Efficient assembly of allenes, 1,3-dienes, and 4H-pyrans by catalytic regioselective nucleophilic addition to electron-deficient 1,3-conjugated enynes

Article abstract of DOI:10.1002/chem.200801004

The results of the base-catalyzed highly regioselective nucleophilic addition to electron-deficient 1.3-conjugated enynes, leading to highly functionalized 1.2-allenes, 1,3-dienes, and 4H-pyrans, were reported. The results show that dibenzyl and diethyl malonates can be used as nucleophiles for functionalized 1,2-allenes in excellent yields with high regioselectivity. β-keto compounds are found to react as nucleophiles with electron-deficient 1,3-conjugated enynes to give a heterocyclic compound named 4H-pyran, with potential bioactivity. The results also show that 1,3-Diene is produced by a tandem stereospecific nucleophilic addition to electron-deficient 1,2-allene from the less bulky side and subsequent β-heteroatom elimination, when heteroatom nucleophiles are used.

Full text of DOI:10.1002/chem.200801004

COMMUNICATION
DOI: 10.1002/chem.200801004
Efficient Assembly of Allenes, 1,3-Dienes, and 4H-Pyrans by Catalytic
Regioselective Nucleophilic Addition to Electron-Deficient 1,3-Conjugated
Enynes
Xiuzhao Yu, Hongjun Ren, Yuanjing Xiao, and Junliang Zhang*[a]
Catalytic nucleophilic addition[1] to electron-deficient ole-
fins is an example of one of the cornerstones in modern syn-
thetic organic chemistry, since the atom economy[2] of such
addition reactions can be 100%. In this context, acroleins,
acrylates, acrylnitriles, vinyl ketones, and a-nitroalkenes
have been well studied as electrophiles for the 1,4-addition
of nucleophiles in past years. Despite this, it is necessary to
develop some readily available substrates as novel electro-
philes for the modern synthetic community. Very recently,
our group[4] and others[3] have found that 2-(1-alkynyl)-2-
alken-1-ones can react with nucleophiles catalyzed by transi-
tion-metals or mediated by electrophiles to give polysubsti-
tuted furans. A cyclopropanation reaction of 2-(1-alkynyl)-2-
alken-1-ones with dimethylsulfoxonium methylide for the
Scheme 1. a) Nucleophilic addition to simple electron-deficient alkenes.
synthesis of 1-alkynylcyclopropyl ketones, which can react
with nucleophiles to afford highly substituted furans under
gold-complex catalysis, was also developed.[5] We hypothe-
sized that, in these transformations, 2-(1-alkynyl)-2-alken-1-
ones might act as electrophiles in the reaction pathway.
Thus, we became interested in the nucleophilic addition of
various nucleophiles to electron-deficient 1,3-conjugated
enynes. On comparison with simple electron-deficient ole-
fins, there is an obvious new regioselectivity issue in this
transformation of electron-deficient 1,3-enynes, that is,
whether or not the reaction occurs by 1,4-addition, 4,5’-addi-
tion, or 4’,5’-addition leading to functionalized alkynes, 1,2-
allenes, or 1,3-dienes, respectively (Scheme 1; EWG=elec-
tron-withdrawing group). Herein, we wish to report our
recent results on the simple base-catalyzed highly regiose-
lective nucleophilic addition to electron-deficient 1,3-conju-
b) Regioselective nucleophilic addition to electron-deficient 1,3-conjugat-
ed enyne 1.
