SNAr-based, facile synthesis of a library of benzothiaoxazepine-1,1′-dioxides

Article abstract of DOI:10.1021/cc1001023

The construction of a library of benzothiaoxazepine-1,1′-dioxides utilizing a one-pot, S_NAr diversification-ODCT₅₀ scavenging protocol is reported. This protocol combines microwave irradiation to facilitate the reaction, in conjunction with a soluble ROMP-derived scavenger (ODCT) to afford the desired products in good overall purity. Utilizing this protocol, a 78-member library was successfully synthesized and submitted for biological evaluation.

Full text of DOI:10.1021/cc1001023

850
J. Comb. Chem. 2010, 12, 850–854
SNAr-Based, Facile Synthesis of a Library of
Benzothiaoxazepine-1,1′-dioxides
Alan Rolfe, Thiwanka B. Samarakoon, Sarra V. Klimberg, Marek Brzozowski,
Benjamin Neuenswander, Gerald H. Lushington, and Paul R. Hanson*
Department of Chemistry, UniVersity of Kansas, 1251 Wescoe Hall DriVe,
Lawrence, Kansas 66045-7582, and The UniVersity of Kansas Center for Chemical Methodologies and
Library DeVelopment (KU-CMLD), 2034 Becker DriVe, Del Shankel Structural Biology Center,
Lawrence, Kansas 66047
ReceiVed June 15, 2010
The construction of a library of benzothiaoxazepine-1,1′-dioxides utilizing a one-pot, SNAr diversification-
ODCT50 scavenging protocol is reported. This protocol combines microwave irradiation to facilitate the
reaction, in conjunction with a soluble ROMP-derived scavenger (ODCT) to afford the desired products in
good overall purity. Utilizing this protocol, a 78-member library was successfully synthesized and submitted
for biological evaluation.
1. Introduction
activity across a variety of biological targets. Such reports
include, inhibition of a variety of enzymes, including HIV
integrase,4 COX-2 (Ampiroxicam),5,6 HCV NS5b RNA-
dependent RNA-polymerase,7 cysteine proteases involved in
the progression of malaria,8 and lipoxygenases.9 In particular,
benzoxazepine-1,1-dioxides have exhibited a wide array of
biological activity, including: (1) histone deacetylase inhibi-
tion (for treatment of cognitive disorders, such as Alzheimers
desease),10 (2) glucokinase activation,11 (3) serotonin 5-HT2C
activation,12 (4) modulation of the histamine H3 receptor,13
(5) inhibition of MDM2-p53,14 (6) inhibition of sodium-
proton exchange, (7) bradykinin B1 receptor antagonism (for
treating Alzheimer’s disease),15 (8) AMPA receptor ago-
nism,16 and (9) inhibition of metalloproteinase.17
Advances in high-throughput screening and the need for
new pharmaceutical leads have led to the emergence of
methods and technologies to access diverse collections of
small molecules. This has led to advances of synthetic
platforms, such as flow-through, microreactors, microwave,
and immobilized reagents/scavengers, and advances in
methodology including new efficient synthetic protocols,
multicomponent reactions, parallel synthesis, and green
chemistry. To this effect, a variety of high-load, soluble
immobilized reagents derived from ring-opening metathesis
polymerization (ROMP) has emerged. These oligomeric
reagents and scavengers have been efficiently utilized in
facilitated protocols for the generation of S- and P-hetero-
cycles.1
2. Results and Discussion
Alongside platform innovation, the advancement of mul-
ticomponent cascade protocols to rapidly access core scaf-
folds in multigram quantities is of high importance. Cascade
or domino reactions are highly efficient pathways that allow
for the synthesis of complex molecules from simple sub-
strates and encompass a variety of transformations.2 With
such scaffolds in hand, the utilization of facilitated purifica-
tion-free protocols utilizing immobilized reagents and scav-
engers, has become a useful method to rapidly access small
molecule libraries. In this regard, we herein report the
synthesis of a library of benzothiaoxazepine-1,1′-dioxides
via a one-pot, SNAr diversification protocol utilizing a
ODCT50 scavenger.
We recently reported the development and application of
a one-pot cascade protocol for the synthesis of benzothiaox-
azepine-1,1′-dioxides and oxathiazepine-1,1′-dioxides.18 With
this method in hand, we envisioned its utilization in the
synthesis of a library of benzothiaoxazepine-1,1′-dioxides
where-by diversification could be incorporated via SNAr
reaction at the aromatic fluoride position with a variety of
nucleophiles (Scheme 1).
