Directed ortho metalation methodology. The N,N-dialkyl aryl O-sulfamate as a new directed metalation group and cross-coupling partner for grignard reagents

Article abstract of DOI:10.1021/ol050393c

(Chemical Equation Presented) The ortho metalation (RLi/THF/-93°C) of 3 followed by quench with a variety of electrophiles constitutes a new general route to substituted aryl O-sulfamates 4a-k. The Kumada-Corriu cross-coupling of O-sulfamates 4e, 4n-s, and 6a with Grignard reagents gives biaryls 9a-m, and the use of 2-halo and boron derivatives 4h, 4i, and 4k for Suzuki-Miyaura cross-coupling and generation of benzynes leads to naphthols 7a and 7b. A relative metalation ranking of the OSONEt₂ is reported.

Full text of DOI:10.1021/ol050393c

ORGANIC
LETTERS
2005
Vol. 7, No. 13
2519-2522
Directed Ortho Metalation Methodology.
The N,N-Dialkyl Aryl O-Sulfamate as a
New Directed Metalation Group and
Cross-Coupling Partner for Grignard
Reagents
Todd K. Macklin and Victor Snieckus*
Department of Chemistry, Queen’s UniVersity, Kingston, ON, K7L 3N6, Canada
snieckus@chem.queensu.ca
Received February 23, 2005
ABSTRACT
The ortho metalation (RLi/THF/
aryl O-sulfamates 4a k. The Kumada
the use of 2-halo and boron derivatives 4h, 4i, and 4k for Suzuki
−
93
°
C) of 3 followed by quench with a variety of electrophiles constitutes a new general route to substituted
−
−
Corriu cross-coupling of O-sulfamates 4e, 4n s, and 6a with Grignard reagents gives biaryls 9a m, and
−
−
−Miyaura cross-coupling and generation of benzynes leads to naphthols 7a
and 7b. A relative metalation ranking of the OSONEt2 is reported.
The conjunction of the directed ortho metalation (DoM)
strategy (Figure 1, 1)1,2 with various transition metal-
catalyzed cross-coupling regimens3 has established a foun-
tainhead of reliable methodology for the regioselective
construction of biaryls in a multitude of aryl-aryl and aryl-
heteroaryl bond-forming combinations.4 In the context of the
subsequent manipulation of directed metalation groups
(DMGs), always an important part of synthetic planning, the
powerful O-carbamate DMG5 and, recently, the sulfonamide
(1) Snieckus, V. Chem. ReV. 1990, 90, 879.
(2) Hartung, C. G.; Snieckus, V. In Modern Arene Chemistry; Astruc,
D., Ed.; Wiley-VCH: Weinheim, Germany, 2002; p 330.
(3) For recent comprehensive reviews, see the dedicated special issue:
Tamao, K.; Hiyama, T.; Negishi, E.-i. (Eds.) J. Organomet. Chem. 2002,
653. Diederich, F., Stang, P. J., Eds. Metal-catalyzed Cross-coupling
Reactions; Wiley-VCH: Weinheim, 1998. Stille coupling: Beletskaya, I.
P. J. Organomet. Chem. 1983, 250, 551. Espinet, P.; Echavarren, A. M.
Angew. Chem., Int. Ed. 2004, 43, 4704. Negishi coupling: King, A. O.;
Negishi, E.-i.; Villani, F. J.; Silveira, A. J. Org. Chem. 1978, 43, 358.
Klement, I.; Rottlander, M.; Tucker, C. E.; Majid, T. N.; Knochel, P.;
Venegas, P.; Cahiez, G. Tetrahedron 1996, 52, 7201. Hiyama coupling:
Hatanaka, Y.; Hiyama, T. Synlett 1991, 845. Denmark, S. E.; Sweis, T. F.
