Direct conversion of cinnamate esters into β,β-disubstituted ketones mediated by cyano-magnesio cuprates

Article abstract of DOI:10.1016/j.tet.2016.05.003

The clean synthesis of unsymmetrical ketones from carboxylic acid derivatives has been a challenge in the organic community dating back over 80 years. Herein we report the conversion of simple alkyl cinnamates to β,β-disubstituted ketones with cyano-magnesio cuprates in high yields with no observation of tertiary alcohol byproduct. The lack of tertiary alcohol is attributed to a putative enolate intermediate that serves as a ketone protecting group. A distinctive steric inhibition trend was observed related to both the size of the R group on the parent ester and the nucleophilic cuprate. Lastly, we demonstrate that this reaction can be coupled with known copper mediated allylic substitution reactions yielding β,γ-disubstituted ketone (8) from parent α-chloro-β,γ-ethylenic ester (7).

Full text of DOI:10.1016/j.tet.2016.05.003

Tetrahedron xxx (2016) 1e4
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Direct conversion of cinnamate esters into
mediated by cyano-magnesio cuprates
b,b-disubstituted ketones
,
b
Douglas T. Genna a , Gary H. Posner
*
a Department of Chemistry, Youngstown State University, WBSH 5053, Youngstown, OH 44555, United States
b Department of Chemistry, The Johns Hopkins University, Baltimore, MD 21218, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The clean synthesis of unsymmetrical ketones from carboxylic acid derivatives has been a challenge in
the organic community dating back over 80 years. Herein we report the conversion of simple alkyl
cinnamates to b,b-disubstituted ketones with cyano-magnesio cuprates in high yields with no obser-
vation of tertiary alcohol byproduct. The lack of tertiary alcohol is attributed to a putative enolate in-
termediate that serves as a ketone protecting group. A distinctive steric inhibition trend was observed
related to both the size of the R group on the parent ester and the nucleophilic cuprate. Lastly, we
demonstrate that this reaction can be coupled with known copper mediated allylic substitution reactions
Received 1 April 2016
Received in revised form 13 April 2016
Accepted 3 May 2016
Available online xxx
Keywords:
Cuprate
Ketone synthesis
Ketene
yielding
b
,g
-disubstituted ketone (8) from parent
a
-chloro-
b
,g
-ethylenic ester (7).
Ó 2016 Elsevier Ltd. All rights reserved.
Conjugate addition
Allylic substitution
1. Introduction
organometallic nucleophile is not reactive (acid chloride to ketone)
or form an in situ protected ketone (Weinreb amide, thiopyridyl
ester) that is unreactive to a second nucleophilic attack (Fig. 1).
The synthesis of ketones from carboxylic acids with nucleophilic
organometallics dates back to Gillman in 19331 and has continued
to receive attention from the chemical community.2 Historically
these reactions have suffered from harsh conditions and the for-
mation of tertiary alcohol byproducts due to over addition of the
participating nucleophilic organometallic reagent.3 We previously
reported that deploying cyanocuprates in these reactions com-
pletely suppresses the formation of tertiary alcohol byproducts.4
This protocol has recently been successfully implemented by
Echevarren in the total syntheses of Rumpellaone A and Hush-
inone.5 Additionally Hatton and Jamison have recently shown that
under flow conditions, CO2 can be converted into ketones, through
a carboxylic acid intermediate, via sequential addition of organo-
lithium or Grignard reagents without formation of the subsequent
tertiary alcohol.6 The formation of tertiary alcohol byproducts is
putatively due to the pre-workup formation of the ketone product,
which readily reacts with organo-copper, -lithium, and -magne-
sium reagents to form the unwanted alcohol. Traditional chemical
alternatives to this problem have involved the treatment of car-
boxylic acid derivatives such as acid halides,7 Weinreb amides,8 or
thiopyridylesters9 with cuprates or Grignard reagents. These re-
actions either form the ketone at low temperature, where the
Fig. 1. Synthesis of ketones from carboxylic acid derivatives.
