Titanium tetraiodide-promoted tandem prins reaction of alkynes with acetals: Synthesis of (Z,Z)-1,5-Diiodo-1,3,5-triarylpenta-1,4-dienes

Article abstract of DOI:10.1246/cl.2010.1052

In the presence of titanium tetraiodide, a tandem Prins reaction of alkynes proceeded with acetals to give (Z,Z)-1,5diiodo-1,3,5-triarylpenta-1,4-dienes in good yields, where an intriguing reversal of the stereoselectivity was observed among titanium tetr

Full text of DOI:10.1246/cl.2010.1052

doi:10.1246/cl.2010.1052
1052
Published on the web August 21, 2010
Titanium Tetraiodide-promoted Tandem Prins Reaction of Alkynes with Acetals:
Synthesis of (Z,Z)-1,5-Diiodo-1,3,5-triarylpenta-1,4-dienes
Makoto Shimizu,* Kanako Okura, Takuya Arai, and Iwao Hachiya
Department of Chemistry for Materials, Graduate School of Engineering, Mie University, Tsu, Mie 514-8507
(Received July 12, 2010; CL-100626; E-mail: mshimizu@chem.mie-u.ac.jp)
In the presence of titanium tetraiodide, a tandem Prins
reaction of alkynes proceeded with acetals to give (Z,Z)-1,5-
diiodo-1,3,5-triarylpenta-1,4-dienes in good yields, where an
intriguing reversal of the stereoselectivity was observed among
titanium tetrahalides.
Table 1. Prins reaction of phenylacetylene with benzaldehyde
dimethylacetal: comparison of reaction conditionsa
I
Ph
I
Ph
Ph
(Z,Z)-2
(2.0 equiv)
Ph
OMe
OMe
TiI4 (1.0 equiv)
OMe
+
Solvent
Temp 1, Time 1
Solvent
Ph
Ph
I
Ph Ph
Temp 2, Time 2
1
Ph
I
Although the Prins reaction of alkenes with carbonyl
compounds provides important C-C bond formations in a regio-
and stereoselective manner, its alkyne analogs have not always
been carried out readily.1 This is due in part to further reactions
of the resulting alkenes. We have recently described useful
reactions using titanium tetraiodide, where the ability of titanium
tetraiodide to iodinate and reduce organic molecules is respon-
sible for the success of facile transformations.2
In an effort to utilize more effectively the iodination ability
of titanium tetraiodide, we have already found the hydro-
iodination reaction of alkenes and alkynes with titanium
tetraiodides.3 The Aza-Prins reaction also proceeded using the
p-tosylimine derived from ethyl glyoxylate.4 This paper de-
scribes an intriguing tandem Prins reaction of alkynes promoted
by titanium tetraiodide to give stereoselectively (Z,Z)-1,5-
diiodo-1,3,5-triarylpenta-1,4-dienes (eq 1).
(Z,E)-2
Temp 1 Time 1 Temp 2 Time 2 Yieldb
Ratioc
/% (Z,Z):(Z,E)
Entry Solvent
/°C
/min
/°C
/h
1
2
3
4
5
6
7
EtCN
THF
PhMe
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
rt
rt
rt
rt
rt
rt
0
5
5
5
5
30
5
5
5
5
0
0
0
0
0
6
6
6
6
6
6
6
6
18
trace
1
4
60
32
58
56
61
59
®
100:0
23:77
86:14
78:22
84:16
65:35
86:14
83:17
0 to rt
0 to rt
0 to rt
0 to rt
8d CH2Cl2
9d CH2Cl2
rt
rt
aThe reaction was carried out according to the typical
procedure (ref. 6).9 bIsolated yield. Determined by H NMR.
dAlkyne was added at 0 °C and then the reaction was carried
out at rt in the dark.
c
1
1) TiI4 (1.0 equiv)
CH2Cl2, rt, 5 min
I
Ar1
I
Table 2. Prins reaction of phenylacetylene with benzaldehyde
dimethylacetal: comparison of amounts of titanium tetraiodide
and alkynea
OMe
Ar2
Ar2
ð1Þ
Ar1 OMe
Ar2
(3.0 equiv)
2)
(Z,Z)
CH2Cl2, 0 °C to rt, 6 h
I
Ph
I
In 2002 Kabalka and co-workers reported an important Prins
reaction of alkynes with aldehydes in the presence of titanium
tetrachloride or tetrabromide to give the corresponding 1,5-
dihalo-1,4-dienes with high (Z,E)-stereoselectivity.5 We carried
out similar reactions using acetals and titanium tetraiodide, and
found that the reaction gave 1,5-diiodopenta-1,4-dienes with
good (Z,Z)-selectivity, which contrasts to the results using
titanium chloride or bromide. Results are summarized in Table 1.
Among the solvents screened, dichloromethane gave the
desired Prins adduct in good yields. The best result was obtained
when the reaction was carried out first mixing the acetal with
titanium tetraiodide in dichloromethane at rt for 5 min, and then
treatment of the whole mixture with alkyne at 0 °C to rt for
6 h to give the adduct 2 in 61% yield with a ratio of
(Z,Z):(Z,E) = 86:14 (Entry 8). In order to improve the diaster-
eoselectivity, we carried out a series of reactions in the presence
of additives. Addition of bases (Na2CO3 and K2CO3), silver salts
(AgOTf and AgBF4), alkene (2-methyl-2-butene), and iodine did
not noticeably improve the yield and diastereoselectivity. We
then examined the ratios of reagents, and Table 2 summarizes
the results.
Ph
Ph
OMe
OMe
(equiv)
CH2Cl2, 0 °C to rt, 6 h
(Z,Z)-2
+
Ph
TiI4 (equiv)
CH2Cl2, rt, 5 min
Ph
I
Ph Ph
1
Ph
I
(Z,E)-2
Ratioc
Entry TiI4/equiv Alkyne/equiv Yieldb/%
(Z,Z):(Z,E)
1
2
3
4
5
6
7
1.0
1.0
1.0
1.25
1.5
2.0
2.5
2.5
3.0
3.5
3.0
3.0
3.0
3.0
71
68
64
70
76
76
67
86:14
91:9
70:30
81:19
73:27
69:31
69:31
aThe reaction was carried out according to the typical
procedure (ref. 6).9 bIsolated yield. Determined by H NMR.
c
1
equiv of alkyne, the best diastereomer ratio of (Z,Z):(Z,E) =
91:9 was obtained (Entry 2). Under the best conditions a variety
of p-substituted benzaldehyde dimethylacetals were subjected to
the present Prins reaction, and Table 3 summarizes the results.
As shown, increasing the ratio of alkyne improved the
product yield, and when the reaction was carried out with 3
Chem. Lett. 2010, 39, 1052-1054
© 2010 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

