Iron-catalyzed homo-coupling of simple and functionalized arylmagnesium reagents

Article abstract of DOI:10.1021/ol050340v

(Chemical Equation Presented) Iron-catalyzed homo-coupling of simple and functionalized arylmagnesium reagents is described. The reaction is highly chemoselective (CN, COOEt and NO₂ groups are tolerated). The procedure was used to perform intramolecular couplings. This cyclization reaction is the key step of the total synthesis of the N-methylcrinasiadine.

Full text of DOI:10.1021/ol050340v

ORGANIC
LETTERS
2005
Vol. 7, No. 10
1943-1946
Iron-Catalyzed Homo-Coupling of Simple
and Functionalized Arylmagnesium
Reagents
Ge´rard Cahiez,* Christophe Chaboche, Florence Mahuteau-Betzer, and
Mathieu Ahr
Laboratoire de Synthe`se Organique Se´lectiVe et de Chimie Organome´tallique
(SOSCO), UMR 8123 CNRS-UCP-ESCOM, 13, BouleVard de l’Hautil,
F-95092 Cergy-Pontoise, France
gerard.cahiez@chim.u-cergy.fr
Received February 17, 2005
ABSTRACT
Iron-catalyzed homo-coupling of simple and functionalized arylmagnesium reagents is described. The reaction is highly chemoselective (CN,
COOEt and NO2 groups are tolerated). The procedure was used to perform intramolecular couplings. This cyclization reaction is the key step
of the total synthesis of the N-methylcrinasiadine.
Since the beginning of the past decade we have undertaken
to develop preparative iron-catalyzed coupling reactions.1 The
interest of this new area of investigation is highlighted by
the increasing number of reports published in the last three
years.2 It should be noted that for large-scale preparation,
iron salts such as FeCl3 or Fe(acac)3 are a valuable alternative
to palladium and nickel complexes used as catalyst for many
coupling procedures3 because they are cheaper and much
more environment-friendly. In the course of our continuing
interest in this field we have recently studied the iron-
catalyzed homo-coupling of aromatic Grignard reagents. A
recent communication4 in this journal prompted us to report
our own results.
The homo-coupling reaction reported by Hayashi is
performed in diethyl ether, at reflux, using 1.2 equiv of 1,2-
dichlororethane as oxidant. For our part, we have decided
to develop the reaction in THF. Indeed, diethyl ether is not
convenient for large-scale application (especially at reflux).
Moreover, the preparation of aromatic Grignard reagents is
easier in THF, and the scope of the reaction is clearly larger
in this solvent (preparation of ArMgCl from aryl chlorides,
preparation of functionalized ArMgX by halogen-magne-
sium exchange etc.).
The results described in Table 1 show that in THF the
reaction can be easily performed at room temperature in the
presence of 3% FeCl3 by using only a stoichiometric amount
of dichloroethane as oxidant (0.6 equiv). Good yields of
homo-coupling product are thus obtained. Interestingly, the
reaction can be applied to heteroaromatic Grignard reagents
(entry 8).
(1) (a) Cahiez, G.; Marquais, S. Pure Appl. Chem. 1996, 68, 669. (b)
Cahiez, G.; Marquais, S. Tetrahedron Lett. 1996, 37, 1773. (c) Cahiez, G.;
Avedissian, H. Synthesis 1998, 1199. (d) Dohle, W.; Koppe, F.; Cahiez,
G.; Knochel, P. Synlett 2001, 12, 1901.
(2) (a) Fu¨rstner, A.; Leitner, A.; Me´ndez, M.; Krause, H. J. Am. Chem.
Soc. 2002, 124, 13856. (b) Fu¨rstner, A.; Leitner, A. Angew. Chem., Int.
Ed. 2002, 41, 609. (c) Quintin, J.; Frank, X. Hocquemiller, R.; Figade`re,
B. Tetrahedron Lett. 2002, 43, 3547. (d) Martin, R.; Fu¨rstner, A. Angew.
Chem., Int. Ed. 2004, 43, 3955. (e) Scheiper, B. Bonnekessel, M.; Krause,
H.; Fu¨rstner, A. J. Org. Chem. 2004, 69, 3943. (f) Nakamura, M.; Matsuo,
K.; Ito, S.; Nakamura, E. J. Am. Chem. Soc. 2004, 126, 3686. (g) Nagano,
T.; Hayashi, T. Org. Lett. 2004, 6, 1297.
(3) Metal-Catalysed Cross-Coupling Reactions; Diederich, F., Stang, P.
J., Eds.; Wiley-WCH: Weinheim, 1998. For review on aryl-aryl coupling
reactions, see: (a) Stanforth, S. Tetrahedron 1998, 54, 263. (b) Hassan, J.;
Se´vignon, M.; Gozzi, C.; Schultz, E.; Lemaire, M. Chem. ReV. 2002, 102,
1359.
From ortho-substituted aryl Grignard reagents the reaction
is slower. Thus, 10 min is enough to react the 3- or
4-methoxyphenylmagnesium bromides 1b and 1c (entries 2
(4) Nagano, T.; Hayashi, T. Org. Lett. 2005, 7, 491.
10.1021/ol050340v CCC: $30.25
© 2005 American Chemical Society
Published on Web 04/21/2005