Notably absent from these transformations is the clean con-
version of a simple alkyl ester into the corresponding ketone, a re-
action notorious for the formation of tertiary alcohol. Inspired by
the reports of Munch-Petersen10 and Lipshutz,11 who in-
dependently reported observing trace ketone formation in copper
mediated conjugate additions to trisubstituted-enoates, we
* Corresponding author. E-mail address: dtgenna@ysu.edu (D.T. Genna).
http://dx.doi.org/10.1016/j.tet.2016.05.003
0040-4020/Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Genna, D. T.; Posner, G. H., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.05.003

2
D.T. Genna, G.H. Posner / Tetrahedron xxx (2016) 1e4
hypothesized that the trace ketone products could exist in situ as
enolates derived from copper mediated conjugate addition (Fig. 1).
Such an enolate would serve as a transient ketone protecting group
that would be unreactive to subsequent 1,2-additions to form ter-
tiary alcohol products, and would not require the use of exotic ester
derivatives. Herein we report the elaboration of this hypothesis
This reaction manifold yielded the desired b-substituted ethyl,
isopropyl, and tert-butyl ketones, respectively, but with decreasing
yields as the size of the alkylating group on the cuprate increased.
Vinyl cuprate yielded the desired enone in low yield, perhaps due to
the decreased transfer ability of vinyl groups from the organo
copper species. Allyl and phenyl cuprates failed to yield any ketone
product with Ph2CuMgBr producing only biphenyl.13
with the conversion of simple cinnamate esters into
b,b-di-
substituted ketones by treatment with excess alkyl cuprate formed
in situ from Grignard reagents and cuprous cyanide in a 2:1 ratio.
Although the full mechanism of this transformation remains to
be elucidated, we propose the following mechanism outlined in
Scheme 3. Initial conjugate addition leads to the formation of Cu-
enolate I,14 which then undergoes a Lewis acid mediated elimina-
tion reaction to yield ketene II. Due to the complex nature of the
reaction, the Lewis acid in question could be Cu, Mg, or a Cu/Mg
mixed salt. Ketene II is then alkylated with excess cuprate to yield
ketone enolate III, which upon aqueous workup yields the desired
ketone 1. It is worth noting that we have previously reported that
2. Results and discussion
Our investigation commenced by treating methyl cinnamate
with 5 equiv Me2CuMgBr, synthesized from 10 equiv MeMgBr and
5 equiv CuCN, in CH2Cl2 solvent. Gratifyingly the desired 4-phenyl-
2-pentanone (1) was isolated in 76% yield (Scheme 1) with no
formation of tertiary alcohol byproduct. Reaction optimization
revealed that 5 equiv of the cuprate were necessary and that CH2Cl2
was the optimal solvent, although the reaction performs modestly
in THF (61% yield). Other alkyl cinnamates were examined with
a clear decrease in overall yield as the R group on the ester in-
creased in size. This is consistent with previous work by Posner
who has shown that the rate of conjugate addition reactions of
ketones, sulfoxides, and sulfones is inversely proportional to the
size of the opposing R group.12
Cu-enolates of type I containing a phenyl ring in the b-position are
uniquely stabilized when compared to lithium enolates of similar
structure.15 This enhanced stability (or increased lifetime) could
facilitate the formation of the ketene II.
R
Yield (%)
Scheme 3.
Me
Et
i-Pr
t-Bu
76
72
60
36
32a
The existence of enolate III was confirmed by quenching a rep-
resentative experiment using methyl cinnamate with Ac2O, yield-
ing acetylated enol ether 6 in 55% yield as a single, but unknown
isomer (Scheme 4). Although the existence of III does not un-
equivocally confirm a ketene pathway, since one could propose an
alternate pathway of initial 1,2 addition followed by immediate 1,4
addition into the enone. However, we believe such an alternate
path is not consistent with known cuprate chemistry which has
demonstrated that treatment of methylcinnamate with 3 equiv
Me2CuMgBr (from CuI) yields 1,4 addition product, methyl 3-
phenylbutanoate.16
Ph
a) Reaction run in THF
Scheme 1.
With methyl cinnamate identified as the ideal substrate, we
next explored the scope of the nucleophilic cuprate (Scheme 2).
Scheme 4.
