Synthesis of aromatic aldehydes by organocatalytic [4+2] and [3+3] cycloaddition of α,β-unsaturated aldehydes

Article abstract of DOI:10.1016/j.tet.2007.01.039

Organocatalytic inter- and intramolecular [4+2] and [3+3] cycloadditions of α,β-unsaturated aldehydes to give polysubstituted aromatic aldehydes are described. High periselectivity for the cycloadditions, with catalyst effects exerted by l-proline and pyrrolidine-HOAc, as well as cocatalyst, additive effects, has been observed.

Full text of DOI:10.1016/j.tet.2007.01.039

Tetrahedron 63 (2007) 2840–2850
Synthesis of aromatic aldehydes by organocatalytic [4D2]
and [3D3] cycloaddition of a,b-unsaturated aldehydes
*
Bor-Cherng Hong, Hsing-Chang Tseng and Shang-Hung Chen
Department of Chemistry and Biochemistry, National Chung Cheng University, Min-Hsiung Chia-Yi, 621 Taiwan, ROC
Received 9 December 2006; revised 19 January 2007; accepted 22 January 2007
Available online 24 January 2007
Abstract—Organocatalytic inter- and intramolecular [4+2] and [3+3] cycloadditions of a,b-unsaturated aldehydes to give polysubstituted
aromatic aldehydes are described. High periselectivity for the cycloadditions, with catalyst effects exerted by L-proline and pyrrolidine–
HOAc, as well as cocatalyst, additive effects, has been observed.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
Recently, we reported on the proline-catalyzed [3+3] and
[4+2] cycloadditions of a,b-unsaturated aldehydes, a meth-
odology successfully applied in the synthesis of (ꢀ)-isopule-
gol hydrate and (ꢀ)-cubebaol.17 From these results it could
be suggested that aromatic aldehydes might also be synthe-
sized by this route, using a secondary amine as catalyst
(Scheme 1). Herein, we report an efficient and novel meth-
odology for the synthesis of aromatic aldehydes from orga-
nocatalyzed [3+3] and [4+2] reactions of a,b-unsaturated
aldehydes. The reaction proceeds under ambient and opera-
tionally simple conditions, requiring neither strong acids nor
active reagents that are usually seen in the formylation reac-
tions of aromatic compounds.
Organocatalysis is emerging as a powerful tool in asym-
metric synthesis and has attracted a great deal of attention
recently.1 Among the organocatalysts explored, secondary
amines are of particular interest. For example, proline2 and
its derivatives,3 MacMillan’s catalyst,4 dibenzylammonium
trifluoroacetate,5 and cysteine derivatives,6 have all been
used successfully in conjugated additions to a,b-unsaturated
compounds. Chiral amino sulfonamide has been used effec-
tively in Mannich reactions.7 Friedel–Crafts alkylation of
indoles with nitroalkenes was accomplished using a thiourea
derivative.8 5,5-Dimethyl-thiazolidine-4-carboxylic acid
(MDTP) was employed in the aldol reaction.9 Even simple
achiral secondary amines (e.g., pyrrolidine) have been re-
ported in the catalyzation of a [2,3] Wittig rearrangement,10
the Mannich reaction,11 the epoxidation of alkenes,12 and
the domino reaction,13 and have been applied in the synthe-
sis of BIRT-377, as well.14
2. Results and discussion
2.1. Organocatalyzed intermolecular cycloadditions
of a,b-unsaturated aldehydes
Although organocatalytic reactions have been extensively
reported in the literature, their application in the efficient syn-
thesis of aromatic aldehydes, compounds of longstanding
interest in both organic and medicinal chemistry,15 has re-
mained elusive. Of the various methods developed for the
preparation of these compounds, most depend upon the for-
mylation of an aromatic precursor, a process that usually
requires harsh reaction conditions and notorious reagents.16
Thus, theefficient synthesisofaromaticaldehydesfromcom-
mercially available compounds (e.g., a,b-unsaturated alde-
hydes) under mild reaction conditions remains a primarytarget.
Reaction of crotonaldehyde A1 with pyrrolidine (I,
25 mol %) and HOAc (25 mol %) in CH3CN at ambient tem-
perature for 24 h afforded p-tolualdehyde 3a in 81% yield
(Table 1, entry 1).18 Reaction of crotonaldehyde A1, pyrrol-
idine (I, 25 mol %), HOAc (25 mol %), and MnO2
(25 mol %) under reflux, however, gave the [3+3] adduct
3a and [4+2] adduct 4a in the ratio 2:1 (entry 2, Table 1).
This result implies that, prior to the aromatization step,
[3+3] rather than [4+2] cycloaddition is favored at lower
reaction temperatures. A series of a,b-unsaturated aldehydes
were caused to react in the presence of I or II under various
conditions; selected results are summarized in Table 1.
In some cases, aromatization of the adducts occurred spon-
taneously without the addition of the aromatization agent
(method A, Table 1). In many cases, the reaction of
Keywords: Organocatalysis; Proline; Cycloaddition; Unsaturated aldehyde.
* Corresponding author. Tel.: +886 52428174; fax: +886 52721040; e-mail:
chebch@ccu.edu.tw
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.01.039

B.-C. Hong et al. / Tetrahedron 63 (2007) 2840–2850
2841
1CHO
7CHO
2
6
H
R1
R2
O
3
R3
R2
5
4
O
7
1
1
2
7
4
3
R1
R2
6
5
6
2
3
H
+
5
4
R3
R1
R3
[3 + 3] adduct
[4 + 2] adduct
1CHO
2
R1
2
1
1
R1
3
4
7
6
CHO
3
4
2
5
7
6
R1
CHO
CHO
6
3
7
5
4
n
n
5
[4 + 2] adduct
[3 + 3] adduct
n
Scheme 1. Retrosynthetic analysis of aromatic aldehydes by [3+3] and [4+2] transformations.
Table 1. Organocatalyzed intramolecular cycloadditions of a,b-unsaturated aldehydes
+ CH3CO2H
R3
R1
R2
N
H
CHO
R1
CHO
+
I
+
R2
CHO
CHO
[4 + 2]
R2
R3
R1
R3
[3 + 3]
CO2H
1
2
N
H
3
4
II
CHO
CHO
CHO
CHO
CHO
Me
CHO
CHO
Me
Pr
Ph
Et
Bu
Me
A1
A2
A3
T (ꢁC) Product(s)
A4
A5
A6
A7
Entry Aldehydes (1, 2) Meth. t (h)
Ratiob (3:4)
Yieldc (%)
I
II
I
II
1
2
3
4
5
6
7
8
A1, A1
A1, A1
A1, A5
A1, A5
A2, A2
A2, A2
A2, A2
A3, A3
A3, A3
A3, A3
A4, A4
A4, A4
A4, A4
A6, A1
A6, A1
A6, A5
A6, A2
A6, A3
A6, A4
A7, A1
A
B
A
C
C
C
C
C
C
C
C
C
C
A
B
B
B
B
B
B
24
4
18
25
81
25
R1¼R2¼H, R3¼CH3, 3a
96:4
66:34
100:0
65:35
100:0
48:52
11:89
14:86
16:74
1:99
3:97
4:96
1:99
3:97
81
84
78
80
75
78
75
71
75
71
71
76
71
20d
63
R1¼R2¼H, R3¼CH3, 3a:4a
R1¼R2¼H, R3¼Ph, 3b
100:0
100:0
22:78
42:58
82:18
10:90
18:82
40:60
10:90
20:80
38:62
0:100
0:100
0:100
0:100
0:100
0:100
0:100
23d
40
(6, 3) 25a
(1, 8) 81a
(6, 8) 32a
R1¼R2¼H, R3¼Ph, 3b
R1¼H, R2¼CH3, R3¼Et, 3c:4c
R1¼H, R2¼CH3, R3¼Et, 3c:4c
R1¼H, R2¼CH3, R3¼Et, 3c:4c
R1¼H, R2¼Et, R3¼Pr, 3d:4d
R1¼H, R2¼Et, R3¼Pr, 3d:4d
R1¼H, R2¼Et, R3¼Pr, 3d:4d
R1¼H, R2¼Pr, R3¼Bu, 3e:4e
R1¼H, R2¼Pr, R3¼Bu, 3e:4e
R1¼H, R2¼Pr, R3¼Bu, 3e:4e
R2¼H, R1¼R3¼CH3, 4f
80
78
(6, 8)
0a
80f
76
(1, 8) 81a
(6, 8) 32a
(6, 8)
9
78
10
11
12
13
14
15
16
17
18
19
20
0a
82f
75
(1, 8) 81a
(6, 8) 32a
78
(6, 8)
72
5
4
6
7
10
8
0a
25
9:91
80f
NAg
NDe
NDe
NDe
NDe
NDe
NDe
NAg 82
NDe 83
NDe 86
NDe 77
NDe 72
NDe 68
NDe 82
81
81
81
81
81
81
R2¼H, R1¼R3¼CH3, 4f
R1¼CH3, R2¼H, R3¼Ph, 4g
R1¼CH3, R2¼H, R3¼Et, 4h
R1¼CH3, R2¼H, R3¼Pr, 4i
R1¼CH3, R2¼H, R3¼Bu, 4j
R1¼Me2C]CHCH2CH2, R2¼H, R3¼CH3, 4k;
R1¼R3¼CH3, R2¼Me2C]CHCH2, 4l, 4k:4l¼71:29
R1¼Me2C]CHCH2CH2, R2¼H, R3¼Ph, 4m
21
22
A7, A5
A7, A2
B
B
7
9
81
81
0:100
0:100
NDe 76
NDe 72
NDe
NDe
R1¼Me2C]CHCH2CH2, R2¼H, R3¼Et, 4n; R1¼CH3,
R2¼Me2C]CHCH2, R3¼Et, 4o, 4n:4o¼67:33
Method A: catalyst, CH3CN, 25 ꢁC. Method B: catalyst, MnO2, CH3CN, reflux. Method C: (1) catalyst, CH3CN, 25 ꢁC and (2) DDQ, C6H6, reflux.
Reaction temperature prior to the exposure of MnO2 or DDQ (aromatization step).
a
The ratios were determined by 1H NMR.
Isolated yields.
Isolated with large amounts of the [3+3] alcohol adducts and dienes, see Ref. 18.
Not determined; complicated mixtures of self- and cross-condensations, and dienes.
Reaction for 64 h.
The [4+2] diene product was obtained in 80% yield, see Ref. 17, which can be converted to 4f by the reaction with DDQ.
b
c
d
e
f
g

2842
B.-C. Hong et al. / Tetrahedron 63 (2007) 2840–2850
aldehyde, catalyst, and MnO2 in a one-pot reaction process
provided the aromatic aldehydes (method B, Table 1). In
certain cases, a strong reagent (e.g., DDQ) was required
to promote aromatization of the diene adducts (method C,
Table 1). Reaction of A1 and A5 with I gave the [3+3] ad-
duct 3b, predominantly (entries 3 and 4 Table 1). For self-
condensation of the b-monoalkylaldehydes bearing g-acidic
protons (e.g., A1, A2, A3, and A4), reaction at lower tem-
perature gave a higher ratio of [3+3] adducts 3a, 3c–3e
(entries 1–2 and 5–13, Table 1). Reaction of prenal A6
with A1 (A2, A3, A4 or A5), catalyzed by pyrrolidine–
HOAc (I), afforded the [4+2] adducts 4f–4j (entries 14–19).
