Directed ortho metalation-based methodology. Halo-, nitroso-, and boro-induced ipso-desilylation. Link to an in situ Suzuki reaction

Article abstract of DOI:10.1021/ol0506563

(Chemical Equation Presented) Treatment of DoM-derived silylated aromatics 2-4 under standard electrophilic halogenation conditions cleanly affords ipso-desilyation products 5-7, while nitration of methoxy-substituted analogues 8, 9 leads to non-ipso isomers 10, 12 and 11, 13, controlled by a silicon steric effect. Sequential ipso-borodesilylation of 2a, 3a, and 20 followed by treatment with aryl halides under Pd-catalyzed conditions constitutes an in situ Suzuki-Miyaura cross-coupling protocol to biaryls and heterobiaryls 23.

Full text of DOI:10.1021/ol0506563

ORGANIC
LETTERS
2005
Vol. 7, No. 13
2523-2526
Directed ortho Metalation-Based
Methodology. Halo-, Nitroso-, and
Boro-Induced ipso-Desilylation. Link to
an in situ Suzuki Reaction†
Zhongdong Zhao and Victor Snieckus*
Department of Chemistry, Queen’s UniVersity, Kingston, ON, K7L 3N6, Canada
snieckus@chem.queensu.ca
Received March 28, 2005
ABSTRACT
Treatment of DoM-derived silylated aromatics 2
7, while nitration of methoxy-substituted analogues 8, 9 leads to non-ipso isomers 10, 12 and 11, 13, controlled by a silicon steric effect.
Sequential ipso-borodesilylation of 2a, 3a, and 20 followed by treatment with aryl halides under Pd-catalyzed conditions constitutes an in situ
Suzuki Miyaura cross-coupling protocol to biaryls and heterobiaryls 23.
−4 under standard electrophilic halogenation conditions cleanly affords ipso-desilyation products
5
−
−
In the 30 year evolution of modern organosilicon chemistry,1
during which its rich and broad impact on organic methodol-
ogy, total synthesis, and industrial applications has been
amply demonstrated, the total output of arylsilane chemistry
has constituted a minor component1a despite the compre-
hensive and careful physical organic studies of Eaborn2 and
others,3 which have potentially set a platform for a synthetic
playground. A salient feature is marked by kinetic studies
that show ipso-protodesilyation/proton-deuterium exchange
rates4 kdeSi/kH,D ) 104, which stimulated brief studies of other
electrophile-induced desilylation reactions.1a,5 Our long-
standing interest6 and that of others7 have stimulated an
exploratory study of electrophile-induced desilylation reac-
tions for arylsilanes derived by directed ortho metalation
(4) Eaborn, C.; Pande, K. C. J. Chem. Soc. 1960, 1566.
(5) (a) Dey, K.; Eaborn, C.; Walton, D. R. M. Organomet. Chem. Synth.
1970/1971, 1, 151. (b) Felix, G.; Dunogue`s, J.; Calas, R. Angew. Chem.,
Int. Ed. Engl. 1979, 18, 402. (c) Bennetau, B.; Dunogue`s, J. Synlett 1993,
171.
(6) (a) Reed, J. N. Ph.D. Thesis, University of Waterloo, Waterloo,
Canada, 1984. (b) Mills, R. J.; Horvath, R.; Sibi, M. P.; Snieckus, V.
Tetrahedron Lett. 1985, 26, 1145. (c) Bourguignon, M. L.; Snieckus, V.
Unpublished results, University of Waterloo, Waterloo, Canada, 1987. (d)
Mills, R. J.; Taylor, N. J.; Snieckus, V. J. Org. Chem. 1989, 54, 4372. (e)
Beaulieu, F.; Snieckus, V. J. Org. Chem. 1994, 59, 6508. (f) MacNeil, S.
L.; Familoni, O. B.; Snieckus, V. J. Org. Chem. 2001, 66, 3662. For an
intramolecular carbodesilylation, see: Sibi, M. P.; Shankaran, K.; Alo, B.
I.; Hahn, W. R.; Snieckus, V. Tetrahedron Lett. 1987, 28, 2933.
(7) (a) Krizan, T. D.; Martin, J. C. J. Am. Chem. Soc. 1983, 105, 6155.
(b) Taylor, S. L.; Lee, D. Y.; Martin, J. C. J. Org. Chem. 1983, 48, 4156.
