Lewis acid catalyzed addition of pyrazoles to alkynes: Selective synthesis of double and single addition products

Article abstract of DOI:10.1002/ejoc.200800353

Silver and zinc salts were found to efficiently catalyze the addition of an N-H bond of pyrazoles to alkynes. With silver triflate as a catalyst, two pyrazoles regioselectively attacked the same carbon atom of the C≡C bond of aliphatic terminal alkynes to give gem-dipyrazolylalkanes predominantly. Replacement of silver triflate with zinc triflate allows us to achieve double addition of pyrazoles to aromatic terminal alkynes. In contrast to the selective double addition, the corresponding single addition of aliphatic and aromatic terminal alkynes exclusively proceeded in the presence of a catalytic amount of silver nitrate. Internal alkynes also participated in the single addition reaction with the aid of silver triflate as a catalyst. The notable feature of this protocol is the utilization of an addition reaction being optimal from environmental and atom-economical points of view. The reaction mechanism is also described. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800353

FULL PAPER
DOI: 10.1002/ejoc.200800353
Lewis Acid Catalyzed Addition of Pyrazoles to Alkynes: Selective Synthesis of
Double and Single Addition Products
Teruhisa Tsuchimoto,*[a] Kazuki Aoki,[a] Tatsuya Wagatsuma,[a] and Yuichi Suzuki[a]
Keywords: Addition reactions / Alkynes / Nitrogen heterocycles / Regioselectivity / Synthetic methods
Silver and zinc salts were found to efficiently catalyze the
addition of an N–H bond of pyrazoles to alkynes. With silver
triflate as a catalyst, two pyrazoles regioselectively attacked
the same carbon atom of the CϵC bond of aliphatic terminal
alkynes exclusively proceeded in the presence of a catalytic
amount of silver nitrate. Internal alkynes also participated in
the single addition reaction with the aid of silver triflate as a
catalyst. The notable feature of this protocol is the utilization
alkynes to give gem-dipyrazolylalkanes predominantly. Re- of an addition reaction being optimal from environmental
placement of silver triflate with zinc triflate allows us to
achieve double addition of pyrazoles to aromatic terminal al-
kynes. In contrast to the selective double addition, the corre-
sponding single addition of aliphatic and aromatic terminal
and atom-economical points of view. The reaction mecha-
nism is also described.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
We thus envisaged that the development of a Lewis acid
catalyzed double addition of pyrazoles to alkynes[12,13]
would resolve the problems of the previous systems. This
report with a metal triflate catalyst (metal = Ag, Zn) proves
to be the case. Although hydroamination of alkynes is
closely related to the present reaction, double hydroamin-
ation of alkynes has no precedent to the best of our knowl-
edge.[14] Notably, use of silver nitrate (AgNO3) as a catalyst
was found to change the reaction course drastically, giving
only single addition products: pyrazolylalkenes.[15–17] From
a synthetic point of view, pyrazolylalkenes are useful frame-
works for further organic transformations utilizing their
C=C bonds.[18]
Introduction
gem-Dipyrazolylalkanes (gem-DPAs) are highly attract-
ive units due to their two nitrogen coordination sites. In this
context, a large number of main-group and transition-metal
complexes coordinated by gem-DPAs have been synthe-
sized,[1,2] and some complexes show high catalytic activities
for basic organic transformations.[3] Interestingly, platinum
derivatives are important as anticancer agents.[4] gem-DPAs
themselves also exhibit analgesic and anti-inflammatory ac-
tions.[5] In addition to the synthetic and biological signifi-
cances, nickel and group 11 metal complexes show unique
optical properties.[6] gem-DPAs thus play a vital role in a
variety of aspects, but their syntheses have relied mainly
on the following four types:[7] (1) Double substitution of
dihaloalkanes with metal pyrazolates (metal = Na, K).[8] (2)
Brønsted acid catalyzed double substitution of acetals with
pyrazoles.[9] (3) Addition and substitution sequence of alde-
hydes with pyrazoles catalyzed by a Lewis acid.[10] (4) Treat-
ment of dipyrazolyl ketones with aldehydes under cobalt
catalysis, releasing CO2 gas.[11] All these protocols, however,
produce their respective byproducts, which is unfavorable in
view of atom economy. Among the four types, protocols (1)
and (4) seem to have been the most frequently utilized so
far. However, the strong basic conditions for type (1) re-
strict the scope of the dihaloalkanes. In method (4), virulent
phosgene is required for making the dipyrazolyl ketones.
