Discovery of chemical reactions through multidimensional screening

Article abstract of DOI:10.1021/ja0674744

Multidimensional reaction screening of ortho-alkynyl benzaldehydes with a variety of catalysts and reaction partners was conducted in an effort to identify new chemical reactions. Reactions affording unique products were selected for investigation of prel

Full text of DOI:10.1021/ja0674744

Published on Web 01/17/2007
Discovery of Chemical Reactions through Multidimensional
Screening
Aaron B. Beeler,* Shun Su, Chris A. Singleton, and John A. Porco, Jr.*
Contribution from the Department of Chemistry and Center for Chemical Methodology and
Library DeVelopment (CMLD-BU), Boston UniVersity, 590 Commonwealth AVenue,
Boston, Massachusetts 02215
Received October 18, 2006; E-mail: porco@bu.edu
Abstract: Multidimensional reaction screening of ortho-alkynyl benzaldehydes with a variety of catalysts
and reaction partners was conducted in an effort to identify new chemical reactions. Reactions affording
unique products were selected for investigation of preliminary scope and limitations.
type reaction after screening 10,000 reaction mixtures.7 A more
recent example was reported by Liu and co-workers8 wherein
Introduction
Reaction development has historically been guided by
problems in total synthesis or interest in developing chemical
transformations of broad scope and utility.1,2 Chemical meth-
odology development has increasingly relied on systematic
evaluation of catalysts3 and other variables including solvent,
temperature, and supporting ligands.4,5 Screening approaches
have increased the efficiency of reaction development6 with
regard to discovery of active catalysts or conditions but have
generally been focused on specific transformations of interest.
a novel carbon-carbon bond-forming reaction of alkynes and
alkenes was discovered using DNA-templated synthesis.
As a part of our overall interest in the synthesis of new
chemotypes and structural frameworks, we have initiated a
program to identify novel chemical transformations using
“multidimensional screening”. In this approach, substrates may
be reacted with various catalysts and reaction partners in an
array format and analyzed for unique reaction processes. Herein,
we report our initial studies on this mode of reaction screening
and the identification and exploration of several new transfor-
mations discovered during initial screening efforts.
An emerging but underdeveloped method for chemical
reaction discovery involves high-throughput screening. A few
examples have been reported in which new reactions were
discovered through screening of either multicomponent systems
or reaction partners and catalysts. For example, Weber and co-
workers reported the discovery of a novel multicomponent, Ugi-
Results and Discussion
Significant research has been reported utilizing cycloisomer-
ization of o-alkynyl benzaldehydes and related substrates.
Yamamoto and others have reported numerous approaches to
afford putative metal-“ate” dipolar intermediates (1a) that may
be reacted further to afford a variety of structures including
naphthyl ketones 2 (Scheme 1a). Iwasawa and co-workers have
reported group VI transition metal-mediated cycloisomerizations
to afford Fischer carbene intermediates (1b) which subsequently
undergo further reactions to afford polycyclic structures such
as 3 (Scheme 1b).9 Several examples10 have been reported in
(1) For recent reviews on reaction method development related to natural
product synthesis, see: (a) Nicolaou, K. C.; Snyder, S. S. Proc. Natl. Acad.
Sci. U.S.A. 2004, 101, 11929.
(2) For recent reviews on focused reaction method development, see: Taylor,
M. S.; Jacobsen, E. N. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5368.
(3) (a) Taylor, S. J.; Morken, J. P. Science 1998, 280, 267. (b) Lavastre, O.;
Morken, J. P. Angew. Chem., Int. Ed. 1999, 38, 3163. (c) Stambuli, J. P.;
Stauffer, S. R.; Shaughnessy, K. H.; Hartwig, J. F. J. Am. Chem. Soc. 2001,
124, 2677. (d) Reetz, M. T. Angew. Chem., Int. Ed. 2001, 40, 284. (e)
Evans, M. A.; Morken, J. P. J. Am. Chem. Soc. 2002, 124, 9020. (f) Evans,
M. A.; Morken, J. P. J. Am. Chem. Soc. 2002, 124, 9020. (g) Evans, C. A.;
Miller, S. J. Curr. Opin. Chem. Biol. 2002, 6, 333. (h) Srinivasan, N.;
Ganesan, A. Chem. Commun. 2003, 916. (i) Ireland, T.; Fontanet, F.; Tchao,
G.-G. Tetrahedron Lett. 2004, 45, 4383. (j) McWilliams, C. J.; Sidler, R.
