Air-stable solid aryl and heteroaryl organozinc pivalates: Syntheses and applications in organic synthesis

Article abstract of DOI:10.1002/chem.201403015

A wide range of air-stable, solid, polyfunctional aryl and heteroarylzinc pivalates were efficiently prepared by either magnesium insertion or Hal/Mg exchange followed by transmetalation with Zn(OPiv)₂ (OPiv=pivalate). By reducing the amount of

Full text of DOI:10.1002/chem.201403015

DOI: 10.1002/chem.201403015
Full Paper
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Organozinc Reagents
Air-Stable Solid Aryl and Heteroaryl Organozinc Pivalates:
Syntheses and Applications in Organic Synthesis
Sophia M. Manolikakes,[a] Mario Ellwart,[a] Christos I. Stathakis,[b] and Paul Knochel*[a]
Abstract: A wide range of air-stable, solid, polyfunctional
aryl and heteroarylzinc pivalates were efficiently prepared by
either magnesium insertion or Hal/Mg exchange followed by
transmetalation with Zn(OPiv)2 (OPiv=pivalate). By reducing
the amount of LiCl the air stability could be significantly en-
hanced compared with previously prepared reagents. An al-
ternative route is directed magnesiation using TMPMgCl·LiCl
(TMP=2,2,6,6-tetramethylpiperidyl) followed by transmetala-
tion with Zn(OPiv)2 or, for very sensitive substrates, direct
zincation by using TMPZnOPiv. These zinc reagents not only
show excellent stability towards air, but they also undergo
a broad range of CÀC bond-formation reactions, such as al-
lylation and carbocupration reactions, as well as addition to
aldehydes and 1,4-addition reactions. Acylation reactions
can be performed by using an excess of TMSCl to overcome
side reactions of the omnipresent pivalate anion.
Introduction
RZnOPiv·Mg(OPiv)Cl·LiCl. The air-stability of such zinc organo-
metallics was substantially superior to organozinc pivalates
prepared by magnesium insertion (or exchange).[5b] In the pres-
ence of sensitive functionalities such as an aldehyde or a nitro
group, the milder zinc amide base TMPZnOPiv·Mg(OPiv)-
Cl·LiCl[5c] (3) may be used for highly selective metalation reac-
tions to give the desired organozinc reagents, which undergo
a range of reactions with various electrophiles.
Organozinc reagents play a major role in organometallic
chemistry due to their high compatibility with a broad variety
of functional groups.[1] Moreover, they are valuable reagents
for transition-metal mediated CÀC bond-formation reactions,
such as Negishi cross-coupling,[2] allylation,[3] or acylation[4] re-
actions. However, their limited stability towards air and mois-
ture represents a serious drawback for their practical use in the
laboratory and for industrial applications.
Previous work describes mainly the behavior of organozinc
pivalates in Negishi cross-coupling reactions. Herein, we have
expanded the scope of these new air-stable organometallics.
We have now investigated the reactivity of organozinc piva-
lates in 1,4-additions,[7] carbocuprations[8] as well as allylations,
acylation reactions and their addition to aldehydes.
To overcome this problem, we recently developed a method
for the preparation of aryl and heteroaryl zinc pivalates, which
are easy-to-handle solids with exceptional stability when ex-
posed to air.[5] These zinc reagents can be prepared by magne-
sium insertion or halogen–magnesium exchange followed by
transmetalation with Zn(OPiv)2·2LiCl (1a, OPiv=pivalate) to
give the corresponding aryl, heteroaryl, and benzylic zinc re-
agents of general formula RZnOPiv·Mg(OPiv)X·2LiCl (X=Cl, Br,
I).[5a] A halogen–lithium exchange followed by transmetalation
with Zn(OPiv)2 (1b) proved to be a feasible way to prepare 2-
pyridylzinc reagents.[5d] Another possible route is directed met-
alation using the sterically hindered base TMPMgCl·LiCl[6] (2,
TMP=2,2,6,6-tetramethylpiperidyl) and subsequent addition of
Zn(OPiv)2 (1b), giving organozinc reagents of the type
Results and Discussion
As shown previously, reducing the amount of the hygroscopic
lithium chloride from 2.5 to 1.25 equivalent improves the air-
and moisture-stability of the corresponding zinc reagents.[5b]
Therefore, we have performed the transmetalation step not
with Zn(OPiv)2·2LiCl (1a) but with the LiCl-free salt Zn(OPiv)2
(1b). Thus, the magnesium insertion reaction was performed
in the presence of 1.25 equivalent of LiCl[9] at ambient temper-
ature followed by addition of solid Zn(OPiv)2 (1b, 1.2 equiv;
Scheme 1, method A). Exchange reactions were performed by
using iPrMgCl·LiCl (1.1 equiv) at low temperature, and subse-
quent transmetalation with 1b gave the desired organozinc
pivalates (method B). In both cases, the solid organozinc piva-
lates were obtained after solvent evaporation in high vacuum
(0.1 mmHg, 3–6 h).
