Selective magnesiation or zincation of highly functionalized alkenes and cycloalkenes using 2,2,6,6-tetramethylpiperidyl bases

Article abstract of DOI:10.1002/anie.201006641

Smooth and mild: Mg or Zn TMP bases (TMP=2,2,6,6-tetramethylpiperidyl) allow the smooth metalation of various types of polyfunctional unsaturated substrates. Several sensitive functional groups such as ester, nitro, or trifluoromethylcarbonyl groups are t

Full text of DOI:10.1002/anie.201006641

Communications
DOI: 10.1002/anie.201006641
Metalation of Alkenes
Selective Magnesiation or Zincation of Highly Functionalized Alkenes
and Cycloalkenes Using 2,2,6,6-Tetramethylpiperidyl Bases**
Tomke Bresser and Paul Knochel*
Dedicated to Professor Carmen Najera on the occasion of her 60th birthday
The preparation of substituted aromatic molecules and
heterocycles is of great importance because of the potential
biological activity of such structures, which are present in
many pharmaceuticals or agrochemicals.[1] The functionaliza-
tion of these compounds has often been achieved by directed
metalation using various bases.[2] Mg and Zn TMP bases
complexed with lithium chloride, such as TMPMgCl·LiCl (1,
TMP = 2,2,6,6-tetramethylpiperidyl),[3] TMP2Mg·2 LiCl (2),[4]
TMPZnCl·LiCl (3),[5] and TMP2Zn·2MgCl2·2 LiCl (4)[6] have
proven to be especially versatile metalating agents. In
contrast to aromatic and heteroaromatic systems, the directed
deprotonation of functionalized non-aromatic and olefinic
systems is more difficult and sensitive, as substituents such as
a nitro or a trifluoromethylcarbonyl group are usually not
tolerated. Furthermore, when the alkenes contain an ester or
a nitrile substituent, lithiation temperatures between À113
and À958C are required.[7] Herein, we report that the
kinetically very active TMP bases 1–4 allow the smooth
metalation of various substituted olefins of type 5 under
practical reaction conditions to give highly functionalized
unsaturated organometallic compounds of type 6 (Scheme 1).
Quenching of these compounds with various electrophi-
les E+ provides polyfunctional alkenes of type 7–9 with
high chemoselectivity. Remarkably, this method allows the
first reported preparation of a-zincated nitroolefins
(6: FG1=NO2; MetX = ZnCl) and b-zincated trifluoromethyl
ketones (6: FG2 = COCF3; FG1 = NMe2; MetX = ZnCl; see
Tables 1–3). Also, the zincation or magnesiation of various
unsaturated esters can now be carried out under practical
conditions (between À308C and 258C).
The reaction of ethyl (2E)-3-ethoxyacrylate ((E)-5a) with
TMPMgCl·LiCl (1; 1.2 equiv, THF, 258C, 0.5 h) led to a highly
regioselective magnesiation at the 2-position to afford the
magnesium reagent (E)-6a (> 90%, Scheme 2a). The stereo-
selective copper-mediated acylation[8] of (E)-6a with 2-furoyl
chloride (2 equiv) provided the E-ketoester ((E)-7a) in 80%
yield. Similarly, the functionalized magnesium reagent (E)-6a
was acylated with pivaloyl chloride and morpholine-4-car-
bonyl chloride to give the E-1,4-dicarbonyl compounds
(E)-7b and c in 58 and 84% yield, respectively (Table 1,
entries 1 and 2). The copper-catalyzed allylation[8] of (E)-6a
with 3-bromocyclohexene or its addition to CyCHO stereo-
selectively provided the ester (E)-7d (83%; Table 1, entry 3)
and the lactone 7e (85%; entry 4). The sensitive dihydrofuran
5b[9] was cleanly metalated with TMP2Zn·2 LiCl (4; 0.6 equiv,
258C, 0.5 h) to afford the diorganozinc compound 6b
(>90%). A copper-mediated acylation[8] with PhCOCl pro-
vides the ketoester 7 f in 80% yield (Scheme 2b). The zinc
reagent 6b was also allylated with ethyl 2-(bromomethyl)a-
crylate[10] or underwent a Negishi cross-coupling reaction[11]
with 1-chloro-4-iodobenzene (3% [Pd(dba)2], 6% P(2-
furyl)3, 258C, 3 h)[12] to give the expected dihydrofurans 7g
and h in 83 and 55% yield, respectively (Table 1, entries 5 and
6). The related tetrahydropyridine 5c[9] requires a stronger
Scheme 1. Chemoselective metalation of functionalized alkenes.
