Synthesis of 1,4-Diketones via Titanium-Mediated Reductive Homocoupling of α-Haloketones

Article abstract of DOI:10.1055/s-0037-1610245

1,4-Diketones have been synthesized via a reductive homocoupling of α-haloketones. Addition of a Grignard reagent to titanium(IV) isopropoxide affords a low-valent titanium(III) intermediate that is believed to mediate a radical dimerization reaction. The

Full text of DOI:10.1055/s-0037-1610245

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© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–D
letter
A
en
N. N. Le et al.
Letter
Synlett
Synthesis of 1,4-Diketones via Titanium-Mediated Reductive
Homocoupling of -Haloketones
Nathan N. Le
Ti(OiPr)4 + EtMgBr
"Ti(OiPr)3"
O
O
R
X
Aimee M. Rodriguez
James R. Alleyn
+
R
X
R
O
R
O
Michael R. Gesinski*
R = aryl or heteroaromatic
X = Cl or Br
11 examples
22–90%
Southwestern University, 1001 E. University Avenue, George-
town, TX 78626, USA
gesinskm@southwestern.edu
Received: 15.06.2018
Accepted after revision: 23.07.2018
Published online: 20.08.2018
to observe titanocyclopropane 3 in the absence of an
electrophile led to extrusion of ethylene and a dispropor-
tionation reaction to form a titanium(III) intermediate.10
DOI: 10.1055/s-0037-1610245; Art ID: st-2018-v0375-l
Abstract 1,4-Diketones have been synthesized via a reductive homo-
coupling of -haloketones. Addition of a Grignard reagent to titani-
um(IV) isopropoxide affords a low-valent titanium(III) intermediate that
is believed to mediate a radical dimerization reaction. The reaction
works well for a variety of aromatic -haloketones including heteroaro-
matic compounds.
2 EtMgBr
Ti(OiPr)4
Ti(OiPr)2
–2 iPrOMgBr
–C2H6
2
1
Ti(OiPr)4
–C2H4
(iPrO)2Ti
(iPrO)2Ti
Ti(OiPr)3
2
3
Key words homocoupling, low-valent titanium, 1,4-diketone, radical
dimerization, Kulinkovich reagent
Scheme 1 Formation of low valent titanium species
While there have been considerable reports on the reac-
tivity of titanocyclopropane 3, there has been a dearth of
interest in the titanium(III) species generated as a result of
disproportionation. To our knowledge, titanium(III) inter-
mediates generated in this way have been disclosed to me-
diate three reactions: reductive pinacol coupling,10 reduc-
tive ring cleavage of isoxazoles and isoxazolines,11 and re-
ductive coupling of propargylic alcohols.12 Herein we
disclose an efficient reductive coupling of -haloketones
mediated by Ti(OiPr)4/EtMgBr to afford 1,4-diketones.
1,4-Diketones are valuable building blocks for the syn-
thesis of five-membered heterocyclic compounds, such as
furans, thiophenes, and pyrroles.1 Most commonly, this
structural motif is accessed by conjugate addition of an acyl
anion equivalent (Breslow intermediate) to an ,-unsatu-
rated ketone through a Stetter reaction.2 While many other
procedures exist,3 there are few reports of reductive cou-
pling approaches to these molecules4 and most rely on het-
erogeneous conditions involving nickel catalysts.5
In 1989, O. G. Kulinkovich and co-workers first reported
the formation of 1-alkylcyclopropanols from simple car-
boxylic esters in the presence of titanium isopropoxide and
two equivalents of ethylmagnesium bromide.6 Studies have
shown that this reaction proceeds through η2-alkenyl-tita-
nium complex 2 that is formed through double transmeta-
lation of titanium(IV) isopropoxide with ethylmagnesium
bromide followed by -hydride elimination of intermediate
1 (Scheme 1).7 In the presence of unsaturated substrates,
the reactivity of this reagent reflects the structural contri-
butions of η2-alkenyl-titanium(II) complex 2, which is capa-
ble of ligand exchange with alkenes, and titanocyclopro-
pane 3.8 The latter serves as a 1,2-dianion generating a cy-
clopropanol when exposed to esters.9 Subsequent attempts
Because it is readily available and inexpensive, 2-bromo-
acetophenone (4) was chosen as the ideal model system to
optimize conditions for the reductive coupling (Table 1).