(c)Yamamoto, Y.; Yanagi, A. Heterocycles 1982, 19, 168. (d) Effenberger,
F.; Krebs, A. J. Org. Chem. 1984, 49, 4687. (e) Hari, Y.; Shoji, Y.; Aoyama,
T. Synthesis 2004, 8, 1183.
† Dedicated to the memory of Colin Eaborn (1923-2004) in appreciation
of his insightful mechanistic work in organosilicon chemistry.
(1) (a) Colvin, E. Silicon in Organic Synthesis; Butterworth: New York,
1981; p 125. (b) Fleming, I.; Dunogue`s, J.; Smithers, R. Org. React. 1989,
37, 57. (c) Brook, M. Silicon in Organic, Organometallic, and Polymer
Chemistry, Wiley: New York, 2000, p 569. (d) Fleming, I. Science of
Synthesis; Thieme: Stuttgart, 2002; Vol. 4, p 685.
(2) Eaborn, C. J. Organomet. Chem. 1975, 100, 43.
(3) (a) Freiser, H.; Eagle, M. V.; Speier, J. J. Am. Chem. Soc. 1953, 75,
2821. (b) Bott, R. W.; Eaborn, C.; Greasley, P. M. J. Chem. Soc. 1964,
4804. (c) Berwin, H. J. Chem. Commun. 1972, 237. (d) Al-Omran, F.; Ridd,
J. H. J. Chem. Soc., Perkin Trans. 2 1983, 1185. (e) Herrlich, M.; Hampel,
N.; Mayr, H. Org. Lett. 2001, 3, 1629.
10.1021/ol0506563 CCC: $30.25
© 2005 American Chemical Society
Published on Web 05/20/2005

(DoM) protocols. Herein, we report preliminary studies on
electrophilic halo-, nitroso-, and boro-induced ipso-desily-
lations (Figure 1, 1, path a), the steric effect of silicon groups
Table 1. ipso-Halodesilylation Reactions of Compounds 2-4
yield
%
compd R
hal+/solvent/temp product hal R
2a
2a
H
H
ICl/CH2Cl2/rt
5a
5b
5c
5d
6a
6b
6c
7a
7b
7c
7d
7e
7f
I
Br
H
H
86
92 (82)b
Br2/CH2Cl2/0 °C-rt
Figure 1.
2b 4-NO2 Br2/CH2Cl2/mwc
Br 4-NO2 70
Cl
I
Br
Cl
I
2a
3a
3a
3a
4a
H
H
H
H
H
NCS/MeCN/reflux
ICl/CH2Cl2/rt
Br2/CH2Cl2/reflux
NCS/MeCN/mwd
ICl/CH2Cl2/rt
H
H
H
H
H
70
71
78
65
66
promoting non-ipso electrophilic substitution (particularly
with E+ ) NO2 ) in the presence of electron-donating groups
(EDGs) (1, path b), and the conjunction of the borodesily-
lation procedure (1, path a, E+ ) BX2 ) with the Suzuki
cross-coupling regimen. Considered in sum, these results
provide new extensions and opportunities in DoM-mediated,
regioselective construction of aromatics and certain comple-
mentarity with the direct usage of arylboronic acids for the
synthesis of biaryls and heterobiaryls.10
+
+ 8,9
4b 4-Me ICl/CH2Cl2/rt
4a Br2/CH2Cl2/reflux
4b 4-Me Br2/CH2Cl2/reflux
4c
4a
I
4-Me 76
77
H
Br H
Br 4-Me 76e
Br 5-Me 53
5-Me Br2/CH2Cl2/reflux
H
NCS/MeCN/mwd
Cl
H
NR
a Hal+ ) 1.5-5 equiv, t ) 3-15 h. b NBS/MeCN/reflux. c Microwave:
150 W/25′ min. d On SiO2/250 W/10′ min. e See ref 6f.
Results of halo-induced ipso-desilylation studies using I+-,
Br+-, and Cl+-generating11 reagents for three prototypical,
powerful, and commonly used directed metalation group
(DMG)-bearing aromatics 2-4 are summarized in Table 1.
