One step preparation of 1,4-diketones from methyl ketones and α-bromomethyl ketones in the presence of ZnCl2·t-BuOH·Et2NR as a condensation agent

Article abstract of DOI:10.1055/s-2000-6418

1,4-Diketones have been prepared in one step from methyl ketones and α-bromomethyl ketones under the action of ZnCl₂·t-BuOH·Et₂NR as a condensation agent with moderate to high yields. The mechanistic pathway of the reaction is proposed to go through aldol condensation of ketones followed by 1,3-dehydro-bromination of aldol products and cleavage of activated cyclopropyl intermediates.

Full text of DOI:10.1055/s-2000-6418

PAPER
1259
One Step Preparation of 1,4-Diketones from Methyl Ketones and
a-Bromomethyl Ketones in the Presence of ZnCl2·t-BuOH·Et2NR as a
Condensation Agent
Natali M. Nevar, Alexander V. Kel’in,*† Oleg G. Kulinkovich*
Department of Chemistry, Belarussian State University, Fr. Skorina Av. 4, 220080 Minsk, Belarus
Fax (172)208821; E-mail: organic@chem.bsu.unibel.by
Received 19 January 2000; revised 20 April 2000
Abstract: 1,4-Diketones have been prepared in one step from me-
thyl ketones and a-bromomethyl ketones under the action of
ZnCl2·t-BuOH·Et2NR as a condensation agent with moderate to
high yields. The mechanistic pathway of the reaction is proposed to
go through aldol condensation of ketones followed by 1,3-dehydro-
bromination of aldol products and cleavage of activated cyclopro-
pyl intermediates.
Key words: a-bromo ketones, 1,4-diketones, aldol condensation,
3-bromo-2-hydroxy ketones, activated cyclopropanes
1,4-Diketones are useful synthetic intermediates for the
preparation of five-membered carbocyclic and heterocy-
clic compounds.1 Among the most convenient methods
for the synthesis of asymmetrical 1,4-diketones,2-15 the
Michael-Stetter addition of aldehydes to a,b-unsaturated
ketones,6-10 as well as alkylation of stabilized alkaline
metal enolates,10-13 enamines,13,14 and tin enolates15 by
a-halocarbonyl compounds should be mentioned. Howev-
er, to our knowledge, the Michael-Stetter method does
Scheme
not give satisfactory results with electron-poor aromatic
substrates,10 and the last three methods are restricted
mainly by aromatic or symmetrical aliphatic starting nu-
cleophiles, which should be prepared from the corre-
sponding carbonyl compounds.
a
a
1
a
b
c
d
e
f
R1
2
a
b
c
d
e
f
R2
Me
Me
Recently, we have reported a new simple and regioselec-
tive method for the preparation of 1,4-diketones directly
from methyl ketones and a-bromo ketones.16,17 This meth-
od is based on the thermodynamically controlled cross al-
dol condensation of methyl ketones with a-bromo ketones
followed by 1,3-dehydrobromination of the aldol prod-
ucts and cleavage of the corresponding intermediate acti-
vated cyclopropyl derivatives to 1,4-diketones. Using this
approach, we have developed two main preparative proce-
dures. The first is based on the application of two separate
stages: aldol condensation of methyl ketones with a-bro-
mo ketones in the presence of magnesium bases, and sub-
sequent conversion of the aldol products into
1,4-diketones by treatment with tertiary amine.16 In the
second procedure, we have succeeded in combining these
both stages into one using titanium isopropoxide as the
condensation agent.17
Et
Ph
C6H13
4-BrC6H4
Ph
3-O2NC6H4
4-O2NC6H4
2-(5-bromothienyl)
2-(5-cyanothienyl)
2-naphthyl
PhCH=CH
4-MeOC6H4
4-MeO2CC6H4
4-CH3COC6H4
4-O2NC6H4
3-O2NC6H4
4-BrC6H4
2-thienyl
g
h
i
g
j
k
l
m
n
In this paper, we propose another simple one step proce-
dure for the preparation of 1,4-diketones 5a-r from meth-
yl ketones 1a-n and a-bromo ketones 2a-g, which gives
2-(5-bromothienyl)
better results for the synthesis of products with strong a Compounds 3−5: R1, R2, see Table 1.
Synthesis 2000, No. 9, 1259–1262 ISSN 0039-7881 © Thieme Stuttgart · New York

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N. M. Nevar et al.
