoisomer was determined
by HPLC using a Chiralcel OD column (n-hexane/i-PrOH
lysed by H NMR spectroscopy to determine the diastereo-
selectivity obtained. Finally, the residue was purified by
chromatography on silica gel (n-hexane/EtOAc mixtures)
obtaining the desired product as a mixture of two diastereo-
isomers.
80:20, flow-rate 1.0 mLminÀ1):
tmaj =51.01 min, tmin =
1
121.02 min; er 56:44; H NMR (400 MHz, CDCl3): d=7.42–
7.20 (m, 9H), 6.86 (m, 3H) 6.78 (t, J=7.0 Hz, 1H), 5.93 (bs,
1H), 5.16 (bdd, J1 =J2 =11.8 Hz, 2H), 4.73 (bs, 1H), 3.84
(bs, 1H), 2.41 (dt, J=13.3 and 2.3 Hz, 1H), 2.3 (m, 1H).
1H NMR (600 MHz, CD3CN): d=7.38 (m, 5H), 7.34 (m,
1H), 7.18 (m,3H), 6.93 (dt, J=7.5, 1.2 Hz, 1H) 6.8 (d, J=
8.2 Hz, 1H), 6.74 (d, 2H), 6.72 (d, 1H), 5.75 (dt, J=9.5 and
2.6 Hz, 1H), 5.12 (bs, 2H), 4.92 (m, 1H), 4.61 (b d, J=
7.8 Hz, 1H), 2.41 (ddd, J=13.1, 5.4 and 2.7 Hz, 1H), 2.02
(m,1H); 13C NMR (100 MHz, CD3CN): d=155.9, 153.5,
148.1, 128.3, 128.8, 128.3, 128.2, 128.0, 125.6, 124.5,121.1,
117.7, 116.8, 113.4, 78.7, 66.8, 48.1, 32.7.
2-(1H-Indol-2-yl)-N-phenylchroman-4-amine (7a): N-Phe-
nylsalicylaldimine 1a (19.7 mg) was reacted following the
general procedure. 1H NMR of the crude mixture showed
the presence 7a as a mixture of two diastereoisomers in a
14:1 ratio. Chromatography on silica gel (n-hexane/EtOAc
90:10) afforded 7a as a viscous oil; yield: 60%. The er of the
major diastereoisomer was determined by HPLC using a
Chiralcel AD-H column (n-hexane/i-PrOH 90:10, flow-rate
0.75 mLminÀ1): tmaj =42.6 min, tmin =38.0 min, er 88:12; the
er of the minor diastereoisomer was determined by HPLC
using a Chiralcel AD-H column (n-hexane/i-PrOH 90:10,
flow-rate 0.75 mLminÀ1): tmaj =45.4 min, tmin =49.4 min, er
1
Full assignments of H and 13C NMR signals of 6a and 6a’
were obtained by HSQC and HMBC bi-dimensional se-
quences in CD3CN as the solvent and NOE spectra were ac-
quired in order to establish the relative stereochemistry. The
relative stereochemistry was found to be cis for 6a and trans
for 6a’.
1
83.5:16.5; H NMR (400 MHz, CDCl3): d=(major diastereo-
isomer) 8.47 (bs, 1H), 7.62–7.5 (m, 2H), 7.38 (d, J=8.1 Hz,
1H), 7.31–7.15 (m, 5H), 7.15–7.06 (m, 1H), 7.03–6.92 (m,
2H), 6.84–6.70 (m, 2H), 6.46 (bs, 1H), 5.51 (dd, J=10.7 and
2.0 Hz, 1H), 5.03 (dd, J=10.2,6.0 Hz, 1H), 2.86 (ddd, J=
13.5, 5.8 and 2.3 Hz, 1H), 2.32–2.19 (m, 1H); 13C NMR
(100 MHz, CDCl3): d=(major diastereoisomer) 154.5, 147.6,
9a: The er of the product was determined by HPLC using
a Chiralcel AD-H column (n-hexane/i-PrOH 80:20, flow-
rate 0.75 mLminÀ1):
tmaj =27.3 min,
tmin =30.3 min, er
3404
asc.wiley-vch.de
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 3399 – 3406

Catalytic Asymmetric Inverse-Electron-Demand (IED) [4+2]Cycloaddition of Salicylaldimines
138.6, 136.3, 129.58, 129.52, 127.9, 126.9, 126.6, 125.8, 121.7,
120.8, 120.7, 120.4, 119.8, 113.55, 113.50, 112.5, 111.8, 99.2,
83.0, 44.1, 37.5; ESI-MS: m/z=475 [M+ +Na].
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1
Full assignments of H and 13C NMR signals of 7a were
obtained by HSQC and HMBC bi-dimensional sequences in
CDCl3 as the solvent. NOE spectra were acquired in order
to establish the relative stereochemistry that was found to
be cis.
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Acknowledgements
Financial support from Universitꢀ di Bologna, Polo Scientifi-
co-Didattico di Rimini and MIUR Italy (National Project
“Stereoselezione in Sintesi Organica: Metodologie ed Appli-
cazioni”) is gratefully acknowledged.
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