Carbamoyl translocations by an anionic ortho-fries and cumulenolate α-acylation pathway: Regioselective synthesis of polysubstituted chromone 3- and 8-carboxamides

Article abstract of DOI:10.1002/anie.200704360

(Chemical Equation Presented) Completing the circle: A synthesis of chromone 3- and 8-carboxamides (3 and 4) from 2-but-2-ynoyl aryl O-carbamates 1 has been achieved via common intermediate 2 in a regioselective manner. Repetitive metalation reactions and an iridium-catalyzed B2₂pin ₂ borylation lead to the construction of polysubstituted chromones, which are key components of many bioactive compounds.

Full text of DOI:10.1002/anie.200704360

Angewandte
Chemie
DOI: 10.1002/anie.200704360
Synthetic Methods
Carbamoyl Translocations by an Anionic ortho-Fries and
Cumulenolate a-Acylation Pathway: Regioselective Synthesis of
Polysubstituted Chromone 3- and 8-Carboxamides**
Todd K. Macklin,* Jane Panteleev, and Victor Snieckus*
In memory of Albert I. Meyers
In an initial planned foray towards the total synthesis of
schumanniophytine 1,[1] we envisaged (Scheme 1) a concise
route incorporating
a double intramolecular reaction
Scheme 1. Proposed retrosynthetic analysis of schumanniophytine (1).
Scheme 2. Synthesis of chromone 3-carboxamide 5i and 8-carbox-
amide 6i.
sequence of a remote anionic-Fries rearrangement[2] and a
Michael addition (see intermediate 2). While this concept was
not placed to the test because of our failure to prepare the
requisite precursor 2,[3] model studies on the conveniently
synthesized 2-but-2-ynoyl aryl O-carbamate 4i (Scheme 2)
led to the discovery of two new anionic aryl O-carbamoyl
rearrangements that give isomeric chromones 5i and 6i which
proceed in essentially quantitative yield under standard
conditions mediated by lithium diisopropylamide (LDA)
and lithium 2,2,6,6-tetramethylpiperidide (LTMP), respec-
tively. The original concept aside (Scheme 1), which repre-
sents a successful ortho-Fries/Michael addition reaction (4i!
6i, Scheme 2), it was recognized that the chromone hetero-
cycle represents major classes of natural products[4] and is a
key component for a plethora of bioactive molecules,
commercial drugs, and agrochemicals.[5] This realization
gave us impetus to extend these initial studies.[6] Herein we
report the preliminary results of our synthetic and mecha-
nistic findings which demonstrate: a) the preparation of
3- and 8-substituted chromones, systems represented by
bioactive substances 7[7] and 8[8] which are difficult to access
and are related to the important class of antibacterial
4-quinolone drugs ciproflaxacin (9),[9] for which there is a
[*] T. K. Macklin, Prof. V. Snieckus
Department of Chemistry, Queen’s University
Kingston, Ontario K7L 3N6 (Canada)
Fax: (+1)613-533-6089
classical heterocyclic interconversion;[10] b) repetitive metal-
ation reactions which allow the construction of polysubstitut-
ed chromones (Table 1); and c) the intriguing and unprece-
dented involvement of a cumulenolate intermediate of 4i[11] in
the anionic carbamoyl translocation reaction. Taken together,
this work contributes to the increasing impact of carbanionic-
mediated strategies in synthetic aromatic chemistry. By
adaption of the approach used for the schumanniophytine
alkaloid model compound study (4i, Scheme 2), a series of
2-but-2-ynoyl aryl O-carbamates 4a–k were prepared[12] and
subjected to the strong base-mediated conditions. The results,
which are summarized in Table 1, merit selected comment.
Complications with the 1,2-addition of LDA to unhindered
E-mail: snieckus@chem.queensu.ca
Homepage: http://www.chem.queensu.ca/people/faculty/
snieckus/
J. Panteleev
Department of Chemistry, University of Toronto
Toronto, Ontario, M5S 3H6 (Canada)
[**] We acknowledge with gratitude the NSERC Canada for support
through the Discovery Grant program. We warmly thank Merck
Frosst Canada for unrestricted grant support. J.P. would like to
thank the NSERC for an Undergraduate Student Research Award
(USRA).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Communications
Table 1: Synthesis of chromone 3-carboxamides 5a,c–k and 8-carboxamides 6a,c–f,h–j.
