Iron(III)-catalyzed cyclization of alkynyl aldehyde acetals: Experimental and computational studies

Article abstract of DOI:10.1002/chem.201000686

FeCl₃·6H₂O-and FeBr₃-catalyzed Prins cyclization/halogenation of alkynyl aldehyde acetals has been realized with acetyl chloride or bromide as halogen source in dichloromethane to afford 2-(1-halobenzylidene or alkylidene)

Full text of DOI:10.1002/chem.201000686

DOI: 10.1002/chem.201000686
IronACHTUNGTRENNUNG
Tongyu Xu,[a] Qin Yang,[a] Dongpo Li,[b] Jinhua Dong,[b] Zhengkun Yu,*[a, c] and
Yuxue Li*[c]
Abstract: FeCl3·6H2O- and FeBr3-cata-
lyzed Prins cyclization/halogenation of
alkynyl aldehyde acetals has been real-
ized with acetyl chloride or bromide as
halogen source in dichloromethane to
afford 2-(1-halobenzylidene or alkyli-
efficiently synthesized by FeCl3·6H2O-
catalyzed intramolecular cyclization of
alkynyl aldehyde acetals in acetone
under mild conditions. An oxocarboni-
um species generated in situ is pro-
posed to initiate the reaction, and the
target products are formed via vinylo-
gous carbenium cation and oxete inter-
mediates according to DFT calcula-
tions. Intermolecular reactions of al-
kynes and aldehyde acetals were also
investigated
with
20–40 mol%
dene)-substituted
carbo- and heterocycles, and thus pro-
vides an alternative route for vinylic
five-membered
FeCl3·6H2O catalyst, and produced
a,b-unsaturated enones and chlorinat-
ed indene derivatives. The present pro-
tocol has applications in the synthesis
of carbo-, oxa- and azacycles.
Keywords: cyclization
·
enones
·
halogenation
methods
· iron · synthetic
À
À
C Cl and C Br bond formation. Five-
to eight-membered cyclic enones were
Introduction
promising environmentally benign alternative to traditional
transition metal catalysts.[8–11] In this respect, FeX3-promoted
cyclization of HO- and TsHN-functionalized alkynes with
aldehydes was used to prepare six-membered halogenated
heterocycles and 2-halovinyl ketones.[12] Recently, we found
that stoichiometric FeCl3 and FeBr3 can promote Prins cycli-
zation of alkynyl aldehyde acetals 1 at 08C to form five-
membered halobenzylidene or alkylidene-substituted carbo-
and heterocycles 2 via path a of Scheme 1.[7] With a view to
environmentally benign application of this method, a cata-
Coupling reactions of alkynes with carbonyl compounds
have been utilized to form carbon–carbon and carbon–heter-
oatom bonds.[1–3] As masked carbonyl compounds, acetals
usually act as building blocks in organic synthesis due to
easy deprotection of the acetal functionality.[4,5] Stoichiomet-
ric TiCl4-, SnCl4-, and Me3SiI-based intramolecular Prins
cyclization of alkynyl aldehyde acetals afforded cyclic halo-
vinyl products.[6,7] Recently, iron catalysis has emerged as a
[a] T. Y. Xu, Q. Yang, Prof. Dr. Z. K. Yu
Dalian Institute of Chemical Physics, Chinese Academy of Sciences
457 Zhongshan Road, Dalian 116023 (P. R. China)
Fax : (+86)411-8437-9227
E-mail: zkyu@dicp.ac.cn
liyuxue@mail.sioc.ac.cn
[b] D. P. Li, Prof. Dr. J. H. Dong
School of Pharmaceutical Engineering
Shenyang Pharmaceutical University
103 Wenhua Road, Shenyang, Liaoning 110016 (P. R. China)
[c] Prof. Dr. Z. K. Yu, Dr. Y. X. Li
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
354 Fenglin Road, Shanghai 200032 (P. R. China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201000686.
Scheme 1. FeX3-promoted cyclization of alkynyl acetals.