Dropwise addition of EtMgBr to a mixture of 4 and Ti(OiPr)4
in THF afforded known 1,4-diketone 5 in 55% yield (Table 1,
entry 1).3d While formation of a twofold excess of titanocy-
clopropane 3 is typical for the Kulinkovich cyclopropana-
tion,6 an increase in yield was observed when only a slight
excess of titanium was used (Table 1, entry 2). A survey of
solvents demonstrated that the reaction conditions were
only amenable to THF which is in contrast to reports by
Kulinkovich and coworkers where diethyl ether was used as
the solvent for a pinacol coupling (Table 1, entries 3–5).10
When diethyl ether was used as the solvent, a considerable
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

B
N. N. Le et al.
Letter
Synlett
amount of 1,2-addition products of both the starting
bromoketone and the product were observed (Table 1, en-
try 3). Less polar, nonethereal solvents led to considerable
decomposition of the starting material and no products
were isolated (Table 1, entries 4 and 5).
demonstrated that the disproportionation reaction to form
titanium(III) intermediates is favored when the titanium
and Grignard reagents are premixed and heated.10 For this
reaction, it surprisingly only led to a reduced yield (Table 1,
entries 11 and 12).
This reaction could proceed through a variety of mecha-
nistic pathways depending on the active titanium species
that is formed. Kulinkovich and co-workers have demon-
strated that 1,4-diketones can be generated in the presence
of magnesium salts through a reaction similar to a Darzens
condensation.15 In a subsequent paper, the same authors
also disclosed that the these products are formed when -
bromoketones are exposed to titanium(IV) isopropoxide.16
When either titanium or magnesium were omitted from
the reaction, only starting material was isolated (Table 1,
entries 13 and 14). Therefore, it is likely that the homocou-
pling necessitates the formation of titanocyclopropane 3.
Having run the control experiments, three possible
mechanistic pathways are proposed for the reductive ho-
mocoupling (Scheme 2). In both pathways A and B, titani-
um(III) mediates formation of radical enolate 6. This inter-
mediate can either dimerize to form the 1,4-diketone or ox-
idize another equivalent of titanium(III) to form enolate 7
which can undergo an alkylation to form the same product.
Pathway C involves a two-electron reduction by titanium(II)
intermediates to directly form the same enolate as in path-
way B. Eisch and co-workers have shown that titanium(II) is
the operable reactive species in mixtures where lithium or
aluminum is used to form low-valent titanium intermedi-
ates instead of magnesium.17 If pathway C was the operable
mechanistic route, theoretically only 0.5 equivalents of tita-
nocyclopropane 3 are necessary for the reaction to proceed
to completion. Under these conditions only a trace amount
of product was observed (Table 1, entry 15). Additionally,
when 4 equivalents of TEMPO, a stable radical, was added
to the reaction mixture, the homocoupling was shut down,
and a significant quantity of radical enolate 6 was trapped
by TEMPO (isolated yield: 13%). Based on these experi-
ments, it seems clear that radical 6 is formed in the course
of the reaction. While it is not possible to easily distinguish
between pathways A and B, pathway A is consistent with
previously observed reactivity of these reagents.10,12
Table 1 Optimization of Reaction Conditions13
O
O
TiX, RMgBr
Br
solvent, T °C, 18 h
O
4
5
Entry TiX (equiv)
RMgBr (equiv)
Solvent
Temp Yield
(°C)
(%)
1
Ti(OiPr)4 (2.0)
Ti(OiPr)4 (1.2)
Ti(OiPr)4 (1.2)
Ti(OiPr)4 (1.2)
Ti(OiPr)4 (1.2)
EtMgBr (4.0)
EtMgBr (2.8)
EtMgBr (2.8)
EtMgBr (2.8)
EtMgBr (2.8)
THF
23
23
23
23
23
23
23
23
23
23
23
65
23
23
23
55
2
THF
79
a
3
Et2O
CH2Cl2
–
b
4
–
b
5
toluene
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
–
6
Ti(acac)2OiPr2(1.2)c EtMgBr (2.8)
23
50
37
7
Ti(OnBu)4 (1.2)
TiCl(OiPr)3(1.2)
TiCl4 (1.2)
EtMgBr (2.8)
EtMgBr (2.8)
EtMgBr (2.8)
cHexMgBr (2.8)
EtMgBr (2.8)
EtMgBr (2.8)
EtMgBr (2.8)
none
8
b
9
–
10
11d
12
13
14
15
Ti(OiPr)4 (1.2)
Ti(OiPr)4 (1.2)
Ti(OiPr)4 (2.0)
none
65
15
48
e
–
e
Ti(OiPr)4 (2.0)
Ti(OiPr)4 (0.5)
–
a
EtMgBr (1.2)
–
a Inseparable mixture of 1,2-ethyl addition products was observed.
