Full functionalization of the imidazole scaffold by selective metalation and sulfoxide/magnesium exchange

Article abstract of DOI:10.1002/anie.201309217

A simple, flexible, and straightforward method for the functionalization of all the positions of the imidazole heterocycle through regioselective arylations, allylations, acylations, and additions to aldehydes is disclosed. Starting from the readily avail

Full text of DOI:10.1002/anie.201309217

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DOI: 10.1002/anie.201309217
Heterocycle Functionalization
Full Functionalization of the Imidazole Scaffold by Selective
Metalation and Sulfoxide/Magnesium Exchange**
Christoph Sꢀmann, Estibaliz Coya, and Paul Knochel*
Abstract: A simple, flexible, and straightforward method for
the functionalization of all the positions of the imidazole
heterocycle through regioselective arylations, allylations, acy-
lations, and additions to aldehydes is disclosed. Starting from
the readily available key imidazole 1, highly functionalized
imidazole derivatives have been synthesized in a regioselective
manner from directed metalations and a sulfoxide/magnesium
exchange. Moreover, the selective N3-alkylation followed by
deprotection of N1 (trans-N-alkylation) allows the regioselec-
tive N-alkylation of complex imidazoles.
The N,N-dimethylsulfamoyl group is known to direct
metalations to the ortho position.[2c,4] The TBDMS group
protects the highly acidic C2-position and ensures a selective
metalation at position C5. The AnS(O) group has been
chosen for both its ability to direct the metalation to
position 4 and its replacement through a sulfoxide/magne-
sium exchange[3,5] to furnish the corresponding magnesium
species.
The preparation of 1 is straightforward and accomplished
in two steps from the protected imidazole 2 in 73% overall
yield. Thus, the lithiation of the N1-protected imidazole 2[6] in
THF (À788C, 15 min) and subsequent silylation with
TBDMS-Cl afforded the 2-silylated imidazole 3 in 85%
yield.[7] Magnesiation with TMPMgCl·LiCl[8] (TMP = 2,2,6,6-
tetramethylpiperidyl) in THF (258C, 2 h) followed by reac-
tion with AnS(O)Cl[9] produced the key intermediate 1 in
86% yield (Scheme 2).
T
he imidazole scaffold is present in a plethora of biological
relevant molecules displaying a variety of pharmaceutical
properties.[1] This makes the full functionalization of the
imidazole ring an important target in organic synthesis.[2]
Recently, we demonstrated that a combination of metalation
and sulfoxide/magnesium exchange allows the 7-azaindole
skeleton to be fully functionalized.[3] Herein, we report
a simple, flexible, and straightforward method for the
functionalization of all the positions of the imidazole ring
through regioselective arylations, allylations, acylations, and
additions to aldehydes via zinc and magnesium intermediates.
Thus, we have constructed imidazole 1 bearing an N,N-
dimethylsulfamoyl group at N1, a tert-butyldimethylsilyl
(TBDMS) group at C2, and a 4-methoxy-3,5-dimethylbenze-
nesulfinyl (AnS(O)) group at C5 (Scheme 1).
Scheme 2. Synthesis of the key imidazole 1.
The sulfoxide substituent enables the selective metalation
of imidazole 1 in position 4 with TMPMgCl·LiCl (1.1 equiv,
À308C, 1 h) in quantitative yield.[10] The resulting Mg reagent
4 can be readily functionalized by reaction with various
electrophiles of type 5 to furnish 4-substituted imidazoles 6
(Table 1).
After transmetalation with ZnCl2 (1.1 equiv, À308C,
15 min), Mg reagent 4 undergoes smooth Pd-catalyzed
Negishi cross-coupling reactions.[11] Various electron-rich
and electron-poor electrophiles (0.9 equiv) can be used in
the cross-coupling reactions at 508C in the presence of
[Pd(PPh3)4] (5 mol%) as the catalyst to afford the 4-
substituted imidazoles 6a–d in high yields (Table 1,
entries 1–4). A pyridyl (5e, entry 5) and a vinylic iodide (5 f,
entry 6) also led to the expected products 6e and 6 f,
respectively.[12] Moreover, after transmetalation with ZnCl2
(1.1 equiv), Mg reagent 4 undergoes a CuI-catalyzed allyla-
tion[13] with 5g (0.9 equiv) to give the desired product 6g in
98% yield (entry 7). Furthermore, the CuI-catalyzed acyla-
tion[12] of Mg reagent 4 with benzoyl chloride 5h (0.9 equiv)
affords the corresponding ketone 6h in 82% yield (entry 8).