The same reactions, catalyzed by L-proline (II), afforded
complicated diene mixtures arising from self- and cross-
condensation of aldehydes. Reaction of geranial A7 with
A1 (A5 or A2), catalyzed by pyrrolidine–HOAc (I), pro-
vided the [4+2] adduct 4k–4o, exclusively, albeit with
regioisomers (entries 20–22, Table 1). L-Proline-catalyzed
reaction of these substrates, however, gave complicated
mixtures and low yields (entries 20–22, Table 1). The results
in Table 1 imply that, in many cases, pyrrolidine–HOAc (I)
is a superior catalyst to L-proline (II) in the preparation of
these aromatic aldehydes.
spontaneously transform to the aromatic products, 13 or
16. In contrast, the [4+2] adducts, 15 and 18, were unreactive
under the normal reaction conditions, and a strong aroma-
tization agent, such as DDQ, was required to effect the
aromatization.
Recently, cocatalyst effects have been reported as instrumen-
tal in achieving enhanced chemoselectivity and stereoselec-
tivity.20 Accordingly, various additives (t-Bu3P, pyrrolidine,
Et2NH, and imidazole) were introduced and their effects
were examined in these reactions (entries 5–8, Table 2).
Among these, it is noteworthy that diene 15 was isolated in
91% ee in the reaction with L-proline-t-Bu3P (entry 6, Table
2). Addition of pyrrolidine in the presence of L-proline gave
[3+3] product, exclusively (entry 8, Table 2). Reaction with
the MacMillan’s catalyst afforded [3+3] adduct 13, exclu-
sively, in 73% yield (entry 9, Table 2). Similar reaction con-
ditions were applied to dienealdehyde 6 (entries 10–18, Table
2). Exclusive formation of [4+2] adducts 18 (and then 17)
was achieved by reaction with L-proline alone, or with the
addition of imidazole or t-Bu3P (entries 12–15, Table 2).
Reaction with pyrrolidine–HOAc, MacMillan’s catalyst or
L-proline with the addition of Et2NH and pyrrolidine, prefer-
entially afforded [3+3] adduct 16 (entries 10, 11 and 16–18,
Table 2).
2.2. Organocatalyzed intramolecular cycloadditions
of a,b-unsaturated aldehydes
2.3. Organocatalyzed intramolecular cycloadditions
of a,b,g,d-unsaturated aldehydes
Periselectivity continues to be of great interest in organic
chemistry.19 Observing high periselectivity in the inter-
molecular cycloadditions of a,b-unsaturated aldehydes, we
next turned our attention to achieve similar results in the
analogous intramolecular reaction. Accordingly, dialde-
hydes 5 and 6 were prepared from cyclohexene and cyclo-
heptene, respectively, in four steps (Scheme 2). Reaction
of 5 in CH3CN with 0.5 equiv of pyrrolidine and HOAc at
30 ꢁC for 4 h, followed by the addition of DDQ (2 equiv)
at 30 ꢁC and stirring for 2 h, afforded an 83% yield of the
aromatic aldehydes 13 ([3+3] adduct) and 14 ([4+2] adduct),
in a ratio of 3:1 (Table 2, entry 1). Interestingly, the [3+3]
product 13 was obtained exclusively, in 81% yield, when
the reaction was conducted at ꢀ10 ꢁC, followed by the addi-
tion of DDQ, with stirring, for an additional 2 h at ambient
temperature (entry 2, Table 2). Even more interesting, reac-
tion with L-proline at room temperature, followed by aroma-
tization with DDQ gave the [4+2] product 14 exclusively, in
80% yield (entry 3, Table 2). Under the same reaction con-
ditions but without the addition of DDQ, the [4+2] diene
product 15 was isolated in 80% yield with 80% enantiomeric
excess (entry 3, Table 2). The enantioselectivity increased to
85% ee when the reaction was run at ꢀ10 ꢁC (entry 4, Table
2). From this study, we draw the general conclusion that the
[3+3] adducts, i.e., 19 and 20, are insufficiently stable to be
observed or isolated under the reaction conditions, and
Dihydronaphthalenecarboxylic acid 21 was prepared and
used in the synthesis of NaphMA for an ELISA (enzyme-
linked immunosorbent assay) technique.21 In a related
application, ester 22 has been used for the preparation of
a series of orally active platelet fibrinogen receptor glyco-
protein IIb–IIIa antagonists.22 It was our belief that the cy-
cloaddition mechanism described herein might apply in the
synthesis of these compounds (Scheme 3). Accordingly,
trienedial 27 was prepared from 24 and caused to react
with L-proline to give aromatic aldehyde 23 in 65% yield
(Scheme 4). Chlorite oxidation of aldehyde 23 afforded
the acid 21, followed by reaction with diazomethane to
give ester 22. It is noteworthy that the inverse electron-
demand Diels–Alder reaction was the predominant pathway
in the reaction (Scheme 3).23
3. Conclusion
In summary, organocatalytic intermolecular [3+3] and [4+2]
cycloadditions have been established as effective methodol-
ogies in the preparation of aromatic aldehydes. Further stud-
ies with the analogous intramolecular pathway were also
conducted and high regioselectivity under certain catalyst
R
a
b
CHO
R
n
OHC
n
n
8. n=1, R = CO2Et; 11. n=2, R = CO2Et
9. n=1, R = CH2OH; 12. n=2, R = CH2OH
7. n =1
10. n =2
c
d
5. n=1, R = CHO;
6. n=2, R = CHO
Scheme 2. Preparation of dienealdehydes 5 and 6: (a) RuCl3, NaIO4, CH2Cl2–H2O (2:1); 91% for 7; 90% for 10. (b) (OEt)2P(O)CH2CO2Et, NaH, THF, 0 ꢁC;
87% for 8; 85% for 11. (c) DIBAL-H, CH2Cl2, 0 ꢁC; 81% for 9; 80% for 12. (d) MnO2, CH2Cl2; 90% for 5; 90% for 6.

B.-C. Hong et al. / Tetrahedron 63 (2007) 2840–2850
Table 2. Organocatalyzed intramolecular cycloadditions of a,b-unsaturated aldehydes
2843
H
OHC
OHC
n
n
H
[3 + 3]
[3 + 3]
19. n = 1
20. n = 2
13. n = 1
16. n = 2
OHC
CHO
n
+
5. n = 1
6. n = 2
OHC
H
CHO
DDQ
n
n
H
[4 + 2]
[4 + 2]
15. n = 1
18. n = 2
14. n = 1
17. n = 2
Entry
Aldehydes
T (ꢁC)
t (h)
Methodb
Additive
Products ratio ([3+3]/[4+2])
Yielda (%)
eec (%)
1
2
3
4
5
6
7
8
5, n¼1
5, n¼1
5, n¼1
5, n¼1
5, n¼1
5, n¼1
5, n¼1
5, n¼1
5, n¼1
6, n¼2
6, n¼2
6, n¼2
6, n¼2
6, n¼2
6, n¼2
6, n¼2
6, n¼2
6, n¼2
(30, 30)
(ꢀ10, 30)
(30, 30)
(ꢀ10, 30)
(32, 30)
(30, 30)
(30, 30)
(30, 30)
(30, 30)
(30, 30)
(0, 30)
(30, 30)
(32, 32)
(32, 30)
(0, 30)
(32, 32)
(32, 32)
(32, 32)
(4, 2)
(6, 2)
(6, 2)
(48, 2)
(2, 2)
(4, 2)
(4, 2)
(4, 2)
(5, 2)
(2, 3)
(8, 3)
(5, 2)
(4, 2)
(2, 2)
(66, 2)
(4, 2)
(2, 2)
(3, 2)
A
A
B
B
C
D
E
F
G
A
A
B
C
D
D
E
F
13:14 (75:25)
13:14 (100:0)
13:14 (0:100)
13:14 (33:67)
13:14 (0:100)
13:14 (0:100)
13:14 (50:50)
13:14 (100:0)
13:14 (100:0)
16:17 (57:43)
16:17 (66:34)
16:17 (0:100)
16:17 (0:100)
16:17 (4:96)
16:17 (0:100)
16:17 (62:38)
16:17 (72:28)
16:17 (65:35)
83
81
80
79
48
77
70
75
73
74
75
80
75
76
78
70
75
75
NA
NA
80d
85d
52d
91d
20d
NA
NA
NA
NA
83e
49e
90e
95e
30e
15e
w0e
Imidazole
t-Bu3P
Et2NH
Pyrrolidine
9
10
11
12
13
14
15
16
17
18
Imidazole
t-Bu3P
t-Bu3P
Et2NH
Pyrrolidine
G
a
Isolated yields.
b
Method A: (1) pyrrolidine, HOAc, CH3CN and (2) DDQ, CH2Cl2. Method B: (1) L-proline, CH3CN and (2) DDQ, CH2Cl2. Method C: (1) L-proline, imida-
zole, CH3CN and (2) DDQ, CH2Cl2. Method D: (1) L-proline, t-Bu3P, CH3CN and (2) DDQ, CH2Cl2. Method E: (1) L-proline, Et2NH, CH3CN and (2) DDQ,
CH2Cl2. Method F: (1) L-proline, pyrrolidine, CH3CN and (2) DDQ, CH2Cl2. Method G: MacMillan’s catalyst, TFA, CH3CN and (2) DDQ, CH2Cl2.
The diene products, 15 and 18, were isolated under the same reaction conditions without the treatment with DDQ and the enantiomeric excesses (ee) were
measured by GC–MS (Shimadzu QP 5000, chiral capillary column, gamma-cyclodextrin trifluoroacetyl, Astec Type G-TA, size 30 mꢂ0.25 mm, flow rate
24 mL/min, temperature range: 60–120 ꢁC, gradient: 3 ꢁC/min). Absolute configuration was not determined.
ee of 15.
c
d
e
ee of 18.
and temperature conditions was observed. The reaction pro-
ceeds under ambient conditions, precluding the need for
harsh reagents and reaction conditions, and thus constituting
an unprecedented and efficient synthesis of aromatic alde-
hydes from readily commercially available a,b-unsaturated
aldehydes.
6
11
5
10
7
6
11
10
4
5
2
5
3
11
R2N
10
5
O
6
7
9
10
11
3
6
OHC
[4 + 2]
9
8
7
[3 + 3]
7
8
3
2
1
1 CHO4
9
O
2
4
OHC
9
2
4
8
1
3
8
1
7
6
11
6
11
5
8
7
CHO
5
R2N
O
10
10
4
9
8
11
6
5
10
11
7
[4 + 2]
3
[4 + 2]
10
9
1
2
9
R2N
2
OHC
6
2
9
4
OHC
2
4
4
7
3
3
5
8
3
1
8
1
1
Inverse electron demand
Scheme 3. Possible pathways for the intramolecular cycloaddition of 27.

2844
B.-C. Hong et al. / Tetrahedron 63 (2007) 2840–2850
9
4
7
2
4
6
11
8
1
R10
3
8
5
4
O
10
9
10
11
O
3
5
6
a
d
c
7
O
O
2
R
6
2
R11
7
5
3
9
8
1
1
24
27
25. R = CO2Et
26. R = CH2OH
23. R = CHO
21. R = CO2 H
b
e
f
22. R = CO2Me
Scheme 4. Intramolecular cycloaddition of 27: (a) (OEt)2P(O)CH2CO2Et, NaH, THF, 0 ꢁC; 87%. (b) DIBAL-H, CH2Cl2, 0 ꢁC; 80%. (c) MnO2, CH2Cl2; 90%.
