Directed ortho metalation reaction of aryl O-carbamates on solid support

Article abstract of DOI:10.1021/ol0476220

(Chemical Equation Presented) The first Directed ortho Metalation (DoM) reaction of aryl O-carbamates on polystyrene-divinylbenzene (PS-DVB) resin using a trityl linker is described. Using low temperatures and short metalation times, a range of electrophi

Full text of DOI:10.1021/ol0476220

ORGANIC
LETTERS
2005
Vol. 7, No. 4
629-631
Directed ortho Metalation Reaction of
Aryl O-Carbamates on Solid Support
Claire Milburn, Robert R. Milburn, and Victor Snieckus*
Department of Chemistry, Queen’s UniVersity, Kingston, ON, Canada K7L 3N6.
snieckus@chem.queensu.ca
Received November 18, 2004
ABSTRACT
The first Directed ortho Metalation (DoM) reaction of aryl O-carbamates on polystyrene-divinylbenzene (PS-DVB) resin using a trityl linker is
described. Using low temperatures and short metalation times, a range of electrophiles have been introduced to give, after cleavage from
support, substituted benzyl alcohols in high purity.
Within the rapidly evolving field of synthetic reactions on
solid support,1 anionic chemistry has been limited to enolate
and ylid chemistry using LDA,2 metal halogen exchange
reactions,3 and singular reports of directed ortho metalation
(DoM) reactions using OMOM (PS-DVB resin with a silicon
linker4) and CONR2 (PS-DVB5 and JandaJel,6 both with
aminomethyl linkers) directed metalation groups (DMGs).
As part of efforts to parlay solution-phase DoM7 and cross-
coupling8 strategies for solid-support adaptation (Scheme 1)
regimens,11 we report on the first DoM reaction of aryl
O-carbamates trityl-linked to PS-DVB resin.
In contrast to the previous requirement for higher tem-
peratures (0 °C)4-6 to effect metalation reactions, conditions
that are incompatible for many DMGs (e.g., O-carbamates,
tertiary amides) established for solution-phase chemistry, the
developed low temperature (-78 °C) protocol for metalation-
electrophile quench offers promising potential for generaliza-
tion of DoM reactions on solid support.
Although in previous work9,10 the solid-support Suzuki-
Miyaura cross-coupling on Merrifield resin was linked to
Scheme 1. DoM/Cross-Coupling Connection on Solid Support
(2) Sheng, S.-R.; Zhou, W.; Liu, X.-L.; Song, C.-S. Synth. Commun.
2004, 34, 1011. Griffith, D. L.; O’Donnell, M. J.; Pottorf, R. S.; Scott, W.
L.; Porco, J. A., Jr. Tetrahedron Lett. 1997, 38, 8821.
(3) Mg: Franzen, R. G. Tetrahedron 2000, 56, 685. Zn: Kondo, Y.;
Komine, T.; Fukinami, M.; Uchiyama, M.; Sakamoto, T. J. Comb. Chem.
1999, 1, 123. Li: Farrall, M. J.; Fre´chet, J. M. J. J. Org. Chem. 1976, 41,
3877.
(4) Boehm, T. L.; Showalter, H. D. H. J. Org. Chem. 1996, 61, 6498.
(5) Garibay, P.; Toy, P. H.; Hoeg-Jensen, T.; Janda, K. D. Synlett 1999,
1438. Tois, J.; Loskinen, A. Tetrahedron Lett. 2003, 44, 2093.
(6) Garibay, P.; Vedsø, P.; Begtrup, M.; Hoeg-Jensen, T. J. Comb. Chem.
2001, 3, 332.
(7) Whistler, M. C.; MacNeil, S.; Snieckus, V.; Beak, P. Angew. Chem.,
Int. Ed. 2004, 43, 2206. Hartung, C. G.; Snieckus, V. In Modern Arene
Chemistry; Astruc, D., Ed.; Wiley-VCH: Weinheim, 2002; pp 330-367.
(8) Anctil, E. J.-G.; Snieckus, V. J. Organomet. Chem. 2002, 653, 150.
(9) Chamoin, S.; Houldsworth, S.; Kruse, C. G.; Bakker, W. I.; Snieckus,
V. Tetrahedron Lett. 1998, 39, 4179. Wade, J. V.; Krueger, C. A. J. Comb.
Chem. 2003, 5, 267. Tois, J.; Franzen, R.; Kskinen, A. Tetrahedron 2003,
58, 5395.
and to establish connections with recent solid-support work
on Suzuki-Miyaura,9 Stille,10 and related cross-coupling
(10) Chamoin, S.; Houldsworth, S.; Snieckus, V. Tetrahedron Lett. 1998,
39, 4175.
(11) Booth, S.; Hermkens, P. H. H.; Ottenheijm, H. C. J.; Rees, D. C.
Tetrahedron 1998, 54, 15385. Braese, S.; Kobberling, J.; Griebenow, N.
In Handbook of Organopalladium Chemistry for Organic Synthesis; Negishi,
E-i., Ed.; Wiley: New York, 2002; p 3031.
(1) Krchnak, V.; Holladay, M. W. Chem. ReV. 2002, 102, 61. Seneci, P.
Solid-Phase Synthesis and Combinatorial Technologies; Wiley-Inter-
science: New York, 2000.
10.1021/ol0476220 CCC: $30.25
© 2005 American Chemical Society
Published on Web 01/15/2005

