An Example of Ketone Olefination via Praseodymium-Mediated Barbier Reaction in the Presence of Diethyl Phosphite

Article abstract of DOI:10.1055/s-0039-1690096

The first example of carbon double-bond formation via praseodymium-mediated Barbier type reaction of ketones and allyl halides in the presence of diethyl phosphite is reported. The reaction is highly α-regioselective and conveniently carried out under mild conditions in a one-pot fashion. From a synthetic point of view, a series of conjugated alkenes were obtained in moderate to good yields in this one-pot reaction with practical reaction conditions.

Full text of DOI:10.1055/s-0039-1690096

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© Georg Thieme Verlag Stuttgart · New York
2019, 30, 1437–1441
letter
1437
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X. Cao et al.
Letter
Synlett
An Example of Ketone Olefination via Praseodymium-Mediated
Barbier Reaction in the Presence of Diethyl Phosphite
Xu yan Cao
Fei Huang
R4
R4
Pr
O
a
a
R2
+
R3
R1
R2
X
R3
(EtO)2POH
Songlin Zhang*
R1
R5
R5
The First C=C Formation under Barbier Reaction Condations
High Regioselectivity
X = Cl, Br, I
Key Laboratory of Organic Synthesis of Jiangsu Province,
College of Chemistry, Chemical Engineering and Materials
Science, Dushu Lake Campus, Soochow University, Suzhou,
215123, P. R. of China
One-Pot Fashion
zhangsl@suda.edu.cn
Received: 25.03.2019
Accepted after revision: 20.05.2019
Published online: 25.06.2019
conditions. It is well known that the Barbier reaction14 can
be used without preparing the organometallic reagent.
Based on our recent work,15 herein, we would like to report
the utility of praseodymium as a mediating metal in the
Barbier reaction of carbonyl compounds with allyl halides
to produce conjugated alkenes in the presence of diethyl
phosphite (Scheme 1).
DOI: 10.1055/s-0039-1690096; Art ID: st-2019-b0172-l
Abstract The first example of carbon double-bond formation via pra-
seodymium-mediated Barbier type reaction of ketones and allyl halides
in the presence of diethyl phosphite is reported. The reaction is highly
-regioselective and conveniently carried out under mild conditions in a
one-pot fashion. From a synthetic point of view, a series of conjugated
alkenes were obtained in moderate to good yields in this one-pot reac-
tion with practical reaction conditions.
R3
R2
R1
X = I, Cl, Br
O
R1
Pr, I2, THF
(EtO)2POH
R4
+
X
R3
R4
R2
Key words Barbier type reaction, ketones, diethyl phosphite, -regi-
oselective, conjugated alkenes
Scheme 1 Ketone olefination via Pr-mediated Barbier reaction in the
presence of diethyl phosphite
Olefins not only play an important role in the synthesis
of many compounds, they are also found in the structure of
numerous natural products and pharmaceutical agents.1
The olefination of carbonyl compounds is a very important
transformation to afford olefins in organic synthesis. The
Wittig reaction,2 Julia reaction,3 and Peterson reaction,4,5
provide highly effective and general methods. However, the
need for ylides, which were generated by a stepwise proce-
dure, could not be avoided in these reactions. Accordingly,
Wong6 and Hopf7 afforded conjugated diene utilizing an
elimination reaction mediated by strong base. Moreover,
several reactions employing Ni,8 Pd,9 and Ru10 complexes
have been used to synthesize conjugated alkenes; however,
although this strategy is useful, it is less practical because
of the use of precious metal.