9264
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Chem. Eur. J. 2010, 16, 9264 – 9272

FULL PAPER
lytic procedure using FeX3 as catalyst and cheap and readily
available halogen sources (path a’) is desirable. Intrigued by
the structural feature of acetals 1, we reasonably envisioned
that formal intramolecular [2+2] cycloaddition of the alkyn-
yl and oxocarbonium moieties in intermediate A or nucleo-
philic attack of the ethoxyl oxygen atom at the vinyl carbe-
nium carbon atom in species B may generate oxete C, lead-
ing to cyclic enone 4 through an eliminative ring-opening
pathway (path b). Herein we report FeCl3·6H2O- and FeBr3-
catalyzed Prins cyclization/halogenation of alkynyl aldehyde
diethyl acetals 1 with acetyl chloride or bromide as halogen
source, FeCl3·6H2O-catalyzed cyclization of the same type
of acetals to cyclic enones, and mechanistic studies by DFT
calculations.
entry 7). At least 10 mol% excess of acetyl chloride was
necessary for the acetal substrate to reach 100% conversion
(Table 1, entries 7 and 9–11). The catalyst loading affected
the reaction rate and selectivity for the target product
(Table 1, entries 7, 12 and 13). In THF, the reaction became
complicated (Table 1, entry 14). Thus, the conditions for cat-
alytic Prins cyclization of 1a were optimized to 5 mol%
FeCl3·6H2O as catalyst, CH2Cl2 as solvent, 1.2 equiv
MeCOCl as halogen source, 2 h at ambient temperature
under nitrogen atmosphere.
Next, the present Prins cyclization method was extended
to a variety of alkynyl aldehyde diethyl acetals under the
optimal conditions (Table 2). With 5 mol% FeCl3·6H2O as
catalyst (Method A), the O-linked alkynyl acetals 1a–g un-
derwent the desired Prins cyclization/chlorination to afford
2a–g in 74–87% yields (Table 2, entries 1–7). Reactions of
TsN-linked alkynyl acetal substrates 1h–l produced the
target products 2h–l in 48–81% yield (Table 2, entries 8–
Results and Discussion
FeCl3·6H2O and FeBr3-catalyzed Prins cyclization/halogena-
tion of alkynyl aldehyde diethyl acetals 1: In our initial
study, we tried to carry out a non-metal-catalyzed reaction
of acetal 1a to prepare 2a in dichloromethane, and found
that the expected cyclization seldom occurred (Table 1,
entry 1), while the reaction proceeded well in the presence
of 1.0 equiv of FeCl3 (Table 1, entry 2).[7] On reducing the
loading of FeCl3 to a catalytic amount (e.g., 5 mol%) and
using acetyl chloride (1.2 equiv) as halogen source, the reac-
tion proceeded catalytically to form the target product 2a in
44–59% yields at 0–408C (Table 1, entries 3–5). As an alter-
native catalyst, the cheap, nontoxic, and readily available
FeCl3·6H2O was used in the same reaction and exhibited
better catalytic efficiency than FeCl3 (Table 1, entries 6–8),
affording 2a in 83% yield at room temperature (Table 1,
12), while treatment of CACTHNGUTER(NNUG COOR)2-linked alkynyl acetal 1m
only generated 2m in moderate yield (52%, Table 2,
entry 13) under the stated conditions. All results are compa-
rable with those obtained from the stoichiometric reactions
of 1 with anhydrous FeCl3.[7] However, treatment of 1a with
5 mol% FeBr3 and 1.2 equiv MeCOBr only led to an insepa-
rable mixture. Unexpectedly, with 5 mol% FeBr3 as catalyst
and an excess of acetyl bromide (2.2 equiv) as halogen
source (Method B), the reaction of 1a afforded a dibromide
product of type 3 (i.e., 3a) in 66% yield (Table 2, entry 1).
