An efficient synthesis of diaryl ketones by iron-catalyzed arylation of aroyl cyanides

Article abstract of DOI:10.1002/anie.200453696

An alternative to acyl chlorides: Iron(III)-catalyzed arylation of aroyl and heteroaroyl cyanides with aryl magnesium reagents (see example in scheme) provides an easy and mild approach to polyfunctionalized diaryl ketones in yields up to 98%.

Full text of DOI:10.1002/anie.200453696

Communications
Organomagnesium Reagents
which indicate that the preparation of benzophenone deriv-
atives by the acylation of organometallics is only a moderately
efficient reaction.[1a]
We then examined the use of acyl cyanides 1 as the
acylating agents[11,12] and found that they readily react with
various aromatic organomagnesium compounds of type 2
leading to polyfunctional benzophenone derivatives of type 3
(Scheme 1 and Table 1). Acyl cyanides are more powerful
An Efficient Synthesis of Diaryl Ketones by Iron-
Catalyzed Arylation of Aroyl Cyanides**
Christophe Duplais, Filip Bures, Ioannis Sapountzis,
Tobias J. Korn, GØrard Cahiez, and Paul Knochel*
Dedicated to Professor Klaus T. Wanner
on the occasion ofhis 50th birthday
The acylation of organometallic intermediates with acid
chlorides is an important method for the preparation of
polyfunctional ketones. This functionality is present in a great
variety of pharmaceutical and material-science target mole-
cules.[1] Many organometallic reagents have been used for
performing acylations, and organomanganese reagents have
proved to be especially useful.[2] Polyfunctional organozinc
compounds have also been used frequently, and smooth
acylations can be performed in the presence of stoichiometric
amounts of CuCN·2LiCl[3] or in the presence of a palladium
catalyst.[4] The preparation of functionalized arylzinc reagents
is less straightforward[5] and requires cobalt catalysis[6] or the
use of activated zinc powder (Rieke zinc).[7]
Recently we reported a general method for preparation of
polyfunctional arylmagnesium halides of type 2 using I/Mg- or
Br/Mg-exchange reactions.[8] We envisioned using these
organometallics for the preparation of polyfunctionalized
diaryl ketones by their reaction with acid chlorides. In
preliminary experiments we treated benzoyl chloride with
PhMgCl at various temperatures and obtained yields between
50–58%. We then turned our attention towards [Fe(acac)3]-
catalyzed reactions.[9,10] The reaction of PhMgCl with
PhCOCl in the presence of [Fe(acac)3] (5 mol%) at 08C or
208C afforded benzophenone in only 38–53% yield. Exten-
sive variation of the experimental reaction conditions (con-
centration, addition time, inverse addition) did not improve
these results. This is in agreement with literature reports
Scheme 1. [Fe(acac)3]-catalyzed reactions of functionalized magnesium
reagents with acyl cyanides. For the functional groups (FG), see
Table 1.
acylating agents than acid chlorides, since the cyano group
enhances the reactivity of the adjacent carbonyl group. In
contrary, the chlorine atom of acid chlorides plays the role of
a donor by a mesomeric effect. The reaction of benzoyl
cyanide (1a) and phenylmagnesium chloride (2a) without the
iron catalyst furnished a higher yield than that obtained for
the addition of phenylmagnesium chloride (2a) to benzoyl
chloride (75% vs. 58% at 08C).
However, the use of catalytic amounts of [Fe(acac)3]
(5 mol%) was beneficial for the reaction of 4-ethoxycarbo-
nylphenylmagnesium chloride (2b) with benzoyl cyanide
(1a), increasing the yield from 58% to 80% at À108C.[13]
Thus, the reaction of PhMgCl (2a) with PhCOCN (1a)
provided benzophenone (3a) in 84% yield (entry 1 of
Table 1). Similarily, functionalized organomagnesium com-
pounds 2b and 2c reacted in the presence of [Fe(acac)3]
(5 mol%) with PhCOCN (1a) at À108C within 0.5 h, furnish-
ing the expected benzophenones 3b and 3c in 80 and 78%
yield, respectively (entries 2 and 3). Functionalized acyl
cyanides bearing a chlorine (1b), a methoxy (1c), or a
ethoxycarbonyl group (1d) in para position, (entries 4–12)
reacted with various arylmagnesium reagents (2b–f), leading
to the diaryl ketones 3d–l in good yields. Interestingly, an
ortho-substituted arylmagnesium species like 2e reacted as
well, furnishing the benzophenone 3i in 66% yield (entry 9).
Also ketones bearing heterocyclic groups were prepared. The
reaction of acyl cyanide 1c with the heterocyclic Grignard
reagent 2 f led to furyl ketone 3l in 78% yield (entry 12).
Heterocyclic acyl cyanides, like pyridine derivative 4, reacted
under our standard conditions (À108C, 0.5 h) with various
aryl magnesium reagents, such as 2a, 2b, and 2d, to give
pyridyl ketones 5a–c in 75–86% yields (Scheme 2).
[*] C. Duplais, Dipl.-Chem. F. Bures, Dipl.-Chem. I. Sapountzis,
Dipl.-Chem. T. J. Korn, Prof. Dr. P. Knochel
Department Chemie
Ludwig-Maximilians-Universität München
Butenandtstrasse 5–13, Haus F
81377 München (Germany)
Fax: (+49)089-2180-77680
E-mail: paul.knochel@cup.uni-muenchen.de
Prof. G. Cahiez
Laboratoire de Synth›se Organique SØlective et
Chimie OrganomØtallique CNRS-UCP-ESCO
13, Boulevard de L’Hautil
95092 Cergy-Pontoise cedex (France)
[**] We thank the Fonds der Chemischen Industrie, the DFG and CNRS
(financial support to T.J.K.), and Aventis Pharma (Frankfurt a.M.,
financial support to I.S.) for supporting this research program. We
thank BASF AG (Ludwigshafen), Degussa AG (Hanau), and
In summary, we have shown that the arylation of aryl and
heteroaryl acyl cyanides with functionalized aryl and hetero-
aryl magnesium species is efficiently catalyzed by [Fe(acac)3]
(5 mol%), furnishing a range of new polyfunctional diaryl
ketones.
Chemetall GmbH (Frankfurt a. M.) for generous gifts of chemicals.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
2968
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/anie.200453696
Angew. Chem. Int. Ed. 2004, 43, 2968 –2970