D.; Sun, Y.; Mathre, D. J. J. Assoc. Lab. Auto. 2005, 10, 394.
(4) Gooding, O. W.; Lindberg, T.; Miller, W.; Munyak, E.; Vo, L. Org. Process
Res. DeV. 2001, 5, 283.
(5) (a) Hawkins, J. M.; Makowski, T. W. Org. Process Res. DeV. 2001, 5,
328. (b) Kobayashi, S.; Kakimoto, K.; Sugiura, M. Org. Lett. 2002, 8, 1319.
(c) Blume, F.; Zemolka, S.; Fey, T.; Kranich, R.; Schamlz, H.-G. AdV.
Synth. Catal. 2002, 344, 868. (d) Ding, K.; Du, H.; Yuan, Y.; Long, J.
Chem.-Eur. J. 2004, 10, 2872.
(6) For examples of automated screening of reaction conditions, see: (a) Harre,
M.; Neh, H.; Schulz, C.; Tilstam, U.; Wessa, T.; Weinmann, H. Org.
Process Res. DeV. 2001, 5, 335. (b) von Wangelin, A. J.; Neumann, H.;
Gordes, D.; Klaus, S.; Jiao, H.; Spannenberg, A.; Kruger, T.; Wendler, C.;
Thurow, K.; Stoll, N.; Beller, M. Chem.-Eur. J. 2003, 9, 2273. (c) Di, L.;
McConnell, O. J.; Kerns, E. H.; Sutherland, A. G. J. Chromatogr., B 2004,
809, 231. (d) Dinter, C.; Weinmann, H.; Merten, C.; Schutz, A.; Blume,
T.; Sander, M.; Harre, M.; Neh, H. Org. Process Res. DeV. 2004, 8, 482.
(e) Rudolph, J.; Lormann, M.; Bolm, C.; Dahmen, S. AdV. Synth. Catal.
2005, 347, 1361.
(7) Weber, L.; Illgen, K.; Almstetter, M. Synlett 1999, 366.
(8) (a) Kana, W. M.; Rosenman, M. M.; Sakurai, K.; Snyder, T. M.; Liu, D.
R. Nature 2004, 431, 545. (b) Miller, S. J. Nat. Biotechnol. 2004, 22, 1378.
(9) (a) Iwasawa, N.; Shido, M.; Kusama, H. J. Am. Chem. Soc. 2001, 123,
5814. (b) Kusama, H.; Takaya, J.; Iwasawa, N. J. Am. Chem. Soc. 2002,
124, 11592. (c) Kusama, H.; Funami, H.; Shido, M.; Hara, Y.; Takaya, J.;
Iwasawa, N. J. Am. Chem. Soc. 2005, 127, 2709.
(10) (a) Asao, N.; Takahashi, K.; Lee, S.; Kasahara, T.; Yamamoto, Y. J. Am.
Chem. Soc. 2002, 124, 12650. (b) Asao, N.; Nogami, T.; Takahashi, K.;
Yamamoto, Y. J. Am. Chem. Soc. 2002, 124, 764. (c) Asao, N.; Kasahara,
T.; Yamamoto, Y. Angew. Chem., Int. Ed. 2003, 115, 3628. (d) Asao, N.;
Nogami, T.; Lee, S.; Yamamoto, Y. J. Am. Chem. Soc. 2003, 125, 10921.
(e) Kusama, H.; Funami, H.; Takaya, J.; Iwasawa, N. Org. Lett. 2004, 6,
605. (f) Asao, N.; Aikawa, H.; Yamamoto, Y. J. Am. Chem. Soc. 2004,
126, 7459. (g) Asao, N.; Aikawa, H.; Yamamoto, Y. J. Am. Chem. Soc.