In most of the reactions carried out by Method B, dibro-
mides 3a, 3b, 3d, 3g–i, 3k, and 3l, were predominantly gen-
erated with formation of the E isomers, and the highest
yield of 89% was reached for 3g (Table 2, entry 7). With
benzoxyaryl alkyne acetal 1c as substrate, no identifiable
product could be isolated, presumably due to complicated
reactions involving the BnO moiety (Table 2, entry 3). In
three cases, the monobromide products of type 2 (i.e., 2e’,
2 f’ and 2j’) were formed as the major products (Table 2, en-
Table 1. Screening of conditions for Prins cyclization of 1a.[a]
tries 5, 6, and 10). However, the reaction of CACTHNURGTNEUNG(COOEt)2-
linked alkynyl acetal 1m produced cyclic enone 4m as the
isolated product (Table 2, entry 13), that is, a reaction occurs
via path b of Scheme 1.
Entry
Cat./mol%
MeCOCl
[equiv]
T
[8C]
t
Yield[b]
[%]
G
[h]
FeCl3·6H2O-catalyzed intramolecular cyclization of alkynyl
aldehyde diethyl acetals 1 to cyclic enones 4: Encouraged
by the result obtained in entry 13 of Table 2, reactions of 1
via path b were explored. The reaction of acetal 1a was ini-
tially carried out to screen the reaction conditions (Table 3).
Treatment of 1a with 10 mol% FeCl3 in CH2Cl2 at ambient
temperature afforded a 2-chlorovinyl oxacycle product of
type 2, namely 2a, in 19% yield [Table 3, entry 1 and
Eq. (1)],[7] and FeCl3·6H2O only showed low catalytic activi-
ty (Table 3, entry 2). However, in CH3NO2 solution 1a was
catalytically converted to the target product, cyclic enone
4a, in about 60% yield with 5 mol% FeCl3 or FeCl3·6H2O
as catalyst (Table 3, entries 3 and 4), whereas the failure of
same reaction to take place in solvents such as 1,2-dichloro-
ethane (DCE), CH3CN, 1,4-dioxane, THF, and EtOH dem-
1
2
3
4
5
6
7
8
1.2
RT
0
0
RT
40
0
10
0.5
3
3
0.8
5
2
0.3
2
2
2
<5
77[7]
48
59
44
54
83
48
65
71
81
77
63
FeCl3/100
FeCl3/5
FeCl3/5
FeCl3/5
FeCl3·6H2O/5
FeCl3·6H2O/5
FeCl3·6H2O/5
FeCl3·6H2O/5
FeCl3·6H2O/5
FeCl3·6H2O/5
FeCl3·6H2O/3
FeCl3·6H2O/10
FeCl3·6H2O/5
1.2
1.2
1.2
1.2
1.2
1.2
1.0
1.1
1.3
1.2
1.2
1.2[c]
RT
40
9
RT
RT
RT
RT
RT
RT
10
11
12
13
14
6
0.7
1
[d]
–
[a] Conditions: 1a, 0.50 mmol; CH2Cl2, 5 mL; under N2 atmosphere.
[b] Yields of isolated products. [c] THF (5 mL) as the solvent. [d] Compli-
cated reaction.
Chem. Eur. J. 2010, 16, 9264 – 9272
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Z. Yu, Y. Li et al.
