Stereoselective preparation of polyfunctional alkenylindium(III) halides and their cross-coupling with unsaturated halides

Article abstract of DOI:10.1002/chem.201500943

The direct insertion of indium powder to cycloalkenyl iodides in the presence of LiCl in THF allows the preparation of new highly functionalized cycloalkenylindium(III) derivatives. In addition, we discovered that, in contrast to many metal insertions to alkenyl iodides which proceed with a loss of stereochemistry, the insertion of In/LiCl to stereodefined (Z)- and (E)-styryl iodides in THF proceeded with high retention of stereochemistry. After a palladium-catalyzed cross-coupling, various polyfunctionalized (Z)- and (E)-stilbenes were obtained with high stereoselectivity.

Full text of DOI:10.1002/chem.201500943

DOI: 10.1002/chem.201500943
Communication
&
CÀC Coupling
Stereoselective Preparation of Polyfunctional Alkenylindium(III)
Halides and Their Cross-Coupling with Unsaturated Halides
Zhi-Liang Shen and Paul Knochel*[a]
powder into functionalized E- and Z-styryl iodides as well as
Abstract: The direct insertion of indium powder to cyclo-
their subsequent Pd-catalyzed stereoselective cross-coupling
alkenyl iodides in the presence of LiCl in THF allows the
with unsaturated iodides.
preparation of new highly functionalized cycloalkenylin-
Thus, we have treated 3-iodocyclohex-2-enone (1a) with
dium(III) derivatives. In addition, we discovered that, in
indium powder (2 equiv) and lithium chloride (2 equiv) in THF
contrast to many metal insertions to alkenyl iodides which
at 558C for 12 h leading to a full conversion and affording the
proceed with a loss of stereochemistry, the insertion of In/
indium(III) species 2a in 78% yield, as determined by GC analy-
LiCl to stereodefined (Z)- and (E)-styryl iodides in THF pro-
sis of reaction aliquots quenched with a THF solution of iodine
ceeded with high retention of stereochemistry. After a pal-
(Scheme 1). In the absence of lithium chloride, less than 10%
ladium-catalyzed
cross-coupling, various polyfunc-
tionalized (Z)- and (E)-stilbenes were obtained with high
stereoselectivity.
Organometallics that are compatible with many functionalities
are important nucleophilic intermediates in organic synthe-
sis.[1–3] The tolerance of functional groups is essential to short-
en long natural product syntheses since such reagents avoid
the need for protecting and deprotecting steps.[4] Recently, we
and others reported that the insertion of indium into aryl and
heteroaryl iodides[5] or benzylic chlorides[6] is dramatically accel-
erated by the presence of lithium chloride,[7–10] allowing the
preparation of functionalized organoindium species. The high
functional group tolerance of indium(III) organometallics[11–12]
led us to examine the preparation of polyfunctional alkenylin-
dium(III) reagents for organic synthesis. In fact, organoindi-
um(III) derivatives have been shown to be compatible with var-
ious functional groups.[13] The insertion rate of a metal into
a carbon–halide bond highly depends on the activation of its
surface, and lithium chloride has been found to be an excellent
activator for many metals, such as magnesium,[7] zinc,[8] alumi-
num,[9] and manganese.[10] Although such activation leads to
a fast insertion, the stereoselectivity of the metal insertion into
E- and Z-alkenyl halides usually cannot be controlled.[14] Metal
insertions are dominated by electron-transfer reaction steps,[15]
which implies the formation of free radical intermediates, and
therefore lead to a loss of stereoselectivity. The use of zinc acti-
vated by lithium chloride has allowed a stereoselective inser-
tion to some electron-poor alkenyl bromides.[16] Herein, we
report a mild preparation of highly functionalized alkenylindiu-
m(III) reagents[17] and the stereoselective insertion of indium
Scheme 1. Preparation of organoindium reagent 2a by In/LiCl insertion and
its subsequent palladium-catalyzed cross-coupling with aryl bromide 3a.
insertion was observed. The organoindium reagent 2a readily
underwent a palladium-catalyzed cross-coupling with 4-bro-
moacetophenone (3a) in N,N-dimethylacetamide (DMAC)[11e] at
808C for 12 h leading to the expected 3-arylated cyclohexe-
none 4a in 87% yield. This reaction sequence has some gener-
ality and the organoindium reagent 2a underwent couplings
with aryl bromide 3b and iodide 3c affording the correspond-
ing cyclohexenones 4b and 4c in high yields (Table 1, entries 1
and 2). Similarly, we have prepared the 2-methyl-3-indium cy-
clohexenone derivative 2b (558C, 16 h, 90% yield) and the 3-
indium cyclopentenone reagent 2c (558C, 20 h, 66% yield)
under similar reaction conditions. These indium species under-
went smooth cross-couplings with electron-poor and electron-
rich aryl halides leading to the 3-arylated enones 4d–4h in
53–94% yields (entries 3–7). In addition, we noted that the
indium insertion to a-iodostyrene (1d) proceeded also
smoothly to generate the corresponding organoindium 2d in
68% yield (558C, 12 h), which cross-coupled with aryl iodide
3c to produce the expected product 4i in 91% yield (entry 8).