The CuI-catalyzed alkynylation[13] of Mg reagent 4 with
bromoacetylene 5i[14] (0.9 equiv) provides the highly func-
tionalized acetylene 6i in 53% yield (entry 9).
Scheme 1. Imidazole 1 as the key intermediate for full functionaliza-
tion. An=4-methoxy-3,5-dimethylphenyl.
[*] C. Sꢀmann, E. Coya, Prof. Dr. P. Knochel
Department Chemie, Ludwig-Maximilians-Universitꢀt Mꢁnchen
Butenandtstrasse 5-13, Haus F, 81377 Mꢁnchen (Germany)
E-mail: Paul.Knochel@cup.uni-muenchen.de
[**] We thank the European Research Council under the European
Community’s Seventh Framework Programme (FP7/2007–2013;
ERC grant agreement no. 227763) and the Deutsche Forschungs-
gemeinschaft (DFG) for financial support. E.C. thanks the Basque
government for financial funding. We also thank BASF SE (Lud-
wigshafen), W. C. Heraeus (Hanau), and Chemetall GmbH (Frank-
furt) for the generous gift of chemicals. We thank Dr. I. Tirotta for
preliminary experiments.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201309217.
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Table 1: Functionalization at position 4 of imidazole 1.
ried out to furnish the corresponding 4- and 5-substituted
imidazoles 8 (Table 2).
After transmetalation with ZnCl2 (1.2 equiv, À788C,
15 min), the Mg reagents 7 readily undergo Pd-catalyzed
Negishi cross-coupling reactions. Thus, the allyl-substituted
imidazole-magnesium derivative 7a reacts with 5a and 5j
(0.9 equiv) in the presence of [Pd(PPh3)4] (5 mol%) at 508C
to afford the corresponding cross-coupling products 8a and
8b in 71 and 90% yield, respectively (Table 2, entries 1 and
2). The alkenyl-imidazole 6 f also readily undergoes Pd-
catalyzed Negishi cross-coupling reactions after the sulfoxide/
magnesium exchange to produce the Mg reagent 7b and
a subsequent transmetalation with ZnCl2 (1.2 equiv; entries 3
and 4). Similarly, Pd-catalyzed Negishi reactions of Mg
species 7c–e furnish the corresponding cross-coupling prod-
ucts 8 f,g and 8i–k in high yields (entries 6, 7, 9–11).
The CuI-catalyzed acylation of Mg reagents 7 furnished
only protonated products. However, the Pd-catalyzed acyla-
tion developed by Negishi et al.[17] leads to the desired
ketones. Thus, the magnesiated imidazole 7b reacts with
benzoyl chloride 5h (0.9 equiv) and [Pd(PPh3)4] (5 mol%)
after transmetalation with ZnCl2 (1.2 equiv) to afford the
corresponding ketone 8e in 79% yield (entry 5). The
imidazole 7c also furnishes the corresponding ketone 8h in
66% yield under the same reaction conditions (entry 8).
As anticipated, the magnesiated imidazoles undergo not
only arylations, allylations, and acylations, but also direct
addition to aldehydes. Thus, the magnesium species 7c of
imidazole 6a reacts with 4-fluorobenzaldehyde (5l, 0.9 equiv)
to afford the hydroxyarylated imidazole 8l in 98% yield
(Scheme 3).
Entry
Organomagnesium
reagent[a]
Electrophile
Product (yield [%])[b]
1
2
3
4
4
4
4
4
5a, R=CO2Et
5b, R=CF3
5c, R=Cl
6a: 84[c]
6b: 72[c]
6c: 71[c]
6d: 60[c]
5d, R=OMe
5
4
5e
6e: 60[c]
6
7
4
4
5 f
6 f: 83[c]
5g
6g: 98[d]
8
9
4
4
5h
6h: 82[e]
Scheme 3. Selective sulfoxide/Mg exchange in position 5 of the imid-
azole ring by using iPrMgCl·LiCl, and subsequent addition to aldehyde
5l.
