Development of the Ireland-Claisen rearrangement of allyl-2-alkoxyacetate bearing an allylic amine and the transformation to 3-hydroxy-4- hydroxymethylpyrrolidine

Article abstract of DOI:10.1002/jccs.201100630

An unprecedented Ireland-Claisen rearrangement of allylglycolate bearing an allylic amine was realized, affording the corresponding product with excellent diastereoselectivity and in high yield. The product was analyzed by X-ray crystallography, and demon

Full text of DOI:10.1002/jccs.201100630

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Article
Development of the Ireland–Claisen Rearrangement of Allyl-2-alkoxyacetate Bearing
an Allylic Amine and the Transformation to 3-Hydroxy-4-hydroxymethylpyrrolidine
Yung-Son Hon,* Ching-Zong Luo, Bor-Cherng Hong* and Ju-Hsiou Liao
Department of Chemistry and Biochemistry, National Chung Cheng University, Chia-Yi 62102, Taiwan, R.O.C.
(Received: Oct. 27, 2011; Accepted: Nov. 28, 2011; Published Online: Jan. 17, 2012; DOI: 10.1002/jccs.201100630)
An unprecedented Ireland–Claisen rearrangement of allylglycolate bearing an allylic amine was realized,
affording the corresponding product with excellent diastereoselectivity and in high yield. The product was
analyzed by X-ray crystallography, and demonstrated the transformation to the 4-hydroxymethylpyrroli-
din-3-ol.
Keywords: Ireland–Claisen rearrangement; Synthesis; Allylglycolate; Allylic amine.
Selected allylglycolate variants for the Ire-
land–Claisen rearrangement
Scheme I
INTRODUCTION
For nearly a century, the Claisen Rearrangement1 has
played a pivotal role in organic synthesis, and a variety of
modifications have been discovered for different purposes.
Among the variant rearrangements, the Ireland–Claisen re-
arrangement2 is one of the most interesting protocols, effi-
ciently providing g,d-unsaturated carbonyl compounds
with high stereoselectivity.3 Recently, the observation of
Claisen rearrangements in biological systems has further
attracted scientists’ interests,4 resulting in the development
of the organocatalysis Claisen rearrangements.5 Tradition-
ally, the Ireland–Claisen rearrangements of the corre-
sponding allylglycolate (e.g., 1–4) have received much at-
tention,6 and the reactions of the variants bearing oxygen or
nitrogen at different positions of the starting substrates
have been reported (Scheme I).7 Nevertheless, the Ireland–
Claisen rearrangement of an allylglycolate bearing an allyl-
ic amine (e.g., 5),8 as depicted in Scheme I, has received lit-
tle attention. It would be interesting to explore the reaction
of such substrates, to reveal the stereoselectivity of the
transformation, and to identify synthetic applications.
Herein we report such observations and an application to-
ward the synthesis of 4-hydroxymethylpyrrolidin-3-ol, an
important intermediate in the synthesis of nucleotides or
sodium channel blockers.9
tection of 9a followed by reduction afforded the allylic
amine 11a, which was reacted with 2-(benzyloxy)acetic
acid to provide the trans-glycolate 12a (Scheme II). On the
other hand, the cis-glycolate 12a11 was prepared starting
from the allylether 13 by a similar reaction sequence
(Scheme II).
Scheme II Preparation of the allylglycolate 12a
RESULTS AND DISCUSSION
Initially, the trans-glycolate 12a was prepared through
a sequence of reactions starting from 1-(tert-butyldimeth-
ylsilyloxy)but-2-yn-4-ol (6)10 by mesylation and amination
(MsCl, Et3N, CH2Cl2, 0 °C, 30 min; Bn2NH, toluene, re-
flux, 4 h; 89%) to give the propargyl amine 9a. Depro-
At the outset of the study, the rearrangement of cis-
glycolate 12a was carried out using various Lewis acids,
Lewis bases, and solvents, see Table 1. The series of
screenings revealed that the best yield was obtained by the
Dedicated to the memory of Professor Yung-Son Hon (1955–2011).
* Corresponding author. Tel: + 886-5-2428174; Fax: +886-5-2721040; E-mail: chebch@ccu.edu.tw
J. Chin. Chem. Soc. 2012, 59, 273-282
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273

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Hon et al.
Table 1. Reaction condition screening for the rearrangement
Table 2. Scope of the rearrangement of cis-glycolate 12
Entry
Base
Solvent Lewis acid Time (h) Yield b (%)
Entry
1
Product
Yield (%)a
90
drb
1
2
3
4
5
6
7
8
9
LDA
THF
THF
TMSCl
TMSCl
TMSCl
TMSCl
TMSCl
TMSCl
TBSCl
13
13
13
12
12
12
13
12
14
90
82
54
73
69
79
76
65
76 c
17a R1 = R2 = Bn
>95:5
LiHMDS
2
17b R1 = allyl, R2 = Bn
17c R1 = Ph, R2 = Me
17d R1 = c-C6H11, R2 = Bn
17e R1 = R2 = i-C3H7
81
82
63
71
79
57
90
58
67
60
>95:5
16:1
NaHMDS THF
3
KHMDS
LDA
THF
toluene
Ether
THF
4
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
4:1
5
LDA
6
17f R1 = R2 = pyrrolidine
17g R1 = R2 = piperidine
17h R1 = Me, R2 = Bn
17i R1 = allyl, R2 = c-C6H11
17j R1 = PMB, R2 = Bn
17k R1 = R2 = N3
LDA
7
LDA
THF
TMSOTf
TMSOTf
8
NEt3
CH2Cl2
9
b Isolated yields; unless otherwise noted, dr (cis:trans) >95:5. c dr
(cis:trans) = 75:25.
10
11
a Isolated yield. b Determined by 1H NMR of the crude products.
reaction conditions involving LDA–TMSCl in THF at am-
bient temperature for 13 h, followed by in situ treatment of
diazomethane to give a 90% yield of the trans-17 as the
only observable diastereomer (Table 1, entries 1). Replace-
ment of LDA by LiHMDS, NaHMDS, or KHMDS under
the same reaction conditions afforded a lower yield of the
products, 54–82%, (Table 1, entries 2–4). The reaction un-
der LDA–TMSCl condition in other solvents, e.g., toluene,
Et2O, provided lower yields, 69–79% (Table 1, entries
5–6). Replacement of TMSCl by other acids, such as
TBSCl or TMSOTf, also gave lower yields, (Table 1, en-
tries 7–8). It is noteworthy that the reaction with Et3N-
TMSOTf in CH2Cl2 yielded a 3:1 ratio of the cis/trans mix-
ture of 17 (Table 1, entry 9). The structure of the product
syn–17 was unambiguously confirmed based on the X-ray
analysis (Figure 1).
With the optimized conditions in hand, a series of
cis-glycolates 12 was prepared according the aforemen-
tioned protocol and subjected to the rearrangement condi-
tions. The results are summarized in Table 2, and, for most
cases, the reaction gave syn-17 in good yields (57–90%)
with excellent diastereoselectivities, except for two exam-
ples. For the case of 17c, the diastereomeric ratio dropped
to 16:1, then decreased to 4:1, for the case of 17k in which
the two substituents on the nitrogen were azide, Table 2,
entries 3 and 11.
The reaction conditions of the Ireland-Claisen rear-
rangement were alternatively applied to the trans-glycolate
12, prepared according the aforementioned protocol, fol-
lowed by esterification, to afford the anti-17 as the major
isomers (Table 3). For most cases, the anti-isomers were
the only observable products (dr: >95:5). In a few cases,
the diastereomeric ratio dropped to 3:1 or 7:1 (Table 3, en-
tries 2, 3, 8, and 11).
Finally, we explored the possibility of extending the
product to 4-(hydroxymethyl)pyrrolidin-3-ol (Scheme III).
The syn-17 was converted to the anti-lactam 18 by depro-
tection of the allyl group and spontaneous lactamization
(Pd–C, MeOH–HOAc, 100 °C, 3d), followed oxidative
Fig. 1. Stereo plots of the X-ray crystal structures of
syn-17a: C, gray; N, blue; O, red, and the
ORTEP diagram.
274
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JOURNAL OF THE CHINESE
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Ireland-Claisen Rearrangement of Allyl-2-alkoxyacetate
Table 3. Scope of the rearrangement of trans-glycolate 12
In summary, an unprecedented Ireland–Claisen rear-
rangement of an allylglycolate bearing an allylic amine was
realized, affording the corresponding methyl 2-alkoxy-3-
aminomethylpent-4-enoate with excellent yields and dia-
stereoselectivity. The structure of the product was con-
firmed unambiguously by X-ray analysis of the appropriate
product. Transformations of the products to the cis- and
trans-4-hydroxymethylpyrrolidin-3-ol were achieved.