Angewandte
Chemie
Table 1: Ketones 3a–l obtained by the FeIII-catalyzed reaction of aryl acyl
cyanides 1a–d with aryl magnesium halides 2a–f (Scheme 1).
Entry Acyl
Grignard
Product
Yield [%][a]
cyanide reagent
1
2
84
Scheme 2. [Fe(acac)3]-catalyzed reactions of heterocyclic pyridyl acyl
cyanide 4.
80
78
74
89
84
98
68
66
83
71
78
Experimental Section
Typical procedure for the arylation of aroyl cyanides.
3k (entry 11, Table 1): A dry and argon-flushed 10-mL flask
equipped with a stirring bar and a rubber septum was charged with
anhydrous THF (5 mL) and 4-iodobenzonitrile (374 mg, 2.4 mmol).
The solution was cooled to À208C and isopropylmagnesium chloride
(1.9 mL, 1.4m in THF, 2.6 mmol) was added slowly. The reaction
mixture was stirred at this temperature until the exchange reaction
was complete (30 min, checked by GC analysis of reaction aliquots).
The resulting solution was then transferred dropwise over 25 min by
cannula into a second 50-mL flask, which contained a solution of 1d
(406 mg, 2.0 mmol) and [Fe(acac)3] (35 mg, 0.1 mmol) in anhydrous
THF (10 mL) stirred at À108C. At the end of the addition, the
reaction mixture was quenched with aq. NH4Cl (10 mL), diluted with
water (25 mL), and extracted with Et2O (3 ” 25 mL). The combined
organic layers were washed with aq. NaHCO3 (10 mL), brine (2 ”
20 mL), and dried (MgSO4) and were concentrated in vacuo. The
residue was purified by flash chromatography on silica gel (pentane/
diethyl ether 4:1) yielding the diaryl ketone 3k (397 mg, 71%) as a
colorless solid (m.p. 110–1128C).
3
4
5
6
Received: January 8, 2004 [Z53696]
Keywords: acyl cyanides · homogeneous catalysis · iron ·
.
ketones · organomagnesium reagents
7
[1] a) R. K. Dieter, Tetrahedron 1999, 55, 4177; b) N. J. Lawrence, J.
Chem. Soc. Perkin Trans. 1 1998, 1739; c) Modern Organocopper
Chemistry (Ed.: N. Krause), Wiley-VCH, Weinheim, 2002.
[2] a) G. Cahiez, P.-Y. Chavant, E. Metais, Tetrahedron Lett. 1992,
33, 5245; b) G. Cahiez, B. Laboue, Tetrahedron Lett. 1992, 33,
4439; c) G. Cahiez, B. Laboue, Tetrahedron Lett. 1989, 30, 7369;
d) G. Cahiez, B. Laboue, Tetrahedron Lett. 1989, 30, 3545; e) G.
Cahiez, Tetrahedron Lett. 1981, 22, 1239.
[3] a) P. Knochel, M. C. P. Yeh, S. C. Berk, J. Talbert,J. Org. Chem.
1988, 53, 2390; b) M. J. Rozema, A. Sidduri, P. Knochel, J. Org.
Chem. 1992, 57, 1956; c) P. Knochel, N. Millot, A. L. Rodriguez,
C. E. Tucker, Org. React. 2001, 58, 417.
[4] a) E. Negishi, V. Bagheri, S. Chatterjee, F. T. Luo, J. A. Miller,
T. A. Stoll, Tetrahedron Lett. 1983, 24, 5181; b) D. Wang, Z.
Zhang, Org. Lett. 2003, 5, 4645.
[5] a) T. N. Majid, P. Knochel, Tetrahedron Lett. 1990, 31, 4413.
[6] a) H. Fillon, C. Gosmini, J. Pꢀrichon, J. Am. Chem. Soc. 2003,
125, 3867; b) I. Kazmierski, C. Gosmini, J.-M. Paris, J. Pꢀrichon,
Tetrahedron Lett. 2003, 44, 6417; c) H. Fillon, C. Gosmini, J.
Pꢀrichon, Tetrahedron 2003, 59, 8199.
8
9
10
11
12
[7] a) A. Guijarro, D. M. Rosenberg, R. D. Rieke, J. Am. Chem. Soc.
1999, 121, 4155; b) R. D. Rieke, Science 1989, 246, 1260; c) R. M.
Wehmeyer, R. D. Rieke, Tetrahedron Lett. 1988, 29, 4513.
[8] a) P. Knochel, W. Dohle, N. Gommermann, F. F. Kneisel, F.
Kopp, T. Korn, I. Sapountzis, V. A. Vu, Angew. Chem. 2003, 115,
4438; Angew. Chem. Int. Ed. 2003, 42, 4302; b) A. E. Jensen, W.
[a] Yield of isolated, analytically pure product.
Angew. Chem. Int. Ed. 2004, 43, 2968 –2970
www.angewandte.org
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2969

