Synthesis of acridines by the [4 + 2] annulation of arynes and 2-aminoaryl ketones

Article abstract of DOI:10.1021/jo1000687

(Figure Presented) The reaction of 2-aminoaryl ketones and arynes generated by the treatment of various o-(trimethylsilyl)aryl triflates with CsF results in [4 + 2] annulation to afford substituted acridines in good yields.

Full text of DOI:10.1021/jo1000687

pubs.acs.org/joc
Synthesis of Acridines by the [4 þ 2] Annulation of Arynes
and 2-Aminoaryl Ketones
Donald C. Rogness and Richard C. Larock*
Department of Chemistry, Iowa State University, Ames, Iowa 50011
larock@iastate.edu
Received January 21, 2010
The reaction of 2-aminoaryl ketones and arynes generated by the treatment of various
o-(trimethylsilyl)aryl triflates with CsF results in [4 þ 2] annulation to afford substituted acridines
in good yields.
Introduction
ketones and aldehydes. Using similar mild conditions, it
was initially found that 2-aminoacetophenone and o-(trime-
thylsilyl)phenyl triflate react to produce 9-methylacridine in
a 68% yield (eq 2).
The use of arynes as building blocks in the construction of
heteroaromatic structures has become increasingly popular
in recent years.1 The electrophilic coupling of arynes, in
particular, as opposed to transition-metal-catalyzed or peri-
cyclic reactions, has produced a number of very useful
syntheses of biologically active heteroaromatics, including
indoles,2 benzofurans,3 quinoxalines,4 thiazines,3 oxazines,3
benzotriazoles,5 benzoxazines,6 clavilactones,7 indoloqui-
nones,8 carbazoles,9 dibenzofurans,9 dibenzothiophenes,9
and phenanthridines.10
Recently, our group reported the reaction of arynes and
ortho-heteroatom-substituted benzoates, which affords
medicinally relevant acridones, xanthones, and thiox-
anthones in good overall yields under very mild reaction
conditions (eq 1).11 The success of this novel methodology
led us to examine the corresponding ortho-substituted
Acridines have demonstrated important biological activity,12
including activity against cancer13 due to their ability to
intercalate into DNA and disrupt unwanted cellular pro-
cesses.14 This unique property of acridines has been exploited
in many areas of medicine. As a result, significant biological
activity toward viruses,15 bacteria,16 parasites,17 fungus,18
Alzheimer’s disease,19 and HIV/AIDS20 has also been reported.
(1) Chen, Y.; Larock, R. C. In Modern Arylation Methods; Ackerman, J.,
Ed.; Wiley-VCH: New York, 2009; p 401.
(2) Beller, M. A.; Breindl, C.; Riermeier, T. H.; Tillack, A. J. Org. Chem.
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2006, 128, 11040.
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Lenger, S. R.; Linke, S. R.; White, A. J. P.; Wilton, D.; Barret, A. G. M.
J. Am. Chem. Soc. 2006, 128, 14042.
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A.; Goodell, J. R.; Kaur, H.; Billadeau, D. D.; Ferguson, D. M.; Hiasa, H.
Eur. J. Pharmacol. 2009, 602, 223. (b) Goodell, J. R.; Ougolkov, A. V.; Hiasa,
H.; Kaur, H.; Remmel, R.; Billadeau, D. D.; Ferguson, D. M. J. Med. Chem.
2008, 51, 179. (c) Kapuriya, N.; Kapuriya, K.; Zhang, X.; Chou, T. C.;
Kakadiya, R.; Wu, Y. T.; Tsai, T. H.; Chen, Y. T.; Lee, T. C.; Shah, A.;
Naliapara, Y.; Su, T. L. Bioorg. Med. Chem. 2008, 16, 5413. (d) Martins, C.;
Gunaratnam, M.; Stuart, J.; Makwana, V.; Greciano, O.; Reszka, A. P.;
Kelland, L. R.; Neidle, S. Bioorg. Med. Chem. 2007, 17, 2293. (e) Nelson,
E. M.; Tewey, K. M.; Liu, L. F. Proc. Natl. Acad. Sci. U.S.A. 1984, 81, 1361.
(14) Belmont, P.; Dorange, I. Expert Opin. Ther. Pat. 2008, 18, 1211.
(15) Taraporewala, I. B. Tetrahedron Lett. 1991, 32, 39.