Results and Discussion
We first studied the effect of Lewis acid catalysts in the
reaction of 1-octyne (1a) with pyrazole (2a) (Table 1). Treat-
ment of 1a and 2a with 5 mol-% of In(OTf)3 (Tf =
SO2CF3), which is a prominent catalyst for the double ad-
dition of heterocyclic arenes to alkynes,[13] in PhCl at
130 °C for 20 h gave only 2,2-bis(pyrazol-1-yl)octane (3aa),
albeit in a low yield (Table 1, Entry 1). To our great delight,
the yield of 3aa was improved dramatically by the replace-
ment of In(OTf)3 with AgOTf, though 1:1 adducts of 4aa–
6aa were also produced in 13% yield (Table 1, Entry 2). No
higher yield of 3aa was achieved with the increased amount
of 2a (Table 1, Entry 3). The use of 2 mol equiv. of 2a rela-
tive to the amount of 1a led to nonselective double addition
(Table 1, Entry 4). The use of 10 mol-% of Zn(OTf)2 gave
3aa in a good yield, though its lower loading made the reac-
tion sluggish, where 7aa, the stereoisomer of 6aa, was also
formed (Table 1, Entries 5 and 6). Other metal triflate cata-
[a] Department of Applied Chemistry, School of Science and Tech-
nology, Meiji University,
Higashimita, Tama-ku, Kawasaki, 214-8571, Japan
Fax: +81-44-934-7228
E-mail: tsuchimo@isc.meiji.ac.jp
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2008, 4035–4040
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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T. Tsuchimoto, K. Aoki, T. Wagatsuma, Y. Suzuki
FULL PAPER
lysts resulted in lower efficiencies (Table 1, Entries 7–10). be responsible for the negative resonance effect of the 2-
The promising activity of AgOTf prompted us to survey the pyridyl group that makes the β-carbon atom more electro-
effect of other silver salts. In sharp contrast to the selective philic.[20] The reaction of ethyl propiolate (1l) proceeded
double addition observed with AgOTf as well as with also in a Michael fashion (Table 2, Entry 13). In addition to
AgClO4 and AgPF4, AgNO3 was found to be a crucial cata- 2a, 4-methylpyrazole (2b) added successively to 1a (Table 2,
lyst for accessing the single addition, in which 4aa was selec- Entry 14).
tively obtained among 4aa–7aa (Table 1, Entries 2 and 11–
15). No reaction proceeded without a catalyst (Table 1,
Entry 16).
Table 2. Lewis acid catalyzed double addition of pyrazoles to alky-
nes.[a]
Table 1. Lewis acid catalyzed addition of pyrazole to 1-octyne.[a]
Entry R1CϵCR2 (1)
t [h]
Yield [%]
Yield [%] of
of 3[b]
1:1 adducts[b]
1
2
3
4
5
6
7
8
HexCϵCH (1a)
20
40
50
100
70
80
50
50
80
74 (3aa)
73 (3ba)
79 (3ca)
70 (3da)
65 (3ea)
72 (3fa)
12 (3ga)
70 (3ga)
61 (3ha)
74 (3ia)
70 (3ja)
61 (3ka)
82 (3la)
83 (3ab)
12
19
18
15
12
17
Ph(CH2)2CϵCH (1b)
BnCϵCH[c] (1c)
NC(CH2)3CϵCH (1d)
AcO(CH2)3CϵCH (1e)
PI(CH2)3CϵCH (1f)
PhCϵCH (1g)
Entry Lewis acid
Conv. [%]
Yield [%]
Yield [%] and ratio of
of 1a[b]
of 3aa[b]
4aa–7aa[b]
67 (4ga, 5ga)[d]
1
2
In(OTf)3
AgOTf
AgOTf
AgOTf
Zn(OTf)2
Zn(OTf)2
Cu(OTf)2
Au(OTf)3
Bi(OTf)3
Sc(OTf)3
AgClO4
AgPF4
AgSbF6
AgCl
