A convenient synthesis of α-substituted β,γ-unsaturated ketones and esters via the direct addition of substituted allylic zinc reagents prepared by direct insertion

Article abstract of DOI:10.1055/s-0033-1338415

A practical and convenient procedure for the synthesis of α-substituted β,γ-unsaturated ketones and esters has been developed. Substituted allylic zinc reagents, prepared via direct metal insertion in substituted allylic halides, react readily with a broad range of acid chlorides and chloroformates furnishing the corresponding α-substituted β,γ-unsaturated ketones and esters in high yield and perfect regioselectivity. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0033-1338415

1870▌
PAPER
paper
A Convenient Synthesis of α-Substituted β,γ-Unsaturated Ketones and Esters
via the Direct Addition of Substituted Allylic Zinc Reagents Prepared by
Direct Insertion
Synthesis of α-Substituted β,γ-Unsaturated Ketones and Esters
Christoph Sämann, Paul Knochel*
Ludwig-Maximilians-Universität München, Department Chemie, Butenandtstraße 5–13, Haus F, 81377 München, Germany
Fax +49(89)218077680; E-mail: paul.knochel@cup.uni-muenchen.de
Received: 20.02.2013; Accepted after revision: 25.03.2013
Dedicated to Professor Scott E. Denmark on the occasion of his 60th birthday
for the synthesis of substituted allylic zinc reagents from
Abstract: A practical and convenient procedure for the synthesis of
allyl halides or phosphonates.4
α-substituted β,γ-unsaturated ketones and esters has been devel-
oped. Substituted allylic zinc reagents, prepared via direct metal in-
sertion in substituted allylic halides, react readily with a broad range
of acid chlorides and chloroformates furnishing the corresponding
α-substituted β,γ-unsaturated ketones and esters in high yield and
perfect regioselectivity.
β,γ-Unsaturated ketones are versatile building blocks in
organic chemistry.5 Although a number of synthetic meth-
ods have been disclosed, only a few have been proven
practical and useful. The acylation of olefins allows the
synthesis of β,γ-unsaturated ketones, but generates α,β-
unsaturated ketones as side-products.6 The reaction of
various allylic organometallics with acyl halides is also
reported in literature. Silicon,7 tin,8 copper,9 rhodium,10
manganese,11 titanium,12 mercury,13 cadmium,14 and
indium15 are some of the metal powders reported earlier to
synthesize β,γ-unsaturated ketones. But these protocols
are mostly neither simple nor straightforward and are
therefore of limited application. Since the reaction of al-
lylic zinc reagents with acid chlorides16 or nitriles17 is a
promising approach, we focused on the development of an
addition reaction using the now readily available substi-
tuted allylic zinc reagents. Herein, we wish to report a
simple and flexible synthesis of α-substituted β,γ-unsatu-
rated ketones and esters through the addition of substitut-
ed allylic zinc reagents to a broad range of acid chlorides
and chloroformates.
Key words: organozinc reagents, addition, unsaturated ketones and
esters, insertion, allylic halides
The reaction of allylic organometallic reagents with car-
bonyl derivatives is of high importance in synthetic organ-