Entry Substrate[a]
Base
(equiv)
Product
Yield
[%][b]
Entry Substrate[a]
Base
(equiv)
Product
Yield
[%][b]
LTMP
(1.5)
LTMP
(1.5)
1
81
54[c]
0
13
79[f]
90
LTMP
(1.2)
sBuLi
(2.3)
LTMP
(1.5)
2
3
4
5
6
7
14
15
16
17
18
19
LTMP
(1.1)
LTMP
(5.0)
86
LTMP
(2.1)
LDA
(1.1)
0
99
LTMP
(2.2)
LTMP
(2.2)
93
44[c]
85
97
LTMP
(1.1)
sBuLi
(2.5)
LTMP
(1.5)
90
LTMP
(1.3)
sBuLi
(2.6)
LTMP
(2.2)
36[c]
LTMP
(1.1)
sBuLi
(2.5)
LTMP
(3.0)
8
46[c]
20
21
65
LTMP
(1.5)
LTMP
(20)
9
92
84
0
[a] Prepared by DoM of the corresponding aryl O-carbamate. Conditions:
sBuLi (1.2 equiv), ꢀ788C, 30 min; then MgBr2·OEt2 (2.5 equiv),
ꢀ788C!08C; then N-methoxy-N-methylbut-2-ynamide (1.2 equiv),
08C!RT, 2 h; 61–77%. [b] Prepared by DoM of the corresponding aryl
O-carbamate. Conditions: LTMP, ꢀ788C!RT, 2–12 h. [c] Conditions:
LTMP, ꢀ788C, 10 min; then sBuLi, ꢀ788C!RT. [d] Conditions: sBuLi
(1.2 equiv) ꢀ788C, 30 min; then CuCN·2LiCl (2 equiv), ꢀ788C, 30 min;
then 2-butynoyl chloride (2 equiv), ꢀ788C!RT, 1 h; 34–48%. [e] Pre-
pared by metal-halogen exchange from the corresponding aryl bis-
bromide. Conditions: tBuLi (2.1 equiv), ꢀ788C, 10 min; then
MgBr2·OEt2 (2.5 equiv), ꢀ788C!08C; then N-methoxy-N-methylbut-2-
ynamide (1.2 equiv), 08C!RT, 12 h. [f] LTMP, ꢀ788C!508C, 1 h.
[g] Reaction performed at ꢀ1008C.
LTMP
(3.0)
10
LTMP
(1.1)
11
12
86
93
LTMP
(2.1)
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ynones led the use of LTMP, a more hindered base, for the
remaining reactions of derivatives 4a–h, 4j, and 4k. Con-
versions of unsubstituted and methyl-substituted O-carba-
mates 4a, 4c, and 4d (entries 1, 5, and 7) as well as the
methylenedioxy derivative 4j (entry 18) proceed smoothly to
give chromones 5a, 5c, 5d, and 5j, respectively, under LTMP
conditions. However, their corresponding transformations
into chromones 6a, 6c, 6d, and 6j (entries 2, 6, 8, and 19)
require a sequential LTMP/sBuLi procedure: the second step
with a stronger base was essential to achieve kinetic ortho-
carbamoyl deprotonation to enable an ortho-Fries migrat-
ion.[13] The 3-fluoro compound 4b (entries 3 and 4) failed to
afford chromone 5b or 6b, presumably as a result of
complications arising from benzyne formation.[14] On the
other hand, the lack of such presumed difficulties in the case
of the bromosubstituted 4e is noteworthy:[15] not only is
3-carbamoylchromone 5e (entry 9) obtained efficiently, but a
known lateral metalation/carbamoyl migration[16] gives the
acetamide chromone 6e (entry 10) in high yield. The chloro
O-carbamates 4 f and 4g, which were expected to cause less
concern with respect to benzyne formation, smoothly under-
went the isomeric carbamoyl transfer/Michael cyclization
reactions to afford the expected products 5 f, 6 f, and 5g
(entries 11–13), respectively. Methoxy aryl O-carbamate 4h
(entry 15) required increased concentrations of LTMP
(5 equiv) to favor formation of 6h, presumably as a result of
coordination and competitive directed ortho-metalation
(DoM) arising from the presence of the OMe group.[17] The
original test substrate 4i (entries 16 and 17) benefits from
synergistic DoM[18] to give 5i and 6i in the best overall yields
for this general route. The biaryl O-carbamate 4k (entry 20)
furnishes the 8-aryl chromone 5k, which is structurally related
to several naturally occurring[19] and synthetic[20] antitumor
agents. Structural differences notwithstanding, the unsuccess-
ful conversion of 4k (entry 21) into 6k is indicative of the
difficulties in proving that the (original untested concept)
formation of 2 is a key step in the synthesis of schumannio-
phytine (1).[1]
The availability of the new 8-carbamoylchromones 6
inspired us to perform additional DoM reactions. Thus,
treatment of 6a (Scheme 4) with LHMDS, to necessarily
Scheme 4. Differential borylation and arylation of chromone 6a.