This led us to examine the stereochemistry of indium insertion
into the carbon–iodine bond of stereodefined styryl iodides.[18]
Thus, we treated Z- and E-(2-iodovinyl)benzonitrile (1e)[19]
with indium powder and lithium chloride (558C, 18–24 h) lead-
ing to the styrylindium reagents Z-2e and E-2e in 85% yield
(Scheme 2). Remarkably, the Z-styrylindium Z-2e retained its
stereochemistry almost completely and an iodolysis showed
[a] Z.-L. Shen, Prof. Dr. P. Knochel
Department Chemie, Ludwig-Maximilians-Universität München
Butenandtstrasse 5–13, Haus F, 81377 München (Germany)
E-mail: paul.knochel@cup.uni-muenchen.de
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201500943.
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Communication
the same reaction in other ethereal solvents led to either low
yield or relatively low stereochemistry (DME: 82% yield, Z:E=
90:10; tBuOMe: 22% yield, Z:E=99:1; tetrahydropyran: 80%
yield, Z:E=81:19; 1,4-dioxane: 68% yield, Z:E=98:2). Subse-
quently, Pd-catalyzed cross-coupling of Z-2e with ethyl 4-iodo-
benzoate (3c) using 4 mol% PEPPSI-IPr[21,22] led to the unsym-
metrical Z-stilbene Z-4j in 92% yield and a Z:E ratio of 98:2.
Also, the styrylindium reagent E-2e showed by iodolysis a E:Z
purity of 96:4. Pd-catalyzed cross-coupling of E-2e with the
aryl iodide 3c produced the E-stilbene E-4j in 78% yield and
an E:Z ratio of 95:5.
Table 1. Preparation of alkenylindium(III) reagents 2a–2d and subse-
quent palladium-catalyzed cross-coupling with aryl halides 3b–3 f.
Entry
Indium reagent
Electrophile[a]
Product[b]/Yield[c]
1
2
2a (12 h, 78%)
3b
3c
4b: 98%
4c: 96%
2a
Subsequently, the method was extended to the preparation
of a variety of styrylindium(III) reagents using various styryl io-
dides. As shown in Table 2, unsubstituted Z-1 f and E-1 f were
converted to the corresponding indium reagents Z-2 f and E-
2 f in 51–72% yields with high stereoselectivities (entries 1 and
2). Styryl iodides 1g–1i bearing a halogen substituent either in
the ortho or para position readily underwent the insertion re-
actions without touching the halogen substituent, leading to
the desired styrylindium(III) reagents 2g–2i in 70–83% yields
and excellent stereoretention (>95:5 d.r., entries 3–5). The
presence of an ester or acetyl substituent in the starting styryl
iodides 1j–1k was well tolerated and the resulting indium re-
agents E-2j and Z-2k were obtained under the standard condi-
tions in 73–86% yields and 98:2 d.r. (entries 6 and 7).
In the same manner, the palladium-catalyzed cross-coupling
of Z–2e and E-2e with aryl iodides 3g and 3h proceeded well,
leading to the corresponding stilbenes 4k and 4l in 69–80%
yields and high stereoselectivities (Table 3, entries 1–4). Unsub-
stituted styrylindium(III) reagents Z-2 f and E-2 f also under-
went efficient cross-coupling with iodoarenes 3c and 3i with
good yields and high level of stereoselectivities (entries 5 and
6). The palladium-catalyzed cross-coupling reactions of indium
reagents Z-2g, E-2h, and Z-2i with electrophiles 3j and 3k
proceeded smoothly to furnish the corresponding products
4o–4q in 65–94% yields and high stereoretention (entries 7–
9). This behavior of cross-coupling was further extended to the
use of organoindium reagents E-
3
4
2b (16 h, 90%)
3b
3d
4d: 91% (<10%)[d]
2b
4e: 88%
5
6
2c (20 h, 66%)
3c
3e
4 f: 79%
4g: 94%
2c
7
8
2c
3 f
3c
4h: 53%
4i: 91%
2d (12 h, 68%)
[a] 0.7 equivalents of electrophile was used. [b] The cross-coupling reac-
tions were performed in DMAC at 808C for 12 h using 5 mol%
[PdCl2(PPh3)2]. [c] Yield of isolated, analytically pure product. [d] The same
reaction using 4-chlorobenzonitrile as an electrophile led to <10% yield
of the product 4d.