1053
Table 3. Prins reaction of alkynes with acetalsa
X
X
Me
TiX4 (1.0 equiv)
CH2Cl2, rt, 8 h
+
Ph
Me
R
R
Ph
Me
(E)-4
32% 92: 8
Ph
OMe
3
(Z)-4
(3.0 equiv)
CH2Cl2, 0 °C to rt, 6 h
Ar
TiI4 (1.0 equiv)
+
OMe
TiBr4
TiI4
I
I
I
Ar
CH2Cl2, rt, 5 min
58% 85:15
R
Ar
Ar Ar
I
1
X
X
X
Ph
X
(Z,Z)-2
(Z,E)-2
OMe
(1.0 equiv)
Ph
TiX4 (1.0 equiv)
+
Yieldb/% Ratioc (Z,Z):(Z,E)
CH2Cl2, rt, 5 min CH2Cl2, -78 °C ~ rt, 18 h
OMe
Ph
Ph
Ph Ph
Entry
R
Ar
Ph
(Z)-5
(E)-5
TiCl4
TiBr4
20% 47:53
28% 50:50
1
1
2
3
4
5
6
7
Me
MeO Ph
Cl Ph
NO2 Ph
H
H
H
Ph
57
40
62
0
70
57
52
55:44
40:60
74:26
®
68:32
40:52
70:30
I
Ph
+
Ph Ph
I
(Z)-6
33% 95:5
(E)-6
TiI4
4-MeOC6H4
4-ClC6H4
4-BrC6H4
Scheme 1. Examination of stereochemistry.
aThe reaction was carried out according to the typical
Ph
X
(MeO)X2Ti
c
1
X
procedure (ref. 6).9 bIsolated yield. Determined by H NMR.
X3Ti
X
OMe
X
OMe
TiX4
OMe
OMe
TiX4
Ph
Ph
OMe
Ph OMe
Ph
Ph
1
Table 4. Prins reaction of alkynes with benzaldehyde dimeth-
ylacetal: comparison of TiX4
X
X
OMe X
(2)
Ph
Ph
X
Ph
X
X
Ph Ph
(2.0 equiv)
OMe
Ph
Ph
Ph
TiX4 (1.0 equiv)
CH2Cl2, rt, 5 min
+
(Z )-5
(Z )-7
Ph
Ph
Ph
X
CH2Cl2, 0 °C to rt, 6 h
Ph
OMe
(Z,Z)-2
(Z,E)-2
1
OMe
Ph
(MeO)TiX3
X
Entry
X
Yielda/%
Ratiob (Z,Z):(Z,E)
Ph
(MeO)TiX4
OMe
OMe Ph
X
Ph
X
1
2
3
F
0
67
68
1
®
4:96
11:89
Ph
(3)
Ph
X
Ph
(MeO)TiX3
Ph
Cl
Br
b
X
OMe
(E )-7
(E )-5
A
Ph
Ph
X
aIsolated yield. Determined by H NMR.
X
TiX2(OMe)
Ph
Regarding the acetals, electron-donating substituents de-
creased the diastereomer ratios, whereas chlorophenyl derivative
recorded a slightly decreased diastereomer ratio (Entries 1 to 3).
Among the alkynes studied here, an electron-donating methoxy
derivative gave the highest yield although the best diastereose-
lectivity was obtained with simple phenylacetylene (Entry 6).
We next examined the effects of the titanium halides. Table 4
summarizes the results.
OMe
X
X
Ph
X
X
TXi4
OMe X
Ph
Ph
(4)
Ph
Ph
Ph
Ph
Ph
(Z,Z )-2
(Z )-7
X
TiX2(OMe)
Ph
OMe Ph
Ph Ph
TiX4
OMe Ph
(5)
Ph
Ph
X
Ph
X
(E )-7
(Z,E )-2
Ph
X
Scheme 2. Plausible mechanism of the reaction.
Although the reaction did not proceed with titanium
tetrafluoride, reversal of the diastereoselectivity was observed
in the cases with titanium tetrabromide and tetrachloride. In
order to explain the stereoselectivity of the halotianation of
alkynes, we first carried out hydroiodination and hydrobromi-
nation of 1-phenylpropyne, and Scheme 1 summarizes the
results.
formation of titanates, titanium tetrachloride and tetrabromide
may be preferred to the iodide analog. Subsequent concerted
second Prins reactions give (Z,Z)-1,5-dihalo-1,3,5-triarylpenta-
1,4-diene with titanium tetraiodide (eq 4) and its (Z,E)-counter-
parts with chloro and bromo derivatives (eq 5).
Both titanium tetrabromide and tetraiodide gave (E)-1-halo-
1-phenylpropenes 4 as major products, indicating that the initial
halotitanation in the absence of methoxide species proceeded
in a syn-selective manner for both titanium halides. However,
the reaction of the acetal with one equivalent of alkyne gave
different results. While the reaction with titanium tetraiodide
was stereoselective, giving (Z)-iodoalkene 6,7 that with titanium
tetrabromide or tetrachloride gave an almost 1:1 mixtute of
the (Z)- and (E)-isomers 5. On the basis of these results the
following mechanisms are proposed (Scheme 2).
In conclusion we have found that a stereoselective tandem
Prins reaction proceeded with alkynes and acetals to give (Z,Z)-
1,5-diiodo-1,3,5-triarylpenta-1,4-dienes using titanium tetra-
iodide, whereas their (Z,E)-counterparts were obtained with
titanium tetrabromide or tetrachloride. The difference of the
diastereoselectivity may be explained by assuming either a
concerted cyclic mechanism or a separated ion pair model.
This work was supported by Grant-in-Aids for Scientific
Research (B) and on Innovative Areas from JSPS and MEXT.
A concerted mechanism might operate in the titanium
tetraiodide promoted reactions, leading to the stereoselective
formation of a (Z)-adduct 7 (eq 2), whereas formation of (E)-
adduct 7 is explained by assuming involvement of a titanate
species A which has a precedent in the tetrahydropyranyl ring-
like transition state with titanium tetrabromide (eq 3).8 For the
References and Notes
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© 2010 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

