Preparation of Solid, Substituted Allylic Zinc Reagents and Their Reactions with Electrophiles

Article abstract of DOI:10.1002/anie.201504354

The treatment of various allylic chlorides or bromides with zinc dust in the presence of lithium chloride and magnesium pivalate (Mg(OCOtBu)₂) in THF affords allylic zinc reagents which, after evaporation of the solvent, produce solid zinc reagents that display excellent thermal stability. These allylic reagents undergo Pd-catalyzed cross-coupling reactions with PEPPSI-IPent, as well as highly regioselective and diastereoselective additions to aryl ketones and aldehydes. Acylation with various acid chlorides regioselectively produces the corresponding homoallylic ketones, with the new C-C bond always being formed on the most hindered carbon of the allylic system.

Full text of DOI:10.1002/anie.201504354

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International Edition: DOI: 10.1002/anie.201504354
German Edition: DOI: 10.1002/ange.201504354
Organozinc Reagents
Preparation of Solid, Substituted Allylic Zinc Reagents and Their
Reactions with Electrophiles
Mario Ellwart and Paul Knochel*
Dedicated to Professor Ei-ichi Negishi on the occasion of his 80th birthday
Abstract: The treatment of various allylic chlorides or
bromides with zinc dust in the presence of lithium chloride
and magnesium pivalate (Mg(OCOtBu)2) in THF affords
allylic zinc reagents which, after evaporation of the solvent,
produce solid zinc reagents that display excellent thermal
stability. These allylic reagents undergo Pd-catalyzed cross-
coupling reactions with PEPPSI-IPent, as well as highly
regioselective and diastereoselective additions to aryl ketones
and aldehydes. Acylation with various acid chlorides regiose-
lectively produces the corresponding homoallylic ketones, with
À
the new C C bond always being formed on the most hindered
carbon of the allylic system.
A
llylic organometallics are an important class of organome-
tallic reagents owing to their enhanced reactivity compared to
the corresponding alkyl, aryl, or even benzylic organometal-
lics.[1] For example, allylic magnesium halides are much more
reactive than all other classes of Grignard reagents.[2,3] This
behavior can be explained by the higher ionic character of the
Scheme 1. Preparation of functionalized solid allylic zinc pivalates of
type 1 from the corresponding allylic halides of type 2 by using Zn,
Mg(OPiv)2, and LiCl. For determination of the half-lives (t1/2) see the
Supporting Information. Values given in brackets show the half-lives
when the reagents were stored at À248C. [a] Complexed Mg(OPiv)X
(X=Cl, Br) and LiCl are omitted for clarity.
À
allylic C Mg bond. Although allylic derivatives of most main-
group elements have been reported,[4] allylic zinc reagents are
by far the most useful reagents in synthetic organic chemis-
try[5] since they display high reactivity and are at the same
time compatible with a range of functional groups, including
ester[6] or cyano functions.[7] Furthermore, allylic zinc reagents
are conveniently prepared through insertion of zinc (in the
form of commercially available zinc powder) into the
corresponding allylic bromide.[8] Recently, we reported the
preparation of solid aryl-, heteroaryl-, and benzylzinc
reagents that are air stable but still display high reactivity
for forming new carbon–carbon bonds.[9] Herein, we report
the synthesis of the first solid allylic zinc reagents of type 1,
which were obtained through the insertion of zinc[10] in the
presence of LiCl[11] and magnesium pivalate (Mg(OPiv)2;
OPiv = OCOtBu) into various allylic bromides or chlorides of
type 2. After evaporation of the solvent, solid allylic zinc
derivatives are obtained as white or yellow powders. Iodo-
metric titration[12] indicated that these zinc compounds were
obtained in 51–90% yield (see Scheme 1). Important func-
tional groups such as esters or nitriles are tolerated in these
reagents (see 1e–h). Although these solids react rapidly with
air and moisture, they are stable for an extended period of
time. The allylic zinc reagents 1a–d are thermally very stable
(t1/2 > 2 years) at 258C as a solid under argon. The ester-
substituted zinc reagents (1e–f) have somewhat lower room
temperature stability (t1/2 = 16–17 weeks). The stability of 1 f
is increases to give a half-life of 40 weeks when stored at
À248C. The nitrile-substituted allylic zinc species 1g–h are
more sensitive (t1/2 = 33–59 d) but again, storage at À248C
increases their stability significantly (t1/2 = 50–152 d). The
presence of LiCl and Mg(OPiv)2 is essential for the success of
the preparation of these allylic zinc reagents.[13] The role of
LiCl is to activate the zinc powder, whereas Mg(OPiv)2 was
found to be essential for the long-term stability of the solid
allylic reagents.[14]
We first examined the reactivity of the new allylic zinc
pivalates in Pd-catalyzed cross-couplings. Buchwald and co-
workers recently reported that prenylzinc bromide undergoes
smooth cross-coupling with various unsaturated bromides in
the presence of a Pd precatalyst and a sterically hindered
phosphine ligand (CPhos).[15] Consequently, we examined the
cross-coupling of the allylic zinc reagents of type 1 with aryl
bromides in the presence of various Pd catalysts. In our hands,
PEPPSI-IPent, which was discovered by Organ and co-
workers,[16] gave by far the best results. Accordingly, prenyl-
[*] M. Ellwart, Prof. Dr. P. Knochel
Ludwig-Maximilians-Universität München, Department Chemie
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/anie.201504354.