[a] S. M. Manolikakes, M. Ellwart, Prof. Dr. P. Knochel
Department Chemie
Ludwig-Maximilians-Universitꢀt Mꢁnchen
Butenandtstrasse 5–13, Haus F, 81377 Mꢁnchen (Germany)
Fax: (+49)89-2180-77680
E-mail: paul.knochel@cup.uni-muenchen.de
[b] Dr. C. I. Stathakis
Although, we call these reagents organozinc pivalates and
associate these compounds with the formula “RZnOPiv”, this is
certainly an oversimplification because it does not take ac-
count of the magnesium and lithium salts present in these
Pharmathen S.A., 9th km Thermi-Thessaloniki
Thessaloniki 57001 (Greece)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201403015.
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Table 1. Organozinc pivalates prepared by magnesium insertion (meth-
od A) or Hal/Mg exchange (method B).
Entry
Substrate
Method
T [8C], t [h]
Product[a]
Yield
[%][b]
A
25, 2
1
2
92
92
4a
4b
5a
5b
Scheme 1. Synthesis of organozinc pivalates through Mg insertion (meth-
od A) or Hal/Mg exchange (method B) followed by transmetalation with
Zn(OPiv)2. [a] Mg(OPiv)Hal·LiCl omitted for clarity.
B
À30, 0.5
B
25, 4
mixtures. Structural studies in solution and on the crystal per-
formed by Mulvey and Hevia indicate that these reagents are
actually organozinc halides complexed with magnesium piva-
late and lithium chloride.[10] Therefore, a more accurate way to
describe these trimetallic clusters would be the general formu-
la: “RZnHal·Mg(OPiv)2·LiCl” (Hal=Br, I, Cl). For clarity, we will
use the formula RZnOPiv in this manuscript.
3
4
5
91
92
82
4c
4d
4e
5c
5d
5e
A
25, 3
A
25, 2
By using method A, 2-bromo-4-chloro-1-methoxybenzene
(4a) reacted readily with Mg (2.5 equiv) in the presence of LiCl
(1.25 equiv) to give, after transmetalation with Zn(OPiv)2 (1b),
the desired organozinc pivalate 5a in 92% yield (Table 1,
entry 1). The more sensitive 4-ethyl iodobenzoate (4b) was
converted into the corresponding organozinc reagent by per-
forming a Mg/I exchange using iPrMgCl·LiCl (1.1 equiv, À308C,
30 min) followed by addition of 1b according to method B to
furnish the zinc reagent 5b in 92% yield (entry 2). By using the
same method at ambient temperature, 4-substituted iodoben-
zene 4c was converted into zinc reagent 5c in 91% yield
(entry 3). The electron-rich halides 4d–f underwent smooth
Mg-insertion at 258C in 2–3 h to give, after transmetalation
with Zn(OPiv)2 (1b), zinc pivalates 5d–f in 79–92% yield (en-
tries 4–6). 4-Bromobenzonitrile (4g) as well as bromopyrimi-
dine 4h were converted into the corresponding organozinc
species 5g–h by using iPrMgCl·LiCl (1.1 equiv, 08C, 1–12 h) and
subsequent addition of Zn(OPiv)2 (1b, 1.2 equiv) in 72–84%
yield (entries 7 and 8). A Mg-insertion was also performed on
3-bromobenzothiophene (4i, 258C, 3 h) leading, after transme-
talation with 1b, to the zinc reagent 5i in 91% yield (entry 9).
The resulting solid organozinc reagents showed enhanced
air-stability compared with zinc pivalates prepared using Zn-
(OPiv)2·2LiCl.[5a] When, for instance, reagent 5a was exposed to
air, 91% of the initial activity was retained after 1 h exposure
at 258C. Even after 4 h air exposure, 81% of the original activi-
ty remained.[11] The zinc reagents not only displayed high sta-
bility towards air and moisture, but they also showed high re-
activity in copper-catalyzed allylation reactions. Thus, zinc piva-
late 5a reacted readily with 3-bromocyclohexene (6a,
1.1 equiv, À208C, 2 h) in the presence of 10 mol% CuCN·2
LiCl[4b] to give the expected product 7a in 81% yield
(Scheme 2). The organozinc pivalate 5b showed similar reactiv-
ity and furnished, after reaction with 6a (1.1 equiv) in the pres-
ence of CuCN·2LiCl (10 mol%) within 1 h at À208C, the de-
sired product 7b in 78% yield. By using the same conditions,
zincated pyrimidine 5h afforded allylated heterocycle 7c in
81% yield.
A
25, 1
6
7
79
72
4 f
5 f
B
0, 12
4g
5g
B
0, 1
8
9
84
91
4h
4i
5h
5i
A
25, 3
[a] Complexed Mg(OPiv)X (X=Br, I) and LiCl are omitted for clarity. [b] De-
termined by titration against iodine; see the Supporting Information.
Scheme 2. Copper-catalyzed allylation of various zinc reagents with 3-bro-
mocyclohexene (6a). [a] Mg(OPiv)Hal·LiCl omitted for clarity.
