FeCl3-catalyzed nucleophilic substitution of Baylis-Hillman adducts with alcohols

Article abstract of DOI:10.1080/00397910801929622

FeCl₃-catalyzed nucleophilic substitution reaction of Baylis-Hillman adducts with alcohols is described. The present protocol allows for the efficient syntheses of many kinds of functional ethers. This conversion is also a green route because water is the only side product. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910801929622

Synthetic Communicationsw, 38: 1617–1628, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910801929622
FeCl3-Catalyzed Nucleophilic Substitution
of Baylis–Hillman Adducts with Alcohols
Xueshun Jia, Peichao Zhao, Xiaotao Liu, and Jian Li
Department of Chemistry, Shanghai University, Shanghai, China
Abstract: FeCl3-catalyzed nucleophilic substitution reaction of Baylis–Hillman
adducts with alcohols is described. The present protocol allows for the efficient
syntheses of many kinds of functional ethers. This conversion is also a green route
because water is the only side product.
Keywords: Alcohol, Baylis–Hillman adduct, ether, FeCl3, nucleophilic substitution
The Morita–Baylis–Hillman (MBH) reaction has become one of the powerful
carbon–carbon bond-forming methods in organic synthesis.[1] The MBH
reaction provides molecules possessing hydroxy, alkenyl, and electron-with-
drawing groups in close proximity, which makes it valuable in a number of
stereoselective transformation processes.[2] Furthermore, many strategies/
methodologies have been successfully employed in the syntheses of biologi-
cally active molecules and natural products.[3] Among these transformations,
using their acetates as substrates other than the Baylis–Hillman adducts them-
selves predominate because the direct substitution of the hydroxyl group of
Baylis–Hillman adducts is usually difficult. As a result, the direct use of
Baylis–Hillman alcohols in organic synthesis without acetylation continues
to be a challenge Moreover, most transformations occurred at the alkenyl
carbon position to give the linear products.[4–8]
Received October 8, 2007
Address correspondence to Xueshun Jia, Department of Chemistry, Shanghai
University, Shanghai 200444, China. E-mail: xsjia@mail.shu.edu.cn
1617

1618
X. Jia et al.
As a continuation of our previous work, we are interested in exploring the
versatility of alcohols as nucleophiles by extending this novel nucleophilic
class to the conversion of Baylis–Hillman adducts.[9] Herein we report an
efficient and selective substitution of Baylis–Hillman adducts with alcohols
catalyzed by FeCl3. In this process, the hydroxyl group of Baylis–Hillman
adducts could be efficiently substituted without further treatment using our
method (Scheme 1).
Our initial experiment was carried out with Baylis–Hillman adduct 1a
and benzyl alcohol as model substrates in the presence of FeCl3. To
our delight, the present substitution reaction proceeded smoothy under
reflux with acetonitrile as solvent, whereas no reaction occurred at room temp-
erature. As expected, both the substitution product 3 (47%) and its
linear isomer 4 (28%) were isolated. (The isolated 3 is stable; however, 3
could transform partly to 4 under the FeCl3/MeCN conditions after stirring
for 2 days.) Then a series of experiments were conducted to achieve the
optimal conditions. We found that only 5 mol% FeCl3 is sufficient to
promote the present conversion. It was also noteworthy to mention that the
reaction proceeds smoothly without exclusion of moisture or air from the
reaction mixture. On the other hand, this substitution shows a remarkable
solvent effect. For instance, with 1,4-dioxane used as solvent, no reaction
occurred even under reflux, whereas the employment of N,N-dimethylforma-
mide (DMF) gave a very complicated mixture. Thus, the optimal reaction
condition was finally confirmed.
Subsequently, various structurally diverse alcohols were treated with
MBH adduct 1a to undergo the corresponding transformation (Table 1,
entries 1–7). All reactions proceeded smoothly and finished within 2 h.
A variety of Baylis–Hillman adducts were screened to test the scope and
generality, and the results are summarized in Table 1. In most cases, the sub-
stitution reactions catalyzed by FeCl3 work well under the optimal conditions.
Initially we applied 4-methyl-substituted MBH adduct 1b to react with
ethanol, and the corresponding substitution products 3 and 4 were isolated
with 99% total yield (Table 1, entries 8). The mixture of 3 and 4 was
separated efficiently by column chromatography using ethyl acetate and
petroleum ether (1:10) as eluent. Encouraged by this result, several other
alcohols were also treated, and high performances were founded in such
cases (Table 1, entries 9 and 10). Besides the high yields, the reaction time
Scheme 1. 1a: R ¼ Ph, 1b: R ¼ p-MePh, lc: R ¼ m-MeOph, ld: R ¼ p-MeOPh, 1e:
R ¼ p-t-BuPh, 1f: R ¼ p-ClPh, lg: R ¼ p-O2NPh, 2a: R0 ¼ Me, 2b: R0 ¼ Et, 2c:
R0 ¼ i-Pr, 2d: R0 ¼ t-Bu, 2e: R0 ¼ n-Bu, 2f: R0 ¼ ClCH2CH2, 2g: R0 ¼ PhCH2.

Nucleophilic Substitution of Baylis–Hillman Adducts
1619
Table 1. FeCl3-catalyzed nucleophilic substitution of Baylis–Hillman adducts
Isolated yield (%)
Entry
Baylis–Hillman adduct 1
Alcohol 2
Time (h)
3
4
1
2
3
CH3OH 2a
C2H5OH 2b
1
0.7
1
27
50
35
20
26
20
4
2
18
10
5
6
1a
1
1
25
41
16
31
‘
7
8
0.7
47
58
28
41
C2H5OH
20 min
9
10
11
1b
1c
20 min
20 min
2
60
53
45
26
43
40
C2H5OH
C2H5OH
12
13
14
2
2
54
53
52
21
31
37
10 min
15
16
17
10 min
10 min
20 min
48
54
60
34
36
38
1d
1e
1f
C2H5OH
C2H5OH
18
19
20
20 min
20 min
18
51
54
41
42
42
36
21
22
18
18
28
50
20
22
is shortened to 20 min. Then a series of electron-rich MBH adducts were
applied to the present conversion, and all gave satisfactory results. The
presence of electron-donating groups such as tert-butyl on the aromatic ring
seems to facilitate the proceeding of the reaction to a great extent. In most
cases, good to excellent yields were obtained (Table 1, entries 11–19).