Reagents and conditions: a) LHMDS (1.5 equiv), THF, ꢀ788C, 10 min;
then TMEDA (3 equiv), sBuLi (3 equiv), ꢀ788C, 30 min; then B(OMe)3
(4 equiv), ꢀ788C, 1 h; b) [Pd2(dba)3] (0.01 equiv), S-Phos (0.02 equiv),
1-bromo-4-fluorobenzene (1.1 equiv), K3PO4 (2 equiv), PhMe, 1008C,
2 h; c) [Ir(OMe)(cod)]2 (0.02 equiv), dtbpy (0.04 equiv), B2pin2
(0.6 equiv), hexanes, 808C, 18 h; d) [Pd(PPh3)4] (0.02 equiv), 1-bromo-
4-fluorobenzene (1.1 equiv), Na2CO3 (10 equiv), DME/H2O (4:1),
808C, 4 h. LHMDS=lithium hexamethyldisilazide, TME-
DA=N,N,N’,N’-tetramethylethylenediamine, dba=dibenzylideneace-
tone, S-Phos=dicyclohexylphosphino-2’,6’-dimethoxy-1,1’-biphenyl,
cod=1,5-cyclooctadiene, dtbpy=4,4’-di-tert-butyl-2,2’-bipyridyl,
B2pin2 =bis(pinacolato)diboron, DME=1,2-dimethoxyethane.
effect the formation of a protected dienolate,[21] followed by
DoM and treatment with B(OMe)3 afforded the 7-borylated
chromone, which was immediately subjected to modern
Suzuki cross-coupling conditions[22] to furnish the 7-(4-fluo-
rophenyl)chromone 10 in reasonable yield. To provide
regiochemical complementarity, advantage was taken of the
ꢀ
substituent effects from the C H activation/borylation route
by using B2pin2 in the presence of an iridium catalyst.[23] Thus,
subjecting 6a to one-pot borylation/Suzuki cross-coupling
conditions[24] afforded isomeric 6-(4-fluorophenyl)chromone
11 in very good yield.
A mechanistic study of the LDA-mediated reaction was
undertaken on the high-yielding conversion of 4i into [D]-5i
(Scheme 5). First, treatment of 4i with LDA (1.1 equiv) at
ꢀ788C for 1 hour and subsequent trapping with AcOH and
AcOD at ꢀ788C gave the 1,2-dienones (a-allenyl ketones)
[H]-13 and [D]-13, respectively in reasonable yields (21%
The evidence that the formation of the C8 carbanion was
possible under sBuLi conditions (entries 2, 6, ,8, and 19)
prompted us to investigate trapping experiments with other
electrophiles at low temperatures. Thus, using sequential
LTMP/sBuLi metalation of unsubstituted 2-but-2-ynoyl
phenyl O-carbamate (4a; Scheme 3) followed by TMSCl
and MeSSMe treatment led to the formation of 8-silyl- and
8-thiomethylchromones 5l and 5m, respectively, in modest
overall yields.
1
monodeuterium incorporation was determined by H NMR
spectroscopy). This result confirms the generation of the
kinetic cumulenolate intermediate 12 and its a-carbonyl
protonation, in agreement with previous experimental and
semiempirical calculations (MNDO).[25] Treatment of 4i with
LDA (1.1 equiv, ꢀ788C, 20 min) followed by quenching with
MeOH at ꢀ788C gave (2E)-aryl-3-methoxy-but-2-en-1-one
15 (confirmed by NOE experiments), which is the expected
thermodynamically stable diastereomer resulting from
a-carbonyl protonation and 1,4-addition of the generated
methoxide.[26,27] Allowing the cumulenolate 12 to warm to
room temperature to promote carbamoyl transfer resulted in
the appearance of a deep red solution indicative of the
formation of the lithium dienolate 16; this was confirmed by
the rapid disappearance of color upon treatment with AcOD
to give a clear solution and a high yield of [D]-5i (> 95%
Scheme 3. One-pot DoM/chromone 3-carboxamide synthesis.
