A facile, versatile, and mild morita-baylis-hillman-type reaction for the modular one-pot synthesis of highly functionalized MBH adducts

Article abstract of DOI:10.1002/ejoc.201200371

Morita-Baylis-Hillman derivatives have been extensively investigated as intermediates in the preparation of important classes of compounds. However, there are intrinsic limitations regarding the structure of the Michael electrophile acceptors, the aldehydes, and the catalysts. Therefore, this transformation has several drawbacks, including, for example, its long reaction times. Herein we present a simple, general, fast, and high-yielding protocol for the one-pot synthesis of Morita-Baylis-Hillman derivatives. Our approach is driven by a lithium selenolate Michael/aldol operation with concomitant O-functionalization/selenoxide elimination cascade sequences. Here we describe a one-pot, fast, and high-yielding methodology for the synthesis of different Morita-Baylis-Hillman derivatives by a four-component cascade reaction. The cascade is based on a Michael/aldol/O-functionalization/selenoxide elimination sequence. This protocol completely avoids the manipulation of selenium species with an unpleasant odor.

Full text of DOI:10.1002/ejoc.201200371

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FULL PAPER
DOI: 10.1002/ejoc.201200371
A Facile, Versatile, and Mild Morita–Baylis–Hillman-Type Reaction for the
Modular One-Pot Synthesis of Highly Functionalized MBH Adducts
Bruno A. Sousa*[a] and Alcindo A. Dos Santos[a]
Keywords: Multicomponent reactions / Domino reactions / Michael addition / Aldol reactions / Selenium
Morita–Baylis–Hillman derivatives have been extensively in-
vestigated as intermediates in the preparation of important
classes of compounds. However, there are intrinsic limita-
tions regarding the structure of the Michael electrophile ac-
ceptors, the aldehydes, and the catalysts. Therefore, this
transformation has several drawbacks, including, for exam-
ple, its long reaction times. Herein we present a simple, ge-
neral, fast, and high-yielding protocol for the one-pot synthe-
sis of Morita–Baylis–Hillman derivatives. Our approach is
driven by a lithium selenolate Michael/aldol operation with
concomitant O-functionalization/selenoxide elimination cas-
cade sequences.
Introduction
Results and Discussion
Among all C–C bond-formation reactions, the aldol and
Michael reactions have always been among the most impor-
tant methodologies. Moreover, Michael/aldol tandem reac-
tions, in addition to promoting multiple C–C bond forma-
tions, also lead to important carbon skeletons that can be
strategically employed as building blocks for the synthesis
of a large number of natural products.[1] Metal organochal-
cogenolates are an important class of nucleophiles in
Michael/aldol tandem reactions due to their excellent Pear-
son’s soft nucleophilicity and extremely low Brønsted basic-
ity. Furthermore, the easy removal of the chalcogen moiety
by oxidative elimination leading to Morita–Baylis–Hillman
(MBH) adducts makes these entities appealing for this
transformation. The possibility of generating these nucleo-
philes in situ from commercially available elemental chal-
cogen is also an attractive alternative, as no malodorous
chemicals/starting materials need to be handled and the fi-
nal chalcogen oxidized derivative byproduct is innocuous
and odorless.[2] In the last years, MBH derivatives, espe-
cially carbonates[3,4] and acetates,[5–15] have been described
as important intermediates in the synthesis of different
frameworks, and these compounds have become important
as MBH precursors, It has been reported that they also rep-
resent a valuable class of substrates for synthetic pur-
poses.[16–19] In this work, we report our results on the first
general, high-yielding, and fast tandem reaction protocol
for the synthesis of different MBH derivatives by using lith-
ium selenolates as the initial nucleophile.
It has been previously demonstrated that lithium n-butyl-
selenolate undergoes selective 1,4-addition to acrylonitrile
as well as acrylic esters in the presence of aldehydes to yield
the corresponding Michael/aldol products. In comparison
to lithium phenylselenolate, usually employed in Michael[20]
and homo-Michael[21] type reactions, n-alkylselenolates are
more reactive and easier to prepare. More specifically, the
preparation of n-butylselenolate makes use of a common
organolithium reagent (nBuLi) and completely avoids the
formation of volatile selenides and diselenides, like that ob-
served when employing MeLi. In an attempt to extend the
methodology and study its scopes and limitations, we envi-
sioned that the Michael/aldol, alkoxide functionalization,
and n-butylselenium moiety elimination sequence could be
possible in a one-pot operation, leading to O-functionalized
MBH derivatives. As a proof-of-principle experiment, we
submitted benzaldehyde and acrylonitrile to a reaction with
lithium n-butylselenolate, followed by quenching the reaction
media with isovaleroyl chloride aiming to isolate the corre-
sponding ester. Expected product 2 was obtained in high yield
and low diastereoselectivity, as depicted in Scheme 1.