2004, 126, 7458. (h) Nakamura, I.; Mizushima, Y.; Gridnev, I. D.;
Yamamoto, Y. J. Am. Chem. Soc. 2005, 127, 9844. (i) Kim, N.; Kim, Y.;
Park, W.; Sung, D.; Gupta, A.-K.; Oh, C.-H. Org. Lett. 2005, 7, 5289. (j)
Sato, K.; Asao, N.; Yamamoto, Y. J. Org. Chem. 2005, 70, 8977. (k) Asao,
N.; Sato, K.; Menggenbateer; Yamamoto, Y. J. Org. Chem. 2005, 70, 3682.
9
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J. AM. CHEM. SOC. 2007, 129, 1413-1419
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A R T I C L E S
Beeler et al.
Scheme 1. Cycloisomerization of Alkynyl Benzaldehydes
Figure 1. Reaction substrate, partners, and catalysts.
which transition metal-catalyzed cycloisomerization intermedi-
ates sustain nucleophilic attack to afford a variety of isoch-
romenes such as 4 and 5 (Scheme 1c,d).11,12 These and related
processes indicate that the putative intermediates may react with
diverse reaction partners in processes that may be metal catalyst-
dependent.13 We therefore considered evaluation of the o-alkynyl
benzaldehyde system in the context of multidimensional screen-
ing of reaction partners, catalysts, and temperature.
Figure 2. Multidimensional reaction screening workflow.
of traditional structure elucidation18 and computation-assisted
structure elucidation.19-21 New reaction processes were then
investigated to probe optimal reaction conditions, preliminary
scope, and plausible reaction pathways.
Reaction Screen Design and Implementation. In our initial
studies, we prepared alkynyl aldehyde 614 for evaluation with
a variety of catalysts and reaction partners at two reaction
temperatures. We selected reaction partners (Figure 1) for their
potential to undergo nucleophilic, electrophilic, and cycload-
dition reactions. Catalyst selection was also based on known,
reactive catalysts for cycloisomerization15 as well as other metal
catalysts known to interact with alkynes or aldehydes or to form
stable Fisher carbenes (Figure 1).16 An initial reaction screen
was performed on an analytical scale (5 µmol), and all reactions
were analyzed using LC/MS/ELSD.17 In this paradigm, reactions
that were productive (those affording >20% conversion to a
major product based on ELSD area) were subsequently scaled
up and purified for further characterization of reaction products
(Figure 2). Isolated products were then subjected to a mixture
An analytical reaction screen was conducted in glass deep
well 96 well plates3b sealed with individual rubber septa. Each
catalyst was prepared as a mixture in dried 4 Å molecular sieves
(0.2 mmol/g).14,22 Using molecular sieve mixtures of the
catalysts addressed issues of preparing a large number of
analytical scale reactions as they were delivered by a resin
dispenser. Duplicates of each reaction were made and incubated
both at room temperature and at 60 °C. Reactions were
incubated for 3 h and subsequently worked up in a 96 well plate
format using supported liquid extraction (SLE) cartridges
preconditioned with saturated aqueous sodium bicarbonate.23
Following elution with dichloromethane, solutions were evapo-
rated and analyzed by LC/MS/ELSD. Each reactant was
(18) Crews, P.; Rodriguez, J.; Jaspars, M. Organic Structure Analysis; Topics
in Organic Chemistry; Oxford University Press: New York, 1998.
(19) For a discussion of computational NMR analysis and structure elucidation,
see: (a) Meiler, J.; Will, M. J. Chem. Inf. Comput. Sci. 2001, 41, 1535.
(b) Elyashberg, M. E.; Blinov, K. A.; Williams, A. J.; Molodtsov, S. G.;
Martin, G. E.; Martirosian, E. R. J. Chem. Inf. Comput. Sci. 2004, 44, 771.
(c) Steinbeck, C. Nat. Prod. Rep. 2004, 21, 512.
(20) (a) Marin, G. E.; Hadden, C. E.; Russel, D. J.; Kaluzny, B. D.; Quido, J.
E.; Duholke, W. K.; Stiemsma, B. A.; Thamann, T. J. J. Heterocycl. Chem.
2002, 39, 1241. (b) Sharman, G. J.; Jones, I. C.; Parnell, M. P.; Willis, M.
C.; Mahon, M. F.; Carlson, D. V.; Williams, A.; Elyashberg, M.; Blinov,
K.; Molodtsov, S. G. Magn. Reson. Chem. 2004, 42, 567.