Acc. Chem. Res. 2002, 35, 835. Suzuki-Miyaura coupling: Miyaura, N.;
Suzuki, A. J. Chem. Soc., Chem. Commun. 1979, 867. Walker, S. D.; Barder,
T. E.; Martinelli, J. R.; Buchwald, S. L. Angew. Chem., Int. Ed. 2004, 43,
1871. Corriu-Kumada-Tamao coupling: Tamao, K.; Sumitani, K.; Ku-
mada, M. J. Am. Chem. Soc. 1972, 94, 4374. Corriu, R. J. P.; Masse, J. P.
J. Chem. Soc., Chem. Commun. 1972, 144. For a recent copper-catalyzed
coupling of siloxanes, see: Lam, P. Y. S.; Deudon, S.; Averill, K. M.; Li,
R.; He, M. Y.; DeShong, P.; Clark, C. G. J. Am. Chem. Soc. 2000, 122,
7600. Copper-catalyzed coupling of boronic acids: Lam, P. Y. S.; Bonne,
D.; Vincent, G.; Clark, C. G.; Combs, A. P. Tetrahedron Lett. 2003, 44,
691 and refs cited therein. Iron-catalyzed coupling: Fu¨rstner, A.; Martin,
R. Angew. Chem., Int. Ed. 2004, 43, 3955 and references cited therein.
(4) Anctil, E. J. G.; Snieckus, V. J. Organomet. Chem. 2002, 653, 150.
Anctil, E. J. G.; Snieckus, V. In Metal-Catalyzed Cross-Coupling Reactions,
2nd ed.; Diederich, F., de Meijere, A., Eds.; Wiley-VCH: Weinheim,
Germany, 2004; p 761.
(5) Sengupta, S.; Leite, M.; Raslan, D. S.; Quesnelle, C.; Snieckus, V.
J. Org. Chem. 1992, 57, 4066. A useful element of the O-carbamate is its
proclivity for anionic ortho Fries rearrangement exposing a phenol that,
upon triflation and Ni-catalyzed hydride reduction, also achieves its removal
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chemistry. However, at -93 °C (internal temperature by
thermocouple measurement), the simply prepared13 prototype
O-sulfamate 3 underwent smooth ortho metalation to the
intermediate lithiated species, which, upon quench with a
variety of electrophiles, provided products 4 in modest to
excellent yields (Table 1).14 Thus, introduction of standard
Table 1. Metalation and Electrophile Quench of Phenyl
O-Sulfamate 3a
Figure 1.
DMG6 have shown the additional features of latency and
cross-coupling capability (2), hence enhancing the synthetic
utility especially in the context of synthesis of meta-
substituted aromatics. Herein we report preliminary results
that demonstrate that the O-sulfamate (3),7 derived by the
8b
8d
union of OCONR2 and SO2NR2 groups, is a new DMG
and cross-coupling partner in the Kumada-Corriu reaction
and that the 2-halo and boron derivatives 4h, 4i, and 4k
undergo Suzuki-Miyaura cross-coupling and provide a new
entry to the benzyne species. In sum, the reported work
provides new methods of general utility in synthetic aromatic
chemistry.
At the outset, the similarity of the O-sulfamate to OTs,9
OMs,10 and especially OTf11 groups raised concerns that it
would suffer, perhaps with similar propensity, ortho anion-
induced benzyne formation,12 an apprehension that was
verified at the -78 °C temperatures commonly used for DoM
a Typical procedure: (1) 1.1 equiv of s-BuLi/TMEDA/THF/-93 °C/45
min/0.2-0.5 M; (2) E+/-93 °C to room temperature.
(entries 1 and 3) and DMG (entry 2) carbon, sulfur (entry
4), silicon (entry 5), and nitrogen (entry 6) electrophiles
proceeds unexceptionally; furthermore, halogen (entries
7-9), tin (entry 10), and boron (entry 11) electrophiles may
be introduced, thus inviting a study of cross-coupling
chemistry. In the event, the 2-iodo O-sulfamate 4i and, in
one case, the corresponding bromo derivative 4h (entry 7),
when subjected to standard Suzuki-Miyaura cross-coupling
conditions with a selection of arylboronic acids 5, afforded
with retention of a new amide DMG for further DoM chemistry; see: Cai,
X.; Brown, S.; Hodson, P.; Snieckus, V. Can. J. Chem. 2004, 82, 195 and
refs cited therein. For the power and versatility of the O-carbamate DMG
in synthesis, see: Whisler, M. C.; MacNeil, S.; Snieckus, V.; Beak, P.