bAn inseparable mixture of decomposition products was observed
c75 wt % in isopropanol.
dReaction was run through an inverse addition where 2-bromoacetophe-
none was added to a mixture of Ti(OiPr)4 and EtMgBr.
e No reaction was observed.
Other sources of titanium(IV) were also explored in
hopes that fine-tuning the reactivity of the reagents would
improve the efficiency of the reaction. When the less reac-
tive titanium(IV) diisopropoxide bis(acetoacetonate) was
employed, a significant decrease in yield was observed (Ta-
ble 1, entry 6). Unfortunately, increasing the reactivity by
utilizing titanium(IV) butoxide or chlorotitanium(IV) triiso-
propoxide also produced lower yields (Table 1, entries 7 and
8). Finally, addition of titanium(IV) chloride led to complete
decomposition of the starting material (Table 1, entry 9).
Finally, several other reaction conditions were altered in
hopes of improving the reaction yield. Titanocyclopropanes
generated from cyclohexylmagnesium bromide have
demonstrated diminished nucleophilicity in other systems
but had little effect on the homocoupling leading to a slight
decrease in yield (Table 1, entry 10).14 It has also been
O
6
O
O
O
Ti(III)
Ph
Ph
Br
Ph
Pathway A
Ph
Ph
O
4
6
5
Pathway B Ti(III)
Ti(II)
O
Pathway C
Br
O
Ph
4
Ph
7
Scheme 2 Proposed mechanism for the formation of 1,4-diketones
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

C
N. N. Le et al.
Letter
Synlett
Table 2 (continued)
Entry Substrate
A range of substrates were explored to determine the
scope and limitations of the homocoupling (Table 2). While
-chloroketone 9 was found to be a competent substrate,
the chloride resulted in diminished yields of diketone 8 (Ta-
ble 2, entry 2). Addition of electron-donating groups to the
aromatic ring enhanced reaction yields which is consistent
with the proposed mechanism (Table 2, entries 3–5). This is
notable because previously reported methods to form simi-
lar electron-rich diketones proved difficult making this a
complementary approach to symmetric diketone synthe-
sis.18 It is likely that the electron-donating substituent sta-
bilizes the ketone preventing 1,2-addition by the nucleo-
philic titanocyclopropane.19
Product
Yield
(%)a
O
NO2
O
Br
8
–
O2N
O
O2N
20
21
O
Br
9
6b
O
O
22
23
O
O
Br
Table 2 Homocouplings of -Haloketones13
10
6b
O
O
24
25
O
Ti(OiPr)4 (1.2 equiv)
R
X
R
N
EtMgBr (2.8 equiv)
23 °C, THF
R
O
O
O
Br
O
11
22
54
O
Entry Substrate
Product
Yield
(%)a
N
N
26
27
O
O
O
Br
Br
12
1
2
79
44
O
29
O
4
8
8
28
O
O
O
O
Cl
O
Br
O
13
70
51
O
O
O
O
9
30
OMe
31
O
Br
O
S
O
3
4
5
6
81
56
82
90
Br
O
MeO
14
MeO
10
11
S
O
S
32
33
CH3
O
O
a Isolated yields.
Br
b Yield based off of crude NMR data.
