Propargyl bromide as an excellent α-bromoacetone equivalent: Convenient and new route to α-aroylacetones

Article abstract of DOI:10.1021/jo051538w

A variety of α-aroylacetones 4a-g have been prepared in excellent yields following a new protocol wherein α-aminonitriles 1a-g as the aryl acyl anion equivalents readily react with propargyl bromide as the α-bromoacetone equivalent. The alkylated product undergoes one-pot unmasking of the keto functionality along with Markovnikov's hydration of the terminal alkyne with CuSO₄·5H₂O in aqueous methanol at 60 °C to furnish the desired target in excellent isolated yields.

Full text of DOI:10.1021/jo051538w

been equally prominent.1p The most familiar and general strategy
for â-diketone functionality is based on disconnection 1 and
involves either (i) the acylation of the ketones with acyl
Propargyl Bromide as an Excellent
r-Bromoacetone Equivalent: Convenient and
†
New Route to r-Aroylacetones
2
a-d
halides
or (ii) the acylation of acetylacetone followed by
3
a-c
base, which promotes deacetylation.
On the basis of this
Sakkarapalayam M. Mahalingam and
Indrapal Singh Aidhen*
concept, R-aroylacetones in particular have been synthesized.
However, the anion from acetylacetone, being ambident, causes
the reaction with the acylating agent to often be plagued by the
possibility of C and/or O acylation. Besides the structural
influence of the starting substrates, a very delicate control over
the nature of the solvent, the electrophile, the metal counterion,
and the reaction temperature has to be maintained for any
observable chemoselectivity to occur. Presently, 1-aroylbenz-
Department of Chemistry, Indian Institute of Technology
Madras, Chennai 600 036, India
isingh@iitm.ac.in
ReceiVed July 24, 2005
4
5
imidazoles and 1-aroylbenzotriazole have been used for the
aroylations of the anion from acetylacetone and the subsequent
obtainment of the desired targets. A moderate yield (26-30%)
has been observed with the former, whereas the latter, due to
Katritzky, has furnished excellent yields (52-100%) as a result
of greatly reduced O acylation. To the best of our knowledge,
disconnection 2, envisaging the use of the arylacyl anion, has
never been explored toward this end. Because there is no dearth
6
of acyl anion equivalents in the literature, the route appeared
highly attractive. Herein, we report the success of this new route
based on disconnection 2.
A variety of R-aroylacetones 4a-g have been prepared in
excellent yields following a new protocol wherein R-ami-
nonitriles 1a-g as the aryl acyl anion equivalents readily
react with propargyl bromide as the R-bromoacetone equiva-
lent. The alkylated product undergoes one-pot unmasking
of the keto functionality along with Markovnikov’s hydration
of the terminal alkyne with CuSO
methanol at 60 °C to furnish the desired target in excellent
isolated yields.
4
2
‚5H O in aqueous
From the plethora of reagents available for the acyl anion
synthon X, we were attracted by the less frequently used
R-aminonitriles 1 as a result of the simplicity and convenience
7
involved in their preparation on the multigram scale. Also,
unlike alkylations of other acyl anion equivalents that require
much stronger bases, stringent dry conditions, and low temper-
atures, the alkylation of R-aminonitriles is conveniently carried
out at room temperature. The carbanion from the R-amino-
nitriles (1a-g), generated using NaH in DMF, underwent clean
and facile quantitative alkylation with propargyl bromide 2
â-Diketones have been important intermediates in organic
synthesis since the discovery of the Claisen condensation more
than a century ago.1a-j They have served as key building blocks
8
a,b
1
k
in the preparation of heterocyclic compounds such as pyrazoles,
isoxazoles, triazoles, and benzopyran-4-ones.
1
l
1m
1n,o
Their use
as chelating ligands for lanthanides and transition metals has
(Scheme 1). The progress of the reaction could be easily seen
*
To whom correspondence should be addressed. Phone: 0091-44-22574219.
Fax: 0091-44-22574201.