PAPER
Table 1 1,4-Diketones 5a–s Prepared
Producta
5a
R1
Me
Et
R2
Time
(days)
Amine
Et2NH
Et2NH
Yieldd
(%)
Mp (oC) (Solvent)
4-BrC6H4
4-BrC6H4
3
64
84-85f
i-PrOH
5b
3
19
53-54
Et2O
5c
n-C6H13
Me
Me
3
3
Et2NH
Et3N
25
44
oilg
5d
Ph
28-29h
i-PrOH
5e
5f
Ph
Ph
3
3
3
7
7
3
3
7
3
3
7
3
3
3
Et2NH
Et2NH
Et2NH
Et3N
64
75
72
37
144-145i
EtOAc
Ph
4-BrC6H4
116-117j
i-PrOH
5g
5h
5i
PhCH=CH
4-MeOC6H4
4-MeO2CC6H4
4-MeCOC6H4
4-PhCOCH2CH2COC6H4
3-O2NC6H4
4-O2NC6H4
4-O2NC6H4
4-BrC6H4
Ph
116-117k
EtOAc
Ph
105-106l
i-PrOH
Ph
Et3N
97
144-145
EtOAc
86e
5jb
5kc
5l
Ph
Et2NH
Et2NH
Et3N
84e
71
75
66
95
64
71e
75
80
138-139
EtOAc
Ph
198-200
n-BuOH
Ph
92
MeOH
5m
5n
5o
5p
5q
5r
Ph
Et3N
140-142
i-PrOH
4-O2NC6H4
3-O2NC6H4
4-BrC6H4
Et2NH
Et3N
195-196
CHCl3
163-164
EtOAc
2-naphthyl
2-thienyl
Et2NH
Et2NH
Et2NH
153
EtOAc
2-(5-bromothienyl)
2-(5-cyanothienyl)
114
MeOH
2-(5-bromothienyl)
141-142
EtOAc
a For new compounds satisfactory microanalyses were obtained: C + 0.33; H + 0.15.
b Ratio of starting compounds was: 1i/2b/ZnCl2 = 3/1/2.
c Ratio of starting compounds was: 1i/2b/ZnCl2 = 1/3/2.
d Yield of isolated product based on 2.
e Yield of product after isolation and recrystallization.
f Lit.3 mp: 86oC.
g Lit.4 mp: 33-34oC.
h Lit.6 mp: 28-29oC.
i Lit.5 mp: 143-144oC.
j Lit.12 mp: 112-113oC.
k Lit.8 mp 115oC.
l Lit.9 mp 106oC.
Synthesis 2000, No. 9, 1259–1262 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
One Step Preparation of 1,4-Diketones from Methyl Ketones
1261
Table 2 1H NMR Spectra of New 1,4-Diketones (5b, i–r).
Product
5b
1H NMRa d, J (Hz)
(CDCl3): 1.08 (t, 3 H, J = 8), 2.54 (q, 2 H, J = 8), 2.84 (t, 2 H, J = 7), 3.14 (t, 2 H, J = 7), 7.08 (d, 2 H, J = 4), 7.50 (d, 2 H, J = 4)
(acetone-d6): 3.40 (s, 4 H), 3.90 (s, 3 H), 7.30−7.63 (m, 3 H), 7.77-8.20 (m, 6 H)
5ib
5j
(CDCl3): 2.66 (s, 3 H), 3.48 (s, 4 H), 7.44-7.68 (m, 3 H), 7.96-8.24 (m, 6 H)
5k
(CDCl3): 3.50 (s, 8 H), 7.44-7.68 (m, 6 H), 7.98-8.22 (m, 8 H)
5lb
(CDCl3): 3.33 (s, 4 H), 7.03-7.36 (m, 4 H), 7.67-7.97 (m, 2 H), 8.00-8.33 (m, 2 H), 8.50-8.77 (m, 1 H)
(CCl4): 3.30 (s, 4 H), 7.27-7.60 (m, 3 H), 7.80-8.30 (m, 6 H)
5mb
5n
(CDCl3): 3.54 (s, 4 H), 8.20 (d, 4 H, J = 9), 8.38 (d, 4 H, J = 9)
5ob
5p
(CDCl3): 3.33 (s, 4 H), 7.27-7.97 (m, 5 H), 8.03-8.50 (m, 2 H), 8.60-8.83 (m, 1 H)
(CDCl3): 3.46 (t, 2 H, J = 6), 3.60 (t, 2 H, J = 6), 7.46-7.72 (m, 4 H), 7.80-8.20 (m, 6 H), 8.58 (s, 1 H)
(CDCl3): 3.36 (q, 4 H, J = 5), 7.06-7.20 (m, 2 H), 7.56 (d, 1 H, J = 4), 7.66 (dd, 1 H, J = 5, 1.5), 7.80 (dd, 1 H, J = 5, 1.5)
(CDCl3): 3.36 (s, 4 H), 7.14 (d, 1 H, J = 4), 7.56 (d, 1 H, J = 4), 7.66 (d, 1 H, J = 4), 7.76 (d, 1 H, J = 4)
5q
5r
aSpectra were recorded on a Brucker AC200 (200 MHz) spectrometer.