Table 2. FeCl3·6H2O and FeBr3-catalyzed cyclization of 1.[a]
onstrates a remarkable solvent
effect. Furthermore, the cycliza-
tion of 1a proceeded more effi-
ciently in acetone at ambient
temperature to give 4a in 88–
93% yields, although the reac-
tion hardly occurred at 08C
(Table 3, entries 5–8). In all
cases, FeCl3·6H2O exhibited
higher catalytic activity than an-
hydrous FeCl3, presumably due
to extra stabilization of the
metal center by the water mole-
cules of crystallization in
FeCl3·6H2O and water present
in acetone. Unexpectedly, 1a
also efficiently underwent cycli-
zation in acetone in air to form
4a in 93% yield at ambient
temperature or 508C (Table 3,
entries 9 and 10). Trifluoroace-
tic acid (TFA) and hydrochloric
acid promoted the reaction less
efficiently (Table 3, entries 11
Entry
1
Acetal
Yield[b] [%]
Method A
Method B
(83)
(86)
(66, E/Z=10/1)[d]
2
(76, E/Z=2.5/1)[d]
3
4
(80)
(76)
(–)[c]
(69, E/Z=4/1)[d]
(49)
(15)
(54)
(89)
(66)
(72)
and 12), and PtCl2, [Pt
(cod=1,5-cyclooctadiene),
PdCl2, [Rh(cod)2]BF4, CuCl,
and [Au(PPh3)Cl]/AgBF4 did
ACHTUNGTRENNUNG(cod)Cl2]
5
(74)
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
not initiate the same reaction
under the stated conditions.
However, the presence of
5 mol% CuCl2·2H2O led to de-
composition of 1a to its parent
aldehyde 1ac. For comparison,
the reactions of alkynyl dimeth-
yl and dimethylene acetals 1aa
and 1ab and their parent alde-
hyde 1ac were investigated
under the optimized conditions
to form 4a in 68–90% yields at
508C over a period of 2–14 h,
that is, diethyl acetal 1a is more
reactive than its analogues 1aa–
ac, and 1a can undergo more
efficient transformation to form
the target product 4a [Eq. (2)].
The stronger electron-donating
ability of the ethyl group is con-
sidered to stabilize intermediate
C in Scheme 1 and favor forma-
tion of 4a.
6
7
8
9
(80)
(87)
(48)
(81)
10
11
(65)
(66)
(54)
(26, E/Z=5/1)[d]
(38, E/Z=7/1)[d]
Under the optimized condi-
tions as shown for entries 9 and
10 in Table 3, the scope of the
protocol
(Table 4).
was
With
explored
5 mol%
FeCl3·6H2O as catalyst in ace-
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Chem. Eur. J. 2010, 16, 9264 – 9272

Cyclization of Alkynyl Aldehyde Acetals
Table 2. (Continued)
FULL PAPER
alkynyl acetal 1u was converted
to bicyclic enone 4q in 70%
yield. It is noteworthy that sub-
stituents such as OH, OMe,
OBn, MeCO, Cl, alkenyl, and
alkynyl in acetals 1 can tolerate
the reaction conditions. Under
RhI catalysis, enones 4a and 4i
easily underwent 1,4-Michael
addition with aryl boronic acid
5 [Eq. (3); BINAP=2,2’-bis(di-
phenylphosphino)-1,1’-bi-
Entry
Acetal
Yield[b] [%]
Method A
Method B
12
(81)
(52)
(28)
13
(28)
[a] Conditions: 1, 0.50 mmol; CH2Cl2, 5 mL; RT, 2–5 h; under N2 atmosphere. Method A: FeCl3·6H2O,
5 mol%; MeCOCl, 0.60 mmol. Method B: FeBr3, 5 mol%; MeCOBr, 1.1 mmol; 0.5 h. [b] Yields of isolated
products. [c] Complicated reaction. [d] The E/Z ratios were determined by H NMR spectroscopy.