To this effect, a variety of benzothiaoxazepine-1,1′-dioxide
scaffolds 1-9 were synthesized possessing fluorine substitu-
tion at the 6-position with varying functionality at the R1
and R2 positions (Scheme 2, Table 1).
With these scaffolds in hand, diversification of the aryl
fluoride position utilizing an SNAr reaction with 4-isopropyl
phenol {6} was performed on scaffold 1 (Scheme 3, Table
2). Initially, reactions were conducted using conventional
thermal heating, followed by screening of a variety of bases,
solvent and phenol equivalents to yield the desired product
in high conversion (Table 2, entry 1-10). It was found that
utilizing 3 equivalents of phenol {6} in the presence of
Sultams (cyclic sulfonamide analogues) have emerged in
recent years as important targets in drug discovery because
of their extensive chemical and biological profiles.3 Though
not found in nature, a number of benzofused sultams have
recently appeared in the literature, which display potent
* To whom correspondence should be addressed. E-mail: phanson@
ku.edu.
10.1021/cc1001023  2010 American Chemical Society
Published on Web 09/29/2010

Library of Benzothiaoxazepine-1,1′-dioxides
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 6 851
Scheme 1. One-Pot Epoxide Cascade Protocol Library Plan
Scheme 2. Synthesis of Core
Benzothiaoxazepine-1,1′-dioxide Scaffolds 1-9b
11-13). It was found that reaction times could be reduced
to 30 min (Table 2, entry 12), while maintaining conversion
at >95%.
Despite isolating the desired product 1{6} in high yield,
the utilization of 3 equiv of phenol {6} was undesirable for
parallel synthesis. When utilizing amines as the nucleophilic
species, simple silica SPE was employed efficiently to
remove excess amine. However, phenols cannot be removed
by simple silica SPE and the application of aqueous workup
would require the utilization of a robotic platform. Therefore,
it was envisioned that the unreacted nucleophile (phenol,
thiophenol, amine, and sulfonamide) could be scavenged
utilizing the previously reported high load, soluble scavenger
derived from ring-opening metathesis polymerization
(ROMP).19 In this regard, the utilization of oligomeric
dichlorotriazine (ODCT50) was investigated for the removal
of excess phenol {6} from the crude reaction mixture
(Scheme 4).
Table 1. Synthesis of Benzothiaoxazepine-1,1′-dioxide
Scaffolds via Epoxide Cascade Protocol
entry
R1
R2
yield (%)
1
2
3
4
5
6
7
8
9
butyl
propargyl
CH2OBn
CH2O(CH2)2CH3
(S)-CH2OBn
(S)-CH2OBn
CH2OPh
CH2CH2CHdCH
CH2O(CH2)2CH3
(R)-CH2OC(O)Pr
(R)-CH2OBn
1 (73%)
2 (69%)
3 (76%)
4 (84%)
5 (81%)
6 (69%)
7 (79%)
8 (82%)
9 (89%)
(R)-1-phenylethyl
cyclopropane
propargyl
4-methoxybenzyl
butyl
cyclopentyl
4-methoxybenzyl
Utilizing previously published conditions as a starting
point,19 scavenging of the crude reaction mixture utilizing 3
equiv of 2GODCT50 at 110 °C (thermal heating), yielded the
desired crude product in >90% purity by 1H NMR (Table 3,
entries 1-3). Despite these results, having to scavenge crude
reactions for 10 h in a parallel format was not an optimal
protocol for library production. Therefore, we investigated
a two-step sequential procedure could be carried out under
microwave irradiation to yield the desire product in high yield
and purity without the need of conventional purification
techniques. The utilization of 2GODCT50 under microwave
irradiation was investigated (Table 3, entries 4-9), and it
was found that reaction conditions could be reduced to 30
min at 50 °C with final crude purity >95% (Table 3, entry
8).20 Overall, a reaction carried out thermally requiring 8 h
of reaction time and 10 h of scavenging (18 h/reaction) has
been reduced to 30 min of reaction time and 30 min of
scavenging (1 h/reaction) by the utilization of microwave
irradiation.
With these optimized procedures in hand, a prototype
library was investigated on scaffolds 1 and7 utilizing a
variety of phenols. In addition, a number of amines and
sulfonamides were included to probe their potential applica-
tion as nucleophilic species in the SNAr diversification
(Scheme 5, Table 4).