ic chemistry.1 Especially allylic zinc reagents are very
versatile organometallic species since their behavior is
much more predictable than that of the corresponding al-
lylic magnesium or lithium reagents.2 Whereas allylzinc
bromide in THF is readily available by the reaction of zinc
foil with allyl bromide,3 the preparation of substituted
zinc reagents is much more challenging due to competi-
tive homocoupling reactions. Recently, we have reported
the use of commercial zinc powder in the presence of lith-
ium chloride in THF as a cheap and convenient method
Zn (2 equiv)
LiCl (1.1 equiv)
Br
ZnBr·LiCl
2a (83%)
THF, 25 °C, 1 h
1a (1 equiv)
TMS
ZnBr·LiCl
ZnBr·LiCl
ZnCl·LiCl
Ph
ZnCl·LiCl
2b (86%)
2c (92%)
2d (81%)
CO2Et
2e (83%)
CN
ZnBr·LiCl
ZnCl·LiCl
ZnCl·LiCl
ZnCl·LiCl
2g (73%)
2f (89%)
2h (90%)
2i (69%)
Scheme 1 LiCl-mediated preparation of substituted allylic zinc organometallics by direct insertion of zinc powder (yields determined by
iodometric titration18)
SYNTHESIS 2013, 45, 1870–1876
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DOI: 10.1055/s-0033-1338415; Art ID: SS-2013-C0148-OP
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of α-Substituted β,γ-Unsaturated Ketones and Esters
1871
Preliminary experiments had shown that the direct zinc in- range of acid chlorides (Scheme 2 and Table 1). It turned
sertion into allylic halides in the presence of lithium chlo- out that this reaction proceeded under exceedingly mild
ride provides the corresponding allylic zinc reagents conditions (–78 °C, 1 h) and furnished selectively β,γ-un-
almost without formation of homocoupling products. saturated ketones without any traces of the α,β-unsaturat-
Thus, under optimized conditions but-2-en-1-ylzinc bro- ed isomers. Thus, the addition of but-2-en-1-ylzinc
mide (2a) was formed in one hour at 25 °C in 83% yield bromide (2a) to the (hetero)aromatic acid chlorides 3a–c
by dropwise addition of 1-bromobut-2-ene (1a; 1 equiv) furnished selectively the corresponding α-substituted β,γ-
to a suspension of commercial zinc powder (2.0 equiv) unsaturated ketones 4a–c in high yields (Table 1, entries
and dry lithium chloride (1.1 equiv) in THF (Scheme 1). 1–3). Regardless of the substitution pattern of the (het-
This procedure was successfully extended to other allylic ero)aromatic acid chloride, the reaction proceeded in one
halides leading to cinnamylzinc chloride (2b; 86%), (3- hour at –78 °C. Noteworthy, the configuration of the dou-
methylbut-2-en-1-yl)zinc bromide (2c; 92%), (3,7-di- ble bond in the zinc reagent does not affect the reaction
methylocta-2,6-dien-1-yl)zinc bromide (2e; 83%), and course, allowing the use of E- and Z-isomeric mixtures.
cyclohex-2-en-1-ylzinc bromide (2f; 89%). Especially the Cinnamylzinc chloride (2b) reacted in a similar manner.
preparation of zinc reagent 2b is remarkable, since cin- The α-substituted β,γ-unsaturated ketones 4d–f were ob-
namyl chloride is known to readily undergo extensive ho- tained by addition to the corresponding (hetero)aromatic
mocoupling reaction during the synthesis of the acid chlorides 3a, 3b, and 3d in excellent yields (entries
corresponding zinc reagent. It is noteworthy that also 4–6). Interestingly, also with the aliphatic acid chloride 3e