Notably, the 3-methoxyl substituted substrate 1c gave somewhat lower
yields (,50% total yield), which may contribute to the steric hindrance. In

1620
X. Jia et al.
such cases, the behavior of the conversion got great improvement with
increased amount of FeCl3. By using 20 mol% FeCl3, the yields were
increased significantly up to 85% (Table 1, entries 11–13). It is worth men-
tioning that when the 4-methoxylcontaining MBH adduct 1d was used, the
reaction finished very quickly (10 min) together with satisfactory results
(Table 1, entries 14–16). In contrast, when Baylis–Hillman adducts with
electron-withdrawing groups were tried, the reaction became quite sluggish
(Table 1, entries 20–22). In particular, with nitro group substituted
substrate, several alcohols were screened, yet no reaction occurred even
after 72 h under reflux. In addition, the 2-chloro-substituted substrate
appeared to suffer from steric hindrance, and the substrate was recovered com-
pletely after 48 h.
With regard to the mechanism, we believe that the presence of FeCl3
facilitates the substitution of the hydroxyl group in Baylis–Hillman
adducts. A related carbon cation intermediate may be involved, and further
studies on details of mechanism are still under way in our laboratory.
In summary, we have developed a general and efficient method for the
nucleophilic substitution of Baylis–Hillman adducts with alcohols. By
using iron catalyst,[10] the present protocol allows for the efficient syntheses
of many kinds of functionalized ethers. Typically reactions proceed under
mild conditions (without strong acid or base) and avoid the exclusion of air
or moisture. Finally, this conversion was also a green route because water is
the only side product.
EXPERIMENTAL
All 1H NMR spectra were measured in CDCl3 and recorded on Brucker AC–
500 (500-MHz) spectrometer with TMS as the internal standard.13C NMR
spectra were measured in CDCl3 and recorded on Brucker AC–125 (125-
MHz) spectrometer with TMS as the internal standard. IR spectra were
measured with a Perkin-Elmer FT-IR-1600 spectrometer. Mass spectra were
determined with a HP 5989A mass spectrometer. Elemental analyses were
performed on Elemantar Vario EL instrument.
General Procedure
To a stirred solution of 1 mmol of Baylis–Hillman adduct 1 in 2 mL of
CH3CN, 3 mmol of alcohol 2 and 8 mg of FeCl3 (5 mol%) were added. The
resulting mixture was allowed to react under reflux until the completion of
reaction. Subsequently, 2 mL of 0.1 M HCl were successively added to
quench the present reaction and then extracted with CH2Cl2 (5 mL ꢀ 3).
The organic phase was washed with 5 mL of saturated brine and 5 mL of
water, dried over anhydrous Na2SO4, and filtered. The solvent was removed

Nucleophilic Substitution of Baylis–Hillman Adducts
1621
under reduced pressure to give the crude products, which were purified by
column chromatography using ethyl acetate and petroleum ether (1:10) as
1
eluent. The products were identified by IR, H and 13C NMR, mass spectra,
and elemental analyses.
Data
1
Compound 3aa: H NMR (500 MHz, CDCl3) d (ppm): 7.33–7.25 (m, 5H),
6.36–6.34 (t, 1H), 5.96–5.94 (s, 1H), 5.13 (s, 1H), 3.70 (s, 3H), 3.33
(t, 3H); 13C NMR (500 MHz, CDCl3) d (ppm): 166.46, 141.19, 139.57,
128.47, 128.05, 127.67, 125.06, 81.09, 57.20, 51.95; HRMS (EI) m/z calcd.
for C12H14O3: 206.0943; found: 206.0937.
Compound 4aa: 1H NMR (500 MHz, CDCl3) d (ppm): 7.94 (s, 1H), 7.53–7.50
(t, 2H), 7.44–7.39 (m, 3H), 4.24 (s, 2H), 3.85 (s, 3H), 3.44 (s, 3H); 13C NMR
(500 MHz, CDCl3) d (ppm): 168.27, 144.95, 134.86, 129.98, 129.55, 128.76,
128.70, 66.69, 58.48, 52.38; IR (film)/cm21: 2949, 1715, 1631, 1091, 769,
698.
1
Compound 3ab: H NMR (500 MHz, CDCl3) d (ppm): 7.36–7.24 (m, 5H),
6.32–6.31 (t, 1H), 5.93–5.92 (s, 1H), 5.25 (s, 1H), 3.69 (s, 3H), 3.51–3.43
(m, 2H), 1.21–1.19 (t, 3H). Anal. calcd. for C13H16O3: C, 70.89: H, 7.32;
found: C, 70.72; H, 7.35.
1
Compound 4ab: H NMR (500 MHz, CDCl3) d (ppm): 7.93 (s, 1H), 7.55–
7.54 (m, 2H), 7.43–7.38 (m, 3H), 4.28 (s, 2H), 3.84 (s, 3H), 3.63–3.59
(m, 2H), 1.29–1.26 (t, 3H). IR (film)/cm21: 2975, 2951, 2873, 1716, 1632,
1574, 769, 699. Anal. calcd. for C13H16O3: C, 70.89: H, 7.32; found: C,
70.81; H, 7.22.
Compound 3ac: IR (film)/cm21 2972, 1724, 1630, 1378, 1060, 760, 703; 1H
NMR (500 MHz, CDCl3) d (ppm): 7.36–7.25 (m, 5H), 6.31–6.30 (t, 1H),
5.90–5.89 (t, 1H), 5.38 (s, 1H), 3.70 (s, 3H), 3.64–3.57 (m, 1H), 1.20–1.19
(d, 3H), 1.14–1.13 (d, 3H); 13C NMR (500 MHz, CDCl3) d (ppm): 166.69,
142.51, 140.71, 128.38, 127.77, 127.67, 125.47, 76.35, 69.86, 51.88,
22.83, 21.95. Anal. calcd. for C14H18O3: C, 71.77; H, 7.74; found: C,
71.82; H, 7.60.