(2) (a) Movchan, T. I.; Voloshanovskii, I. S. J. Appl. Chem. (Leningrad)
†
This paper is dedicated to Professor N. S. Narasimhan.
1992, 65, 1973-1976. (b) Linn, B. O.; Hauser, C. R. J. Am. Chem. Soc.
1956, 78, 6066-6070. (c) Hauser, C. R.; Hudson, B. E., Jr. In Organic
Reactions.; Adams, R., Bachmann, W. E., Johnson, J. R., Fieser, L. F.,
Snyder, H. R., Eds.; John Wiley & Sons: New York, 1942; Vol. 1, pp
266-289. (d) Casey, M.; Donnelly, J. A.; Ryan, J. C.; Ushioda, S. ARKIVOC
2003, Vii, 310-327.
(3) (a) Berend, L.; Heymann, F. J. Prakt. Chem. 1902, 290-294. (b)
Duff, J. C. J. Chem. Soc. 1914, 105, 2182-2186. (c) McElvain, S. M.;
Weber, K. H. J. Am. Chem. Soc. 1941, 63, 2192-2197. (d) For the use of
sulfonyl-activated acetone toward the synthesis of diketones, see: Fargeas,
V.; Baalouch, M.; Metay, E.; Baffreau, J.; Menard, D.; Gosselin, P.; Berge,
J.-P.; Barthomeuf, C.; Lebreton, J. Tetrahedron 2004, 60, 10359-10364.
(4) Karnik, A. V.; Rane J. P. Indian J. Chem., Sect. B 1998, 37, 1191-
1193.
(5) Katritzky, A. R.; Wang, Z.; Wang, M.; Wilkerson, C. R.; Hall, C.
D.; Akhmedov, N. G. J. Org. Chem. 2004, 69, 6617-6622.
(6) Ager, D. J. In Umpoled Synthons: A SurVey of Sources and Uses in
Synthesis; Hase, T. A., Ed.; John Wiley & Sons: New York, 1987; pp
19-72.
(7) Dyke, S. F.; Tiley, E. P.; White, A. W. C.; Gale, D. P. Tetrahedron
1975, 31, 1219-1222.
(8) (a) Selvamurugan, V.; Aidhen, I. S. Tetrahedron 2001, 57, 6065-
6069. (b) Vijayasaradhi, S.; Aidhen, I. S. Org. Lett. 2002, 4, 1739-1742.
(
1) (a) Claisen, L.; Lowman, O. Ber. Dtsch. Chem. Ges. 1887, 20, 651-
6
54. (b) Claisen, L. Liebigs Ann. Chem. 1896, 291, 100-111. (c) Yoshida,
M.; Fujikawa, K.; Sato, S.; Hara, S. ARKIVOC 2003, Vi, 36-42. (d) Cristau,
H.-J.; Marat, X.; Vors, J.-P.; Pirat, J.-L. Tetrahedron Lett. 2003, 44, 3179-
3
2
6
2
181. (e) Christoffers, J.; Oertling, H.; Fischer, P.; Frey, W. Tetrahedron
003, 59, 3769-3778. (f) Kotha, S.; Manivannan, E. ARKIVOC 2003, iii,
7-76. (g) Kollenz, G.; Dalvi, T. S.; Kappe, C. O.; Wentrup, C. ARKIVOC
000, 1 (1), 74-79. (h) Katritzky, A. R.; Silina, A.; Tymoshenko, D. O.;
Qiu, G.; Nair, S. K.; Steel, P. J. ARKIVOC 2001, Vii, 138-144. (i) Falsone,
F. S.; Kappe, C. O. ARKIVOC 2001, ii, 122-134. (j) Katritzky, A. R.;
Meher, N. K.; Singh, S. K. J. Org. Chem. 2005, 70, 7792-7794. (k) Nagpal,
A.; Unny, R.; Joshi, Y. C. Heterocycl. Commun. 2001, 32, 589-592. (l)
Simoni, D.; Invidiata, F. P.; Rondanin, R.; Grimaudo, S.; Cannizzo, G.;
Barbusca, E.; Porretto, F.; D’Alessandro, N.; Tolomeo, M. J. Med. Chem.
