Meta- and para-difunctionalization of arenes via a sulfoxide-magnesium exchange reaction

Article abstract of DOI:10.1021/ol801431z

(Chemical Equation Presented) The aryl sulfoxide moiety (ArSO) allows an expedient two-step meta-, para-difunctionalization of readily available diaryl sulfoxides. In the first step, the sulfoxide plays the role of a directing metalation group. In the second step, triggered by i-PrMgCl·LiCl, it becomes a leaving group and undergoes a regioselective sulfoxide-magnesium exchange.

Full text of DOI:10.1021/ol801431z

ORGANIC
LETTERS
2008
Vol. 10, No. 17
3891-3894
Meta- and Para-Difunctionalization of
Arenes via a Sulfoxide-Magnesium
Exchange Reaction
Christian B. Rauhut, Laurin Melzig, and Paul Knochel*
Department Chemie und Biochemie, Ludwig-Maximilians-UniVersita¨t,
Butenandtstrasse 5-13, 81377, Mu¨nchen, Germany
paul.knochel@cup.uni-muenchen.de
Received June 25, 2008
ABSTRACT
The aryl sulfoxide moiety (ArSO) allows an expedient two-step meta-, para-difunctionalization of readily available diaryl sulfoxides. In the first
step, the sulfoxide plays the role of a directing metalation group. In the second step, triggered by i-PrMgCl·LiCl, it becomes a leaving group
and undergoes a regioselective sulfoxide-magnesium exchange.
The functionalization of arenes via organometallic intermedi-
ates is of central importance for the preparation of poly-
functional aromatics.1 Whereas arylmagnesium compounds
lation ability6 and would therefore allow access to unusual
substitution patterns of arenes. Furthermore, the sulfoxide
group is a versatile functionality, which has found numerous
applications in organic synthesis.7
are readily prepared via a directed ortho-metalation,2
a
magnesium insertion,3or a halogen-magnesium exchange,4
the use of diaryl sulfoxides for the synthesis of functionalized
arylmagnesium derivatives via a sulfoxide-magnesium
exchange has barely been reported.5 This is surprising since
the sulfoxide group also has an exceptional directing meta-
We have envisaged that sulfoxides of type 1, bearing various
functional groups (FG ) F, Cl, CN, CO2-t-Bu, CF3, alkynyl)
can be magnesiated in the ortho-position using tmpMgCl·LiCl
(2),8 leading after quenching with an electrophile (E1) to arenes
of type 3. A subsequent sulfoxide-magnesium exchange using
i-PrMgCl·LiCl will provide an intermediate magnesium reagent
4, which by reaction with a second electrophile (E2) is giving
meta- and para-difunctionalized aromatics of type 5, a substitu-
tion pattern difficult to reach by standard methods.9 Thus, the
starting diaryl sulfoxides 1a-f can be considered as being
synthetic equivalents of the bis-carbanionic synthon 6 (Scheme
1). To perform successfully this sequence, the sulfoxides 1a-f
(1) (a) Hartung, C. G.; SnieckusV. In Modern Arene Chemistry; Astruc,
D., Ed.; Wiley-VCH: Weinheim, 2002; 330. (b) Schlosser, M. In Organo-
metallics in Synthesis: A Manual; Schlosser, M., Ed.; Wiley: Chichester,
2002; 1. (c) Knochel, P. In Handbook of Functionalized Organometallics;
Knochel, P., Ed.;Wiley-VCH: Weinheim, 2005. (d) Boudier, A.; Bromm,
L. O.; Lotz, M.; Knochel, P. Angew. Chem., Int. Ed. 2000, 39, 4414.
(2) (a) Eaton, P. E.; Lee, C. H.; Xiong, Y. J. Am. Chem. Soc. 1989,
111, 8016. (b) Giuliano, C.; Rohbogner, C. J.; Knochel, P. Angew. Chem.,
Int. Ed. 2007, 46, 7681.
(3) (a) Rieke, R. D. Science 1989, 246, 1260. (b) Rieke, R. D.; Hanson,
M. V. Tetrahedron 1997, 1925. (c) Lee, J.; Velarde-Ortiz, R.; Guijarro,
A.; Wurst, J. R.; Rieke, R. D. J. Org. Chem. 2000, 65, 5428.
(4) (a) Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F. F.; Kopp,
F.; Korn, T.; Sapountzis, I.; Vu, V.-V. Angew. Chem., Int. Ed. 2003, 42,
4302. (b) Krasovskiy, A.; Knochel, P. Angew. Chem., Int. Ed. 2004, 43,
3333.
(5) (a) Ogawa, S.; Furukawa, N. J. Org. Chem. 1991, 56, 5723. (b)
Annunziata, M.; Capozzi, M.; Cardellicchio, C.; Naso, F.; Spina, G.;
Tortorella, P. J. Org. Chem. 2001, 66, 5933. (c) Yamamoto, T.; Ogawa,
S.; Sugawara, M.; Kawai, Y.; Sato, R. Bull. Chem. Soc. Jpn. 2006, 79,
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10.1021/ol801431z CCC: $40.75
Published on Web 08/05/2008
2008 American Chemical Society