(21) Computational structure elucidation was carried out using ACD Labs
Structure Elucidator.
(11) Asao, N.; Chan, C. S.; Takahashi, K.; Yamamoto, Y. Tetrahedron 2005,
61, 11322.
(12) For additional examples of nucleophilic addition to cycloisomerization
intermediates, see: (a) Roesch, K. R.; Larock, R. C. Org. Lett. 1999, 1,
553. (b) Huang, Q.; Larock, R. C. J. Org. Chem. 2003, 68, 950. (c) Dyker,
G.; Hildebrandt, D.; Liu, J.; Merz, K. Angew. Chem., Int. Ed. 2003, 42,
4399. (d) Barluenga, J.; Vaz´quez-Villa, H.; Ballesteros, A.; GonzaÄlez, J.
M. J. Am. Chem. Soc. 2003, 125, 9028. (e) Yue, D.; Ca, N.-D.; Larock, R.
C. Org. Lett. 2004, 5, 1581. (f) Patil, N. T. Yamamoto, Y. J. Org. Chem.
2004, 69, 5139. (g) Asao, N.; Chan, C.-S.; Takahashi, K.; Yamamoto, Y.
Tetrahedron 2005, 61, 11322.
(13) Brummond, K. M.; Mitasev, B. Org. Lett. 2004, 6, 2245.
(14) See the Supporting Information for complete experimental details.
(15) For additional references describing catalytic cycloisomerization of o-
alkynylbenzaldehydes, see: (a) Zhu, J.; Germain, A. R.; Porco, J. A., Jr.
Angew. Chem., Int. Ed. 2004, 43, 1239. (b) Shin, S.; Gupta, A. K.; Rhim,
C. Y.; Oh, C. H. Chem. Commun. 2005, 4429. (c) Patil, N. T.; Pahadi, N.
K.; Yamamoto, Y. J. Org. Chem. 2005, 70, 10096.
(16) (a) Ikeda, S.; Cui, D.-M.; Sato, Y. J. Am. Chem. Soc. 1999, 121, 4712. (b)
Kobayashi, S.; Sugiura, M.; Kitagawa, H.; Lam, W. W.-L. Chem. ReV.
2002, 102, 2227. (c) Meng, J.; Fokin, V. V.; Finn, M. G. Tetrahedron
Lett. 2005, 46, 4543. (d) Padwa, A. HelV. Chim. Acta 2005, 88, 1357.
(17) Fang, L.; Pan, J.; Yan, B. Biotechnol. Bioeng. 2001, 71, 162.
(22) For preparation of catalyst-molecular sieve mixtures, see: (a) Ueno, M.;
Ishitani, H.; Kobayashi, S. Org. Lett. 2002, 4, 3395. (b) Kobayashi, S.;
Ueno, M.; Saito, S.; Mizuki, Y.; Ishitani, H.; Yamashita, Y. Proc. Natl.
Acad. Sci. U.S.A. 2004, 101, 5476.
(23) For examples of parallel workups employing SLE and liquid-liquid
extraction cartridges, see: (a) Johnson, C. R.; Zhang, B.; Fantauzzi, P.;
Hocker, M.; Yager, K. M. Tetrahedron 1998, 54, 4097. (b) Breitenbucher,
J. G.; Johnson, C. R.; Haight, M.; Phelan, J. C. Tetrahedron Lett. 1998,
39, 1295. (c) Johnson, C. R.; Zhang, B.; Fantauzzi, P.; Hocker, M.; Yager,
K. InnoVation Perspect. Solid Phase Synth. Comb. Libr., Collect. Pap.,
Int. Symp. 7th 1999, 209-210. (d) Kulkarni, B. A.; Roth, G. P.; Lobkovsky,
E.; Porco, J. A., Jr. J. Comb. Chem. 2002, 4, 56.
9
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Discovering Chemical Reactions through Screening
A R T I C L E S
Figure 4. X-ray crystal structure of 29.
Scheme 3. Homodimerization of o-Alkynyl Benzaldehydes
Figure 3. Representative catalyst profile for a single reaction partner.