bSpectra were recorded on a Tesla BS-467A (60 MHz) spectrometer.
electron-withdrawing functional groups (5i-o, r) in com- tones in these cases by prolonged reaction time at room
parison with Michael-Stetter10 or titanium isopropoxide17 temperature or heating failed because of the side-reaction
methods. The new procedure is based on the application of amination of the bromo ketone. Moderate yields in the
of anhydrous zinc chloride-amine-tert-butyl alcohol case of bromoacetone 2a depend apparently upon fast
complex as the condensation agent. This reagent was pre- self-condensation due to the presence of methyl ketone
pared by dissolving 25% excess of freshly dried anhy- and bromomethyl ketone fragments in the same molecule.
drous zinc chloride in benzene in the presence of Contrary to the two step procedure,16 alkyl bromomethyl
equimolecular amounts of di- or triethylamine and tert- ketones (except bromoacetone 2a), and aromatic bromo
butyl alcohol. The most reactive complex was found to be ketones with secondary or tertiary a-carbon atoms from
prepared with diethylamine, but in the cases of very reac- the bromine moiety were unreactive under the present re-
tive starting bromo ketones, such as bromoacetone 2a or action conditions.
3¢-nitro-2-bromoacetophenone 2d, triethylamine gave
better results (Scheme, Table 1).
We believe that the reaction pathway through the aldol
condensation of methyl ketones 1a-n and a-bromo ke-
The reactions of methyl ketones 1a-n with a-bromo ke- tones 1a-g with formation of 3-bromo-2-hydroxyketones
tones 2a-g in the presence of zinc reagent were generally 3a-r as intermediates and their subsequent rearrangement
complete at room temperature in 24 hours, but in order to via activated cyclopropyl ketones 4a-r to 1,4-diketones
achieve the highest conversion the mixture was kept for 5a-r is preferable, in this case, rather than possible direct
3-7 days. Methyl ketone reacts only as a nucleophile and alkylation of the enolate of methylketone by bromo ke-
bromo ketone as an electrophile and neither the reversal of tone from the bromine moiety.10-12 Formation of small
the roles of reactants nor self-condensation of amounts of 3-bromo-2-hydroxyketones 3a-r was ob-
components16 (except bromoacetone 2a) has been ob- served by TLC after the start of the reaction, however, the
served.
presence of intermediate 2-hydroxycyclopropylketones
4a-r was not detected. We assume that 2-hydroxycyclo-
propylketones 4a-r are very unstable due to the presence
of strong electron donating and electron withdrawing
groups in vicinal positions on the cyclopropane ring.18
Proposed intermediate 3e, prepared by another method
(see experimental), smoothly afforded 1,4-diketone 5e in
good yield by treatment with the zinc condensation agent
under standard reaction conditions, and this is in agree-
ment with the described mechanism.
Very mild and almost neutral reaction conditions allowed
us to obtain good results with starting compounds contain-
ing different functional groups, including strongly elec-
tron-withdrawing, such as nitro 1j, k; 2d, e, alkoxy-
carbonyl 1h, cyano 2g, acyl 1i, and activated electrophilic
double bond 1f. 1,4-Diacetylbenzene 1i was condensed by
one 5j as well as by both 5k acetyl groups.