As previously described in the literature, there are many
oxidants capable of promoting the oxidation of organic sel-
enides to selenoxides.[22] However, hydrogen peroxide pres-
ents some advantages over other oxidants due to the fact
that its oxidation reaction is much faster than those using
any other oxidants.[16] In addition, hydrogen peroxide has
been shown to be compatible under similar reaction condi-
tions,[2] and its use minimizes selenylated byproducts. More-
over, it is one of the greenest chemicals, as its byproduct is
water. We have found that 6 equiv. of this oxidant led to
the total conversion of the selenylated intermediate into the
MBH adduct in high yields. In these experiments we evalu-
ated the behavior of different aldehydes and Michael ac-
[a] Department of Fundamental Chemistry,
Chemistry Institute of the University of São Paulo,
Av. Prof. Lineu Prestes, 748, Cx.P. 26077, 05508-000 São Paulo,
Brazil
E-mail: bruno.sousa@usp.br
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200371.
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B. A. Sousa, A. A. Dos Santos
FULL PAPER
Scheme 1. One-pot Michael/aldol/O-functionalization selenolate-mediated reaction.
Table 1. Initial screening of aldehydes and the thrid electrophile followed by selenium oxidative elimination.
ceptors as well as acid chlorides and other O-functionaliz- alkoxides were also appropriately functionalized to produce
ing electrophiles, like triisopropylsilyl chloride, Cbz, and a benzyl carbonate (Table 1, Entry 2). It is worth noting
Boc2O (the last two, carbonate precursors). When TIPSCl that even when employing a β-substituted Michael acceptor
was employed as the third electrophile, the selenoxide elimi- (Table 1, Entry 5) the expected product was obtained in a
nation step was not performed due to the sensitivity of very high yield with 3:2dr, the same ratio as that obtained
these groups under oxidative conditions. To test this con- for compound 2, which was not submitted to selenoxide
cept, we started the cascade reactions by employing acrylo- elimination.
nitrile and benzaldehyde as Michael/aldol partners, varying
The same good results were also observed when em-
the third electrophile, followed by oxidative selenium elimi- ploying nonactivated alkyl aldehydes in combination with
nation. The results of these experiments are summarized in different acid chlorides, leading to the expected O-function-
Table 1.
alized MBH products in good yields and in the same reac-
As shown above, in our initial study we have produced tion time (Table 1, Entries 6–8). As it can be observed, in
some different O-functionalized MBH adducts by em- contrast to the classic MBH reaction, this methodology
ploying classical substrates like benzaldehyde and acryloni- shows no limitation when employing nonactivated alde-
trile and some different acid chloride (Table 1, Entries 1–4) hydes, even at low temperatures, yielding the expected prod-
in very good yields. Besides acid chlorides, the intermediate ucts in very short reaction times (45 min).
2
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One-Pot Synthesis of Highly Functionalized MBH Adducts
As the structural diversity of these derivatives must be NOE experiments to be exclusively Z in both cases (Table 2,
widely scalable, the use of different aldehydes as well as dif- Entries 9 and 10), and these results are in agreement with
ferent Michael acceptors and the third electrophiles is very previous results concerning the β-chalcogeno-functionaliza-
important to carry different chemical functions to further tion of acetylenic Michael acceptors.[23–25] The same NOE
transformations. In this context, a wider range of examples enhancement pattern shown in Figure 1 for compound 20
was produced looking forward to extend the methodology. was also observed for compound 19.
Amongst the results displayed in Table 2 it is also worth
Willing to justify the complementarity of the present
noting that β-methyl-substituted acetylenic esters as methodology to the MBH reaction, it is important to inves-
Michael acceptors (Table 2, Entry 9) leads to the expected tigate the drawbacks of the MBH reaction. We have already
products in good yields, showing that the steric hindrance shown that β-methyl-substituted Michael acceptors are very
or electronic effects from the methyl group (Table 1, En- reactive towards this protocol, but one of the most serious
try 5; Table 2, Entries 5 and 6) is not significant when em- drawbacks of the classic MBH reaction is the use of elec-
ploying selenolate nucleophiles.
tron-rich aldehydes. Therefore, we decided to test piperonal
When the Michael acceptors were acetylenic esters, the and 3,4,5-trimethoxybenzaldehyde, two very electron-rich
geometry of the resulting double bond was determined by aromatic aldehydes and, fortunately, both of the aldehydes
Table 2. Evaluation of the Michael acceptors and third electrophiles.[a]
[a] All reactions were conducted under a nitrogen atmosphere; *No hydrogen peroxide added.
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B. A. Sousa, A. A. Dos Santos
FULL PAPER
General Protocol for the One-Pot Preparation of Morita–Baylis–
Hillman Derivatives: In a one-necked, 100-mL round-bottomed
flask previously dried under a nitrogen atmosphere equipped with
a rubber septa and a magnetic stirring bar, containing elemental
selenium (3 mmol, 0.2370 g) was added dry THF (45 mL). To the
resulting suspension was added nBuLi (2 m in hexanes, 1.5 mL)
dropwise under stirring and at room temperature (a light tan solu-
tion was produced). This solution was then cooled to –75 °C by
using a dry ice/ethanol mixture followed by the addition of the
desired aldehyde (3 mmol, 1 equiv.). Three minutes later, the appro-
priated Michael acceptor (3 mmol, 1 equiv.) was added dropwise.