All substrates show highly regioselective ipso reactivity to
give products 5-7. In sharp contrast, all of the corresponding
nonsilylated derivatives show no reaction, leading to recovery
of starting material. As expected, the para-directing effect
of the moderate O-carbamate EDG is evident at least in
iodination and bromination reactions but at higher temper-
atures.12
group. Synthetically useful trends in nitration selectivity were
observed in the series 8b,c, 9b,c to 10b,c, 12b,c conversions
Table 2. Nitration of Benzamides 8 and O-Aryl Carbamates 9
+
To obtain initial appreciation of ipso-desilylative NO2
reactivity, a series of unsubstituted (8a, 9a), TMS-substituted
(8b, 9b) and TIPS-substituted (8c, 9c) benzamides and
O-carbamates containing the powerful OMe EDG were tested
under standard electrophilic nitration conditions.12,13 As
gleaned from Table 2, instead of ipso-desilylation, electro-
philic nitration occurred, assumably dictated by the OMe
DMG
R
C3:C5
yield (%)
CONEt2
H
8a
8b
8c
9a
9b
9c
1:1
4:1
19:1
2:1
14:1
15:1
10a:11a
10b:11b
10c:11c
12a:13a
12b:13b
12c:13c
76a
95a
83b
76
82
78
TMS
TIPS
H
TMS
TIPS
OCONEt2
(8) (a) Haubold, W.; Herdtle, J.; Gollinger, W.; Einholz, W. J. Orga-
nomet. Chem. 1986, 315, 1. (b) Sharp, M. J.; Cheng, W.; Snieckus, V.
Tetrahedron Lett. 1987, 28, 5093. (c) Kaufmann, D. Chem. Ber. 1987, 120,
853, 901. (d) Gross, U.; Kaufmann, D. Chem. Ber. 1987, 120, 991. (e)
Farinola, G. M.; Fiandanese, V.; Mazzone, L.; Naso, F. Chem. Commun.
1995, 2523. (f) Fu, J.-m.; Snieckus, V. Can. J. Chem. 2000, 78, 227. (g)
Hupe, E.; Calaza, M. I.; Knochel, P. Chem. Commun. 2002, 1390.
(9) Recently, a Merck group has reported an in situ metalation-
electrophile quench method that adds convenience to the synthesis of
silylated and boronated indole derivatives; see: Vazquez, E.; Davies, I.
W.; Payack, J. F. J. Org. Chem. 2002, 67, 7551.
(10) For recent reports of electrophile-induced ipso-deboronation studies,
see: (a) Salzbrunn, S.; Simon, J.; Prakash, G. K. S.; Petasis, N. A.; Olah,
G. A. Synlett 2000, 10, 1485. (b) Prakash, G. K. S.; Panja, C.; Mathew, V.
S.; Petasis, N. A.; Olah, G. A. Org. Lett. 2004, 6, 2205.
(11) Chlorination using chlorine was not convenient due to an inability
to control amounts of chlorine added, resulting in the formation of some
dichlorination (15%) and side products.
a See ref 6c. b See ref 6d.
although only a minor steric effect was noted in the change
from TMS 9b to TIPS 9c in the O-carbamate series.
However, a change of conditions to ammonium nitrate10a on
the ortho-silylated O-carbamate 2a led to the formation of
the corresponding 4-, 2-, and ipso-nitro-substituted products,
17, 18, and 19, respectively, in a ratio of 7.5:1.5:1 in
quantitative yield (Scheme 1). The observed selectivity may
be due to the milder nitration conditions. Furthermore, when
nitrosating conditions14 were adapted to the ortho-silylated
O-carbamates 2a, the ipso nitroso product 15 was obtained
in modest yields in addition to recovered starting material.
(12) For details, see General Procedure in Supporting Information.
(13) (a) Eaborn, C.; Salih, Z. S.; Walton, D. R. M. J. Chem. Soc., Perkin
Trans. 2 1972, 172. (b) Dwyer, C. L.; Holzapfel, W. Tetrahedron, 1998,
54, 7843.