gated enynes leading to highly functionalized 1,2-allenes,[6]
1,3-dienes,[7] and 4H-pyrans,[8] respectively. The regioselec-
tivity is controllable by a subtle choice of nucleophile.[9]
Initially, we tested the reaction of 1,3-conjugated enyne
(1a) with carbon-centered nucleophile dimethyl malonate
(2a) in the presence of different catalysts (Table 1). After
some attempts, we were pleased to find that the reaction of
1a with 2a (2.0 equiv) in THF at 08C for 4 h in the presence
of 10 mol% of KOH exclusively afforded 1,2-allene 3aa as
two diastereoisomers in 91% total isolated yield by a 4,5’-
addition reaction. No transition metal or Lewis acid are
needed in the reaction (Table 1, entry 5) and no alkyne or
1
1,3-diene were formed, as detected by H NMR spectroscop-
ic analysis of the crude product. Other bases, such as
Na2CO3 and K2CO3, did not catalyze this transformation in
THF at 08C, but they worked well in DMF at RT (Table 1,
entries 7–10). We also tested organic bases, such as Et3N
and DBU (Table 1, entries 1–2). The reaction proceeded
smoothly in DMF when DBU was used as the catalyst
(Table, entry 2). In contrast, no reaction occurred in the
presence of Et3N (Table 1, entry 1).
[a] X. Yu, Dr. H. Ren, Dr. Y. Xiao, Prof. Dr. J. Zhang
Shanghai Key Laboratory of Green Chemistry and
Chemical Processes Department of Chemistry
East China Normal University
3663 N. Zhangshan Road, Shanghai 200062 (P. R. China)
Fax : (+86)21-6223-5039
E-mail: jlzhang@chem.ecnu.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200801004.
Chem. Eur. J. 2008, 14, 8481 – 8485
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
8481

Table 1. Screening reaction conditions for the addition of malonate 2a to
electron-deficient conjugated enyne 1a.[a]
Table 2. 4,5’-Addition of malonates to various electron-deficient 1,3-con-
jugated enynes 1 lead to highly functionalized 1,2-allenes 3.[a]
Entry
Base
Solvent
T [8C]
t [h]
d.r.[b]
Total yield [%]
Entry Enyne 1
R1/R2/EWG
Total yield of 3 ([%], d.r.)
1
2
3
4
Et3N
DMF
DMF
THF
THF
THF
DMF
THF
DMF
THF
DMF
RT
RT
RT
RT
0
0
0
RT
0
RT
12
2
52
2
4
3
12
50
12
2
–
0
86
31
88
91
77
0
83
0
85
DBU[c]
DBU
1.7:1.0
1.5:1.0
1.6:1.0
1.7:1.0
1.9:1.0
–
1.6:1.0
–
1.7:1.0
1
2
3
Ph/4-MeOPh/CO2Me (1b)
4-MeOph/Ph/CO2Me (1c)
1-naphthyl/Ph/CO2Me (1d)
Ph/Ph/COMe (1e)
Ph/4-MeOPh/COMe (1 f)
n-C4H9/Ph/COMe (1g)
3ba (84, 1.1:1.0)
3ca (93, 1.4:1.0)
3da (87, 1.8:1.0)
3ea (96, 1.2:1.0)
3 fa (91, 1.3:1.0)
3ga (55, 1.1:1.0)
KOH
KOH
KOH
Na2CO3
Na2CO3
K2CO3
K2CO3
5[d]
6
4[b]
5[b]
6[c]
7
7
8
9
10
4-MeOPh/4-MeOPh/COMe (1h) 3ha (95, 15:1.0)
8[b]
9[d]
10[e]
1-naphthyl/Ph/COMe (1i)
3ia (83, 1.7:1.0)
3ab (93, 1.5:1.0)
3ac (92, 1.4:1.0)
1a
1a
[a] The reaction was carried out by using 1a (0.5 mmol) and 2a
(1.0 mmol) in solvent (2 mL). The yield is the isolated yield. [b] d.r.=dia-
[a] All reactions were carried out with enyne 1 (0.5 mmol), dimethyl mal-
onate 2a (1.0 mmol), and KOH (10 mol%) in THF at 08C for 2–12 h,
unless otherwise specified. [b] Two diastereoisomers can be separated
easily by flash column chromatography. [c] 20% of 1g is recovered after
24 h. [d] Diethyl malonate 2b (1.0 mmol) was used instead of 2a. [e] Di-
benzyl malonate 2c (1.0 mmol) was used instead of 2a. [f] The designa-
tion 3ba for the product indicates that the reactants used were 1b and
2a, respectively.
stereoisomer
ratio.