functional groups like an ester or a nitrile were tolerated the addition proceeded smoothly (–20 °C → 25 °C, 2 h)
in the insertion reaction. Hence, 2-(ethoxycarbonyl)cyclo- and led to ketone 4g in 72% yield (entry 7).
hex-2-en-1-ylzinc chloride (2h) and 2-cyanocyclopent-2-
en-1-ylzinc chloride (2i) were obtained from their corre-
O
sponding chlorides in 90% and 69% yield, respectively.
R3
O
R3
R4
Cl
Starting
from
2-chloromethyl-6,6-dimethylbicyc-
3a–f (0.8 equiv)
R1
ZnX·LiCl
R4
lo[3.1.1]hept-2-ene (1g), the corresponding zinc reagent
2g could be synthesized in 73% yield (25 °C, 30 h).4a [2-
(Trimethylsilyl)but-2-en-1-yl]zinc chloride (2d) was gen-
erated from its chloride in the presence of zinc powder (10
equiv) and lithium chloride (3 equiv) in 18 hours at 25 °C
in 81% yield.4b
R1 R2
4a–q (65–99%)
THF, –78 to 25 °C, 1–2 h
R2
2a–g (1 equiv)
X = Cl, Br
Scheme 2 Synthesis of α-substituted β,γ-unsaturated ketones of type
4 via addition of allylic zinc reagents 2 to various acid chlorides of
type 3
We then decided to concentrate our studies to the addition
of these highly reactive allylic zinc reagents to a broad
Table 1 Preparation of α-Substituted β,γ-Unsaturated Ketones of Type 4
Entry
1
Substrate
Acid chloride
Product (Yield %)a
Conditions (Temp, Time)
–78 °C, 1 h
O
O
ZnBr·LiCl
Cl
t-Bu
t-Bu
2a
2a
3a
4a (85)
O
O
Cl
2
3
–78 °C, 1 h
–78 °C, 1 h
S
S
3b
4b (71)
O
O
MeO
MeO
Cl
2a
MeO
OMe
MeO
OMe
4c (65)
3c
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1870–1876

1872
C. Sämann, P. Knochel
PAPER
Table 1 Preparation of α-Substituted β,γ-Unsaturated Ketones of Type 4 (continued)
Entry
4
Substrate
Acid chloride
Product (Yield %)a
Conditions (Temp, Time)
O
O
Ph
ZnCl·LiCl
Cl
–78 °C, 1 h
Ph
2b
t-Bu
t-Bu
3a
4d (90)
O
O
O
Cl
5
6
7
2b
2b
2b
–78 °C, 1 h
S
S
Ph
Ph
3b
4e (77)
O
Cl
–78 °C, 1 h
O
O
3d
4f (84)
O
O
Cl
Cl
–20 °C → 25 °C, 2 h
Cl
Ph
3e
4g (72)
O
O
O
ZnBr·LiCl
Cl
Cl
8
–78 °C, 1 h
t-Bu
t-Bu
2c
4h (93)
3a
O
TMS
TMS
ZnCl·LiCl
9
25 °C, overnight
t-Bu
t-Bu
2d
2d
3a
4i (98)
O
TMS
O
Cl
10
–78 °C, 1 h
S
S
3b
4j (99)
O
O
ZnBr·LiCl
Cl
11
12
13
–78 °C, 1 h
t-Bu
t-Bu
3a
4k (70)
2e
2e
O
O
Cl
O
–78 °C, 1 h
O
3d
4l (79)
O
Cl
O
Cl
2e
–78 °C, 1 h
Cl
3e
4m (74)
Synthesis 2013, 45, 1870–1876
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of α-Substituted β,γ-Unsaturated Ketones and Esters
1873
Table 1 Preparation of α-Substituted β,γ-Unsaturated Ketones of Type 4 (continued)
Entry
14
Substrate
Acid chloride
Product (Yield %)a
Conditions (Temp, Time)
O
O
ZnBr·LiCl
Cl
–78 °C, 1 h
t-Bu
t-Bu
2f
2f
3a
4n (83)
O
O
O
O
Cl
Cl
15
16
–78 °C, 1 h
–78 °C, 1 h
3f
4o (75)
O
O
ZnCl·LiCl
t-Bu
t-Bu
2g
3a
4p (67)
O
O
Cl
17
18
19
20
2g
–78 °C → 25 °C, 2 h
S
S
3b
4q (89)
CO2Et
O
CO2Et
O
ZnCl·LiCl
Cl
–78 °C → 25 °C, overnight
–78 °C → 25 °C, overnight
–78 °C → 25 °C, overnight
O
O
3d
4r (90)
2h
2h
O
CO2Et
O
Cl
Cl
Cl
4s (80)
3g
O
O
CN
CN
Cl
ZnCl·LiCl
Cl
Cl
2i
3g
4t (70)
a Yield of analytically pure isolated product as determined by 1H NMR analysis.
This procedure could be successfully applied to trisubsti- corresponding ketones 4k–m leaving the nonallylic dou-
tuted allylic zinc derivatives. Thus, (3-methylbut-2-en-1- ble bond untouched (entries 11–13).
