Iron-catalyzed cross-coupling of imidoyl chlorides with Grignard reagents

Article abstract of DOI:10.1021/ol0600234

A general, high yielding rapid iron-catalyzed cross-coupling reaction between Grignard reagents and imidoyl chlorides is described. These reactions are typically completed within 5 min, resulting in high yields of 71-96% using 5% iron catalyst in a THF-NM

Full text of DOI:10.1021/ol0600234

ORGANIC
LETTERS
2006
Vol. 8, No. 9
1771-1773
Iron-Catalyzed Cross-Coupling of
Imidoyl Chlorides with Grignard
Reagents
Lars K. Ottesen, Fredrik Ek, and Roger Olsson*
ACADIA Pharmaceuticals AB, Medeon Science Park S-20512, Malmo¨, Sweden
roger@acadia-pharm.com
Received January 4, 2006
ABSTRACT
A general, high yielding rapid iron-catalyzed cross-coupling reaction between Grignard reagents and imidoyl chlorides is described. These
reactions are typically completed within 5 min, resulting in high yields of 71 96% using 5% iron catalyst in a THF NMP solvent mixture.
Functionalized imidoyl chlorides (e.g., R CO2Me) gave excellent yields (89%).
−
−
)
Herein, we report a study of the first iron-catalyzed cross-
coupling reactions between imidoyl chlorides and Grignard
reagents. These reactions, which mainly lead to the formation
of an sp2-sp3 carbon-carbon bond are fast, mild, and
frequently high yielding. Surprisingly, few metal-catalyzed
cross-coupling reactions of imidoyl chlorides have been
studied and those reported so far have used expensive Pd1
or toxic Ni2 catalysts. In contrast, the iron catalysts used
herein are inexpensive, toxicologically benign, and easy to
handle.3 The iron-catalyzed cross-couplings provide an
attractive means of using an amide bond as a synthon for
carbon-carbon bond formation, via an intermediate imidoyl
chloride (eq 1). Recently, Nadin et al. reported one example
of a metal-catalyzed imidoyl chloride cross-coupling generat-
ing an sp2-sp3 bond, a Pd-catalyzed Negishi reaction.1a
In this report, we use the iron-catalyzed cross-coupling
reaction to synthesize analogues of clozapine, an approved
antipsychotic drug, and its metabolite N-desmethylclozapine.4
In the initial studies, n-BuMgCl was added to imidoyl
chloride 1 generated from the corresponding lactam5 (Table
1). Both TLC and GC/MS analyses showed a completed
reaction after 30 min at ambient temperature in THF, and
the butyl derivative 2 was obtained in 42% yield (entry 1).
Decreasing the reaction temperatures gave extended reaction
(1) (a) Nadin, A.; Lopez, J. M. S.; Owens, A. P.; Howells, D. M.; Talbot,
A. C.; Harrison, T. J. Org. Chem. 2003, 68, 2844-2852. (b) Kobayashi,
T.; Sakakura, T.; Tanaka, M. Tetrahedron Lett. 1985, 26, 3463-3466. (c)
Jacobi, P. A.; Liu, H. J. Am. Chem. Soc. 1999, 121, 1958-1959.
(2) Davis, F. A.; Mohanty, P. K.; Burns, D. M.; Andemichael, Y. W.
Org. Lett. 2000, 2, 3901-3903.
(3) (a) Blom, C.; Legros, J.; Paih, J. L.; Zani, L. Chem. ReV. 2004, 104,
6217-6254. (b) Fu¨rstner, A.; Martin, R. Chem. Lett. 2005, 34, 624-629.
For iron-catalyzed cross-coupling of 2-(hetero)aryl chlorides: Fu¨rstner, A.;
Leitner A.; Me´ndez, M.; Krause, H. J. Am. Chem. Soc. 2002, 124, 13856-
13863.
(4) Weiner, D. M.; Meltzer, H. Y.; Veinbergs, I.; Donohue, E. M.;
Spalding, T. A.; Smith, T. T.; Mohell, N.; Harvey, S. C.; Lameh, J.; Nash,
N.; Vanover, K. E.; Olsson, R.; Jayathilake, K.; Lee, M.; Levey, A. I.;
Hacksell, U.; Burstein, E. S.; Davis, R. E.; Brann, M. R. Psychopharma-
cology 2004, 177, 207-216 and references therein.
(5) For synthesis, see Supporting Information.
10.1021/ol0600234 CCC: $33.50
© 2006 American Chemical Society
Published on Web 03/30/2006