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(11) (a) Zhao, J.; Larock, R. C. J. Org. Chem. 2007, 72, 583. (b) Zhao, J.;
Larock, R. C. Org. Lett. 2005, 7, 4273.
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DOI: 10.1021/jo1000687
r
Published on Web 03/11/2010
J. Org. Chem. 2010, 75, 2289–2295 2289
2010 American Chemical Society

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SCHEME 1. Proposed Mechanism
9-Methylacridines have also been used recently in the construction
of new fluorescent probes that emit light at longer wavelengths in
order to inhibit unwanted absorption, autofluorescence, and
scattering by neighboring biological tissue.21 Acridines complexed
with iridium have also been used as triplet state, light emitting
materials for applications in OLEDs.22
Most of the current methods to synthesize acridines
require rather harsh conditions. For example, intramolecu-
lar versions of the original acridine synthesis, the Bernthsen
reaction,23 continue to employ high temperatures and
strongly acidic media.24 Another commonly used method
for preparing acridines involves the reduction of acridones.25
However, until our recent report (eq 1), the syntheses of
acridones have also required high temperatures and strongly
acidic conditions to affect intramolecular electrophilic aro-
matic substitution of N-phenylanthranilic acids.25a,26 Also
published recently were the annulations of 2-oxoaryl azides
and 2-azidobenzenecarbonitrile by benzene, giving rise to a
variety of acridines, including 9-aminoacridine.27
In 2005, Kim et al.28 reported the synthesis of acridines
using 5-arylthianthrenium perchlorates as benzyne precur-
sors to affect [4 þ 2] annulations with ortho-aminoaryl
ketones, esters, and aldehydes (eq 3). Although the scope
of this methodology appears fairly broad, and the yields are
generally good, some drawbacks to this methodology are
evident. Not only is there no commercial source for Kim’s
benzyne precursor, but its synthesis requires the use of a
highly explosive salt, thianthrene cation radical perchlo-
rate.29 In addition, a strongly activated aryl substrate, such
as anisole, is needed in order for the requisite electrophilic
aromatic substitution to take place efficiently. Depending on
the acridine’s ultimate use, one may or may not want the
fluorine and methoxy groups present in the final products.
Lastly, in order to generate benzyne from a 5-arylthianthre-
nium perchlorate, a very strong base, such as LDA, is
needed. These harsh conditions severely limit the types of
functional groups, which can be accommodated. Our ap-
proach to acridines, however, utilizes Kobayashi’s30 very
mild reaction conditions for generating benzynes in situ
through fluorine-induced elimination of o-(trimethylsilyl)-
aryl triflates to affect annulation with commercially avail-
able ortho-aminoaryl ketones and aldehydes.
(17) (a) Fattorusso, C.; Campiani, G.; Kukreja, G.; Persico, M.; Butini,
S.; Romano, M. P.; Altarelli, M.; Ros, S.; Brindisi, M.; Savini, L.; Novellino,
E.; Nacci, V.; Fattorusso, E.; Parapini, S.; Basilico, N.; Taramelli, D.;
Yardley, V.; Croft, S.; Borriello, M.; Gemma, S. J. Med. Chem. 2008, 51,
1333. (b) Giorgio, C. D.; Shimi, K.; Boyer, G.; Delmas, F.; Galy, J. P. Eur. J.
Med. Chem. 2007, 42, 1277. (c) Stocks, P. A.; Bray, P. G.; Barton, V. E.;
Helal, M. A.; Jones, M.; Araujo, N. C.; Gibbons, P.; Ward, S. A.; Hughes,
R. H.; Biagini, G. A.; Davies, J.; Amewu, R.; Mercer, A. E.; Ellis, G.; O’Neill,
P. M. Angew. Chem., Int. Ed. 2007, 46, 6278. (d) Chauhan, P. M. S.;
Srivastava, S. K. Curr. Med. Chem. 2001, 8, 1535.
(18) Patel, N. A.; Sruthi, S. C.; Patel, R. D.; Patel, M. P. Phosphorus,
Sulfur, Silicon Relat. Elem. 2008, 183, 2191.
(19) Dolphin, G. T.; Chierici, S.; Ouberai, M.; Dumy, P.; Garcia, J.
Chembiochem 2008, 9, 952.
(20) Lee, Y.; Hyun, S.; Kim, H. J.; Yu, J. Angew. Chem., Int. Ed. 2007, 47,
134.