After 10 min under stirring at –75 °C the cryogenic bath was re-
moved, and the solution was left to warm back to room tempera-
ture, followed by the slow addition of the third electrophile (1 equiv.
for acid chlorides and 1.2 equiv. all others). The solution was kept
under stirring for an additional 5 min (complete consumption of
the intermediate alkoxide was followed by TLC). In those cases in
which the selenoxide elimination was performed, 5 min after the
addition of the third electrophile the system was opened and 2 mL
(18 mmol, 6 equiv.) of hydrogen peroxide solution (30% v/v) was
added in one portion. The solution was kept under stirring for an
additional 10 min, and then followed by the addition of an ammo-
nium chloride saturated solution (20 mL). After separation, the
Figure 1. Key NOE enhancements for compound 20 double bond
geometry elucidation.
led to the expected product in high yields (Table 2, En-
tries 11 and 12, respectively) under the same reaction condi-
tions.
Conclusions
In conclusion, we have developed a Michal/aldol/O-func-
tionalization/selenoxide elimination tandem protocol for
the one-pot synthesis of important classes of MBH deriva-
tives. The methodology proved to be quite general in terms
of the structure and the functionalization of the Michael
acceptors including those containing a methyl group at the
β position. Both alkyl and aryl nonactivated aldehydes be- aqueous phase was extracted with ethyl acetate (3ϫ10 mL). The
resulting organic phases were combined and dried with magnesium
sulfate, filtered, and concentrated under reduced pressure. The
crude oil was then purified by column chromatography (silica gel;
hexanes/ethyl acetate, 9:1). All the products were characterized by
1H NMR and 13C NMR spectroscopy. The selenides were also
characterized by 77Se NMR spectroscopy. All new compounds were
characterized by HRMS.
have equally well leading to the Michael/aldol intermediates
in very good yields within 45 min. Indeed, even very elec-
tron-rich aldehydes behave equally well. The addition of a
third electrophile is optional and allows the preparation of
densely functionalized products in a one-pot manner from
commercially available starting materials. The starting
selenolate nucleophile can be easily prepared in situ and
is fully compatible with aldehydes, acting specifically as a
Michael nucleophile, which drives the tandem Michael/
aldol sequence. Another important feature to be mentioned
is the fact that the whole procedure is odorless. Neverthe-
less, n-butylselenides like 2, 19, and 20 (or the correspond-
ing alcohols, before O-functionalization) show absolutely
no unpleasant smell like smaller selenides and disselenides
and can be easily manipulated without any discomfort.
3-(Butylselanyl)-2-cyano-1-phenylpropyl 3-Methylbutanoate (2): 1H
NMR (300 MHz, CDCl3): δ = 7.48–7.32 (m, 4 H), 5.98 (dd, J =
11.7, 6.0 Hz, 1 H), 3.39 (ddd, J = 7.8, 6.9, 6.0 Hz, 1 H), 2.71–2.58
(m, 3 H), 2.32–2.25 (m, 2 H), 2.13 (dddd, J = 13.2, 7.6, 6.6, 2.5 Hz,
1 H), 1.67–1.54 (m, 2 H), 1.46–1.30 (m, 2 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 171.70, 136.84, 135.53, 129.51, 129.34,
129.12, 128.98, 127.39, 126.80, 118.77, 118.71, 74.00, 43.49, 41.28,
40.12, 32.59, 32.54, 25.93, 25.55, 25.41, 23.06, 22.62, 21.36, 20.65,
13.75 ppm. 77Se NMR (75 MHz, CDCl3) δ: 169.87, 168.28 ppm.
Last but not least, it must be noted that the use of a IR (KBr): ν = 700, 754, 1001, 1033, 1093, 1118, 1165, 1251, 1292,
˜
1369, 1465, 1743, 1815, 2362, 2873, 2931 cm–1. HRMS: calcd. for
C19H27NNaO2Se 404.1104; found 404.1107.
selenolate as the nucleophile is highly appealing, especially
because at the end of the transformation it can be main-
tained on the structure of the product or easily eliminated
by a very ecofriendly oxidant reagent (H2O2), resulting in
the MBH derivatives in very good yields.
1
2-Cyano-1-phenylallyl 3-Methylbutanoate (5): H NMR (200 MHz,
CDCl3): δ = 7.40 (d, J = 1.0 Hz, 5 H), 6.35 (t, J = 1.1 Hz, 1 H),
6.08 (d, J = 1.0 Hz, 1 H), 6.01 (d, J = 1.3 Hz, 1 H), 2.35–2.28 (m,
2 H), 2.26–2.06 (m, 1 H), 0.96 (dd, J = 6.5, 0.9 Hz, 6 H) ppm. 13C
NMR (50 MHz, CDCl3): δ = 171.45, 135.77, 132.03, 129.21,
128.95, 126.96, 123.42, 116.23, 74.15, 43.28, 25.77, 22.39 ppm. IR
Experimental Section
(KBr): ν = 667, 700, 750, 960, 1010, 1093, 1118, 1165, 1182, 1249,
˜
General Remarks: All air- or moisture-sensitive reactions were car-
ried out in dried (Ͼ100 °C) glassware under a nitrogen atmosphere.
Dried solvents were distilled before use: THF was distilled from
Na/benzophenone. The products were purified by flash chromatog-
raphy on silica gel columns (Macherey-Nagel 60, 0.063–0.2 mm).