naphthyl], while Pd-catalyzed
Suzuki coupling occurred be-
1
tween 4i and
5
[Eq. (4);
XPhos=2-dicyclohexylphosphino-2’,4’,6’-triisopropylbiphen-
yl], which suggests potential applications of cyclic enones 4
in organic synthesis.[13]
Table 3. Screening of conditions for the conversion of 1a to cyclic enone
4a.[a]
The synthetic methodology was then applied for the syn-
thesis of six- to eight-membered cyclic enones by extending
the linker chain in the acetal substrates (Table 5). Reactions
of the less reactive alkynyl acetals were carried out in DCE
at 808C. Thus, in a fashion similar to the synthesis of five-
membered cyclic enones, six-membered cyclic enones 4r–u
were obtained in 85–98% yield from their corresponding al-
kynyl aldehyde acetals 1v–y (Table 5, entries 1–4). The
seven-membered cyclic enones 4v–x were prepared in 33–
65% yields (Table 5, entries 5–7). The rare eight-membered
cyclic enone 4y was only obtained in 23% yield (Table 5,
entry 8), while the reactions of the O- and C-linked acetals
did not produce the desired eight-membered cyclic enone
products.
Entry
Cat./mol%
Solvent
T [oC]
t [h]
Yield[b] [%]
1
2
3
4
5
6
7
8
FeCl3/10
FeCl3·6H2O/10
FeCl3/5
FeCl3·6H2O/5
FeCl3/5
FeCl3·6H2O/5
FeCl3·6H2O/1
FeCl3·6H2O/5
FeCl3·6H2O/5
FeCl3·6H2O/5
TFA/500
CH2Cl2
CH2Cl2
CH3NO2
CH3NO2
acetone
acetone
acetone
acetone
acetone
acetone
CH2Cl2
H2O
RT
RT
RT
RT
RT
RT
RT
0
RT
50
reflux
50
0.5
24
1
1
2
2
6
5
2
19[c]
trace
60
62
88
93
89
trace
93
93
9[d]
10[d]
11
12
0.2
60
2
72
44
37% HCl/700
[a] Conditions: 1a, 0.50 mmol; solvent, 5 mL; under N2 atmosphere.
[b] Yields of isolated products. [c] The product was 2a [see Eq. (1)].
[d] Under air.
FeCl3·6H2O-catalyzed intermolecular reactions of alkynes 8
and acetals 9: Our synthetic method was also applied to
FeCl3·6H2O-catalyzed intermolecular reactions of alkynes 8
and acetals 9 (Table 6). Lewis acid (GaCl3) catalyzed reac-
tion of alkyne 8a and 3-fluorobenzaldehyde is known to
produce an a,b-unsaturated ketone of type 10 (18%) as
major product and a compound of type 11 (6%) as minor
product.[2h] The strongly acidic ion-exchange resin Amber-
tone under air, the O-linked alkynyl acetals underwent effi-
cient intramolecular cyclization to form five-membered
cyclic enones 4a–j in 84–99% yields (Table 4, entries 1–10).
The TsN-linked acetals showed much lower reactivity, pro-
ducing cyclic enones 4k and 4l in 45–87% yields at higher
catalyst loading (20 mol%). With CACTHNURGTNEUNG(COOR)2- or CH2-
linked acetals as substrates, target products 4m–p were also
efficiently obtained in 85–99% yield, and HO-functionalized
lyst-15 and YbACHTNGUTERNNU(G OTf)3 promoted the reactions of alkynes
Chem. Eur. J. 2010, 16, 9264 – 9272
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Z. Yu, Y. Li et al.
Table 4. Synthesis of five-membered cyclic enones 4a–q.[a]
Entry Acetal
T
t
Product
Entry Acetal
T
t
Product
[oC] [h]
(Yield[b] [%])
[oC] [h]
(Yield[b] [%])
1
RT
2
(93)
10
50
5
(89)
2
3
RT 0.5
RT 0.5
(94)
(94)
11
12
50
50
1.5[c]
(87)
(45)
24[c]
4
5
RT 0.5
RT 0.5
(92)
(99)
13
14
50
50
0.2
0.2
(99)
(95)
6
7
50
50
4
(92)
(84)
15
16
50
50
1.5
(85)
(98)
0.5
0.2[d]
8
9
50
50
0.2
0.5
(97)
(99)
17
RT 0.1
(70)
[a] Conditions: 1, 0.50 mmol; FeCl3·6H2O, 5 mol%; acetone, 5 mL. [b] Yields of isolated products. [c] 20 mol% FeCl3·6H2O, 1.5–24 h. [d] 10 mol%
FeCl3·6H2O, 0.2 h.