zenesulfinyl chloride (9, MeOC6H4S(O)Cl)14 affords the
15
desired 4-methoxy-substituted sulfoxides 1c-f (FG: CF3,
Scheme 1. Metalation of Sulfoxides, Followed by a
CN, CO2-t-Bu, alkynyl16) in 70-90% yield. Having
prepared the required diaryl sulfoxides 1a-f, we have
performed the directed metalation step (step 1 of Scheme
1). Thus, the sulfoxide 1a was deprotonated with
tmpMgCl·LiCl at -30 °C within 20 min. After transmeta-
lation to the corresponding zinc reagent (using ZnCl2 in
THF), a Pd-catalyzed (Pd(Ph3)4, 2 mol %) cross-coupling17
with 4-iodobenzonitrile or 4-iodobromobenzene gave the
expected sulfoxides 3a,b in 82-92% yield (entries 1 and
2, Table 1). Reaction of the magnesiated derivative of 1a
(FG ) Cl) with tosyl cyanide led to the nitrile 3c in 73%
yield (entry 3). Similarly, the sulfoxide 1b (FG ) F) was
metalated with tmpMgCl·LiCl at -30 °C within 20 min.
Quenching of this magnesium species with iodine, fol-
lowed by a Negishi cross-coupling with 2-phenylethy-
nylzinc chloride, furnished the product 3d in 95% yield
(entry 4).16
Palladium-catalyzed cross-coupling with 4-iodoanisole
gave the sulfoxide 3e in 93% yield (entry 5). Using similar
procedures, we were able to functionalize the diaryl sulfox-
ides 1c (FG ) CF3), 1d (FG ) TMS-acetylene), 1e (FG )
CO2-t-Bu), and 1f (FG ) CN) in 68-79% yield (entries
6-9). The second step of the synthetic sequence (Scheme
1), i.e., the sulfoxide-magnesium exchange, was >95%
regioselective, providing only the desired magnesium re-
Sulfoxide-Magnesium Exchange Reaction Leading to Meta-
and Para-Difunctionalized Arenes (FG ) F, Cl, CN, CO2-t-Bu,
CF3, Alkynyl)
should undergo a regioselective deprotonation on the aromatic
ring bearing the functional group FG, as well as a regioselective
sulfoxide-magnesium exchange reaction producing an inter-
mediate magnesium reagent of type 4 (and not the alternative
exchange product: ArMgCl; Scheme 1). After extensive ex-
perimentation, we have solved both of these problems by
introducing donor substituents at the para-position of the Ar
group of 1.10 Thus, two types of diaryl sulfoxides proved to be
excellent starting materials: the 4-N,N-dimethylaminophenyl
sulfoxide derivatives 1a,b and the 4-methoxyphenyl sulfoxide
compounds 1c-f. These sulfoxides were prepared by two
convergent and practical synthetic routes (Scheme 2). Thus, the
N,N-dimethylamino-substituted sulfoxides 1a,b were prepared
by the reaction of functionalized arylmagnesium reagents of
type 74 with 4-(dimethylamino)phenyl thiocyanate (8,
Me2NC6H4SCN)11,12 followed by m-CPBA oxidation
(CH2Cl2, -20 °C, 1.1 equiv), leading to sulfoxides 1a (64%)
and 1b13 (69%).
(7) (a) Oae, S.; Kawai, T.; Furukawa, N. Tetrahedron Lett. 1984, 25,
69. (b) Kawai, T.; Furukawa, N. Tetrahedron Lett. 1984, 25, 2549. (c) Oae,