(21) Yan, P.; Xie, A.; Wei, M.; Loew, L. M. J. Org. Chem. 2008, 73, 657.
(22) Li, C.; Sun, P.; Yan, L.; Pan, Yi; Cheng, C. H. Thin Solid Films 2008,
516, 6186.
The reaction of ortho-aminoaryl carbonyl compounds and
alkynes containing electron-withdrawing groups is a process
analogous to our aryne methodology.31 First reported in the
1960s, this chemistry affords good yields of the correspond-
ing 2,3,4-trisubstituted quinolines in one step (eq 4). As with
our acridine synthesis, the initially formed secondary alcohol
rapidly dehydrates and forms the more stable aromatic
system. Because the acridine core is important in so many
areas of chemistry and there are currently very few mild,
functionally tolerant methodologies available for the efficient
synthesis of acridines, it was our goal to investigate the scope of
the process described in eq 2, first through optimization of the
(23) (a) Bernthsen, A. Ann. 1878, 192, 1. (b) Bernthsen, A. Ann. 1884,
224, 1.
(24) (a) Popp, F. D. J. Org. Chem. 1962, 27, 2658. For recent synthetic
routes to 9-methylacridine, see: (b) Crawford, L. A.; McNab, H.; Mount, A.
R.; Wharton, S. I. J. Org. Chem. 2008, 73, 6642. (c) Joseph, J.; Kuruvilla, E.;
Achuthan, A. T.; Ramaiah, D.; Schuster, G. B. Bioconjugate Chem. 2004, 15,
1230.
(25) (a) Sourdon, V.; Mazoyer, S.; Pique, V.; Galy, J. P. Molecules 2001,
6, 673. (b) Lartia, R.; Bertrand, H.; Teulade-Fichou, M. P. Synlett 2006, 610.
(c) Ferencz, L.; Farcasan, V.; Silberg, I. A. Rev. Roum. Chim. 2003, 48, 801.
(d) Kamal, A.; Srinivas, O.; Ramulu, P.; Ramesh, G.; Kumar, P. P. Bioorg.
Med. Chem. Lett. 2004, 14, 4107. (e) Antonini, I.; Polucci, P.; Magnano, A.;
Gatto, B.; Palumbo, M.; Menta, E.; Pescalli, N.; Martelli, S. J. Med. Chem.
2003, 46, 3109.
(28) Yoon, K.; Ha, S. M.; Kim, K. J. Org. Chem. 2005, 70, 5741.
(29) Silber, J.; Shine, H. J. Org. Chem. 1971, 36, 2923.
(30) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983, 1211.
(31) (a) Hendrickson, J. B.; Rees, R. J. Am. Chem. Soc. 1961, 83, 1250.
(b) Taylor, E. C.; Heindel, N. D. J. Org. Chem. 1967, 32, 1666. (c) Sinsky, M.
S.; Bass, R. G. J. Heterocycl. Chem. 1984, 21, 759.
(26) (a) Wu, M.; Wu, W.; Gao, X.; Lin, X.; Xie, Z. Talanta 2008, 75, 995.
(b) Gopinath, V. S.; Thimmaiah, P.; Thimmaiah, K. N. Bioorg. Med. Chem.
2008, 16, 474. (c) Scarpellini-Charras, K.; Boyer, G.; Filloux, N.; Galy, J. P.
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TABLE 1. Optimization Studiesa
entry
aryne precursor (equiv)
fluoride (equiv)b
solvent (mL)
temp (°C)
% yieldc
1
2
3
4
5
7
8
9
10
11
12
13
14
1.2
1.4
1.6
1.2
1.2
1.2
1.2
1.4
1.4
1.4
1.4
1.4
1.2
CsF (3)
CsF (3)
CsF (3)
CsF (2)
CsF (4)
CsF (3)
TBAT (3)
TBAT (3)
TBAT (2)
TBAT (4)
TBAT (3)
TBAT (3)
TBAT (3)
MeCN (10)
MeCN (10)
MeCN (10)
MeCN (10)
MeCN (10)
THF (10)
THF (10)
THF (10)
THF (10)
THF (10)
THF (10)
DME (10)
DME (5)
65
65
65
65
65
65
rt
rt
rt
rt
rt
70
66
52
65
62
15
52
67
63
69
64
70
64
rt
rt
aTo a sealed 6 dram vial containing 2-aminoacetophenone, the benzyne precursor, a stir bar, and half the total volume of solvent was added CsF,
followed by the remainder of the solvent. The reaction was sealed and allowed to stir for a given time before brine (10 mL) was added. The organic layer
was removed, and the aqueous layer was extracted with ethyl acetate (2 ꢀ 15-25 mL). The combined organic layers were dried (Na2SO4) and
concentrated in vacuo before anisole (∼50 mg) was added for quantitative 1H NMR spectroscopic analysis. bEquivalent of CsF per 1 equiv of aryne
precursor. c1H NMR spectroscopic yield.