[c] DBU=1,8-diazabicyclo[5.4.0]undecen-7-ene.
G
[d] Even 1 mol% of KOH worked well on a 15 mmol scale.
To determine the scope of this transformation, various
electron-deficient 1,3-conjugated enynes 1 were studied and
the results are summarized in Table 2. The reaction of 2-ary-
lidene 3-alkynoates 1b–d with dimethyl malonate 2a afford-
ed highly substituted functionalized 1,2-allenoates 3ba–3da
in high yields (Table 2, entries 1–3). Functionalized 1,2-allen-
yl ketones 3ea–3ia could be produced in moderate to excel-
lent yields (Table 2, entries 4–8). When R1 is alkyl group in
the substrate, the reaction takes longer and could not com-
plete after 24 h giving a 55% yield of 3ga and 20% of re-
covered starting material (Table 2, entry 6). The reaction of
enyne 1e with dimethyl malonate 2a provided further evi-
dence for the structure and relative stereochemistry, since
we established the structure and relative stereochemistry of
3ea by single-crystal X-ray diffraction analysis of one of its
stereoisomers (Figure 1a).[10] Dibenzyl and diethyl malonates
can also be employed as nucle-
phenol 2d with 1a proceeds very well at RT in THF under
similar conditions to afford a highly regioselective and ste-
reospecific 4’,5’-addition product, 1,3-diene 4ad, in 99%
yield. No 1,2-allene and alkyne-type products were formed,
1
as detected by H NMR spectroscopic analysis of the crude
products [Eq. (1)]. The high stereoselectivity is quite surpris-
ing because 1a contains two different stereoisomers based
on the double bond; this indicates that the double bond of
the enyne 1a should be involved in the reaction pathway.
Similar to the case of nucleophilic addition of dimethyl mal-
onate 2a, the reactions of (Z)-1j and its stereoisomer (E)-1j
with 2d give the same product, (3Z,4E)-4jd, which further
ophiles to afford the corre-
sponding functionalized 1,2-al-
lenes in excellent yields with
high regioselectivity (Table 2,
entries 9–10). The reactions of
dimethyl malonate 2a with 1,3-
enyne (Z)-1j and its stereoiso-
mer (E)-1j gave the same prod-
uct with the same diastereose-
lectivity; this indicates that they
have the same reaction inter-
mediary (Scheme 2).
Furthermore, it is surprising
but also interesting to observe a
totally different addition mode
when 4-methylthiophenol 2d
was used as the nucleophile in-
stead of dimethyl malonate 2a.
The reaction of 4-methylthio- Figure 1. X-ray crystal structures and line drawings of 1,2-allene 3ed (a) and 1, 3-diene 4ed (b).
8482
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 8481 – 8485

Efficient Assembly of Allenes, 1,3-Dienes, and 4H-Pyrans
COMMUNICATION
Table 3. Regioselective and stereoselective synthesis of highly substituted
functionalized 1,3-dienes.[a–c]
Entry Enyne 1
R1/R2/EWG
NuH 2 Yield of 4 [%]
Scheme 2. Reactions of 2a with (Z)-1j and its stereoisomer (E)-1j lead
to the same product, 3ja. Conditions: KOH (10 mol%), THF, 08C, 2 h.
1
2
3
Ph/4-MeOPh/CO2Me (1b)
4-MeOph/Ph/CO2Me (1c)
1-naphthyl/Ph/CO2Me (1d)
Ph/Ph/COMe (1e)
Ph/4-MeOPh/COMe (1 f)
n-C4H9/Ph/COMe (1g)
4-MeOPh/4-MeOPh/COMe (1h) 2d
1-naphthyl/Ph/COMe (1i)
1a
1a
1a
2d
2d
2d
2d
2d
2d
4bd (99)
4cd (82)
4dd (87)
4ed (94)
4 fd (92)
4gd (80)
4hd (96)
4id (88)
4ae (93)
4af (84)
4ag (77)
confirms that the double bond of the enyne is involved in
the reaction pathway (Scheme 3).