O
H3C
H3C
12
13
This observation is further supported by the enhanced
yield of the sterically encumbered ortho-tolyl diketone 15,
which should be less reactive toward nucleophilic addition,
compared to para-tolyl diketone 13 (Table 2, entry 5). It is
also consistent when comparing aromatic halides; the less
electron-withdrawing bromide 16 proved to be a more
competent substrate than chloride 18 (Table 2, entries 6 and
7). Finally, nitro-substituted aromatic rings resulted in
complete decomposition of the starting material, likely as a
result of titanium(III) intermediates reacting with the nitro
group (Table 2, entry 8).
CH3
O
CH3
O
Br
O
CH3
14
15
Br
O
O
Br
Br
O
Br
Br
Cl
16
18
17
Cl
O
O
7
45
Several nonbenzylic -bromoketones were also tested.
Unfortunately, aliphatic ketones proved to be difficult sub-
strates for this reaction. When -bromoketone 22 was ex-
posed to the reaction conditions, only a trace quantity of
O
Cl
19
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

D
N. N. Le et al.
Letter
Synlett
diketone 23 was observed (Table 2, entry 9). While it was
clear that the reaction readily underwent homocoupling, a
variety of ethyl-substituted alcohols were observed. Alter-
natively, when adamantyl derivative 24 was tested, mostly
decomposition products were observed likely due to a sig-
nificantly retarded homocoupling (Table 2, entry 10).
Finally, the homocoupling was compatible with a vari-
ety of heteroaromatic compounds including pyridine 26,
naphthalene 28, benzofuran 30, and thiophene 32 (Table 2,
entries 11–14). While the yields of these reactions vary, it is
noteworthy that these substrates have not been accessible
via other homodimerization procedures.
(2) (a) Stetter, H. Angew. Chem., Int. Ed. Engl. 1976, 15, 639.
(b) Johnson, J. S. Angew. Chem. Int. Ed. 2004, 43, 1326.
(3) (a) Yasuda, M.; Tsuji, S.; Shigeyoshi, Y.; Baba, A. J. Am. Chem. Soc.
2002, 124, 7440. (b) Liu, C.; Deng, Y.; Wang, J.; Yang, Y.; Tang, S.;
Lei, A. Angew. Chem. Int. Ed. 2011, 50, 7337. (c) Luo, J.; Jiang, Q.;
Chen, H.; Tang, Q. RSC Adv. 2015, 104, 1025. (d) Esumi, N.;
Suzuki, K.; Nishimoto, Y.; Yasuda, M. Org. Lett. 2016, 18, 5704;
and references cited therein.
(4) (a) Jarvis, W. F.; Hoey, M. D.; Finocchio, A. L.; Dittmer, D. C. J. Org.
Chem. 1988, 53, 5750. (b) Nishiyama, Y.; Kobayashi, A. Tetra-
hedron Lett. 2006, 47, 5565.
(5) (a) Peng, Y.; Luo, L.; Yan, C.-S.; Zhang, J.-J.; Wang, Y.-W. J. Org.
Chem. 2013, 78, 10960. (b) Liu, Y.; Xiao, S.; Qi, Y.; Du, F. Chem.
Asian. J. 2017, 12, 673.
In conclusion, a novel process for the synthesis of sym-
metric 1,4-diketones from -haloketones has been devel-
oped. Using low-valent titanium intermediates, this homo-
geneous reaction provides compounds that are comple-
mentary to previously reported syntheses. Additionally, it
has been shown that the mechanism of this reaction likely
involves a largely unexplored titanium(III) intermediate. Fu-
ture work will involve first modifying the reaction condi-
tions to make them compatible with nonaromatic ketones
and then exploiting the reactivity of the titanium inter-
mediate to perform other novel homocouplings as well as
a variety of radical reactions.
(6) (a) Kulinkovich, O. G.; Sviridov, S. V.; Vasilevskii, D. A.;
Pritytskaya, T. S. Russ. J. Org. Chem., Engl. Transl. 1989, 2, 2027.
(b) Kulinkovich, O. G.; Sviridov, S. V.; Vasilevskii, D. A. Synthesis
1991, 23, 234.
(7) (a) Eisch, J. J.; Adeosun, A. A.; Gitua, J. N. Eur. J. Org. Chem. 2003,
4721. (b) Wu, Y.-D.; Yu, Z.-X. J. Am. Chem. Soc. 2001, 123, 5777.