(d) L-Proline, CH3CN; 65%. (e) NaClO2, NaH2PO4, 2-methyl-2-butene, t-BuOH, 25 ꢁC; 80%. (f) CH2N2, CH2Cl2; 90%.
4. Experimental
in vacuo to give the residue. The crude product was purified
by flash column chromatography with 3% EtOAc–hexane to
give adduct 4f (111 mg, 83% yield; Rf ¼0.78 in 10% EtOAc–
hexane) as a yellow oil.
4.1. General
All solvents were reagent grade. All chemicals were pur-
chased from Aldrich and Acros Chemical Co. Reactions
were normally carried out under an argon atmosphere in
flame-dried glassware. Merck silica gel 60 (particle size
0.04–0.063 mm) was employed for flash chromatography.
HPLC was equipped with the ultraviolet and refractive index
detectors. The sample was analyzed and/or separated on a
Spherisorb-Si column (25 cmꢂ10 mm, particle size 8 mm,
Method C: a solution of trans-2-hexenyl aldehyde (196 mg,
2.0 mmol) and L-proline (115 mg, 1.0 mmol) in CH3CN
(14 mL) was stirred at 32 ꢁC for 6 h until the reaction was
completed, monitored by TLC. The solution was concen-
trated in vacuo to give the residue. A solution of the residue
and DDQ (681 mg, 3.0 mmol) in C6H6 (5 mL) was heated to
reflux for 8 h until the reaction was completed, monitored by
TLC. The solution was concentrated in vacuo to give the
residue. The crude product was purified by flash column
chromatography with 3% EtOAc–hexane to give adduct
4d (113 mg, 76% yield; Rf ¼0.69 in 10% EtOAc–hexane)
as a yellow oil.
˚
pore size 60 A) or a m-Porasil column (25 cmꢂ1.0 cm) using
a flow rate of 5 mL/min and ultraviolet and refractive index
detectors (ethyl acetate and hexane eluants). The flow rate of
the indicated elution solvent is maintained at 5 mL/min or
1 mL/min and the retention time of a compound is recorded
accordingly. Melting points are uncorrected. Most com-
pounds were characterized by full spectroscopic (1H
NMR, 13C NMR, DEPT, HMQC, COSY, and NOESY)
4.2.1. 4-Methyl-benzaldehyde (3a). Prepared from croton-
aldehyde (A1) according to the procedure in Section 4.2.
Rf ¼0.21 in 10% EtOAc–hexane, 81% yield, yellow oil;24
IR (neat): 3043, 2927, 2826, 2737, 1695, 1515, 1211, 765,
1
data. H NMR, COSY, and NOESY spectra were obtained
in CDCl3 unless otherwise noted at 400 MHz (Bruker
DPX-400) or 500 MHz (Varian-Unity INOVA-500). 13C
NMR spectra were obtained at 100 MHz or 125 MHz.
1
676 cmꢀ1; H NMR (CDCl3, 500 MHz): d 9.94 (s, 1H),
7.75 (d, J¼7.5 Hz, 2H), 7.30 (d, J¼7.5 Hz, 2H), 2.41 (s,
3H); 13C NMR (CDCl3, 125 MHz): d 191.99 (CH), 145.54
(C), 134.18 (C), 129.84 (2CH), 129.69 (2CH), 21.25
(CH3); MS (m/z, relative intensity): 120 (M+, 85), 91
(100), 65 (37), 63 (18); exact mass calculated for C8H8O
(M+): 120.0575; found: 120.0571.
4.2. Representative procedure for the synthesis
of aromatic aldehyde from a,b-unsaturated
aldehydes (reactions in Table 1)
Method A: to a solution of crotonaldehyde (70 mg,
1.0 mmol) and trans-cinnamaldehyde (132 mg, 1.0 mmol)
in CH3CN (14 mL) were added slowly pyrrolidine (71 mg,
1.0 mmol) and HOAc (60 mg, 1.0 mmol) at 25 ꢁC. The solu-
tion was stirred at 25 ꢁC for 18 h. The reaction was quenched
by the addition of H2O (10 mL). To the solution was added
H2O (10 mL) and extracted with EtOAc (50 mLꢂ2). The
organic solution was washed with brine (10 mL), dried
over Na2SO4, and concentrated in vacuo to give the crude
product. The residue was purified by flash column chromato-
graphy with 3% EtOAc–hexane to give adduct 3b (141 mg,
78% yield; Rf ¼0.76 in 10% EtOAc–hexane) as a yellow oil.
4.2.2. 2-Methyl-benzaldehyde (4a). Prepared from croton-
aldehyde (A1) according to the procedure in Section 4.2.
Rf ¼0.21 in 10% EtOAc–hexane, 84% yield, yellow oil;25
IR (neat): 3065, 2966, 2857, 2736, 1695, 1449, 1293, 835,
1
657 cmꢀ1; H NMR (CDCl3, 500 MHz): d 10.20 (s, 1H),
7.23 (d, J¼7.5 Hz, 1H), 7.42 (dd, J¼7.5, 7.5 Hz, 1H), 7.30
(dd, J¼7.5, 7.5 Hz, 1H), 7.20 (d, J¼7.5 Hz, 1H), 2.61 (s,
3H); 13C NMR (CDCl3, 125 MHz): d 192.72 (CH), 140.64
(C), 133.95 (C), 133.54 (CH), 132.01 (CH), 131.65 (CH),
126.14 (CH), 19.42 (CH3); MS (m/z, relative intensity):
120 (M+, 85), 91 (100), 65 (37), 63 (18); exact mass calcu-
lated for C8H8O (M+): 120.0575; found: 120.0582.
Method B: to a solution of crotonaldehyde (70 mg,
1.0 mmol) and 3-methyl-2-butenal (84 mg, 1.0 mmol) in
CH3CN (14 mL) were added pyrrolidine (71 mg,
1.0 mmol), acetic acid (60 mg, 1.0 mmol), and MnO2
(87 mg, 1.0 mmol). The solution was heated to reflux for
5 h until the reaction was completed, monitored by TLC.
To the solution was added H2O (10 mL) and extracted
with EtOAc (50 mLꢂ2). The organic solution was washed
with brine (10 mL), dried over Na2SO4, and concentrated
4.2.3. Biphenyl-4-carbaldehyde (3b). Prepared from croton-
aldehyde (A1) and cinnamaldehyde (A5) according to the
procedure in Section 4.2. Rf ¼0.76 in 10% EtOAc–hexane,
78% yield, yellow oil;26 IR (neat): 3029, 2925, 2855, 2731,
1
1697, 1601, 1107, 967, 758, 726 cmꢀ1; H NMR (CDCl3,
500 MHz): 10.05 (s, 1H), 7.94 (d, J¼8.0 Hz, 2H), 7.74 (d,
J¼8.0 Hz, 2H), 7.63 (d, J¼7.0 Hz, 2H), 7.46 (dd, J¼8.0,
8.0 Hz, 2H), 7.41 (d, J¼8.0, 8.0 Hz, 1H); 13C NMR

B.-C. Hong et al. / Tetrahedron 63 (2007) 2840–2850
2845
(CDCl3, 125 MHz): d 191.96 (CH), 147.19 (C), 139.69 (C),
135.15 (C), 130.27 (2CH), 129.00 (2CH), 128.46 (CH),
127.68 (2CH), 127.36 (2CH); MS (m/z, relative intensity):
182 (M+, 68), 181 (M+ꢀ1, 72), 167 (42), 149 (100), 97
(38), 7 (56), 57 (80); exact mass calculated for C13H10O
(M+): 182.0732; found: 182.0730.
21), 135 (21), 107 (59), 79 (100), 77 (45); exact mass calcu-
lated for C10H14O (M+): 176.1201; found: 176.1206.
4.2.8. 4-Butyl-3-propyl-benzaldehyde (3e). Prepared from
hept-2-enal (A4) according to the procedure in Section 4.2.
Rf ¼0.63 in 10% EtOAc–hexane, yellow oil; IR (neat): 2958,
2867, 1694, 1584, 1459, 1233, 756 cmꢀ1; 1H NMR (CDCl3,
500 MHz): d 9.95 (s, 1H), 7.66 (s, 1H), 7.63 (d, J¼7.0 Hz,
1H), 7.30 (d, J¼7.0 Hz, 1H), 2.70–2.60 (m, 4H), 1.68–
1.60 (m, 2H), 1.58–1.55 (m, 2H), 1.44–1.40 (m, 2H), 1.01
(t, J¼7.5 Hz, 3H), 0.96 (t, J¼7.5 Hz, 3H); 13C NMR
(CDCl3, 125 MHz): d 192.41 (CH), 148.36 (C), 141.27
(C), 134.41 (C), 130.40 (CH), 129.79 (CH), 127.46 (CH),
34.49 (CH2), 33.06 (CH2), 32.72 (CH2), 24.03 (CH2),
22.78 (CH2), 14.13 (CH3), 13.96 (CH3); MS (m/z, relative in-
tensity): 204 (M+, 4), 203 (M+ꢀ1, 21), 173 (61), 148 (93), 69
(100); exact mass calculated for C14H20O (M+): 204.1514;
found: 204.1507.
4.2.4. 4-Ethyl-3-methyl-benzaldehyde (3c). Prepared from
pent-2-enal (A2) according to the procedure in Section 4.2.
Rf ¼0.69 in 10% EtOAc–hexane, yellow oil; IR (neat):
2967, 2925, 2865, 2709, 1694, 1604, 1379, 830, 786 cmꢀ1
;
1H NMR (CDCl3, 500 MHz): d 9.92 (s, 1H), 7.63 (d,
J¼8.0 Hz, 1H), 7.63 (s, 1H), 7.29 (d, J¼8.0 Hz, 1H), 2.66
(q, J¼7.0 Hz, 2H), 2.66 (s, 3H), 1.22 (t, J¼7.0 Hz, 3H);
13C NMR (CDCl3, 125 MHz): d 192.31 (CH), 149.91 (C),
136.77 (C), 134.42 (C), 131.08 (CH), 128.52 (CH), 127.94
(CH), 26.55 (CH2), 19.09 (CH3), 13.94 (CH3); MS (m/z, rel-
ative intensity): 148 (M+, 6), 135 (43), 123 (32), 97 (60), 81
(60), 71 (60), 57 (100), 55 (94); exact mass calculated for
C10H12O (M+): 148.0888; found: 148.0880.
4.2.9. 2-Butyl-3-propyl-benzaldehyde (4e). Prepared from
hept-2-enal (A4) according to the procedure in Section 4.2.
Rf ¼0.64 in 10% EtOAc–hexane, yellow oil; IR (neat): 2966,
4.2.5. 2-Ethyl-3-methyl-benzaldehyde (4c). Prepared from
pent-2-enal (A2) according to the procedure in Section 4.2.