1054
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7
The compound 6 may be obtained by reduction of the allyl
iodide 5 with titanium tetraiodide.
5
6
G. W. Kabalka, Z. Wu, Y. Ju, Org. Lett. 2002, 4, 1491.
A typical procedure is as follows: To a suspension of TiI4
(Soekawa Chemical Co., used after sublimation, 111 mg,
0.20 mmol) in CH2Cl2 (1.0 mL) in a flask wrapped with
aluminum foil was added a solution of benzaldehyde
dimethylacetal (30.4 mg, 0.20 mmol) in CH2Cl2 (1.0 mL) at
rt. After stirring at rt for 5 min, the mixture was cooled to
0 °C and to it was added a solution of phenylacetylene
(61.3 mg, 0.60 mmol) in CH2Cl2 (1.0 mL). The mixture was
allowed to stand at rt for 6 h with stirring. The reaction was
quenched by the addition of sat. aq NaHCO3 and aq NaHSO3
I
I
I
I
H+
I3Ti
I
TiI4
I
Ph
Ph
Ph
Ph
Ph
Ph
6
5
8
9
L. J. Van Orden, B. D. Patterson, S. D. Rychnovsky, J. Org.
Chem. 2007, 72, 5784.
Supporting Information is available electronically on the
CSJ-Journal Web site, http://www.csj.jp/journals/chem-lett/
index.html.
Chem. Lett. 2010, 39, 1052-1054
© 2010 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/