Reagents and conditions: LTMP (1.3 equiv), THF, ꢀ788C, 10 min;
then sBuLi (2.5 equiv), ꢀ788C, 30 min; then E=TMSCl or MeSSMe
(2.5 equiv), ꢀ788C!RT, 2 h. TMS=trimethylsilyl.
1
deuterium incorporation was determined by H NMR spec-
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Communications
[1] T. K. Macklin, M. A. Reed, V. Snieckus,
Eur. J. Org. Chem. 2007, DOI:10.1002/
ejoc.200701116.
[2] W. Wang, V. Snieckus, J. Org. Chem. 1992,
57, 424 – 426.
[3] For details of unsuccessful reactions, see
T. K. Macklin, PhD thesis, Queenꢀs Uni-
versity (Canada), 2007.
[4] For 2-Aryl-4H-1-benzopyran-4-ones (fla-
vones), see a) G. Forkman, W. Heller,
Biosynthesis of Flavonoids in Comprehen-
sive Natural Products Chemistry, Vol. 1
(Ed.: U. Sankawa), Pergamon, London,
1999, pp. 713 – 748; b) The Handbook of
Natural Flavonoids, Vol. 1–2 (Eds.: J. B.
Harborne, H. Baxter), Wiley, Chichester,
1999; for recent studies, see c) B. Liang, M.
Huang, Z. You, Z. Xiong, K. Lu, R. Fathi,
Scheme 5. Reactions of cumulenolate 12.
J. Chen, Z Yang, J. Org. Chem. 2005, 70,
6097 – 6100; d) D. Yu, C.-H. Chen, A.
troscopy). This result suggested a reaction pathway which
proceeds via the buta-2,3-dienamide 14 followed by intra-
molecular Michael addition of the resulting phenolate and
then protonation to give the chromone product 5i.[28] As
suggested by the need for additional amounts of base for
effective conversion of 4 into 6 (Table 1), this reaction may
also involve the cumulenolate 12, which undergoes anionic
ortho-Fries rearrangement followed by protonation and
Michael addition, although evidence for this suggestion is
currently unavailable.
In conclusion, new general and regioselective syntheses of
chromone derivatives 5 and 6 by anionic carbamoyl translo-
cation reactions have been developed. The reactions, which
involve sequential intramolecular anionic ortho-Fries rear-
rangement and Michael addition that proceed, as suggested
by mechanistic studies (Scheme 5), via an intriguing cumul-
enolate 12, provide routes to chromones which show uncom-
mon and difficult to access C8 substitution[7] as well as
common and biologically significant[8,9] 3-substitution pat-
terns. The DoM reactions (Scheme 3) as well as the comple-
mentary ortho- and iridium catalyzed meta-borylation and
Suzuki cross-coupling chemistry (Scheme 4) provide added
conceptual and practical value for heterocyclic synthesis. As a
proposed tenet, in juxtaposition with Brönsted or Lewis acid-
mediated electrophilic substitution, this study and related
aromatic carbanionic reactions[18] offer advantages for allow-
ing the introduction of varied substituents under mild
conditions with regiochemical control. Potentially of more
general significance, the observation of cumulenolate 12,
which represents a rarely studied species,[25] provides impetus
for increased attention in the synthesis of cumulenes and
allenes,[11] especially in view of recent developments in
transition metal catalyzed reactions.[11]
Brossi, K.-H. Lee, J. Med. Chem. 2004, 47, 4072 – 4082; e) L. F.
Tietze, K. M. Gericke, R. R. Singidi, I. Schuberth, Org. Biomol.
Chem. 2007, 5, 1191 – 1200; for 3-aryl-4H-1-benzopyran-4-ones
(isoflavones), see f) R. Dixon in Comprehensive Natural Prod-
ucts Chemistry, Vol. 1 (Ed.: U. Sankawa), Pergamon, London,
1999, pp. 773 – 823; for recent studies, see g) S. Ruchirawat, N.
Thasana, Synth. Commun. 2001, 31, 1765 – 1769; h) K. Ding, S.
Wang, Tetrahedron Lett. 2005, 46, 3707 – 3709; i) C. Langꢀat-
Thoruwa, T. T. Song, J. Hu, A. L. Simons, P. A. Murphy, J. Nat.
Prod. 2003, 66, 149 – 151.