Communications
Dohle, I. Sapountzis, D. M. Lindsay, V. A. Vu, P. Knochel,
Synthesis 2002, 565.
Chem. 2003, 115, 5513; Angew. Chem. Int. Ed., 42, 5355; k) A.
Fꢁrstner, D. De Souza, L. Parra-Rapado, J. T. Jensen, Angew.
Chem. 2003, 115, 5516; Angew. Chem. Int. Ed., 42, 5358; l) K.
Reddy, P. Knochel, Angew. Chem. 1996, 108, 1812; Angew.
Chem. Int. Ed. Engl. 1996, 35, 1700; m) W. Dohle, F. Kopp, G.
Cahiez, P. Knochel, Synlett 2001, 1901.
[9] a) C. Cardellicchio, V. Fiandanese, G. Marchese, L. Ronzini,
Tetrahedron Lett. 1987, 28, 2053; b) V. Fiandanese, G. Marchese,
V. Martina, L. Ronzini, Tetrahedron Lett. 1984, 25, 4805; c) V.
Fiandanese, G. Marchese, L. Ronzini, Tetrahedron Lett. 1983, 24,
3677.
[10] a) M. Tamura, J. K. Kochi, J. Am. Chem. Soc. 1971, 93, 1487;
b) M. Tamura, J. K. Kochi, Synthesis 1971, 93, 303; c) M. Tamura,
J. K. Kochi, J. Organomet. Chem. 1971, 31, 289; d) R. S. Smith,
J. K. Kochi, J. Org. Chem. 1976, 41, 502; e) G. Cahiez, S.
Marquais, Pure Appl. Chem. 1996, 68, 53; f) G. Cahiez, S.
Marquais, Tetrahedron Lett. 1996, 37, 1773; g) G. Cahiez, H.
Avedissian, Synthesis 1998, 1199; h) A. Fꢁrstner, A. Leitner, M.
Mꢀndez, H. Krause, J. Am. Chem. Soc. 2002, 124, 13856; i) A.
Fꢁrstner, A. Leitner, Angew. Chem. 2002, 114, 632; Angew.
Chem. Int. Ed. 2002, 41, 609; j) A. Fꢁrstner, M. Mꢀndez, Angew.
[11] a) J. Thesing, D. Witzel, A. Brehm, Angew. Chem. 1956, 68, 425;
b) J. F. Normant, C. Piechucki, Bull. Soc. Chim. Fr. 1972, 2402;
c) K. Herrmann, G. Simchen, Synthesis 1979, 204; d) S. Hꢁnig, R.
Schaller, Angew. Chem. 1982, 94, 1; Angew. Chem. Int. Ed. Engl.
1982, 21, 36.
[12] Aryl acyl cyanides are best prepared by the reaction of the
corresponding acyl chlorides with copper cyanide in refluxing
acetonitrile (ref. [11b]).
[13] Lower reaction temperatures like À20, À40, and À808C
increased the yield only slightly to 65, 70, and 68%, respectively.
2970
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2004, 43, 2968 –2970