In an effort to perform this reaction in tandem with other known
copper mediated transformations, we treated
a
-chloro-b,g-ethyl-
enic ester 7 with 5 equiv Me2CuMgBr which yielded
b,g-dimethyl
methyl ketone 8 in 56% yield albeit as a 1:1 mixture of di-
astereomers (Scheme 5). Chemically this reaction was a success,
demonstrating that (1) the reacting substrate can be more than
cinnamate derivatives and (2) Me2CuMgBr can sequentially per-
form an allylic substitution, conjugate addition, and ester enolate to
ketone transformation in high yield over three chemical steps in
one reaction vessel.
Scheme 2.
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D.T. Genna, G.H. Posner / Tetrahedron xxx (2016) 1e4
3
with H2O, transferred to a separatory funnel, and extracted with
CH2Cl2 (3ꢀ). The combined organics were washed with brine,
separated, dried over anhydrous MgSO4, filtered, and concentrated
in vacuo. The crude oil was purified by column chromatography (1%
EtOAc in hexanes) to yield the desired ketone
1 (0.037 g,
0.23 mmol) in 75% yield as a colorless oil. 1H NMR (400 MHz, CDCl3)
d
7.31e7.19 (m, 5H), 3.32e3.29 (m, 1H) 2.75e2.67 (m, 2H), 2.07 (s,
Scheme 5.
3H), 1.28e1.26 (d, 3H, J¼6.8 Hz); 13C NMR (100 MHz, CDCl3)
d 207.8,
146.1, 128.5, 126.7, 126.3, 52.0, 35.4, 30.6, 22.0; IR (cmꢁ1) 3027, 1716,
1493, 1358, 1161 HRMS (ESI) calcd for C11H15O (MþH)þ 185.0937
found 185.0939.
3. Conclusions
In conclusion we have reported the synthesis of
4.1.2. Synthesis of 5-phenyl-hept-3-one (2) in 60% yield (34 mg) from
methylcinnamate. To a 2-dram vial equipped with stir bar under
argon was added CuCN (0.140 g, 1.60 mmol, 5.00 equiv) in THF
(2.5 mL). The vial was cooled to ꢁ78 ꢂC and a 3M solution of EtMgBr
in Et2O (1.03 mL, 3.10 mmol, 10.0 equiv) was added and the reaction
stirred for 30 min. At this time a solution of methylcinnamate
(0.050 g, 0.31 mmol, 1.0 equiv) in THF (1.5 mL) was added. The
reaction was stirred overnight and allowed to slowly warm to room
temperature. At this time the reaction was quenched with H2O,
transferred to a separatory funnel, and extracted with CH2Cl2 (3ꢀ).
The combined organics were washed with brine, separated, dried
over anhydrous MgSO4, filtered, and concentrated in vacuo. The
crude oil was purified by column chromatography (1% EtOAc in
hexanes) to yield the desired ketone 2 (0.034 g, 0.19 mmol) in 60%
b,b-di-
substituted ketones by treating cinnamates with excess
R2CuMgBr. We postulate that this reaction proceeds through
a putative ketene intermediate II, which upon addition of or-
ganometallic copper reagent yields ketone enolate III. This eno-
late serves as an in situ protecting group to prohibit the synthesis
of tertiary alcohol byproducts by subsequent organometallic ad-
dition into the ketone product. It is worth noting that in all ex-
amples reported here no detectable amounts of tertiary alcohol
were observed.
4. Experimental
4.1. Instrumentation and chemicals
yield as a colorless oil. 1H NMR (300 MHz, CDCl3)
d 7.30e7.11 (m,
5H), 3.09e2.94 (m, 1H), 2.76e2.70 (d, 2H, J¼17.4 Hz), 2.37e2.17 (m,
1H and 13C NMR spectra were recorded on Bruker Avance
spectrometers at 400 and 100 MHz or 300 and 75 MHz, re-
spectively, using the residual solvent peak as the internal standard.