Recently, our attention has focused on the concise and
elegant synthesis of olefins by the application of organome-
tallic reagents. Several examples of carbonyl olefination in-
volving Grignard reagents11–13 and diethyl phosphite have
been presented. The only drawback of these methods is the
fact that the organometallic reagents need to be prepared
by a stepwise procedure under water and/or oxygen-free
Initially, benzophenone and allyl bromide were selected
as a model reaction to optimize the reaction conditions (Ta-
ble 1, entries 1–12). First, a range of organophosphorus ad-
ditives were examined with THF as the solvent; the results
are summarized in Table 1. The reaction was dramatically
influenced by the presence of additives. With Ph3P, (EtO)3P,
(EtO)3PO, and (EtO)2P(O)CH2COOEt as additives, no product
was obtained (entries 1–4). With (EtO)2P(O)H as additive,
the product could be obtained in higher yield than achieved
with (PhO)2P(O)H as additive (entries 5 and 6). Subsequent-
ly, the molar ratio of ketone/bromide/Pr/phosphite was also
investigated (entries 7–10). To our delight, the yield could
be further improved through increasing the temperature
from room temperature to 50 °C (entry 12). Thus, the use of
(EtO)2P(O)H as an additive and 50 °C as the reaction tem-
perature with a 1:4:3:1.2 molar ratio of ketone/bro-
mide/Pr/phosphite proved to be the optimal reaction condi-
tions for the reaction.
To investigate the generality of this reaction, the scope
of the substrate with different allyl halides was subsequent-
ly explored; the results are summarized in Table 2.16
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, 1437–1441
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

1438
X. Cao et al.
Letter
Synlett
Table 1 Optimization of Reaction Conditionsa
As shown in Table 2, substituted benzophenones react-
ed with allylic bromide or iodide, giving the corresponding
conjugated dienes with good to excellent yields (entries 1,
2, and 5). Unfortunately, when benzaldehyde or acetophe-
none were employed as substrates, no corresponding prod-
ucts were obtained (entries 3 and 4).
O
Pr, I2, THF
additive
+
Br
To test the regioselectivity of the Barbier type reaction,
3,3-dimethylallyl bromide was employed as the substrate
(Table 2, entries 6 and 7). As expected, no -adducts, which
are the dominant products in conventional Barbier reac-
tions, were observed. Only the -adducts were obtained in
good yields. To further broaden the scope of the reaction,
3,3-dimethylallyl chloride and 3-bromo-2-methylpropene
were employed to react with a series of benzophenones
(entries 8–13). The -adducts were obtained exclusively in
moderate to good yields. The results indicated that the pra-
seodymium-mediated Barbier type reaction was highly -
regioselective. Finally, propyl halide was tested, but the re-
action did not proceed (entry 14).
Entry Additive
Ratiob
Time (h) T (°C)
Yield (%)c
1
2
Ph3P
1:4:3:1.2
1:4:3:1.2
1:4:3:1.2
24
24
24
24
24
24
24
24
24
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
–
(EtO)3P
(EtO)3PO
–
3
–
4
(EtO)2P(O)CH2COOEt 1:4:3:1.2
–
5
(PhO)2P(O)H
(EtO)2P(O)H
(EtO)2P(O)H
(EtO)2P(O)H
(EtO)2P(O)H
(EtO)2P(O)H
(EtO)2P(O)H
(EtO)2P(O)H
1:4:3:1.2
1:4:3:1.2
1:4:3:0.5
1:4:3:2
12
45
27
31
41
34
–
6
7
8
9
1:2.5:2:1.2
According to our previous work12a,13 a similar mecha-
nism was proposed (Scheme 2). Carbonyl compound 1 un-
dergoes nucleophilic addition reaction with the on-site pra-
seodymium reagent 2 to form alkoxide 3. The diethyl phos-
phite 4 reacts with the on-site praseodymium reagent 2 to
form metallic bromide diethoxy(oxo)phosphate 5 and, fi-
nally, elimination of alkoxide 3 mediated by metallic bro-
mide diethoxy(oxo)phosphate 5 affords the carbon double-
bond compound 7.
10
11
12
1:1.6:1.2:1.2 24
1:4:3:1.2
1:4:3:1.2
24
12
0
50
89
a Reaction conditions: To a suspension of benzophenone (0.5 mmol) and
praseodymium (2 mmol) in THF (3 mL) was added allyl bromide and cata-
lytic amounts of I2 under a nitrogen atmosphere at room temperature, and
the mixture was stirred for 2 h, then the additive was added to this mixture
and stirred at 50 °C.
b Benzophenone/allyl bromide/praseodymium/diethyl phosphite.
c Isolated yield based on benzophenone after silica gel chromatography.