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Table 1: PEPPSI-IPent-catalyzed cross-coupling of allylic organozinc
pivalates of type 1 in THF within 4 h at 508C.
zinc pivalate (1b) undergoes cross-coupling with the bro-
mouracil derivative 3a in the presence of 2 mol% of PEPPSI-
IPent. Interestingly, the corresponding prenylzinc bromide
(5b) as a 0.3m solution in THF led only to traces of the cross-
coupling product 4a. This behavior was general and the
functionalized allylic zinc reagent 1 f reacts smoothly with 2-
bromotoluene (3b) in the presence of PEPPSI-IPent
(2 mol%) to produce the cross-coupling product 4b in 79%
yield. Again, the use of the corresponding allylic zinc chloride
5 f led only to traces of the desired product, thus showing the
importance of Mg(OPiv)2 for such cross-couplings
(Scheme 2).
Entry
Zinc Reagent[a]
Electrophile[b]
Product[c]
1
1a
3c
4c: 69%
2
3
1b
1b
3b
3d
4d: 70%
4e: 71%
4
5
1c
1d
3e
3 f
4 f: 77%
4g: 72%
Scheme 2. PEPPSI-IPent-catalyzed cross-coupling of allylic organozinc
reagents (1b,f and 5b,f) in THF within 4 h at 508C. [a] Complexed
Mg(OPiv)X (X=Cl, Br) and LiCl are omitted for clarity.
6
7
1e
1g
3g
3h
4h: 75%
4i: 90%
The reaction scope of this Pd-catalyzed cross-coupling is
quite broad and a range of unsaturated bromides provided the
cross-coupling products (4c–g) in 69–79% yield (Table 1).[17]
The cross-coupling of zinc pivalate 1a with the electron-poor
1-bromo-3-(trifluoromethyl)benzene (3c) and 2 mol% of
PEPPSI-IPent proceeds within 4 h at 508C and provides the
cross-coupling product 4c in 69% yield (entry 1). Remark-
ably, the electron-rich aryl bromides 3b and 3d also undergo
the cross-coupling reaction to afford the expected products
4d–e (70–71% yield, entries 2–3). Similarly, the myrtenylzinc
species 1c reacts with 1-bromo-3-fluorobenzene (3e) to
provide only the linear regioisomer 4 f in 77% yield
(entry 4) after 4 h at 508C. The heteroaromatic bromide 3-
bromopyridine (3 f) was readily allylated with cinnamylzinc
pivalate to give the functionalized heteroaromatic product 4g
in 72% yield (entry 5). By following the same procedure,
ester- and cyano-functionalized organozinc pivalates (1e–h)
were converted into the corresponding polyfunctional cross-
coupling products (4h–j) in 75–90% yield (entries 6–8).
Furthermore, as previously reported for allylic zinc
halides,[18] solid allylic zinc reagents of type 1 react with
electrophiles such as carbonyl derivatives or acid chlorides
with complete regioselectivity (formation of the new carbon–
carbon bond from the most substituted end of the allylic
system) and very high diastereoselectivity, as shown in Table 2
and Scheme 3. The cyclohex-2-en-1-ylzinc reagent 1a
(1.0 equiv) in THF adds to various methyl ketones[7a]
8
1h
3i
4j: 88%
[a] Complexed Mg(OPiv)X (X=Cl, Br) and LiCl are omitted for clarity.
[b] 0.80 equiv of electrophile were used. [c] Yields refer to analytically
pure products.
(0.8 equiv) to give the corresponding homoallylic alcohols
(6a–b) in 89–92% yield with d.r. > 99:1 (Table 2, entries 1–2).