2j and Z-2k (bearing an ester or
acetyl substituent) with aryl io-
dides 3g–3m, providing the ex-
pected stilbenes E-4r, Z-4s, and
Z-4t in 72–84% yields (up to
98:2 d.r., entries 10–12). In addi-
tion, it is noteworthy that impor-
tant functional groups embed-
ded in the coupling partners, in-
cluding nitrile, ester, ketone, and
even aldehyde, were compatible
with the styrylindium(III) re-
agents.
In summary, we have reported
Scheme 2. Preparation of stereodefined cyano-containing Z- and E-styrylindium reagents 2e and their palladium-
catalyzed cross-coupling with ethyl 4-iodobenzoate (3c).
that the direct insertion of
indium powder into cycloalkenyl
iodides in the presence of LiCl in
a Z:E ratio of 98:2.[20] It should be noted that THF is the solvent
THF allows the preparation of new highly functionalized cyclo-
alkenylindium(III) derivatives, such as 1-oxo-cyclohexen-3-yl
of choice for the insertion reaction since the performance of
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Table 2. Stereoselective preparation of styrylindium(III) reagents 2 f–2k.
Table 3. Pd-catalyzed cross-coupling of styrylindium(III) reagents 2e–2k
with electrophiles 3c–3m using 4 mol% PEPPSI-IPr as catalyst.
Entry
Styryl iodide
(E:Z)
Time
Styrylindium reagent
[Yield[a] (E:Z)[b]
]
Entry
Styrylindium
(E:Z)
Electrophile[a]
Product[b]
[Yield[c] (E:Z)[d]
]
1
2
Z-1 f (3:97)
E-1 f (99:1)
48 h
5 d
Z-2 f [51% (5:95)]
E-2 f [72% (98:2)]
1
Z-2e (2:98)
3g
Z-4k [80% (3:97)]
2
3
4
Z-2e (2:98)
E-2e (96:4)
E-2e (96:4)
3h
3g
3h
Z-4l [74% (6:94)]
E-4k [71% (96:4)]
E-4l [69% (96:4)]
3
4
Z-1g (1:99)
E-1h (99:1)
12 h
6 d
Z-2g [83% (2:98)]
E-2h [70% (99:1)]
5
Z-1i (3:97)
70 h
Z-2i [72% (5:95)]
5
6
Z-2 f (5:95)
E-2 f (98:2)
3c[e]
Z-4m [82% (6:94)]
E-4n [89% (97:3)]
3i
6
E-1j (98:2)
Z-1k (1:99)
20 h
18 h
E-2j [73% (98:2)]
Z-2k [86% (2:98)]
7
8
Z-2g (2:98)
E-2h (99:1)
3j
Z-4o [65% (2:98)]
E-4p [94% (98:2)]
7
[a] The yield was determined by GC analysis of reaction aliquots
quenched with a THF solution of iodine against internal standard. [b] The
E:Z ratio was determined by GC analysis.
3k
indium. In addition, we discovered that, in contrast to many
metal insertions to alkenyl iodides which proceed with a loss
of stereochemistry,[23] the insertion of In/LiCl to stereodefined
(Z)- and (E)-styryl iodides in THF led to the corresponding
indium reagents with high retention of stereochemistry. After
palladium-catalyzed cross-coupling, various polyfunctionalized
diastereomerically enriched (Z)- and (E)-stilbenes were ob-
tained.
9
Z-2i (5:95)
E-2j (98:2)
3j
Z-4q [77% (6:94)]
E-4r [74% (98:2)]
10
3g
11
12
Z-2k (2:98)
Z-2k (2:98)
3l
Z-4s [72% (5:95)]
Z-4t [84% (4:96)]
Experimental Section
3m
Typical procedure for the indium insertion: To a 20 mL Schlenk
flask equipped with a magnetic stirrer and a rubber septum was
added LiCl (0.17 g, 4 mmol, 2 equiv) and the flask was dried at
3808C by heat gun for 5 min under high vacuum. After cooling,
the flask was flushed with nitrogen gas, and then anhydrous THF
(6 mL), indium powder (0.46 g, 4 mmol, 2 equiv), an internal stan-
dard (C10H22, 0.2 mL), and alkenyl iodides (2 mmol) were sequential-
ly added. The reaction mixture was stirred vigorously at 558C for
the time indicated in Table 1 and Table 2. The reaction progress
was monitored by GC analysis of reaction aliquots quenched by sa-
turated NH4Cl solution until it showed >95% conversion of the
starting material. The yield of the insertion reaction was deter-
[a] Unless otherwise indicated, 0.7 equivalents of electrophile was used for
the cross-coupling reaction. [b] The cross-coupling reactions were per-
formed in THF/NMP (2:1) at 608C for 24 h using 4 mol% PEPPSI-IPr.