Acylation reactions were performed by using stoichiometric
amounts of CuCN·2 LiCl (1.1 equiv) and an excess of TMSCl
(6.0 equiv). We have observed that in the absence of TMSCl
the reactivity of the acyl chlorides dropped significantly. This
might be due to competitive formation of a mixed anhydride
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Table 2. CuCN·2 LiCl mediated carbometalation of organozinc pivalates
of type 5.
Entry Zinc reagent
Electrophiles
Product (E/Z)
Yield
[%][a]
1)
10b
2) H2O
1
63
60
5b
12c (>95:5)
12d (>95:5)
1)
Scheme 3. Copper-mediated acylation of the zinc reagents 5a and 5b.
10b
2) I2
2
by the reaction of the pivalate anion (PivOÀ) with the acyl chlo-
ride. This mixed anhydride is a weaker acylating reagent,
which results in very slow conversion into the desired prod-
ucts. We assume that the role of the TMSCl is to trap the free
PivOÀ in the form of the silyl ester 9’ (Scheme 3). Under opti-
mized reaction conditions, 5a underwent a smooth acylation
reaction with 2-furoyl chloride (8a) at 258C in 3 h, furnishing
ketone 9a in 96% yield (Scheme 3). The organozinc pivalate
5b reacted in a similar way with either the perfluorinated ben-
zoyl chloride 8b or 4-bromobenzoyl chloride (8c), producing
the desired compounds 9b–c in 62–84% yield.
5e
1)
10a
2)
3
60
48
5i
12e (91:9)
12 f (93:7)
1)
10b
2) H2O
4
5a
Besides allylations and acylations, carbocuprations of alkynes
were also performed in the presence of CuCN·2LiCl (1.1 equiv).
Thus, the pyrimidine derivative 5h reacted with diethyl but-2-
ynedioate (10a, 1.2 equiv, À30 to À108C in THF) to give the
copper intermediate 11, which could be trapped with either
water or allyl bromide (6b, 1.5 equiv, 2 h) leading to the forma-
tion of alkenes 12a and 12b in 63 and 72% yield, respectively.
In both cases, the Z-isomer was the major product (Z/E=9:1;
Scheme 4).[12] The addition of TMSCl proved to be disadvanta-
geous for carbocupration reactions and led only to decomposi-
tion of starting material.
[a] Isolated yield of analytically pure product.
yield (Table 2, entry 1). Likewise, silyl ether 5e reacted with
ethyl propiolate (10b, À308C, 5 h) and furnished, after addi-
tion of an excess of iodine, trisubstituted alkene 12d in 60%
yield (entry 2). A syn-carbocupration was performed by react-
ing benzothiophene derivative 5i with diethyl but-2-ynedioate
(10a, À308C, 15 h). The generated copper intermediate was
then allylated with ethyl 2-(bromomethyl)acrylate (6c,
1.5 equiv, À308C, 2 h) to provide tetrasubstituted alkene 12e
in 60% yield with an E/Z ratio of 91:9 (entry 3). The organozinc
reagent 5a also underwent carbocupration with ethyl propio-
late (10b, 1.2 equiv, À108C, 6 h) in the presence of CuCN·2LiCl
(1.1 equiv) to furnish, after hydrolysis, E-alkene 12 f in 48%
yield (entry 4).
4-(Ethoxycarbonyl)phenylzinc pivalate (5b) reacted under
similar conditions in the presence of CuCN·2LiCl (1.1 equiv)
with ethyl propiolate (10b, À108C, 2 h in THF) to afford, after
quenching with water, the E alkene 12c selectively in 63%
The addition of an organozinc pivalate to an aldehyde has
only been briefly studied.[5a] In preliminary experiments we
have noticed a low reactivity of these organozinc reagents to-
wards aldehydes. This low reactivity can be overcome by the
addition of Ti(OiPr)4.[13] Best results were obtained by using
equimolar amounts of AlMe3 in toluene/THF at 258C, as report-
ed by Woodward et al.[14] The role of AlMe3 may be to facilitate
conversion of RZnX (X=Br, I, OPiv) species into mixed organo-
zinc reagents of type RZnMe (13), which may possess a higher
reactivity than the corresponding organozinc halides
(Scheme 5). Thus, when zinc reagent 5b was treated with
AlMe3 (1.0 equiv, 258C, 10 min), the addition of the resulting
zinc species to benzaldehyde (14, 0.8 equiv, 258C, 2 h) pro-
ceeded smoothly to give alcohol 15a in 94% yield (Scheme 5).
Scheme 4. Carbometalation of diethyl but-2-ynedioate (10a) in the presence
of CuCN·2LiCl by using solid heteroaromatic zinc pivalate 5h.
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Scheme 5. AlMe3-mediated addition of organozinc pivalates of type 5 to
benzaldehyde (14).
Scheme 7. Rhodium-catalyzed 1,4-addition of functionalized organozinc
reagents of type 5 to cyclohex-2-enone (16a) and (E)-chalcone (16b).
Organozinc pivalates 5a,c,f,g reacted similarly and carbinols
15b–e were obtained in 57–72% yield.