FG=functional group.
[*] MSc. T. Bresser, Prof. Dr. P. Knochel
Ludwig Maximilians-Universitꢀt Mꢁnchen, Department Chemie
Butenandtstrasse 5-13, Haus F, 81377 Mꢁnchen (Germany)
Fax: (+49)89-2180-77680
E-mail: paul.knochel@cup.uni-muenchen.de
[**] We thank the Fonds der Chemischen Industrie, the European
Research Council (ERC), and the Deutsche Forschungsgemein-
schaft (DFG) for financial support. We also thank BASF AG
(Ludwigshafen) and Chemetall GmbH (Frankfurt) for the generous
gift of chemicals.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201006641.
Scheme 2. b-Metalation of unsaturated esters using TMP bases 1, 2, and 4,
and subsequent functionalization with electrophiles.
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Angew. Chem. Int. Ed. 2011, 50, 1914 –1917

Table 1: b-Magnesiation or zincation of unsaturated carbonyl compounds
using TMP bases 1–4 and subsequent quenching with electrophiles.
Table 2: a-Metalation of unsaturated nitriles using TMP-bases 1 and 3
and subsequent functionalization with electrophiles.
Entry
Substrate
E+
Product [%][a]
Entry
1
Substrate
E+
Product [%][a]
1
(E)-5a
(E)-7b: 84%[d]
5 f
8b: 68%
(258C, 0.5 h)[b,c]
(258C, 0.5 h)[b,c]
(E)-5a
2
3
(258C, 0.5 h)[b,c]
2
3
4
5 f
MeSSO2Me
I2
8c: R=SMe:70%
8d: R=I: 94%
(E)-7c: 58%[d]
(E)-7d: 83%[e]
(258C, 0.5 h)[b,c]
5 f
(258C, 0.5 h)[b,c]
5 f
(E)-5a
(258C, 0.5 h)[b,c]
p-IC6H4CO2Et
8e: R=C6H4pCO2Et: 80%[d]
(258C, 0.5 h)[b,c]
(E)-5a
4
5
5
6
(258C, 0.5 h)[b,c]
(E)-5g
(E)-8g: 67%[f]
7e: 85%
(258C, 0.5 h)[b,e]
5b
7g: 83%[e]
(258C, 0.5 h)[b,f]
(E)-5h
(Z)-8h: 63%[f]
5b
(258C, 1.5 h)[b,c]
6
(258C, 0.5 h)[b,f]
7h: 55%[g]
(E)-5h
7
(258C, 1.5 h)[b,c]
8i: 88% (E/Z=50:50)[d]
7
8
5c
(À108C, 0.5 h)[b,h]
5c
p-IC6H4OMe
7j: R=C6H4pOMe: 80%[g]
[a] Yield of analytically pure isolated product. [b] Metalation conditions.
[c] TMPMgCl·LiCl. [d] 3% [Pd(dba)2] and 6% P(2-furyl)3 were added.
[e] TMPZnCl·LiCl. [f] 5% CuCN·2 LiCl was added.
p-ClC6H4COCl 7k: R=COC6H4pCl: 50%[d]
(À108C, 0.5 h)[b,h]
TMP base: TMP2Mg·2 LiCl (2). This base can magnesiate the
N-heterocycle 5c at À108C within 0.5 h to give the magne-
sium species 6c (> 90%), reaction of which with PhCHO
(2 equiv) gave the bicyclic lactone 7i in 65% yield (Sche-
me 2c). Similarly, an acylation of the copper derivative of 6c[8]
with 4-chlorobenzoyl chloride or a palladium(0)-catalyzed
cross-coupling reaction[11] using 4-iodoanisole led to the new
tetrahydropyrimidines 7j–k in 50–80% yield (Table 1,
entries 7 and 8).