AgNO3
None
21
3
Ͻ1
PhCϵCH (1g)
23 (4ga)
18 (4ha)
19 (4ia)
14 (4ja)
7
Ͼ99
Ͼ99
Ͼ99
Ͼ99
65
45
Ͼ99
98
84
Ͼ99
95
98
56
81
79
39
71
44
19
58
53
41
75
56
41
3
13 (34:54:12:Ͻ1)
11 (30:49:21:Ͻ1)
45 (87:13:Ͻ1:Ͻ1)
18 (7:7:69:17)
7 (18:12:63:7)
4 (Ͻ1:33:67:Ͻ1)
22 (5:35:49:11)
15 (8:3:72:17)
13 (8:25:56:11)
12 (27:57:16:Ͻ1)
28 (70:26:4:Ͻ1)
45 (87:13:Ͻ1:Ͻ1)
13 (91:9:Ͻ1:Ͻ1)
90 (92:8:Ͻ1:Ͻ1)
0
9[e]
10
11
12
13
14[g]
4-ClC6H4CϵCH (1h)
3[c]
4[d]
5
4-MeOC6H4CϵCH (1i) 30
3-thienyl–CϵCH (1j)
HCϵC–2-pyridyl (1k)
HCϵCCO2Et (1l)
HexCϵCH (1a)
45
5
65
20
[e]
6
7
8
9
10
11
12
13
14
15
16
2[f]
9
[f]
[a] 1: 0.50 mmol, 2a: 2.5 mmol, PhCl: 0.5 mL, AgOTf: 25 µmol for
Entries 1–7, 13 and 14, Zn(OTf)2: 50 µmol for Entries 8–12. [b] Iso-
lated yield based on the alkyne. [c] Bn = PhCH2. [d] 4ga:5ga =
50:50. [e] 2a: 3.5 mmol, Zn(OTf)2: 75 µmol. [f] Ethyl (E)-3-(pyrazol-
1-yl)-2-propenoate (8) was obtained as a single isomer. [g] 4-Meth-
ylpyrazole (2b) instead of 2a was used.
96
Ͻ1
1
0
As already presented, the AgNO3-catalyzed reaction with
the use of 5 mol equiv. of 2a to 1a produced a small amount
of 3aa (Table 1, Entry 15). We were, however, pleased to
find that 3aa was reduced to a negligible amount with the
use of 2 to 1 molar ratio of 2a to 1a (Table 3, Entry 1). We
thus applied the conditions to single addition of other al-
[a] 1a: 0.50 mmol, 2a: 2.5 mmol, PhCl: 0.5 mL, Lewis acid:
25 µmol. [b] Determined by GC by using o-Cl2C6H4 as an internal
standard. [c] 2a: 3.0 mmol. [d] 2a: 1.0 mmol. [e] Zn(OTf)2: 50 µmol.
[f] Au(OTf)3 was prepared in situ from AuCl3 (25 µmol) and AgOTf
(75 µmol).
With each suitable Lewis acid catalyst for the double or kynes (Table 3). Expectedly, all the reactions of aliphatic
single addition reaction, we next examined the substrate and aromatic terminal alkynes provided only pyrazolylal-
scope for the double addition (Table 2). Besides 1a, ali- kenes 4 and 5 as a regioisomeric mixture (Table 3, En-
phatic terminal alkynes with –Ph, –CN, –OAc, and –PI (PI tries 2–5). In the additions of 2a to the terminal carbon
= phthalimidoyl) groups at the end of the alkyl chain re- atom of a CϵC bond, complete Z geometry of the products
acted with 2a predominantly to give 3ba–3fa (Table 2, En- was always observed, that is, the stereoselective formation
tries 1–6). Although the reaction of phenylacetylene (1g) of 5aa–5ja. These results prove that anti addition is involved
with AgOTf resulted predominantly in single addition, as a key step in the reaction process. Perfect anti addition
Zn(OTf)2 improved the case to afford 3ga in 70% yield again took place in the reactions of internal alkynes 1m and
(Table 2, Entries 7 and 8). Various aromatic terminal al- 1n, where AgOTf is superior to AgNO3 as a catalyst
kynes 1h–1k also participated in the double addition of 2a (Table 3, Entries 6 and 7).[21] 3,5-Dimethylpyrazole (2c) also
with the aid of Zn(OTf)2 as a catalyst (Table 2, Entries 9– is available for the single addition to 1a (Table 3, Entry 8).