Entry
Product
17a R1 = R2 = Bn
Yield (%)
dr
1
82
76
72
63
54
58
82
86
62
61
61
>95:5
7:1
2
17b R1 = allyl, R2 = Bn
17c R1 = Ph, R2 = Me
17d R1 = c-C6H11, R2 = Bn
17e R1 = R2 = i-C3H7
3
3:1
4
>95:5
>95:5
>95:5
>95:5
8:1
EXPERIMENTAL
5
Reactions were normally carried out under nitrogen
atmosphere in glassware. Merck silica gel 60 (particle size
0.04-0.063 mm) was employed for flash chromatography.
1H NMR 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. The melting point was recorded on a
melting point apparatus (MPA100 – Automated melting
point system, Stanford Research Systems, Inc.) and is un-
corrected.
6
17f R1 = R2 = pyrrolidine
17g R1 = R2 = piperidine
17h R1 = Me, R2 = Bn
17i R1 = allyl, R2 = c-C6H11
17j R1 = PMB, R2 = Bn
17k R1 = R2 = N3
7
8
9
>95:5
>95:5
7:1
10
11
cleavage (OsO4, NaIO4, acetone–THF–H2O (7:6:1) and re-
duction with LiAlH4 to give 47% yield of 19 in three con-
secutive steps without purification of the intermediates
(Scheme III). Deprotection of 19 (Pd–C, H2, MeOH) af-
forded the pyrrolidine 20, which was further treated with
an aqueous HCl solution to give 4-(hydroxymethyl)pyr-
rolidin-3-ol.12
Typical experimental procedure for the preparation
of trans-glycolate 12a
To a solution of 11a (492 mg, 1.84 mmol), N,N-dicy-
clohexylcarbodiimide (493 mg, 2.39 mmol) and N,N-4-di-
methylaminopyridine (22 mg, 0.18 mmol) in CH2Cl2 (18
mL) was added benzyloxyacetic acid (398 mg, 2.39 mmol)
at 0 °C. The solution was stirred at ambient temperature for
3 h until the completion of reaction, as monitored by TLC.
The solution was filtered to remove the precipitate, and the
filtrate was concentrated in vacuo to give the crude prod-
uct. The residue was purified by flash column chromatog-
raphy with 10% EtOAc-hexane (Rf = 0.57 in 20% EtOAc-
hexane) to afford product trans-glycolate 12a as a yellow
oil (625 mg, 83% yield). Selected spectroscopic data: IR
(CH2Cl2): 3027, 2924, 2797, 1753, 1454, 1193, 1125, 970,
736, 698 cm-1; 1H NMR (CDCl3, 400 MHz): d 7.36-7.23
(m, 15 H), 5.90-5.83 (m, 1 H), 5.79-5.72 (m, 1 H), 4.64 (d, J
= 6.4 Hz, 2 H), 4.62 (s, 2 H), 4.10 (s, 2 H), 3.56 (s, 4 H),
3.07 (d, J = 5.6 Hz, 2 H); 13C NMR (CDCl3, 100 MHz): d
170.0 (C), 139.2 (two C), 137.1 (C), 133.4 (CH), 128.8
(four CH), 128.5 (two CH), 128.2 (four CH), 128.04 (two
CH), 127.99 (CH), 126.9 (two CH), 126.3 (CH), 73.3
(CH2), 67.2 (CH2), 65.0 (CH2), 57.9 (two CH2), 54.7
(CH2); MS (m/z, relative intensity): 415 (M+, 75), 338 (7),
324 (5), 250 (14), 249 (20), 210 (8), 158 (11), 106 (6), 92
(11), 91 (100), 65 (6); exact mass calculate for C27H29NO3
(M+): 415.2147; found 415.2155.
Scheme III
The same reaction sequence was alternatively applied
in the anti-17b to give the cis-4-(hydroxymethyl)pyrroli-
din-3-ol (Scheme IV).
Scheme IV
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Typical experimental procedure for the preparation
of cis-glycolate 12a
Spectroscopic data for syn-17a: IR (CH2Cl2): 3028,
2923, 2851, 1749, 1455, 1266, 1204, 1136, 737, 699 cm-1;
1H NMR (CDCl3, 400 MHz): d 7.33-7.13 (m, 15 H), 5.79-
5.71 (m, 1 H), 5.08-4.99 (m, 2 H), 4.54 (d, J = 11.2 Hz, 1
H), 4.29 (d, J = 2.0 Hz, 1 H), 3.99 (d, J = 11.2 Hz, 1 H), 3.69
(s, 3 H), 3.63 (d, J = 13.6 Hz, 2 H), 3.45 (d, J = 13.6 Hz, 2
H), 2.81-2.73 (m, 2 H) 2.47-2.40 (m, 1 H); 13C NMR
(CDCl3, 100 MHz): d 173.0 (C), 139.2 (two C), 137.8 (C),
135.9 (CH), 129.1 (four CH), 128.2 (four CH), 128.1 (two
CH), 127.8 (two CH), 127.4 (CH), 126.9 (two CH), 117.3
(CH2), 78.7 (CH), 72.5 (CH2), 58.5 (two CH2), 55.0 (CH2),
51.6 (CH3), 46.3 (CH); MS (m/z, relative intensity): 429
(M+, 49), 211 (17), 210 (100), 181 (4), 92 (8), 91 (87), 65
(5); exact mass calculate for C28H31NO3 (M+): 429.2304;
found 429.2298.
To a solution of 16a (1.24 g, 4.66 mmol), N,N-dicy-
clohexylcarbodiimide (1.25 g, 6.05 mmol) and N,N-4-di-
methylaminopyridine (56 mg, 0.46 mmol) in CH2Cl2 (46
mL) was added benzyloxyacetic acid (1.00 g, 6.05 mmol)
at 0 °C. The solution was stirred at ambient temperature for
3 h until the completion of reaction, as monitored by TLC.
The solution was filtered to remove the precipitate, and the
filtrate was concentrated in vacuo to give the crude prod-
uct. The residue was purified by flash column chromatog-
raphy with 10% EtOAc-hexane (Rf = 0.77 in 25% EtOAc-
hexane) to afford product cis-glycolate 12a as a yellow oil
(1.74 g, 90% yield). Selected spectroscopic data: IR
(CH2Cl2): 3028, 2922, 1750, 1455, 1193, 1126, 737, 698
cm-1; 1H NMR (CDCl3, 400 MHz): d 7.36-7.20 (m, 15 H),
5.88-5.76 (m, 1 H), 5.69-5.63 (m, 1 H), 4.64 (d, J = 6.8 Hz,
2 H), 4.60 (s, 2 H), 4.06 (s, 2 H), 3.55 (s, 4 H), 3.10 (d, J =
6.4 Hz, 2 H); 13C NMR (CDCl3, 100 MHz): d 170.0 (C),
139.2 (two C), 137.0 (C), 132.8 (CH), 128.7 (four CH),
128.4 (two CH), 128.2 (four CH), 128.0 (two CH), 127.9
(CH), 126.9 (two CH), 125.7 (CH), 73.3 (CH2), 67.1
(CH2), 60.6 (CH2), 58.1 (two CH2), 50.0 (CH2); MS (m/z,
relative intensity): 415 (M+, 32), 250 (14), 249 (43), 197
(8), 196 (5), 158 (27), 106 (21), 92 (11), 91 (100), 65 (5);
exact mass calculate for C27H29NO3 (M+): 415.2147; found
415.2153.
For anti-17a: 91 mg, 82% yield; Rf = 0.74 (Hexane/
EtOAc = 4 : 1), yellow oil.
Spectroscopic data for anti-17a: IR (CH2Cl2): 3027,
2923, 2851, 2797, 1748, 1494, 1453, 1201, 1128, 916, 745,
698 cm-1; 1H NMR (CDCl3, 400 MHz): d 7.32-7.18 (m, 15
H), 5.68-5.59 (m, 1 H), 5.12-5.08 (m, 2 H), 4.64 (d, J = 12.0
Hz, 1 H), 4.32 (d, J = 12.0 Hz, 1 H), 3.91 (d, J = 5.6 Hz, 1
H), 3.64 (d, J = 13.6 Hz, 2 H), 3.60 (s, 3 H), 3.40 (d, J = 13.6
Hz, 2 H), 2.86-2.81 (m, 1 H) 2.67 (dd, J = 12.8, 5.6 Hz, 1
H), 2.54 (dd, J = 12.8, 8.8 Hz, 1 H); 13C NMR (CDCl3, 100
MHz): d 171.9 (C), 139.3 (two C), 137.40 (CH), 137.39
(C), 129.0 (four CH), 128.2 (two CH), 128.0 (four CH),
127.8 (two CH), 127.7 (CH), 126.7 (two CH), 117.1 (CH2),
80.4 (CH), 72.5 (CH2), 58.3 (two CH2), 54.0 (CH2), 51.4
(CH3), 45.9 (CH); MS (m/z, relative intensity): 429 (M+,
29), 211 (10), 210 (100), 181 (4), 92 (7), 91 (79), 65 (4); ex-
act mass calculate for C28H31NO3 (M+): 429.2304; found
429.2296.