Compound 4ac: IR (KBr)/cm21: 2971, 2876, 1717, 1633, 1575, 1117, 768,
698; 1H NMR (500 MHz, CDCl3) d (ppm): 7.91 (s, 1H), 7.58–7.36
(m, 5H), 4.28 (s, 2H), 3.84 (s, 3H), 3.76–3.70 (m, 1H), 1.25–1.24 (m, 6H),
1.20–1.19 (m, 3H). Anal. calcd. for C14H18O3: C, 71.77; H, 7.74; found: C,
71.65; H, 7.56.
Compound 3ad: IR (film)/cm21: 2975,1723, 1629, 1492, 702; 1H NMR (500
MHz, CDCl3) d (ppm): 7.36–7.19 (m, 5H), 6.28–6.27 (m, 1H), 6.02–6.01
(m, 1H), 5.48 (s, 1H), 3.69 (s, 3H), 1.19 (s, 9H). Anal. calcd. for C15H20O3:
C, 72.55; H, 8.12; found: C, 72.46; H, 8.02.

1622
X. Jia et al.
Compound 4ad: IR (KBr)/cm21: 2958, 1718, 1635, 1061, 759, 697; 1H NMR
(500 MHz, CDCl3) 7.90 (s, 1H), 7.62–7.31 (m, 5H), 4.23 (s, 2H), 3.82 (s, 3H),
1.30(s,9H).Anal.calcd.forC15H20O3:C,72.55;H,8.12;found:C,72.49;H,8.03.
Compound 3ae: IR (film)/cm21: 2956, 2932, 2869, 1724, 1630, 1438, 761,
1
702; H NMR (500 MHz, CDCl3) 7.36–7.24 (m, 5H), 6.31–6.30 (m, 1H),
5.92–5.91 (m, 1H), 3.69 (s, 3H), 3.45–3.35 (m, 2H), 1.59–1.53 (m, 2H)
1.40–1.32 (m, 2H), 0.90–0.68 (t, 3H). Anal. calcd. for C15H20O3: C, 72.55;
H, 8.12; found: C, 72.59; H, 8.07.
Compound 4ae: IR (KBr)/cm21:2955, 1717, 1632, 1377, 1091, 769, 697; 1H
NMR (500 MHz, CDCl3) 7.93 (s, 1H), 7.56–7.38 (m, 5H), 4.27 (s, 2H), 3.84
(s, 3H), 3.56–3.50 (m, 2H), 1.65–1.59 (m, 2H), 1.57–1.36 (m, 2H), 0.94–
0.92 (t, 3H). Anal. calcd. for C15H20O3: C, 72.55; H, 8.12; found: C, 72.38;
H, 8.22.
Compound 3af: 1H NMR (500 MHz, CDCl3) 7.38–7.25 (m, 5H), 6.34 (d, 1H,
J ¼ 1.0 Hz), 5.96 (t, 1H, J ¼ 1.25 Hz), 5.30 (s, 1H), 3.72–3.60 (m, 7H); 13
C
NMR (125 MHz, CDCl3) d (ppm): 166.33, 140.98, 139.24, 128.53, 128.23,
127.68, 125.65, 79.64, 69.38, 52.00, 42.94. Anal. calcd. for C13H15ClO3: C,
61.30; H, 5.94; found C, 61.25; H, 5.99.
Compound 4af: IR (film)/cm21: 2954, 2864, 1719, 1631, 1493, 844, 817, 763,
1
703; H NMR (500 MHz, CDCl3) 7.97 (s, 1H), 7.60–7.39 (m, 5H), 4.36
(s, 2H), 3.84–3.82 (m, 5H), 3.69 (m, 2H). Anal. calcd. for C13H15ClO3: C,
61.30; H, 5.94; found: C, 61.36; H, 5.90.
Compound 3ag: IR (film)/cm21: 2951, 2868, 1722, 1630, 1604, 739, 699; 1H
NMR (500 MHz, CDCl3) 7.40–7.26 (m, 10H), 6.35 (s, 1H), 6.02 (m, 1 Hz),
5.34 (s, 1H), 4.47 (s, 2H), 3.66 (s, 3H); 13C NMR (125 MHz, CDCl3) d
(ppm): 166.33, 141.32, 139.64, 138.21, 128.44, 128.41, 128.02, 127.82,
127.73, 127.67, 125.30, 78.63, 70.84, 51.86. Anal. calcd. for C18H18O3: C,
76.57; H, 6.43; found: C, 76.46; H, 6.49.
Compound 4ag: IR (film)/cm21: 3029, 1715, 1632, 1577, 1068, 741, 698; 1 H
NMR (500 MHz, CDCl3) 7.93 (s, 1H), 7.39–7.24 (m, 10H), 4.62 (s, 2H), 4.34
(s, 2H), 3.06 (s, 3H). Anal. calcd. for C18H18O3: C, 76.57; H, 6.43; found: C,
76.55; H, 6.44.
Compound 3bb: IR (film)/cm21: 2976, 2952, 2873, 1725, 1631, 1512, 814;
1H NMR (500 MHz, CDCl3) d (ppm): 7.24 (d, 2H, J ¼ 8.0 Hz), 7.12
(d, 2H, J ¼ 8.0 Hz), 6.30 (m, 1H), 5.93 (s, 1H), 5.21 (s, 1H), 3.67 (s, 3H),
3.50–3.40 (m, 2H), 2.32 (s, 3H), 1.19 (m, 3H); 13C NMR (125 MHz,
CDCl3) d (ppm): 166.44, 141.62, 137.44, 137.04, 129.02, 127.50, 124.70,
78.86, 64.59, 51.74, 21.17, 15.32. Anal. calcd. for C14H18O3: C, 71.77; H,
7.74; found: C, 71.80; H, 7.72.