[c] Yield of isolated, analytically pure product. [d] The E:Z ratio was deter-
mined by GC analysis. [e] 0.5 equivalents of electrophile 3c was used.
mined by GC analysis of reaction aliquots quenched with a THF so-
lution of iodine.
Typical procedure for palladium-catalyzed cross-coupling reac-
tions using alkenylindium(III) reagents 2a–d: The supernatant so-
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lution of the prepared alkenylindium(III) reagents 2a–d in THF was
carefully transferred into another pre-dried and nitrogen-flushed
flask (without the remaining indium powder; otherwise relatively
low yield of the cross-coupling product was obtained) with a sy-
ringe. Then THF was carefully removed under vacuum and the
flask was flushed with nitrogen gas. DMAC (6 mL), aryl halide
(0.7 equiv), and [PdCl2(PPh3)2] (70 mg, 0.10 mmol, 5 mol%) were se-
quentially added and the reaction mixture was stirred at 808C for
12 h. Then, the reaction mixture was quenched with saturated
NH4Cl solution (20 mL) followed by extraction with ethyl acetate
(3”20 mL). The combined organic phases were washed with brine
(20 mL), dried over Na2SO4, and concentrated in vacuo. The crude
residue obtained was purified by silica gel column chromatography
using ethyl acetate and isohexane as eluant to give the analytically
pure product.
Typical procedure for palladium-catalyzed cross-coupling reac-
tions using styrylindium(III) reagents 2e–k: The supernatant solu-
tion of the prepared styrylindium(III) reagents 2e–k in THF was
carefully transferred into another pre-dried and nitrogen-flushed
flask (without the remaining indium powder) with a syringe. N-
Methyl-2-pyrrolidone (NMP, 3 mL), aryl iodide (0.5–0.7 equiv), and
PEPPSI-IPr (54 mg, 0.08 mmol, 4 mol%) were sequentially added
and the reaction mixture was stirred at 608C for 24 h. Then the re-
action mixture was quenched with saturated NH4Cl solution
(20 mL) followed by extraction with ethyl acetate (3”20 mL). The
combined organic phases were washed with brine (10 mL), dried
over Na2SO4, and concentrated in vacuo. The crude residue ob-
tained was purified by silica gel column chromatography using
ethyl acetate and isohexane as eluant to give the analytically pure
product.
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Acknowledgements
The research leading to these results has received funding
from the European Research Council under the European Com-
munity’s Seventh Framework Programme (FP7/2007–2013) ERC
grant agreement no. 227763. We thank BASF SE (Ludwigsha-
fen), W. C. Heraeus GmbH (Hanau), and Rockwood Lithium
GmbH (Hoechst) for the gift of chemicals.
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Keywords: alkenylindium
palladium · stereoselectivity
·
C–C coupling
·
indium
·
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[19] The insertion of indium to E-(2-bromovinyl)benzonitrile proceeded slug-
gishly under the same conditions. The insertion reaction proceeded
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[20] See Supporting Information for the GC method for the determination
of the yield and Z:E ratio of the formed alkenylindium(III) reagent by
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Communication
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[21] J. Nasielski, N. Hadei, G. Achonduh, E. A. B. Kantchev, C. J. O’Brien, A.
Lough, M. G. Organ, Chem. Eur. J. 2010, 16, 10844.
[23] Indium is up to now the only metal that undergoes insertion to alkenyl
iodides with retention of the configuration. The use of zinc dust is not
general and limited to some isolated examples (see ref. [16a]).
[22] The same reaction performed by using other catalyst (4 mol%) and
ligand (8 mol%) led to relatively low yield but with the same stereo-
chemistry ([Pd(PPh3)4]: 88% yield; [PdCl2(PPh3)2]: 75% yield; Pd(OAc)2/S-
Phos: 66% yield; [NiCl2(PPh3)2]: 0% yield).
Received: March 9, 2015
Published online on March 27, 2015
Chem. Eur. J. 2015, 21, 7061 – 7065
www.chemeurj.org
7065
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