(8) Cohen, S. A.; Auburn, P. R.; Bercaw, J. E. J. Am. Chem. Soc. 1983,
105, 1136.
(9) Kulinkovich, O. G.; de Meijere, A. Chem. Rev. 2000, 100, 2789.
(10) Matiushenkov, E. A.; Sokolov, N. A.; Kulinkovich, O. G. Synlett
2004, 77.
(11) Churykau, D. H.; Zinovich, V. G.; Kulinkovich, O. G. Synlett 2004,
1949.
(12) Tian, G.-Q.; Kaiser, T.; Yang, J. Org. Lett. 2010, 12, 288.
(13) Example Experimental Procedure
Ti(OiPr)4 (0.18 mL, 0.602 mmol) was added to a solution of 2-
bromoacetophenone (4, 100. mg, 0.502 mmol) in THF (5 mL) at
room temperature. EtMgBr (0.47 mL, 1.41 mmol, 3 M in Et2O)
was then added dropwise over 20 min during which the reac-
tion mixture turned from clear to yellow to black. After 18 h,
water (5 mL) was added, and the mixture was extracted EtOAc
(3 × 5 mL). The combined organic layers were washed with
brine (1 × 10 mL), dried with MgSO4, and concentrated in vacuo.
Purification by column chromatography (15% EtOAc/hexanes)
afforded 1,4-diketone 8 as a white powder (47 mg, 79%). The
spectral data was in agreement with reported data.18 Rf = 0.27
(15% EtOAc/hexanes). 1H NMR (500 MHz, C6D6):  = 7.89 (d,
J = 7.5 Hz, 4 H), 7.15–7.11 (m, J = 7.5 Hz, 2 H), 7.05 (t, J = 7.5 Hz,
4 H), 3.46 (s, 4 H). 13C NMR (125 MHz, CDCl3):  = 198.9, 136.9,
133.3, 128.7, 128.3, 32.7. IR (ATR): 2905, 1675, 1593, 1446, 1353
cm–1. HRMS (ESI/MeOH): m/z calcd for C16H14O2 [M + H]+:
239.1067; found: 239.1070.
Funding Information
Acknowledgment is made to the Donors of the American Chemical
Society Petroleum Research Fund for partial support of this research.
This work was also partially supported by the Robert A. Welch Foun-
dation (AF-0005), the Howard Hughes Medical Institute through the
Undergraduate Science Education Program (52007558), and South-
western University’s Faculty-Student Collaborative Projects fund.
A
m
ecria
n
C
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e
mcai
l
S
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ecity
P
erteolu
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Research
F
u
n
d
)(
Acknowledgment
The authors gratefully acknowledge Drs. Willis Weigand and Carmen
Velez at Southwestern University for their support with NMR and IR
spectroscopy. Additionally, mass spectral data were obtained at The
University of Texas at Austin Mass Spectrometry Facility.
(14) Wolan, A.; Six, Y. Tetrahedron 2010, 66, 3097.
(15) Kel’in, A. V.; Kulinkovich, O. G. Synthesis 1996, 28, 330.
(16) Kulinkovich, O. G.; Kel’in, A. V.; Semin, P. V. Zh. Org. Khim. 1995,
31, 1166.
(17) Eisch, J. J.; Gitua, J. N.; Otieno, P. O.; Shi, X. J. Organomet. Chem.
2001, 624, 229.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610245.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
(18) Ceylan, M.; Gürdere, M. B.; Budak, Y.; Kazaz, C.; Seçen, H. Syn-
thesis 2004, 1750.
References and Notes
(19) Cadoret, F.; Retailleau, P.; Six, Y. Tetrahedron Lett. 2006, 47,
7749.
(1) (a) Koenig, B. Product Class 9: Furans, In Science of Synthesis, Vol.
9 Maas, G.; Fürstner, A., Ed.; Thieme: Stuttgart, 2002, 183.
(b) Ferreira, V. F.; De Souza, M. C. B. V.; Cunha, A. C.; Pereira, L.
O. R.; Ferriera, M. L. G. Org. Prep. Proced. Int. 2001, 33, 411.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D