9
10
11
12
7e
(À308C, 20 min)[b,h]
7e
I2
7l: R=I: 88%
7m: R=Cl: 67%
7n: R=allyl: 64%[e]
Cl3F3C2
(À308C, 20 min)[b,h]
7e
allyl bromide
(À308C, 20 min)[b,h]
7e
p-IC6H4OMe 7o: R=C6H4pOMe: 68%[g]
(À308C, 20 min)[b,h]
Deprotonation of the lactone 7e using TMP2Mg·2 LiCl (2;
À308C, 20 min) gave the corresponding Mg intermediate,
which was quenched with iodine to give the iodolactone 7l in
88% yield (Table 1, entry 9). Chlorination of this Mg reagent
with Cl3F3C2 or a copper-catalyzed allylation with allyl
bromide[8] or a palladium-catalyzed Negishi cross-coupling
reaction[11] led to the functionalized lactones 7m–o in 64–68%
yield (Table 1, entries 10–12). Ethyl (2E)-3-(phenylsulfony-
l)acrylate ((E)-5d)[9] was also smoothly zincated at 258C using
TMPZnCl·LiCl (3; 1.2 equiv, 15 min). The metalation also
occurs at the b-position to afford the corresponding organo-
zinc that undergoes a copper-mediated allylation[8] with ethyl
2-(bromomethyl)acrylate[10] to furnish the ester (E)-7p in
67% yield (Table 1, entry 13).
13
14
(E)-5d
(E)-7p: 67%[e]
(258C, 15 min)[b,i]
(E)-5e
(E)-7r: 85%[e]
(258C, 0.5 h)[b,i]
[a] Yield of analytically pure isolated product.[b] Metalation conditions.
[c] TMPMgCl·LiCl. [d] 1.1 equiv CuCN·2 LiCl was added. [e] 5% CuCN·2
LiCl was added. [f] TMP2ZnCl·2 LiCl. [g] 3% [Pd(dba)2] (dba=trans,trans-
dibenzylidineacetone) and 6% P(2-furyl)3 were added. [h] TMP2MgCl·2 LiCl.
[i] TMPZnCl·LiCl.
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Communications
Table 3: a-Metalation of unsaturated nitroolefins using TMPZnCl·LiCl 3
and subsequent functionalization with electrophiles.
Entry
Substrate
E+
I2
Product [%][a]
1
5i
9b: 89%
(08C, 15 min)[b,c]
2
5j
9d: 55%[d]
(À208C, 1.0 h)[b,c]
Scheme 3. Metalation of an unsaturated trifluoromethyl ketone and nitriles
using TMP bases 1 and 3, and subsequent functionalization. Pr=propyl,
tfp=P(2-furyl)3.
3
4
5j
allyl bromide
I2
9e: R=allyl: 70%[e]
9 f: R=I: 70%
(À208C, 1.0 h)[b,c]
5j
(À208C, 1.0 h)[b,c]
2-chloro-5-iodopyrimidine[11] to give the unsaturated nitrile
8a in 93% yield (Scheme 3b). The magnesium reagent 6 f was
also trapped with 4-(dimethylamino)benzaldehyde, MeS-
SO2Me, iodine, or submitted to a Negishi cross-coupling
reaction[11] to prove the new functionalized unsaturated
nitriles 8b–e in 68-94% yield (Table 2, entries 1–4). Reaction
of the dihydrofuran acetonitrile (E)-5g[9] with TMPZnCl·LiCl
(3; 1.2 equiv) led to a stereoselective zincation (258C, 0.5 h)
to afford the alkenylzinc compound (E)-6g that underwent a
palladium-catalyzed cross-coupling with 4-iodo-benzoni-
trile[11] to produce the dinitrile (E)-8 f in 62% yield (Sche-
me 3c). The zinc reagent (E)-6g is remarkably stable with
respect to b-elimination, and reacted with allyl bromide to
give (E)-8g in 67% yield (Table 2, entry 5). Also, the
pyrrolidyl acrylonitrile ((E)-5h)[9] was easily magnesiated
with TMPMgCl·LiCl (1; 1.2 equiv, 258C, 1.5 h) to provide the
Mg species, which was allylated with 3-bromocyclohexene in
the presence of 5% CuCN·2 LiCl[8] to give the aminonitrile
(Z)-8h in 63% yield (Table 2, entry 6). Palladium-catalyzed
cross-coupling of the Mg compound with 4-iodo-chloroben-
zene[11] generated the nitrile 8i as an E/Z mixture (88%,
entry 7).