Some limitations of this procedure should also be men-
tioned. Moderate yields were obtained with electron-rich
aromatic ketone 1g and akyl methyl ketones 1b, c (except
acetone 1a), apparently due to their low reactivity. At-
tempts to increase a low conversion ratio of starting ke-
In conclusion, the method described can be useful for
preparation of functionalized asymmetrical 1,4-diketones
in mild conditions. Best results are obtained with starting
Synthesis 2000, No. 9, 1259–1262 ISSN 0039-7881 © Thieme Stuttgart · New York

1262
N. M. Nevar et al.
PAPER
(prepared as described above) and the mixture was stirred for 1 h,
allowed to stand at r.t. for 3 days, quenched with cold 5% aq H2SO4,
and filtered. The crystalline product was washed successively with
benzene, H2O, and MeOH. Combined filtrates were placed in a sep-
aratory funnel, the organic layer was separated, washed twice with
5% aq NaCl, and dried (Na2SO4). The solvent was evaporated under
vacuum, and the residue was crystallized from MeOH to afford an
additional amount of product. Yield of 5e: 1.25 g, 69%.
compounds containing electron withdrawing functional
groups.
1H NMR spectra were recorded on a Tesla-BS 467A (60 MHz) and
Brucker AC-200 (200 MHz) spectrometers (Table 2). Methyl ke-
tones 1a-m, and a-bromo ketones 2b-e were commercially avail-
able. 2-Acetyl-5-bromothiophene (1n) was prepared by
bromination of 2-acetylthiophene with NBS.19 a-Bromo ketones 2a,
f-g were synthesized by bromination of the corresponding ketones
with dioxane dibromide.20 5-Cyano-2-acetylthiophene was synthe-
sized by reaction of 5-iodo-2-acetylthiophene with copper (I) cya-
nide.21 The solvents, t-BuOH and Et2NH, Et3N were dried by
distillation from Na before use.
References and Notes
†New address: Department of Chemistry (MC111), University
of Illinois at Chicago, 845 West Taylor Street, Room 4500,
Chicago, Illinois 60607-7061, USA
1, 4-Diketones 5a-r; General Procedure
Fax +(312)3550836; E-mail: akelin@uic.edu
Commercial anhyd ZnCl2 (2.72 g, 20 mmol) was placed into a one-
neck, 25-mL round-bottom flask and dried by melting under vacu-
um (1 torr) at 250-350 °C for 15 min. After cooling under vacuum
to r.t., benzene (10 mL), di- or triethylamine (Table 1) (15 mmol),
and t-BuOH (1.4 mL, 15 mmol) were successively added. The mix-
ture was stirred until zinc chloride was fully dissolved (approx 2 h),
and methyl ketone (1a-n) (15 mmol) and a-bromo ketone (2a-g)
(10 mmol) were successively dded. The mixture was stirred for
1 h, allowed to stand for 3-7 days at r.t., quenched with 5% aq
H2SO4 and filtered (in the cases of precipitation of crystalline dike-
tones). Crystalline products were washed successively with ben-
zene, H2O and MeOH, and recrystallized (Table 1). Quenched
mixture or combined filtrates were placed in a separatory funnel, the
organic layer was separated, washed twice with 5% aq NaCl and
dried (Na2SO4). The solvent was evaporated under vacuum, and the
residue was crystallized by mixing with MeOH (10 mL) to afford
an additional amount of diketone (5e-r). Compounds 5a-d were
isolated by column chromatography (silica gel) using benzene or
(1) Ellison, R. A. Synthesis 1973, 397.
Ho, T. L. Synth. Commun. 1974, 4, 265.
Hudlicky, T.; Price, J. D. Chem. Rev. 1989, 89, 1467.
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Sato, T.; Okazaki, H.; Otera, J.; Nozaki, H. J. Am. Chem. Soc.
1988, 110, 5209; and references cited therein.
(3) Severin, T.; Konig, D.; Chem. Ber. 1974, 107, 1499.
(4) Ballini, R.; Bartoli, G. Synthesis 1993, 965.
(5) Moriarty, R.; Prakash, O.; Duncan, M. P. J. Chem. Soc.,
Perkin Trans. 1 1987, 559.
(6) Stetter, H.; Schreckenberg, M. Chem. Ber. 1974, 107, 2453.
(7) Stetter, H. Angew. Chem., Int. Ed. Engl. 1976, 15, 639.
(8) Stetter, H.; Hilboll, G.; Kuhlmann, H. Chem. Ber. 1979, 112,
84.
(9) Stetter, H.; Jonas, F. Chem. Ber. 1981, 114, 564.
(10) Roth, B. D.; Ortwine, D. F.; Hoefle, M. L; Stratton, C. D.;
Sliskovic, D. R., Wilson, M. W.; Newton, R. S. J. Med. Chem.