with benzaldehydes to form products 10 more efficien-
tly.[2g,3d] In our case, by using 20 mol% FeCl3·6H2O in DCE
at 808C, 8a reacted with benzaldehyde diethyl acetal 9a to
afford the desired product 10a (56%) with minor formation
of 11a (24%; Table 6, entry 1), whereas the reaction of 8a
and benzaldehyde (9a’) formed 10a and 11a in much lower
yields (Table 6, entry 2), that is the aldehyde is less reactive
than its diethyl acetal. However, in the presence of ethanol
the same reaction of 8a and 9a’ generated 10a (50%) and
11a (23%) more efficiently (Table 6, entry 3), which sug-
gests that ethanol facilitates the reaction due to formation
of the more reactive acetal species 9a from 9a’ in situ. In-
creasing the catalyst loading to 40 mol% in toluene at
1008C reversed the product selectivities, so that the reac-
tions of 8a with 9a–c afforded 11a–c (55–67%) as the
major products, while the reactions in DCE under the same
conditions gave 11a–c as the minor products (Table 6, en-
tries 4–8), that is, a remarkable solvent effect is active here,
too. With aliphatic aldehyde acetals, terminal alkyne, and di-
alkyl alkyne as substrates, the reactions only produced
enone products of type 10 (Table 6, entries 9–13). Efficient
Suzuki coupling between 11a and 5 to form 12 in 91% yield
[Eq. (5); SPhos=2-dicyclohexylphosphino-2’,6’-dimethoxybi-
phenyl] demonstrates potential application of products 11.
Intramolecular cyclization of 1 catalyzed by FeCl3·6H2O
and FeBr3 is proposed to proceed as shown in Scheme 1. A
similar mechanism is proposed for the intermolecular reac-
tions of alkynes with acetals to form enones 10 as well as 11
9268
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Cyclization of Alkynyl Aldehyde Acetals
FULL PAPER
Table 5. Synthesis of six- to eight-membered cyclic enones 4r–y.[a]
the carbonium carbon at an aromatic CH group in tautomer
H of species G forms intermediate I, followed by substitu-
Entry
Acetal
Method t [h]
Yield[b] [%]
tion with FeCl3ACTHNUTRGNEUNG(OEt) anion to produce 11. We suggest that
water acts as a ligand to stabilize the catalyst during the re-
action.
1
A
A
0.3
0.3
(85)
(98)
Computational studies on the reaction mechanism: To un-
derstand the reaction mechanism better, DFT[14] studies
were performed with the Gaussian 03 program suite[15] by
using the B3LYP method and the 6-311+G** basis set.[16]
The optimized structures were all checked with harmonic vi-
bration frequency calculations, and the atomic charges were
calculated by NBO analysis.[17] The calculated reaction path-
ways and optimized structures are shown in Scheme 3 and
Figure 1, respectively. As shown in Scheme 3, the nucleo-
philic attack of C4 at C1 in oxocarbonium cation I leads to
vinyl cation II over a small barrier of 3.8 kcalmolÀ1. The
possible [2+2] transition state between I and IV was safely
excluded by a two-dimensional relaxed potential-energy sur-
face (PES) scan. A relaxed PES scan along C1–C5 of inter-
mediate I suggests that species III resulting from attack of
C5 at C1 does not exist (see Supporting Information for de-
tails). This is consistent with the charge distributions shown
in Figure 1. It is not the positively charged C5 (+0.105) but
the negatively charged C4 (À0.111) that nucleophilically at-
tacks the positively charged C1 (+0.484). Thus, nucleophilic
attack of the methoxyl oxygen atom at the carbenium
carbon atom in II forms oxete IV. Ring opening of the four-
membered oxacycle in IV via transition state Ts-3 over a