reaction conditions and second by examining its scope and
limitations.
reaction conditions, 1.4 equiv of benzyne precursor and 4.2
equiv of TBAT in THF (10 mL) at ambient temperature can
be used (entry 13 = conditions B).
With two sets of optimized reaction conditions in hand, a
series of ortho-aminoaryl carbonyl compounds have been
examined in this process, including ortho-aminoacetophe-
nones, ortho-aminobenzophenones, and ortho-aminoanthr-
aquinones (Table 2). The parent system gave a respectable
70% yield under both sets of reaction conditions. When
inductively electron-withdrawing groups, such as 4,5-di-
methoxy (2a) and 4,5-methylenedioxy (3a) groups, were
introduced onto the aromatic ring, conditions A gave
increased yields, while conditions B gave the opposite results
(entries 3-6). A similar result was obtained with 2-amino-
3,5-dibromoacetophenone (entries 7 and 8). It is hypothe-
sized that the favorable performance of this substrate may
be attributed to the steric bulkiness of the 3-bromo sub-
stituent, in that its large size can push the nitrogen lone pair
out of conjugation, thus increasing the nucleophilicity of the
nitrogen. In general, it is observed that substrates containing
both electron-donating groups and halogens are tolerated
well under our optimized reaction conditions. In addition,
conditions A proved to be more effective for all acetophe-
nones examined. This trend is not observed for the benzo-
phenones (entries 9-18). In fact, conditions B proved to give
better results overall with these substrates, although the
reason is not yet completely understood. Consistent with the
acetophenones is the fact that benzophenones containing
electron-donating groups or halogens are well-tolerated and
give good yields of the corresponding acridines when reacted
with benzyne (entries 11-18). As demonstrated in entries
13-16, a chlorine substituent can be placed on either ring of
the benzophenone system and the overall yield is not
affected. In general, all of the benzyne reactions with the
benzophenones afford clean thin layer chromatograms,
except the reaction of 2-amino-5-nitrobenzophenone, which
gave a complicated, inseparable mixture. We were pleased to
see that 2-aminoanthraquinone (11a) reacted with benzyne
efficiently using conditions A to produce the corresponding
fused six-membered ring system 11b (entries 20 and 21).
Although only moderate yields were obtained, 2-amino-
fluorenone (13a) reacted with benzyne to form another
fused five-membered ring system (entries 23 and 24). The
Results and Discussion
Initial studies on optimization of the reaction between 2-
aminoacetophenone and o-(trimethylsilyl)phenyl triflate fo-
cused on determining the appropriate solvent. The major
byproduct in this annulation reaction, which can also be
isolated by column chromatography, is the N-arylated pro-
duct C (Scheme 1). The byproduct is formed when the aryl
carbanion of intermediate A is protonated, therefore pre-
venting it from attacking the neighboring carbonyl group
(Route B).
Formation of the desired annulated product over the
arylated byproduct can sometimes be sensitive to solvents
containing acidic protons, such as acetonitrile (MeCN).11 In
our reaction, however, MeCN proved to be a superior
solvent over tetrahydrofuran (THF) (another commonly
used solvent in benzyne chemistry) when CsF is used as the
benzyne initiator (Table 1, entries 1-5). It is worth mention-
ing that even though 1 equiv of water [a proton source that
can promote Route B (Scheme 1)] is formed for every equiv
of acridine produced, the addition of drying agents, such as
molecular sieves, MgSO4, CaO, or MgO, failed to improve
the overall yield. However, this observation is not entirely
surprising since at least four other sources of protons are
expected to be present in the reaction mixture at any given
time: the ammionium cation and the methyl ketone (both
sources can provide protons intra- or intermolecularly),
unreated amine, and the solvent (MeCN). DME is the best
solvent when employing 3 equiv of tetrabutylammonium
triphenyldifluorosilacate (TBAT) as the fluoride source
(Table 1, entry 13). The remaining key reaction parameters,
time, temperature, etc., have been examined, and it has been
found that 1.2 equiv of the benzyne precursor and 3.6 equiv
of CsF in MeCN (10 mL) at 65 °C afford the highest yield of
acridine (entry 1 = conditions A). As an alternative set of
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JOCArticle
TABLE 2. Reactions of Benzyne with Amine-Containing Acetophenones, Benzophenones, and Anthraquinones
aExperimental details for conditions A and conditions B can be found in the Experimental Section. bReaction was performed at 0 °C.