4[b]
5[b]
6[c]
7
8[b]
9[d]
10[e]
11
2d
2e
2 f
2g
[a] All reactions were carried out with enyne 1 (0.5 mmol), 2d/2e/2 f/2g
(0.75 mmol), and K2CO3 (10 mol%) in THF at RT for 0.5–2 h. [b] Yields
are isolated yields. [c] The stereoselectivity is more than 95% if the ste-
reoselectivity issue exists.
Scheme 3. Reactions of 2d with (Z)-1j and its stereoisomer (E)-1j lead
to the same product (2Z,3E)-4jd. Conditions: K2CO3 (10 mol%), THF,
RT, 1 h.
Scheme 4. DBU-catalyzed formal [3+3] cycloaddition of b-keto com-
pounds with 1a.
Various 1,3-enynes 1 and heteroatom nucleophiles 2d–g
were then studied and typical results are listed in Table 3.
Points to note: 1) not only arylenethiols, such as 4-methyl-
thiophenol 2d and 2-naphthalenethiol 2e, but also benzyl
mercaptan 2 f can act as S nucleophiles to give highly func-
tionalized tetrasubstituted 1,3-dienes 4bd–af with high re-
gioselectivity and stereoselectivity in good to excellent
yields (Table 3, entries 1–8); 2) initial results showed that
pyrrolidine 2g can act as a N nucleophile reacting with
enyne 1a to afford the corresponding substituted 3-pyrroli-
dinyl 1,3-diene 4ag in 77% yield (Table 3, entry 11); and
3) the structure and relative stereochemistry of the products
was established by single-crystal X-ray diffraction analysis
of (3Z,4E)-4ed (Figure 1b).[11]
cient 1,3-enynes is proposed in Scheme 5. The addition of a
nucleophilic anion, generated by the deprotonation of the
nucleophile in the presence of base, to electron-deficient
enyne 1 afforded intermediate 1,2-allenic/propargylic anion
Some initial results showed that b-keto compounds can
also react as nucleophiles with electron-deficient 1,3-conju-
gated enynes to give a very interesting heterocyclic com-
pound, 4H-pyran, with potential bioactivity[8] by a formal
[3+3] cycloaddition (cascade[12] intermolecular/intramolecu-
lar nucleophilic addition; Scheme 4). Although K2CO3 can
catalyze this transformation in THF, DBU gives better re-
sults.
A plausible mechanism for this simple base-catalyzed
highly regioselective nucleophilic addition to electron-defi-
Scheme 5. Plausible mechanism for the simple base-catalyzed highly re-
gioselective nucleophilic addition to electron-deficient 1,3-enynes.
Chem. Eur. J. 2008, 14, 8481 – 8485
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8483

J. Zhang et al.
(190.5 mg) in 99% yield. 1H NMR (500 MHz, CDCl3): d=7.79 (s, 1H),
7.71–7.69 (m, 2H); 7.39–7.37 (m, 5H), 7.31 (d, J=7.5 Hz, 2H), 7.24 (t,
J=7.5 Hz, 2H), 7.18 (d, J=7.5 Hz, 1H), 7.12 (d, J=7.5 Hz, 2H), 6.69 (s,
1H), 3.72 (s, 3H), 2.37 ppm (s, 3H); 13C NMR (125.8 MHz, CDCl3): d=
166.81, 142.51, 139.09, 136.55, 135.45, 134.29, 133.92, 130.48, 129.94,
129.74, 129.26, 128.43, 128.38, 128.31, 127.79, 127.72, 127.16, 52.37,
21.27 ppm; MS (70 eV): m/z (%): 386 (100) [M+]; HRMS: m/z: calcd for
C25H22O2S: 386.1341; found: 386.1343.