Rf ¼0.70 in 10% EtOAc–hexane, yellow oil;27 IR (neat):
1696, 1456, 1112 cmꢀ1 1H NMR (CDCl3, 500 MHz):
;
d 10.28 (s, 1H), 7.66 (d, J¼7.5 Hz, 1H), 7.36 (d, J¼
8.0 Hz, 1H), 7.24 (dd, J¼8.0, 7.5 Hz, 1H), 3.00 (t,
J¼7.0 Hz, 2H), 2.62 (t, J¼8.0 Hz, 2H), 1.65–1.41 (m, 6H),
0.99 (t, J¼8.0 Hz, 3H), 0.94 (t, J¼7.0 Hz, 3H); 13C NMR
(CDCl3, 125 MHz): d 192.7 (CH), 143.6 (C), 141.8 (C),
135.1 (CH), 134.1 (C), 129.3 (CH), 125.9 (CH), 34.7 (CH2),
34.4 (CH2), 27.1 (CH2), 24.5 (CH2), 23.1 (CH2), 14.1 (CH3),
13.8 (CH3); MS (m/z, relative intensity): 204 (M+, 4), 203
(M+ꢀ1, 21), 173 (61), 148 (93), 69 (100); exact mass calcu-
lated for C14H20O (M+): 204.1514; found: 204.1511.
2962, 2925, 2857, 2709, 1694, 1604, 1455, 830, 756 cmꢀ1
;
1H NMR (CDCl3, 500 MHz): d 10.29 (s, 1H), 7.66 (d,
J¼7.5 Hz, 1H), 7.37 (d, J¼7.5 Hz, 1H), 7.24 (dd, J¼
7.5, 7.5 Hz, 1H), 3.05 (q, J¼7.5 Hz, 2H), 2.37 (s, 3H), 1.19
(t, J¼7.5 Hz, 3H); 13C NMR (CDCl3, 125 MHz): d 192.79
(CH),145.35(C),137.31(C),135.92(CH), 133.69(C),129.65
(CH), 126.01 (CH), 21.14 (CH2), 19.00 (CH3), 15.21 (CH3);
MS (m/z, relative intensity): 148 (M+, 100), 147 (M+ꢀ1, 86),
119 (49), 105 (50), 91 (44), 77 (31); exact mass calculated
for C10H12O (M+): 148.0888; found: 148.0886.
4.2.10. 2,4-Dimethyl-benzaldehyde (4f). Prepared from
crotonaldehyde (A1) and 3-methyl-but-2-enal (A6) accord-
ing to the procedure in Section 4.2. Rf ¼0.78 in 10%
EtOAc–hexane, 82% yield, yellow oil;28 IR (CHCl3):
4.2.6. 3-Ethyl-4-propyl-benzaldehyde (3d). Prepared from
hex-2-enal (A3) according to the procedure in Section 4.2.
Rf ¼0.67 in 10% EtOAc–hexane, yellow oil; IR (neat):
1
2961, 2926, 2867, 1695, 1605, 1380, 1195, 901, 756 cmꢀ1
;
2966, 1696, 1232 cmꢀ1; H NMR (CDCl3, 500 MHz): d
1H NMR (CDCl3, 500 MHz): d 9.94 (s, 1H), 7.67 (s, 1H),
7.61 (d, J¼7.5 Hz, 1H), 7.28 (d, J¼7.5 Hz, 1H), 2.70 (q,
J¼7.5 Hz, 2H), 2.65 (t, J¼7.5 Hz, 2H), 1.62 (q, J¼7.5 Hz,
2H), 1.23 (t, J¼7.5 Hz, 3H), 0.98 (t, J¼7.5 Hz, 3H); 13C
NMR (CDCl3, 125 MHz): d 192.39 (CH), 147.91 (C),
142.80 (C), 134.63 (C), 129.77 (CH), 129.49 (CH), 127.50
(CH), 34.98 (CH2), 25.13 (CH2), 23.90 (CH2), 14.98
(CH3), 14.16 (CH3); MS (m/z, relative intensity): 176 (M+,
80), 147 (100), 129 (54), 119 (42), 105 (48), 57 (68); exact
mass calculated for C12H16O (M+): 176.1201; found:
176.1206.
10.81 (s, 1H), 7.67 (d, J¼8.0 Hz, 1H), 7.14 (d, J¼8.0 Hz,
1H), 7.04 (s, 1H), 2.61 (s, 3H), 2.36 (s, 3H); 13C NMR
(CDCl3, 125 MHz): d 192.38 (CH), 144.58 (C), 140.60 (C),
132.52 (CH), 132.37 (CH), 131.92 (C), 127.04 (CH), 21.65
(CH3), 19.56 (CH3); MS (m/z, relative intensity): 135
(M++1, 33), 97 (21), 87 (75), 74 (100); exact mass calculated
for C9H10O (M+): 134.0732; found 134.0729.
4.2.11. 5-Methyl-biphenyl-2-carbaldehyde (4g). Prepared
from cinnamaldehyde (A5) and 3-methyl-but-2-enal (A6)ac-
cording to the procedure in Section 4.2. Rf ¼0.69 in 10%
EtOAc–hexane, 86% yield, yellow oil; IR (neat): 2849,
1689, 1603, 1395, 1119 cmꢀ1; 1H NMR (CDCl3, 500 MHz):
d 9.92 (s, 1H), 7.93 (d, J¼8.0 Hz, 1H), 7.47–7.40 (m, 3H),
7.38–7.33 (m, 2H), 7.31–7.26 (m, 1H), 7.23 (s, 1H), 2.45 (s,
3H); 13C NMR (CDCl3, 125 MHz): d 192.12 (CH), 146.12
(C), 144.54 (C), 137.95 (C), 131.47 (C), 131.32 (CH), 130.00
(2CH), 128.64 (CH), 128.33 (2CH), 128.07 (CH), 127.65
(CH), 21.82 (CH3); MS (m/z, relative intensity): 196 (M+,
100), 195 (M+ꢀ1, 100), 152 (45), 43 (80); exact mass calcu-
lated for C14H12O (M+): 196.0888; found 196.0891.
4.2.7. 3-Ethyl-2-propyl-benzaldehyde (4d). Prepared from
hex-2-enal (A3) according to the procedure in Section 4.2.
Rf ¼0.68 in 10% EtOAc–hexane, yellow oil; IR (neat):
2967, 1695, 1455, 1113 cmꢀ1
;
1H NMR (CDCl3,
500 MHz): d 10.27 (s, 1H), 7.65 (d, J¼7.0 Hz, 1H), 7.38
(d, J¼7.5 Hz, 1H), 7.25 (dd, J¼7.5, 7.0 Hz, 1H), 2.97 (t,
J¼8.0 Hz, 2H), 2.68 (q, J¼8.0 Hz, 2H), 1.58–1.49 (m,
2H), 1.21 (t, J¼8.0 Hz, 3H), 1.02 (t, J¼8.0 Hz, 3H); 13C
NMR (CDCl3, 125 MHz): d 192.70 (CH), 143.41 (C),
143.17 (C), 134.26 (CH and C), 129.29 (CH), 126.20
(CH), 29.25 (CH2), 25.67 (CH2), 25.28 (CH2), 15.56
(CH3), 14.38 (CH3); MS (m/z, relative intensity): 176 (M+,
4.2.12. 2-Ethyl-4-methyl-benzaldehyde (4h). Prepared
from pent-2-enal (A2) and 3-methyl-but-2-enal (A6)

2846
B.-C. Hong et al. / Tetrahedron 63 (2007) 2840–2850
according to the procedure in Section 4.2. Rf ¼0.71 in 10%
500 MHz): d 10.24 (s, 1H), 7.55 (d, J¼8.0 Hz, 1H), 7.14
(d, J¼8.0 Hz, 1H), 4.90 (t, J¼7.5 Hz, 1H), 3.37 (d,
J¼7.5 Hz, 2H), 2.59 (s, 3H), 2.35 (s, 3H), 1.77 (s, 3H),
1.68 (s, 3H); 13C NMR (CDCl3, 125 MHz): d 193.01 (CH),
143.21 (C), 140.26 (C), 138.90 (C), 132.94 (C), 132.68 (C),
129.91 (CH), 128.17 (CH), 121.14 (CH), 28.33 (CH2), 25.64
(CH3), 21.02 (CH3), 18.04 (CH3), 14.35 (CH3); MS (m/z,
relative intensity): 202 (M+, 26), 159 (100), 131 (58), 115
(35); exact mass calculated for C14H18O (M+): 202.1358;
found: 202.1366.
EtOAc–hexane, 77% yield, yellow oil; IR (neat): 2966,
1696, 1455, 1232, 1112 cmꢀ1
;
1H NMR (CDCl3,
500 MHz): d 10.19 (s, 1H), 7.69 (d, J¼8.0 Hz, 1H), 7.13
(d, J¼8.0 Hz, 1H), 7.07 (s, 1H), 3.00 (q, J¼7.5 Hz, 2H),
2.37 (s, 3H), 1.23 (t, J¼7.5 Hz, 3H); 13C NMR (CDCl3,
125 MHz): d 192.0 (CH), 147.1 (C), 144.9 (C), 132.1
(CH), 131.2 (C), 130.9 (CH), 127.1 (CH), 25.7 (CH2), 21.7
(CH3), 16.3 (CH3); MS (m/z, relative intensity): 148 (M+,
100), 147 (M+ꢀ1, 81), 119 (41), 77 (23); exact mass calcu-
lated for C10H12O (M+): 148.0888; found: 148.0887.
4.2.17. 5-(4-Methyl-pent-3-enyl)-biphenyl-2-carbalde-
hyde (4m). Prepared from cinnamaldehyde (A5) and gera-
nial (A7) according to the procedure in Section 4.2.
Rf ¼0.67 in 10% EtOAc–hexane, 82% yield, yellow oil; IR
4.2.13. 4-Methyl-2-propyl-benzaldehyde (4i). Prepared
from hex-2-enal (A3) and 3-methyl-but-2-enal (A6) accord-
ing to the procedure in Section 4.2. Rf ¼0.69 in 10% EtOAc–
hexane, 72% yield, yellow oil; IR (neat): 2966, 1696, 1455,
1
(neat): 2849, 1689, 1485, 1119 cmꢀ1; H NMR (CDCl3,
1
1112, 817 cmꢀ1; H NMR (CDCl3, 500 MHz): d 10.19 (s,
500 MHz): d 9.92 (s, 1H), 7.94 (d, J¼8.0 Hz, 1H), 7.48–
7.30 (m, 5H), 7.30 (d, J¼8.0 Hz, 1H), 7.24 (s, 1H), 5.15 (t,
J¼6.5 Hz, 1H), 2.71 (t, J¼7.5 Hz, 2H), 2.41–2.29 (m, 2H),
1.676 (s, 3H), 1.53 (s, 3H); 13C NMR (CDCl3, 125 MHz):
d 192.2 (CH), 148.9 (C), 146.1 (C), 138.0 (C), 132.8 (C),
131.6 (C), 130.8 (CH), 130.1 (2CH), 128.3 (2CH), 128.1
(CH), 128.0 (CH), 127.6 (CH), 123.0 (CH), 36.3 (CH2),
29.5 (CH2), 25.7 (CH3), 17.7 (CH3); MS (m/z, relative inten-
sity): 264 (M+, 14), 135 (100), 107 (54), 77 (31); exact mass
calculated for C19H20O (M+): 264.1514; found: 264.1513.
1H), 7.70 (d, J¼8.0 Hz, 1H), 7.12 (d, J¼8.0 Hz, 1H), 7.04
(s, 1H), 2.93 (t, J¼8.0 Hz, 2H), 2.36 (s, 3H), 1.62 (q,
J¼7.5 Hz, 2H), 0.86 (t, J¼7.5 Hz, 3H); 13C NMR (CDCl3,
125 MHz): d 192.1 (CH), 145.8 (C), 144.9 (C), 132.0
(CH), 131.9 (CH), 131.7 (C), 127.5 (CH), 34.9 (CH2), 25.6
(CH2), 20.0 (CH3), 14.4 (CH3); MS (m/z, relative intensity):
162 (M+, 84), 161 (M+ꢀ1, 53), 147 (100), 119 (33), 77 (25);
exact mass calculated for C11H14O (M+): 162.1045; found:
162.1045.