Mixtures of ethyl acetate and hexane were generally used as
chromatography eluents. Analytical TLC was performed on pre-
coated silica gel plates (Merck silica gel 60 F254). Visualization was
accomplished with UV light, vanillin, or phosphomolybdic acid
solution. 1H and 13C NMR spectra were recorded with a Bruker
AC-200 or 300 [200 or 300 MHz (1H) and 50 or 75 MHz (13C)]
spectrometer in CDCl3. Chemical shifts are reported in ppm (δ)
with respect to TMS, and CHCl3 was used as the internal standard.
1290, 1369, 1456, 1467, 1496, 1743, 2229, 2360, 2873, 2931, 2960,
3035, 3066 cm–1. HRMS: calcd. for C15H17NNaO2 266.1157; found
266.1156.
Methyl 2-Methylene-5-phenyl-3-[(3-phenylpropanoyl)oxy]pentanoate
1
(12): H NMR (300 MHz, CDCl3): δ = 7.34–7.06 (m, 10 H), 6.23
(dd, J = 0.5 Hz, 1 H), 5.72–5.55 (m, 2 H), 3.74 (s, 3 H), 2.95 (t, J
= 7.7 Hz, 2 H), 2.69–2.55 (m, 4 H), 2.14–1.87 (m, 2 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 171.77, 165.63, 141.17, 140.31,
139.85, 128.54, 128.40, 128.35, 128.32, 126.36, 125.98, 125.35,
71.62, 51.99, 35.84, 35.83, 31.72, 30.91 ppm. IR (film): ν = 699,
˜
750, 817, 959, 1030, 1077, 1142, 1198, 1248, 1273, 1295, 1354, 1364,
1438, 1454, 1495, 1603, 1632, 1737, 2861, 2930, 2951, 3002, 3027,
4
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One-Pot Synthesis of Highly Functionalized MBH Adducts
3062, 3086 cm–1. HRMS: calcd. for C22H24NaO4 375.1572; found
375.1568.
7.21 (m, 5 H), 6.72 (d, J = 1.0 Hz, 1 H), 4.20 (qd, J = 7.1, 3.3 Hz,
2 H), 2.65 (t, J = 7.3 Hz, 2 H), 2.11 (s, 3 H), 1.77–1.55 (m, 1 H),
1.50–1.28 (m, 2 H), 1.22 (t, J = 7.1 Hz, 3 H), 0.97–0.80 (m, 3
H) ppm. 13C NMR (50 MHz, CDCl3): δ = 169.26, 165.70, 147.14,
138.37, 128.20, 127.89, 127.03, 127.00, 73.77, 60.68, 32.56, 28.75,
22.44, 21.01, 14.01, 13.42 ppm. 77Se NMR (38 MHz, CDCl3): δ =
(E/Z)-2-Cyano-1-phenylbut-2-en-1-yl Hexanoate (7): 1H NMR
(500 MHz, CDCl3): δ = 7.44–7.32 (m, 7 H), 6.63–6.52 (m, 2 H),
6.34–6.30 (m, 1 H), 2.43 (dtd, J = 13.4, 7.5, 3.9 Hz, 3 H), 2.07–
2.01 (m, 4 H), 1.73–1.61 (m, 2 H), 1.32 (dddt, J = 9.5, 6.6, 4.7,
3.5 Hz, 6 H), 0.93–0.85 (m, 4 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 172.53, 172.26, 145.82, 145.46, 136.53, 128.74, 126.58,
126.21, 117.12, 116.76, 116.61, 115.08, 74.49, 69.05, 34.22, 34.13,
371.36 ppm. IR (KBr): ν = 700, 760, 970, 1024, 1107, 1228, 1292,
˜
1371, 1454, 1573, 1693, 1745, 2362, 2870, 2927, 2958 cm–1. HRMS:
calcd. for C18H24NaO4Se 407.0737; found 407.0744.
2-Cyano-1-phenylallyl 3-Phenylpropanoate (3): 1H NMR (500 MHz,
CDCl3): δ = 7.40–7.28 (m, 5 H), 7.27–7.22 (m, 2 H), 7.20–7.12 (m,
3 H), 6.31 (d, J = 1.2 Hz, 1 H), 5.97 (d, J = 1.0 Hz, 1 H), 5.85 (d,
31.12, 24.43, 22.19, 16.98, 14.84, 13.80 ppm. IR (film): ν = 699,
˜
735, 835, 866, 972, 1001, 1093, 1108, 1159, 1236, 1271, 1380, 1453,
1495, 1640, 1743, 2222, 2862, 2872, 2932, 2957, 3034, 3065,
3090 cm–1. HRMS: calcd. for C17H21NNaO2 294.1470; found
294.1470
J = 1.3 Hz, 1 H), 2.99–2.94 (m, 2 H), 2.80–2.68 (m, 2 H) ppm. 13
C
NMR (126 MHz, CDCl3): δ = 171.23, 139.99, 135.68, 132.04,
Methyl 3-Acetoxy-2-methylenenonanoate (11): 1H NMR (500 MHz,
CDCl3): δ = 6.34–6.19 (m, 1 H), 5.76 (t, J = 1.1 Hz, 1 H), 5.61
(ddd, J = 8.1, 4.4, 1.1 Hz, 1 H), 3.78 (s, 3 H), 2.08 (s, 3 H), 1.46–
1.11 (m, 10 H), 0.91–0.85 (m, 4 H) ppm. 13C NMR (126 MHz,
CDCl3): δ = 169.89, 165.73, 140.26, 124.92, 71.82, 51.86, 34.25,
129.27, 128.99, 128.63, 128.34, 127.01, 126.48, 123.14, 116.24,
74.43, 35.78, 30.79 ppm. IR (film): ν = 699, 751, 848, 955, 1001,
˜
1028, 1079, 1144, 1190, 1239, 1372, 1412, 1454, 1496, 1586, 1603,
1624, 1745, 2228, 2864, 2932, 3030, 3063, 3087, 3109 cm–1. HRMS:
calcd. for C19H17NNaO2 314.1157; found 314.1152.