High Resolution Mass Spectrum-Fast Atom Bombardment (HRMS-
FAB) mass spectra were obtained using a VG70SE double focusing
magnetic sector mass spectrometer (VG Analytical, Manchester, UK
now Micromass/Waters) equipped with a Csþ ion gun (28 kV @
2H),1.70e1.55 (m, 2H), 0.96e0.91 (t, 3H, J¼7.2 Hz), 0.79e0.74 (t, 3H,
J¼6.6 Hz); 13C NMR (75 MHz, CDCl3)
d 210.7, 144.4, 128.4, 127.5,
126.2, 49.3, 43.0, 36.7, 29.2, 12.0, 7.6; IR (cmꢁ1) 3028, 1714, 1454,
1377, 759; HRMS (ESI) calcd for C13H19O (MþH)þ 191.1430 found
191.1434.
4.1.3. 2,6-Dimethyl-5-phenyl-3-heptanone (3) in 47% yield (31 mg)
from methylcinnamate. To a 2-dram vial equipped with stir bar
under argon was added CuCN (0.140 g, 1.60 mmol, 5.00 equiv) in
THF (2.5 mL). The vial was cooled to ꢁ78 ꢂC and a 2.9 M solution of
iPrMgBr in Et2O (1.06 mL, 3.10 mmol,10.0 equiv) was added and the
reaction stirred for 30 min. At this time a solution of methyl-
cinnamate (0.050 g, 0.31 mmol, 1.0 equiv) in THF (1.5 mL) was
added. The reaction was stirred overnight and allowed to slowly
warm to room temperature. At this time the reaction was quenched
with H2O, transferred to a separatory funnel, and extracted with
CH2Cl2 (3ꢀ). The combined organics were washed with brine,
separated, dried over anhydrous MgSO4, filtered, and concentrated
in vacuo. The crude oil was purified by column chromatography (1%
EtOAc in hexanes) to yield the desired ketone 3 (0.031 g, 0.15 mmol)
2
mA), an off-axis multiplier and a MSS data system (MasCom,
Bremen, Germany). The resolution of the instrument was set at
10,000 (100 ppm peak width). Samples were mixed with m-
nitrobenzyl alcohol matrix deposited on the target of a direct in-
sertion probe for introduction into the source. For accurate mass
measurements, a mass scan range was employed with the matrix
containing 10% polyethylene glycol (PEG) or polyethylene glycol,
monomethyl ether (PEGMME) mass calibrant. Fourier Transform-
Infrared (FTIR) experiments were performed on a Bruker Vector
22 instrument. Optical rotation values were obtained using
a 100 mm quartz cell on a JASCO P-1010 polarimeter with a 589 nm
source. Thin-layer chromatography was performed with Silicycle
ꢀ
glass-backed 20 cmꢀ20 cm extra-hard layer 250
m
m thickness 60 A
plates with F254 indicator cut down to 20 mmꢀ67 mm for analytical
purposes. Anhydrous solvents were prepared utilizing a SPBT-101
bench top solvent purifier from LC Technology Solutions Inc. Cu-
prous cyanide (99%), a free-flowing light green solid, was pur-
chased from Strem Chemicals Inc. and used as provided. Allylic
chloride 7 was synthesized as previously reported.4 All other
chemicals were purchased from Sigma Aldrich and used as
provided.
in 47% yield as a colorless oil. 1H NMR (300 MHz, CDCl3)
d 7.30e7.10
(m, 5H), 2.99e2.92 (m, 1H), 2.83e2.80 (d, 2H, J¼6.9 Hz), 2.46e2.37
(m, 1H), 1.90e1.78 (m, 1H), 1.00e0.89 (m, 6H), 0.88e0.86 (d, 3H,
J¼6.9 Hz), 0.75e0.73 (d, 3H, J¼6.9 Hz); 13C NMR (75 MHz, CDCl3)
d
213.8, 143.7, 128.2, 128.0, 126.0, 47.7, 46.7, 41.2, 33.0, 20.8, 20.4,
17.9, 17.8; IR (cmꢁ1) 2964, 1711, 1466, 752, 701; HRMS (ESI) calcd for
C
15H23O (MþH)þ 219.1743 found 219.1747.