The successful synthesis of the 16-membered prototype
library yielded an average crude purity of 70%, final yield
of 59.5% and an average final purity of 98.3% after
automated preparative reverse phase HPLC. Taking these
results in hand, we proposed the synthesis of a 72-membered
library (Scheme 6), with the remaining scaffolds 1-9 and
the corresponding nucleophilic species {1-21} (Figure 1).
Scheme 3. Optimization of SNAr of Phenol {6} on Scaf-
fold 1
Table 2. Optimization of Intermolecular SNAr Conditions with
a Phenol Nucleophile
entry equiv {6} temp (°C) solvent base
time conversiona (%)
1
2
3
4
5
6
7
8
1
1
1
1
3.
2
3
3
3
3
3
3
3
110
110
110
110
110
110
110
110
80
150
150
150
150
DMF DBU
12 h
19
40
53
55
>95
82
37
56
60
>95
>95
>95c
68
DMF K2CO3 12 h
DMF Cs2CO3 12 h
DMSO Cs2CO3 12 h
DMSO Cs2CO3 12 h
DMSO Cs2CO3 12 h
DMSO Cs2CO3 4 h
DMSO Cs2CO3 8 h
DMSO Cs2CO3 12 h
DMSO Cs2CO3 8 h
DMSO Cs2CO3 1 h
DMSO Cs2CO3 30 min
DMSO Cs2CO3 10 min
9
10
11b
12b
13b
a Crude conversion determined by 1H NMR. b Reactions carried out
under microwave irradiation. c Isolated yield after column chro-
matography 89%.
Cs2CO3 and DMSO gave the desired product in >95%
conversion after heating at 110 °C for 8 h (Table 2, entry
10). Further optimization of the reaction conditions was
investigated with the aim of reducing reaction times via the
implementation of microwave irradiation (Table 2, entries

852 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 6
Rolfe et al.
Scheme 4. Optimization and Utilization of ODCT as an Efficient Scavenger of Phenol {6}
Table 3. Optimization of Scavenging Protocol
Scheme 6. Proposed 72-Member Library of
Benzothiaoxazepine-1,1′-dioxides
entry
2GODCT50 (equiv)
temp (°C)
time
puritya (%)
1
2
3
1
3
3
3
3
3
3
3
3
1
150
150
110
150
150
150
100
50
10 h
10 h
10 h
1 h
30 min
10 min
30 min
30 min
30 min
70
>90
>90
>90
>95
80
>95
>95
80
4b
5b
6b
7b
8b
9b
a
is proposed that the failure of nucleophile {2} was due to
unfavorable steric interactions.
30
Purity analyzed by H NMR spectroscopy (experimental error 5%).
b Reactions carried out under microwave irradiation (Anton Parr 300
synthesizer).
Conclusion
In conclusion, we have developed an efficient protocol for
the diversification of benzothiaoxazepine-1,1′-dioxides via
intermolecular diversification with a variety of nucleophilic
species. A ROMP-derived oligomeric scavenger ODCT50 was
Scheme 5. Synthesis of the Corresponding Prototype Library
from Scaffolds 1 and 7
Table 5. Successful Run of 62 Members of the 78-Member
Proposed Library
entrya yieldb (%) purityc (%) entrya yieldb (%) purityc (%)
2{1}
2{2}
2{3}
2{4}
2{5}
2{6}
2{7}
2{8}
2{9}
2{10}
3{1}
3{2}
3{4}
3{5}
3{6}
3{7}
3{8}
3{9}
3{11}
3{13}
3{16}
3{17}
3{20}
3{21}
4{1}
4{2}
4{3}
4{4}
4{15}
4{16}
4{17}
28
NA
12
31
26
28
18
19
25
22
41
NA
51
31
77
47
39
49
51
44
34
42
33
31
59
NA
53
58
34
41
57
83
NA
50
72
77
80
89
83
92
4{21}
5{1}
5{3}
5{5}
5{6}
5{16}
5{17}
5{18}
6{1}
6{3}
6{4}
6{5}
6{6}
6{9}
6{16}
6{17}
6{18}
6{19}
7{3}
7{9}
7{14}
7{15}
8{1}
8{3}
8{5}
8{6}
8{7}
8{8}
8{11}
9{6}
9{16}
29
32
28
35
40
22
24
28
52
46
87
62
35
52
56
52
29
31
82
41
64
48
55
34
35
28
40
32
24
50
57
92
100
78
100
92
100
97
92
99
100
79
100
100
99
94
98
100
97
78
74
94
99
100
97
Table 4. Prototype Library Utilizing Scaffold 1
crude
final
crude
final
purityc yieldb purityc
purityc yieldb purityc
entrya
(%)
(%)
(%)
entrya
(%)
(%)
(%)
1{1}
1{3}
1{4}
1{11}
1{15}
1{17}
1{19}
7{1}
73
87
74
77
52
50
45
74
60
60
61
61
49
62
42
61
100
100
91
100
100
97
7{4}
7{5}
7{6}
7{11}
7{16}
7{17}
7{19}
10
70
71
92
77
87
51
60
80
72
66
71
74
67
44
39
63
100
100
92
100
95
100
100
100
92
100
NA
95
100
99
100
100
100
100
91
99
100
a Reaction conditions: Sultam
1
or
7
(0.136 mmol,
1
equiv),
nucleophile (0.408 mmol, 3 equiv), Cs2CO3 (4 equiv), dry DMSO (1
M), ODCT50 (0.408 mmol, 3 equiv). b Purified by an automated
preparative reverse phase HPLC (detected by mass spectroscopy).