31.61, 28.86, 25.23, 22.51, 21.00, 13.98 ppm. IR (film): ν = 604,
˜
1
1-Phenyl-2-(phenylsulfonyl)allyl Acetate (17): H NMR (300 MHz,
637, 726, 817, 855, 919, 964, 1033, 1063, 1118, 1157, 1197, 1236,
1273, 1292, 1370, 1439, 1459, 1633, 1725, 1747 cm–1. HRMS: calcd.
for C13H22NaO4 265.1415; found 265.1407.
2-Cyano-5-methylhex-1-en-3-yl 3-Methylbutanoate (8): 1H NMR
(500 MHz, CDCl3): δ = 6.02 (d, J = 0.4 Hz, 1 H), 6.00 (d, J =
0.8 Hz, 1 H), 5.37 (ddt, J = 8.8, 5.6, 0.7 Hz, 1 H), 2.25–2.21 (m, 2
H), 2.12 (ddq, J = 13.2, 7.4, 6.6 Hz, 1 H), 1.77 (ddd, J = 13.6, 8.8,
6.1 Hz, 1 H), 1.66 (dsept, J = 7.8, 6.5 Hz, 1 H), 1.59–1.56 (m, 1
H), 0.98–0.93 (m, 12 H) ppm. 13C NMR (126 MHz, CDCl3): δ =
172.02, 132.42, 123.33, 116.21, 71.51, 43.34, 41.78, 25.73, 24.33,
CDCl3): δ = 7.78–7.71 (m, 2 H), 7.61–7.40 (m, 4 H), 7.27–7.14 (m,
5 H), 6.67 (dd, J = 0.4 Hz, 1 H), 6.65–6.62 (m, 1 H), 5.97 (t, J =
1.0 Hz, 1 H), 1.89 (d, J = 0.5 Hz, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 168.84, 150.08, 139.52, 136.12, 133.43, 129.03, 128.75,
128.57, 128.31, 128.13, 127.28, 71.30, 20.68 ppm. IR (film): ν =
˜
534, 562, 572, 597, 630, 688, 698, 750, 780, 845, 909, 920, 961, 991,
1023, 1081, 1135, 1167, 1225, 1307, 1316, 1372, 1447, 1495, 1585,
1746, 2933, 3033, 3065 cm–1. HRMS: calcd. for C17H16NaO4S
339.0667; found 339.0670.
2-Cyano-1-cyclohexylallyl Benzoate (16): 1H NMR (500 MHz,
CDCl3): δ = 8.12–8.05 (m, 2 H), 7.62–7.55 (m, 1 H), 7.50–7.43 (m,
2 H), 6.10 (s, 1 H), 6.03 (d, J = 0.9 Hz, 1 H), 5.31 (d, J = 7.9 Hz,
1 H), 2.00–1.90 (m, 2 H), 1.85–1.67 (m, 4 H), 1.34–1.02 (m, 5
H) ppm. 13C NMR (126 MHz, CDCl3): δ = 165.43, 133.46, 133.42,
129.77, 129.47, 128.56, 121.91, 116.48, 77.81, 40.07, 28.85, 28.25,
22.59, 22.33, 22.31, 22.04 ppm. IR (film): ν = 947, 994, 1060, 1092,
˜
1117, 1166, 1183, 1249, 1293, 1370, 1389, 1468, 1742, 2227, 2874,
2934, 2961 cm–1. HRMS: calcd. for C13H21NNaO2 246.1470; found
246.1467.
1
2-Cyano-1-phenylallyl Acetate (6): H NMR (500 MHz, CDCl3): δ
= 7.41–7.32 (m, 5 H), 6.33 (t, J = 1.2 Hz, 1 H), 6.04 (d, J = 1.0 Hz,
1 H), 5.98 (d, J = 1.4 Hz, 1 H), 2.15 (s, 3 H) ppm. 13C NMR
(126 MHz, CDCl3): δ = 169.31, 135.71, 132.08, 129.25, 128.96,
26.07, 25.63, 25.51 ppm. IR (film): ν = 712, 976, 1026, 1069, 1107,
˜
1177, 1270, 1316, 1451, 1601, 1723, 2226, 2855, 2931 cm–1. HRMS:
calcd. for C17H19NNaO2 292.1313; found 292.1308.