S.; Takeda, T.; Wakabayashi, S. Heterocycles 1989, 28, 99. (d) Furukawa,
N.; Shibutani, T.; Fujihara, H. Tetrahedron Lett. 1989, 30, 7091. (e)
Furukawa, N.; Ogawa, S.; Matsumura, K.; Shibutani, T.; Fujihara, H. Chem.
Lett. 1990, 20, 979. (f) Shibutani, T.; Fujihara, H.; Furukawa, N. Tetrahedron
Lett. 1991, 32, 2943. (g) Uenishi, J.; Yamamoto, A.; Takeda, T.; Waka-
bayashi, S.; Oae, S. Heteroat. Chem. 1992, 3, 73. (h) Guillaneux, D.; Kagan,
H. B. J. Org. Chem. 1995, 60, 2502. (i) Hoffmann, R. W.; Ho¨lzer, B.;
Knopff, O.; Harms, K. Angew. Chem., Int. Ed. 2000, 39, 3072. (j) Satoh,
T.; Taguchi, D.; Suzuki, C.; Fujisawa, S. Tetrahedron 2001, 57, 493. (k)
Satoh, T.; Akita, K. Chem. Pharm. Bull. 2003, 51, 181. (l) Kagan, H. B.;
LuukasT. O. In Transition Metals for Organic Synthesis; Beller, M., Bolm,
C., Eds.; Wiley-VCH: Weinheim, 2004; 479. (m) Capozzi, M.; Cardellic-
chio, C.; Naso, F. Eur. J. Org. Chem. 2004, 9, 1845. (n) Senanayake, C. H.;
Krishnamurthy, D.; Lu, Z.-H.; Han, Z.; Gallou, I. Tetrahedron 2005, 61,
6386. (o) Cardellicchio, C.; Naso, F.; Capozzi, M. Phosphorus, Sulfur Silicon
Relat. Elem. 2005, 180, 1161. (p) Blakemore, P. R.; Marsden, S. P.; Vater,
H. D. Org. Lett. 2006, 8, 773. (q) Manchena, O. G.; Bolm, C. Org. Lett.
2006, 11, 2349. (r) Sugiyama, S.; Shimizu, H.; Satoh, T. Tetrahedron Lett.
2006, 47, 8771. (s) Satoh, T. Chem. Soc. ReV. 2007, 36, 1561. (t) Ferber,
B.; Kagan, H. B. AdV. Synth. Catal. 2007, 349, 493. (u) Brebion, F.;
Goddard, J.-P.; Fensterbank, L.; Malacria, M. Org. Lett. 2008, 10, 1917.
(8) Krasovskiy, A.; Krasovskaya, V.; Knochel, P. Angew. Chem., Int.
Ed. 2006, 45, 2958.
On the other hand, the reaction of functionalized
arylmagnesium reagents of type 74 with 4-methoxyben-
Scheme 2. Preparation of Sulfoxides of Type 1
(9) Rohbogner, C. J.; Giuliano, C.; Knochel, P. Angew. Chem., Int. Ed.
2008, 47, 1503.
(10) Key for the regioselectivity of the sulfoxide-magnesium exchange
is an electronic differentiation of the two aromatic rings attached to the
sulfoxide moiety. Thus, the most stable organometallic species is always
formed (the one bearing the most electron-withdrawing substituent).
(11) Brewster, R. Q.; Schroeder, W. Org. Synth. 1943, 19, 79.
(12) Jendralla, H.; Chen, L. Synthesis 1990, 827.
(13) Lang, S. A.; Fields, T. L.; Wilkinson, R. G.; Kang, S. M.; Lin,
Y. J. Eur. Pat. Appl. 1984, 38.
(14) Peyronneau, M.; Roques, N.; Mazieres, S.; Le Roux, C. Synlett
2003, 631.
(15) Yano, T.; Sakaguchi, I.; Katsura, G.; Yoshikawa, N. PCT Int. Appl.
2002, 51.
(16) For more details, see the Supporting Information.
(17) (a) Negishi, E.; Valente, L. F.; Kobayashi, M. J. Am. Chem. Soc.
1980, 102, 3298. (b) Negishi, E. Acc. Chem. Res. 1982, 15, 340. (c) Zeng,
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3892
Org. Lett., Vol. 10, No. 17, 2008