Angew. Chem., Int. Ed. 2004, 43, 2206.
(6) Milburn, R. R.; Snieckus, V. Angew. Chem., Int. Ed. 2004, 43, 892.
Milburn, R. R.; Snieckus, V. Angew. Chem., Int. Ed. 2004, 43, 888.
(7) Review: Benson, G. A.; Spillane, W. J. In The Chemistry of Sulphonic
Acids, Esters, and their DeriVatiVes; Patai, S., Rappoport, Z., Eds.; Wiley:
New York, 1991; p 987 ff. O-Sulfamates are of interest in medicinal
chemistry; see: Spillane, W. J.; McGrath, P.; Brack, C.; O’Byrne, A. B. J.
Org. Chem. 2001, 66, 6313 and refs cited therein. For use of O-sulfamates
in Ru-catalyzed C-H-activated processes, see: Wehn, P. M.; Lee, J.; Du
Bois, J. Org. Lett. 2003, 5, 4823 and refs cited therein. For thia-Fries
rearrangement of O-sulfamates, see: Benson, G. A.; Maughan, P. J.; Shelly,
D. P.; Spillane, W. J. Tetrahedron Lett. 2001, 42, 8729 and refs cited therein.
(8) (a) Metallinos, C.; Nerdinger, S.; Snieckus, V. Org. Lett. 1999, 1,
1183. (b) Sibi, M. P.; Snieckus, V. J. Org. Chem. 1983, 48, 1935. (c) Gray,
M.; Chapell, B. J.; Felding, J.; Taylor, N. J.; Snieckus, V. Synlett 1998,
422. (d) MacNeil, S. L.; Familoni, O. B.; Snieckus, V. J. Org. Chem. 2001,
66, 3662 and refs cited therein.
(9) DoM chemistry of this function has, to the best of our knowledge,
not been achieved. For cross-coupling chemistry, see: Tang, Z.-Y.; Hu,
Q.-S. J. Am. Chem. Soc. 2004, 126, 3058 (Suzuki-Miyaura). Roy, A. H.;
Hartwig, J. F. J. Am. Chem. Soc. 2003, 125, 8704 (Kumada-Corriu).
(10) For Suzuki-Miyaura cross-coupling, see: Percec, V.; Golding, G.
M.; Smidrkal, J.; Weichold, O. J. Org. Chem. 2004, 69, 3447.
(11) For Negishi coupling, see: Quesnelle, C. A.; Familoni, O. B.;
Snieckus, V. Synlett 1994, 349.
(12) Benzyne generation may be achieved by elimination from 1,2-
dihalides; see: Wittig, G.; Benz, E. Chem. Ber. 1959, 92, 1999. Franzen,
V.; Joschek, H. I.; Mertz, C. J. Liebigs Ann. Chem. 1962, 654, 82. Seyferth,
D.; Menzel, H. H. A. J. Org. Chem. 1965, 30, 649. Brewer, J. P. N.; Heaney,
H. Tetrahedron Lett. 1965, 4709. By DMG-induced deprotonation-halide
elimination, see: Pansegrau, P. D.; Rieker, W. F.; Meyers, A. I. J. Am.
Chem. Soc. 1988, 110, 7178. Clark, R. D.; Caroon, J. M. J. Org. Chem.
1982, 47, 2804. By fluoride-mediated elimination from ortho-TMS aryl
halides and triflates, see: Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem.
Lett. 1983, 1211. Tsukazaki, M.; Snieckus, V. Heterocycles 1992, 33, 533.
Hamura, T.; Hosoya, T.; Yamaguchi, H.; Kuriyama, Y.; Tanabe, M.;
Miyamoto, M.; Yasui, Y.; Matsumoto, T.; Suzuki, K. HelV. Chim. Acta
2002, 85, 3589.
(13) Gupta, S. K. Synthesis 1977, 39.