Table 2 Ketone Olefination via Pr-Mediated Barbier Type Reaction in the Presence of Diethyl Phosphitea
R4
R4
O
a
Pr
a
R2
R3
+
X
R3
R1
R2
(EtO)2POH
R1
R5
R5
X = Cl, Br, I
Entry
1
Ketone
Bromide
Product
Yield (%)b
O
Br
2a
89
1a
2aa
Br
O
2a
2
3
83
Cl
1b
Cl
Cl
2ba
Cl
O
Br
2a
–
2ca
1c
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, 1437–1441

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Table 2 (continued)
Entry
Ketone
Bromide
Product
Yield (%)b
CHO
Br
4
–
Br
2da
2a
Br
1d
O
O
I
5
91
2b
O
O
1e
O
2eb
2ac
2fc
O
Br
6
7
70
78
2c
2c
1a
O
Br
1f
O
Cl
8
88
2d
Ph
1g
2gd
O
Cl
9
75
2d
Cl
Cl
1b
Cl
Cl
2bd
O
Br
10
11
53
55
2e
2e
1a
1h
2ae
2he
O
Br
O
O
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, 1437–1441

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X. Cao et al.
Letter
Synlett
Table 2 (continued)
Entry
12
Ketone
Bromide
Product
Yield (%)b
O
Br
57
2e
F
1i
F
F
2ie
F
O
Br
13
14
52
2e
2f
Ph
Ph
1g
1a
2ge
2af
O
Br
–
a Reaction conditions: To a suspension of ketone (0.5 mmol) and praseodymium (1.5 mmol) in THF (3 mL) was added bromide (2 mmol) and catalytic amounts
of I2 under a nitrogen atmosphere at room temperature, and the mixture was stirred for 2 h, then diethyl phosphate (0.6 mmol) was added to this mixture and
stirred at 50 °C for 12 h.
b Isolated yields based on ketone after silica gel chromatography.
In summary, we have documented the first example of
carbon double-bond formation via Barbier type reaction of
allyl halides with carbonyl compounds mediated by praseo-
dymium in the presence of diethyl phosphite. As a comple-
ment to the traditional carbonyl olefination, the carbon
double-bond formation was highly -regioselective. In this
work, a straightforward strategy to synthesize conjugated
alkenes in moderate to good yields was developed.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690096.
S
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p
p
orit
n
gInformati
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S
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p
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orit
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gInformati
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References and Notes
(1) (a) Nicolaou, K. C.; Ramphal, J. Y.; Petasis, N. A.; Serhan, C. N.
Angew. Chem. Int. Ed. Engl. 1991, 30, 1100; Angew. Chem. 1991,
103, 1119. (b) Sandri, J.; Viala, J. J. Org. Chem. 1995, 60, 6627.
(c) Lucet, D.; Gall, T. L.; Mioskowski, C. Angew. Chem. Int. Ed.
1998, 37, 2580; Angew. Chem. 1998, 110, 2724. (d) Kotti, S. R. S.
S.; Timmons, C.; Li, G.-G. Chem. Biol. Drug Des. 2006, 67, 101.
(e) Takao, K.; Munakata, R.; Tadano, K. Chem. Rev. 2005, 105,
4779. (f) Alvarez, R.; Vaz, B.; Gronemeyer, H.; deLera, A. R. Chem.
Rev. 2014, 114, 1–125.
Funding Information
The study was supported by the Project of Scientific and Technologic
Infrastructure of Suzhou (No. SZS201207) and by the National Natural
Science Foundation of China (No. 21072143). We gratefully acknowl-
edge the Priority Academic Program Development of Jiangsu Higher
(2) (a) Wittig, G.; Geissler, G. Justus Liebigs Ann. Chem. 1953, 580,
44. (b) Wittig, G.; Schollkopf, U. Chem. Ber. 1954, 97, 1318.
Education Institutions for funding the project.
N
ati
o
n
a
lNaturalS
c
i
e
n
c
e
F
o
u
n
d
ati
o
n
of
C
h
i
n
a
(2
1
0
7
2
1
4
3)
(EtO)2P(O)H
4
CH2PrBr
(EtO)2P(O)H
O
OEt
H
O
(EtO)2P(O)PrBr
5
CH2PrBr
R2
OPrBr
2
P OEt
R1
R2
R1
R2
R1
PrBr
R1
O
R2
PrBr
1
3
7
6
Scheme 2 Possible reaction mechanism
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, 1437–1441

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X. Cao et al.