126.98, 123.20, 116.21, 74.38, 20.91 ppm. IR (film): ν = 700, 743,
˜
(Z)-Ethyl 3-(Butylselanyl)-2-{phenyl[(triisopropylsilyl)oxy]methyl}-
but-2-enoate (18): H NMR (300 MHz, CDCl3): δ = 7.46–7.17 (m,
856, 918, 962, 1027, 1226, 1372, 1454, 1496, 1749, 2229, 2938, 3035,
1
3066, 3112 cm–1. CAS: 143165-00-8.
5 H), 6.29 (q, J = 0.9 Hz, 1 H), 4.30 (qd, J = 7.1, 4.5 Hz, 2 H),
2.74–2.57 (m, 2 H), 2.25 (s, 3 H), 1.67–1.55 (m, 2 H), 1.49–1.37 (m,
3 H), 1.32 (t, J = 7.1 Hz, 3 H), 1.22–1.12 (m, 6 H), 1.10–1.08 (m,
14 H), 0.91 (t, J = 7.3 Hz, 3 H) ppm. 13C NMR (50 MHz, CDCl3):
δ = 167.39, 156.42, 144.58, 130.48, 127.76, 126.15, 125.37, 70.76,
60.65, 31.27, 24.67, 23.17, 21.76, 18.06, 17.93, 17.68, 14.32, 13.62,
12.31, 12.24 ppm. 77Se NMR (38 MHz, CDCl3): δ = 431.88 ppm.
2-Cyano-5-methylhex-1-en-3-yl Acetate (9): 1H NMR (500 MHz,
CDCl3): δ = 6.03 (d, J = 0.6 Hz, 2 H), 6.00 (d, J = 0.9 Hz, 2 H),
5.36 (ddt, J = 8.7, 5.7, 0.7 Hz, 2 H), 2.10 (s, 6 H), 1.76 (ddd, J =
13.6, 8.7, 6.1 Hz, 2 H), 1.70–1.61 (m, 2 H), 1.60–1.53 (m, 1 H), 0.95
(dd, J = 6.5, 1.6 Hz, 13 H) ppm. 13C NMR (126 MHz, CDCl3): δ
= 169.92, 132.53, 123.17, 116.20, 71.80, 41.73, 24.34, 22.55, 22.13,
20.95 ppm. IR (film): ν = 612, 949, 1023, 1061, 1123, 1229, 1372,
˜
IR (KBr): ν = 580, 678, 734, 775, 837, 883, 1058, 1093, 1161, 1246,
˜
1468, 1749, 2227, 2873, 2934, 2961 cm–1. CAS: 853195-08-1.
1369, 1465, 1550, 1685, 2357, 2866, 2937 cm–1. HRMS: calcd. for
C26H44NaO3SeSi 535.2122; found 535.2113.
1
2-Cyano-5-methylhex-1-en-3-yl 3-Phenylpropanoate (10): H NMR
(500 MHz, CDCl3): δ = 7.30–7.26 (m, 2 H), 7.21–7.18 (m, 4 H),
5.96 (s, 1 H), 5.89 (d, J = 0.9 Hz, 1 H), 5.37–5.32 (m, 1 H), 2.95
(t, J = 7.7 Hz, 2 H), 2.70–2.66 (m, 2 H), 1.76–1.68 (m, 1 H), 1.59–
1.49 (m, 2 H), 0.92–0.89 (m, 7 H) ppm. 13C NMR (126 MHz,
CDCl3): δ = 171.82, 140.00, 132.48, 128.54, 128.28, 126.40, 123.10,
116.21, 71.76, 41.75, 35.75, 30.81, 24.27, 22.62, 22.06 ppm. IR
Methyl 3-[(tert-butoxycarbonyl)oxy]-4-methyl-2-methylenepentano-
ate (13): H NMR (200 MHz, CDCl3): δ = 6.39 (d, J = 1.0 Hz, 2
H), 5.84 (t, J = 1.1 Hz, 2 H), 5.32 (dd, J = 5.7, 1.1 Hz, 2 H), 3.82
(s, 6 H), 2.16–1.98 (m, 2 H), 1.51 (s, 1 H), 0.99–0.94 (m, 12 H) ppm.
13C NMR (50 MHz, CDCl3): δ = 166.01, 153.05, 139.55, 125.91,
1
82.12, 78.71, 52.01, 31.78, 27.80, 18.79, 17.11 ppm. IR (KBr): ν =
˜
(film): ν = 699, 751, 949, 986, 1061, 1077, 1123, 1148, 1242, 1291,
˜
792, 817, 862, 956, 1072, 1122, 1165, 1255, 1280, 1369, 1462, 1629,
1745, 1362, 1881, 1974 cm–1. HRMS: calcd. for C13H22NaO5
281.1364; found 281.1359.
1370, 1454, 1468, 1497, 1606, 1742, 2226, 2872, 2933, 2959, 3029,
3064, 3087, 3109 cm–1. HRMS: calcd. for C17H21NNaO2 294.1470;
found 294.1484.