Compound 4bb: IR (film)/cm21: 2872, 1715, 1631, 1091, 814; 1H NMR (500
MHz, CDCl3) d (ppm): 7.90 (s, 1H), 7.45 (d, 2H, J ¼ 8.0 Hz), 7.21 (d, 2H,
J ¼ 8.5 Hz), 4.29 (s, 2H), 3.82 (s, 3H), 3.63–3.54 (m, 2H), 2.37 (s, 3H), 1.28
(m, 3H). Anal. calcd. for C14H18O3: C, 71.77; H, 7.74; found: C, 71.79; H, 7.68.

Nucleophilic Substitution of Baylis–Hillman Adducts
1623
Compound 3bc: IR (film)/cm21: 2972, 2927, 1725, 1631, 1512, 813; 1H NMR
(500 MHz, CDCl3) d (ppm): 7.24 (d, 2H, J ¼ 8.0 Hz), 7.12 (d, 2H,
J ¼ 8.0 Hz), 6.30 (q, 1H), 5.90 (m, 1H), 5.34 (s, 1H,), 3.70 (s, 3H), 3.62–3.54
(m, 1H), 2.32 (s, 3H), 1.19–1.18 (d, 3H, J ¼ 6.0 Hz), 1.14 (d, 3H, J ¼ 6.0 Hz).
Anal. calcd. for C15H20O3: C, 72.55; H, 8.12; found: C, 72.50; H, 8.14.
Compound 4bc: IR (film)/cm21: 2972, 1716, 1632, 1375, 1122, 812; 1H NMR
(500 MHz, CDCl3) d (ppm): 7.89 (s, 1H), 7.48 (d, 2H, J ¼ 8.0 Hz), 7.20
(d, 2H, J ¼ 8.0 Hz), 4.28 (s, 2H), 3.81 (s, 3H), 3.76–3.69 (m, 1H), 2.37
(s, 3H), 1.24 (m, 6H). Anal. calcd. for C15H20O3: C, 72.55; H, 8.12; found:
C, 72.59; H, 8.09.
1
Compound 3bg: IR (film)/cm21: 2950, 2922, 2865, 1722, 1630, 819; H
NMR (500 MHz, CDCl3) 7.30–7.13 (m, 9H), 6.33 (s, 1H), 6.02 (t, 1H,
J ¼ 1.25 Hz), 5.30 (s, 1H), 4.45 (q, 2H, J ¼ 1.5 Hz), 3.64 (s, 3H), 2.32
(s, 3H). Anal. calcd. for C19H20O3: C, 77.00; H, 6.80; found: C, 76.95; H, 6.88.
Compound 4bg: IR (film)/cm21: 2975, 2894, 2839, 1723, 1631, 712, 788; 1H
NMR (500 MHz, CDCl3) d (ppm): 7.90 (s, 1H), 7.42–7.19 (m, 9H), 4.62
(s, 2H), 4.35 (s, 2H), 3.81 (s, 3H), 2.35 (s, 3H). Anal. calcd. for C19H20O3:
C, 77.00; H, 6.80; found: C, 77.22; H, 6.76.
Compound 3cb: IR (film)/cm21: 2975, 2894, 2839, 1723, 1631, 712, 788; 1H
NMR (500 MHz, CDCl3) d (ppm): 7.26–7.22 (m, 1H), 6.95–6.90 (m, 2H),
6.82–6.80 (m, 1H), 6.32 (t, 1H, J ¼ 1.0 Hz), 5.90 (t, 1H, J ¼ 1.25 Hz), 5.23
(s, 1H), 3.79 (s, 3H), 3.71 (s, 3H), 3.52–3.45 (m, 2H), 1.21 (t, 3H). Calcd.
for C14H18O4: C, 67.18; H, 7.25; found: C, 67.21; H, 7.31.
1
Compound 4cb: H NMR (500 MHz, CDCl3) d (ppm):7.90 (s, 2H), 7.32
(t, 1H, J ¼7.75 Hz), 7.16 (d, 1H, J ¼ 7.5 Hz), 7.11 (d, 1H, J ¼ 7.5 Hz),
6.95–6.93 (m, 1H), 4.29 (s, 2H), 3.84 (s, 3H), 3.83 (s, 3H), 3.62 (q, 2H,
J ¼ 10.5 Hz), 1.28 (t, 3H, J ¼7.0 Hz). Anal. calcd. for C14H18O4: C, 67.18;
H, 7.25; found: C, 67.33; H, 7.31.
Compound 3cc: IR (film)/cm21: 2972, 1723, 1630, 1603, 1379, 1150, 758,
1
711; H NMR (500 MHz, CDCl3) d (ppm): 7.26–7.22 (m, 1H), 6.95–6.91
(m, 2H), 6.81–6.79 (m, 1H), 6.30 (d, 1H, J ¼ 0.5 Hz), 5.87 (t, 1H,
J ¼ 2.5 Hz), 5.36 (s, 1H), 3.79 (s, 3H), 3.71 (s, 3H), 3.62–3.55 (m, 1H),
1.20–1.19 (d, 3H, J ¼ 6.0 Hz), 1.15–1.14 (d, 3H, J ¼ 6.0 Hz). Calcd. for
C15H20O4: C, 68.16; H, 7.63; found: C, 68.13; H, 7.67.
Compound 4cc: IR (film)/cm21: 2971, 1715, 1633, 1375, 792, 693; 1H NMR
(500 MHz,CDCl3) d (ppm): 7.88 (s, 1H), 7.32 (t, 1H, J ¼ 8.0 Hz), 7.18–7.13
(m, 2H), 6.94–6.92 (m, 1H), 4.30 (s, 2H), 3.84 (s, 3H), 3.83 (s, 3H), 3.77–3.72
(m, 1H), 1.24 (d, 6H, J ¼ 6.0 Hz). Anal. calcd. for C15H20O4: C, 68.16; H,
7.63; found: C, 68.25; H, 7.69.