very small barrier of 1.6 kcalmolÀ1 yields intermediate V,
which is much more stable (40.5 kcalmolÀ1) than intermedi-
ate II. However, formation of V must overcome a barrier of
17.2 kcalmolÀ1 from II to transition state Ts-2. Therefore,
formation of V is difficult at lower temperature and thus II
is easily trapped by high concentrations of chloride anion to
form product P1. At higher temperature and with low con-
centration of chloride anion, thermodynamically stable V is
formed to produce product P2. Intermediate II acts as a
branching point in this reaction. Product P1 can be regarded
as the product under kinetic control, whereas P2 is the prod-
uct under thermodynamic control. In our previous study,[7]
reactions of 1 with stoichiometric FeCl3 afforded products of
type P1 at 08C, and in the presence of halogen sources such
as MeCOX (X=Cl, Br) and FeX3 as catalysts reactions of 1
also produced products P1. However, FeCl3·6H2O-catalyzed
cyclization of 1 efficiently produced products of type P2 at
between room temperature and 808C in the absence of hal-
ogen sources. The present theoretical studies are very con-
sistent with our observations and revealed the two reaction
pathways shown in Scheme 1.
2
3
A
A
0.2
0.2
(98)
(96)
4
5
6
7
8
B
B
B
B
2
(33)
(51)
(65)
(23)
1.5
2
30
[a] Conditions: 1, 0.50 mmol; in air. Method A: acetone, 5 mL; 5 mol%
FeCl3·6H2O; 508C. Method B: DCE, 2 mL; 20 mol% FeCl3·6H2O; 808C.
[b] Yields of isolated products.
(Scheme 2). Oxocarbonium cation D is initially generated
by interaction of the catalyst with the acetal substrate. Spe-
cies D is cyclized with the alkyne to form oxete E, which is
then transformed into enone 10 via intermediate F. When
an aryl alkyne is used, intramolecular nucleophilic attack of
Conclusion
FeCl3·6H2O- and FeBr3-catalyzed Prins cyclization/halogen-
ation of alkynyl aldehyde acetals has been efficiently realiz-
ed with acetyl chloride or bromide as the halogen source to
Scheme 2. Proposed mechanism for the intermolecular reactions of al-
kynes 8 with acetals 9.
Chem. Eur. J. 2010, 16, 9264 – 9272
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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9269

Z. Yu, Y. Li et al.
Table 6. FeCl3·6H2O-catalyzed intermolecular reactions of alkynes 8 with acetals 9.[a]
odology has demonstrated its
potential applications in the ef-
ficient synthesis of carbo-, oxa-
and azacyclic compounds.
Entry
1
Substrates
Method/t [h]
Yield[b] [%]
10
11
Experimental Section
ꢀ
PhC CMe (8a)
PhCH
N
A/4
General considerations: All manipula-
tions of air- and/or moisture-sensitive
compounds were carried out under ni-
trogen atmosphere by standard
Schlenk techniques. Reaction solvents
were dried and distilled prior to use by
literature methods. 1H and 13C{1H}
10a (56)
10a (35)
10a (50)
10a (27)
11a (24)
11a (18)
11a (23)
11a (60)
2
8a
8a
8a
PhCHO (9a’)
9a’
9a
A/24
A/12
B/3
3[c]
4
NMR spectra were recorded on
a
Bruker DRX-400 spectrometer, and
all chemical shift values refer to
dTMS =0.00 ppm or CDCl3 (d(1H)=
5
8a
A/6
7.26, d
performed on
(13C)=77.16 ppm). HRMS was
ACHTUNGTRENNUNG
a
Waters GC-TOF
10b (60)
10b (28)
11b (27)
11b (55)
CA156 mass spectrometer. All melting
points are uncorrected. Analytical
TLC plates (Sigma-Aldrich silica gel
6
7
8a
8a
9b
B/3
60F200
) were viewed by UV light
(254 nm). Chromatographic purifica-
tions were performed on SDZF silica
gel 160. FeCl3·6H2O was purchased
from Alfa Aesar Co. Known products
were identified by comparison of their
NMR features with the reported data
of the authentic samples.