yl)zinc bromide (2c) reacted selectively in one hour at
–78 °C with 4-(tert-butyl)benzoyl chloride (3a) to afford
the corresponding α,α-disubstituted β,γ-unsaturated ke-
The cyclic allylic zinc reagents 2f–i showed an analogous
behavior. The addition reaction of cyclohex-2-en-1-ylzinc
bromide (2f) and the acid chlorides 3a and 3f afforded se-
tone 4h in 93% yield (entry 8). Remarkably, the addition
lectively the corresponding α-substituted β,γ-unsaturated
of [2-(trimethylsilyl)but-2-en-1-yl]zinc chloride (2d) to
ketones 4n and 4o in high yields (83% and 75%, entries
the acid chlorides 3a and 3b furnished the corresponding
14 and 15). Moreover, the cyclic zinc reagent 2g reacted
ketones 4i and 4j in almost quantitative yields of 98% and
with the (hetero)aromatic acid chlorides 3a and 3b to the
99%, respectively (entries 9 and 10). Also the trisubstitut-
ketones 4p and 4q containing a terminal double bond in
67% and 89% yield, respectively (entries 16 and 17). Al-
so, the zinc reagent 2h underwent the addition reaction
ed allylic zinc reagent 2e, that contains another double
bond besides the allylic one, could be employed in the ad-
dition reaction. (Hetero)aromatic acid chlorides 3a and 3d
with the (hetero)aromatic acid chlorides 3d and 3g
as well as an aliphatic one 3e were used to synthesize the
smoothly and furnished the corresponding ketones 4r and
4s in high yields (90% and 80%, entries 18 and 19). The
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1870–1876

1874
C. Sämann, P. Knochel
PAPER
Table 2 Preparation of α-Substituted β,γ-Unsaturated Esters of Type 6
Entry
1
Substrate
Chloroformate
Product (Yield %)a
Conditions (Temp, Time)
O
O
Ph
ZnCl·LiCl
EtO
Ph
–78 °C, 1 h
EtO
Cl
2b
5a
6a (64)
O
O
O
O
O
2
2b
2b
–78 °C → 25 °C, 2 h
O
O
O
Cl
Cl
Cl
Ph
5b
5c
5b
6b (78)
O
O
3
4
–78 °C → 25 °C, 2 h
–20 °C → 25 °C, 2 h
Ph
6c (82)
O
ZnBr·LiCl
O
2c
6d (70)
a Yield of analytically pure isolated product as determined by 1H NMR analysis.
addition of 2-cyanocyclopent-2-en-1-ylzinc chloride (2i) stituted β,γ-unsaturated ketones and esters in hands, the
to acid chloride 3g led to the α-substituted β,γ-unsaturated diene precursor 7 for a RCM was readily synthesized in
ketone 4t (70% yield, entry 20).
only one step via the diastereoselective addition1 of allyl-
magnesium chloride to the carbonyl moiety of 4d in al-
most quantitative yield (Scheme 3). The subsequent RCM
using the second generation of Grubbs’ catalyst21 fur-
nished diastereoselectively the cyclopentene derivative 8
in 97% yield.
Due to the lack of a convenient and practical direct syn-
thesis for α-substituted β,γ-unsaturated esters in the liter-
ature, our method was extended to this direction. As
shown in Table 2, the allylic zinc reagents 2b and 2c re-
acted readily under optimized conditions with various
chloroformates and formed the desired esters. Cinnamyl- In summary, we have described a simple, convenient, and
zinc chloride (2b) added to aliphatic 5a, aromatic 5b as straightforward protocol for the selective synthesis of α-
well as to allylic chloroformates 5c affording the corre- substituted β,γ-unsaturated ketones and esters via the di-
sponding α-substituted β,γ-unsaturated esters in 64%, rect addition of substituted allylic zinc reagents to a broad
78%, and 82% yield, respectively (Table 2, entries 1–3). range of acid chlorides and chloroformates. Besides the
The trisubstituted allylic zinc reagent 2c showed a similar convenient synthesis of the allylic zinc reagents through
behavior and furnished ester 6d in 70% yield (entry 4).
the lithium chloride-mediated zinc insertion in allylic ha-
lides, the notable advantages of this methodology are the
mild reaction conditions, the short reaction times as well
as the high yields. Further studies of this work are current-
ly underway in our laboratory.
Ring-closing metathesis (RCM) represents one of the
most powerful and versatile tool in organic synthesis for
the formation of C=C bonds19 and has proven to be highly
important for natural product synthesis.20 With the α-sub-
MgCl
O
HO
HO
(1.1 equiv)
THF
Grubbs II
(0.05 equiv)
Ph
Ph
Ph
0–25 °C, 1.5 h
THF, reflux, 4 h
t-Bu
t-Bu
t-Bu
4d (1 equiv)
7: > 98% (rac)
dr > 99%
8: 97% (rac)
dr > 99%
Scheme 3 Diastereoselective addition of allylmagnesium chloride to 4d and subsequent ring-closing metathesis forming the cyclopentene
derivative 8
Synthesis 2013, 45, 1870–1876
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of α-Substituted β,γ-Unsaturated Ketones and Esters
1875
For complete experimental procedures, analytical data, and NMR
spectra see the Supporting Information.
References
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R. In Modern Carbonyl Chemistry; Otera, J., Ed.; Wiley-
VCH: Weinheim, 2000, Chap. 10. (b) Denmark, S. E.;
Almstead, N. G. In Modern Carbonyl Chemistry; Otera, J.,
Ed.; Wiley-VCH: Weinheim, 2000, Chap, 11.