Scheme 2. Products Derived from Known Reaction Processes
strates. In the event, treatment of o-alkynyl benzaldehyde 28
with 2 equiv of AgOTf in CH3CN led to production of a novel
compound (1:1 dr) with a very different 1H NMR spectrum from
dimeric product 37. X-ray crystal structure analysis (Figure 4)14
of one diastereomer revealed the product to be polycyclic dimer
29 (Scheme 3b). After reaction optimization, homodimers 27
and 29 were isolated in 65 and 50% yield, respectively (20%
AgOTf, 1 equiv of H2O, CH3CN).
On the basis of the reaction outcomes using substrates 6 and
28, we propose that both dimerization reactions may be initiated
by activation of 6 to afford the vinyl metal pyrylium 30.10,11
Dimerization of 30 Via exo [3 + 2]-cycloaddition affords
intermediate 3127 (Scheme 4a), although a mechanism in which
a single organometallic monomer couples with a benzopyrylium
salt (e.g., 32) cannot be discounted. The requirement of a
metallo-benzopyrylium intermediate was further demonstrated
by isolation of benzopyrylium species 32 after incubation of 6
in CDCl3 with 1 equiv of AgOTf followed by filtration through
silica gel. A dimeric product was not observed after stirring 32
for 24 h, supporting the likely involvement of organo-silver
intermediates in the dimerization process.
Scheme 5 outlines a proposed pathway to afford polycyclic
dimer 29. Intermediate 31 may rearrange, through 1,2-migration,
to exocyclic enol ether 33, which subsequently undergoes
intramolecular addition to the oxonium28 to afford 34. Addition
of water and protonation affords 29 and its C9 diastereomer
29′ (50%, dr ) 1:1). The C9 stereochemistry of 29 and 29′ was
confirmed by 2-D NMR experiments14 and is seemingly
established by the enol ether geometry for intermediate 33.
A pathway to afford homodimer 27 then follows from the
general process described in Scheme 5. In this case, the
subsequently profiled by ELSD signal, and productive reactions
were chosen on the basis of this analysis.14 A representative
catalyst profile for a single reaction partner (diethyl malonate
13) is illustrated in Figure 3. In this example, several products
were observed in reactions with Cu(CH3CN)4PF6, Au(OAc)3,
AgSbF6, and Pd(OAc)2. Reactions identified during the screen-
ing process were subsequently repeated, and products were
isolated for structure elucidation. Several products were identi-
fied that were derived from known reactions.14 However, we
also identified reactions leading to new chemotypes derived from
known and novel pathways.
Reaction Products Derived from Known Cycloisomeriza-
tion Processes. The reaction screen produced a number of
products derived from reported reaction processes.14 In particu-
lar, we included reaction partners in which known reactions may
occur, such as enol ether 1124 and terminal alkyne 15.9e,g,12c
Reaction profiles of 11 and 15 revealed the expected reaction
products derived from cycloaddition of the putative dipolar
intermediate (cf. 1a, Scheme 1) and subsequent rearrangement
to afford naphthyl ketones 25 and 26 (Scheme 2).
Novel Chemotypes Derived from Homodimerization Pro-
cesses. Inspection of reaction profiles revealed that a common
product was observed in many of the reactions employing
AgSbF6, Au(OAc)3, Rh(cod)2BF4, and Pd(OAc)2 as catalysts.
1
In light of the complexity of the H NMR spectrum obtained,
structure elucidation was assisted by computational analysis21
of the 13C, 1H-1H COSY, HMQC, and HMBC data14 resulting
in a single suggested structure, homodimerization product 27
(Scheme 3).25,26 To further probe the requirements for ho-
modimerization, we conducted reactions with alternative sub-
(26) For dimerizations of 1,3-dipoles, see: (a) Hendrickson, J. B.; Farina, J. S.
J. Org. Chem. 1980, 45, 3361. (b) Krishna, U. M.; Deodler, K. D.; Trivedi,
G. K.; Mobin, S. M. J. Org. Chem. 2004, 69, 967.
(24) Asao, N.; Aikawa, H. J. Org. Chem. 2006, 71, 5249.
(25) For examples of related dimers, see: (a) Zhdanov, Yu. A.; Verin, S. V.;
Korobka, I. V.; Kuznetsov, E. V. Khim. Geterotsikl. Soedin. 1988, 9, 1185.