1,4-Addition reactions to conjugated double bonds are gen-
erally performed with organocuprates.[7f–l] However, solid func-
tionalized zinc pivalates of type 5 showed only moderate reac-
tivity toward a Michael addition to cyclohex-2-enone in the
presence of CuCN·2LiCl and TMSCl. Thus, when zinc reagent
5b was treated with cyclohex-2-enone (16, 0.8 equiv) in the
leading to arylated ketone 17e in 91% yield. Heterocyclic re-
agent 5i underwent such Michael-addition to cyclohex-2-
enone (16a), leading to 3-substituted benzothiophene 17 f in
91% yield (Scheme 7). Zinc reagent 5b also underwent 1,4-ad-
dition to the acyclic Michael acceptor (E)-chalcone (16b) to
give the desired ketone 17g in 84% yield. The use of a,b-unsa-
turated esters led only to decomposition of starting materials
and only low conversions into the desired products could be
observed by GC-analysis.
Although aryl and heteroaryl halides used for the prepara-
tion of solid organozinc pivalates of type 5 are readily avail-
able, it was envisioned that these organometallics could be
prepared by directed metalation, which would allow the scope
of our preparations to be expanded to include various arenes
and heteroarenes as convenient starting materials. The sterical-
ly hindered base TMPMgCl·LiCl (2) was used to deprotonate
various carbo- and heterocycles[6] and the resulting magnesium
reagents were transmetalated by using Zn(OPiv)2 (1b)
(Table 3).[5b] This procedure gives access to a range of new
solid zinc reagents that show very high stability when exposed
to air.
Scheme 6. 1,4-Addition of functionalized organozinc reagent 5b to cyclo-
hex-2-enone (16a). [a] Determined by GC-analysis of hydrolyzed reaction
aliquots. [b] Isolated yield of analytically pure product.
presence of CuCN·2LiCl (1.1 equiv, 258C) only a low conversion
into the desired product 17a was observed (Scheme 6). The
1,4-addition of zinc pivalates of type 5 was improved by using
a method reported by Frost,[15] whereby rhodium-catalyzed ad-
dition of 2-heteroarylzinc reagents to Michael acceptors was
used. This method was derived from the rhodium-catalyzed
addition of organoboron reagents to a,b-unsaturated carbon-
yls, pioneered by Hayashi and Miyaura.[16] Hence, in the pres-
ence of 3 mol% [Rh(COD)Cl]2, 5b added readily to the Michael
acceptor 16a to give the desired product 17a in 95% yield
(Scheme 6).
Thus, ethyl 3-fluorobenzoate (18a) was readily metalated by
using 2 (1.1 equiv 08C, 2 h) and led, after transmetalation with
Zn(OPiv)2 (1b, 1.2 equiv), to the formation of zinc reagent 19a
in 92% yield (Table 3, entry 1). Chloro-substituted derivative
18b and the Boc-protected ester 18c also reacted under simi-
lar conditions (08C, 3–6 h), furnishing, after solvent evapora-
tion, solid organozinc pivalates 19b–c in 93–95% yield (en-
tries 2 and 3). Trisubstituted pyridine 18d was also metalated
by using TMPMgCl·LiCl (2, 1.1 equiv) at À408C for 2 h and,
after subsequent transmetalation with Zn(OPiv)2 (1b), zinc re-
agent 19d was obtained in 84% yield. Zincated pyrazine deriv-
atives 19e–f were obtained in the same way in 86–89% yield
by treating 18e and 18 f with base 2 (1.1 equiv, À20 to
À458C, 2–4 h) followed by transmetalation with Zn(OPiv)2 (1b)
(entries 5 and 6). Trisubstituted pyrimidine 18g and 2,4-dime-
thoxypyrimidine (18h) were both metalated by using
The 4-substituted organozinc pivalates 5c, 5d, and 5g un-
derwent Michael addition with cyclohexe-2-one (16a) under
the same conditions using 3 mol% [Rh(COD)Cl]2, and the corre-
sponding cyclohexanone derivatives 17b–d were obtained in
88–97% yield (Scheme 7). Disubstituted zinc reagent 5a also
underwent a smooth rhodium-catalyzed 1,4-addition to 16a,
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TMPMgCl·LiCl (2, 1.1 equiv) at 258C within 30 min and provid-
ed, after transmetalation with 1b, solid organozinc reagents
19g–h in 85–92% yield (entries 7 and 8). Isoquinoline 18i was
readily magnesiated by using 2 (1.1 equiv, 258C, 1 h) and, after
transmetalation to Zn(OPiv)2 (1b), reagent 19i was obtained in
85% yield (entry 9). Ester substituted bromofuran 18j required
a lower temperature of À258C for the metalation with 2
(1.1 equiv, 1 h), however, after addition of zinc pivalate (1b)
the perfectly stable zinc species 19j was obtained in 77% yield
(entry 10). Finally, by following this procedure, pyrazole deriva-
tives 18k–l were converted into the corresponding zinc re-
agents 19k–l in 83–85% yield (entries 11 and 12). As described
in our previous work, aryl and heteroaryl zinc pivalates of type
19 proved to be excellent nucleophiles in Negishi cross-cou-
plings.[5b] Herein, we report further reactions of the solid zinc
reagents of type 19. Thus, zinc reagent 19a was treated with
allyl bromide (6b, 1.2 equiv, À208C, 1 h, THF) in the presence
of 10 mol% CuCN·2LiCl, which furnished the trisubstituted
benzene derivative 20a in 98% yield (Scheme 7). Acylation
was performed under similar conditions used for the reagents
of type 5 (Scheme 3). Thus, when organozinc pivalate 19a was
treated with benzoyl chloride (8d) and CuCN·2LiCl (1.1 equiv)
in the presence of an excess of TMSCl, ketone 20b was ob-
tained in 89% yield. TMSCl is necessary for such an acylation;
in its absence only traces of the desired product were obtained
(Scheme 8).