4.2.14. 2-Butyl-4-methyl-benzaldehyde (4j). Prepared
from hept-2-enal (A4) and 3-methyl-but-2-enal (A6) accord-
ing to the procedure in Section 4.2. Rf ¼0.74 in 10% EtOAc–
hexane, 68% yield, yellow oil; IR (neat): 2966, 1696, 1455,
4.2.18. 2-Ethyl-4-(4-methyl-pent-3-enyl)-benzaldehyde
(4n). Prepared from pent-2-enal (A2) and geranial (A7)
according to the procedure in Section 4.2. Rf ¼0.63 in 10%
EtOAc–hexane, yellow oil; IR (neat): 2967, 2924, 2724,
1
1
1112 cmꢀ1; H NMR (CDCl3, 500 MHz): d 10.16 (s, 1H),
1692, 1600, 1384, 823 cmꢀ1; H NMR (CDCl3, 500 MHz,
7.68 (d, J¼7.5 Hz, 1H), 7.11 (d, J¼7.5 Hz, 1H), 7.03 (s,
1H), 2.95 (t, J¼7.5 Hz, 2H), 2.35 (s, 3H), 1.59–1.51 (m,
2H), 1.41–1.33 (m, 2H), 0.90 (t, J¼7.5 Hz, 3H); 13C NMR
(CDCl3, 125 MHz): d 192.13 (CH), 146.15 (C), 144.98
(C), 131.94 (2CH), 131.86 (C), 127.47 (CH), 34.83 (CH2),
32.48 (CH2), 22.92 (CH2), 22.06 (CH3), 14.27 (CH3); MS
(m/z, relative intensity): 176 (M+, 81), 161 (45), 147 (100),
105 (45), 77 (41); exact mass calculated for C12H16O
(M+): 176.1201; found: 176.1201.
2:1 ratio): d 10.21 (s, 1H), 7.71 (d, J¼7.5 Hz, 1H), 7.15 (d,
J¼7.5 Hz, 1H), 7.07 (s, 1H), 5.12 (t, J¼7.0 Hz, 1H), 3.02
(m, 2H), 2.65 (t, J¼7.0 Hz, 2H), 2.29 (q, J¼7.5 Hz, 2H),
1.66 (s, 3H), 1.52 (s, 3H), 1.24 (t, J¼7.5 Hz, 3H); 13C
NMR (CDCl3, 125 MHz): d 192.22 (CH), 149.09 (C),
147.09 (C), 132.69 (C), 132.05 (CH), 131.43 (C), 130.43
(CH), 126.56 (CH), 123.07 (CH), 36.24 (CH2), 29.48
(CH2), 25.77 (CH2), 25.67 (CH3), 17.65 (CH3), 16.38
(CH3); MS (m/z, relative intensity): 216 (M+, 10), 121
(53), 93 (49), 69 (41); exact mass calculated for C15H20O
(M+): 216.1515; found: 216.1514.
4.2.15. 2-Methyl-4-(4-methyl-pent-3-enyl)-benzaldehyde
(4k). Prepared from crotonaldehyde (A1) and geranial (A7)
according to the procedure in Section 4.2. Rf ¼0.65 in 10%
EtOAc–hexane, yellow oil;29 IR (neat): 2965, 2922, 2858,
2726, 1692, 1383, 814 cmꢀ1; 1H NMR (CDCl3, 500 MHz):
d 10.21 (s, 1H), 7.71 (d, J¼7.5 Hz, 1H), 7.17 (d, J¼7.5 Hz,
1H), 7.07 (s, 1H), 5.14 (t, J¼7.0 Hz, 1H), 2.67–2.64 (m,
2H), 2.65 (s, 3H), 2.30 (t, J¼7.5 Hz, 2H), 1.68 (s, 3H),
1.55 (s, 3H); 13C NMR (CDCl3, 125 MHz): 192.49 (CH),
148.95 (C), 140.61 (C), 132.69 (C), 132.35 (CH), 132.15
(C), 131.98 (CH), 126.47 (CH), 123.06 (CH), 36.17 (CH2),
29.48 (CH2), 25.65 (CH3), 19.63 (CH3), 17.66 (CH3), 14.33
(CH3); MS (m/z, relative intensity): 202 (M+, 26), 159
(100), 131 (58), 115 (35); exact mass calculated for
C14H18O (M+): 202.1358; found: 202.1366.
4.2.19. 2-Ethyl-4-methyl-3-(3-methyl-but-2-enyl)-benz-
aldehyde (4o). Prepared from pent-2-enal (A2) and geranial
(A7) according to the procedure in Section 4.2. Rf ¼0.63
in 10% EtOAc–hexane; IR (neat): 2967, 2924, 2724, 1692,
1600, 1384, 823 cmꢀ1 1H NMR (CDCl3, 500 MHz):
;
d 10.22 (s, 1H), 7.59 (d, J¼7.5 Hz, 1H), 7.14 (d, J¼7.5 Hz,
1H), 4.93 (t, J¼6.0 Hz, 1H), 3.37 (d, J¼6.0 Hz, 2H), 3.04
(q, J¼7.5 Hz, 2H), 2.34 (s, 3H), 1.78 (s, 3H), 1.68 (s, 3H),
1.19 (t, J¼7.5 Hz, 3H); 13C NMR (CDCl3, 125 MHz):
d 192.63 (CH), 145.17 (C), 143.90 (C), 139.41 (C), 132.44
(C), 132.15 (C), 129.75 (CH), 128.45 (CH), 122.07 (CH),
27.69 (CH2), 25.62 (CH3), 21.02 (CH2), 20.98 (CH3), 18.02
(CH3), 16.19 (CH3); MS (m/z, relative intensity): 216 (M+,
10), 121 (53), 93 (49), 69 (41); exact mass calculated for
C15H20O (M+): 216.1515; found: 216.1514.
4.2.16. 2,4-Dimethyl-3-(3-methyl-but-2-enyl)-benzalde-
hyde (4l). Prepared from crotonaldehyde (A1) and geranial
(A7) according to the procedure in Section 4.2. Rf ¼0.65 in
10% EtOAc–hexane, yellow oil; IR (neat): 2965, 2922,
4.2.20. Hexanedial (7). To a solution of cyclohexene (2.5 g,
30.5 mmol) in CH2Cl2–H2O (2:1, 200 mL) were added
ruthenium (III) chloride (2.4 g, 11.8 mmol) and NaIO4
2858, 2726, 1692, 1383, 814 cmꢀ1 1H NMR (CDCl3,
;

B.-C. Hong et al. / Tetrahedron 63 (2007) 2840–2850
2847
(9.8 g, 46.0 mmol) at 25 ꢁC. The solution was stirred for 3 h
at the same temperature until the reaction was completed,
monitored by TLC. The reaction was quenched by the addi-
tion of saturated aqueous Na2S2O3 solution (50 mL).
The solution was extracted with EtOAc (100 mLꢂ2),
washed with brine, dried over Na2SO4, and concentrated in
vacuo to give the crude product. The residue was purified by
flash column chromatography with 20% EtOAc–hexane
(Rf ¼0.31 in 30% EtOAc–hexane) to give 7 as a light yellow
oil (3.1 g, 91% yield);30 IR (neat): 2952, 2726, 1736, 1365,
1173 cmꢀ1; 1H NMR (CDCl3, 500 MHz): d 9.68 (br s, 2H),
2.42–2.38 (m, 4H), 1.61–1.54 (m, 4H); 13C NMR (CDCl3,
125 MHz): d 201.9 (2CH), 43.4 (2CH2), 21.3 (2CH2); MS
(m/z, relative intensity): 114 (M+, 3), 99 (42), 81 (86), 70
(79), 43 (100); exact mass calculated for C6H10O2 (M+):
114.0681; found: 114.0681.
(1.28 g, 14.7 mmol) and the solution was stirred at 30 ꢁC
under N2 for 2 h. The solution was filtered through filter
paper, washed with EtOAc, and the filtrate was concentrated
in vacuo to give the crude product. The residue was purified
by flash column chromatography with 15% EtOAc–hexane
(Rf ¼0.38 in 20% EtOAc–hexane) to give dialdehyde 5 as
a light yellow oil (439 mg, 90% yield);33 IR (neat): 2952,
1736, 1173, 1091 cmꢀ1 1H NMR (CDCl3, 500 MHz):
;
d 9.33 (d, J¼7.5 Hz, 2H), 6.75–6.64 (m, 2H), 6.01–5.89
(m, 2H), 2.24–2.19 (m, 4H), 1.46–1.38 (m, 4H); 13C NMR
(CDCl3, 125 MHz): d 193.57 (2CH), 157.80 (2CH),
132.69 (2CH), 31.91 (2CH2), 26.82 (2CH2); MS (m/z, rela-
tive intensity): 166 (M+, 1), 121 (27), 108 (23), 67 (90), 41
(100); exact mass calculated for C10H14O2 (M+):
166.0994; found: 166.0993.
4.2.24. Heptanedial (10). Prepared from cycloheptene
according to the procedure in Section 4.2.20. Rf ¼0.66 in
66% EtOAc–hexane, 85% yield, yellow oil;34 IR (neat):
4.2.21. Deca-2,8-dienedioic acid dimethyl ester (8). To
a solution of NaH (1.3 g, 52.5 mmol) in THF (50 mL)
was slowly added diethylphosphonoacetic acid ethyl ester
(11.8 g, 52.5 mmol) at 0 ꢁC under N2. The solution was
stirred for 10 min, followed by the slow addition of dialde-
hyde 7 (2.0 g, 17.5 mmol) and stirred for 2 h at 25 ꢁC until
the reaction was completed, monitored by TLC. The reac-
tion was quenched by the addition of H2O (50 mL). The so-
lution was extracted with EtOAc (50 mLꢂ2), washed with
brine, dried over Na2SO4, and concentrated in vacuo to
give the crude product. The residue was purified by flash col-
umn chromatography with 10% EtOAc–hexane (Rf ¼0.21 in
10% EtOAc–hexane) to give 8 as a light yellow oil (3.9 g,
1
2936, 2861, 1716, 1365, 1404, 1134, 954 cmꢀ1; H NMR
(CDCl3, 400 MHz): d 9.92 (br s, 2H), 2.41 (t, J¼7.0 Hz,
4H), 1.65–1.58 (m, 4H), 1.36–1.27 (m, 2H); 13C NMR
(CDCl3, 100 MHz): d 202.24 (2CH), 43.53 (2CH2), 28.52
(CH2), 21.68 (2CH2); MS (m/z, relative intensity): 128
(M+, 5), 111 (17), 101 (40), 83 (51), 73 (100), 57 (65), 55
(78); exact mass calculated for C7H12O2 (M+): 128.0837;
found: 128.0831.
4.2.25. Undeca-2,9-dienedioic acid diethyl ester (11). Pre-
pared from 10 according to the procedure in Section 4.2.21.