Typical experimental procedure for the Ireland-
Claisen rearrangement of glycolate 12a, preparation
of syn-17a
To a solution of cis-glycolate 12a (110 mg, 0.26
mmol) in dry THF (4 mL) was added a solution of lithium
diisopropylamide in THF (2.0 M in THF, 0.26 mL, 0.52
mmol) at -78 °C. The solution was stirred for 15 h, fol-
lowed by the addition of chloro trimethylsilane (TMSCl,
0.10 mL, 0.78 mmol). The solution was gradually warm up
to room temperature and stirred for 13 h, followed by the
addition of saturated aqueous NH4Cl (3 mL). The solution
was extracted with EtOAc (5 mL ´ 3), dried over MgSO4,
and concentrated in vacuo to give the crude product as yel-
low oil. The residue was dissolved in CH2Cl2, followed by
the slow addition of a solution of diazomethane in ether,
monitored by TLC. The solution was concentrated in vacuo
to give the crude product. The residue was purified by flash
column chromatography with 10% EtOAc-hexane (Rf =
0.68 in 20% EtOAc-hexane) to afford product syn-17a as a
yellow oil (104 mg, 90% yield).
For syn-17b: 516 mg, 81% yield; Rf = 0.63 (Hexane/
EtOAc = 5 : 1); yellow oil.
Spectroscopic data for syn-17b: IR (CH2Cl2): 3065,
3028, 2949, 2925, 2803, 1752, 1455, 1260, 1202, 1136,
918, 740, 698 cm-1; 1H NMR (CDCl3, 400 MHz): d 7.30-
7.21 (m, 10 H), 5.85-5.74 (m, 2 H), 5.15-5.00 (m, 4 H),
4.69 (d, J = 11.2 Hz, 1 H), 4.37 (d, J = 2.0 Hz, 1 H), 4.26 (d,
J = 11.2 Hz, 1 H), 3.71 (s, 3 H), 3.68 (d, J = 13.6 Hz, 1 H),
3.46 (d, J = 13.6 Hz, 1 H), 3.10 (dd, J = 14.0, 6.0 Hz, 1 H),
2.96 (dd, J = 14.0, 6.8 Hz, 1 H), 2.79-2.73 (m, 2 H), 2.41
(dd, J = 17.2, 10.4 Hz, 1 H); 13C NMR (CDCl3, 100 MHz):
d 173.2 (C), 139.3 (C), 137.8 (C), 135.8 (CH), 135.4 (CH),
129.0 (two CH), 128.2 (four CH), 127.9 (two CH), 127.6
(CH), 126.9 (CH), 117.6 (CH2), 117.4 (CH2), 78.5 (CH),
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Ireland-Claisen Rearrangement of Allyl-2-alkoxyacetate
72.8 (CH2), 58.3 (CH2), 56.8 (CH2), 54.7 (CH2), 51.6
(CH3), 46.1 (CH); MS (m/z, relative intensity): 379 (M+,
49), 161 (11), 160 (100), 92 (5), 91 (73); exact mass calcu-
late for C24H29NO3 (M+): 379.2147; found 379.2138.
For anti-17b: 78 mg, 76% yield; Rf = 0.69 (Hexane/
EtOAc = 4 : 1); yellow oil.
7.6 Hz, 1 H), 3.49 (s, 3 H), 3.28 (dd, J = 14.4, 7.2 Hz, 1 H),
3.17-3.12 (m, 1 H), 2.86 (s, 3 H); 13C NMR (CDCl3, 100
MHz): d 171.4 (C), 149.1 (C), 137.5 (C), 136.4 (CH), 128.9
(two CH), 128.3 (two CH), 127.9 (two CH), 127.8 (CH),
117.8 (CH2), 116.1 (CH), 112.2 (two CH), 79.3 (CH), 72.8
(CH2), 53.6 (CH2), 51.2 (CH3), 45.7 (CH), 39.8 (CH3); MS
(m/z, relative intensity): 339 (M+, 100), 121 (9), 120 (100),
105 (7), 91 (11), 77(5); exact mass calculate for C21H25NO3
(M+): 339.1834; found 339.1831.
Spectroscopic data for anti-17b: IR (CH2Cl2): 3065,
3028, 2948, 2838, 2801, 1750, 1454, 1258, 1202, 1132,
917, 739, 698 cm-1; 1H NMR (CDCl3, 400 MHz): d 7.33-
7.21 (m, 10 H), 5.87-5.69 (m, 2 H), 5.14-5.05 (m, 4 H),
4.72 (d, J = 12.0 Hz, 1 H), 4.37 (d, J = 12.0 Hz, 1 H), 3.98
(d, J = 4.4 Hz, 1 H), 3.67 (s, 3 H), 3.61 (d, J = 13.6 Hz, 1 H),
3.50 (d, J = 13.6 Hz, 1 H), 3.07-2.96 (m, 2 H), 2.87-2.79
(m, 1 H), 2.72 (dd, J = 12.8, 6.8 Hz, 1 H), 2.50 (dd, J = 12.8,
7.6 Hz, 1 H); 13C NMR (CDCl3, 100 MHz): d 172.1 (C),
139.2 (C), 137.6 (C), 137.5 (CH), 135.6 (CH), 129.1 (two
CH), 128.3 (two CH), 128.0 (two CH), 127.8 (two CH),
127.7 (CH), 126.7 (CH), 117.3 (CH2), 116.9 (CH2), 80.1
(CH), 72.6 (CH2), 58.2 (CH2), 56.7 (CH2), 53.7 (CH2), 51.5
(CH3), 45.8 (CH); MS (m/z, relative intensity): 379 (M+,
63), 161 (11), 160 (93), 92 (8), 91 (100), 65 (5); exact mass
calculate for C24H29NO3 (M+): 379.2147; found 379.2144.
For syn-17c: 97 mg, 82% yield; Rf = 0.68 (Hexane/
EtOAc = 5 : 1); yellow oil.
For syn-17d: 98 mg, 63% yield; Rf = 0.50 (Hexane/
EtOAc = 8 : 1); yellow oil.
Spectroscopic data for syn-17d: IR (CH2Cl2): 2927,
2853, 1751, 1454, 1248, 1203, 1137, 915, 838, 737, 698
cm-1; 1H NMR (CDCl3, 400 MHz): d 7.35-7.20 (m, 10 H),
5.82-5.73 (m, 1 H), 5.04 (dd, J = 10.4, 2 Hz, 1H), 4.96 (dd,
J = 17.6, 2 Hz, 1H), 4.68 (d, J = 11.2 Hz, 1 H), 4.40 (d, J =
2.0 Hz, 1 H), 4.19 (d, J = 11.2 Hz, 1 H), 3.67 (s, 3 H), 3.64
(s, 2 H), 2.80 (dd, J = 12.8, 9.6 Hz, 1 H), 2.54-2.49 (m, 1 H),
2.45 (dd, J = 12.8, 5.2 Hz, 1 H), 2.41-2.17 (m, 1 H), 1.87-
1.80 (m, 1 H), 1.76-1.64 (m, 3 H), 1.58-0.98 (m, 6 H); 13
C
NMR (CDCl3, 100 MHz): d 173.4 (C), 141.3 (C), 138.0
(C), 136.0 (CH), 128.6 (two CH), 128.2 (two CH), 128.1
(two CH), 127.8 (two CH), 127.5 (CH), 126.5 (CH), 117.1
(CH2), 78.4 (CH), 72.6 (CH2), 59.6 (CH), 55.2 (CH2), 52.0
(CH2), 51.5 (CH3), 47.2 (CH), 29.8 (CH2), 27.7 (CH2), 26.3
(CH2), 26.2 (CH2), 26.1 (CH2); MS (m/z, relative inten-
sity): 421 (M+, 44), 203 (13), 202 (100), 120 (11), 92 (4),
91 (54), 55 (5); exact mass calculate for C27H35NO3 (M+):
421.2617; found 421.2624.
Spectroscopic data for syn-17c: IR (CH2Cl2): 2950,
1
2870, 1752, 1599, 1507, 1203, 1133, 748, 694 cm-1; H
NMR (CDCl3, 400 MHz): d 7.39-7.30 (m, 5 H), 7.23-7.17
(m, 2 H), 6.74-6.64 (m, 3 H), 5.95-5.85 (m, 1 H), 5.13-5.07
(m, 2 H), 4.75 (d, J = 11.2 Hz, 1 H), 4.25 (d, J = 11.2 Hz, 1
H), 4.10 (d, J = 2.8 Hz, 1 H), 3.70 (s, 3 H), 3.61 (dd, J =
14.8, 8.8 Hz, 1 H), 3.26 (dd, J = 14.8, 6.0 Hz, 1 H), 2.99-
2.93 (m, 1 H), 2.89 (s, 3 H); 13C NMR (CDCl3, 100 MHz): d
172.3 (C), 149.3 (C), 137.6 (C), 134.7 (CH), 129.1 (two
CH), 128.3 (two CH), 127.9 (two CH), 127.8 (CH), 118.4
(CH2), 116.4 (CH), 112.3 (two CH), 78.3 (CH), 72.4 (CH2),
54.2 (CH2), 51.7 (CH3), 46.3 (CH), 38.9 (CH3); MS (m/z,
relative intensity): 339 (M+, 100), 121 (8), 120 (100), 91
(6); exact mass calculate for C21H25NO3 (M+): 339.1834;
found 339.1840.