12). The isomer distributions of the 1:1 adducts derived
from 1g–1j that are specified in Table 2 should be informa- here. Path A is a route including a cation intermediate and
tive for mechanistic considerations.[19] Among the aromatic path
proceeds through concerted mechanism
From a mechanistic viewpoint, two routes are possible
B
a
alkynes, only 1k accepted 2a exclusively at the β-carbon (Scheme 1). On the basis of our previous demonstra-
atom of the CϵC bond. The Michael-like addition should tions,[13,16] there are some critical differences between the
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Eur. J. Org. Chem. 2008, 4035–4040

Lewis Acid Catalyzed Addition of Pyrazoles to Alkynes
Table 3. Lewis acid catalyzed single addition of pyrazoles to alky- (Table 1, Entries 2–4 and 11–15). Treatment of 4aa with
nes.[a]
10 mol-% of Zn(OTf)2 in PhCl at 130 °C gave a mixture of
6aa and 7aa [Equation (3)], which clearly shows that 6 and
7 are formed by isomerization of 4.
Entry R1CϵCR2 (1)
t [h]
Yield [%] of
Ratio of
4 and 5[b]
4:5[c]
1
2
3
4
HexCϵCH (1a)
20
20
20
20
25
70
50
24
86 (4aa, 5aa)
95 (4ba, 5ba)
88 (4da, 5da)
89 (4ga, 5ga)
56 (4ja, 5ja)
51 (4ma)
92:8
Ph(CH2)2CϵCH (1b)
NC(CH2)3CϵCH (1d)
PhCϵCH (1g)
84:16
87:13
48:52
52:48
–
5
3-thienyl–CϵCH (1j)
BuCϵCBu (1m)
PhCϵCMe (1n)
HexCϵCH (1a)
6[d]
7[e]
8[f]
85 (4na, 5na)
59 (4ac, 5ac)
15:85
79:21
[a] 1: 0.250 mmol, 2a: 0.500 mmol, PhCl: 0.25 mL, AgNO3:
12.5 µmol for Entries 1–5 and 8, AgOTf: 50.0 µmol for Entries 6
and 7. [b] Isolated yield based on the alkyne. [c] Determined by
GC analysis. [d] The reaction was performed in the presence of
(iPr)2NEt (50.0 µmol). [e] The reaction was carried out in p-
MeClC6H4 instead of PhCl at 140 °C. [f] 3,5-Dimethylpyrazole (2c)
instead of 2a was used.
Scheme 1. Proposed routes for the addition of pyrazoles to alkynes.
two routes to discriminate which route is operative. Thus,
when R1 or R2 is aryl or alkyl, respectively, like 1n, attack
of 2 (pz–H) to 1 in path A should proceed regioselectively
due to the much higher ability of the aryl group to stabilize
positive charges, though a mixture of anti and syn adducts 4
and 4Ј are formed, because the sp-hybridized cation center
accepts pz–H from both x and y sites. On the contrary, path
B should provide regioisomeric 4 and 5 by stereoselective
anti addition because pz–H attacks 1 from the side opposite
to a coordinated Lewis acid (LA),[22] where the regioselec-
tivity seems to depend on the nucleophile and/or LA
used.[23] According to these considerations, the exclusive
anti addition to give regioisomers 4 and 5 observed in
Table 3 strongly suggests that path B is operative under sil-
ver catalysis. Moreover, the formation of 4ga and 5ga with
AgOTf as a catalyst (Table 2, Entry 7) also supports path
B. However, all of the Zn(OTf)2-catalyzed reactions gave
only 4 (Table 2, Entries 8–11). Thus, considering that path
A works only when Zn(OTf)2 is a catalyst, the perfect regio-
selectivities should be rationally understood. Although the
mechanistic details from 4 to 3 are hard to discuss, the Ag-
OTf-catalyzed reaction of 4aa with 2a in PhCl at 130 °C
proceeded at almost the same reaction rate as that of 1a
with 2a (Table 1, Entry 2), giving 3aa in a higher yield
[Equation (1)]. The result suggests that 4 is an intermediate
of 3 and that the addition process from 4 to 3 is the rate-
determining step (RDS). In addition to this, AgOTf was
found to catalyze the elimination of 2a from 3aa [Equa-
tion (2)]. Because almost no elimination occurs in the pres-
(1)
(2)
(3)
Additionally, the fact that the ratio of 6aa and 7aa varies
ence of 2a, these results may explain why the successful depending on the reaction time exhibits that 6aa, which is
double addition reaction requires an excess amount of pyr- gradually isomerized in part to 7aa, is the kinetically fa-
azoles relative to the amount of alkynes. Finally, we investi- vored isomer. Moreover, no further isomerization of 6aa to
gated a route for the formation of 6 and 7, and Zn(OTf)2 7aa after 20 h results from an equilibrium between 6aa and
was used as a catalyst for this purpose, because no 7aa is 7aa under the reaction conditions, and the resulting higher
generated from the silver-catalyzed reactions of 1a with 2a ratio of 6aa suggests that 6aa is also thermodynamically
Eur. J. Org. Chem. 2008, 4035–4040
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4037

T. Tsuchimoto, K. Aoki, T. Wagatsuma, Y. Suzuki
FULL PAPER
908 equipped with JAIGEL-SIL S-043–15 column. All melting
points were measured with a Yanaco Micro Melting Point appara-
tus and are uncorrected. Chlorobenzene was distilled under an ar-
gon atmosphere from calcium chloride just prior to use. p-Chloro-
toluene and N,N-diisopropylethylamine were stored over 4 Å MS
before use. All alkynes 1a–1n and pyrazoles 2a–2c were commer-
cially available and used as received.