c Purity was determined by HPLC with peak area (UV) at 214 nm.
93
100
100
100
100
NA
100
99
100
92
100
In comparison to the prototype library, crude purity was
on average lower because of the presence of either starting
material or unknown byproduct. Overall, 59 of 78 members
in this library yielded the desired products in 12-82% yield
with 47 in 90% purity or greater after automated preparative
reverse phase HPLC. It was found that submission of
scaffolds 2 and 5 to the library reaction conditions gave poor
yield and in most cases reaction failed (12 examples) because
of the formation of unidentified byproduct. Additionally it
100
100
100
95
100
100
95
a Reaction conditions: Sulfonamide (0.136 mmol, 1 equiv), nucleophile
(0.408 mmol, 3 equiv), Cs2CO3 (4 equiv), and dry DMSO (1M), ODCT50
(0.408 mmol, 3 equiv). b Purified by an automated preparative reverse-
phase HPLC (detected by mass spectroscopy). c Purity was determined by
HPLC with peak area (UV) at 214 nm.

Library of Benzothiaoxazepine-1,1′-dioxides
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 6 853
Figure 1. Phenols, amines, and sulfonamide nucleophiles for library synthesis.
successfully utilized to scavenge excess nucleophilic species
yielding the desired compounds in good crude purity. A total
of 76 compounds were synthesized utilizing this protocol
and evaluation of the biological activity of these compounds
in high-throughput screens is currently underway.
using a GeneVac EZ-2 plus evaporator. Automated prepara-
tive reverse-phase HPLC purification was performed using
an Agilent 1200 Mass-Directed Fractionation system (Prep
Pump G1361 w/gradient extension, Make-up pump G1311A,
pH modification pump G1311A, HTS PAL autosampler, UV-
DAD detection G1315D, Fraction Collector G1364B, and
Agilent 6120 quadrapole spectrometer G6120A). The pre-
parative chromatography conditions included a Waters X-
Bridge C18 column (19 × 150 mm, 5um, w/19 × 10 mm
guard column), elution with a water and CH3CN gradient
which increases 20% in CH3CN content over 4 min at a flow
rate of 20 mL/min (modified to pH 9.8 through addition of
NH4OH by using an auxiliary pump), and sample dilution
in DMSO. The preparative gradient, triggering thresholds,
and UV wavelength were selected based on the HPLC
analysis of each crude sample. The analytical method
employed an Agilent 1200 RRLC system with UV detection
(Agilent 1200 DAD SL) and mass detection (Agilent 6224
TOF). The analytical method conditions included a Waters
Aquity BEH C18 column (2.1 × 50 mm, 1.7 µm) and elution
with a linear gradient of 5% CH3CN in pH 9.8 buffered
aqueous NH4HCO3 to 100% CH3CN at 0.4 mL/min flow rate.
The purity was determined using UV peak area at 214 nm.