5
(E)-5k
9h: 57%(E/Z=80:20)[f]
(E)-9i: 70%[e]
(À508C, 0.5 h)[b,c]
6
7
8
(E)-5l
(À508C, 1.0 h)[b,c]
(E)-5l
(À508C, 1.0 h)[b,c]
9j: 49% (E/Z=60:40)[e]
(E)-9k: 72%[e]
(E)-5m
(À508C, 0.5 h)[b,c]
[a] Yield of analytically pure isolated product. [b] Metalation conditions.
[c] TMPZnCl·LiCl. [d] 1.1 equiv CuCN·2 LiCl was added. [e] 5% CuCN·2
LiCl was added. [f] 3% [Pd(dba)2] and 6% P(2-furyl)3 were added.
a-Metalated nitroolefins are elusive intermediates and
their preparation has not been reported to date.[15] This
metalation can be achieved using TMPZnCl·LiCl (3). Thus,
the dithiolane nitroolefin (5i)[9] was smoothly zincated using
TMPZnCl·LiCl (3; 1.2 equiv) at 08C within 15 min to provide
the a-zincated nitroolefin 6i (> 95%), which was allylated
with ethyl 2-(bromomethyl)acrylate[8,10] to afford the nitro-
olefin 9a in 78% yield (Scheme 4a). The zinc species 6i was
also iodinated; the resulting iodide 9b was isolated in 89%
yield (Table 3, entry 1). Remarkably, the diphenylnitroolefin
(5j)[9] could be converted into the alkenylzinc 6j using
TMPZnCl·LiCl (3; 1.2 equiv, À208C, 1.0 h). This zinc reagent
underwent a palladium-catalyzed cross-coupling with 1-iodo-
4-(trifluoromethyl)benzene[11] to give the triarylated nitro-
olefin 9c in 55% yield (Scheme 4b). Additionally, the
zincated nitroolefin was quenched with 2-furoyl chloride,
allyl bromide, or iodine to provide the corresponding nitro-
olefins 9d–f in 55–70% yield (Table 3, entries 2–4). Similarly,
Remarkably, TMPZnCl·LiCl (3) also allows the b-zinca-
tion (258C, 0.5 h) of (3E)-4-(dimethylamino)-1,1,1-trifluoro-
but-3-en-2-one ((E)-5e),[9] which bears a sensitive CF3CO
group. Acylation[8] of the resulting organozinc (E)-6e with
PhCOCl led to the expected new functionalized amine (E)-7q
in 80% yield (Scheme 3a). Allylation of intermediate (E)-6e
led to the dienic trifluoromethyl ketone (E)-7r (85%,
entry 14) after double-bond isomerization during chromato-
graphic purification. Alkenylmagnesium compounds of type
6, which bear an electron-withdrawing group such as a
nitrile,[13] were previously prepared by a Br/Mg exchange
reaction using iPrMgCl·LiCl starting from an a-bromoni-
trile.[14]
Remarkably, when using TMPMgCl·LiCl (1; 1.2 equiv),
the unsaturated nitrile 5 f[9] was directly magnesiated (258C,
0.5 h) to give the magnesium reagent 6 f (> 90%) that
undergoes
a palladium(0)-catalyzed cross-coupling with
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Angew. Chem. Int. Ed. 2011, 50, 1914 –1917

pentane 1:9), the nitroolefin (E)-9i (397 mg, 70%) was
isolated as a yellow oil.
Received: October 22, 2010
Published online: January 18, 2011
Keywords: magnesium · metalations · nitroalkenes ·
.