Rf ¼0.88 in 33% EtOAc–hexane, 87% yield, yellow oil;34 IR
1
87% yield);31 IR (neat): 2952, 1736, 1437, 1172 cmꢀ1; H
1
NMR (CDCl3, 500 MHz): d 6.85 (dt, J¼16.0, 7.0 Hz, 2H),
5.73 (d, J¼16.0 Hz, 2H), 4.10 (q, J¼7.0 Hz, 4H), 2.18–
2.09 (m, 4H), 1.45–1.36 (m, 4H), 1.20 (t, J¼7.0 Hz, 6H);
13C NMR (CDCl3, 125 MHz): d 166.40 (2C), 148.44
(2CH), 121.46 (2CH), 59.98 (2CH2), 31.69 (2CH2), 27.28
(2CH2), 14.08 (2CH3); MS (m/z, relative intensity): 254
(M+, 6), 135 (100), 107 (54), 57 (45); exact mass calculated
for C14H22O4 (M+): 254.1518; found: 254.1517.
(neat): 2931, 2860, 1719, 1635, 1268, 982, 771 cmꢀ1; H
NMR (CDCl3, 500 MHz): d 6.88 (dt, J¼16.0, 7.0 Hz, 2H),
5.74 (d, J¼16.0 Hz, 2H), 4.41 (q, J¼7.0 Hz, 4H), 2.15–
2.11 (m, 4H), 1.44–1.27 (m, 6H), 1.22 (t, J¼7.0 Hz, 6H);
13C NMR (CDCl3, 125 MHz): d 166.50 (2C), 148.82
(2CH), 121.30 (2CH), 59.97 (2CH2), 31.86 (2CH2), 28.46
(CH2), 27.64 (2CH2), 14.11 (2CH3); MS (m/z, relative inten-
sity): 268 (M+, 1), 222 (14), 177 (100), 176 (76), 150 (98),
149 (70), 121 (67), 79 (29); exact mass calculated for
C15H24O4 (M+): 268.1675; found: 268.1680.
4.2.22. Deca-2,8-diene-1,10-diol (9). To a solution of 8
(1.0 g, 3.94 mmol) in CH2Cl2 (30 mL) was added a solution
of DIBAL-H (1 M in hexane, 11.8 mL, 11.8 mmol) at
ꢀ78 ꢁC. The solution was stirred for 2 h at 0 ꢁC until the
reaction was completed, monitored by TLC. The reaction
was quenched by the addition of saturated aqueous potas-
sium sodium tartrate (10 mL). The solution was extracted
with 10% t-BuOH–EtOAc (50 mLꢂ2), dried over Na2SO4,
and concentrated in vacuo to give the crude product. The
residue was purified by flash column chromatography with
50% EtOAc–hexane (Rf ¼0.24 in 50% EtOAc–hexane) to
give alcohol 9 as a colorless oil (542 mg, 81% yield);32 IR
4.2.26. Undeca-2,9-diene-1,11-diol (12). Prepared from 11
according to the procedure in Section 4.2.22. Rf ¼0.26 in
50% EtOAc–hexane, 83% yield, yellow oil;32 IR (neat):
3336, 2924, 2854, 1667, 736 cmꢀ1 1H NMR (CDCl3,
;
500 MHz): d 5.66–5.61 (m, 4H), 4.06 (d, J¼5.5 Hz, 4H),
2.04–2.01 (m, 4H), 1.50 (br s, 2H), 1.36–1.31 (m, 4H),
1.31–1.28 (m, 2H); 13C NMR (CDCl3, 125 MHz): d
133.18 (2CH), 128.94 (2CH), 63.65 (2CH2), 31.98 (2CH2),
28.76 (2CH2), 28.37 (CH2); MS (m/z, relative intensity):
184 (M+, 1), 137 (17), 123 (25), 111 (40), 97 (68), 83 (63),
57 (100), 55 (87); exact mass calculated for C11H20O2
(M+): 184.1463; found: 184.1473.
(neat): 3342, 2930, 1691, 1462, 970 cmꢀ1 1H NMR
;
(CDCl3, 500 MHz): d 5.64–5.46 (m, 4H), 4.01–3.88 (m,
4H), 3.04 (br s, 2H), 2.01–1.88 (m, 4H), 1.34–1.28 (m,
4H); 13C NMR (CDCl3, 125 MHz): d 132.52 (2CH),
128.90 (2CH), 63.10 (2CH2), 31.83 (2CH2), 28.41 (2CH2);
MS (m/z, relative intensity): 170 (M+, 3), 135 (23), 83
(51), 57 (89), 41 (100); exact mass calculated for
C10H14O2 (M+): 170.1307; found: 170.1305.
4.2.27. Undeca-2,9-dienedial (6). Prepared from 12 accord-
ing to the procedure in Section 4.2.23. Rf ¼0.63 in 63%
EtOAc–hexane, 90% yield, yellow oil;32 IR (neat): 2926,
2856, 1686, 1455, 799, 659 cmꢀ1 1H NMR (CDCl3,
;
500 MHz): d 9.40 (d, J¼8.0 Hz, 2H), 6.76 (dt, J¼15.5,
6.5 Hz, 2H), 6.04–6.00 (m, 2H), 2.28–2.24 (m, 4H), 1.48–
1.42 (m, 4H), 1.34–1.30 (m, 2H); 13C NMR (CDCl3,
125 MHz): d 193.81 (2CH), 158.26 (2CH), 132.83 (2CH),
4.2.23. Deca-2,8-dienedial (5). To a solution of diol 9
(500 mg, 2.94 mmol) in CH2Cl2 (50 mL) was added MnO2

2848
B.-C. Hong et al. / Tetrahedron 63 (2007) 2840–2850
32.28 (2CH2), 28.38 (CH2), 27.31 (2CH2); MS (m/z, relative
intensity): 180 (M+, 2), 138 (14), 98 (49), 97 (35), 82 (100),
71 (66), 70 (57), 67 (67); exact mass calculated for C11H16O2
(M+): 180.1150; found: 180.1158.
4.3.1. Indan-5-carbaldehyde (13). Prepared from 5 accord-
ing to the procedure in Section 4.3. Rf ¼0.64 in 10% EtOAc–
hexane, 75% yield, yellow oil; IR (neat): 2967, 1696, 1455,
1
1112 cmꢀ1; H NMR (CDCl3, 500 MHz): d 9.94 (s, 1H),
7.71 (s, 1H), 7.64 (d, J¼8.0 Hz, 1H), 7.34 (d, J¼8.0 Hz,
1H), 2.95 (m, 4H), 2.12 (tt, J¼7.5, 7.5 Hz, 2H); 13C NMR
(CDCl3, 125 MHz): d 192.37 (CH), 152.08 (C), 145.29
(C), 135.22 (C), 128.92 (CH), 125.17 (CH), 124.80 (CH),
33.16 (CH2), 32.36 (CH2), 25.35 (CH2); MS (m/z, relative in-
tensity): 146 (M+, 86), 145 (M+ꢀ1, 37), 117 (100), 91 (39),
77 (20); exact mass calculated for C10H10O (M+): 146.0732;
found: 146.0735.
4.3. Representative procedure for the intramolecular
reaction of a,b-unsaturated aldehydes (reactions
in Table 2)
Method A: to a solution of 5 (33.2 mg, 0.2 mol) in CH3CN
(5 mL) were added slowly pyrrolidine (7.1 mg, 0.1 mmol)
and HOAc (6 mg, 0.1 mmol) at 30 ꢁC. The solution was
stirred at 30 ꢁC for 4 h. To the solution was added H2O
(10 mL) and extracted with EtOAc (50 mLꢂ2). The organic
solution was washed with brine (10 mL), dried over Na2SO4,
and concentrated in vacuo to give the crude product. A solu-
tion of the crude 15 and DDQ (136 mg, 0.3 mmol) in CH2Cl2
(2 mL) was stirred for 2 h until the reaction was completed,
monitored by TLC. The solution was concentrated in vacuo
and the crude product was purified by flash column chroma-
tography with 3% EtOAc–hexane to give 13 and 14 (24 mg,
83% yield; Rf ¼0.64 in 10% EtOAc–hexane) as a yellow oil.
4.3.2. Indan-4-carbaldehyde (14). Prepared from 5 accord-
ing to the procedure in Section 4.3, with DDQ. Rf ¼0.64 in
10% EtOAc–hexane, 80% yield, yellow oil; IR (neat):
2967, 1696, 1456, 1112 cmꢀ1; 1H NMR (CDCl3, 500 MHz):
d 10.13 (s, 1H), 7.61 (d, J¼8.0 Hz, 1H), 7.45 (d, J¼7.5 Hz,
1H), 7.30 (dd, J¼8.0, 7.5 Hz, 1H), 3.27 (t, J¼8.0 Hz, 2H),
2.92 (t, J¼7.5 Hz, 2H), 2.13 (tt, J¼8.0, 7.5 Hz, 2H); 13C
NMR (CDCl3, 125 MHz): d 193.07 (CH), 146.64 (C),
146.51 (C), 132.52 (C), 130.19 (CH), 129.45 (CH), 126.93
(CH), 32.29 (CH2), 31.98 (CH2), 25.46 (CH2); MS (m/z, rel-
ative intensity): 146 (M+, 97), 145 (M+ꢀ1, 51), 117 (100), 91
(24); exact mass calculated for C10H10O (M+): 146.0732;
found: 146.0735.
Method B (without aromatization): a solution of 5 (33.2 mg,
0.2 mmol) and L-proline (11.4 mg, 0.1 mg) in CH3CN
(5 mL) was stirred at 30 ꢁC for 6 h until the reaction was
completed, monitored by TLC. To the solution was added
H2O (10 mL) and extracted with EtOAc (50 mLꢂ2). The
organic solution was washed with brine (10 mL), dried
over Na2SO4, and concentrated in vacuo to give the residue.
The crude product was purified by flash column chromato-
graphy with 20% EtOAc–hexane to give adduct 15 (24 mg,
80% yield; Rf ¼0.64 in 10% EtOAc–hexane) as a yellow oil.
4.3.3. 5,6-Dihydro-naphthalene-2-carboxylic acid methyl
ester (15). Prepared from 5 according to the procedure
in Section 4.3, without aromatization. Rf ¼0.64 in 10%
EtOAc–hexane, 73% yield, yellow oil; IR (neat): 2960,
2714, 1674, 1457, 1112 cmꢀ1; 1H NMR (CDCl3, 500 MHz):
d 9.37 (s, 1H), 6.08–6.00 (m, 2H), 5.75–5.68 (m, 1H), 2.53–
2.45 (m, 2H), 1.98–1.89 (m, 1H), 1.86–1.78 (m, 1H), 1.58–
1.35 (m, 4H); 13C NMR (CDCl3, 125 MHz): d 191.67 (CH),
143.54 (C), 142.76 (CH), 140.73 (CH), 125.38 (CH), 44.67
(CH), 41.89 (CH), 26.29 (CH2), 25.81 (CH2), 23.16 (CH2);
MS (m/z, relative intensity): 148 (M+, 53), 119 (48), 91
(100); exact mass calculated for C10H12O (M+): 148.0888;
found: 148.0886.
Method B (with aromatization): diene 15 was prepared from
the above procedure without the purification by flash column
chromatography. A solution of the crude 15 and DDQ
(136 mg, 0.3 mmol) in CH2Cl2 (2 mL) was stirred for 2 h
until the reaction was completed, monitored by TLC. The
solution was concentrated in vacuo and the crude product
was purified by flash column chromatography with 3%
EtOAc–hexane to give 14 (13.1 mg, 80% yield; Rf ¼0.64
in 10% EtOAc–hexane) as a yellow oil.