Compound 3cg: IR (film)/cm21: 2951, 2837, 1717, 1633, 1602, 775, 738,
1
700; H NMR (500 MHz, CDCl3) d (ppm): 7.34–7.22 (m, 7H), 6.98 (d, 1H,
J ¼ 7.5 Hz), 6.94 (d, 1H, J ¼ 7.5 Hz), 6.84–6.81 (m, 1H), 6.35 (t, 1H,
J ¼ 1.0 Hz), 6.00 (t, 1H, J ¼ 1.5 Hz), 5.32 (s, 1H), 4.51–4.46 (m, 2H), 3.78

1624
X. Jia et al.
(s, 3H), 3.68 (s, 3H); 13C NMR (125 MHz, CDCl3) d (ppm):166.35, 159.71,
141.25, 141.23, 138.20, 129.44, 128.41, 127.78, 127.68, 125.48, 120.24,
113.48, 113.19, 78.49, 70.93, 55.26, 51.89. Anal. calcd. for C19H20O4: C,
73.06; H, 6.45; found: C, 73.17; H, 6.58.
Compound 4cg: IR (film)/cm21: 3029, 1710, 1632, 1067, 850, 738; 1H NMR
(500 MHz, CDCl3) d (ppm): 7.92 (s, 1H), 7.39–7.25 (m, 7H), 7.14–7.09
(m, 2H), 6.92 (m, 1H), 4.63 (s, 2H), 4.36 (s, 2H), 3.83 (s, 3H), 3.78 (s, 3H).
Anal. calcd. for C19H20O4: C, 73.06; H, 6.45; found: C, 73.17; H, 6.26.
1
Compound 3db: IR (film)/cm21: 2954, 2840, 1722, 1610, 1088, 825; H
NMR (500 MHz, CDCl3) d (ppm): 7.28–7.25 (m, 2H), 6.87–6.84 (m, 2H),
6.30 (t, 1H, J ¼ 1.25 Hz), 5.94 (t, 1H, J ¼ 1.5 Hz), 5.19 (s, 1H), 3.79
(s, 3H), 3.69 (s, 3H), 3.49–3.42 (m, 2H), 1.20 (m, 3H). Anal. calcd. for
C14H18O4: C, 67.18; H, 7.25; found: C, 67.25; H, 7.20.
Compound 4db: IR (film)/cm21: 2951, 2872, 1711, 1628, 1603, 1089, 841;
1H NMR (500 MHz, CDCl3) d (ppm): 7.89 (s, 1H), 7.54 (q, 2H,
J ¼ 4.5 Hz), 6.93 (q, 2H, J ¼ 4.5 Hz), 4.30 (s, 2H), 3.83 (s, 3H), 3.82
(s, 3H), 3.62 (q, 2H, J ¼ 6.0 Hz), 1.28 (t, 3H, J ¼ 6.0 Hz). Anal. calcd. for
C14H18O4: C, 67.18; H, 7.25; found: C, 67.12; H, 7.32.
Compound 3dc: IR (film)/cm21: 2970, 1722, 1610, 1586, 1061, 839; 1H NMR
(500 MHz, CDCl3) d (ppm): 7.27–7.25 (m, 2H), 6.89–6.86 (m, 2H), 6.30
(d, 1H, J ¼ 1.0 Hz), 5.91 (t, 1H, J ¼ 1.5 Hz), 5.32 (s, 1H), 3.79 (s, 3H),
3.70 (s, 3H), 3.61–3.56 (m, 1H), 1.18 (d, 3H, J ¼ 6.0 Hz), 1.14 (d, 3H,
J ¼ 6.0 Hz). Anal. calcd. for C15H20O4: C, 68.16; H, 7.63; found: C, 68.21;
H, 7.57.
Compound 4dc: IR (film)/cm21: 2971, 1712, 1629, 1604, 1055, 839; 1H NMR
(500 MHz, CDCl3) d (ppm):, 7.88 (s, 1H), 7.58–7.56 (m, 2H), 6.93 (q, 2H,
J ¼ 4.5 Hz), 4.30 (s, 2H), 3.83 (s, 3H), 3.82 (s, 3H), 3.77–3.71 (m, 1H),
1.18 (d, 6H, J ¼ 6.5 Hz). Anal. calcd. for C15H20O4: C, 68.16; H, 7.63;
found: C, 68.20; H, 7.59.
1
Compound 3dg: IR (film)/cm21: 3030, 1721, 1629, 1608, 1067, 827; H
NMR (500 MHz, CDCl3) 7.34–7.26 (m, 7H), 6.88–6.87 (q, 2H), 6.34
(t, 1H, J ¼ 1.25 Hz), 6.04 (t, 1H, J ¼ 1.75 Hz), 5.28 (s, 1H),4.46 (d, 2H,
J ¼ 3.0 Hz), 3.80 (s, 3H), 3.68 (s, 3H). Anal. calcd. for C19H20O4: C, 73.06;
H, 6.45; found: C, 73.18; H, 6.26.
Compound 4dg: IR (film)/cm21: 3030, 1709, 1269, 1603, 1066, 782, 741,
700; 1H NMR (500 MHz, CDCl3) d (ppm): 7.89 (s, 1H), 7.50–7.29
(m, 7H), 6.86 (m, 2H), 4.64 (s, 2H), 4.37 (s, 2H), 3.81 (s, 3H), 3.68 (s, 3H).
Anal. calcd. for C19H20O4: C, 73.06; H, 6.45; found: C, 72.88; H, 6.58.
Compound 3eb: IR (film)/cm21: 2964, 2870, 1725, 1631, 1091, 823; 1H NMR
(500 MHz, CDCl3) d (ppm): 7.33 (d, 2H, J ¼ 8.5 Hz), 7.27 (d, 2H,
J ¼ 8.0 Hz), 6.31 (t, 1H, J ¼ 0.5 Hz), 5.94 (t, 1H, J ¼ 1.5 Hz), 5.24 (s, 1H),
3.69 (s, 3H), 3.52–3.42 (m, 2H), 1.29 (s, 9H), 1.20 (t, 3H, J ¼ 7.0 Hz).