more stable than 7aa. A possible isomerization mechanism
exemplified by the reaction of 4aa is summarized in
Scheme 2. Thus, formation of alkyl cation 9 by the reaction
of 4aa with a metal triflate (LA) and subsequent [1,3]-hy-
drogen shift induces the isomerization of 4aa to 6aa.[24] Suc-
cessively, 6aa is isomerized to 7aa by generation of cation 10
followed by bond rotation and elimination of LA. Although
three conformers, 9, 9Ј, and 9ЈЈ, possibly exist in the isomer-
ization process, conformer 9 without steric hindrance be-
tween the pentyl and pyrazolyl groups seems to be the most
favorable, which should result in the predominant forma-
tion of 6aa. The hydrogen bonding shown in 9 also might
contribute to the formation process of 6aa. The participa-
General Procedure for the Lewis Acid Catalyzed Double Addition of
Pyrazole to Alkynes: AgOTf (6.4 mg, 25 µmol) or Zn(OTf)2
(18.2 mg, 50.0 µmol or 27.3 mg, 75.0 µmol) was placed in a 20-mL
Schlenk tube, which was heated at 80 °C for 15 min or 150 °C for
2 h under vacuum, respectively. The tube was cooled to room tem-
perature and filled with argon. To this was added pyrazole
(170.2 mg, 2.500 mmol or 238.3 mg, 3.500 mmol), chlorobenzene
tion of the hydrogen bonding may be explained by the fact (0.5 mL), and an alkyne (0.500 mmol) successively, and the re-
that the Ha signal (δ = 5.87 ppm) appears downfield relative
sulting mixture was stirred at 130 °C. After the time specified in
to the corresponding Hb signal (δ = 5.33 ppm) in their H
1
Table 2, saturated NaHCO3 aqueous solution (1 mL) was added,
NMR spectra.[25]
and the mixture was extracted with ethyl acetate (3ϫ5 mL). The
combined organic layer was dried with anhydrous sodium sulfate.
Filtration and evaporation of the solvent followed by column
chromatography on silica gel (hexane/ethyl acetate) gave the corre-
sponding gem-dipyrazolylalkane 3 and an isomeric mixture of pyr-
azolylalkenes 4, 5, and/or 6. The double addition of 4-methylpyr-
azole to 1-octyne presented in Table 2 (Entry 14) was carried out
similarly as above. These results are summarized in Table 2. All
gem-dipyrazolylalkanes were fully characterized by 1H and 13C
NMR spectroscopy and HRMS (see Supporting Information).
General Procedure for the Lewis Acid Catalyzed Single Addition of
Pyrazole to Alkynes: AgNO3 (2.12 mg, 12.5 µmol) or AgOTf
(12.8 mg, 50.0 µmol) was placed in a 20-mL Schlenk tube, which
was heated at 80 °C in vacuo for 15 min. The tube was cooled to
room temperature and filled with argon. To this was added pyr-
Scheme 2. A possible isomerization mechanism.
azole (34.0 mg, 0.500 mmol), chlorobenzene or p-chlorotoluene
(0.25 mL), and an alkyne (0.250 mmol) successively, and the re-
sulting mixture was stirred at 130 or 140 °C. After the time speci-
fied in Table 3, saturated NaHCO3 aqueous solution (1 mL) was
added, and the mixture was extracted with ethyl acetate (3ϫ5 mL).