The 2,3-disubstitured allylic zinc species 1c reacts with
furfural (5c) with complete regio- and diastereoselectivity
to give the alcohol 6c in 89% yield (entry 3). Cinnamylzinc
pivalate (1d) displays similar behavior and gives the anti-
alcohol 6d in 86% yield with d.r. > 99:1. This zinc reagent
enables stereocontrol of three contiguous centers and its
addition to 2-trimethylsilyloxy cyclohexanone (5e) provides
the alcohol 6e in 80% yield (d.r. = 95:5; entry 5). The
structure of alcohol 6e was confirmed by X-ray analysis.[19]
The functionalized solid zinc reagent 1e reacts smoothly with
3-bromobenzaldehyde (5 f) to furnish the secondary alcohol
6 f in 91% (d.r. = 97:3; entry 6). Finally, the functionalized
zinc reagents 1 f–g, which bear an ester or cyano function in
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Table 2: Diastereoselective preparation of homoallylic alcohols of type 6
using functionalized solid allylic zinc pivalates of type 1.[a]
Entry
Zinc Reagent[b]
Electrophile
Product[c]
1
1a
5a
6a: 89%
d.r.> 99:1
2
1a
5b
6b: 92%
d.r.=94:6
Scheme 3. Reaction of the functionalized solid allylic zinc pivalates
(1a–h) with acid chlorides (7a–f). [a] Complexed Mg(OPiv)X (X=Cl,
Br) and LiCl are omitted for clarity. [b] 0.80 equiv of electrophile were
used. [c] Yields refer to analytically pure products. [d] The reaction
mixture was warmed to RT overnight.
3
4
5
6
1c
1d
1d
1e
5c
5d
5e
5 f
6c: 89%
d.r.> 99:1
6d: 86%
d.r.> 99:1
The method was also applicable to the synthesis of various
b,g-unsaturated ketones of type 8 through addition of the
functionalized solid allylic zinc pivalates of type 1 to acid
chlorides in the absence of any transition metal catalyst
(Scheme 3). Accordingly, the allylic reagents 1a and 1b react
in THF under very mild conditions (1 h, À788C) with 4-
chlorobenzoyl chloride (7a) and 4-methoxybenzoyl chloride
(7b) to give the b,g-unsaturated ketones 8a–c in 78–95%
yield without any trace of the a,b-unsaturated isomers.
Interestingly, the competitive formation of a mixed anhydride
through reaction of the pivalate anion (PivOÀ) with the acyl
chloride was not observed.[9e] Starting from 3-bromobenzoyl
chloride (7c) or 4-(tert-butyl)benzoyl chloride (7d), the
corresponding b,g-unsaturated ketones 8d–e were obtained
in 68–75% yield when using the functionalized organozinc
pivalate 1e. Furthermore, the addition of the cyano-function-
alized solid zinc reagent 1 f to thiophene-2-carbonyl chloride
(7e) selectively furnished the corresponding ketone 8 f in
77% yield.
In summary, we have prepared salt-stabilized solid allylic
zinc pivalates from the corresponding allylic bromides or
chlorides through a one-pot insertion under mild conditions
with commercial zinc powder, LiCl, and Mg(OPiv)2. After
evaporation of the solvent, the resulting solid allylic zinc
reagents can be stored under argon for an extended period of
time (t1/2 between ca. 5 weeks and > 2 years). These reagents
show excellent reactivity in Pd-catalyzed cross-coupling
reactions with aryl bromides when using PEPPSI-IPent and
they undergo smooth additions to methyl ketones and
aldehydes with high diastereoselectivity. In addition, the
regioselective acylation of the reagents with acid chlorides
produce b,g-unsaturated ketones. Further applications are
currently underway in our laboratories.
6e: 80%
d.r.=95:5
6 f: 91%
d.r.=97:3
7
8
1 f
5g
5c
6g: 92%
d.r.> 99:1
1g
6h: 91%
d.r.> 99:1
[a] Reaction conditions: 0.80 equiv of electrophile, THF, À788C, 1 h.
[b] Complexed Mg(OPiv)X (X=Cl, Br) and LiCl are omitted for clarity.
[c] Yields refer to analytically pure products; The d.r. value was
determined by NMR and/or GC analysis of the crude product.
position 2, react with the ferrocenyl methyl ketone (5g) and
furfural (5c) to furnish the products 6g–h in 91–92% yield
and d.r. > 99:1 (entries 7–8). In the case of the addition of the
allylic zinc pivalate 1 f to 5g, spontaneous lactonization
leading to the bicyclic product 6g was observed (entry 7).[19]
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b) C. I. Stathakis, S. Bernhardt, V. Quint, P. Knochel, Angew.
Acknowledgements
Chem. Int. Ed. 2012, 51, 9428; Angew. Chem. 2012, 124, 9563;
c) C. I. Stathakis, S. M. Manolikakes, P. Knochel, Org. Lett. 2013,
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Buchwald, P. Knochel, Org. Lett. 2013, 15, 5754; e) S. M.
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We would like to thank the Deutsche Forschungsgemein-
schaft (DFG) for financial support. We also thank Rockwood
Lithium GmbH for the generous gift of chemicals.
Keywords: acylation · carbonyl addition · cross-coupling ·
organozinc reagents · palladium
[10] Zinc dust with a purity > 98% was purchased from Sigma–
Aldrich and was activated with 1,2-dibromoethane (see the
Supporting Information).
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Received: May 13, 2015
Published online: July 17, 2015
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