For anti-17d: 79 mg, 63% yield; Rf = 0.49 (Hexane/
EtOAc = 9 : 1); yellow oil.
Spectroscopic data for anti-17d: IR (CH2Cl2): 2927,
1
2853, 1748, 1452, 1265, 1203, 1131, 736, 699 cm-1; H
NMR (CDCl3, 400 MHz): d 7.33-7.19 (m, 10 H), 5.71-5.62
(m, 1 H), 5.06-5.01 (m, 2 H), 4.67 (d, J = 11.6 Hz, 1 H),
4.34 (d, J = 11.6 Hz, 1 H), 3.99 (d, J = 4.8 Hz, 1 H), 3.66 (s,
3 H), 3.66-3.55 (m, 2 H), 2.74 (dd, J = 12.4, 5.2 Hz, 1 H),
2.66-2.59 (m, 1 H), 2.55 (dd, J = 12.4, 8.0 Hz, 1 H), 2.41-
2.35 (m, 1 H), 1.78-1.71 (m, 4 H), 1.24-0.96 (m, 6 H); 13
C
For anti-17c: 73 mg, 72% yield; Rf = 0.74 (Hexane/
EtOAc = 4 : 1); yellow oil.
NMR (CDCl3, 100 MHz): d 172.2 (C), 141.3 (C), 137.58
(C), 137.56 (CH), 128.5 (two CH), 128.2 (two CH), 127.92
(two CH), 127.89 (two CH), 127.7 (CH), 126.4 (CH),
116.8 (CH2), 80.2 (CH), 72.6 (CH2), 59.2 (CH), 54.9
(CH2), 51.4 (CH3), 50.9 (CH2), 46.9 (CH), 29.2 (CH2), 28.0
(CH2), 26.4 (CH2), 26.21 (CH2), 26.15 (CH2); MS (m/z, rel-
ative intensity): 421 (M+, 27), 203 (15), 202 (100), 120
(15), 92 (6), 91 (83), 55 (8); exact mass calculate for
Spectroscopic data for anti-17c: IR (CH2Cl2): 2948,
2871, 1747, 1599, 1507, 1346, 1204, 1132, 993, 749, 695
cm-1; 1H NMR (CDCl3, 400 MHz): d 7.39-7.29 (m, 5 H),
7.22-7.18 (m, 2 H), 6.69-6.66 (m, 3 H), 5.85-5.76 (m, 1 H),
5.15-5.08 (m, 2 H), 4.83 (d, J = 11.6 Hz, 1 H), 4.40 (d, J =
11.6 Hz, 1 H), 3.93 (d, J = 4.8 Hz, 1 H), 3.60 (dd, J = 14.4,
J. Chin. Chem. Soc. 2012, 59, 273-282
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C27H35NO3 (M+): 421.2617; found 421.2613.
(M+, 15), 91 (9), 85 (4), 84 (100); exact mass calculate for
C18H25NO3 (M+): 303.1834; found 303.1839.
For syn-17e: 124 mg, 71% yield; Rf = 0.44 (Hexane/
EtOAc = 4 : 1); yellow oil.
For anti-17f: 70 mg, 58% yield; Rf = 0.55 (CH2Cl2/
MeOH = 10 : 1); yellow oil.
Spectroscopic data for syn-17e: IR (CH2Cl2): 2965,
1751, 1455, 1382, 1254, 1207, 1174, 1133, 916, 843, 736,
698, 668, 595 cm-1; 1H NMR (CDCl3, 400 MHz): d 7.39-
7.27 (m, 5 H), 5.88-5.79 (m, 1 H), 5.07-4.99 (m, 2 H), 4.74
(d, J = 11.2 Hz, 1 H), 4.42 (d, J = 1.6 Hz, 1 H), 4.35 (d, J =
11.2 Hz, 1 H), 3.73 (s, 3 H), 3.03-2.96 (m, 2 H), 2.68-2.58
(m, 2 H), 2.51-2.45 (m, 1 H), 1.00-0.96 (m, 12 H); 13C
NMR (CDCl3, 100 MHz): d 173.8 (C), 138.1 (C), 136.2
(CH), 128.2 (two CH), 127.7 (two CH), 127.5 (CH), 117.0
(CH2), 78.1 (CH), 72.4 (CH2), 51.5 (CH3), 47.8 (two CH),
47.5 (CH), 46.4 (CH2), 21.7 (two CH3), 20.1 (two CH3);
MS (m/z, relative intensity): 333 (M+, 26), 304 (4), 115 (7),
114 (100), 91 (18), 72 (13); exact mass calculate for
C20H31NO3 (M+): 333.2304; found 333.2309.
Spectroscopic data for anti-17f: IR (CH2Cl2): 2951,
2925, 2788, 1750, 1455, 1258, 1201, 1132, 916, 736, 698
cm-1; 1H NMR (CDCl3, 400 MHz): d 7.36-7.28 (m, 5 H),
5.84-5.75 (m, 1 H), 5.16-5.08 (m, 2 H), 4.75 (d, J = 11.6
Hz, 1 H), 4.39 (d, J = 11.6 Hz, 1 H), 3.96 (d, J = 4.8 Hz, 1
H), 3.71 (s, 3 H), 2.84-2.77 (m, 1 H), 2.73-2.70 (m, 1 H),
2.58-2.42 (m, 5 H), 1.71-1.66 (m, 4 H); 13C NMR (CDCl3,
100 MHz): d 172.2 (C), 137.6 (C), 137.4 (CH), 128.3 (two
CH), 127.9 (two CH), 127.7 (CH), 117.0 (CH2), 80.2 (CH),
72.8 (CH2), 56.2 (CH2), 54.2 (two CH2), 51.5 (CH3), 46.5
(CH), 23.5 (two CH2); MS (m/z, relative intensity): 303
(M+, 10), 91 (18), 85 (6), 84 (100), 55 (6); exact mass cal-
culate for C18H25NO3 (M+): 303.1834; found 303.1836.
For syn-17g: 65 mg, 57% yield; Rf = 0.21 (Hexane/
EtOAc = 5 : 1); yellow oil.
For anti-17e: 71 mg, 54% yield; Rf = 0.50 (Hexane/
EtOAc = 1 : 1); yellow oil.
Spectroscopic data for anti-17e: IR (CH2Cl2): 2964,
2928, 2869, 1752, 1455, 1386, 1361, 1253, 1206, 1118,
915, 735, 698 cm-1; 1H NMR (CDCl3, 400 MHz): d 7.37-
7.28 (m, 5 H), 5.75-5.66 (m, 1 H), 5.09-5.04 (m, 2 H), 4.75
(d, J = 12.0 Hz, 1 H), 4.40 (d, J = 12.0 Hz, 1 H), 4.03 (d, J =
4.4 Hz, 1 H), 3.72 (s, 3 H), 2.98-2.91 (m, 2 H), 2.74-2.64
(m, 1 H), 2.44 (dd, J = 12.8, 7.2 Hz, 1 H), 0.93 (d, J = 6.4
Hz, 12 H); 13C NMR (CDCl3, 100 MHz): d 172.4 (C),
137.75 (C), 137.73 (CH), 128.3 (two CH), 128.0 (two CH),
127.7 (CH), 116.6 (CH2), 80.0 (CH), 72.7 (CH2), 51.4
(CH3), 47.6 (two CH), 47.2 (CH), 45.5 (CH2), 20.8 (two
CH3), 20.7 (two CH3); MS (m/z, relative intensity): 333
(M+, 5), 115 (8), 114 (100), 91 (22), 72 (15), 70 (4); exact
mass calculate for C20H31NO3 (M+): 333.2304; found
333.2304.
Spectroscopic data for syn-17g: IR (CH2Cl2): 2930,
2852, 1752, 1600, 1455, 1267, 1197, 1132, 750, 698 cm-1;
1H NMR (CDCl3, 400 MHz): d 7.37-7.27 (m, 5 H), 5.83-
5.74 (m, 1 H), 5.07-5.01 (m, 2 H), 4.76 (d, J = 11.6 Hz, 1
H), 4.41 (d, J = 11.6 Hz, 1 H), 4.35 (d, J = 3.2 Hz, 1 H), 3.72
(s, 3 H), 2.80-2.73 (m, 1 H), 2.52 (dd, J = 12.4, 10.4 Hz, 1
H), 2.45-2.43 (m, 2 H) 2.20-2.13 (m, 3 H), 1.53-1.47 (m, 4
H), 1.42-1.39 (m, 2 H); 13C NMR (CDCl3, 100 MHz): d
173.4 (C), 138.0 (C), 136.0 (CH), 128.2 (two CH), 128.1
(two CH), 127.6 (CH), 117.3 (CH2), 78.7 (CH), 73.1 (CH2),
59.5 (CH2), 54.7 (two CH2), 51.6 (CH3), 45.0 (CH), 26.2
(two CH2), 24.5 (CH2); MS (m/z, relative intensity): 317
(M+, 46), 99 (6), 98 (100), 91 (8); exact mass calculate for
C19H27NO3 (M+): 317.1991; found 317.1981.