A/10
10c (55)
10c (27)
11c (23)
11c (67)
8
9
8a
8a
9c
B/6
A/2
Typical procedure for FeCl3·6H2O and
FeBr3-catalyzed Prins cyclization/halo-
genation of alkynyl aldehyde acetals 1
(synthesis of 2 and 3): Compound 1
(0.5 mmol) and CH3COCl (47 mg,
0.6 mmol) were added to a suspension
of FeCl3·6H2O (6.8 mg, 5 mol%) in
CH2Cl2 (5 mL). The mixture was
stirred at ambient temperature and
monitored by TLC analysis on silica
gel. When the starting acetal substrate
was completely consumed, the resul-
tant mixture was concentrated under
reduced pressure. The resulting resi-
due was purified by flash column chro-
matography on silica gel (eluent: pe-
troleum ether (60–908C)/diethyl ether
20/1) to afford the target product 2.
(67)
10
11
12
8a
A/8
A/2
A/1
(42)
(72)
(47)
ꢀ
PhC CH (8b)
9a
9d
8b
ꢀ
13
nPrC CnPr (8c)
9d
A/24
(23)
[a] Conditions: alkyne 8, 1.0 mmol; 9, 1.2 mmol; in air. Method A: 20 mol% FeCl3·6H2O, 4 mL DCE, 808C.
Method B: 40 mol% FeCl3·6H2O, 4 mL toluene, 1008C. [b] Yields of isolated products. [c] EtOH (1.0 mmol)
was added.
Typical procedure for the synthesis of
cyclic enones 4: FeCl3·6H2O (6.8 mg,
5 mol%) was added to a solution of 1
(0.5 mmol) in acetone (5 mL) in air.
The mixture was stirred at room tem-
afford (E)-2-(1-halobenzylidene or alkylidene)-substituted
five-membered carbo- and heterocycles and thus provide an
perature, and monitored by TLC analysis on silica gel. When 1 was com-
pletely consumed (0.5 h), all volatile substances were evaporated from
the resultant mixture under reduced pressure. The resulting residue was
purified by flash column chromatography on silica gel (eluent: petroleum
ether (60–908C)/diethyl ether 10/1) to afford the target enone product 4.
4e: white solid, 99% yield; m.p. 62–638C; 1H NMR (400 MHz, CDCl3,
258C): d=7.39 and 7.20 (each s, 2:1H, aromatic CH), 6.60 (t, 1H, CH),
4.99 and 4.92 (each m, 2:2H, OCH2), 2.37 ppm (s, 6H, CH3); 13C{1H}
NMR (100 MHz, CDCl3, 258C): d=191.3 (Cq, C=O), 140.2 (Cq), 139.2
(CH), 138.3 and 138.2 (Cq), 134.4 and 126.6 (aromatic CH), 76.8 and 75.4
(OCH2), 21.4 ppm (CH3); HRMS calcd for C12H11O2 [MÀCH3]+:
187.0759; found: 187.0767.
À
À
alternative route for vinylic C Cl and C Br bond forma-
tion. An efficient protocol for the synthesis of five- to eight-
membered cyclic enones has been developed by means of
FeCl3·6H2O-catalyzed intramolecular cyclization of alkynyl
aldehyde acetals under mild conditions. An oxocarbenium
species generated in situ is proposed to initiate the reaction,
and the cyclic enone product is formed via an oxete inter-
mediate according to DFT calculations. The present meth-
9270
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Chem. Eur. J. 2010, 16, 9264 – 9272

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Received: March 18, 2010
Published online: June 25, 2010
9272
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ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 9264 – 9272