1
999, 42, 4961-4969. (m) Alekseev, V. V.; Zelinin, K. N.; Yakimovich,
S. I. Russ. J. Org. Chem. 1995, 31, 705-727. (n) Ellis, G. P. The Chemistry
of Heterocyclic Compounds. In Chromanones and Chromones; Ellis, G.
P., Ed.; Interscience: New York; Vol. 33, pp 495-555. (o) Raston, C. L.;
Salem, G. J. Chem. Soc., Chem. Commun. 1984, 1702-1703. (p) Gar-
novskii, A. D.; Kharixov, B. I.; Blanco, L. M.; Garnovskii, D. A.; Burlov,
A. S.; Vasilchenko, I. S.; Bondarenko, G. I. J. Coord. Chem. 1999, 46,
3
65-375.
1
0.1021/jo051538w CCC: $33.50 © 2006 American Chemical Society
Published on Web 11/24/2005
J. Org. Chem. 2006, 71, 349-351
349

SCHEME 1
TABLE 1. Products Obtained after Hydrolysis of Alkylated
Intermediates 3a-g Using CuSO4‚5H2O, CH3OH/H2O (3:1) at 60 °C
by the gradual decrease of the yellow color of the carbanion.
The formation and obtainment of the alkylated product 3a in
quantitative yield after the standard workup and purification was
1
confirmed by H NMR. The two protons from the methylene
unit of the propargyl residue were diastereotopic in nature and
appeared as a mutually coupled doublet of doublets, one centered
at δ 3.43 and the other centered at 3.56 with J ) 16.6 and 2.5
Hz. The alkynic proton appeared as a triplet at δ 2.62 with J )
2
.5 Hz. Purified 3a and the other alkylated products 3b-g,
without any purification, were directly subjected to hydrolysis
using CuSO4‚5H2O in aqueous methanol at 60 °C for unmasking
9
of the carbonyl group. However, gratifyingly, these reaction
conditions resulted in both the clean unmasking of the keto
functionality along with the conversion of the propargyl residue
to the acetonyl unit and, thereby, furnishing R-aroylacetones
4
a-g in excellent yields (90-95%; Table 1). Apparently, the
hydration of the terminal alkyne in the Markovnikov’s fashion
would explain the formation of the acetonyl unit. However,
mechanistically, the isomerization of the acetylenic ketone 5 to
the allenic ketone 6 under the reaction conditions described and
the subsequent addition of water in Michael fashion to arrive
at the obtained product cannot be ruled out. It is worth noting
that, with the successful formation of the R-aroylacetones,
propargyl bromide has surfaced as an elegant equivalent to the
sensitive R-bromoacetone or the carbonyl-protected R-bromo-
acetone that otherwise one would have used for the implementa-
tion of the unexplored strategy. If Markovnikov’s hydration of
the terminal alkyne is operating, the successful use of CuSO4‚
a
Isolated yields of the products which were recovered as mixtures of
1
b
the keto-enol tautomers evidenced by H NMR in CDCl3. Determined
1
by H NMR of product 4.
In conclusion, quantitative propargylation of R-aminonitriles
as aryl acyl anion equivalents, followed by the one-pot unmask-
ing of the keto functionality along with the hydration of the
terminal alkyne in excellent yield, has provided a completely
new and highly convenient protocol for R-aroylacetones hitherto
unreported in the literature.
5
H2O would be worth noting. Toward this end, several other
inorganic salts, either in stoichiometric or in catalytic amounts,
have been used; however, the use of the Cu(II) species has not
1
0
4,11
4
been reported. The structures of known products 4a,
4b,
Experimental Section
4
12
13
14,15
16
4
c, 4d, 4e, 4f,
and 4g are supported by microanalysis
1
13
1
and H/ C NMR data, which show H singlets between δ 6.04-
The starting R-aminonitriles 1a-f were prepared using the
7
6
9
.54 corresponding to the R-olefinic protons and signals at δ
literature procedure. The unreported R-aminonitrile 1g was pre-
13
pared using the same protocol and was fully characterized before
use.