For anti-17g: 93 mg, 82% yield; Rf = 0.26 (Hexane/
EtOAc = 2 : 1); yellow oil.
For syn-17f: 90 mg, 79% yield; Rf = 0.61 (CH2Cl2/
MeOH = 10 : 1); yellow oil.
Spectroscopic data for anti-17g: IR (CH2Cl2): 2931,
2853, 1752, 1455, 1260, 1207, 1121, 1027, 916, 736, 698
cm-1; 1H NMR (CDCl3, 400 MHz): d 7.36-7.28 (m, 5 H),
5.79-5.73 (m, 1 H), 5.12-5.05 (m, 2 H), 4.78 (d, J = 11.6
Hz, 1 H), 4.39 (d, J = 11.6 Hz, 1 H), 3.97 (d, J = 4.4 Hz, 1
H), 3.74 (s, 3 H), 2.88-2.81 (m, 1 H), 2.59 (dd, J = 12.8, 8.4
Hz, 1 H), 2.34-2.21 (m, 5 H), 1.49-1.45 (m, 4 H), 1.39-1.35
(m, 2 H); 13C NMR (CDCl3, 100 MHz): d 172.3 (C), 137.82
(C), 137.75 (CH), 128.2 (two CH), 127.9 (two CH), 127.7
(CH), 116.5 (CH2), 79.9 (CH), 72.8 (CH2), 58.8 (CH2),
54.8 (two CH2), 51.5 (CH3), 44.8 (CH), 25.9 (two CH2),
24.4 (CH2); MS (m/z, relative intensity): 317 (M+, 80), 302
Spectroscopic data for syn-17f: IR (CH2Cl2): 2951,
2929, 2788, 1752, 1455, 1278, 1202, 1132, 916 737, 698
cm-1; 1H NMR (CDCl3, 400 MHz): d 7.37-7.28 (m, 5 H),
5.86-5.77 (m, 1 H), 5.10-5.04 (m, 2 H), 4.77 (d, J = 11.6
Hz, 1 H), 4.40 (d, J = 11.6 Hz, 1 H), 4.28 (d, J = 2.8 Hz, 1
H), 3.72 (s, 3 H), 2.76-2.69 (m, 2 H), 2.54-2.51 (m, 2 H),
2.38-2.32 (m, 3 H), 1.75-1.68 (m, 4 H)); 13C NMR (CDCl3,
100 MHz): d 173.0 (C), 137.9 (C), 136.1 (CH), 128.2 (two
CH), 128.0 (two CH), 127.7 (CH), 117.3 (CH2), 79.0 (CH),
72.9 (CH2), 57.0 (CH2), 54.0 (two CH2), 51.6 (CH3), 46.8
(CH), 23.6 (two CH2); MS (m/z, relative intensity): 303
278
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J. Chin. Chem. Soc. 2012, 59, 273-282

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Ireland-Claisen Rearrangement of Allyl-2-alkoxyacetate
(30), 138 (80), 137 (84), 124 (13), 122 (16), 98 (53), 91
(100), 86 (10), 85 (65), 84 (45), 83 (10), 65 (11), 55 (26);
exact mass calculate for C19H27NO3 (M+): 317.1991; found
317.1999.
H), 3.72 (s, 3 H), 3.13 (d, J = 6.4 Hz, 2 H), 2.74-2.61 (m, 2
H), 2.45-2.37 (m, 2 H), 1.76-1.56 (m, 6 H), 1.25-0.99 (m, 4
H); 13C NMR (CDCl3, 100 MHz): d 173.5 (C), 138.2 (CH),
138.0 (C), 136.0 (CH), 128.2 (two CH), 127.8 (two CH),
127.5 (CH), 117.1 (CH2), 115.7 (CH2), 78.5 (CH), 72.7
(CH2), 60.3 (CH), 54.0 (CH2), 51.61 (CH2), 51.55 (CH),
47.1 (CH), 30.0 (CH2), 28.3 (CH2), 26.3 (CH2), 26.21
(CH2), 26.17 (CH2); MS (m/z, relative intensity): 371 (M+,
57), 153 (9), 152 (100), 91 (12), 70 (16), 55 (5); exact mass
calculate for C23H33NO3 (M+): 371.2460; found 371.2465.
For anti-17i: 82 mg, 62% yield; Rf = 0.27 (Hexane/
EtOAc = 9 : 1); yellow oil.
For syn-17h: 104 mg, 90% yield; Rf = 0.26 (Hexane/
EtOAc = 2 : 1); yellow oil.
Spectroscopic data for syn-17h: IR (CH2Cl2): 2949,
2845, 2790, 1751, 1455, 1266, 1202, 1137, 1025, 917, 740,
698 cm-1; 1H NMR (CDCl3, 400 MHz): d 7.31-7.21 (m, 10
H), 5.85-5.76 (m, 1 H), 5.11-5.04 (m, 2 H), 4.74 (d, J = 11.2
Hz, 1 H), 4.39 (d, J = 2.8 Hz, 1 H), 4.34 (d, J = 11.2 Hz, 1
H), 3.72 (s, 3 H), 3.52 (d, J = 12.8 Hz, 1 H), 3.42 (d, J = 12.8
Hz, 1 H), 2.83-2.77 (m, 1 H), 2.70 (dd, J = 12.0, 10.0 Hz, 1
H), 2.29 (dd, J = 12.0, 5.6 Hz, 1 H), 2.14 (s, 3 H); 13C NMR
(CDCl3, 100 MHz): d 173.1 (C), 137.8 (two C), 135.7
(CH), 129.0 (two CH), 128.22 (two CH), 128.15 (two CH),
128.0 (two CH), 127.7 (CH), 126.9 (CH), 117.5 (CH2),
78.5 (CH), 73.0 (CH2), 62.5 (CH2), 58.4 (CH2), 51.6 (CH3),
45.8 (CH), 42.2 (CH3); MS (m/z, relative intensity): 353
(M+, 7), 135 (9), 134 (100), 92 (4), 91 (64), 65 (3); exact
mass calculate for C22H27NO3 (M+): 353.1991; found
353.1998.
Spectroscopic data for anti-17i: IR (CH2Cl2): 2927,
2854, 1751, 1453, 1257, 1202, 1131, 1027, 995, 915, 735,
698 cm-1; 1H NMR (CDCl3, 400 MHz): d 7.40-7.28 (m, 5
H), 5.81-5.68 (m, 2 H), 5.15-4.94 (m, 4 H), 4.76 (d, J = 11.6
Hz, 1 H), 4.39 (d, J = 11.6 Hz, 1 H), 3.99 (d, J = 3.6 Hz, 1
H), 3.71 (s, 3 H), 3.15-3.01 (m, 2 H), 2.75-2.69 (m, 2 H),
2.47-2.40 (m, 2 H), 1.74-1.64 (m, 5 H), 1.26-1.11 (m, 5 H);
13C NMR (CDCl3, 100 MHz): d 172.3 (C), 138.1 (CH),
137.8 (C), 137.7 (CH), 128.2 (two CH), 127.9 (two CH),
127.6 (CH), 116.6 (CH2), 115.6 (CH2), 79.9 (CH), 72.7
(CH2), 59.9 (CH), 53.9 (CH2), 51.4 (CH3), 50.5 (CH2), 46.6
(CH), 28.87 (CH2), 28.85 (CH2), 26.4 (CH2), 26.24 (CH2),
26.22 (CH2); MS (m/z, relative intensity): 371 (M+, 25),
153 (12), 152 (100), 91 (15), 70 (25), 55 (9); exact mass
calculate for C23H33NO3 (M+): 371.2460; found 371.2453.
For syn-17j: 104 mg, 67% yield; 0.54 (Hexane/
EtOAc = 5 : 1); mp. 56-58 °C; yellow solid.
For anti-17h: 94 mg, 86% yield; Rf = 0.55 (Hexane/
EtOAc = 3 : 1); yellow oil.
Spectroscopic data for anti-17h: IR (CH2Cl2): 2949,
2924, 2844, 2791, 1749, 1454, 1265, 1206, 1135, 1025,
917, 737, 699 cm-1; 1H NMR (CDCl3, 400 MHz): d 7.34-
7.22 (m, 10 H), 5.82-5.72 (m, 1 H), 5.16-5.10 (m, 2 H),
4.76 (d, J = 11.6 Hz, 1 H), 4.39 (d, J = 11.6 Hz, 1 H), 4.00
(d, J = 4.4 Hz, 1 H), 3.68 (s, 3 H), 3.57 (d, J = 13.2 Hz, 1 H),
3.36 (d, J = 13.2 Hz, 1 H), 2.91-2.84 (m, 1 H), 2.67 (dd, J =
12.8, 7.2 Hz, 1 H), 2.41 (dd, J = 12.8, 7.6 Hz, 1 H), 2.11 (s,
3 H); 13C NMR (CDCl3, 100 MHz): d 172.2 (C), 138.9 (C),
137.6 (C), 137.4 (CH), 129.2 (two CH), 128.3 (two CH),
128.0 (two CH), 127.9 (two CH), 127.7 (CH), 126.8 (CH),
116.9 (CH2), 79.9 (CH), 72.7 (CH2), 62.5 (CH2), 57.6
(CH2), 51.5 (CH3), 45.5 (CH), 42.2 (CH3); MS (m/z, rela-
tive intensity): 353 (M+, 84), 135 (9), 134 (100), 92 (6), 91
(65), 65 (4); exact mass calculate for C22H27NO3 (M+):
353.1991; found 353.1997.