Experimental Section
General Procedures. All air and moisture sensitive
reactions were carried out in flame- or oven-dried glassware
under argon atmosphere using standard gastight syringes,
cannula, and septa. Stirring was achieved with oven-dried,
magnetic stir bars. CH2Cl2 was purified by passage through
the Solv-Tek purification system employing activated
Al2O3.21 Et3N was purified by passage over basic alumina
and stored over KOH. Flash column chromatography was
performed with SiO2 from Sorbent Technology (30930M-
25, Silica Gel 60A, 40-63 um). Thin layer chromatography
was performed on silica gel 60F254 plates (EM-5717,
Merck). Deuterated solvents were purchased from Cambridge
Isotope laboratories. 1H and 13C NMR spectra were recorded
on a Bruker Avance operating at 500 and 126 MHz,
respectively. High-resolution mass spectrometry (HRMS) and
FAB spectra were obtained in one of two manners: (i) on a
VG Instrument ZAB double-focusing mass spectrometer and
(ii) on a LCT Premier Spectrometer (Micromass UK Limited)
operating on ESI (MeOH). All library syntheses was carried
out in 1 dram vials utilizing Anton Parr Synthon 3000
microwave platform. Parallel evaporations were performed
General Procedure A for the Synthesis of Benzothi-
aoxazepine-1,1′-dioxide Scaffolds 1-9. Into a microwave
vial (0.5-2.0 mL) was added 2,6-difluorobenzene sulfon-
amide (2 mmol), anhydrous Cs2CO3 (6 mmol), BnEt3NCl
(0.2 mmol), epoxide (2 mmol) and dry dioxane/DMF (1:1,

854 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 6
Rolfe et al.
(2) (a) Nicolaou, K. C.; Chen, J. S. Chem. Soc. ReV. 2009, 11,
2993–3009. (b) Enders, D.; Grondal, C.; Hu¨ttl, M. R. M.
Angew. Chem., Int. Ed. 2007, 46, 1570–1581. (c) Tietze, L. F.;
Beifuss, U. Angew. Chem., Int. Ed. Engl. 1993, 32, 131–163.
(d) Tietze, L. F., Brasche, G., Gericke, K. M., Eds.; Wiley-
VCH: Weinheim, Germany, 2006. (e) Rolfe, A.; Young, K.;
Hanson, P. R. Eur. J. Org. Chem. 2008, 5254–5262.
(3) (a) Drews, J. Science 2000, 287, 1960–1964. (b) Scozzafaa,
A.; Owa, T.; Mastrolorenzo, A.; Supuran, C. T. Curr. Med.
Chem. 2003, 10, 925–953.
(4) Zhuang, L.; Wai, J. S.; Embrey, M. W.; Fisher, T. E.;
Egbertson, M. S.; Payne, L. S.; Guare, J. P., jr.; Vacca, J. P.;
Hazuda, D. J.; Felock, P. J.; Wolfe, A. L.; Stillmock, K. A.;
Witmer, M. V.; Moyer, G.; Schleif, W. A.; Gabryelski, L. J.;
Leonard, Y. M.; Lynch, J. J., Jr.; Michelson, S. R.; Young,
S. D. J. Med. Chem. 2003, 46, 453–456.
1M). The microwave vial was heated at 110 °C for 20 min,
after such time the reaction was purified (directly loading
of crude reaction mixture) by flash chromatography (8:2
hexane/EtOAc) to afford the desired sultam.
General Procedure B for the Synthesis of Library
Members. Into a 1-dram vial was added Cs2CO3 (0.17 g,
0.54 mmol, 3 equiv), a stock solution of corresponding
sultam (0.136 mmol) in dry DMSO (70 µL) (stock solution
A) and nucleophile (0.40 mmol, 3 equiv). The reaction was
heated in microwave at 110 °C for 30 min, followed by
cooling to RT. To the crude reaction mixture was added a
stock solution of ODCT50 (70 mg) in dry CH2Cl2 (1 mL),
and the crude reaction mixture was heated at 60 °C for an
additional 30 min in the microwave. After such time, the
crude reaction mixture was diluted (hexane:EtOAc, 1 mL)
and filtered through a silica SPE, flushing with solvent
(hexane:EtOAc, 5 mL). The resulting organic filtrate was
concentrated and analyzed by HPLC (UV 214 nm). Crude
material with purity below 90% was submitted to purification
by mass-directed fractionation (MDF).
(5) Levy, L. Drugs Future 1992, 17, 451–454.
(6) Rabasseda, X.; Hopkins, S. L. Drugs Today 1994, 30, 557–
563.