[5] For examples, see a) antiasthmatic: F. Bois, A. Desfougeres, A.
Boumendjel, A.-M. Mariotte, G. Bessard, F. Caron, P. Devillier,
Bioorg. Med. Chem. Lett. 1997, 7, 1323 – 1326; b) antioestro-
genic: K. A. Ismail, T. A. El Aziem, Eur. J. Med. Chem. 2001, 36,
243 – 253; c) antitumor: Y. M. Lin, M. T. Flavin, C. S. Cassidy, A.
Mar, F. C. Chen,Bioorg. Med. Chem. Lett. 2001, 11, 2101 – 2104;
d) antiviral: N. De Meyer, A. Haemers, L. Mishra, H. K. Pandey,
L. A. Pieters, D. A. Vanden Berghe, A. J. Vlietinck, J. Med.
Chem. 1991, 34, 736 – 746; e) CNS agents: J. Bolos, S. Gubert, L.
Anglada, J. M. Planas, C. Burgarolas, J. M. Castello, A. Sacristan,
J. A. Ortiz, J. Med. Chem. 1996, 39, 2962 – 2970; f) anticoagu-
lants: M. Di Braccio, G. Roma, G. Leoncini, M. Poggi, Farmaco
1995, 50, 703 – 711; g) insecticides: L. Crombie, J. L. Josephs, J.
Chem. Soc. Perkin Trans. 1 1993, 2591 – 2597.
[6] The value of model studies for the discovery of new reactions has
been amply praised by synthetic chemists of the past. “Chemical
synthesis always has some element of planning in it. But, the
planning should never be too rigid. Because, in fact, the specific
objective which the synthetic chemist uses as the excuse for his
activity is often not of special importance in the general sense;
rather, the important things are those that he finds out in the
course of attempting to reach his objective.” R. B. Woodward,
Proc. Robert A. WelchFound. Conf. Chem. Res. 1969, 12, 3.
[7] S. G. Jagadeesh, G. L. David Krupadanam, G. Srimannarayana,
Synth. Commun. 2001, 31, 1547 – 1557.
[8] J. A. Macritchie, M. J. OꢀMahony, S. D. Lindell, (Agrevo UK
Ltd.), WO 9827080, 1998.
[9] G. L. Drusano, H. C. Standiford, K. Plaisance, A. Forrest, J.
Leslie, J. Caldwell, Antimicrob. Agents Chemother. 1986, 30,
444 – 446; for an effective antibiotic against anthrax, see T.
Kihira, J. Sato, T. Shibata, J. Infect. Chemother. 2004, 10, 97 – 100.
[10] S. Sato, H. Kumagai, S. Matsuba, T. Kumazawa, J.-I. Onodera,
M. Suzuki, J. Heterocycl. Chem. 1999, 36, 1345 – 1347.
[11] Allenes are currently of considerable synthetic interest: a) M. A.
Tuis in Cyclizations of Allenes (Eds.: E. Krause, A. Hashmi, K.
Stephen), Wiley-VCH, Weinheim, 2004, pp. 817 – 845; b) S. Ma,
Received: September 21, 2007
Published online: February 11, 2008
Keywords: anionic reactions · heterocycles · metalation ·
.
organolithium reagents · synthetic methods
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Chemie
Chem. Rev. 2005, 105, 2829 – 2871; for selected recent studies, see
c) Y.-L. Shi, M. Sin, Org. Lett. 2005, 7, 3057 – 3060; d) A. R.
Banaag, M. A. Tius, J. Am. Chem. Soc. 2007, 129, 5328 – 5329; for
allenolate intermediates, see e) A. D. Martinez, J. P. Deville, J. L.
Stevens, V. Behar, J. Org. Chem. 2004, 69, 991 – 992; f) C. D.
Vanderwal, D. A. Vosburg, E. J. Sorensen, Org. Lett. 2001, 3,
4307 – 4310; for a-lithioallenes and heteroatom-containing
allenes, see g) C. Najera, M. Yus in The Chemistry of Organo-
lithium Compounds, Vol. 2 (Eds.: Z. Rappoport, I. Marek),
Wiley, Chichester, 2006, pp. 258 – 268; h) L. Brandsma, J. W.
Zwikker in Science of Synthesis, Vol. 8a (Eds.: M. Majewski, V.
Snieckus), Thieme, Stuttgart, 2006, pp. 271 – 283.