(b) Verin, S. V.; Kuznetsov, E. V.; Zhdanov, Yu. A. Khim. Geterotsikl.
Soedin. 1989, 6, 750.
(27) For a discussion and computational analysis regarding [3 + 2] (Huisgen)
versus [4 + 2] cycloaddition of benzopyrylium 1,3-dipoles, see: Straub,
B. F. Chem. Commun. 2004, 1726.
(28) Reinhard, R.; Schlegel, J.; Maas, G. Tetrahedron 2002, 58, 10329.
9
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Scheme 4. Cycloisomerization and [3 + 2] Dimerization
Figure 5. Products derived from cycloisomerization/addition of diethyl
malonate.
Scheme 7. Reaction Pathway to Products 38 and 39
Scheme 5. Proposed Reaction Pathway Leading to Polycyclic
Dimer 29
chemistry of 27 is based on the exo [3 + 2]-cycloaddition mode,
which is also evident from the stereochemistry observed for
29.
The discovery of a “background” reaction across a number
of reaction profiles thus led us to uncover a novel homodimer-
ization process. By altering the aromatic substitution of the
starting material, we were able to produce a novel chemotype,
polycyclic dimer 29, which exhibits an extraordinary level of
skeletal complexity.
Reaction Products Derived from Addition of 1,3-Dicar-
bonyls. A promising reaction discovered in the screening process
was cycloisomerization/nucleophilic addition using diethyl
malonate.29 Reactions affording new products were detected in
the profile employing Au(OAc)3, AgSbF6, PtCl2, and Rh(cod)2-
BF4 as catalysts.14 The structures of the new products were
determined to be isochromene 38 and the derived ring-opened
product 39 (Figure 5).
Scheme 6. Proposed Reaction Pathway to Homodimerization
Product 27
Scheme 7 outlines a proposed pathway for cycloisomerization/
nucleophilic addition to afford isochromene 38 and benzyliden-
emalonate 39. Initial activation of the alkyne through a metal-π
complex leads to the putative metallo-benzopyrylium species
40.10 Deprotonation of diethyl malonate by the vinyl metal-
“ate” species affords gold enolate 13′, which undergoes nu-
cleophilic addition to the derived benzopyrylium 41, affording
isochromene 38. Alternatively, coordination of Au(OAc)3 to the
isochromene oxygen (42) promotes elimination and protonation
of the enol ether to afford benzylidenemalonate 39. Further
optimization of the reaction conditions showed that use of 10
mol % of Au(OAc)3 and microwave irradiation (110 °C, 10
min) afforded 38 (62%) along with ring-opened product 39
(20%). Under these conditions, reactions proceeded to full
conversion; however, we were not able to fully suppress the
pathway leading to 39. Use of CH3CN as solvent produced
exclusively 39 (90% yield).
additional dimethoxy aryl substitution may lead to oxonium
intermediate 35 (Scheme 6). Fragmentation of the pentacyclic
framework leads to oxonium species 36, which may be followed
by addition of water to afford hemiketal 37. Re-aromatization
then affords the observed isochromene ketoaldehyde product
27 as a single diastereomer. Assignment of the relative stereo-
(29) For related additions of 1,3-diketonates, see: (a) Fischer, G. W.; Zimmer-
mann, T.; Weissenfels, M. Z. Chem. 1981, 21, 446. (b) Asao, N.; Yudha,
S. S.; Nogami, T.; Yamamoto, Y. Angew. Chem., Int. Ed. 2005, 44, 5526.
9
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Discovering Chemical Reactions through Screening
A R T I C L E S
Scheme 9. Proposed Reaction Pathway for Addition of
Table 1. Scope of Cycloisomerization/Addition Reactionsa
1,3-Cyclohexanedione
Table 2. Reactions with Additional 1,3-Dicarbonyls
a Conditions: (a) Au(OAc)3 (10 mol %), C2H4Cl2 (0.4 M), microwave
110 °C (300 W); (b) Rh(cod)2BF4 (5 mol %), C2H4Cl2 (0.4 M).
Figure 6. Unreactive dicarbonyl compounds.