6/7, which can then undergo subsequent protonation (proton
from the nucleophile) to give 1,2-allene 3 or alkyne 8. The
alkyne 8, if formed, can then undergo a quick rearrange-
ment to give 1,2-allene 3 under the basic conditions.[13] 1,3-
Diene 4 was produced by a tandem stereospecific nucleo-
philic addition to electron-deficient 1,2-allene[14] from the
less bulky side and subsequent b-heteroatom elimination
when heteroatom nucleophiles, such as thiols and amines,
were used, since these heteroatom groups are also good
leaving groups. 4H-Pyrans were afforded by a cascade inter-
molecular/intramolecular nucleophilic addition under base
catalysis.
In summary, we have demonstrated that electron-deficient
1,3-conjugated enynes can serve as novel and readily avail-
able[15] electrophiles for the nucleophilic addition. The addi-
tion patterns depend on the nucleophiles. 4,5’-Addition lead-
ing to functionalized 1,2-allenes was realized when carbon-
centered nucleophiles, such as malonates, were used, where-
as functionalized 1,3-dienes were formed by a 4’,5’-addition
mode if heteroatom nucleophiles were applied and 4H-
pyrans were afforded by a formal [3+3] cycloaddition. This
methodology provides an efficient, atom-economic, and
mild route to synthesize highly functionalized 1,2-allenes,
1,3-dienes, and 4H-pyrans, which are useful building blocks
in organic synthesis. Investigations by our group into the
synthetic applications, scope, and asymmetric catalysis of
these reactions are actively underway.
Synthesis of 4H-pyran 5a:
A solution of acetylactone (60 mg,
0.60 mmol), methyl 2-benzylidene-4-phenylbut-3-ynoate 1a (131.0 mg,
0.50 mmol), and DBU (7.6 mg, 0.05 mmol) in DMF (2 mL) was stirred at
1008C. After stirring for 12 h, the reaction was complete, as determined
by TLC analysis. After cooling down to RT, H2O (10 mL) was added and
the mixture was extracted by diethyl ether (3”15 mL). The combined or-
ganic layers were washed with saturated brine solution and dried over
MgSO4. After filtration and evaporation, the residue was purified by
column chromatography on silica gel (hexanes/ethyl ether 3:1) to afford
164.3 mg (91%) of 5a. 1H NMR (500 MHz, CDCl3): d=7.30–7.18 (m,
10H), 4.83 (s, 1H), 4.19 (d, J=14.0 Hz, 1H), 4.01 (d, J=14.0 Hz, 1H),
3.72 (s, 3H), 2.27 (s, 3H), 2.15 ppm (s, 3H); 13C NMR (125.8 MHz,
CDCl3): d= 198.52, 166.71, 159.18, 157.19, 144.39, 136.95, 128.65, 128.45,
128.42, 128.38, 128.13, 126.93, 126.58, 115.82, 109.26, 51.52, 39.09, 37.15,
29.84, 18.90 ppm; MS (EI): m/z (%): 362 (89.76) [M]+, 285 (100);
HRMS: m/z: calcd for C23H22O4: 362.1518; found: 362.1518.
Acknowledgements
Financial supports from the National Science Foundation of China
(20702015) and the Shanghai Municipal Committee of Science and Tech-
nology are greatly appreciated. This work was also sponsored by the
Shanghai Pujiang Program (07pj14039), Shanghai Shuguang Program
(07SG27) and the Shanghai Leading Academic Discipline Project
(B409).