To functionalize position 2, the TBDMS group was
selectively removed by treatment with tetra-n-butylammo-
nium fluoride (TBAF, 1 equiv) at 08C, which furnished the
unprotected imidazoles 9 quantitatively while leaving the
N,N-dimethylsulfamoyl group at N1 untouched. Both
TMPMgCl·LiCl and TMP2Zn·2MgCl·2LiCl have been
employed for the metalation of imidazoles 9. Fully function-
alized imidazoles 11 were obtained after quenching the
resulting metalated imidazole derivatives 10 and 10’[10] with
a broad range of electrophiles.
5i
6i: 53[f]
[a] Metalation with TMPMgCl·LiCl (1.1 equiv). [b] Yield of isolated
product. [c] Negishi cross-coupling: ZnCl2 (1.1 equiv); then [Pd(PPh3)4]
(5 mol%) with R-I (0.9 equiv). [d] Allylation: 1 equiv CuCN·2 LiCl with
allyl bromide (0.9 equiv). [e] Acylation: CuCN·2LiCl (1 equiv) with
ArC(O)Cl (0.9 equiv). [f] Alkynylation: CuCN·2LiCl (1 equiv) with alkynyl
bromide (0.9 equiv)).
The next functionalization was performed in position 5 by
a sulfoxide/magnesium exchange.[3,5] Treatment of imidazoles
6 with iPrMgCl·LiCl[15] (1.2 equiv) at À788C led within 1 h to
the corresponding Mg species 7 in quantitative yield.[10,16]
Subsequently, various functionalization reactions were car-
The CuI-catalyzed allylation reaction of the Zn reagent
10a with 5g (1.1 equiv) leads to the desired fully functional-
ized imidazole 11a in 81% yield (Table 3, entry 1). Addition-
ally, a Pd-catalyzed Negishi cross-coupling with 5k (0.9 equiv)
produces the highly functionalized imidazole 11b in 76%
yield (entry 2). Furthermore, the Zn reagent 10b undergoes
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Table 2: Functionalization at position 5 of imidazoles 6.
Table 2: (Continued)
Entry
Organomagnesium
Electrophile
Product (yield [%])[b]
Reagent[a]
Entry
Organomagnesium
Reagent[a]
Electrophile
Product (yield [%])[b]
11
7e
5b
8k: 68[c]
[a] Exchange with iPrMgCl·LiCl (1.2 equiv). [b] Yield of isolated product.
[c] Negishi cross-coupling: ZnCl2 (1.1 equiv); then [Pd(PPh3)4] (5 mol%)
with R-I (0.9 equiv). [d] Negishi acylation: ZnCl2 (1.1 equiv); then
[Pd(PPh3)4] (5 mol%) with ArC(O)Cl (1.1 equiv).
1
2
7a
7a
5a, R=CO2Et
5j, R=CN
8a: 71[c]
8b: 90[c]
a smooth CuI-catalyzed allylation with 5g (0.9 equiv) to
furnish imidazole 11c in 86% yield (entry 3). The Pd-
catalyzed Negishi cross-coupling reactions with 5a
(1.1 equiv) and 5j (0.9 equiv) produce the highly functional-
ized imidazole derivatives 11d and 11e in 72 and 95% yield,
respectively (entries 4 and 5). To demonstrate the higher
reactivity of the Mg reagent 10b’ compared to the diimida-
zolylzinc reagent 10b, the Grignard reagent 10b’ was
submitted to an addition reaction with aldehyde 5l
(1.1 equiv), which furnished alcohol 11 f in 92% yield
(entry 6). Moreover, 10b’ reacts smoothly with 5m
(0.9 equiv) to afford thioether 11g in 93% yield (entry 7).