Scheme 8. Unexpected Reactions with 1,3-Dicarbonyls
ization to enol 54, likely stabilized through intramolecular
hydrogen bonding (cf. inset, Scheme 9),31 led to internal
protonation of the enol ether followed by nucleophilic addition
to afford tetracyclic ketal 53.32
When the dicarbonyl species was changed to â-keto ester
43, the reaction afforded 44 in 85% yield (Table 1, entry 2)
employing 5 mol % of Rh(cod)2BF4 (25 °C). Cyclic â-ketoester
45 afforded a 70% yield of isochromene 46 (Table 1, entry 3).
Furthermore, reaction of alkynyl benzaldehyde 28 afforded the
expected addition products in moderate yields (Table 1, entries
4 and 5). Unfortunately, reactions with malonates 49 and 50
were unsuccessful; use of butynyl malonate 51 afforded only
trace amounts of the cycloisomerization/addition product. The
lack of reactivity of 49-51 (Figure 6) is likely due to a higher
pKa (∼18) relative to the successful dicarbonyl substrates in
Table 1 (pKa ) 14-16).30
Interestingly, reaction with 1,3-cyclohexanedione 52 afforded
an unknown product in moderate yield (68%) (Scheme 8).
Computational structure elucidation14,21 suggested structure 53,
which was further verified by traditional analysis. A proposed
pathway to produce tetracyclic ketal 53 proceeded through initial
cycloisomerization and nucleophilic addition of the 1,3-cyclo-
hexanedione, affording intermediate 54 (Scheme 9). Tautomer-
Further scope of cyclic 1,3-dicarbonyls was demonstrated
with hydroxy pyrone 56 (50% yield of 57) and hydroxy
coumarin 58 (58% yield of 59) (Table 2). The latter reaction
also proceeded in moderate yield with alkynyl aldehyde 28 to
afford polycyclic ketal 60 (Table 2, entry 3). X-ray crystal
structure analysis14 of 57 (Figure 7a) further verified initial NMR
structural assignments. Notably, a substructure search of the
Beilstein natural product database revealed that products 59 and
60 contain the core structural motif found in cyclolycoserone
(61) and related natural products (Figure 7b).33
Reaction Products Derived from Tandem Friedel-Crafts
Addition. Analysis of reaction profiles for dimethylaniline 23
(31) A stochastic conformational search was done using the Molecular Operating
Environment (MOE).
(32) For related reactions of 1,3-dicarbonyls, see: (a) Lee, Y. R.; Kim, B. S.
Tetrahedron Lett. 1997, 38, 2095. (b) Lee, Y. R.; Suk, J. Y.; Kim, B. S.
Org. Lett. 2000, 2, 1387. (c) Halland, N.; Velgaard, T.; Jorgensen, K. A.
J. Org. Chem. 2003, 68, 5067. (d) Milan, M.; Viktor, M.; Rudolf, K.; Dusan,
I. Curr. Org. Chem. 2004, 8, 695. (e) Hsung, R. P.; Kurdyumov, A. V.;
Sydorenko, N. Eur. J. Org. Chem. 2005, 23.
(33) (a) Zdero, C.; Bohlmann, F.; Niemeyer, H. M. Phytochemistry 1988, 27,
1821. (b) Zderom, C.; Bohlmann, F.; Niemeyer, H. M. Phytochemistry 1988,
27, 2953.
(30) (a) Olmstead, W. N.; Bordwell, F. G. J. Org. Chem. 1980, 45, 3299. (b)
Arnett, E. M.; Harrelson, J. A., Jr. J. Am. Chem. Soc. 1987, 109, 809.
9
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Beeler et al.
Figure 8. Polycyclic ketal natural product.
formation of new products catalyzed by PtCl2, AgOTf, Rh(cod)2-
BF4, and Au(OAc)3 at 60 °C.14 Preparative scale reactions using
AgOTf and Au(OAc)3 as catalysts failed to provide any isolable
products while Rh(cod)2BF4 afforded dimer 27. Interestingly,
use of PtCl2 uniquely afforded bicyclic ketal 66 (Scheme 11).