1990, 33, 21.
1
benzene-hexane mixtures as the eluent. H NMR data are listed in
Table 2.
(11) Kapf, S.; Paal, C. Ber. Dtsch. Chem. Ges. 1888, 21, 3053.
(12) Koutek, B.; Pavlickova, L.; Soucek, M. Collect. Czech. Chem.
Commun. 1974, 39, 192.
(13) Chiu, P. -K.; Sammes, M. P. Tetrahedron 1988, 44, 3531.
(14) Stork, G.; Brizzolara, A.; Landesman, H.; Szmuszkovicz, J.;
Terrel, R. J. Am. Chem. Soc. 1963, 85, 207.
4-Bromo-3-hydroxy-1,3-diphenylbutan-1-one (3e)
a-Bromoacetophenone (2b) (1.99 g, 10 mmol) was added to a solu-
tion of t-BuOMgBr◊Et2O16 (11 mmol) in benzene (5 mL). The mix-
ture was stirred for 24 h, quenched with cold 5% aq H2SO4, washed
twice with 5% aq NaCl, and dried (Na2SO4). The solvent was evap-
orated under vacuum, and the residue was crystallized from CCl4/
hexane (1:1) (10 mL) to afford erythro-2,4-dibromo-3-hydroxy-
1,3-diphenylbutan-1-one.16
(15) Yasuda, M.; Katoh, Y; Shibata, I.; Baba, A.; Matsuda, H.;
Sonoda, N. J. Org. Chem. 1994, 59, 4386.
Yasuda, M.; Tsuji, S; Shibata, I.; Baba, A. J. Org. Chem.
1997, 62, 8282.
(16) Kel’in, A. V.; Kulinkovich, O. G. Synthesis 1996, 330.
(17) Kulinkovich, O. G.; Kel’in, A. V.; Senin, P. V. Zh. Org. Khim.
1995, 31, 1166; Russ. J. Org. Chem. 1995, 31, 1060.
(18) Kulinkovich, O. G. Usp. Khim. 1993, 62, 887; Russ. Chem.
Rev. 1993, 62, 839.
Reissig, H. -U. Top. Curr. Chem. 1988, 144, 73.
(19) Smirnov, V. A.; Lipkin, A. E. Khim. Geterotsikl. Soedin.
1973, 185; Chem. Abstr. 1973, 78, 124377.
(20) Yanovskaya, L. A.; Terent’ev, A. P.; Zh. Obshch. Khim. 1952,
22, 1598; Chem. Abstr. 1953, 47, 9258.
(21) Jones, J. R.; Pearson, G. M.; Spinelli, D; Consiglio, G.;
Arnone, C. J. Chem. Soc., Perkin Trans. 2 1985, 557.
Yield: 1.79 g (90%); mp: 99-100 ∞C (dec).
1H NMR (CCl4): d = 3.40 (d, 1H, J = 10 Hz), 3.83 (d, 1H, J = 10
Hz), 5.00 (s, 1H), 5.93 (s, 1H), 6.90-7.50 (m, 8H), 7.70-7.90 (m,
2H).
Zinc powder (0.98 g, 15 mmol) was added in small portions with
stirring and cooling (0 °C) to the mixture of erythro-2,4-dibromo-3-
hydroxy-1,3-diphenylbutan-1-one (3.98 g, 10 mmol) and HOAc
(20 mL). After the zinc dissolved (5-10 min) the mixture was
poured into H2O (200 mL), and extracted with benzene (40 mL).
The organic layer was separated, successively washed with 5% aq
Na2CO3, 5% aq NaCl, and dried (Na2SO4). Benzene was evaporated
under vacuum at 35 ∞C to afford 4-bromo-3-hydroxy-1,3-diphe-
nylbutan-1-one16 (3e). Yield: 2.56 g (80%).
Article Identifier:
1437-210X,E;2000,0,09,1259,1262,ftx,en;M04000SS.pdf
1,4-Diphenylbutane-1,4-dione (5e) from 3-Bromo-2-hydroxy-
ketone (3e)
A solution of (3e) (3.19 g, 10 mmol) in benzene (3 mL) was added
to the solution of ZnCl2·t-BuOH·Et3N (15 mmol) in benzene (7 mL)
Synthesis 2000, No. 9, 1259–1262 ISSN 0039-7881 © Thieme Stuttgart · New York