Experimental Section
Keywords: alkenes · allenes · heterocycles · nucleophilic
addition · regioselectivity
Synthesis of 1,2-allene 3aa (Table 1, entry 5): Solid KOH (0.05 mmol,
3 mg) was added in one portion to a solution of dimethyl malonate (2a;
1.0 mmol, 132 mg) and methyl 2-benzylidene-4-phenylbut-3-ynoate (1a;
0.5 mmol, 131 mg) in THF (2 mL) at 08C. The reaction mixture was then
stirred until the enyne 1a had been consumed, as determined by TLC
analysis. H2O (5 mL) was added to quench the reaction and the mixture
was extracted by diethyl ether (3”10 mL). The combined organic layer
was dried over MgSO4. After filtration and concentration, the residue
was purified by column chromatography on silica gel (hexanes/ethyl ace-
tate 2:1) to give 3aa (d.r.=1.7:1.0) in 91% yield.
First fraction: Solid; 1H NMR (500 MHz, CDCl3): d=7.39–7.30 (m, 10H),
6.83 (d, J=1.0 Hz, 1H), 4.74 (dd, J=12.0, 1.0 Hz, 1H), 3.97 (d, J=
12.0 Hz, 1H), 3.71 (s, 3H), 3.40 (s, 3H), 3.39 ppm (s, 3H); 13C NMR
(125.8 MHz, CDCl3): d=165.50, 210.67, 167.70, 167.68, 138.70, 131.37,
128.80, 128.46, 128.38, 128.28, 127.70, 127.52, 106.78, 101.68, 55.60, 53.41,
52.36, 52.32, 44.29 ppm; MS (70 eV): m/z (%): 394 (1.98) [M]+, 105 (100)
[C6H5CO]+; HRMS: m/z: calcd for C23H22O6: 394.1416; found: 394.1416.
Second fraction: Colorless oil; 1H NMR (500 MHz, CDCl3): d=6.78 (d,
J=2.0 Hz, 1H), 7.25–7.38 (m, 10H); 4.74 (dd, J=12.0, 2.0 Hz, 1H), 4.04
(d, J=12.0 Hz, 1H), 3.82 (s, 3H), 3.71 (s, 3H), 3.43 ppm (s, 3H);
13C NMR (125.8 MHz, CDCl3): d=210.81, 167.82, 167.46, 165.43, 138.77,
131.39, 128.82, 128.36, 128.33, 128.28, 127.50, 127.39, 106.66, 101.51, 55.66,
52.68, 52.31, 52.24, 44.23 ppm; MS (70 eV): m/z (%): 394 (2.09) [M]+,
105 (100) [C6H5CO]+; HRMS m/z: calcd for C23H22O6: 394.1416; found:
394.1416.
[1] Comprehensive Organic Synthesis, Vol. 4 (Eds.: B. M. Trost, I. Flem-
ing, L. A. Paquette), Pergamon, Oxford, 1991, Chapters 1.1–1.6,
pp. 1–268.
[2] a) B. M. Trost, Science 1991, 254, 1471; b) B. M. Trost, Angew.
Chem. 1995, 107, 285; Angew. Chem. Int. Ed. Engl. 1995, 34, 259.
[3] a) T. Yao, X. Zhang, R. C. Larock, J. Am. Chem. Soc. 2004, 126,
11164; b) T. Yao, X. Zhang, R. C. Larock, J. Org. Chem. 2005, 70,
7679; c) Y. H. Liu, S. Zhou, Org. Lett. 2005, 7, 4609; d) N. T. Patil,
H. Wu, Y. Yamamoto, J. Org. Chem. 2005, 70, 4531.
[4] Y. Xiao, J. Zhang, Angew. Chem. 2008, 120, 1929; Angew. Chem. Int.
Ed. 2008, 47, 1903.
[5] J. Zhang, H. G. Schmalz, Angew. Chem. 2006, 118, 6856; Angew.
Chem. Int. Ed. 2006, 45, 6704.
[6] 1,2-Allenes are useful building blocks in organic synthesis, see:
a) Modern Allene Chemistry, Vols. 1–2 (Eds.: N. Krause, A. S. K.
Hashmi),Wiley-VCH, Weinheim, 2004; b) S. Ma, Chem. Rev. 2005,
105, 2829; c) S. Ma, Aldrichimica Acta 2007, 40, 91; for a very recent
review on the synthesis of allenes, see: d) K. M. Brummond, J. E.