All reactions were carried out under an argon atmosphere in flame-
dried glassware. Syringes that were used to transfer anhydrous sol-
vents or reagents were purged with argon prior to use. THF was
continuously refluxed and freshly distilled from sodium benzophe-
none ketyl under N2. Yields refer to isolated yields of compounds
estimated to be >95% pure as determined by 1H NMR (25 °C) anal-
ysis and capillary GC. Column chromatography was performed us-
ing silica gel (0.040–0.063 mm, 230–400 mesh ASTM) from
Merck, unless otherwise indicated. All reagents were obtained from
commercial sources unless stated otherwise.
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Allylic Zinc Reagents via Direct Zinc Insertion in the Presence
of Lithium Chloride; But-2-en-1-ylzinc Bromide (2a); Typical
Procedure
A dry, argon-flushed Schlenk flask equipped with a magnetic stir-
ring bar and a septum was charged with Zn powder (1.31 g, 20
mmol) and LiCl (466 mg, 11 mmol). LiCl was dried in vacuo using
a heat gun (450 °C, 5 min). After the addition of THF (10 mL), the
Zn powder was activated with 1,2-dibromoethane (0.05 mL, 2
mol%) and Me3SiCl (0.1 mL, 5 mol%). Subsequently, a solution of
1-bromobut-2-ene (1a; 1.35 g, 10.0 mmol) in THF (10 mL) was
added dropwise at 25 °C and stirred for 1 h. Then, the remaining Zn
powder was allowed to settle down and the supernatant solution was
transferred into a dry, argon-flushed Schlenk flask. Iodometric
titration18 furnished a concentration of 0.42 M (83% yield).
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α-Substituted β,γ-Unsaturated Ketones via Direct Addition of
Allylic Zinc Reagents to Acid Chlorides; 1-[4-(tert-Butyl)phe-
nyl]-2-methylbut-3-en-1-one (4a); Typical Procedure
A dry, argon-flushed Schlenk flask equipped with a magnetic stir-
ring bar and a septum was charged with a solution of 4-(tert-bu-
tyl)benzoyl chloride (3a; 315 mg, 1.6 mmol) in THF (1.5 mL) and
cooled down to –78 °C. Subsequently, the freshly prepared allylic
zinc reagent 2a (4.75 mL, 2.00 mmol, 0.42 M in THF) was added
dropwise and the reaction mixture was stirred at –78 °C for 1 h. The
mixture was quenched with sat. aq NH4Cl (10 mL) and extracted
with EtOAc (3 × 20 mL). The combined organic phases were dried
(Na2SO4) and concentrated in vacuo. The crude residue obtained
was purified by flash column chromatography (silica gel, pentane–
Et2O, 50:1) to give the analytically pure product 4a as a colorless oil
(294 mg, 85%).22
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IR (ATR): 3080, 3055, 3039, 2964, 2933, 2905, 2870, 1678, 1634,
1604, 1455, 1408, 1364, 1268, 1220, 1191, 1109, 993, 974, 963,
916, 847, 790, 719 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.96 (d, J = 8.6 Hz, 2 H), 7.50 (d,
J = 8.9 Hz, 2 H), 5.95–6.11 (m, 1 H), 5.08–5.27 (m, 2 H), 4.10–4.25
(m, 1 H), 1.28–1.48 (m, 12 H).
13C NMR (75 MHz, CDCl3): δ = 200.8, 156.7, 138.4, 133.7, 128.5,
125.5, 116.3, 45.4, 35.1, 31.1, 17.1.
MS (EI, 70 eV): m/z (%) = 216 (M+, 1), 162 (27), 161 (100), 160 (6),
146 (23), 118 (24), 115 (8), 91 (14).
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HRMS: m/z calcd for C15H20O: 216.1514; found: 216.1501.
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Acknowledgment
We thank the European Research Council (ERC) under the Euro-
pean Community’s Seventh Framework Programme (FP7/2007-
2013) ERC Grant Agreement No. 227763 for financial support. We
also thank BASF SE (Ludwigshafen), W. C. Heraeus (Hanau), and
Chemetall GmbH (Frankfurt) for the generous gift of chemicals.
(15) Yadav, J. S.; Srinivas, D.; Reddy, G. S.; Himabindu, K.
Tetrahedron Lett. 1997, 36, 8745.
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
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© Georg Thieme Verlag Stuttgart · New York
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Synthesis 2013, 45, 1870–1876
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