Table 3. Organozinc pivalates of type 19 prepared by selective metala-
tion using TMPMgCl·LiCl (2) followed by transmetalation with Zn(OPiv)2
(1b).
Entry
Substrate
T
[8C]
t
[h]
Product[a]
Yield
[%][b]
1
0
2
6
3
92
93
95
18a
18b
19a
19b
2
3
0
0
18c
18d
18e
18 f
19c
19d
19e
19 f
4
5
6
À40
À45
À20
2
2
4
84
86
89
7
8
9
25
25
25
0.5
0.5
1
92
85
85
18g
18h
19g
19h
Scheme 8. CuCN·2LiCl-mediated reactions of functionalized organozinc
reagent 19a with allyl bromide (6b) and benzoyl chloride (8d).
Chloro-derivative 19b was allylated in a similar way by using
3-bromo-2-methylpropene (6d, 1.2 equiv, À208C, 1 h) in the
presence of 10 mol% CuCN·2LiCl to give the product 20c in
87% yield (Table 4, entry 1). Acylation of 19b by using either
3-chlorobenzoyl chloride (8e, 1.0 equiv, À45 to 258C, 2 h) or
cyclopropanecarbonyl chloride (8 f, 1.0 equiv, 0 to 258C, 2 h),
after transmetalation with CuCN·2LiCl (1.1 equiv) and in the
presence of an excess of TMSCl, furnished ketones 20d–e in
71–85% yield (entries 2 and 3). The Boc-protected zinc reagent
19c was allylated with ethyl 2-(bromomethyl)acrylate (6c,
1.0 equiv, À208C, 5 h) to give the desired product 20 f in 80%
yield (entry 4). The heterocyclic zinc reagents 19d and 19e
also underwent smooth acylation reactions with 3,4,5-trime-
thoxybenzoyl chloride (8g, 1.0 equiv, À20 to 258C, 4 h) and cy-
clohexanecarbonyl chloride (8h, 1.0 equiv, 0 to 258C, 2 h), to
give ketones 20g–h in 68–93% yield (entries 5 and 6). Zincat-
ed pyrazine derivative 19 f as well as zincated pyrimidine 19g
were allylated by using 3-bromocyclohex-1-ene (6a, 1.0 equiv,
À208C, 2 h) in the presence of 10 mol% CuCN·2LiCl to provide
18i
18j
19i
19j
10
11
À25
1
1
77
83
25
18k
19k
12
À30
0.5
85
18l
19l
[a] Complexed Mg(OPiv)Cl and LiCl are omitted for clarity. [b] Determined
by titration with iodine; see the Supporting Information.
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Table 4. CuCN·2LiCl mediated reactions of organozinc pivalates of type
19.
Table 4. (Continued)
Entry Zinc reagent
Electrophile
Product
Yield
[%][a]
Entry Zinc reagent
Electrophile
Product
Yield
[%][a]
MeSO2SMe
12
98[b]
19i
21
20n
1
87[b]
19b
6d
20c
13
74[c]
19j
8a
8d
20o
20p
2
85[c]
14
79[c]
19b
8e
20d
19k
3
71[c]
15
82[b]
19b
8 f
6c
20e
20 f
19l
6a
20q
4
80[b]
[a] Isolated yield of analytically pure product. [b] 10 mol% CuCN·2LiCl
was used. [c] 6.0 equiv TMSCl and 1.1 equiv CuCN·2LiCl were used.
19c
the desired products 20i–j in 89–93% yield (entries 7 and 8).
Zincated pyrimidine 19g and zincated isoquinoline 19i were
also acylated by using cyclopropanecarbonyl chloride (8 f,
1.0 equiv, 258C, 2 h) and furnished, after aqueous workup, ke-
tones 20k and 20m in 56–95% yield (entries 9 and 11). Zincat-
ed pyrimidine derivative 19h reacted with 3-bromo-2-methyl-
propene (6d, 1.2 equiv, À208C, 1 h) to give allylated product
20l in 93% yield (entry 10). Zincated furan derivative 19j un-
derwent smooth acylation by using 2-furoyl chloride (8a,
1.0 equiv, 258C, 2 h) to furnish the desired ketone 20o in 74%
yield (entry 13). Pyrazole derivative 19k was acylated with ben-
zoyl chloride (8d, 1.0 equiv, À208C, 2 h) to give ketone 20p in
79% yield (entry 14). Finally, zinc reagent 19l underwent
smooth allylation reaction with 3-bromocyclohex-1-ene (6a,
1.0 equiv, À208C, 2 h) leading to the product 20q in 82% yield
(entry 15).