Anal. calcd. for C17H24O3: C, 73.88; H, 8.75; found: C, 73.93; H, 8.77.

Nucleophilic Substitution of Baylis–Hillman Adducts
1625
Compound 4eb: IR (film)/cm21: 2967, 1716, 1632, 1609, 1366, 836; 1H NMR
(500 MHz, CDCl3) d (ppm): 7.91 (s, 1H), 7.50 (d, 2H, J ¼ 8.5 Hz), 7.44 (t, 2H,
J ¼ 8.0 Hz), 4.30 (s, 2H), 3.82 (s, 3H), 3.64–3.60 (m, 2H), 1.34 (s, 9H), 1.28
(m, 3H). Anal. calcd. for C17H24O3: C, 73.88; H, 8.75; found: C, 73.76; H, 8.79.
Compound 3ec: IR (film)/cm21: 2977, 2871, 1726, 1631, 1462, 820; 1H NMR
(500 MHz, CDCl3) d (ppm): 7.32 (d, 2H, J ¼ 8.0 Hz), 7.26 (d, 2H,
J ¼ 8.0 Hz), 6.30 (d, 1H, J ¼ 2.5 Hz), 5.91 (t, 1H, J ¼ 2.5 Hz), 5.37
(s, 1H), 3.69 (s, 3H), 3.64–3.57 (m, 1H), 1.29 (s, 9H), 1.18 (d, 3H,
J ¼ 6.5 Hz), 1.15 (d, 3H, J ¼ 6.5 Hz); 13C NMR (125 MHz, CDCl3) d
(ppm): 166.73, 150.47, 142.17, 137.50, 127.21, 125.28, 125.26, 76.00,
69.63, 51.83, 34.58, 31.46, 22.74, 21.99. Anal. calcd. for C18H26O3 C,
74.45; H, 9.02; found: C, 74.42; H, 9.23.
1
Compound 4ec: H NMR (500 MHz, CDCl3) d (ppm): 7.89 (s, 1H), 7.26
(d, 2H, J ¼ 8.5 Hz), 7.43 (d, 2H, J ¼ 8.5 Hz), 4.30 (t, 1H, J ¼ 4.5 Hz), 3.83
(s, 3H), 1.33 (s, 9H), 1.26 (d, 6H, J ¼ 6.0 Hz). Anal. calcd. for C18H26O3 C,
74.45; H, 9.02; found: C, 74.38; H, 9.15.
Compound 3eg: 1H NMR (500 MHz, CDCl3) 7.36–7.26 (m, 9H), 6.35 (d, 1H,
J ¼ 1.0 Hz), 6.03 (t, 1H, J ¼ 1.5 Hz), 5.33 (s, 1H), 4.47 (m, 2H), 3.67 (s, 3H),
1.30 (s, 9H). Anal. calcd. for C22H26O3: C, 78.07; H, 7.74; found: C, 78.20; H,
7.63.
Compound 4eg: IR (film)/cm21: 3030, 1715, 1629, 1608, 1109, 839, 737,
699; 1H NMR (500 MHz, CDCl3) d (ppm): 7.92 (s, 1H), 7.46–7.33
(m, 9H), 4.63 (s, 2H), 4.36 (s, 2H), 3.81 (s, 3H), 1.33 (s, 9H). Anal. calcd.
for C22H26O3: C, 78.07; H, 7.74; found: C, 78.21; H, 7.69.
Compound 3fb: IR (film)/cm21: 2973, 2828, 2896, 1724, 1631, 1596, 818; 1H
NMR (500 MHz, CDCl3) d (ppm): 7.29 (s, 4H), 6.33 (t, 1H, J ¼ 1.0 Hz), 5.96
(t, 1H, J ¼ 1.5 Hz), 5.20 (s, 1H), 3.70 (s, 3H), 3.52–3.40 (m, 2H), 1.20 (t, 3H,
J ¼ 7.0 Hz). Anal. calcd. for C13H15ClO3: C, 61.30; H, 5.94; found: C, 61.26;
H, 6.03.
Compound 4fb: IR (film)/cm21: 2958, 2925, 1718, 1632, 1091, 815; 1H NMR
(500 MHz, CDCl3) d (ppm): 7.87 (s, 1H), 7.50–7.48 (m, 2H), 7.40–7.37
(m, 2H), 4.25 (s, 2H), 3.84 (s, 3H), 3.63–3.57 (m, 2H), 1.26 (t, 3H, J ¼ 7.0
Hz). Anal. calcd. for C13H15ClO3: C, 61.30; H, 5.94; found: C, 61.36; H, 6.01.
Compound 3fc: IR (film)/cm21: 2972, 2929, 1721, 1630, 1596, 818; 1H NMR
(500 MHz, CDCl3) d (ppm): 7.29 (s, 4H), 6.31 (t, 1H, J ¼ 1.0 Hz), 5.92 (t, 1H,
J ¼ 1.25 Hz), 5.33 (s, 1H), 3.70 (s, 3H), 3.62–3.55 (m, 1H), 1.18 (d, 3H,
J ¼ 6.0 Hz), 1.12 (d, 3H, J ¼ 6.5 Hz). Anal. calcd. for C14H17ClO3 C,
62.57; H, 6.38; found: C, 62.41; H, 6.47.
Compound 4fc: IR (film)/cm21: 2971, 1718, 1634, 1592, 1376, 1094, 811; 1H
NMR (500 MHz, CDCl3) d (ppm): 7.85 (s, 1H), 7.52 (m, 2H, J ¼ 5.3 Hz),
7.38 (d, 2H), 4.25 (s, 2H), 3.83 (s, 3H), 3.75–3.69 (m, 1H), 1.24 (d, 6H,
J ¼ 6.0 Hz). Anal. calcd. for C14H17ClO3: C, 62.57; H, 6.38; found: C,
62.53; H, 6.39.