Table 1. Iron-Catalyzed Homo-Coupling of Aryl Grignard
Reagentsa
Table 2. Iron-Catalyzed Homo-Coupling of ortho-Substituted
Aryl Grignard Reagentsa
a The reactions were carried out by stirring the aryl Grignard reagent
(10 mmol), 1,2-dihalogenoethane (6 mmol), and FeCl3 (0.3 mmol) in THF
at room temperature for 10 min. b Isolated yield. c Reaction time was 4 h.
magnesium bromides were easily and efficiently prepared
from the corresponding aryl iodide and isopropylmagnesium
bromide in THF at -40 °C. Similarly, 2-nitrophenylmag-
Table 3. Iron-Catalyzed Homo-Coupling of Functionalized
Aryl Grignard Reagentsa
a Reactions were carried out by stirring the aryl Grignard reagent (10
mmol), 1,2-dichloroethane (6 mmol), and FeCl3 (0.3 mmol) in THF at room
temperature for 1 h. b Isolated yield. c Isolated as the corresponding picrate.
Reaction time was 4 h.
and 3), whereas the coupling of the 2-methoxyphenylmag-
nesium bromide 1i lasts 4 h (81%, Table 2, entry 1).
Interestingly, we found that the reaction is clearly accelerated
by using 1,2-dibromo- or 1,2-diiodoethane in place of 1,2-
dichloroethane as oxidant since the reaction is then completed
within 10 min (entries 1 and 2).
From the more hindered mesitylmagnesium bromide 1j
the reaction is still more difficult. Under standard conditions
(1,2-dichloroethane), poor yields of homo-coupling product
2j were obtained whatever the reaction time (entry 3). In
this case, a dramatic improvement was observed when the
reaction was performed with 1,2-dibromo- or 1,2-diiodo-
ethane since the yield jumped from 6% to 60% (entries 4
and 5).
From a preparative point of view, the synthesis of simple
symmetrical biaryls is not very challenging. Thus we have
turned our attention to the preparation of highly function-
alized molecules (Table 3).
a Reactions were carried out by stirring the aryl Grignard reagent (10
mmol), 1,2-diodoethane (10 mmol), and FeCl3 (0.3 mmol) in THF at -40
°C (entries 1-3) for 2 h or at room temperature for 1 h (entries 4 and 5).
b Isolated yield.
Recently, in collaboration with the Knochel group we have
described the preparation of functionalized aryl Grignard
reagents via an iodine-magnesium exchange reaction.5 Thus,
cyanophenylmagnesium bromides and carbethoxyphenyl-
1944
Org. Lett., Vol. 7, No. 10, 2005