Spectroscopic data for syn-17j: IR (CH2Cl2): 2926,
2834, 1751, 1611, 1509, 1455, 1249, 1203, 1136, 1030,
741, 698 cm-1; 1H NMR (CDCl3, 400 MHz): d 7.31-7.13
(m, 12 H), 6.81 (d, J = 8.0 Hz, 2 H) 5.79-5.71 (m, 1 H),
5.08-5.04 (m, 2 H), 4.54 (d, J = 11.2 Hz, 1 H), 4.30 (d, J =
1.6 Hz, 1 H), 3.98 (d, J = 11.2 Hz, 1 H), 3.73 (s, 3 H), 3.69
(s, 3 H), 3.64 (d, J = 13.6 Hz, 1 H), 3.58 (d, J = 13.2 Hz, 1
H), 3.42 (d, J = 13.6 Hz, 1 H), 3.36 (d, J = 13.2 Hz, 1 H),
2.82-2.74 (m, 2 H), 2.45-2.37 (m, 1 H); 13C NMR (CDCl3,
100 MHz): d 173.3 (C), 158.8 (C), 139.6 (C), 138.0 (C),
136.1 (CH), 131.4 (C), 130.5 (two CH), 129.3 (two CH),
128.4 (two CH), 128.3 (two CH), 127.9 (two CH), 127.6
(CH), 127.1 (CH), 117.5 (CH2), 113.8 (two CH), 78.8
(CH), 72.7 (CH2), 58.5 (CH2), 57.9 (CH2), 55.4 (CH3), 54.9
(CH2), 51.9 (CH3), 46.5 (CH); MS (m/z, relative intensity):
459 (M+, 47), 241 (7), 240 (43), 122 (7), 121 (100), 91 (15);
exact mass calculate for C29H33NO4 (M+): 459.2410; found
459.2415.
For syn-17i: 78 mg, 58% yield; Rf = 0.46 (Hexane/
EtOAc = 8 : 1); yellow oil.
Spectroscopic data for syn-17i: IR (CH2Cl2): 2928,
2853, 1752, 1453, 1258, 1201, 1135, 1051, 995, 916, 735,
697 cm-1; 1H NMR (CDCl3, 400 MHz): d 7.39-7.27 (m, 5
H), 5.84-5.75 (m, 2 H), 5.15-4.99 (m, 4 H), 4.75 (d, J = 11.2
Hz, 1 H), 4.41 (d, J = 2.4 Hz, 1 H), 4.35 (d, J = 11.2 Hz, 1
J. Chin. Chem. Soc. 2012, 59, 273-282
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279

Article
Hon et al.
For anti-17j: 70 mg, 61% yield; 0.36 (Hexane/EtOAc
= 8 : 1); yellow oil.
Spectroscopic data for anti-17j: IR (CH2Cl2): 2923,
119.1 (CH2), 78.8 (CH), 72.9 (CH2), 51.8 (CH3), 51.6
(CH2), 47.0 (CH); MS (m/z, relative intensity): 275 (M+,
12), 113 (11), 112 (4), 92 (8), 91 (100), 82 (4), 65 (7); exact
mass calculate for C14H17N3O3 (M+): 275.1270; found
275.1276.
1
1748, 1540, 1508, 1456, 1247, 739, 698 cm-1; H NMR
(CDCl3, 400 MHz): d 7.32-7.14 (m, 12 H), 6.81 (d, J = 8.4
Hz, 2 H) 5.67-5.58 (m, 1 H), 5.16-5.04 (m, 2 H), 4.65 (d, J
= 11.6 Hz, 1 H), 4.32 (d, J = 11.6 Hz, 1 H), 3.91 (d, J = 5.6
Hz, 1 H), 3.78 (s, 3 H), 3.65 (d, J = 6.4 Hz, 1 H), 3.62-3.59
(m, 4 H), 3.38 (d, J = 13.6 Hz, 1 H), 3.34 (d, J = 13.6 Hz, 1
H), 2.87-2.80 (m, 1 H), 2.66 (dd, J = 12.8, 5.6 Hz, 1 H),
2.52 (dd, J = 12.8, 8.8 Hz, 1 H); 13C NMR (CDCl3, 100
MHz): d 172.0 (C), 158.5 (C), 139.6 (C), 137.50 (CH),
137.46 (C), 131.3 (C), 130.2 (two CH), 129.0 (two CH),
128.3 (two CH), 128.0 (two CH), 127.8 (two CH), 127.7
(CH), 126.7 (CH), 117.1 (CH2), 113.4 (two CH), 80.5
(CH), 72.5 (CH2), 58.2 (CH2), 57.6 (CH2), 55.2 (CH3), 53.9
(CH2), 51.5 (CH3), 45.9 (CH); MS (m/z, relative intensity):
459 (M+, 45), 241 (7), 240 (39), 122 (4), 121 (100), 91 (13);
exact mass calculate for C29H33NO4 (M+): 459.2410; found
459.2415.
Typical experimental procedure for the preparation
of 18
To a solution of syn-17b (548 mg, 1.45 mmol) and
acetic acid (7.5 mL) in MeOH (7.5 mL) was added Pd/C
(31 mg, 0.29 mmol) at room temperature. The solution was
stirred under H2 atmosphere (1 atm) for 3 days, followed by
filtrating through Celite and concentrated in vacuo to give
the crude product as brown oil. The residue was purified by
flash column chromatography with 10% EtOAc-hexane (Rf
= 0.46 in 20% EtOAc-hexane) to afford product anti-18 as
a yellow oil (383 mg, 86% yield).
Spectroscopic data for anti-18: IR (CH2Cl2): 2925,
2856, 2360, 2337, 1697, 1492, 1440, 1253, 1130, 1081,
919, 738, 698 cm-1; 1H NMR (CDCl3, 400 MHz): d 7.42-
7.23 (m, 10 H), 5.77-5.69 (m, 1 H), 5.16-5.08 (m, 3 H),
4.87 (d, J = 12.0 Hz, 1 H), 4.51 (d, J = 14.4 Hz, 1 H), 4.40
(d, J = 14.4 Hz, 1 H), 3.98 (d, J = 8.0 Hz, 1 H), 3.34-3.28
(m, 1 H), 2.97-2.89 (m, 2 H); 13C NMR (CDCl3, 100 MHz):
d 172.3 (C), 137.9 (C), 136.1 (CH), 135.9 (C), 128.8 (two
CH), 128.3 (two CH), 128.2 (two CH), 128.1 (two CH),
127.8 (CH), 127.7 (CH), 117.6 (CH2), 80.1 (CH), 72.3
(CH2), 47.5 (CH2), 46.7 (CH2), 44.3 (CH); MS (m/z, rela-
tive intensity): 307 (M+, 15), 202 (5), 201 (34), 200 (6), 174
(4), 92 (9), 91 (100), 77 (4), 65 (12); exact mass calculate
for C20H21NO2 (M+): 307.1572; found 307.1575.
For syn-18: 325 mg, 78% yield; 0.38 (Hexane/EtOAc
= 4 : 1); yellow oil.
For syn-17k: 71 mg, 60% yield; 0.58 (Hexane/EtOAc
= 4 : 1); yellow oil.
Spectroscopic data for syn-17k: IR (CH2Cl2): 2924,
1
2869, 2100, 1751, 1455, 1203, 1127, 738, 698 cm-1; H
NMR (CDCl3, 400 MHz): d 7.36-7.31 (m, 5 H), 5.82-5.73
(m, 1 H), 5.19-5.14 (m, 2 H), 4.80 (d, J = 11.6 Hz, 1 H),
4.39 (d, J = 11.6 Hz, 1 H), 4.17 (d, J = 3.2 Hz, 1 H), 3.75 (s,
3 H), 3.44 (dd, J = 12.0, 8.4 Hz, 1 H), 3.35 (dd, J = 12.0, 6.4
Hz, 1 H), 2.77-2.75 (m, 1 H); 13C NMR (CDCl3, 100 MHz):
d 171.7 (C), 137.2 (C), 133.3 (CH), 128.4 (two CH), 128.2
(two CH), 128.0 (CH), 119.5 (CH2), 77.6 (CH), 72.9 (CH2),
52.0 (CH2), 51.9 (CH3), 47.1(CH); MS (m/z, relative inten-
sity): 275 (M+, 3), 149 (6), 113 (14), 105 (5), 92 (9), 91
(100), 83 (4), 82 (4), 81 (5), 71 (5), 69 (4), 65 (8), 57 (7), 55
(6); exact mass calculate for C14H17N3O3 (M+): 275.1270;
found 275.1275.