2292 J. Org. Chem. Vol. 75, No. 7, 2010

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JOCArticle
TABLE 3. Reactions of ortho-Aminoaryl Ketones with Various Aryne Precursorsa
aAll reactions were carried out using reaction conditions A (see the Experimental Section). bIsolated yields.
J. Org. Chem. Vol. 75, No. 7, 2010 2293

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JOCArticle
central five-membered ring of the fluorenone substrate
increases the intramolecular distance between the nucleo-
phile and the electrophile, and this may explain the dec-
rease in yield when compared with the corresponding
benzophenone and anthraquinone systems (entries 9, 10
and 20, 21).
Lastly, a couple of 2-aminobenzaldehydes were examined.
However, yields were drastically reduced (entries 25-27).
For example, the parent aldehyde substrate, 2-aminobenzal-
dehyde (14a), gave only a 38% yield of the desired product,
even though the crude mixture produced a thin layer chro-
matogram indicating only one spot and the starting material
was entirely gone (entry 25). Concern that the substrate
might self-polymerize, as warned by the manufacturer,
forced us to run the reaction at 0 °C. Our hesitation in
heating the reaction mixture was supported by the results
reported in entry 25 where an even lower yield was obtained.
Aminobenzaldehyde 15a gave a low yield similar to 14a when
reacted with benzyne.
After a number of carbonyl substrates were examined, we
turned our focus to other arynes (Table 3). Initially, symme-
trical benzynes were investigated, thus regioisomeric product
mixtures were avoided. The parent substrate 1a and benzyne
precursor 16b reacted to afford acridine 16c (entry 1) in a
lower yield compared to that of entry 1 of Table 1. This trend
was also observed when substrate 2a was allowed to react
with the same benzyne precursor (entry 2). On the other
hand, substrate 4a gave an improved yield when compared
with entry 7 of Table 1. Substrate 4a performed well in all
cases. For example, nearly quantitative yields of the desired
acridines were obtained in the reactions reported in entries 5
and 7. Again, this may best be explained by the steric
bulkiness of the 3-bromo substituent next to the amino
group, as it can push the nitrogen lone pair out of conjuga-
tion, thus making it more nucleophilic toward the aryne. To
our delight, the anthraquinone 11a afforded a good yield,
even when reacted with the more electron-rich benzyne
precursor 17b (entry 6).
aminoaryl carbonyl compound attacks one end of the
benzyne unsaturation, generating aryl carbanion A, which
can follow one of two paths, Route A or Route B. Route A
produces the desired product through attack on the car-
bonyl group by intermediate A to form a zwitterion B,
which then undergoes a proton transfer, followed by
subsequent dehydration. As previously mentioned, the
major byproduct observed in these reactions is arylation
of the nitrogen, which presumably proceeds via Route B.
It is believed that the proton transfer occurs intramolecu-
larly from the ammonium intermediate, rather than
the water produced in the reaction, because the addition
of drying agents did not beneficially affect the overall
yield.
Conclusions
Acridines have proven to be important in many areas of
chemistry, including medicine and materials. So far, how-
ever, only methodologies requiring harsh, functionality-
intolerant conditions have been reported. As a result, there
exists a need for a methodology that is mild enough to
tolerate a diverse array of functionality, while remaining
practical in terms of the length of the synthesis. We have
developed a convenient and mild methodology for the con-
struction of acridines in one step starting from commercially
available ortho-aminoacetophenones, ortho-aminobenzo-
phenones, and ortho-aminoanthraquinones and appropriate
aryne precursors. ortho-Aminobenzaldehydes, on the other
hand, give poor yields when subjected to our optimized
reaction conditions. Although it is hypothesized that these
aldehydes may be self-polymerizing, this has not been pro-
ven, and currently, we are exploring alternative conditions.