(14) In an attempt to trap the thermodynamically generated anion,
treatment of 3 under Martin conditions (1g: LiTMP/TMSCl ) 1:2.1:10)
(Krizan, T. D.; Martin, J. C. J. Am. Chem. Soc. 1983, 105, 6155) led to
SM (35%), 4e (41%), and 2,2,6,6-tetramethyl-1-(2-(trimethylsilyl)phenyl)-
piperidine (19%) by GC analysis.
2520
Org. Lett., Vol. 7, No. 13, 2005

Scheme 1
Table 2. Suzuki-Miyaura Cross-Coupling 2-Bromo-, 2-Iodo-,
and 2-Pinacolboronate O-Phenylsulfamate 4h, 4i, and 4ka
a Knochel protocol: (1) 1.1 equiv of i-PrMgCl/Et2O/-78 °C/30
min; (2) 10 equiv of furan/-78 °C to rt; (3) cat. HCl/MeOH/reflux/3
h.
bromide as a standard Grignard partner (Table 3). While
using nonliganded (entries 1 and 2) and phosphine mono-
(entry 3) and bidentate (entry 4) Ni catalysis already provided
reasonable yields of product 8, use of Cp-containing catalysts
(entries 5-9) showed considerable enhancement in yields,
with the air-stable, conveniently handled NiClCpIMes per-
forming as a superb catalyst at low loading in ether at room
temperature to afford 8 in quantitative yield.18
Table 3. Optimization of Conditions for the Ni-Catalyzed
Phenyl O-Sulfamate 3-p-Tolyl Grignard Cross-Coupling
Reaction
entry
catalyst/ligand
solvent
temp (°C)
yield (%)a
1
2
3
4
5
6
7
8
9
Ni(acac)2
NiCl2
PhMe
PhMe
PhMe
PhMe
Et2O
PhMe
THF
PhMe
Et2O
120
120
120
120
40
120
40
40
29
72
63
74
83
91
83
85
>99
a Typical procedure: 1 equiv of ArX/5 mol % Pd(PPh3)4/DME/2 M Na2-
CO3/80 °C/16 h. b Performed with 2 equiv of ArX/10 mol % Pd(PPh3)4/40
h.
NiCl2/P(t-Bu)3
NiCl2/dppf
NiClCpPPh3
NiClCpPPh3
NiClCplMes
NiClCplMes
NiClCplMes
products 6 in excellent yields (Table 2). One inverted partner
combination was tested (entry 8) to demonstrate that
comparable yields may be obtained from reactions of either
combination of cross-coupling partners.
40
a Determined by GC (undecane as internal standard).
Reaction block experiments defined conditions for benzyne
trapping of 4h using furan as the diene to give 7-oxaben-
zonorbornadiene, which was converted to 7a in 21% yield
(Scheme 1). Subjection of the ortho-bromo O-sulfamates 4l
and 4m to metal-halogen exchange at -10 °C in the
presence of furan followed by catalytic HCl treatment
afforded naphthols 7a (concurrent protodesilylation) and 7b
in 50 and 31% yields, respectively. Improvement of yields
was achieved by adapting the Knochel protocol for Grignard
generation15 on 4i, which, after furan trap and acid hydrolysis,
furnished 7a in 70% yield.16
Using this optimized set of conditions, cross-coupling
reactions of selected aryl O-sulfamate-aryl Grignard reagent
(15) Sapountzis, I.; Lin, W.; Fischer, M.; Knochel, P. Angew. Chem.,
Int. Ed. 2004, 43, 4364.
(16) Generalization of this result is being pursued.
(17) Pd(PPh3)4, (IPr)Pd(allyl)Cl (Navarro, O.; Kaur, H.; Mahjoor, P.;
Nolan, S. P. J. Org. Chem. 2004, 69, 3173), and Fe(acac)3 (Fu¨rstner, A.;
Leitner, A.; Menendez, M. M.; Krause, H. J. Am. Chem. Soc. 2002, 124,
13856) catalysis was ineffective and led to recovery of starting material.