The combined organic layer was dried with anhydrous sodium sul-
fate. Filtration and evaporation of the solvent followed by column
chromatography on silica gel (hexane/ethyl acetate) gave the corre-
sponding pyrazolylalkene 4 and/or 5. The single addition of 3,5-
dimethylpyrazole to 1-octyne presented in Table 3 (Entry 8) was
carried out similarly as above. In the cases of 4ba and 5ba, 4da and
5da, 4ga and 5ga, and 4ac and 5ac, further separation was per-
formed with preparative recycling HPLC. These results are summa-
rized in Table 3. All pyrazolylalkenes appearing in Tables 1–3 were
Conclusions
We have achieved the selective double and single addition
of pyrazoles to alkynes, for the first time, by appropriate
choice of the Lewis acid catalyst. The highlight of our strat-
egy is attributed to the utilization of an addition scaffold
that is environmentally benign and completely atom eco-
nomical. The wide substrate scope based on the remarkable
functional group compatibility enhances the utility of this
protocol. Studies on application of single and double ad-
dition products are currently underway.
1
fully characterized by H and 13C NMR spectroscopy and HRMS
(see Supporting Information).
Supporting Information (see footnote on the first page of this arti-
cle): Spectral and analytical data, 1H and 13C NMR spectra for all
compounds.
Experimental Section
General Remarks: All manipulations were conducted with standard
Schlenk techniques under an argon atmosphere. Nuclear magnetic
resonance spectra were taken with
a
JEOL ECA-400 (1H,
400 MHz; 13C, 100 MHz) or JEOL ECA-500 (1H, 500 MHz; 13C,
125 MHz) spectrometer by using tetramethylsilane (1H) or CDCl3
(13C) as an internal standard. Analytical gas chromatography was
performed with a Shimadzu model GC-18A instrument equipped
with a capillary column of ID-BPX5 (5% phenyl polysilphenylene-
siloxane, 30 mϫ0.25 mmϫ0.25 µm) with the use of nitrogen as a
carrier gas. High-resolution mass spectra (HRMS) were obtained
with a Mariner spectrometer. Preparative recycling high-perform-
ance liquid chromatography (HPLC) was performed with JAI LC-
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[13]
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Detailed information concerning isomer distributions in ad-
dition to spectral and analytical data of 1:1 adducts produced
in the reactions of Table 2, Entries 1–6 and 12–14 are provided
in the Supporting Information.
[15]
[5]
[6]
[7]
[8]
[16]
[17]
[18]
[9]
[10]
[11]
[19]
[20]
[21]
a) T. Sakamoto, H. Nagata, Y. Kondo, K. Sato, H. Yamanaka,
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Kondo, M. Shirakawa, H. Yamanaka, Synthesis 1984, 245–247.
The single addition of 1m and 1n with the use of 20 mol-% of
AgNO3 instead of AgOTf also proceeded in comparable yields
Eur. J. Org. Chem. 2008, 4035–4040
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4039

T. Tsuchimoto, K. Aoki, T. Wagatsuma, Y. Suzuki
FULL PAPER
(50% yield from 1m, 76% yield from 1n). However, an isomer
of 4ma in the reaction of 1m was produced in a small amount
(1% yield) together with 4ma. In the case of 1n, a mixture of
four isomers including 4na and 5na was produced.
[22] For anti addition through a concerted mechanism, see: H. M.
Weiss, K. M. Touchette, J. Chem. Soc., Perkin Trans. 2 1998,
1523–1528.
[24] For LA-catalyzed isomerization of C=C bonds through [1,3]-
hydrogen shift, see: M. Rubina, M. Conley, V. Gevorgyan, J.
Am. Chem. Soc. 2006, 128, 5818–5827.
[25] Proton signals that participate in hydrogen bonding such as
C–H···X (X = heteroatom) are known to be shifted downfield
in 1H NMR spectra. For example, see: H. Kawasaki,
G. Sakane, T. Shibahara, Inorg. Chem. Commun. 2005, 8, 777–
781.
[23] In ref.[13], N-methylpyrrole goes mainly to the Ph-attached
carbon atom of 1n, contrary to the regioselectivity observed in
Table 3, Entry 7.
Received: April 7, 2008
Published Online: July 4, 2008
4040
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 4035–4040