Some unsymmetrical aryne precursors, when reacted with
our amino carbonyl substrates, led to single regioisomers in
good yields.
Experimental Section
We next explored some unsymmetrical benzyne precur-
sors in order to establish the regioselectivity of our metho-
dology. First, benzyne precursor 18b was examined, and as
expected, on the basis of previous related literature,32 the
reaction with substrate 4a led to only one regioisomer in an
excellent yield (entry 7). The structure of this compound was
confirmed by 2D NOE experiments (see the Supporting
Information). Substrate 6a efficiently reacted with 18b to
produce a single regioisomer, as well (entry 8). In addition,
the naphthalyne precursor 19b demonstrated impressive
regioselectivity, where the amino group attacks the least
hindered carbon of the aryne. Thus, the reactions of 19b
with substrates 6a and 9a produced the single regioisomers
24c and 25c, respectively. The structure of 24c was estab-
lished through X-ray crystallography (see the Supporting
Information).
Representative Procedure for the Annulation of Arynes and 2-
Aminoaryl Carbonyl Compounds. Conditions A: To a dry 5 dram
vial containing a solution of amino substrate (0.5 mmol) and the
aryne precursor (0.6 mmol) in MeCN (10 mL, anhydrous) was
added CsF (1.8 mmol). The vial was sealed and placed in an oil
bath, where it was allowed to stir for 24 h at 65 °C. The reaction
mixture was then poured into brine (5 mL), and the organic layer
was separated. The water layer was extracted with ethyl acetate
(2 ꢀ 15 mL), and the organic layers were combined, dried
(Na2SO4), and concentrated in vacuo. The crude product was
then subjected to flash chromatography using gradient solvent
combinations of ethyl acetate and hexane or dichloromethane
and hexanes to yield a 71% yield of 6b as a yellow solid: mp =
149-151 °C; 1H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 8.0 Hz,
1 H), 8.05 (s, 1 H), 7.75 (ddd, J = 1.2, 6.4, 8.8 Hz, 1 H), 7.69 (d,
J = 8.0 Hz, 1 H), 7.55-7.62 (m, 4 H), 7.37-7.44 (m, 3 H), 7.25
(dd, J = 1.6, 9.2 Hz, 1 H), 2.60 (s, 3 H); 13C NMR (100 MHz,
CDCl3) δ 149.3, 149.0, 147.0, 140.5, 136.2, 130.6, 129.9,
129.6, 128.59, 128.55 128.0, 127.0, 126.6, 125.3, 125.0, 123.7,
115.5, 22.3; HRMS (EI) calcd for C20H15N 269.1205, found
269.1209. Conditions B: To a dry 5 dram vial containing a
solution of the amino substrate (0.5 mmol) and aryne precursor
(0.7 mmol) in DME (10 mL, anhydrous) was added TBAT (2.1
equiv). The vial was sealed, and the mixture was allowed to stir
at room temperature for 24 h. The workup and purification
procedures for conditions A were then employed to yield a 72%
This acridine synthesis is thought to proceed through
the mechanism proposed in Scheme 1. After the benzyne is
generated through fluorine-induced 1,2-elimination of
TMS-OTf, the nucleophilic amino group of the ortho-
(32) (a) Liu, Z.; Shi, F.; Martinez, P. D. G.; Raminelli, C.; Larock, R. C.
J. Org. Chem. 2008, 73, 219. (b) Blackburn, T.; Romtohul, Y. K. Synlett
2008, 1159. (c) Jayanth, T. T.; Cheng, C. H. Angew. Chem., Int. Ed. 2007, 46,
5921.
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JOCArticle
yield of compound 6b (see conditions A for characterization
data).
preparation of some of the aryne precursors. We also thank
Dr. Arkady Ellern and the Molecular Structure Laboratory
of Iowa State University for their help with the X-ray
crystallography.
Acknowledgment. We thank the National Institute of
General Medical Sciences (GM070620 and GM079593)
and the National Institutes of Health Kansas University
Center of Excellence in Chemical Methodology and
Library Development (P50 GM069663) for their generous
financial support, as well as Dr. Feng Shi for his help in the
Supporting Information Available: Experimental proce-
dures and characterization of previously unreported products.
This material is available free of charge via the Internet at http://
pubs.acs.org.
J. Org. Chem. Vol. 75, No. 7, 2010 2295