Table 1. ortho-Magnesiation of Functionalized Sulfoxides
Followed by Electrophilic Reaction
Table 2. Sulfoxide-Magnesium Exchange of Functionalized
Sulfoxides Followed by Electrophilic Reaction
a Isolated yield of analytically pure product. b After transmetalation to
zinc using zinc chloride 1 M in THF; Ar1 ) pC6H4NMe2; Ar2 ) pC6H4-
OMe.
a Isolated yield of analytically pure product referring to 0.8 equiv of
electrophile. b After transmetalation to zinc using zinc chloride 1 M in
THF.
Org. Lett., Vol. 10, No. 17, 2008
3893

10, which is a serotonin reuptake inhibitor.19 Thus, the
sulfoxide 1b (FG ) F) was metalated with tmpMgCl·LiCl
at -30 °C within 20 min. Quenching of the resulting
magnesium species with (S)-(4-chlorophenyl)benzene thio-
sulfonate20 led to the expected sulfide 11 in 82% yield. This
sulfoxide was treated with i-PrMgCl·LiCl at -50 °C furnish-
ing the corresponding magnesium intermediate within 3 h,
which reacted cleanly with the iminium salt 1221 to give the
serotonin reuptake inhibitor 1018 in 82% yield (Sch-
eme 3).
Scheme 3. Two-Step Preparation of the Serotonin Reuptake
Inhibitor 10
In summary, we have developed an efficient two-step
sequence allowing a meta-, para-difunctionalization of
aromatics using the chameleon chemical behavior of the
sulfoxide moiety (ArSO). This versatile functional group acts
asametalationdirectinggroupinthepresenceoftmpMgCl·LiCl
(2) and as a leaving group in the presence of i-PrMgCl·LiCl,
generating a new Grignard reagent. Further extensions of
the use of the sulfoxide group for generating polyfunctional
Grignard reagents are currently being studied in our labo-
ratories.
agents 4 (and not the alternative cleavage product ArMgCl).
Thus, the reaction of 3a with i-PrMgCl·LiCl at -50 °C within
1 h, followed by cross-coupling with 4-iodobenzonitrile,
furnished the terphenyl 5a in 81% yield (entry 1, Table 2).18
A range of polyfunctional compounds (5c-f) was obtained
in 83-87% yield, applying the same procedure to the
sulfoxides 3c-f (entries 6-9). Interestingly, the bromine-
substituted sulfoxide 3b undergoes a selective sulfoxide-
magnesium exchange within 5 h at -50 °C and gives with
3,4-dichlorobenzaldehyde the alcohol 5b in 63% yield (entry
2), showing that this sulfoxide/magnesium exchange is faster
than the corresponding Br/Mg exchange. Diaryl sulfoxides
3g-i bearing sensitve functional groups (CO2-t-Bu, CN)
reacted smoothly with i-PrMgCl·LiCl and were trapped
successfully with electrophiles, producing the compounds
5g-i in 68-88% yield (entry 7-9). We have applied this
sequence to the preparation of the biological active sulfide
Acknowledgment. We thank the Fonds der Chemischen
Industrie and the DFG for financial support and Chemetall
GmbH (Frankfurt) and BASF AG (Ludwigshafen) for
generous gifts of chemicals.
Supporting Information Available: Experimental pro-
cedures and full characterization of all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL801431Z
(19) Polivka, Z.; Dobrovsk, K.; Silhankova, A.; Sindelar, K.; Mickova,
R.; Valenta, V.; Krejci, I. PCT Int. Appl. WO 9717325, 1997.
(20) Fujiki, K.; Tanifuji, N.; Sasaki, Y.; Yokoyama, T. Synthesis 2002,
343.
(18) Performing the sulfoxide-magnesium exchange reaction in THF
led to 10-35% of protonated Grignard reagent 4. In spite of numerous
deuteration experiments, the proton source could not be identified. However,
by using 2-methyltetrahydrofuran, this protonation could be reduced to
10-20%.
(21) (a) Millot, N.; Piazza, C.; Avolio, S.; Knochel, P. Synthesis 2000,
941. (b) Gommermann, N.; Koradin, C.; Knochel, P. Synthesis 2002, 2143.
3894
Org. Lett., Vol. 10, No. 17, 2008