TMP bases · zinc
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Scheme 4. a-Metalation of unsaturated nitroolefins using TMPZnCl·LiCl (3) and
subsequent functionalization with electrophiles.
2-cyclohexyl-nitroethylene ((E)-5k)[9] was zincated with
TMPZnCl·LiCl (3; 1.2 equiv, À508C, 0.5 h) to give the zinc
species (E)-6k, which was trapped with allyl bromide[8] to give
the a-functionalized nitroolefin (E)-9g in 77% yield (Sche-
me 4c). Furthermore, the zincated nitroolefin (E)-6k under-
went a palladium(0)-catalyzed cross-coupling[11] with ethyl
4-iodobenzoate to give the nitro derivative 9h (57% yield,
E/Z = 80:20; Table 3, entry 5). Likewise, b-trans-nitrostyrene
((E)-5l) reacted with the zinc base 3 (1.2 equiv, À508C, 1.0 h),
and the resulting alkenylzinc reagent underwent a copper-
mediated allylation[8] with allyl bromide to give (E)-9i as one
isomer in 70% yield (Table 3, entry 6). However, trapping the
zincated nitrostyrene (E)-5l with 3-bromocyclohexene led to
the allylated product 9j as a 60:40 mixture of isomers (49%,
entry 7).
[3] a) A. Krasovskiy, V. Krasovskaya, P. Knochel, Angew. Chem.
2006, 118, 3024; Angew. Chem. Int. Ed. 2006, 45, 2958; b) W. Lin,
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Knochel, Org. Lett. 2009, 11, 3406; e) C. Despotopoulou, L.
Klier, P. Knochel, Org. Lett. 2009, 11, 3326.
[4] a) G. C. Clososki, C. J. Rohbogner, P. Knochel, Angew. Chem.
2007, 119, 7825; Angew. Chem. Int. Ed. 2007, 46, 7681; b) C. J.
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1526; Angew. Chem. Int. Ed. 2008, 47, 1503; c) M. Mosrin, N.
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[5] a) M. Mosrin, P. Knochel, Org. Lett. 2009, 11, 1837; b) T. Bresser,
M. Mosrin, G. Monzon, P. Knochel, J. Org. Chem. 2010, 75, 4686;
c) P. Knochel, G. Monzon, Synlett 2010, 304; d) P. Knochel, F.
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Chem. Commun. 2008, 47, 6387.
Finally, 2-[(E)-2-nitrovinyl]thiophene ((E)-5m)[9] was
metalated at the a-position of the nitro group with
TMPZnCl·LiCl (3; 1.2 equiv, 0.5 h, À508C) and the resulting
zinc species was trapped with allyl bromide to give the new
substituted olefin (E)-9k in 72% yield (Table 3, entry 8).
In summary, we have shown that the kinetically highly
active bases 1–4 allow a smooth magnesiation or zincation of
several new classes of highly functionalized olefins. In
particular, new b-zincated unsaturated trifluoromethyl
ketones and a-zincated nitroolefins have been prepared and
successfully reacted with electrophiles. Further extensions of
this work are currently underway.
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[9] See the Supporting Information.
[10] J. Villiꢁras, M. Rambaud, Org. Synth. 1988, 66, 220.
[11] E. Negishi, Acc. Chem. Res. 1982, 15, 340.
Experimental Section
Typical procedure for the metalation of substituted vinylic substrates
((E)-9i):
[12] a) V. Farina, B. Krishnan, J. Am. Chem. Soc. 1991, 113, 9585;
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TMPZnCl·LiCl (3; 1.3m in THF, 2.77 mL, 3.6 mmol) was added
to a solution of b-trans-nitrostyrene ((E)-5l; 450 mg, 3.0 mmol) in
THF (3 mL) at À508C and the mixture was stirred for 1 h. After this
time, CuCN·2 LiCl (1m solution in THF, 0.15 mL, 5 mol%) was
added. After 5 min of stirring, allyl bromide (720 mg, 6.0 mmol) was
added and the mixture was slowly warmed to À208C over 2 h. After
the workup and purification by flash chromatography (ether/2-methyl
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