The reaction likely involves a Friedel-Crafts reaction of phenol
24 with a benzopyrylium intermediate to afford intermediate
67.36 The regiochemical outcome (C versus O addition to the
oxonium intermediate) of the reaction was determined by
HMQC and HMBC analysis.14 A reaction pathway related to
the formation of 66 (cf. Scheme 9) may be proposed in which
intermediate 67 exhibits hydrogen bond organization (Chem-
3D 67, Scheme 11) leading to protonation of the isochromene
and nucleophilic attack by the phenolic oxygen to afford
tetracycle 66. After reaction optimization, 66 was obtained in
58% yield using microwave irradiation (20% PtCl2, DCE, 130
°C, 300 W).14 Control reactions excluding PtCl2 under otherwise
identical conditions provided only starting materials. Notably,
a search of the Beilstein natural product database revealed
anthrabenzoxocinone37 (68, Figure 8), which contains the
bicyclic ketal motif present in 66. The unique capability of Pt-
(II) catalysis for formation of 66 demonstrates the utility of
multidimensional screening to identify the appropriate metal
catalyst/reaction partner combinations.
Figure 7. (a) X-ray crystal structure of 57. (b) Structure of the natural
product cyclolycoserone 61.
Scheme 10. Friedel-Crafts Addition/Annulation of Phenols
Scheme 11. Friedel-Crafts Addition/Annulation of Phenols
Conclusion
Multidimensional reaction screening of ortho-alkynyl ben-
zaldehydes with a variety of catalysts and reaction partners was
conducted in an effort to identify new chemical reactions. In
this initial case study, a screening approach led to the identifica-
tion of a number of new reaction types including homodimer-
ization, nucleophilic addition of dicarbonyls, addition/oxidation,
and Friedel-Crafts addition/annulation, several of which af-
forded novel molecular frameworks. In a number of cases, a
non-intuitive dependence of metal catalyst on the particular
reaction process was observed. Computational-assisted structure
elucidation was successfully utilized in efforts to ascertain
structures of unknown reaction products. Additional applications
of multidimensional reaction screening and expansion of the
methodologies toward the synthesis of novel chemical libraries
are currently underway and will be reported in due course.
revealed production of the unique triarylmethane derivative 62
(Scheme 10). This ketone is apparently derived from cyclo-
isomerization/Friedel-Crafts addition to afford adduct (63)
followed by ring opening to para-quinoid34 intermediate 64. A
second nucleophilic addition affords the observed ketone 62.35
The reaction was also successful when alkynyl benzaldehyde
28 was utilized, affording 65 in moderate yield (48%).
Acknowledgment. This work was generously supported by
the NIGMS CMLD Initiative (P50 GM067041). We thank Dr.
Emil Lobkovsky (Cornell University) for X-ray crystal structure
Reaction Products Derived from Friedel-Crafts Addition/
Annulation of Phenols. A reaction profile of phenol 24 showed
(36) A mechanism in which O addition of the phenol is followed by O to C
migration may also be possible. For a discussion of O to C glycosylation,
see: (a) Matsumoto, T.; Hosoya, T.; Suzuki, K. Tetrahedron Lett. 1990,
31, 4629. (b) Matsumoto, T.; Hosoya, T.; Suzuki, K. Synlett 1991, 709.
(37) Herath, K. B.; Jayasuriya, H.; Guan, Z.; Schulman, M.; Ruby, C.; Sharma,
N.; MacNaul, K.; Menke, J. G.; Kodali, S.; Gaogoci, A.; Wang, J.; Singh,
S. B. J. Nat. Prod. 2005, 68, 1437.
(34) Tachikawa, T.; Handa, C.; Tokita, S. J. Photopolym. Sci. Technol. 2003,
16, 187.
(35) For consecutive Friedel-Crafts additions using dimethylaniline, see: Zhu,
C. F.; Wu, A. B. Thermochim. Acta 2005, 425, 7.
9
1418 J. AM. CHEM. SOC. VOL. 129, NO. 5, 2007

Discovering Chemical Reactions through Screening
A R T I C L E S
analyses and Professors John Snyder, James Panek, and Scott
Schaus for helpful discussions. We also thank Waters Corpora-
tion, CEM Corporation, and Zinsser North America for as-
sistance with instrumentation and Advanced Chemistry Devel-
opment (ACD) Laboratories for assistance with structure
elucidation software.
Supporting Information Available: Complete experimental
procedures and compound characterization data including X-ray
crystal structure data for 29 and 57. This material is available
free of charge via the Internet at http://pubs.acs.org.
JA0674744
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