5
68[c]
19d
8g
20g
6
93[c]
19e
8h
6a
6a
20h
20i
20j
7
89[b]
19 f
8
93[b]
The methods described above for the preparation of solid
organozinc reagents might be incompatible with the presence
of sensitive functionalities such as an aldehyde or related car-
bonyl groups. To overcome this limitation, we envisioned the
use of a milder zinc amide base for preparing the solid zinc
pivalates. In his pioneering work, Kondo introduced lithium di-
tert-butyl-tetramethylpiperidino zincate (tBu2Zn(TMP)Li) as an
excellent base for the directed metalation of aromatics.[17]
Other zincates and related ate bases have also been report-
19g
9
95[c]
19g
8 f
20k
10
93[b]
ed.[18] Recently, we prepared
TMPMgCl·LiCl (2) with Zn(OPiv)2 (1b, 1.05 equiv) to give the
corresponding zinc amide, tentatively written as
TMPZnOPiv·Mg(OPiv)Cl·LiCl (3; Scheme 9).[5c] This base proved
to be compatible with functionalities such as a nitro group, an
aldehyde, or sensitive heteroaromatic rings, and gives access
to a multitude of new solid organozinc pivalates, which show
excellent stability towards air.[11]
a new base by treating
19h
6c
8 f
20l
11
56[c]
19i
20m
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tion present in the benzothiophene derivative 22e, which was
converted into the stable organozinc reagent 23e in 89%
yield (entry 5). Caffeine (22 f) was also metalated at 258C
within 30 min to give zincated caffeine derivative 23 f in 95%
yield (entry 6).
The resulting organozinc reagents of type 23 show a reactivi-
ty that was similar to those of type 19 (Table 3). Thus, zinc piv-
alate 23a was iodinated by using an excess of iodine at 258C
to furnish halogenated pyridazine 24a in 92% yield
(Scheme 10). Copper-mediated reactions also proceeded readi-
ly. When 23a was treated with 3-bromocyclohex-1-ene (6a,
1.2 equiv) in the presence of 10 mol% CuCN·2LiCl, the allylat-
Scheme 9. Preparation of the zinc base 3 by transmetalation of TMP-
MgCl·LiCl (2) with Zn(OPiv)2 (1b). [a] Complexed Mg(OPiv)Cl and LiCl are
omitted for clarity.
Table 5. Organozinc pivalates prepared by selective metalation using
TMPZnOPiv (3).
Entry
Substrate
T
[8C]
t
[h]
Product[a]
Yield
[%][b]
1
25
0.5
75[b]
22a
22b
23a
23b
2
3
90[c]
2
2
90[b]
50
91[b]
22c
23c
4
5
6
160[c]
1
76[d]
89[d]
95[d]
Scheme 10. Reactions of functionalized organozinc reagent 23a with various
electrophiles. [a] Only trace amounts of 24c were observed without the ad-
dition of TMSCl.
22d
22e
23d
23e
25
0.5
0.5
ed product 24b was obtained in 90% yield. As described for
zinc reagents of type 5 and 19, the acylation reactions re-
quired the presence of an excess of TMSCl. Hence, when 23a
was treated with TMSCl (6.0 equiv), the acylation with benzoyl
chloride (8d, 2.5 equiv) provided ketone 24c in 96% yield. The
reaction with 2-furoyl chloride (8a, 2.5 equiv) also proceeded
well and furnished the desired product 25d in 87% yield.
Zincated pyrazine derivative 23b was also iodinated with
iodine (2.0 equiv, 30 min, 258C) to give 2-chloro-3-iodopyrazine
(24e) in 93% yield (Table 6, entry 1). An allylation reaction
using 3-bromocyclohex-1-ene (6a, 1.2 equiv) in the presence
of 10 mol% CuCN·2LiCl provided the product 24 f in 91%
yield (entry 2). Iodolysis of zinc pivalate 23c furnished tetrasub-
stituted benzene derivative 24g in 91% yield (entry 3). Acyla-
tion reactions on 23c in the presence of an excess of TMSCl
and stoichiometric amounts of CuCN·2LiCl by using cyclobuta-
necarbonyl chloride (8i, 2.5 equiv, À308C, 30 min) or perfluori-
nated benzoyl chloride 8b (2.5 equiv, 08C, 12 h) provided the
corresponding ketones 24h and 24i both in 95% yield (en-
tries 4–5). Trichloroarylzinc reagent 23d was allylated by using
3-bromo-2-methylpropene (6d, 1.2 equiv, À208C, 45 min) to
give alkene 24j in 94% yield (entry 6). Acylation of 23d was
performed by using cyclobutanecarbonyl chloride (8i, À208C,
25
22 f
23 f
[a] Complexed Mg(OPiv)Cl and LiCl are omitted for clarity. [b] Determined
by GC-analysis; see the Supporting Information. [c] Using microwave irra-
diation. [d] Determined by titration against iodine; see the Supporting In-
formation.