DeForrest, Synthesis 2007, 795.
[7] 1,3-Dienes are useful building blocks for cycloaddition reactions, es-
pecially Diels–Alder reactions, see: a) F. Fringuelli, A. Taticchi,
Dienes in the Diels–Alder Reaction; Wiley: New York, 1990; b) W.
Oppolzer in Comprehensive Organic Synthesis, Vol. 5 (Eds.: B. M
Trost, I. Fleming), Pergamon Press, Oxford, UK, 1991, Chapter 4.1,
pp. 315–400; c) W. R. Roush in Comprehensive Organic Synthesis
(Eds.: B. M Trost, I. Fleming), Pergamon Press, Oxford, UK, 1991,
Vol. 5, Chapter 4.4, pp. 513–550.
Synthesis of 1,3-diene (2Z,3E)-4ad [Eq. (1)]: Solid K2CO3 (0.05 mmol,
6.9 mg) was added to a solution of 4-methylthiophenol 2d (0.75 mmol,
93.1 mg) and 1a (0.5 mmol, 131.0 mg) in THF (2 mL) at RT. The reaction
mixture was then stirred until the enyne 1a had been consumed, as deter-
mined by TLC analysis. After the routine workup, the crude product was
purified by column chromatography on silica gel to give (2Z,3E)-4ad
8484
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 8481 – 8485

Efficient Assembly of Allenes, 1,3-Dienes, and 4H-Pyrans
COMMUNICATION
[8] 4H-Pyrans are bioactive compounds, see: K. Urbahns, E. Horvµth,
J.-P. Stasch, F. Mauler, Bioorg. Med. Chem. Lett. 2003, 13, 2637, and
references therein.
0.0289, wR2=0.0789; a=14.66600(10), b=15.82580(10), c=
11.1284(2) Š; a=90, b=95.751(2), g=908; V=2037.11(4) Š3; T=
296(2) K; Z=4; reflections collected/unique=21969/3345 (Rint
=
[9] Regioselectivity control is an important issue in organic synthesis,
for recent reviews, see: a) J.-J. Brunet, R. Poli, Chemtracts 2004, 17,
381; b) M. Beller, J. Seayad, A. Tillack, H. Jiao, Angew. Chem. 2004,
116, 3448; Angew. Chem. Int. Ed. 2004, 43, 3368; c) M. Schlosser, F.
Mongin, Chem. Rev. Soc. 2007, 36, 1161; d) M. T. Reetz, Angew.
Chem. 2008, 120, 2592; Angew. Chem. Int. Ed. 2008, 47, 2556; e) for
selected recent examples, see: Y. Yamamoto, N. Momiyama, H. Ya-
mamoto, J. Am. Chem. Soc. 2004, 126, 5962; f) K. M. Miller, T. F. Ja-
mison, J. Am. Chem. Soc. 2004, 126, 15342; g) S. Ma, L. Lu, J.
Zhang, J. Am. Chem. Soc. 2004, 126, 9645; h) S. Kamijo, C. Kanaza-
wa, Y. Yamamoto, J. Am. Chem. Soc. 2005, 127, 9260; i) N. P. Grim-
ster, C. Gauntlett, C. R. A. Godfrey, M. J. Gaunt, Angew. Chem.
2005, 117, 3185; Angew. Chem. Int. Ed. 2005, 44, 3125; j) V. I. Timo-
khin, S. S. Stahl, J. Am. Chem. Soc. 2005, 127, 17888; k) S. Chaudhu-
ry, W. A. Donaldson, J. Am. Chem. Soc. 2006, 128, 5984; l) E. M.
Beck, N. P. Grimster, R. Hatley, M. J. Gaunt, J. Am. Chem. Soc.
2006, 128, 2528; m) R. Shintani, W.-L. Duan, T. Hayashi, J. Am.