2524
Org. Lett., Vol. 7, No. 13, 2005

Scheme 1
Table 3. Ortho-DMG-Substituted Arylboronopinacolates 21 by
ipso-Borodesilylation
These results illustrate advantages for the synthesis of
oxidized (19) and reduced (16) products as well as 1,2,3-
contiguously substituted aromatics (14 from 12b), which are
difficult to prepare by classical electrophilic chemistry.15
While attempts to date in electrophilic fluorination, cya-
nation, amination, and Friedel-Crafts acylation16 have been
relatively unproductive, ipso-borodesilyation has led to useful
results (Table 3). Thus, treatment of ortho-silylated DMG
aromatics 2a, 3a, and 20, usually cleanly obtained by DoM
chemistry, with either BCl3 or BBr3 at ambient temperatures
followed by derivatization with pinacol17,18 afforded good
to excellent yields of the ortho-boronopinacolates 21.12 In
the carboxamide series, tertiary (entry 1) and secondary
amides, including the TFA-labile cumyl amide19 (entry 2),
are successful reactants. 2-Silylated O-carbamates (entry 3),20
a secondary sulfonamide (entry 5), and an indole (entry 6)9
also furnish pure, usually crystalline, boronated derivatives.
Interestingly, the bis-TMS substrate (entry 4) provides the
monoborodesilylated product, a result with implications for
further ipso-desilylative chemistry.
Although the boronopinacolates described in Table 3 are
useful Suzuki cross-coupling partners, the development of
an in situ ipso-borodesilyation-coupling procedure was
undertaken for the potential convenient utility in medicinal
chemistry and library generation programs. Thus, under mild
conditions using either BCl3 or BBr3 interchangeably without
significant change in yield, substrates 2a, 3a, and 20 were
converted over a 2 h period into their intermediate dihalo-
boranes 22,8c which, when treated with aryl bromides or
iodides under typical Suzuki-Miyaura coupling conditions,
afforded the biaryl or heterobiaryl products 23 (Table 4).21
a Yields of isolated products. b Contains pinacol; calculated by NMR.
c Yields of corresponding arylboronic acids via DoM, which was used
directly in the subsequent cross-coupling reactions. d Fu, J.-m.; Sharp, M.
J.; Snieckus, V. Tetrahedron Lett. 1988, 29, 5459. e Yields of corresponding
boroxazine derivatives. f Sharp, M. J. M.S. Thesis, University of Waterloo,
Waterloo, Canada, 1986. g See ref 8b. h Performed with 3 equiv of BBr3
and microwave conditions (50 W/80 °C/30 min). i Addition of pinacol and
NEt3 at room temperature for 1.5 h instead of evaporation in a vacuum.
Thus, borono tertiary (entries 1 and 2) and secondary
benzamides (entries 3 and 4) afforded clean coupling results
with bromobenzene as a partner. Phenyl O-carbamates
underwent coupling with a range of aryl bromides (entries
5 and 6) and 2-bromonaphthalene (entry 7), as well as
3-bromopyridine (entry 8), to afford synthetically useful
yields of biaryl products. A secondary sulfonamide (entry
9) and the 2-TMS, N-carbamoyl indole (entries 10 and 11),
a useful substance for C-7 DoM chemistry,22 give coupled
products in good yields.
This ipso-borodesilylative methodology offers the follow-
ing features: (a) the starting arylsilanes are stable, readily
(21) Typical One-Pot ipso-Borodesilylation-Cross-Coupling Proce-
dure. A solution of BBr3 (1.0 M, 0.48 mL) in CH2Cl2 was added dropwise
by syringe to a stirred solution of arylsilane (0.4 mmol) in anhydrous CH2-
Cl2 (4 mL) at 0 °C under an argon atmosphere. The reaction mixture was
stirred at room temperature for 2 h after which time TLC monitoring
indicated completion of the reaction. After evaporation to dryness, bro-
mobenzene (0.33 mmol) and Ph(PPh3)4 (3 mol %) were added, and the
whole was degassed for 15 min. Degassed glyme (4 mL) and 2 M Na2CO3
solution (1 mL) were added by syringe. The mixture was then heated to
reflux for 5 h, cooled to room temperature, and poured into water (10 mL),
and the whole was extracted with Et2O (3 × 10 mL). The organic layer
was washed with saturated NaCl, dried (Na2SO4), and subjected to filtration,
and the filtrate was evaporated to dryness. The residue was purified by
flash column chromatography (EtOAc/hexanes, 1:5) to afford the biaryl
compound.
(14) (a) Birkofer, L.; Franz, M. Chem. Ber. 1971, 104, 3062. (b) Uemura,
S.; Toshimitsu, A.; Okano, M. J. Chem. Soc., Perkin Trans. 1 1978, 1076.
(15) For example, nitration of 2-methoxyphenol affords a 1:1 mixture
of the 4- and 6-nitro derivatives; see ref 12b.