solid-phase DoM via use of o-DMG aryl boronic acids,
extensive attempts to carry out DoM on this resin were
unsuccessful. The demonstration that PS-DVB resin4,6 and
the trityl linker12 are stable to n-BuLi encouraged the use of
the versatile, commercially available trityl chloride resin,
which may be used for the loading of alcohols, phenols,
carboxylic acids and amines.13
Table 1. Solution-Phase DoM on a Trityl Aryl O-Carbamate
To initiate the study, the reaction conditions for substrate
loading onto polymer support, DoM, and substrate cleavage
from the support were established using a trityl group to
model the solid support (Scheme 2).14 Typical conditions
E+
E
yield (%)a
MeI
Me
2a
2b
2c
2d
2e
2f
90
80
83
91
86
74
ClCONEt2
C2Cl6
BrCH2CH2Br
I2
CONEt2
Cl
Br
I
Scheme 2. Optimized Trityl Loading and Cleavage Conditions
TMSCl
TMS
a Isolated yield of purified products.
conditions determined for the solid-phase model (Table 1),
using either I2 or MeI quenches, resulted in product:starting
material ratios indicating only 50% deprotonation (Table 2,
Table 2. Optimization of Solid-Support DoM Conditions for
the Trityl-Linked Aryl O-Carbamate
for loading trityl resins (pyr or DMAP/THF)12,15 were not
effective for our system. However, after some experimenta-
tion, DBU/CH2Cl2/rt/48 h was found to give the highest
yields and reproducible trityl ether formation. Cleavage of
the substrate from the trityl linker was also not uncompli-
cated. Application of organic acids (e.g., TFA) resulted in
significant and instantaneous oxidation of the benzyl alcohol
product to the benzaldehyde, which could be reduced but
never fully suppressed by the addition of (iPrO)3SiH to the
reaction mixture.16 Application of mineral acids, on the other
hand, eliminated undesired oxidation completely, and optimal
conditions were established as 4.8 M HCl/THF/rt/24 h.
Solution-phase DoM reactions of the model system were
uneventful. The use of standard s-BuLi/TMEDA metalation
conditions for carbamates,17 followed by quench with various
electrophiles and acid-catalyzed cleavage of the trityl group,
led to the expected products in very good yields with no
evidence of benzylic metalation18 byproducts (Table 1).
Commercial trityl chloride resin (styrene-1% DVB) was
subjected to the previously optimized etherification condi-
tions (DBU/CH2Cl2/rt/48 h). Initial application of the DoM
purity (%)a
s-BuLi time mL THF/
entry (equiv) (h)
g resin TMEDA E+
E
4
2
1
2
3
4
5
6
7
8
1.2
2.4
5
7
5
5
5
5
0.5
1
1
1
1
1
1
1
10
10
10
10
20
20
20
30
yes
yes
yes
yes
yes
no
I2
I2
I2
I2
I2
I2
I
56
53
35
55
32
19
44
47
65
45b
68
81
89
99
I
I
I
I
I
no
no
MeI Me 11
MeI Me 1
a Purity determined via GC analysis using an external standard
(undecane). b 4-(Hydroxymethyl)phenol observed.
entry 1).19 Increasing the amount of s-BuLi improved the
ratio, but beyond 5 equiv the additional s-BuLi was found
to be detrimental and attack on the carbamate became a
significant side reaction (entries 2-4). Since the detrimental
influence of excess reagent is counterintuitive, we surmised
that this effect was the result of poor swelling of the resin
in the increasing amounts of hexanes of the s-BuLi solutions.
This conjecture was borne out by dilution experiments that
showed that increasing the amount of THF in the reaction
(optimized at THF/hexane ratio of 10:1, entry 8) gave
(12) Li, Z.; Ganesan, A. Synlett 1998, 405.
(13) Novabiochem, Merck Ltd., San Diego, California.
(14) For metal halogen exchange with tritylated benzyl alcohol: Song,
Z. J.; Zhao, M.; Frey, L.; Li, J.; Tan, L.; Chen, C. Y.; Tschaen, D. M.;
Tillyer, R.; Grabowski, E. J. J.; Volante, R.; Reider, R. J.; Kato, Y.; Okada,
S.; Nemoto, T.; Sato, H.; Skao, A.; Mase, T. Org. Lett. 2001, 3, 3357.
R-Metalation of dihydrofuran containing trityl-protected alcohol: Paquette,
L. A.; Behrens, C. Heterocycles 1997, 46, 31.
(15) Chen, C.; Randall, L. A. A.; Miller, R. B.; Jones, A. D.; Kurth, M.
J. J. Am. Chem. Soc. 1998, 116, 2661.
(16) Milburn, C. The Dircted ortho Metalation Reaction of Aryl
O-Carbamates on Solid Support; Queen’s University: Kingston, ON,
Canada, 2001.
(19) Purity determined by GC analysis using a HP 6840 GC equipped
with a fused silica stationary phase (0.5 µm fused) capillary column (0.53
mm i.d.).
(17) Snieckus, V. Chem. ReV. 1990, 90, 879.
(18) Azzena, U.; Pilo, L.; Sechi, A. Tetrahedron 1998, 54, 12389.
630
Org. Lett., Vol. 7, No. 4, 2005