mixture according to GC/MS analysis. Me3SiCH2MgCl has
successfully been used in iron-catalyzed cross-coupling with
alkenyl triflate generating the corresponding silyl-function-
alized compound.7 Furthermore, adding PhMgCl to 1,
creating an sp2-sp2 carbon-carbon bond, gave ca. 55% yield
of 7 with all the tested solvents, i.e., THF, THF-NMP, and
Et2O. The lower yield compared with aliphatic reagents is
explained by a competing homocoupling of the aryl Grignard
reagent producing biphenyl.8 No reaction took place between
ethynylmagnesium bromide and 1 using the iron-catalyzed
conditions developed for alkyl Grignards.
By focusing on clozapine analogues, imidoyl chlorides
8-105 reacted with N-methyl-piperidinylmagnesium chlo-
ride9 to give azepines 11-13 in good yields (71-86%,
Scheme 1).10 This also showed that basic amines were
compatible with the reaction conditions.
Table 1. Iron-Catalyzed Cross-Coupling of Imidoyl Chloride 1
temp/time yield
entry
R
solvent/catalyst
THF/ -
(min)
(%)a
1
2
3
4
5
6
7
8
9
n-Bu (2)
n-Bu (2)
n-Bu (2)
n-Bu (2)
n-Bu (2)
n-Bu (2)
rt/30
rt/5
42
22
96
20
THF/Fe(acac)3
THF-NMP/Fe(acac)3 rt/5
THF-NMP rt/30
THF-NMP/Fe(acac)3 -78 °C/5 94
THF-NMP/FeCl3
rt/5
96
93
27
95
cyclohexyl (3)
t-Bu (4)
THF-NMP/Fe(acac)3 rt/5
THF-NMP/Fe(acac)3 rt/5
1,3-dioxan-2-ylethyl THF-NMP/Fe(acac)3 rt/5
(5)
10 Me (6)
11 Me3SiCH2
THF-NMP/Fe(acac)3 rt/5
THF-NMP/Fe(acac)3 rt/5
17
0
(72)b
55c
Scheme 1. Synthesis of Clozapine Analogues
12 Ph (7)
THF-NMP/Fe(acac)3 rt/30
a Isolated yields. b The yield in the parentheses refers to R ) Me, the
desilylated product 6. c With 6 equiv of the Grignard reagent.
times, and at -40 °C, no reaction was observed. Adding an
iron catalyst (Fe(acac)3, 5 mol %) to the reaction mixture
increased the reaction rate; at room temperature, the imidoyl
chloride 1 was consumed within 5 min. Disappointingly, the
iron-catalyzed reaction gave a lower yield (22%) compared
with the 42% yield obtained in the uncatalyzed reaction
(entry 2 vs 1). However, using a THF-N-methyl-2-pyrroli-
dinone (NMP) solvent mixture reported by Cahiez et al.,6
an excellent isolated 96% yield of compound 2 was achieved
(entry 3). Using the THF-NMP solvent mixture, iron-free
reaction conditions still generated a low yield (20%) of 2
(entry 4). This confirmed the significance of the iron catalyst
in the high yielding, rapid reactions. Even at -78 °C, using
the previously detailed iron-catalyzed conditions, the reaction
was completed within 5 min, with a 94% isolated yield (entry
5). Furthermore, the iron catalysts FeCl3 and Fe(acac)3 were
interchangeable, with no difference in the reaction outcome
observed using either catalyst at room temperature (entries
3 and 6).
The mild reaction conditions (-78 °C and 5 min reaction
time, entry 5) indicated the possibility of having additional
functionalities present during the reaction.11 The ester deriva-
tive 14 was reacted with n-BuMgCl at -40 °C for 5 min,
which resulted in selective formation of 15 in an excellent
89% yield (Scheme 2). No products from the anticipated
Scheme 2. Reaction between the Grignard Reagent and
Ester-Functionalized Imidoyl Chloride
The reaction between the more sterically demanding
cyclohexylmagnesium chloride and imidoyl chloride 1 af-
forded derivative 3 in an excellent, isolated 93% yield (entry
7). Encouragingly, under standard conditions, the steric-
ally encumbered t-BuMgCl still gave product 4 (entry
8), although only in low yield (27%). The functionalized
Grignard reagent, (1,3-dioxan-2-yl)ethylmagnesium chloride,
gave 5 in 95% yield (entry 9). Methylmagnesium chloride
failed to efficiently react, giving 6 in a low yield (17%) with
major recovery of starting material.7 Interestingly, the
((trimethylsilyl)methyl)magnesium chloride (entry 11) gave
the desilylated methyl product 6 as the sole product in 72%
yield. No silylated product was detected in the reaction
competing addition to the ester functionality were isolated.
Running the reaction in the absence of Fe(acac)3 at -10 °C
gave a complex product mixture.
A Weinreb amide-functionalized imidoyl chloride 16
selectively reacted either at the imidoyl chloride or at the
(8) (a) Cahiez, G.; Chaboche, C.; Mahutesu-Betzer, F.; Arh, M. Org.
Lett. 2005, 7, 1943-1943. (b) Nagano, T.; Hayashi, T. Org. Lett. 2005, 7,
491-493.
(9) Engelhardt, E. L.; Zell, H. C.; Saari, W. S.; Christy, M. E.; Dylion
Colton, C. J. Med. Chem. 1965, 8, 829-835.
(6) Cahiez, G.; Avedissian, H. Synthesis 1998, 1199.
(7) Scheiper, B.; Bonnekessel, M.; Krause, H.; Fu¨rstner, A. J. Org. Chem.
2004, 69, 3943-3949.
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Org. Lett., Vol. 8, No. 9, 2006