(16) Various Lewis acid (AlCl3)-catalyzed acylation attempts led to
protodesilylation products together with recovery of starting material.
(17) Wong, K.; Chien, Y.; Liao, Y. L.; Lin, C.; Chou, M.; Leung, M. J.
Org. Chem. 2002, 67, 1041.
(18) For the preparation of stable diethanolamine adducts of boronic
acids, see ref 8b.
(19) Metallinos, C.; Nerdinger, S.; Snieckus, V. Org. Lett. 1999, 1, 1183.
(20) For a phenanthrene O-carbamate case, see ref 8e.
(22) Hartung, C. G.; Fecher, A.; Chapell, B.; Snieckus, V. Org. Lett.
2003, 5, 1899.
Org. Lett., Vol. 7, No. 13, 2005
2525

Martin conditions7a,b) not requiring -78 °C9 and hence
amenable to scale-up; (b) since ipso-borodesilyations proceed
quantitatively, as evidenced by high yields of isolated
boronopinacolates, the uncertainty associated with the boron
intermediates (boronic acid, half-ester acid, borinic acid,
boroxane) obtained by direct treatment with B(OR)3 elec-
trophiles,23 as also reflected in product yields, is eliminated;
(c) in contrast to the coupling reactions of the boronic acid
derivatives, those of the solutions of the intermediate
dihaloboranes proceed under homogeneous conditions and
involve simple evaporative rather than acidic or aqueous
workup to give comparable yields of products (Table 4); and
(d) although requiring an extra step for the preparation of
the silanes, the ipso-borodesilyation reaction constitutes a
general and efficient route to stable arylboronates (Table 3).
In summary, preliminary results of electrophile-induced
ipso-desilylation chemistry have shown that (a) facile halo-
and nitroso-induced ipso reactions proceed on simple DMG-
bearing substrates (2-4 and 2a, respectively), (b) nitration
conditions lead to non-ipso but substitution products 10b and
12b, which can be converted to synthetically useful 1,2,3-
substituted aromatics, e.g., 14, and (c) ipso-borodesilylation
provides24 a method for the convenient synthesis of pure
boronopinacolates 21 (Table 3) and also serves as part of a
DoM-initiated method for an in situ Suzuki cross-coupling
synthetic protocol for biaryls and heterobiaryls (Table 4).
Mechanistic and further preparative studies are in progress.
Table 4. In Situ ipso-Borodesilylation and Suzuki
Cross-Coupling of Ortho-DMG-Substituted Arylsilanes
Acknowledgment. NSERC Canada is warmly acknowl-
edged for consistent support of our synthetic programs.
Z.Z.D. is grateful for an R.S. McLaughlin Fellowship. We
thank Justin Morin for providing some starting materials.
Supporting Information Available: Experimental pro-
cedures and characterization of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL0506563
a Yields of isolated products using ArBr coupling partners. b Yields of
isolated products using ArI coupling partners. c Yields obtained by direct
coupling with boronic acids. d Fu, J.-m. Ph.D Thesis, University of Waterloo,
Waterloo, Canada, 1990. e Performed with 1.5 mol % Pd(PPh3)4. f See ref
8b. g See Table 3, footnote f. h BBr3 was added at -25 °C, and the reaction
mixture was stirred at this temperature for 1 h.
(23) For other stable pyridyl boronates that participate in cross-coupling,
see: Hodgson, P. B.; Salingue, F. H. Tetrahedron Lett. 2004, 45, 685. For
a review on heterocyclic boronic acids, see: Tyrrell, E.; Brookes, P.
Synthesis 2003, 4, 469.
(24) Fluoride-mediated carbodesilylation is another synthetically useful
E+-induced FG transfer reaction of arylsilanes; see refs 6b and 7d and:
Effenberger, F.; Spiegler, W. Chem. Ber. 1985, 118, 3900. For ipso-
cyanodesilylation, see: (a) Bennetau, B.; Dunogue`s, J.; Babin, P. Tetra-
hedron 1993, 49, 10843. (b) Calle, M.; Cuadrado, P.; Gonzalez-Nogal, A.
M.; Valero, R. Synthesis 2001, 1949.
purified (chromatography, crystallization), and obtained by
clean, high-yielding DoM reactions under conditions (e.g.,
2526
Org. Lett., Vol. 7, No. 13, 2005