complete and clean DoM reactions. TMEDA, a standard
additive to solution-phase DoM of O-aryl carbamates, was
found to be detrimental, and its exclusion from the solid-
support reactions resulted in significantly improved results
(compare entries 5 and 6).
Application of the optimized conditions20 to other elec-
trophiles demonstrated the generality of the solid-support
DoM reaction, yielding products in moderate to high purity19
and good yield (Table 3).21 As evident, the bulkier electro-
appear to require higher temperature for metalation. Incor-
poration of halogen electrophiles (Table 3, entries 3-5)
provides potential DoM-transition metal catalyzed coup-
ling links26 to Suzuki-Miyaura,22 Stille23 Heck,24 and
Sonogashira25 reactions,26 thereby augmenting the potential
for parallel synthesis and library generation. Further efforts
in these directions are in progress.
Acknowledgment. The NSERC/CSC Combinatorial
Chemistry Grant Program is gratefully achnowledged for
support of this work. C.M. and R.R.M. thank Queen’s
University and Shire Pharmaceuticals for a Graduate Award
(1998-2000) and Fellowship, respectively.
Table 3. Generalization of the Solid-Support DoM Reaction
for the Trityl-Linked Aryl O-Carbamate
Supporting Information Available: Experimental details
and data. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL0476220
(20) Procedure. To the loaded resin, swelled with THF (30 mL/g of
resin) and cooled to -78 °C was added s-BuLi (5 equiv) dropwise, and the
mixture was stirred gently for 1 h. The electrophile was added dropwise
(20 equiv), and the reaction mixture was stirred for 10 min at -78 °C and
allowed to warm to room temperature over 6 h. The reaction mixture was
subjected to filtration, and the polymer was successively washed with THF
10 mL × 5/g resin), H2O (10 mL × 5/g resin), THF (10 mL × 5/g resin),
H2O (10 mL × 5/g resin), and acetonitrile (10 mL × 5/g resin). The polymer
was then swelled with THF (10 mL/g of resin), 4.8 M HCl (10 equiv) was
added, and the reaction mixture was stirred gently at room temperature for
24 h. The reaction mixture was subjected to filtration, and the polymer
was washed with THF (3×). The filtrate was partitioned between Et2O/
H2O and treated with aqueous Na2CO3 until neutral. The aqueous phase
was extracted with Et2O (2×), the organic layer was successively washed
with aqueous NaHCO3 (1×), H2O (1×) and brine and dried (Na2SO4), and
the solvent was removed in vacuo to give the product.
(21) Yields determined by GC analysis (HP 6840 GC with fused silica
stationary phase (0.5 µm) capillary column (0.53 mm i.d.)) using an external
standard (undecane).
(22) Chemler, S. R.; Trauner, D.; Danishefsky, S. J. Angew. Chem., Int.
Ed. 2001, 40, 106. Suzuki, A. J. Organomet. Chem. 1999, 576, 147.
(23) Farina, V.; Krishnamurthy, V.; Scott, W. J. The Stille Reaction; John
Wiley & Sons: New York, 1998.
entry
E+
E
purity (%) yield (%)a
1
2
3
4
5
6
MeI
Me
2a
99
79
79
70
69
45
77
75
45
68
46
29
ClCONEt2
C2Cl6
BrCH2CH2Br Br
CONEt2 2b
Cl
2c
2d
2e
2f
I2
I
TMSCl
TMS
a Yields determined via GC analysis using an external standard
(undecane).
philes gave lower product yields and purities compared to
those of smaller electrophiles. Product stability may also
contribute to the low yield and purity observed, e.g., the TMS
quench product (entry 6) may undergo protodesilylation
under the conditions used for substrate cleavage from the
resin.
(24) Link, J. T. Org. React. 2002, 60, 157.
In summary, we have devised a trityl-linked PS-DVB resin
suitable for solid-support DoM chemistry of aryl O-carbam-
ates at -78 °C. Since low-temperature conditions are oblig-
atory for many DMGs,17 the aryl O-carbamate, qualitatively
the most powerful DMG,17 may serve as a prototype for DoM
reactions, overcoming previous solid-support systems4-6 that
(25) Brandsma, L.; Vasilevsky, S. F.; Verkruijsse, H. D. Application of
Transition Metal Catalysts in Organic Synthesis; Springer: Berlin, 1998;
pp 179-225. Sonogashira, K. In Metal-Catalyzed Cross-Coupling Reactions;
Diederich, F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, Germany, 1998;
pp 203-229.
(26) Anctil, E.; Snieckus, V. In Metal-Catalyzed Cross-Coupling Reac-
tions, 2nd ed.; Diederich, F., de Meijere, A., Eds.; Wiley-VCH: New York,
2004, in press.
Org. Lett., Vol. 7, No. 4, 2005
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