(18) High activity of NiClCpIMes may be attributed to the presence of
a low-valent electron-rich metal center owing to a strongly Lewis basic,
electron σ-donating carbene ligand whose steric nature accelerates the
reductive elimination step, see: Bohm, V. P. W.; Gstottmayr, C. W. K.;
Weskamp, T.; Herrmann, W. A. Angew. Chem., Int. Ed. 2001, 40, 3387.
Huang, J.; Nolan, S. P. J. Am. Chem. Soc. 1999, 121, 9889.
Encouraged by the results of O-carbamate5 and related
phenol-derived cross-coupling partners,9-11 we screened a
number of nickel catalysts17 on 3 using p-tolylmagnesium
Org. Lett., Vol. 7, No. 13, 2005
2521

simple biaryls (entries 1, 3, and 5-8) and a tertaryl
(completing a metal-tuned coupling sequence, entry 2),
N-protected anilines (entries 3 and 4) and azabiaryls (entries
9-12) were unexceptionally obtained.19,20 To obtain pre-
liminary evidence for the hierarchal position of the O-
sulfamate vis-a´-vis other DMGs,2 inter- and intramolecular
competition experiments were carried out (Figure 2). Thus,
Table 4. Ni-Catalyzed Aryl Cross-Coupling of Aryl
O-Sulfamates with Aryl Grignard Reagentsa
Figure 2. Ratios of D-incorporation products from intra- and
intermolecular DoM competition experiments.
treatment of 4-CONEt2 phenyl O-sulfamate (4t) under the
standard conditions for 10 min followed by CD3OD quench
led to the formation of 10a and 10b in a 17:1 ratio based on
d1-NMR. Using the same experimental protocol, a 1:1
mixture of N,N-diethyl phenyl O-carbamate and 3 afforded
deuterated 11 and 12 in a 23:1 ratio. Thus, the O-sulfamate
is a relatively poor DMG compared to the tertiary amide
and the tertiary O-carbamate, which are near the top of the
qualitatively assessed ranking list.2
In conclusion, we have shown that the O-sulfamate is a
new, albeit moderate strength, DMG. ortho-Halo and boron
products 4h, 4i, and 4k participate in Suzuki-Miyaura cross-
coupling, and, perhaps more significantly, the O-sulfamates
themselves undergo Kumada-Corriu coupling, both reac-
tions leading to functionalized and potentially bioactive
biaryls (Tables 2 and 4). The new reactions extend DoM
concepts and protocols for application in synthetic endeavors.
Acknowledgment. We are grateful to NSERC Canada
for support under the DG program and thank Francoise
Sauriol and Mark Reed for expert NMR assistance and
starting material provision, respectively. We are most grateful
to Frontier Scientific for samples of boronic acids, which
allowed expansion of the scope of this methodology.
Supporting Information Available: Experimental pro-
cedures and characterization data of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL050393C
a Typical procedure: 1.2-2.5 equiv of Ar′MgBr/1-2.5 mol %
NiClCpIMes/Et2O/0-40 °C/0.1-19 h. b Deprotection/acylation: 10 equiv
of hydroxylamine HCl/2 equiv of NEt2/2:1 EtOH-H2O/90 °C/24 h, then
1.2 equiv of acetic anhydride/2 equiv of NEt3/CH2Cl2/rt/1 h.
(19) Attempts to de-O-sulfamoylate 4n in a manner analogous to that
used for arylsulfonamides6 led only to the formation of p-isopropylanisole
in low yield.
(20) To demonstrate a further DoM-cross-coupling link of potential
synthetic utility, the prototype phenyl O-sulfamate 3 was subjected to cross-
coupling with p-tolylboronic acid under Suzuki conditions to afford 8 albeit
in modest 64% yields (GC) using 20 mol % Ni(acac)2/dppp and 2 equiv of
p-TolylB(OH)2/K3PO4 in PhMe at 90 °C for 24 h.
combinations were carried out to afford biaryl products
9a-m in synthetically useful yields (Table 4). Aside from
2522
Org. Lett., Vol. 7, No. 13, 2005