1626
X. Jia et al.
Compound 3fg: IR (film)/cm21: 3031, 1720, 1631, 1595, 1088, 820, 737, 698;
1H NMR (500 MHz, CDCl3) d (ppm): 7.33–7.27 (m, 9H), 6.36 (t, 1H,
J ¼ 1.0 Hz), 6.06 (t, 1H, J ¼ 0.8 Hz), 4.62 (s, 2H), 3.77 (s, 2H); 13C NMR
(125 MHz, CDCl3) d (ppm): 166.16, 140.95, 138.34, 137.95, 133.81,
129.22, 128.67, 128.51, 127.83, 127.76, 125.48, 77.94, 70.92, 51.97. Anal.
calcd. for C18H17ClO3 C, 68.25; H, 5.41; found: C, 68.17; H, 5.47.
Compound 4fg: IR (film)/cm21: 3030, 2918, 2861, 1713, 1632, 1591, 1089,
1
844, 737, 700; H NMR (500 MHz, CDCl3) d (ppm): 7.86 (s, 1H), 7.45–
7.35 (m, 9H), 4.62 (s, 2H), 4.30 (s, 2H), 3.83 (s, 3H). Anal. calcd. for
C18H17ClO3: C, 68.25; H, 5.41; found: C, 68.13; H, 5.56.
ACKNOWLEDGMENT
We thank the National Natural Science Foundation of China (Nos. 20472048
and 20572068) for support of this work.
REFERENCES
1. (a) Ciganek, E. Org. React. 1997, 51, 201; (b) Basavaiah, D.; Rao, P. D.;
Hyma, R. S. The Baylis-Hillman reaction: A novel carbon-carbon bond forming
reaction. Tetrahedron 1996, 52, 8001; (c) Basavaiah, D.; Rao, A. J.;
Satyanarayana, T. Recent advances in the Baylis-Hillman reaction and appli-
cations. Chem. Rev. 2003, 103, 811.
2. (a) Ramachandran, P. V.; Madhi, S.; Bland-Berry, L.; Reddy, M. V. R. M.;
O’Donnel, J. Catalytic enantioselective synthesis of glutamic acid derivatives
via tandem conjugate addition-elimination of activated allylic acetates under
chiral PTC conditions. J. Am. Chem. Soc. 2005, 127, 13450; (b) Kabalka, G.;
Venkataiah, W. B.; Dong, G. Palladium-catalyzed regio- and stereoselective
cross-coupling of Baylis-Hillman adducts and bimetals: a novel method for the
synthesis of substituted allylsilanes and allylgermanes. Organometallics 2005,
24, 762–764; (c) Chung, Y. M.; Gong, J. H.; Kim, T. H.; Kim, J. N. Synthesis
of ethyl 3-cyano-2-methylcinnamates and 3-cyano-2-methylcinnamonitriles from
the Baylis–Hillman acetates. Tetrahedron Lett. 2001, 42, 9023; (d) Singh, V.;
Saxena, R.; Batra, S. Simple and efficient synthesis of substituted 2-pyrrolidi-
nones, 2-pyrrolones, and pyrrolidines from enaminones of Baylis-Hillman
derivatives of 3-isoxazolecarbaldehydes. J. Org. Chem. 2005, 70, 353;
(e) Patra, A.; Roy, A. K.; Batra, S.; Bhaduri, A. P. NaBH4-mediated facile
reduction of esters of Baylis-Hillman adducts: An efficient approach to substituted
propane-1,3-Diols. Synlett 2003, 1819.
3. (a) Radha Krishna, P.; Nasingam, M.; Kannan, V. Use of a Baylis–Hillman adduct
in the stereoselective synthesis of syributins via a RCM protocol. Tetrahedron Lett.
2004, 45, 4773; (b) Rodgen, S. A.; Schaus, S. E. Efficient construction of the
Clerodane Decalin Core by an asymmetric Morita-Baylis-Hillman reaction/
Lewis acid promoted annulation strategy. Angew. Chem., Int. Ed. 2006, 45,
4929; (c) Drewes, S. E.; Roos, G. H. P. Synthetic potential of the tertiary-
amine-catalysed reaction of activated vinyl carbanions with aldehydes.

Nucleophilic Substitution of Baylis–Hillman Adducts
1627
Tetrahedron 1988, 44, 4653; (d) Brzezinski, L. J.; Rafel, S.; Leahy, J. M. The
asymmetric Baylis-Hillman reaction. J. Am. Chem. Soc. 1997, 119, 4317;
(e) Wori, W.; Kuroda, S.; Dekura, F. Formation of silazirconacyclopentene via
Zirconium-Silene complex and alkyne. J. Am. Chem. Soc. 1999, 121, 5591;
(f) Trost, B. M.; Thiel, O. R.; Tsui, H. C. Total syntheses of furaquinocin A, B,
and E. J. Am. Chem. Soc. 2003, 125, 13155.
4. (a) Basavaiah, D.; Kumaragurubaran, N. The Baylis–Hillman chemistry in
aqueous media: a convenient synthesis of 2-methylenealkanoates and alkaneni-
triles. Tetrahedron Lett. 2001, 42, 477; (b) Kim, J. N.; Lee, H. J.; Lee, K. Y.;
Gong, J. H. Regioselective allylic amination of the Baylis-Hillman adducts: An
easy and practical access to the Baylis-Hillman adducts of N-Tosylimines.
Synlett 2002, 173; (c) Basavaiah, D.; Reddy, R. J.; Rao, J. S. Applications of
Baylis–Hillman adducts: a simple, convenient, and one-pot synthesis of 3-ben-
zoylquinolines. Tetrahedron Lett. 2006, 47, 73; (d) Basavaiah, D.;
Suguna, H. R.; Muthukumaran, K.; Kumaragurubaran, N. Synthetic applications
of the Baylis–Hillman Adducts: A simple stereoselective synthesis of (E)-3-
(Nitroxymethyl)alk-3-en-2-ones. Tetrahedron 2000, 56, 5905; (e) Basavaiah, D.;
Suguna, H. R.; Padmaja, K.; Krishnamacharyulu, M. The Baylis-Hillman
reaction: An expedient synthesis of (Z)-keto allyl bromides and chlorides. Tetra-
hedron 1999, 55, 6971; (f) Basavaiah, D.; Suguna, H. R.; Muthukumaran, K.;
Kumaragurubaran, N. Stereoselective transformation of Baylis-Hillman adducts
into (3E)-3-(Alkoxymethyl)alk-3-en-2-ones. Synthesis 2000, 217.