Chem. Soc. 2006, 128, 5268; n) S. Brandau, E. Maerten, K. A. Jør-
gensen, J. Am. Chem. Soc. 2006, 128, 14986; o) L.-C. Campeau, M.
Bertrand-Laperle, J.-P. Leclerc, E. Villemure, S. Gorelsky, K.
Fagnou, J. Am. Chem. Soc. 2008, 130, 3276; p) for a review on the
regioselective addition of organocopper reagents to 1,3-conjugated
enynes with an acceptor group at the 1-position, see: N. Krause, An-
dreas Gerold, Angew. Chem. 1997, 109, 194; Angew. Chem. Int. Ed.
Engl. 1997, 36, 186.
0.0199); number of observations [I>2s(I)]=3248; parameters=244.
CCDC 664022 (3ea) and 684235 (3Z,4E)-4ed) contain the supple-
mentary crystallographic data for this paper. These data can be ob-
tained free of charge form The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
[12] For representative reviews on cascade or domino reaction see:
a) L. F. Tietze, Chem. Rev. 1996, 96, 115–136; b) L. F. Tietze, M. E.
Lieb, Curr. Opin. Chem. Biol. 1998, 2, 363; c) J. Rodriguez, Synlett
1999, 505; d) L. F. Tietze, G. Brasche, K. M. Gericke, Domino Reac-
tions in Organic Synthesis, Wiley-VCH, Weinheim, 2006; e) Multi-
component reactions often involve domino process, see: Multicom-
ponent Reactions (Eds.: J. Zhu, H. Bienaymꢁ), Wiley-VCH, Wein-
heim, 2005; f) for a very recent nice example in this journal, see: Y.
Coquerel, M.-H. Filippini, D. Bensa, J. Rodriguez, Chem. Eur. J.
2008, 14, 3078, and references therein.
[13] B. B. Snider, D. K. Spindell, J. Org. Chem. 1980, 45, 5017.
[14] For examples of the nucleophilic addition of heteroatom nucleo-
philes to electron-deficient 1,2-allenes, see: a) R. W. Spencer, T. F.
Tam, E. Thomas, V. J. Robinson, A. Krantz, J. Am. Chem. Soc. 1986,
108, 5589; b) T. Sugita, M. Eida, H. Ito, N. Komatsu, K. Abe, M.
Suama, J. Org. Chem. 1987, 52, 3789.
[15] Electron-deficient 1,3-enynes are easily prepared by the cross-cou-
pling reaction of a-bromo(iodo)-a,b-unsaturated esters or ketones
G
with terminal alkynes, see: a) R. Rossi, F. Bellina, C. Bechini, L.
Mannina, P. Verganmini, Tetrahedron 1998, 54, 135; b) W.-M. Dai, J.
Wu, K. C. Fong, M. Y. H. Lee, C. W. Lau, J. Org. Chem. 1999, 64,
5062; c) Y. Wang, D. J. Burton, Org. Lett. 2006, 8, 5295; d) refer-
ences [3–5]; for a recent review, see: e) H. Doucet, J.-C. Hierso,
Angew. Chem. 2007, 119, 850; Angew. Chem. Int. Ed. 2007, 46, 834.
[10] X-ray data for one stereoisomer of compound 3ea: C23H21O5; Mw =
377.40; monoclinic; space group=P2(1); MoKa; final R indices [I>
2s(I)], R1=0.0509, wR2=0.1144; a=13.0956(16), b=8.0263(10),
c=19.516 (2) Š; a=90, b=95.751(2), g=908; V=2040.9(4) Š3; T=
293(2) K; Z=4; reflections collected/unique=9959/3958 (Rint
=
0.0907); number of observations [I>2s(I)]=2081; parameters=265.
[11] X-ray data for compound (3Z,4E)-4ed: C25H22OS, Mw =370.49;
monoclinic; space group=Cc; MoKa; final R indices [I>2s(I)], R1=
Received: May 26, 2008
Published online: August 7, 2008
Chem. Eur. J. 2008, 14, 8481 – 8485
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8485