Interestingly, the corresponding diimidazolylzinc reagent 10b
does not undergo the two reactions mentioned above, but
leads only to the hydrolyzed species. The Mg reagent 10bꢀ
reacts with benzoyl chloride 5h (1.1 equiv) and [Pd(PPh3)4]
(5 mol%) after transmetalation with ZnCl2 (1.2 equiv) to give
the corresponding ketone 11h in 58% yield (entry 8).
Furthermore, after transmetalation with ZnCl2 (1.2 equiv),
Mg species 10c successfully undergoes a Pd-catalyzed Negishi
cross-coupling reaction to furnish imidazole 11i in 75% yield
(entry 9). Moreover, 10c also reacts readily with 5m
(0.9 equiv) to afford the thioether 11j in 70% yield (entry 10).
Depending on the substitution pattern, N-protected
imidazoles have shown the tendency to tautomerize, thereby
leading to mixtures of isomers after deprotection (triggered
by steric factors).[18] N-Sulfamoyl-protected imidazoles are
known to react with alkylating reagents exclusively through
their unsubstituted N atom.[19] Hence, we have used a slightly
amended method to that developed by Sames and co-
workers,[2a] and treated the fully functionalized imidazole
derivatives of type 11 with the Meerwein reagent (trimethyl-
oxonium tetrafluoroborate, 1 equiv) to generate the corre-
sponding imidazolium salts 12. The N,N-dimethylsulfamoyl
group at the N1-position is then cleaved by the addition of
HCl (conc.) to furnish the alkylated imidazoles 13 as only one
isomer.[20] Noteworthy, this method allows the selective
preparation of regioisomers 13a/b as well as 13c/13d
(Scheme 4).
3
4
5
7b
7b
7b
5 f
5k
5h
8c: 88[c]
8d: 98[c]
8e: 79[d]
6
7
8
7c
7c
7c
5 f
5c
5h
8 f: 60[c]
8g: 70[c]
8h: 66[d]
9
10
7d
7d
5a, R=CO2Et
5c, R=Cl
8i: 85[c]
8j: 80[c]
In summary, we have developed a general, selective, and
flexible synthetic method to prepare complex substituted
imidazoles in a regioselective manner starting from key
intermediate 1 through directed metalations and a sulfoxide/
magnesium exchange. Moreover, we demonstrated the selec-
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Table 3: Functionalization at position 2 of imidazoles 8.
Table 3: (Continued)
Entry Organometallic
reagent[a,b]
Electrophile
Product (yield [%])[c]
Entry Organometallic
reagent[a,b]
Electrophile
Product (yield [%])[c]
10
10c
5m
11j: 70[g]
[a] Metalation with TMP2ZnCl·2 MgCl2·2 LiCl (1.2 equiv). [b] Metalation
with TMPMgCl·LiCl (1.2 equiv). [c] Yield of isolated product. [d] Allyla-
tion: CuCN·2LiCl (1 equiv) with allyl bromide (1.1 equiv). [e] Negishi
cross-coupling: [Pd(PPh3)4] (5 mol%) with Ar-I (0.9 or 1.1 equiv).
[f] Addition to aldehyde (1.1 equiv). [g] Addition to S-arylbenzene
thiosulfonate (0.9 equiv). [h] Negishi acylation: ZnCl2 (1.1 equiv); then
[Pd(PPh3)4] (5 mol%) with ArCOCl (1.1 equiv). [i] Negishi cross-cou-
pling: ZnCl2 (1.1 equiv); then [Pd(PPh3)4] (5 mol%) with Ar-I (0.9 equiv).
1
10a
5g
11a: 81[d]
2
3
10a
10b
5k
5g
11b: 76[e]
11c: 86[d]
Scheme 4. Selective methylation with the Meerwein reagent at N3 of
the imidazole ring and subsequent deprotection at N1.
4
5
10b
10b
5a, R=CO2Et 11d: 72[e]
5j, R=CN
11e: 95[e]
tive N3-alkylation followed by deprotection of N1 (trans-N-
alkylation), thus allowing the regioselective N-alkylation of
complex imidazoles. Further extensions of this work are
currently underway in our laboratories.
Received: October 22, 2013
Published online: December 18, 2013
6
7
10b’
10b’
5l
11 f: 92[f]
Keywords: imidazole · magnesium · metalation · sulfoxides ·
.
zinc
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