4.1.4. Synthesis of acetylated ketone enolate of methyl-4-phenyl-bu-
tan-2-one (6) in 55% yield (17 mg) from methylcinnamate. To a 2-
dram vial equipped with stir bar under argon was added CuCN
(0.140 g, 1.60 mmol, 5.00 equiv) in CH2Cl2 (2.5 mL). The vial was
cooled to ꢁ78 ꢂC and a 3 M solution of MeMgBr in Et2O (1.03 mL,
3.10 mmol, 10.0 equiv) was added and the reaction stirred for
30 min. At this time a solution of methylcinnamate (0.050 g,
0.31 mmol, 1.0 equiv) in CH2Cl2 (1.5 mL) was added. The reaction
was stirred for 7 h and allowed to slowly warm to room tempera-
ture over that time period. At this time the reaction was quenched
4.1.1. General procedure for converting cinnamates into 4-methyl-4-
phenyl-butan-2-one (1). To a 2-dram vial equipped with stir bar
under argon was added CuCN (0.140 g, 1.60 mmol, 5.00 equiv) in
CH2Cl2 (2.5 mL). The vial was cooled to ꢁ78 ꢂC and a 3M solution of
MeMgBr in Et2O (1.03 mL, 3.10 mmol, 10.0 equiv) was added and
the reaction stirred for 30 min. At this time a solution of methyl-
cinnamate (0.050 g, 0.31 mmol, 1.0 equiv) in CH2Cl2 (1.5 mL) was
added. The reaction was stirred overnight and allowed to slowly
warm to room temperature. At this time the reaction was quenched
Please cite this article in press as: Genna, D. T.; Posner, G. H., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.05.003

4
D.T. Genna, G.H. Posner / Tetrahedron xxx (2016) 1e4
with Ac2O (0.732 mL, 7.75 mmol, 25.0 equiv) and stirred for 5 min.
The reaction was treated with H2O and the biphasic mixture was
transferred to a separatory funnel and extracted with EtOAc (3ꢀ).
The combined organics were dried over anhydrous MgSO4, filtered,
and concentrated in vacuo. The crude oil was purified by column
chromatography (3% EtOAc in hexanes) to yield the desired acety-
lated ketone enolate 6 (0.033 g, 0.17 mmol) in 55% yield as a col-
1714, 1494, 1356, 1166, 738, 699; HRMS calcd for C14H20O (Mþ)
204.1514 found 204.1517.
Acknowledgements
The authors wish to thank The Johns Hopkins University for fi-
nancial support.
orless oil. 1H NMR (400 MHz, CDCl3)
d 7.29e7.18 (m, 5H); 5.15e5.12
(d, 1H, J¼9.6 Hz); 3.68e3.58 (m, 1H); 2.14 (s, 3H); 1.91 (s, 3H);
1.33e1.31 (d, 3H, J¼8 Hz) 13C NMR (100 MHz, CDCl3)
d 168.9, 145.5,
References and notes
128.4, 126.8, 126.1, 122.5, 35.9, 31.6, 22.6, 19.5, 14.1 IR (cmꢁ1) 2964,
1753, 1370, 1216, 1162, 760 HRMS (ESI) calcd for C13H16O2Na
(MþNa)þ 227.1048 obsv. 227.1042.
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allylic chloride 7. To a 1-dram vial equipped with stir bar under
argon was added CuCN (0.040 g, 0.45 mmol, 5.0 equiv) in THF
(0.4 mL). The vial was cooled to ꢁ78 ꢂC. A 3M solution of MeMgBr in
Et2O (0.30 mL 0.90 mmol, 10.00 equiv) was added and the reaction
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diastereomer obtained via repeated column chromatography. 1H
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NMR (400 MHz, CDCl3)
d 7.29e7.13 (m, 5H), 2.72e2.64 (m, 1H),
2.54e2.49 (m, 1H), 2.46e2.39 (m, 1H), 2.35e2.22 (m, 3H), 2.12 (s,
3H), 2.06 (s, 3H), 0.93e0.91 (d, 3H, J¼6.8 Hz), 0.81e0.79 (d, 3H,
J¼6.8 Hz); 13C NMR (100 MHz, CDCl3)
d 209.2, 129.0, 128.9, 128.2,
125.8, 49.2, 47.3, 39.8, 33.3, 30.3, 17.0, 15.8; IR (cmꢁ1) 3061, 2964,
Please cite this article in press as: Genna, D. T.; Posner, G. H., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.05.003