Spectroscopic data for syn-18: IR (CH2Cl2): 2923,
1
2854, 1695, 1434, 1253, 1124, 738, 698 cm-1; H NMR
(CDCl3, 400 MHz): d 7.39-7.22 (m, 10 H), 6.00-5.91 (m, 1
H), 5.16-5.09 (m, 2 H), 4.91 (d, J = 12.0 Hz, 1 H), 4.78 (d, J
= 12.0 Hz, 1 H), 4.49 (d, J = 14.8 Hz, 1 H), 4.45 (d, J = 14.8
Hz, 1 H), 4.06 (d, J = 6.4 Hz, 1 H), 3.28-3.18 (m, 2 H), 3.01-
2.94 (m, 1 H); 13C NMR (CDCl3, 100 MHz): d 171.9 (C),
137.8 (C), 136.0 (C), 133.8 (CH), 128.7 (two CH), 128.3
(two CH), 128.1 (two CH), 127.8 (two CH), 127.7 (CH),
127.6 (CH), 117.8 (CH2), 77.8 (CH), 72.0 (CH2), 49.3
(CH2), 46.5 (CH2), 41.9 (CH); MS (m/z, relative intensity):
307 (M+, 25), 202 (13), 201 (84), 200 (13), 174 (27), 110
(5), 92 (9), 91 (100), 65 (11); exact mass calculate for
C20H21NO2 (M+): 307.1572; found 307.1576.
For anti-17k: 72 mg, 61% yield; 0.55 (Hexane/
EtOAc = 4 : 1); yellow oil.
Spectroscopic data for anti-17k: IR (CH2Cl2): 2924.,
2869, 2100, 1749, 1455, 1266, 1200, 1119, 739, 698 cm-1;
1H NMR (CDCl3, 400 MHz): d 7.36-7.30 (m, 5 H), 5.78-
5.69 (m, 1 H), 5.21-5.17 (m, 2 H), 4.70 (d, J = 11.2 Hz, 1
H), 4.41 (d, J = 11.2 Hz, 1 H), 3.96 (d, J = 6.8 Hz, 1 H), 3.73
(s, 3 H), 3.49 (d, J = 5.6 Hz, 2 H), 2.80-2.74 (m, 1 H); 13C
NMR (CDCl3, 100 MHz): d 171.7 (C), 137.0 (C), 134.5
(CH), 128.4 (two CH), 128.14 (two CH), 128.07 (CH),
280
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© 2012 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
J. Chin. Chem. Soc. 2012, 59, 273-282

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Ireland-Claisen Rearrangement of Allyl-2-alkoxyacetate
Typical experimental procedure for the preparation
of 19
CH), 128.5 (two CH), 128.3 (two CH), 127.8 (CH), 127.5
(two CH), 127.0 (CH), 79.7 (CH), 72.0 (CH2), 61.7 (CH2),
60.5 (CH2), 59.5 (CH2), 55.1 (CH2), 43.0 (CH).
To a solution of anti-18 (264 mg, 0.84 mmol) in ace-
tone (12.6 mL), H2O (1.8 mL), and THF (10.8 mL) was
added NaIO4 (901 mg, 4.22 mmol) and a solution of OsO4
in H2O (0.4 M, 54 mL). The solution was stirred at room
temperature for 2 h until the completion of reaction, as
monitored by TLC. To the reaction mixture was added satu-
rated aqueous Na2SO3 solution (5 mL), and removed the or-
ganic solvent under vacuum. The solution was extracted
with EtOAc (5 mL ´ 3), dried over MgSO4, and concen-
trated in vacuo to give the crude aldehyde product as yel-
low oil. To the solution of this crude product in dry THF
(24 mL) was added LiAlH4 (352 mg, 9.24 mmol) at 0 °C.
The solution was heated to reflux for 15 h, followed by the
addition of saturated aqueous NaOH solution (0.5 mL).
The solution was filtered to remove the precipitate, and the
filtrate was dried over MgSO4, concentrated in vacuo to
give the crude product. The residue was purified by flash
column chromatography with 20% EtOAc-hexane (Rf =
0.22 in 20% EtOAc-hexane) to afford product anti-19 as a
yellow oil (135 mg, 55% yield).
Spectroscopic data for anti-19: 1H NMR (CDCl3, 400
MHz): d 7.35-7.23 (m, 10 H), 4.48 (s, 2 H), 4.08-4.04 (m, 1
H), 3.72 (dd, J = 10.0, 4.4 Hz, 1 H), 3.64 (dd, J = 10.0, 4.0
Hz, 1 H), 3.61 (s, 2 H), 3.16 (dd, J = 10.0, 6.8 Hz, 1 H), 2.75
(dd, J = 9.2, 6.8 Hz, 1 H), 2.67 (dd, J = 9.2, 2.8 Hz, 1 H),
2.40 (dd, J = 10.0, 4.4 Hz, 1 H), 2.32-2.30 (m, 1 H); 13C
NMR (CDCl3, 100 MHz): d 138.23 (C), 138.16 (C), 128.7
(two CH), 128.40 (two CH), 128.36 (two CH), 127.68 (two
CH), 127.65 (CH), 127.2 (CH), 81.3 (CH), 71.4 (CH2),
66.1 (CH2), 60.5 (CH2), 60.0 (CH2), 56.5 (CH2), 46.3 (CH);
IR (CH2Cl2): 3351, 3062, 3029, 2923, 2861, 2798, 1454,
1093, 1068, 738, 698 cm-1; MS (m/z, relative intensity):
297 (M+, 26), 206 (5), 191 (10), 160 (6), 120 (28), 92 (9),
91 (100), 65 (5); exact mass calculate for C19H23NO2 (M+):
297.1729; found 297.1723.
Typical experimental procedure for the preparation
of 21
To a solution of anti-19 (253 mg, 0.85 mmol) in
MeOH (9 mL) was added Pd/C (18 mg, 0.17 mmol) at room
temperature. The solution was stirred under H2 atmosphere
(1 atm) for 2 days, followed by filtrating through Celite and
concentrated in vacuo to give the crude product as brown
oil. To a solution of the residue in MeOH (8 mL) was
slowly added a solution of aqueous HCl solution (12 M, 0.4
mL) at room temperature. The solution was stirred for 2 h
and concentrated in vacuo to give anti-21 as brown oil.
(124 mg, 95% yield). Brown oil.
Spectroscopic data for anti-21: 1H NMR (hydrochlo-
ride, D2O, 400 MHz): d 4.49-4.46 (m, 1 H), 3.73-3.63 (m, 3
H), 3.50 (dd, J = 12.4, 4.8 Hz, 1 H), 3.33 (d, J = 11.5 Hz, 1
H), 3.23 (dd, J = 12.4, 5.6 Hz, 1 H), 2.49-2.57 (m, 1 H); 13
C
NMR (hydrochloride, D2O, 100 MHz): d 71.9 (CH), 60.9
(CH2), 52.1 (CH2), 47.9 (CH), 46.6 (CH2).
For syn-21: 86 mg, 78% yield; yellow oil.
Spectroscopic data for syn-21: 1H NMR (DMSO-d6,
400 MHz): d 9.32 (br s, 1 H), 9.12 (br s, 1 H), 5.37 (br s, 1
H), 4.29-4.26 (m, 1 H), 3.62 (dd, J = 10.8, 7.2 Hz, 1 H),
3.45 (dd, J = 11.2, 7.2 Hz, 1 H), 3.29-3.18 (m, 2 H), 3.08-
3.04 (m, 1 H), 2.91-2.85 (m, 1 H), 2.26-2.19 (m, 1 H); 13
C
NMR (DMSO-d6, 100 MHz): d 68.8 (CH), 58.2 (CH2),
53.0 (CH2), 46.1 (CH), 45.5 (CH2).
Supporting Information Available
Spectra data for the new compounds.
ACKNOWLEDGMENT
We acknowledge the financial support for this study
from the National Science Council, Taiwan, ROC (NSC
97-2113-M-194-001-MY3). Thanks to the National Center
for High-Performance Computing (NCHC) for their assis-
tance in literature searching, and the instrument center of
National Science Council for compounds analysis.
For syn-19: 214 mg, 68% yield; 0.29 (Hexane/EtOAc
= 1 : 4); yellow oil.
Spectroscopic data for syn-19: IR (CH2Cl2): 3396,
3028, 2917, 2795, 1494, 1454, 1092, 739, 702, 666, 604
cm-1; 1H NMR (CDCl3, 400 MHz): d 7.36-7.27 (m, 10 H),
4.57 (d, J = 12.0 Hz, 1 H), 4.42 (d, J = 12.0 Hz, 1 H), 4.29-
4.24 (m, 1 H), 3.78-3.77 (m, 2 H), 3.64 (d, J = 12.8 Hz, 1
H), 3.60 (d, J = 12.8 Hz, 1 H), 3.03 (dd, J = 9.6, 6.4 Hz, 1
H), 2.82-2.77 (m, 1 H), 2.54-2.48 (m, 3 H); 13C NMR
(CDCl3, 100 MHz): d 138.6 (C), 137.9 (C), 128.7 (two
REFERENCES
1. For recent reviews, see: (a) Castro, A. M. M. Chem. Rev.
2004, 104, 2939-3002. (b) Majumdar, K. C.; Alam, S.;
Chattopadhyay, B. Tetrahedron 2008, 64, 597. (c) Gonda, J.