2.5-96.7 in the C NMR spectrum for the R-olefinic carbons.
All of the â-diketones 4a-g contained the corresponding keto
General Procedure for the Preparation of r-Aroylacetones
forms as minor tautomers. The minor keto structures were
4
(
a-g. To a suspension of sodium hydride (1.2 mmol) in dry DMF
1
13
characterized by H singlets between δ 3.99-4.45 and by
C
1 mL) under an inert nitrogen atmosphere was added a solution
NMR signals between δ 48.3-55.1, and the relative amounts
of the R-aryl aminonitrile (1a-g; 1.1 mmol) in dry DMF (3.5 mL)
in a dropwise manner at room temperature (ca. 27-30 °C). After
stirring the reaction mixture for 30 min at room temperature, a
solution of the propargyl bromide 2 (1 mmol) in dry DMF (3.5
mL) was added dropwise. The reaction mixture was stirred for an
additional 1 h at room temperature to ensure the completion of the
reaction. After the completion of the reaction, saturated ammonium
chloride solution (10 mL) was added. The aqueous layer was
extracted with dichloromethane (3 × 15 mL). The combined
dichloromethane layer was dried over anhydrous sodium sulfate
and evaporated to obtain the alkylated compound (3a-g), and the
residue was directly subjected to hydrolysis. To a solution of
1
were estimated by H NMR.
(
9) Buechi, G.; Liang, P. H.; Wuest, H. Tetrahedron Lett. 1978, 31,
763-2764.
10) Baidossi, W.; Lahav, M.; Blum, J. J. Org. Chem. 1997, 62, 669-
72 (and references therein).
11) (a) Ukai, K.; Oshima, K.; Matsubara, S. J. Am. Chem. Soc. 2000,
22, 12047-12048. (b) Muir, W. M.; Ritchie, P. D.; Lyman, D. J. J. Org.
2
6
1
(
(
Chem. 1966, 31, 3790-3793.
(
(
(
12) Garg, H. G. J. Indian Chem. Soc. 1961, 38, 211-212.
13) Fehnel, E. A. J. Org. Chem. 1958, 23, 432-434.
14) Dyke, S. F.; Brown, D. W.; Sainsbury, M.; Hardy, G. J. Chem.
Soc. C 1971, 3219-3222.
CuSO
4 2 3 2
‚5H O (2 mmol) in CH OH/H O (3:1, 12 mL) was added
(
(
15) Tasaki, T. Acta Phytochim. 1927, 3, 250-315.
16) Evans, D. F. J. Chem. Soc. 1961, 1987-1993.
the alkylated compound (3a-g; 1 mmol), and the contents were
3
50 J. Org. Chem., Vol. 71, No. 1, 2006

heated at 60 °C. After 1.5 h, the solvents were evaporated on a
rotary evaporator, and to the residue was added water (10 mL).
The aqueous layer was extracted with dichloromethane (3 × 10
mL), and the combined organic layer was dried over anhydrous
sodium sulfate. The solvent was removed under reduced pressure,
and the product was purified by silica gel column chromatography
MHz NMR instrument under the IRPHA scheme and the ESI-
MS facility under the DST-FIST program. S.M.M. is thankful
to IIT-Madras for the fellowship.
1
Supporting Information Available: General methods, H and
C spectra of compounds 3a,b and 4a,b,e, DEPT experiment of
13
(
hexane/ethyl acetate, 9:1), affording the R-aroylacetone (4a-g)
compound 4a, and HRMS spectra of compounds 3a and 4b,e.
This material is available free of charge via the Internet at
http://pubs.acs.org.
in excellent yield (90-95%).
Acknowledgment. We thank CSIR, New Delhi, for the
funding of the new project in the year 2005 [01(1971)/05/EMR-
II]. We thank DST, New Delhi, for the funding toward the 400-
JO051538W
J. Org. Chem, Vol. 71, No. 1, 2006 351