Weinreb amide depending on the reaction conditions used
(Scheme 3). The Fe(acac)3-catalyzed reaction gave 17 in 70%
sized from amide 20 in 72% yield over two steps using
standard conditions. The intermediate imidoyl chloride was
concentrated at reduced pressure and used in the following
cross-coupling without further purification.
In summary, we have developed a general, high yielding,
rapid iron-catalyzed cross-coupling reaction between Grig-
nard reagents and imidoyl chlorides. Under the mild reac-
tion conditions, functionalities such as esters are un-
affected. Selective additions of Grignard reagents at either
the Weinreb amide or the imidoyl chloride functionality were
achieved in a substrate incorporating both. Applying the
herein developed conditions on a privileged core structure
gave facile access to bioisosteric analogues of clozapine. In
addition, the mild reaction conditions make this protocol an
efficient alternative for the synthesis of imines compared to
the forced conditions normally used in condensation reac-
tions.
Scheme 3. Selective Addition of Grignard Reagents
Discriminating between Weinreb Amide and Imidoyl Chloride
Functionalities
Acknowledgment. We thank Mrs. Sine Mandrup Ber-
tozzi for expert analytical assistance.
Supporting Information Available: Synthetic procedures
and the characterization of compounds 1-19. This ma-
terial is available free of charge via the Internet at
http://pubs.acs.org.
yield,12 and the major byproduct (5%) was the demethoxy-
lated amide 18.13 Selective addition to the Weinreb amide
(16) was achieved in 83% yield, to afford 19, by applying
standard Grignard reaction conditions at 0 °C in THF, in
the absence of the iron catalyst.
OL0600234
As demonstrated in Scheme 4, the iron-catalyzed reaction
(10) The dibenzodiazepine clozapine analogue 11 has been specifically
exemplified and claimed in the patent literature together with some other
close piperidyl clozapine analogues. Although a generic synthetic methodol-
ogy was described (the final step was a condensation reaction giving the
imine functionality using phosphorus pentoxide in phosphorus oxychloride
at reflux overnight), no physical data supporting the claimed structure 11
was presented. Hardy, R. A., Jr. 11-(4-Piperidyl)dibenzodiazepines.
US4045445, 1977.
is not limited to cyclic compounds. Imine 2114 was synthe-
Scheme 4. Synthesis of Imine 21
(11) Dohle, W.; Kopp, F.; Cahiez, G.; Knochel, P. Synlett 2001, 1901-
1904.
(12) Only 0.95 equiv of Grignard reagent was used because of the
competing demethoxylation reaction. The use of 2 equiv of Grignard reagent
gave 18 in 66% yield.
(13) (a) Lubell, W. D.; Jamison, T. F.; Rapoport, H. J. Org. Chem. 1990,
55, 3511-3522. (b) Sibi, M. P.; Marvin, M.; Sharma, R. J. Org. Chem.
1995, 60, 5016-5023.
(14) Nakagawa, M.; Kawate, T.; Kakikawa, T.; Yamada, H.; Matsui, T.
Tetrahedron 1993, 49, 1739-1748.
Org. Lett., Vol. 8, No. 9, 2006
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