(Z)-Ethyl 2-[Acetoxy(phenyl)methyl]-3-(butylselanyl)acrylate (19):
1H NMR (200 MHz, CDCl3): δ = 7.56 (d, J = 1.0 Hz, 1 H), 7.41–
Methyl 2-{[(tert-butoxycarbonyl)oxy](phenyl)methyl}acrylate (14):
1H NMR (200 MHz, CDCl3): δ = 7.45–7.23 (m, 5 H), 6.48 (dd, J
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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Job/Unit: O20371
/KAP1
Date: 08-05-12 10:18:56
Pages: 7
B. A. Sousa, A. A. Dos Santos
FULL PAPER
= 1.4, 0.9 Hz, 1 H), 6.41 (t, J = 0.8 Hz, 1 H), 5.92 (dd, J = 1.4,
0.8 Hz, 5 H), 3.71 (s, 3 H), 1,45 (s, 9 H) ppm. 13C NMR (50 MHz,
CDCl3): δ = 165.39, 152.41, 139.69, 137.53, 128.47, 127.64, 125.85,
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of H NMR, 13C NMR, and 77Se NMR spectra.
82.63, 75.82, 52.00, 27.76 ppm. IR (KBr): ν = 698, 765, 864, 974,
˜
1091, 1155, 1257, 1276, 1296, 1369, 1435, 1631, 1739, 2360, Acknowledgments
2978 cm–1. CAS: 956833-12-8.
Benzyl (2-Cyano-1-phenylallyl)carbonate (4): 1H NMR (300 MHz,
CDCl3): δ = 7.43–7.33 (m, 10 H), 6.17 (t, J = 1.2 Hz, 1 H), 6.08
(dd, J = 6.5, 1.2 Hz, 2 H), 5.18 (d, J = 2.6 Hz, 2 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 134.95, 134.63, 131.98, 130.20, 129.53,
129.01, 128.77, 128.67, 128.40, 127.03, 122.75, 115.95, 77.98,
The authors would like to thank Fundação de Amparo à Pesquisa
do Estado de São Paulo (FAPESP), Conselho Nacional de Pes-
quisa e Desenvolvimento (CNPq), and Coordenação de Aper-
feiçoamento de Pessoal de Nível Superior (CAPES) for financial
support and the University of São Paulo for the provided infra-
structure. The authors are also thankful to Professor Fernando
Antônio Santos Coelho from the Chemistry Institute of the Uni-
versity of Campinas (IQM-UNICAMP) and Professor Pedro H.
Cury Camargo from the Chemistry Institute of the University of
São Paulo (IQ-USP) for their helpful suggestions.
70.39 ppm. IR (KBr): ν = 698, 755, 785, 911, 956, 1252, 1384, 1456,
˜
1497, 1754, 2229, 2956, 3036, 3066, 3090, 3111 cm–1. HRMS: calcd.
for C18H15NNaO3 316.0949; found 316.0948.
(E/Z)-Methyl 2-[Acetoxy(phenyl)methyl]but-2-enoate (20): 1H
NMR (200 MHz, CDCl3): δ = 7.40–7.30 (m, 5 H), 7.19 (q, J =
7.4 Hz, 1 H), 6.99 (s, 1 H), 6.71 (p, J = 1.2 Hz, 1 H), 6.26 (qd, J =
7.2, 1.3 Hz, 1 H), 3.73 (d, J = 0.5 Hz, 3 H), 2.20 (s, 3 H), 2.13 (s,
3 H), 2.11–2.05 (m, 3 H), 2.01 (d, J = 7.4 Hz, 3 H) ppm. 13C NMR
(50 MHz, CDCl3): δ = 169.93, 169.51, 166.29, 142.72, 139.38,
138.56, 138.38, 132.14, 131.76, 128.35, 128.25, 128.06, 127.43,
127.29, 125.83, 74.42, 70.75, 51.81, 51.36, 21.08, 20.92, 15.55,
[1] B. Barry, G. D. Hall, Chem. Rev. 2009, 109, 4439.
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14.84 ppm. IR (KBr): ν = 698, 734, 916, 1024, 1145, 1234, 1369,
˜
1436, 1741, 2360, 2954 cm–1. HRMS: calcd. for C14H16NaO4
271.0946; found 271.0949.
[5] W. Zhong, Y. Zhao, W. Su, Tetrahedron 2008, 64, 5491.
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2008, 64, 7183.
(E/Z)-Methyl 2-{[(tert-butoxycarbonyl)oxy](phenyl)methyl}but-2-en-
oate (15): 1H NMR (200 MHz, CDCl3): δ = 7.46–7.29 (m, 5 H),
7.22 (q, J = 7.4 Hz, 1 H), 6.81 (s, 1 H), 6.52 (t, J = 1.3 Hz, 1 H),
6.32 (qd, J = 7.2, 1.2 Hz, 1 H), 3.75 (s, 3 H), 2.09 (dd, J = 7.3,
1.2 Hz, 3 H), 2.02 (d, J = 7.5 Hz, 3 H), 1.53 (s, 9 H), 1.50 (s, 9
H) ppm. 13C NMR (50 MHz, CDCl3): δ = 166.47, 166.22, 152.89,
152.48, 142.90, 140.02, 138.46, 138.21, 131.72, 128.35, 128.23,
128.07, 127.47, 127.21, 125.90, 82.38, 73.55, 51.89, 51.36, 27.75,
[8] S. GowriSankar, C. G. Lee, J. N. Kim, Tetrahedron Lett. 2004,
45, 6949.