Letter
Synlett
(c) Wittig, G.; Schlosser, M. Tetrahedron 1962, 18, 1023.
(d) Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863.
(3) (a) Lee, G. H.; Lee, H. K.; Choi, E. B.; Kim, B. T.; Pak, C. S. Tetrahe-
dron Lett. 1995, 36, 5607. (b) Pospisil, J.; Pospisil, T.; Marko, I. E.
Org. Lett. 2005, 7, 2373.
(4) (a) Ager, D. J. Org. React. 1990, 38, 1–223. (b) Staden, L. F.;
Gravestock, D.; Ager, D. J. Chem. Soc. Rev. 2002, 31, 195.
(5) Lakhrissi, M.; Chapleur, Y. Angew. Chem. Int. Ed. Engl. 1996, 35,
750.
diethyl ether (3 × 10 mL), and dried over anhydrous Na2SO4. The
solvent was removed by evaporation under reduced pressure.
Purification by column chromatography on silica gel afforded
olefins (300–400 mesh, petroleum ether as eluent).
Buta-1,3-diene-1,1-diyldibenzene (2aa)
Yield: 91.7 mg (89%); colorless oil. 1H NMR (400 MHz, CDCl3):
 = 7.40–7.25 (m, 8 H), 7.23–7.20 (m, 2 H), 6.71 (d, J = 11.0 Hz,
1 H), 6.44 (dt, J = 16.9, 10.5 Hz, 1 H), 5.42–5.36 (m, 1 H), 5.15–
5.10 (m, 1 H). 13C NMR (101 MHz, CDCl3):  = 143.26, 142.21,
139.77, 135.08, 130.54, 128.64, 128.32, 128.29, 127.71, 127.63,
127.52, 118.73. HRMS (EI+): m/z [M+] calcd for C16H14: 206.1096;
found: 206.1089.
(6) Wong, K. T.; Hung, Y. Y. Tetrahedron Lett. 2003, 44, 8033.
(7) Hopf, H.; Hänel, R.; Trætteberg, M.; Bakken, P. Eur. J. Org. Chem.
1998, 467.
(8) Dennis, K. P. N.; Luh, T. Y. J. Am. Chem. Soc. 1989, 11, 9119.
(9) (a) Mitsudo, T.; Kadokura, M.; Watanabe, Y. J. Org. Chem. 1987,
52, 1695. (b) Negishi, E. I.; Huang, Z.-H.; Wang, G.-W.; Mohan,
S.; Wang, C.; Hattori, H. Acc. Chem. Res. 2008, 41, 1474.
(10) Murelli, R. P.; Snapper, M. L. Org. Lett. 2007, 9, 1749.
(11) (a) Li, Y.; Hu, Y.-Y.; Zhang, S.-L. Chem. Commun. 2013, 49, 10635.
(b) Hu, Y.-Y.; Zhao, T.; Zhang, S.-L. Chem. Eur. J. 2010, 16, 1697.
(12) (a) Wang, T.-Q.; Hu, Y.-Y.; Zhang, S.-L. Org. Biomol. Chem. 2010,
8, 2312. (b) Qi, W.-K.; Wang, P.-P.; Fan, L.-Y.; Zhang, S.-L. J. Org.
Chem. 2013, 78, 5918.
(13) Cui, H.; Li, Y.; Zhang, S.-L. Org. Biomol. Chem. 2012, 10, 2862.
(14) (a) Li, J.-L.; Hu, D.-C.; Liang, X.-P.; Wang, Y.-C.; Wang, H.-S.; Pan,
Y.-M. J. Org. Chem. 2017, 82, 9006. (b) Xie, Y.-. Y.; Wang, Y.-. C.;
Qu, H.-. E.; Tan, X.-. C.; Wang, H.-. S.; Pan, Y.-. M. Adv. Synth.