Angew. Chem. Int. Ed. 2004, 3516. (d) Majumdar, K. C.;
Bhattacharyya, T.; Chattopadhyay, B.; Sinha, B. Synthesis
2009, 2117.
2. For reviews, see: (a) Chai, Y. C.; Hong, S.-P.; Lindsay, H. A.;
J. Chin. Chem. Soc. 2012, 59, 273-282
© 2012 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.jccs.wiley-vch.de
281

Article
Hon et al.
McFarland, C.; McIntosh, M. C. Tetrahedron 2002, 58,
Shimamoto, K.; Ohfune, Y. Tetrahedron Lett. 2004, 45,
5869-5872. (l) Kazmaier, U.; Paehler, S.; Endermann, R.;
Haebich, D.; Kroll, H.-P.; Riedl, B. Bioorg. Med. Chem.
2002, 10, 3905-3914. (m) Pal, U.; Del Valle, J. R.;
Ranatunga, S.; Ariyarathna, Y. Org. Lett. 2009, 11, 5298-
5301. (n) Sharma, V.; Kelly, G. T.; Watanabe, C. M. H. Org.
Lett. 2008, 10, 4815-4818.
2905. For recent examples of the Ireland–Claisen Rear-
rangement in synthesis, see: (b) Tellam, J. P.; Kociok-Kohn,
G.; Carbery, D. R. Org. Lett. 2008, 10, 5199. (c) Ylioja, P.
M.; Mosley, A. D.; Charlot, C. E.; Carbery, D. R. Tetrahe-
dron Lett. 2008, 49, 1111.
3. For a recent example, see: Tellam, J. P.; Kociok-Kohn, G.;
Carbery, D. R. Org. Lett. 2008, 10, 5199.
8. For an only example, see: Hauske, J. R.; Julin, S. M. Tetrahe-
dron Lett. 1993, 34, 4909-4912.
4. For a recent example, see: Khanjin, N. A.; Snyder, J. P.;
Menger, F. M. J. Am. Chem. Soc. 1999, 121, 11831.
9. (a) Huang, H.; Greenberg, M. M. J. Org. Chem. 2008, 73,
2695-2703. (b) Marquez, V. E.; Wang, P.; Nicklaus, M. C.;
Maier, M.; Manoharan, M.; Christman, J. K.; Banavali, N.
K.; Mackerell, A. D. Nucleosides Nucleotides 2001, 20, 451-
460. (c) Besada, P.; Gonzalez Moa, M. J.; Teran, C. Synthesis
2008, 2363-2368. (d) Ok, D.; Li, C.; Abbadie, C.; Felix, J. P.;
Fisher, M. H.; Garcia, M. L.; Kaczorowski, G. J.; Lyons, K.
A.; Martin, W. J.; Priest, B. T.; Smith, M. M.; Brande, S. W.;
Matthew, J. W.; William, H. P. Bioorg. Med. Chem. Lett.
2006, 16, 1358-1361.
5. Kirsten, M.; Rehbein, J.; Hiersemann, M.; Strassner, T. J.
Org. Chem. 2007, 72, 4001.
6. For select examples, see: (a) Burke, S. D.; Zhao, Q. J. Org.
Chem. 2000, 65, 1489-1500. (b) Hong, J. H.; Oh, C.-H.; Cho,
J.-H. Tetrahedron 2003, 59, 6103-6108. (c) Marchart.;
Mulzer, J.; Enev, V. S. Org. Lett. 2007, 9, 813-816. (d) Jung,
D. Y.; Kang, S.; Chang, S.; Kim, Y. H. Synlett 2006, 86-90.
(e) Mues, H.; Kazmaier, U. Synthesis 2001, 3, 487-498. (f)
Kazmaier, U.; Mues, H.; Krebs, A. Chem. Eur. J. 2002, 8,
1850-1855. (g) Mues, H.; Kazmaier, U. Synthesis 2001,
487-498. (h) Francais, A.; Bedel, O.; Picoul, W.; Meddour,
A.; Courtieu, J.; Haudrechy, A. Tetrahedron: Asymmetry
2005, 16, 1141-1156. (i) Morimoto, Y.; Takaishi, M.;
Kinoshita, T.; Sakaguchi, K.; Shibata, K. Chem. Commun.
2002, 42-43. (j) Wen, S.-J.; Yao, Z.-J. Org. Lett. 2004, 6,
2721-2724. (k) Izzo, I.; Avallone, E.; Corte, L. D.; Maulucci,
N.; Riccardis, F. D.Tetrahedron: Asymmetry 2004, 15, 1181-
1186.
10. For preparation conditions, see: (a) Najdi, S. D.; Olmstead,
M. M.; Schore, N. E. J. Organometal. Chem. 1992, 431, 335-
358. (b) Toshima, H.; Aramaki, H.; Ichihara, A. Tetrahedron
Lett. 1999, 40, 3587-3590. (c) MacMahon, S.; Fong, R.;
Baran, P. S.; Safonov, I.; Wilson, S. R.; Schuster, D. I. J. Org.
Chem. 2001, 66, 5449-5455. (d) Schering, A. G. US Patent
7,001,916, 2006. (e) Kawamura, T.; Inagaki, F.; Narita, S.;
Takahashi, Y.; Hirata, S.; Kitagaki, S.; Mukai, C. Chem. Eur.
J. 2010, 16, 5173-5183. (f) Pour, M.; Negishi, E.-I. Tetrahe-
dron Lett. 1996, 37, 4679-4682.
7. (a) Mulzer, J.; Giester, G.; Gilbert, M. Helv. Chim. Acta.
2005, 88, 1560. (b) Burke, S. D.; Zhao, Q. J. Org. Chem.
2000, 65, 1489-1500. (c) Shin, K. J.; Moon, H. R.; George,
C.; Marquez, V. E. J. Org. Chem. 2000, 65, 2172-2178. (d)
Probst, N. P.; Haudrechy, A.; Plé, K. J. Org. Chem. 2008, 73,
4338-4341. (e) Hong, J. H.; Oh, C.-H.; Cho, J.-H. Tetrahe-
dron 2003, 59, 6103-6108. (f) Français, Bedel, O.; Picoul,
W.; Meddour, A.; Courtieu, J.; Haudrechy, A. Tetrahedron:
Asymmetry 2005, 16, 1141-1155. (g) Picoul, W.; Urchegui,
R.; Haudrechy, A.; Langlois, Y. Tetrahedron Lett. 1999, 40,
4797-4800. (h) Davies, S. G.; Garner, A. C.; Nicholson, R.
L.; Osborne, J.; Roberts, P. M.; Savory, E. D.; Smith, A. D.;
Thomson, J. E. Org. Biomol. Chem. 2009, 7, 2604-2611. (i)
Izzo, I.; Avallone, E.; Corte, L. D.; Maulucci, N.; Riccardis,
F. D. Tetrahedron: Asymmetry 2004, 15, 1181-1186. (j)
Morimoto, Y.; Takaishi, M.; Kinoshita, T.; Sakaguchi, K.;
Shibata, K. Chem. Commun. 2002, 42-43. (k) Sakaguchi, K.;
Yamamoto, M.; Kawamoto, T.; Yamada, T.; Shinada, T.;
11. For preparation, see: (a) Marshall, J. A.; Garofalo, A. W. J.
Org. Chem. 1996, 61, 8732-8738. (b) Righi, G.; Pescatore,
G.; Bonadies, F.; Bonini, C. Tetrahedron 2001, 57, 5649-
5656. (c) Mauleon, P.; Krinsky, J. L.; Toste, F. D. J. Am.
Chem. Soc. 2009, 131, 4513-4520. (d) Soulie, J.; Ta, C.;
Lallemand, J.-Y. Tetrahedron 1992, 48, 443-452. (e) Mitch-
ell, M.; Qaio, L.; Wong, C.-H. Adv. Synth. Cat. 2001, 343, 6-
7. (f) Lohse-Fraefel, N.; Carreira, E. M. Chem. Eur. J. 2009,
15, 12065-12081. (g) Kumaraswamy, G.; Ramakrishna, D.;
Santhakumar, K. Tetrahedron: Asymmetry 2010, 21, 544-
548. (h) Sodeoka, M.; Yamada, H.; Shibasaki, M. J. Am.
Chem. Soc. 1990, 112, 4906-4911. (i) Ding, P.; Miller, M. J.;
Chen, Y.; Helquist, P.; Oliver, A. Jayne; W. O. Org. Lett.
2004, 6, 1805-1808.
12. The synthetic material was identical in all respects (1H, 13
C
NMR) to the literature data: Karlsson, S.; Hogberg, H. E. Tet-
rahedron: Asymmetry 2001, 12, 1977-1982.
282
www.jccs.wiley-vch.de
© 2012 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
J. Chin. Chem. Soc. 2012, 59, 273-282