Thus, when 3,6-dichloropyridazine (22a) was treated with
zinc base 3 (1.1 equiv) at 258C for 30 min, the solid zinc re-
agent 23a was obtained in 75% yield after solvent evapora-
tion (Table 5, entry 1). This zincated pyridazine showed excel-
lent stability and, after 4 h exposure to air, 95% of the initial
activity remained.[11] Under microwave irradiation, 2-chloropyra-
zine (22b) was regioselectively metalated with 3 at 908C
within 2 h to give the organozinc pivalate 23b in 90% yield
(entry 2).
Trichlorobenzene 22d was also readily deprotonated by
TMPZnOPiv (3, 1.1 equiv) under microwave irradiation (1608C,
1 h) to give, after solvent evaporation, zinc species 23d in
76% yield (entry 4). This mild base tolerates an aldehyde func-
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30 min) and ketone 24k was obtained in 95% yield (entry 7).
Benzothiophene 23e underwent smooth iodolysis to give iodi-
nated heterocycle 24l in 89% yield (entry 8). An allylation reac-
tion by using 6a (2.5 equiv, À208C, 10 h) furnished the corre-
sponding product 24m in 95% yield (entry 9). Metalated caf-
feine 23 f reacted readily with allyl bromide 6d (1.2 equiv,
À208C, 4 h) or with acyl chloride 8j (2.5 equiv, À208C, 15 h) to
give caffeine derivatives 24n–o in 73–94% yield (entries 10
and 11).
Table 6. Reactions of organozinc pivalates of type 23 with various elec-
trophiles leading to products of type 24.
Entry Zinc reagent
Electrophile
Product
Yield
[%][a]
1
I2
93
23b
24e
2
91[b]
Conclusion
23b
6a
24 f
We have described a set of efficient preparations of solid, air-
stable zinc reagents by using either Mg insertion or a bromine-
or iodine–magnesium exchange. Alternatively, directed metala-
tion performed with TMPMgCl·LiCl (2) followed by transmetala-
tion with Zn(OPiv)2 (1b), or directed zincation by using the
base “TMPZnOPiv” (3) were used to produce a range of solid
zinc pivalates. We have shown that the stability of these zinc
reagents can be enhanced by reducing the amount of LiCl
present. The reactivity scope of these zinc reagents was inves-
tigated. Not only Negishi cross-couplings but also copper-
mediated carbocupration, acylation, and allylation reactions
were efficiently performed with organozinc pivalates. In addi-
tion, AlMe3-mediated addition to aldehydes, or Rh-catalyzed
1,4-addition reactions are also possible. These solid zinc re-
agents open a range of new potential applications of zinc
compounds in organic synthesis. By lowering the sensitivity to-
wards air and moisture, these zinc compounds are much more
practical to use in conventional synthesis or in high-through-
put screenings. Further investigation of these solid, air-stable
organozinc reagents is currently underway in our laboratories.
3
I2
91
23c
24g
4
95[c]
23c
8i
24h
5
95[c]
23c
8b
6d
24i
24j
6
94[b]
23d
7
95[c]
Experimental Section
23d
8i
24k
24l
(5-Chloro-2-methoxyphenyl)zinc pivalate (5a)
A dry and argon-flushed Schlenk-flask equipped with a magnetic
stirring bar and a septum was charged with magnesium turnings
(304 mg, 12.5 mmol), flame-dried anhydrous LiCl (318 mg,
7.50 mmol), and THF (15 mL). 2-Bromo-4-chloro-1-methoxybenzene
(1.11 g, 5.0 mmol) was added. If necessary, the Schlenk-flask was
placed in a water bath for cooling during the initial heat evolution
of the insertion reaction. The progress of the insertion reaction
was monitored by GC-analysis of reaction aliquots quenched with
aq. sat. NH4Cl solution and/or I2. Upon completion of the insertion
after 2 h at 258C, solid Zn(OPiv)2 (1.61 g, 6.00 mmol) was added in
one portion. After stirring at 258C for 15 min, the solvent was care-
fully removed in vacuo. The arylzinc pivalate 5a was obtained as
a pale-gray solid. Titration with iodine gave a concentration of the
active zinc species of 1.01 mmolgÀ1, which corresponds to a yield
of 92%.
8
I2
89
23e
9
95[b]
23e
6a
6d
8j
24m
10
94[b]
23 f
24n
24o
11
73[c]
(5-Chloro-2-methoxyphenyl)(furan-2-yl)methanone (9a)
(5-Chloro-2-methoxyphenyl)zinc pivalate (5a, 0.99 g, 1.01 mmolgÀ1
,
23 f
1.0 mmol) dissolved in anhydrous THF (3 mL) was cooled to
À208C. TMSCl (652 mg, 6.0 mmol) was added followed by 30 min
stirring. CuCN·2 LiCl (1m in THF, 1 mL, 1 mmol) and furan-2-carbon-
yl chloride (8a, 130 mg, 1.0 mmol) were added subsequently and
[a] Isolated yield of analytically pure product. [b] 10 mol% CuCN·2LiCl
were used. [c] 1.1 equiv CuCN·2LiCl and 6.0 equiv TMSCl were used.