4.3.4. 5,6,7,8-Tetrahydro-naphthalene-2-carbaldehyde
(16). Prepared from 6 according to the procedure in Section
4.3. Rf ¼0.91 in 33% EtOAc–hexane, 75% yield, yellow oil;
IR (neat): 2960, 2625, 2721, 1694, 1604, 1568, 1455, 1045,
753, 676 cmꢀ1; 1H NMR (CDCl3, 500 MHz): d 9.90 (s, 1H),
7.58–5.55 (m, 2H), 7.18 (d, J¼8.0 Hz, 1H), 2.82–2.80 (m,
4H), 1.80–1.81 (m, 4H); 13C NMR (CDCl3, 125 MHz):
d 192.37 (CH), 144.89 (C), 138.01 (C), 134.18 (C), 130.81
(CH), 129.81 (CH), 126.60 (CH), 29.86 (CH2), 29.21
(CH2), 22.82 (CH2), 22.70 (CH2); MS (m/z, relative inten-
sity): 160 (M+, 71), 131 (100), 115 (20), 104 (19), 92 (37);
exact mass calculated for C11H12O2 (M+): 160.0888; found:
160.0885.
Method C: the same procedure as method B was employed,
except that imidazole was added with L-proline in the
reaction.
Method D: the same procedure as method B was employed,
except that t-Bu3P was added with L-proline in the reaction.
Method E: the same procedure as method B was employed,
except that Et2NH was added with L-proline in the reaction.
Method F: the same procedure as in method B was em-
ployed, except that pyrrolidine was added with L-proline in
the reaction.
4.3.5. 5,6,7,8-Tetrahydro-naphthalene-1-carbaldehyde
(17). Prepared from 6 according to the procedure in Section
4.3, without aromatization. Rf ¼0.58 in 10% EtOAc–hexane,
85% yield, yellow oil; IR (neat): 2928, 2857, 2753, 1693,
Method G: the same procedure as method B was employed,
except that L-proline was replaced by (2S,5S)-2-tert-butyl-
3-methyl-5-phenylmethyl-4-imidazolidinone (MacMillan’s
Imidazolidinone OrganoCatalystsÔ) and trifluoroacetic
acid in the reaction.
1584, 1295, 1023, 889, 777 cmꢀ1 1H NMR (CDCl3,
;
500 MHz): d 10.24 (s, 1H), 7.60 (d, J¼7.0 Hz, 1H), 7.28
(d, J¼7.0 Hz, 1H), 7.25 (dd, J¼7.0, 7.0 Hz, 1H), 3.18 (t,
J¼6.0 Hz, 2H), 2.81 (t, J¼6.0 Hz, 2H), 1.84–1.78 (m, 4H);

B.-C. Hong et al. / Tetrahedron 63 (2007) 2840–2850
2849
13C NMR (CDCl3, 125 MHz): d 193.20 (CH), 139.62 (C),
138.63 (C), 135.08 (CH), 133.96 (C), 130.60 (CH), 125.50
(CH), 29.92 (CH2), 26.28 (CH2), 22.73 (CH2), 22.19
(CH2); MS (m/z, relative intensity): 160 (M+, 76), 131
(100), 129 (19), 115 (24), 91 (47); exact mass calculated
for C11H12O (M+): 160.0888; found: 160.0833.
130.22 (CH), 129.20 (CH), 32.19 (CH2), 31.77 (CH2), 26.39
(CH2); MS (m/z, relative intensity): 178 (M+, 3), 149 (8), 97
(28), 83 (100), 57 (49), 55 (43); exact mass calculated for
C11H14O2 (M+): 178.0994; found: 178.1000.
4.3.10. 5,6-Dihydro-naphthalene-2-carbaldehyde (23).
Prepared from 27 according to the procedure in Section
4.3, method B, without the addition of DDQ. Rf ¼0.79 in
33% EtOAc–hexane, 65% yield, yellow oil; IR (neat):
4.3.6. 4a,5,6,7,8,8a-Hexahydro-naphthalene-1-carbalde-
hyde (18). Prepared from 6 according to the procedure in
Section 4.3, without aromatization. Rf ¼0.52 in 33%
EtOAc–hexane, 80% yield, yellow oil; IR (neat): 2922,
1
2922, 2854, 1762, 1688, 1625, 1241, 770 cmꢀ1; H NMR
(CDCl3, 500 MHz): d 9.92 (s, 1H), 7.61 (d, J¼7.5 Hz, 1H),
7.49 (s, 1H), 7.23 (d, J¼7.5 Hz, 1H), 6.51 (d, J¼9.5 Hz,
1H), 6.12–6.01 (m, 1H), 2.86 (t, J¼7.5 Hz, 2H), 2.36–2.32
(m, 2H);13CNMR(CDCl3, 125 MHz):d192.16(CH), 142.89
(C), 135.23 (C), 134.83 (C), 130.17 (CH), 128.81 (CH),
128.17 (CH), 126.36 (CH), 27.85 (CH2), 22.70 (CH2); MS
(m/z, relative intensity): 158 (M+, 80), 129 (89), 109 (42),
103 (66), 95 (60), 94 (63), 83 (94), 55 (100); exact mass cal-
culated for C11H10O (M+): 158.0732; found: 158.0773.
2856, 1644, 1463, 1384, 677 cmꢀ1 1H NMR (CDCl3,
;
500 MHz): d 9.50 (s, 1H), 6.70 (dd, J¼9.5, 2.0 Hz, 1H), 6.15–
6.12 (m, 1H), 6.04 (d, J¼9.5 Hz, 1H), 2.95 (m, 1H), 2.29–
2.23(m, 1H),2.10–2.06(m,1H),1.89–1.87(m,1H),1.80–1.74
(m, 2H), 1.37–1.15 (m, 4H); 13C NMR (CDCl3, 125 MHz):
d 193.72 (CH), 145.00 (CH), 142.84 (CH), 140.87 (C),
123.30 (CH), 41.08 (CH), 39.96 (CH), 32.46 (CH2), 28.76
(CH2), 26.51 (CH2), 26.44 (CH2); MS (m/z, relative inten-
sity): 162 (M+, 23), 119 (17), 115 (12), 91 (100); exact mass
calculated for C11H14O (M+): 162.1045; found: 162.1049.
4.3.11. 5,6-Dihydro-naphthalene-2-carboxylic acid (21).
To a solution of 23 (48 mg, 0.30 mmol) and 2-methyl-2-
butene (2 mL, 18.8 mmol) in t-BuOH (7 mL) was added
a freshly prepared solution of sodium chlorite (140 mg,
1.55 mmol) in 20% w/w aqueous NaH2PO4 (2.4 g in 12 mL
of H2O) at room temperature and the resulting solution was
stirred for 4 h. The mixture was diluted with ethyl acetate
(30 mL) and washed with water (4 mL). The aqueous phase
was extracted with ethyl acetate (30 mL) and the combined
organic layers were dried over Na2SO4 and concentrated in
vacuo to give the crude product. The residue was purified by
flash column chromatography with 30% EtOAc–hexane
(Rf ¼0.45 in 33% EtOAc–hexane) to give diol 21 as a yellow
oil (42 mg, 80% yield); IR (neat): 3029, 2927, 2857, 1689,
1431, 1279, 1020, 771 cmꢀ1; 1H NMR (CDCl3, 500 MHz):
d 7.84 (d, J¼8.0 Hz, 1H), 7.72 (s, 1H), 7.17 (d, J¼8.0 Hz,
1H), 6.50 (d, J¼9.5 Hz, 1H), 6.09–6.07 (m, 1H), 2.85 (t,
J¼8.5 Hz, 2H), 2.36–2.31 (m, 2H); 13C NMR (CDCl3,
125 MHz): d 171.03 (CH), 141.68 (C), 134.28 (C), 129.39
(CH), 128.73 (CH), 127.72 (C), 127.65 (CH), 127.22
(CH), 127.16 (CH), 27.67 (CH2), 22.75 (CH2); MS (m/z,
relative intensity): 174 (M+, 73), 129 (100), 115 (17), 77
(13), 57 (12); exact mass calculated for C11H10O2 (M+):
174.0681; found: 174.0672.
4.3.7. Undeca-2,4,9-trienedioic acid diethyl ester (25).
Prepared from 2435 according to the procedure in Section
4.2.21. Rf ¼0.70 in 33% EtOAc–hexane, 87% yield, yellow
oil; IR (neat): 2987, 1763, 1712, 1375, 1242, 468, 677 cmꢀ1
;
1H NMR (CDCl3, 500 MHz): d 7.21 (dd, J¼15.5, 11.0 Hz,
1H), 6.90 (dt, J¼16.0, 7.0 Hz, 1H), 6.14 (dd, J¼15.5,
11.0 Hz, 1H), 6.07–6.03 (m, 1H), 5.80–5.74 (m, 2H), 4.18–
4.12 (m, 4H), 2.20–2.14 (m, 4H), 1.60–1.54 (m, 2H), 1.26–
1.22 (m, 6H); 13C NMR (CDCl3, 125 MHz): d 167.09 (C),
166.48 (C), 148.82 (CH), 144.55 (CH), 143.02 (CH),
128.95 (CH), 121.76 (CH), 119.64 (CH), 60.12 (2CH2),
32.12 (CH2), 31.39 (CH2), 26.90 (CH2), 14.11 (CH3), 14.17
(CH3); MS (m/z, relative intensity): 266 (M+, 7), 221 (21),
119 (61), 114 (40), 81 (88), 67 (69); exact mass calculated
for C15H22O4 (M+): 266.1518; found: 266.1523.
4.3.8. Undeca-2,4,9-triene-1,11-diol (26). Prepared from
25 according to the procedure in Section 4.2.22. Rf ¼0.54
in 66% EtOAc–hexane, 80% yield, yellow oil; IR (neat):
3353, 3015, 2925, 2856, 1663, 1444, 1370, 1217, 990,
668 cmꢀ1 1H NMR (CDCl3, 500 MHz): d 6.16 (dd,
;
J¼15.5, 10.5 Hz, 1H), 6.00 (dd, J¼15.5, 10.5 Hz, 1H),
5.69–5.58 (m, 4H), 4.10 (d, J¼6.0 Hz, 2H), 4.04–4.02 (m,
2H), 2.08–2.01 (m, 4H), 1.96 (s, 2H), 1.47–1.41 (m, 2H);
13C NMR (CDCl3, 125 MHz): d 134.66 (CH), 132.39
(CH), 131.50 (CH), 129.71 (CH), 129.64 (CH), 129.17 (CH),
63.65 (CH2), 62.97 (CH2), 31.98 (CH2), 31.51 (CH2), 28.48
(CH2); MS (m/z, relative intensity): 182 (M+, 1), 107 (25), 95
(35), 93 (41), 83 (54), 67 (100), 55 (77); exact mass calcu-
lated for C11H18O2 (M+): 182.1307; found: 182.1297.