Catal. 2014, 356, 3347. (c) Wang, Y.; Li, J.; He, Y.; Xie, Y.; Wang,
H.; Pan, Y. Adv. Synth. Catal. 2015, 357, 3229. (d) Wang, Y.-C.;
Xie, Y.-Y.; Qu, H.-E.; Wang, H.-S.; Pan, Y.-M.; Huang, F.-P. J. Org.
Chem. 2014, 79, 4463. (e) Wang, X.; Li, S.-Y.; Pan, Y.-M.; Wang,
H.-S.; Liang, H.; Chen, Z.-F.; Qin, X.-H. Org. Lett. 2014, 16, 580.
(15) Wu, S.; Li, Y.; Zhang, S.-L. J. Org. Chem. 2016, 81, 8070.
(16) General Procedure for Synthesis of Dienes (2aa–af)
To a suspension of carbonyl compound (0.5 mmol) and praseo-
dymium (1.5 mmol) in THF (3 mL) was added halide (2 mmol)
and catalytic amounts of I2 under a nitrogen atmosphere at
room temperature. The mixture was stirred for 2 h, then diethyl
phosphite (0.6 mmol) was added and the mixture was stirred at
65 °C for 12 h. The reaction was then quenched with dilute
hydrochloric acid and the resulting mixture was extracted with
Methyl-4-(4-methyl-1-phenylpenta-1,3-dien-1-yl)benzene
(2fc)
Yield: 96.7 mg (78%); colorless oil. 1H NMR (400 MHz, CDCl3):
 = 7.37–7.29 (m, 1 H), 7.26–7.04 (m, 8 H), 6.84 (d, J = 11.4 Hz,
1 H), 5.93 (dd, J = 18.3, 11.5 Hz, 1 H), 2.34 (d, J = 25.6 Hz, 3 H),
1.87 (s, 3 H), 1.74 (d, J = 4.2 Hz, 3 H). 13C NMR (101 MHz, CDCl3):
 = 140.49, 140.44, 139.87, 139.78, 137.44, 137.23, 136.79,
130.69, 130.61, 128.98, 128.93, 128.20, 128.18, 127.62, 127.46,
127.07, 126.97, 124.45, 123.86, 123.47, 123.36, 26.59, 21.39,
21.21, 18.74, 18.72. HRMS (EI+): m/z [M+] calcd for C19H20
248.3490; found: 248.3484.
[1,1′-Biphenyl]-4-yl(phenyl)methanone (2gd)
:
Yield: 136.4 mg (88%); colorless oil. 1H NMR (400 MHz, CDCl3):
 = 7.65–7.54 (m, 3 H), 7.52–7.27 (m, 10 H), 7.21 (dd, J = 13.9,
6.7 Hz, 1 H), 6.91 (dd, J = 23.6, 11.4 Hz, 1 H), 5.98 (dd, J = 33.3,
11.4 Hz, 1 H), 1.89 (s, 3 H), 1.76 (d, J = 6.4 Hz, 3 H). 13C NMR (101
MHz, CDCl3):  = 142.13, 140.87, 139.75, 139.39, 139.36, 137.98,
137.95, 131.19, 130.72, 128.90, 128.87, 128.29, 127.88, 127.71,
127.38, 127.30, 127.21, 127.13, 127.03, 126.95, 126.88, 124.88,
124.59, 123.39, 26.64, 18.79. HRMS (EI+): m/z [M+] calcd for
C
24H22: 310.4400; found: 310.4421.
(3-Methylbuta-1,3-diene-1,1-diyl)dibenzene (2ae)
1
Yield: 58.3 mg (53%); white oil. H NMR (400 MHz, CDCl3):  =
7.25 (q, J = 5.7 Hz, 3 H), 7.19–7.04 (m, 9 H), 6.58 (s, 1 H), 4.91 (d,
J = 13.5 Hz, 2 H), 1.40 (s, 3 H). 13C NMR (101 MHz, CDCl3):  =
143.43, 142.56, 141.64, 140.78, 130.87, 130.46, 128.22, 128.06,
127.60, 127.35, 119.24, 22.20. HRMS (EI+): m/z [M+] calcd for
C
17H16: 220.3150; found: 220.3135.
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, 1437–1441