(7) Hendrick, R. T.; Spencer, S. R.; Blake, J. F.; Fell, J. B.;
Fischer, J. P.; Stengel, P. J.; Leveque, V. J. P.; LePogam, S.;
Rajyaguru, S.; Najera, I.; Joesy, J. A.; Swallow, S. Bioorg.
Med. Chem. Lett. 2009, 19, 410–414.
(8) Valente, C.; Guedes, R. C.; Moreira, R.; Iley, J.; Gut, J.;
Rosental, P. J. Biorg. Med. Chem. Lett. 2006, 16, 4115–4119.
(9) Misu, Y.; Togo, H. Org. Biomol. Chem. 2003, 1, 1342–1346.
(10) Rogers, K. Patzke, H. U.S. Patent 0050,545P Nov 12, 2005.
(11) Campbell, L.; Pike, K. G.; Suleman, A.; Waring, M. J.
W.O.Patent 050,101 May 2, 2008.
(12) Matsumoto, T.; Kamo, I.; Nomura, I. W.O. Patent 8,007,661
Jan 17, 2008.
(13) Santora, V. J.; Covel, J. A.; Ibarra, J. B.; Semple, G.; Smith,
B.; Smith, J.; Weinhouse, M. I.; Schultz, J. A. W.O. Patent
8, 097, 261 Jan 10, 2008.
(14) Fotouhi, N.; Haley, G. J.; Simonsen, K. B.; Vu, B. T.; Webber,
S. E. W.O. Patent 6,097,261 Sep. 21, 2006.
(15) Askew, jr., B. C.; Aya, T.; Biswas, K.; Cai, G.; Chen, J. J.;
Fotsch, C. H.; Han, N.; Human, J. B.; Li, A.; Liu, Q.; Peterkin,
T.; Qian, W.; Riahi, B.; Yuan, C. C.; Zhu, J. W.O. Patent
6,036,664 Apr 6, 2006.
Acknowledgment. This research was made possible by
generous funds provided by the National Institute of General
Medical Sciences [Pilot-Scale Libraries Program (P41
GM076302)], and The University of Kansas Center for
Chemical Methodologies and Library Development (KU-
CMLD) (P50 GM069663). Undergraduate funding was
provided by the NIH K-INBRE award and KU Center for
Research (S.V.K and M.B).
Supporting Information Available. Experimental pro-
cedures, tabulated results for all libraries, and full charac-
terization data for representative compounds. This material
is available free of charge via the Internet at http://pubs.
acs.org.
(16) Grove, S. J. A.; Zhang, M.; Shahid, M. W.O. Patent 2,100,865
Dec 19, 2002.
(17) Duan, J.; Chen, L.: Cherney, R. J.; Decicco, C. P.; Voss, M. E.;
W.O. Patent 1, 994, 126 Aug 19, 1988.
(18) Rolfe, A.; Samarakoon, T. B.; Hanson, P. R. Org. Lett. 2010,
References and Notes
(1) For reviews concerning ROMP reagents, see: (a) Barrett,
A. G. M.; Hopkins, B. T.; Ko¨bberling, J. Chem. ReV 2002,
102, 3301–3324. (b) Flynn, D. L.; Hanson, P. R.; Berk, S. C.;
Makara, G. M. Curr. Opin. Drug DiscoVery DeV. 2002, 5,
571–579. (c) Harned, A. M.; Probst, D. A.; Hanson, P. R.
The Use of Olefin Metathesis in Combinatorial Chemistry:
Supported and Chromatography-Free Syntheses. In Handbook
of Metathesis; Grubbs, R. H., Ed.: Wiley-VCH: Weinheim,
Germany, 2003; pp 361-402. (d) Harned, A. M.; Zhang, M.;
Vedantham, P.; Mukherjee, S.; Herpel, R. H.; Flynn, D. L.;
Hanson, P. R. Aldrichimica Acta 2005, 38, 3–16.
12, 1216–1219.
(19) Rolfe, A.; Probst, D.; Volp, K. A.; Omar, I.; Flynn, D.;
Hanson, P. R. J. Org. Chem. 2008, 73, 8785–8790.
(20) 3 equivalents of scavenger was utilized as previous results
had demonstrated that DMSO adds to 2GODCT50 to form an
activated species and hence would be scavenged by it from
the crude reaction mixture, see ref 19.
(21) Grubbs, R. H.; Rosen, R. K. Organometallics 1996, 15,
1518–1520.
CC1001023