4.3.12. 5,6-Dihydro-naphthalene-2-carboxylic acid
methyl ester (22). To a solution of 21 (30 mg, 0.17 mmol)
in CH2Cl2 (10 mL) was added a freshly prepared solution
of CH2N2 in Et2O at room temperature and the resulting so-
lution was stirred for 30 min. The solution was concentrated
in vacuo to give the crude product. The residue was purified
by flash column chromatography with 10% EtOAc–hexane
(Rf ¼0.81 in 33% EtOAc–hexane) to give diol 22 as a yellow
oil (28 mg, 90% yield); IR (neat): 3029, 2928, 2860, 1721,
4.3.9. Undeca-2,4,9-trienedial (27). Prepared from 26
according to the procedure in Section 4.2.23. Rf ¼0.36 in
33% EtOAc–hexane, 90% yield, yellow oil; IR (neat):
1436, 1280, 1194 cmꢀ1 1H NMR (CDCl3, 500 MHz):
;
d 7.76 (d, J¼8.0 Hz, 1H), 7.66 (s, 1H), 7.13 (d, J¼8.0 Hz,
1H), 6.47 (d, J¼9.5 Hz, 1H), 6.06 (dd, J¼9.5, 5.0 Hz, 1H),
3.88 (s, 3H), 2.83 (t, J¼8.0 Hz, 2H), 2.34–2.30 (m, 2H);
13C NMR (CDCl3, 125 MHz): d 167.22 (CH), 140.90 (C),
134.20 (C), 129.51 (CH), 128.40 (C), 127.72 (C), 127.56
(CH), 127.23 (CH), 126.74 (CH), 51.98 (CH3), 27.60
(CH2), 22.80 (CH2); MS (m/z, relative intensity): 188 (M+,
46), 157 (21), 129 (100), 85 (11), 71 (19), 64 (25); exact
2926, 2857, 2810, 2730, 1682, 1636, 1446, 769, 677 cmꢀ1
;
1H NMR (CDCl3, 500 MHz): d 9.54–9.49 (m, 2H), 7.06
(dd, J¼15.0, 10.5 Hz, 1H), 6.82 (dt, J¼15.5, 7.0 Hz, 1H),
6.35–6.30 (m, 1H), 6.25–6.21 (m, 1H), 6.14–6.06 (m, 2H),
2.39–2.34 (m, 2H), 2.29–2.25 (m, 2H), 1.72–1.66 (m, 2H);
13C NMR (CDCl3, 125 MHz): d 193.81 (CH), 193.59
(CH), 157.41 (CH), 152.07 (CH), 145.21 (CH), 133.06 (CH),

2850
B.-C. Hong et al. / Tetrahedron 63 (2007) 2840–2850
mass calculated for C12H12O2 (M+): 188.0837; found:
188.0834.
Thozet, A.; Ciufolini, M. A. Org. Lett. 2004, 6, 3281; (h) Fan,
Q.; Lin, L.; Liu, J.; Huang, Y.; Feng, X.; Zhang, G. Org. Lett.
€
2004, 6, 2185; (i) Groger, H. Adv. Synth. Catal. 2001, 343, 547.
16. For recent review, see: (a) Kantlehner, W. Eur. J. Org. Chem.
2003, 2530; (b) L€ucke, B.; Narayana, K. V.; Martin, A.;
Acknowledgements
€
Jahnisch, K. Adv. Synth. Catal. 2004, 346, 1407; (c) de
Financial support for this study from the National Science
Council, ROC is gratefully acknowledged.
Angelis, A.; Ingallina, P.; Perego, C. Ind. Eng. Chem. Res.
2004, 43, 1169; (d) Ryu, I.; Sonoda, N. Angew. Chem., Int.
Ed. 1996, 35, 1050.
17. Hong, B.-C.; Wu, M.-F.; Tseng, H.-C.; Liao, J.-H. Org. Lett.
2006, 8, 2217.
Supplementary data
18. For promising examples in organocatalysis by pyrrolidine and
acetic acid, see: (a) See Ref. 10; (b) Erkkilae, A.; Pihko, P. M.
J. Org. Chem. 2006, 71, 2538; (c) Li, D.-P.; Guo, Y.-C.; Ding,
Y.; Xiao, W.-J. Chem. Commun. 2006, 799; (d) Ramachary,
D. B.; Ramakumar, K.; Kishor, M. Tetrahedron Lett. 2005,
46, 7037; (e) Ji, C.; Peng, Y.; Huang, C.; Wang, N.; Jiang, Y.
Synlett 2005, 986; (f) Mase, N.; Tanaka, F.; Barbas, C. F.
Org. Lett. 2003, 5, 4369.
19. For selected examples, see: (a) Ussing, B. R.; Hang, C.;
Singleton, D. A. J. Am. Chem. Soc. 2006, 128, 7594; (b)
Nakazaki, A.; Nakai, T.; Tomooka, K. Angew. Chem., Int.
Ed. 2006, 45, 2235; (c) Marmsaeter, F. P.; Vanecko, J. A.;
West, F. G. Org. Lett. 2004, 6, 1657; (d) Deubel, D. V.;
Schlecht, S.; Frenking, G. J. Am. Chem. Soc. 2001, 123,
10085; (e) Leach, A. G.; Houk, K. N.; Davies, I. W.
Synthesis 2005, 3463; (f) Fujita, M.; Oshima, M.; Okuno, S.;
Sugimura, T.; Okuyama, T. Org. Lett. 2006, 8, 4113.
20. Peelen, T. J.;Chi,Y.;Gellman,S.H.J. Am. Chem. Soc.2005, 127,
11598; Mase, N.; Nakai, Y.; Ohara, N.; Yoda, H.; Takabe, K.;
Tanaka, F.; Barbas, C. F., III. J. Am. Chem. Soc. 2006, 128, 734.
21. Marco, M.-P.; Hammock, B. D.; Kurth, M. J. J. Org. Chem.
1993, 58, 7548.
22. (a) Okumura, K.; Shimazaki, T.; Aoki, Y.; Yamashita, H.;
Tanaka, E.; Banba, S.; Yazawa, K.; Kibayashi, K.; Banno, H.
J. Med. Chem. 1998, 41, 4036; (b) Okumura, K.; Yokoyama,
I.; Shimazaki, T.; Miyamoto, M.; Yamashita, H.; Kibayashi,
K.; Yutaka, T.; Yazawa, K. Eur. Pat. Appl. EP 709370, 1996.
23. For organocatalytic inverse electron-demand Diels–Alder reac-
tions, see: Juhl, K.; Jørgensen, K. A. Angew. Chem., Int. Ed.
2003, 42, 1498 and Ref. 6.
24. The NMR spectrum of 3a was identical with that of an authen-
tic sample purchased from Aldrich Chem. Co.
25. The NMR spectrum of 4a was identical with that of an authen-
tic sample purchased from Aldrich Chem. Co.
Selected spectral data for the compounds (3–27). Supple-
mentary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2007.01.039.
References and notes
1. For recent review, see: (a) Dalko, P. I.; Moisan, L. Angew.
Chem., Int. Ed. 2004, 43, 5138; (b) Notz, W.; Tanaka, F.;
Barbas, C. F., III. Acc. Chem. Res. 2004, 37, 580; (c) Seayad,
J.; List, B. Org. Biomol. Chem. 2005, 3, 719; (d) Berkessel,
€
A.; Groger, H. Asymmetric Organocatalysis: From Biomimetic
Concepts to Applications in Asymmetric Synthesis; Wiley: New
York, NY, 2005; For a recent example in aqueous media, see:
Hayashi, Y.; Sumiya, T.; Takahashi, J.; Gotoh, H.; Urushima,
T.; Shoji, M. Angew Chem., Int. Ed. 2006, 45, 958.
2. Fonseca, M. T. H.; List, B. Angew. Chem., Int. Ed. 2004, 43,
3958.
ꢀ
3. (a) Brandau, S.; Landa, A.; Franzen, J.; Marigo, M.; Jørgensen,
K. A. Angew. Chem., Int. Ed. 2006, 45, 4305; (b) Knudsen,
K. R.; Mitchell, C. E. T.; Ley, S. V. Chem. Commun. 2006,
66; (c) Cobb, A. J.; Shaw, D. M.; Longbottom, D. A.; Gold,
J. B.; Ley, S. V. Org. Biomol. Chem. 2005, 3, 84.
4. Brown, S. P.; Goodwin, N. C.; David, W. C.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2003, 125, 1192.
5. Yang, J. W.; Fonseca, M. T. H.; List, B. Angew. Chem., Int. Ed.
2004, 43, 6660.
6. Hayashi, Y.; Gotoh, H.; Tamura, T.; Yamaguchi, H.; Masui, R.;
Shoji, M. J. Am. Chem. Soc. 2005, 127, 16028.
7. Kano, T.; Yamaguchi, Y.; Tokuda, O.; Maruoka, K. J. Am.
Chem. Soc. 2006, 127, 16408.
8. Herrera, R. P.; Sgarzani, V.; Bernardi, L.; Ricci, A. Angew.
Chem., Int. Ed. 2005, 44, 6576.
9. Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F., III. J. Am. Chem.
Soc. 2001, 123, 5260.
10. McNally, A.; Evans, B.; Gaunt, M. J. Angew. Chem., Int. Ed.
2006, 45, 2116.
26. Su, W.; Urgaonkar, S.; Verkade, J. G. Org. Lett. 2004, 6, 1421.
27. Flippin, L. A.; Muchowski, J. M.; Carter, D. S. J. Org. Chem.
1993, 58, 2463.
28. The NMR spectrum of 4f was identical with that of an authentic
sample purchased from TCI Chem. Co.
11. Zhuang, W.; Jørgensen, A. Angew. Chem., Int. Ed. 2004, 43,
4476.
29. Thomas, A. F.; Guntz-Dubini, R. Helv. Chim. Acta 1976, 59,
2261.
30. Lopez, S.; Fermandez-Trillo, F.; Castedo, L.; Saa, C. Org. Lett.
2003, 5, 3725.
31. Hon, Y.-S.; Chu, K.-P.; Hong, P.-C.; Lu, L. Synth. Commun.
1992, 429.
32. Iriye, R.; Toya, T.; Makino, J.; Aruga, R.; Doi, Y.; Handa, S.;
Tanaka, H. Agric. Biol. Chem. 1988, 52, 989.
33. Nicolaou, K. C.; Montagnon, T.; Baran, P. S. Angew. Chem.,
Int. Ed. 2002, 41, 993.
34. Roels, J.; Metz, P. Synlett 2001, 789.
35. Chen, S.-H.; Hong, B.-C.; Su, C.-F.; Sarshar, S. Tetrahedron
Lett. 2005, 51, 8899.
12. (a) Armstrong, A. Angew Chem., Int. Ed. 2004, 43, 1460; (b)
Aggarwal, V. K.; Lopin, C.; Sandrinelli, F. J. Am. Chem. Soc.
2003, 125, 7596.
13. Ramachary, D. B.; Barbas, C. F. J. Org. Chem. 2004, 69, 5838.
14. Chowdari, N. S.; Barbas, C. F. Org. Lett. 2005, 7, 807.
15. (a) Sano, Y.; Shiina, I. Tetrahedron Lett. 2006, 47, 1631; (b)
Peng, X.; Shindo, K.; Kanoh, K.; Inomata, Y.; Choi, S.-K.;
Misawa, N. Appl. Microbiol. Biotechnol. 2005, 69, 141; (c)
Bolm, C.; Zani, L.; Rudolph, J.; Schiffers, I. Synthesis 2004,
2173; (d) Wroczynski, P.; Wierzchowski, J. Analyst 2000,
125, 511; (e) Lee, K.; Maleczka, R. E., Jr. Org. Lett. 2006, 8,
1887; (f) Wang, Y.-G.; Cui, S.-L.; Lin, X.-F. Org. Lett. 2006,
8, 1241; (g) Godet, T.; Bonvin, Y.; Vincent, G.; Merle, D.;