nesium bromide 1p can also be prepared from 2-iodoni-
trobenzene 3p and phenylmagnesium bromide at -40 °C in
THF.6
Scheme 2. Iron-Catalyzed Homo-Coupling of
2-Fluoro-3-carbethoxy-4-pyridylmagnesium Bromide
To develop a new way to prepare highly functionalized
biaryl compounds, we have tried to apply the homo-coupling
reaction conditions described herein to these functionalized
aryl Grignard reagents. In fact, the main difficulty is to avoid
the competitive cross-coupling reaction between the starting
arylmagnesium reagent and the isopropyl iodide formed
during the iodine-magnesium exchange reaction (ArI +
i-PrMgX f ArMgX + i-PrI). By working with 1,2-
dichloroethane as oxidant, the homo-coupling occurs too
slowly to be efficient,7 especially when the reaction has to
be performed below -20 °C to prevent the decomposition
of the Grignard reagent. Fortunately, we have found that with
1,2-dibromo- or 1,2-diiodoethane the homo-coupling reaction
occurs successfully even at -35 °C (Table 3).
It was tempting to try to perform intramolecular coupling
reactions from di-Grignard reagents such as 5 (Scheme 3).
Dicyanobiphenyls 2k-m (entries 1-3) as well as dicar-
bethoxybiphenyls 2n and 2o (entries 4 and 5) were thus
prepared in satisfactory yields. Under similar coupling
conditions, the 2,2′-dinitrobiphenyl 2p was prepared from
the corresponding Grignard reagent 1p in 41% yield (Scheme
1). This yield is satisfactory for this very challenging
example.
Scheme 3. Iron-Catalyzed Intramolecular Coupling Reaction
Scheme 1. Iron-Catalyzed Homo-Coupling of
2-Nitrophenylmagnesium Bromide
Thus the diiodo compound 4 reacted with i-PrMgBr at room
temperature for 30 min to give 5. Then, the treatment of the
di-Grignard 5 with 1,2-dibromoethane in the presence of 3%
FeCl3 provided the dihydrophenanthrene 6 in 76% overall
yield.
It is interesting to note that via such an intramolecular
cyclization reaction it is possible to obtain a “cross-coupling”
product using a “homo-coupling” reaction. This is exempli-
fied by the following total synthesis of N-methylcrinasiadine,
a natural product extracted from Lapiedra martinezii (Ama-
ryllidaceae).9 The 2,2′-diiodo-N-methyl-4,5-methylenedioxy-
benzanilide 9 was prepared in 8 steps from piperonal
We have also applied these coupling conditions to the
functionalized pyridylmagnesium bromide 1q. The starting
2-fluoro-3-carbethoxy-4-iodopyridine 3q was synthesized in
66% yield from 2-fluoro-3-iodopyridine according to a
procedure reported by Que´guiner.8 It was then reacted with
i-PrMgBr at -40 °C for 1 h to give the Grignard reagent
1q. This latter was then treated with 1,2-diiodoethane in the
presence of 3% FeCl3 to give the homo-coupling product
2q in 33% overall yield (Scheme 2). All of these results show
that this homo-coupling procedure is highly chemoselective.
Scheme 4. Preparation of
2,2′-Diiodo-N-methyl-4,5-methylenedioxybenzanilide 910
(5) (a) Boymond, L.; Ro¨ttla¨nder, M.; Cahiez, G.; Knochel, P. Angew.
Chem, Int. Ed. 1998, 37, 1701. (b) Rottla¨nder, M.; Boymond, L.; Be´rillon,
L.; Lepreˆtre, A.; Varchi, G.; Avolio, S.; Laaziri, H.; Que´guiner, G.; Ricci,
A.; Cahiez, G.; Knochel, P. Chem. Eur. J. 2000, 6, 767. For a review, see:
Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F. F.; Kopp, F.; Korn,
T.; Sapountzis, I.; Anh Vu, V. Angew. Chem., Int. Ed. 2003, 42, 4302.
(6) Sapountzis, I.; Knochel, P. Angew. Chem., Int. Ed. 2002, 4, 1610.
(7) Until 40% yield of cross-coupling product between the starting aryl
Grignard reagent and i-PrI were obtained. The iron-catalyzed cross-coupling
reaction between arylmagnesium reagent and secondary alkyl halide in THF
has been reported: (a) Nakamura, M.; Matsuo, K.; Ito, S.; Nakamura, E. J.
Am. Chem. Soc. 2004, 126, 3686. (b) Martin, R.; Fu¨rstner, A. Angew. Chem.,
Int. Ed. 2004, 43, 3955. The reaction can also be performed in ether:
Nagano, T.; Hayashi, T. Org. Lett. 2004, 6, 1297.
(8) Rocca, P.; Cochennec, C.; Marsais, F.; Thomas-dit-Dumont, L.;
Mallet, M.; Godard, A.; Que´guiner, G. J. Org. Chem. 1993, 58, 7832.
Org. Lett., Vol. 7, No. 10, 2005
1945

(Scheme 4). The di-Grignard reagent 10 was then prepared
through iodine-magnesium exchange. Under the coupling
conditions previously used, it afforded the N-methylcrina-
siadine 11 in 39% overall yield (Scheme 5).
Scheme 6. Mechanism for the Homo-Coupling Reaction
Scheme 5. Preparation of N-Methylcrinasiadine
In summary, we have developed an efficient iron-catalyzed
homo-coupling reaction of aryl Grignard reagents. It should
be noted that the reaction is chemoselective. Thus, various
functionalized aryl and heteroarylmagnesium reagents have
been used successfully to prepare polyfunctionalized biaryl
and biheteroaryl compounds. Moreover, this procedure
allows perfomance of intramolecular coupling reactions.
A plausible mechanism is proposed in Scheme 6. The role
of the 1,2-dihaloethane is to oxidize the iron (Fen f Fen+2
)
after the reductive elimination step. It should be noted that
the oxidation states of the iron species involved in the
catalytic cycle are uncertain. A couple FeI/FeIII or Fe0/FeII
can be proposed,11 but a recent study1a,b puts forward a couple
Fe-II/Fe0.
Acknowledgment. The authors thank the CNRS and the
Ecole Supe´rieure de Chimie Organique et Mine´rale (ES-
COM) for their financial support as well as the Ministe`re de
l′Education Nationale et de la Recherche for its financial
support and a grant to M.A.
(9) Suau, R.; Gomez, A. I.; Rico, R. Phytochemistry 1990, 29, 1710.
(10) 6-Bromopiperonal 7 was prepared according to Conrad, P. C.;
Kwiatkowski, P. L.; Fuchs, P. L. J. Org. Chem. 1987, 52, 586. 6-Iodo-
piperonal 8 was prepared from 7 according to Bogucki, D. E.; Charlton, J.
L. J. Org. Chem. 1995, 60, 588. For the oxidation of 8 to the corresponding
carboxylic acid (8 to 9, step 1), see: Padwa, A.; Brodney, M. A.; Lynch,
S. M. J. Org. Chem. 2001, 66, 1716.
Supporting Information Available: Detailed experi-
mental procedures and complete compound characterization
data. This material is available free of charge via the Internet
at http://pubs.acs.org.
(11) (a) Neumann, S. M.; Kochi, J. K. J. Org. Chem. 1975, 40, 599. (b)
Smith, R. S.; Kochi, J. K. J. Org. Chem. 1976, 41, 502.
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