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Prabhakar, B. Jagadeesh, Tetrahedron Lett. 2005, 46, 639.
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1990.
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[13] O. Roy, A. Riahi, F. Hénin, J. Muzart, Tetrahedron 2000, 56,
8133.
15.57, 14.87 ppm. IR (KBr): ν = 696, 744, 887, 1091, 1163, 1255,
˜
1280, 1369, 1438, 1745, 2360, 2978 cm–1. HRMS: calcd. for
C17H22NaO5 329.1365; found 329.1369.
[14] M. Shi, Y. Shi, Y. Jiang, J. Am. Chem. Soc. 2008, 130, 7202.
[15] K. Y. Lee, C. G. Lee, T. H. Kim, J. N. Kim, Bull. Korean Chem.
Soc. 2004, 1, 33.
Ethyl 2-[Acetoxy(3,4,5-trimethoxyphenyl)methyl]acrylate (22): 1H
NMR (200 MHz, CDCl3): δ = 6.65 (d, J = 1.2 Hz, 1 H), 6.61 (s, 2
H), 6.42 (d, J = 1.0 Hz, 1 H), 5.85 (t, J = 1.2 Hz, 1 H), 4.20 (q, J
= 7.1 Hz, 2 H), 3.86 (d, J = 3.9 Hz, 9 H), 2.15 (s, 3 H), 1.26 (t, J =
7.1 Hz, 3 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 169.38, 164.92,
[16] T. Satyanarayana, A. J. Rao, D. Basavaiah, Chem. Rev. 2003,
103, 811.
[17] R. S. Porto, F. Coelho, Synth. Commun. 2004, 34, 3037.
153.10, 139.70, 137.88, 133.20, 125.41, 104.77, 73.13, 60.95, 60.72, [18] L. K. Kohn, C. H. Pavam, D. Veronese, F. Coelho, J. E.
De Carvalho, W. P. Almeida, Eur. J. Med. Chem. 2006, 41, 738.
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2006, 435.
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2000, 39, 2764.
[21] J. Xu, L. Wu, X. Huang, J. Org. Chem. 2011, 76, 5598.
[22] Y. Nishibayashi, S. Uemura, “Selenoxide Elimination and [2,3]-
Sigmatropic Rearrangement” in Organoselenium Chemistry:
Synthesis and Reactions (Ed.: T. Wirth), Wiley, New York,
2011.
56.04, 21.10, 14.02 ppm. IR (KBr): ν = 831, 1029, 1124, 1232, 1330,
˜
1369, 1423, 1462, 1504, 1591, 1631, 1714, 1743, 2330, 2362, 2835,
2943, 2985 cm–1. HRMS: calcd. for C17H22NaO7 361.1263; found
361.1257.
Ethyl 2-{Acetoxy(benzo[d][1,3]dioxol-5-yl)methyl}acrylate (21): 1H
NMR (200 MHz, CDCl3): δ = 6.88 (tt, J = 2.0, 1.2 Hz, 2 H), 6.80
(dd, J = 7.8, 0.6 Hz, 1 H), 6.63 (t, J = 1.3 Hz, 1 H), 6.42 (t, J =
1.0 Hz, 1 H), 5.98 (s, 2 H), 5.88 (dd, J = 1.6, 1.0 Hz, 1 H), 4.26–
4.13 (m, 2 H), 2.13 (s, 3 H), 1.27 (t, J = 7.1 Hz, 3 H) ppm. 13C
NMR (50 MHz, CDCl3): δ = 190.25, 169.35, 164.88, 147.58,
139.77, 131.54, 128.64, 125.05, 121.73, 108.09, 101.13, 72.92, 60.93,
[23] J. P. Marino, H. N. J. Nguyen, Org. Chem. 2002, 67, 6291.
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2006, 106, 1032.
21.08, 14.00 ppm. IR (KBr): ν = 731, 808, 862, 929, 1039, 1097,
˜
1145, 1228, 1367, 1444, 1487, 1504, 1631, 1720, 1745, 2358, 2904,
2980 cm–1. HRMS: calcd. for C15H16NaO6 315.0845; found
315.0839.
Received: March 23, 2012
Published Online: ᭿
6
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20371
/KAP1
Date: 08-05-12 10:18:56
Pages: 7
One-Pot Synthesis of Highly Functionalized MBH Adducts
Morita–Baylis–Hillman Derivatives
B. A. Sousa,* A. A. Dos Santos ........ 1–7
A
Facile, Versatile, and Mild Morita–
Baylis–Hillman-Type Reaction for the
Modular One-Pot Synthesis of Highly
Functionalized MBH Adducts
Here we describe a one-pot, fast, and high-
yielding methodology for the synthesis of
different Morita–Baylis–Hillman deriva-
tives by a four-component cascade reac-
tion. The cascade is based on a Michael/
aldol/O-functionalization/selenoxide elim-
ination sequence. This protocol completely
avoids the manipulation of selenium spe-
cies with an unpleasant odor.
Keywords: Multicomponent reactions
Domino reactions / Michael addition / Al-
dol reactions / Selenium
/
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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7