5. (a) Cho, C. W.; Krische, M. J. Regio- and stereoselective construction of g-
butenolides through phosphine-catalyzed substitution of Morita-Baylis-Hillman
acetates: an organocatalytic allylic alkylation. Angew. Chem., Int. Ed. 2004, 43,
6689; (b) Cho, C. W.; Kong, J. R.; Krische, M. J. Phosphine-catalyzed regiospeci-
fic allylic amination and dynamic kinetic resolution of Morita-Baylis-Hillman
acetates. Org. Lett. 2004, 6, 1337; (c) Park, H.; Cho, C. W.; Krische, M. J.
Phosphine-catalyzed allylic substitution of Morita-Baylis-Hillman acetates:
synthesis of N-protected b-Aminophos- phonic Acid esters. J. Org. Chem. 2006,
71, 7892; (d) Wang, L. C.; Luiz, A. L.; Agapiou, K.; Jang, H. Y.;
Krischer, M. J. Organocatalytic Michael Cycloisomerization of Bis(enones): The
Intramolecular Rauhut-Currier Reaction. J. Am. Chem. Soc. 2002, 124, 2402;
(e) Jellerichs, B. G.; Kong, J. R.; Krischer, M. J. Catalytic enone cycloallylation
via concomitant activation of latent nucleophilic and electrophilic partners:
merging organic and transition metal catalysis. J. Am. Chem. Soc. 2003, 125, 7758.
6. (a) Roy, O.; Riahi, A.; Henin, F.; Muzart, T. Synergy or competition between
palladium-catalysis and KF/Alumina-mediation for the allylic substitution of
the acetates of Baylis–Hillman adducts by phenols. Tetrahedron 2000, 56,
8133; (b) Trost, B. M.; Toste, D. F. Deracemization of Baylis-Hillman adducts.
J. Am. Chem. Soc. 2000, 122, 3534–3535; (c) Kim, J. N.; Lee, H. J.;
Gong, J. H. Synthesis of enantiomerically enriched Baylis–Hillman alcohols
from their acetates: combination of kinetic resolution during the salt formation
with (DHQD)2PHAL and following asymmetric induction during hydrolysis
with NaHCO3 as a water surrogate. Tetrahedron Lett. 2002, 43, 9141;
(d) Trost, B. M.; Thiel, O. R.; Tsui, H. C. DYKAT of Baylis-Hillman Adducts:
Concise total synthesis of furaquinocin E. J. Am. Chem. Soc. 2002, 124, 11616.
7. (a) Trost, B. M.; Calkins, T. L.; Oertelt, C.; Zambrano, J. Catalyst controlled dia-
stereoselective N-alkylations of a-amino esters. Tetrahedron Lett. 1998, 39, 1713;
(b) Rajesh, S.; Banerji, B.; Iqbal, J. Palladium(0)-catalyzed regioselective
synthesis of a-dehydro-b-amino esters from amines and allyl acetates: synthesis

1628
X. Jia et al.
of a a-dehydro-b-amino acid derived cyclic peptide as a constrained-b-Turn
mimic. J. Org. Chem. 2002, 67, 7852.
8. Trost, B. M.; Machacek, M. R.; Tsui, H. C. Development of aliphatic alcohols as
nucleophiles for palladium-catalyzed DYKAT reactions: Total synthesis of (þ)-
hippospongic acid A. J. Am. Chem. Soc. 2005, 127, 7014.
9. (a) Li, J.; Wang, X. X.; Zhang, Y. M. Remarkable rate acceleration of water-
promoted nucleophilic substitution of Baylis–Hillman acetate: a facile and
highly efficient synthesis of N-substituted imidazole. Tetrahedron Lett. 2005,
46, 5233; (b) Li, J.; Wang, X. X.; Zhang, Y. M. Direct and highly efficient
synthesis of (Z)-allyl iodides from Baylis-Hillman adducts promoted by TMSCl/
NaI system. Synlett 2005, 1039; (c) Li, J.; Qian, W. X.; Zhang, Y. M. SmI2-
mediated elimination reaction of Baylis–Hillman adducts controlled by tempera-
ture: a facile synthesis of trisubstituted alkenes and 1,5-hexadiene derivatives with
E-stereoselectivity. Tetrahedron 2004, 60, 5793; (d) Li, S. Y.; Li, J.; Jia, X. S.
Samarium metal promoted facile C-Acetylation of Baylis-Hillman adducts in
the presence of iron(III) chloride and iodine. Synlett 2007, 7, 1115.
10. (a) Bolm, C.; Legros, J.; Le Paih, J.; Zani, L. Iron-Catalyzed Reactions in Organic
Synthesis. Chem. Rev. 2004, 104, 6217; (b) Choudhary, V. R.; Jana, S. K.;
Kiran, B. P. Alkylation of benzene by benzyl chloride over H-ZSM-5 zeolite
with its framework Al completely or partially substituted by Fe or Ga. Catal.
Lett. 1999, 59, 217; (c) Choudhary, V. R.; Jana, S. K. Benzylation of benzene
by benzyl chloride over Fe-, Zn-, Ga- and In-modified ZSM-5 type zeolite
catalyst. Appl. Catal. A 2002, 224, 51; (d) Pai, S. G.; Bajpai, A. R.;
Deshpande, A. B.; Samant, S. D. Friedel-Crafts Benzylation of Arenes Using
FeCl3 Impregnated Montmorillonite K10. Synth. Commun. 1997, 27, 2267;
(e) Pai, S. G.; Bajpai, A. R.; Deshpande, A. B.; Samant, S. D. Benzylation of
arenes in the presence of Montmorillonite K10 modified using aqueous and aceto-
nitrile solutions of FeCl3. J. Mol. Catal. A 2000, 156, 233.