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[6] a) A. Krasovskiy, V. Krasovskaya, P. Knochel, Angew. Chem. 2006, 118,
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Rohbogner, A. Unsinn, P. Knochel, Org. Process Res. Dev. 2010, 14, 339;
c) T. Kunz, P. Knochel, Angew. Chem. 2012, 124, 1994; Angew. Chem. Int.
Ed. 2012, 51, 1958.
[7] Rh-catalysis: a) M. Sakai, H. Hayashi, N. Miyaura, Organometallics 1997,
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2013, 125, 10268; Angew. Chem. Int. Ed. 2013, 52, 10084; g) Y. Minko, M.
Pasco, H. Chechik, I. Marek, Beilstein J. Org. Chem. 2013, 9, 526; h) W.
Gati, F. Couty, T. Boubaker, M. M. Rammah, M. B. Rammah, G. Evano,
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also: i) J. F. Normant, A. Alexakis, Synthesis 1981, 841; j) N. Krause in
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2002; k) N. Chinkov, D. Tene, I. Marek in Metal-Catalyzed Cross-Coupling
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[9] In the absence of LiCl, the solubility dropped significantly, which re-
duced the reactivity of the corresponding zinc reagent.
the reaction mixture was stirred for 3 h at 258C. After quenching
with an aqueous NH4Cl/NH3(conc.) (8:1, 4 mL) the mixture was ex-
tracted with ethyl acetate (5ꢁ8 mL). The combined organic layers
were dried over Na2SO4 and, after filtration, the solvents were
evaporated in vacuo. Purification by flash chromatography (silica
gel; isohexane/EtOAc=5:1) afforded the product 9a (227 mg,
1
96%) as a white solid. M.p. 78.6–80.68C; H NMR (300 MHz, CDCl3):
d=7.63 (dd, J=0.8, 1.7 Hz, 1H), 7.43–7.34 (m, 2H), 7.04 (dd, J=0.8,
3.6 Hz, 1H), 6.91 (d, J=8.8 Hz, 1H), 6.53 (dd, J=1.7, 3.6 Hz, 1H),
3.77 ppm (s, 3H); 13C NMR (75 MHz, CDCl3): d=181.5, 156.3, 152.8,
147.7, 132.0, 129.4, 129.4, 125.7, 120.9, 113.2, 112.6, 56.4 ppm; IR
(ATR): n˜ =2923, 2853, 1643, 1600, 1561, 1486, 1460, 1403, 1386,
1312, 1301, 1284, 1274, 1252, 1228, 1181, 1153, 1131, 1098, 1077,
1018, 984, 966, 945, 938, 900, 891, 882, 858, 810, 772, 736, 677,
640, 618 cmÀ1; MS (70 eV, EI): m/z (%)=236 (100) [M]+, 219 (70),
207 (85), 291 (28), 184 (16), 157 (17), 139 (21), 126 (35), 111 (29), 75
(20), 63 (24); HRMS (EI): m/z calcd for C12H9ClO3: 236.0240; found:
236.0236.
Acknowledgements
The research leading to these results received funding from
the European Research Council under the European Communi-
ty’s Seventh Framework Programme (FP7/2007–2013) ERC
grant agreement no. 227763. We thank the Fonds der Chemi-
schen Industrie and the Deutsche Forschungsgemeinschaft
(DFG) for financial support. We also thank BASF SE (Ludwigsha-
fen), Heraeus Holding GmbH (Hanau), and Rockwood Lithium
GmbH (Frankfurt) for generous gifts of chemicals.
[10] A. Hernꢅn-Gꢆmez, E. Herd, E. Hevia, A. R. Kennedy, P. Knochel, K. Koszi-
nowski, S. M. Manolikakes, R. E. Mulvey, C. Schnegelsberg, Angew. Chem.
2014, 126, 2744; Angew. Chem. Int. Ed. 2014, 53, 2706.
[11] See the Supporting Information for more detailed stability studies.
[12] The Z/E ratio was determined by GC-analysis of the crude hydrolyzed
reaction mixture. The stereochemistry was confirmed by a NOESY ex-
periment (see the Supporting Information).
[13] a) F. Langer, L. Schwink, A. Devasagayaraj, P.-Y. Chavant, P. Knochel, J.
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Keywords: copper
methods · zinc
· magnesium · metalation · synthetic
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Received: April 9, 2014
Published online on && &&, 0000
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FULL PAPER
&
Organozinc Reagents
S. M. Manolikakes, M. Ellwart,
C. I. Stathakis, P. Knochel*
&& – &&
Air-Stable Solid Aryl and Heteroaryl
Organozinc Pivalates: Syntheses and
Applications in Organic Synthesis
Reactive but stable: The preparation of
polyfunctional, air-stable, solid aryl and
heteroaryl organozinc pivalates by
described. The zinc reagents show ex-
cellent stability in air (up to 4 h at 258C)
and undergo a range of reactions in-
cluding allylation, acylation, and carbo-
cupration reactions, additions to alde-
hydes, and 1,4-addition reactions (see
scheme).
either Mg insertion or Hal–Mg (Hal=Br,
I) exchange, followed by transmetala-
tion with Zn(OPiv)2 (OPiv=pivalate) or
alternatively by directed metalation is
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