[16] A. V. Kalinin, M. A. J. Miah, S. Chattapadhyay, M. Tsukazaki,
M. Wicki, T. Nguen, A. L. Coelho, M. Kerr, V. Snieckus, Synlett
1997, 839 – 841.
[17] The apparent decreased directing power of the O-carbamate
group compared with the OMe group (V. Snieckus, Chem. Rev.
1990, 90, 879 – 933) may be because of O-carbamate coordina-
tion or p stacking with the neighboring lithio cumulenolate, thus
inhibiting a favorable geometric alignment for DoM, see P.
Beak, S. T. Kerrick, D. J. Gallagher, J. Am. Chem. Soc. 1993, 115,
10628 – 10636.
ꢀ
[18] a) T. Macklin, V. Snieckus in Handbook of C H Transforma-
tions, Vol. 1 (Ed.: G. Dyker), Wiley-VCH, Weinheim, 2005,
pp. 106 – 118; b) C. G. Hartung, V. Snieckus in Modern Arene
Chemistry (Ed.: D. Astruc), Wiley-VCH, Weinheim, 2002,
pp. 330 – 367.
[12] Standard directed ortho-metalation followed by transmetalation
with MgBr2·OEt2 and treatment of the resulting Grignard
reagents with N-methoxy-N-methylbut-2-ynamide according to
the excellent Weinreb amide approach (S. Nahm, S. M. Weinreb,
Tetrahedron Lett. 1981, 22, 3815 – 3818) afforded products in
modest to good yields. Substrates that failed in this reaction (4b
and 4 f) could be prepared by transmetalation with CuCN·2LiCl
and treatment of the resulting cuprate reagents with 2-butynoyl
chloride (see the Supporting Information).
[19] R. Ratnayake, E. Lacey, S. Tennant, J. H. Gill, R. J. Capon, Org.
Lett. 2006, 8, 5267 – 5270.
[20] S. Wang, K. Ding, G. Tang, R. Wang, C.-Y. Yang, Z. Nikolovska-
Coleska, (University of Michigan, USA), WO 099193, 2006.
[21] H.-J. Liu, J. Yip, K.-S. Shia, Tetrahedron Lett. 1997, 38, 2253 –
2256, and references therein.
[13] The low yields of products 6c, 6d, and 6j are undoubtedly due to
competitive thermodynamically driven benzylic and methylene-
dioxy deprotonation which ultimately disfavors ortho to
O-carbamate deprotonation and subsequent ortho-Fries rear-
rangement, even in the presence of excess LTMP (up to 8 equiv)
and thus results, by default, in the formation of chromones 5. In
an attempt to trap a thermodynamically generated anion,
treatment of 4j under Martin conditions (4j/LTMP/TMSCl =
1:1.5:1.5–1:1.5:3, see T. D. Krizan, J. C. Martin, J. Am. Chem.
Soc. 1983, 105, 6155 – 6157) led to several TMS products
including those with benzylic and methylene bridge incorpora-
tion (1H NMR spectroscopic evidence). For a viewpoint of the
ability of the methylenedioxy group to prevent desired aromatic
anionic chemistry under strong base conditions, see C. A. James,
PhD thesis, University of Waterloo (Canada), 1998.
[14] E. Masson, M. Schlosser, Eur. J. Org. Chem. 2005, 4401 – 4405.
[15] In the monohalobenzene series, bromobenzene undergoes the
most rapid benzyne formation, see F. W. Bergstrom, R. E.
Wright, C. Chandler, W. A. Gilkey, J. Org. Chem. 1936, 1,
170 – 178; J. F. Bunnett, Acc. Chem. Res. 1972, 5, 139 – 147, for
substituted aryl halides, predicting relative rates of aryne
formation as a function of halide is complicated, see P. P.
Wickham, K. H. Reuter, D. Senanayake, H. Guo, M. Zalesky,
W. J. Scott, Tetrahedron Lett. 1993, 34, 7521 – 7524.
[22] T. E. Barder, S. D. Walker, J. R. Martinelli, S. L. Buchwald, J.
Am. Chem. Soc. 2005, 127, 4685 – 4696.
[23] T. Ishiyama, N. Miyaura in Handbook of C-H Transformations,
Vol. 1 (Ed.: G. Dyker), Wiley-VCH, Weinheim, 2005, pp. 126 –
131.
[24] S. Paul, G. A. Chotana, D. Holmes, R. C. Reichle, R. E.
Maleczka, Jr., M. R. Smith III, J. Am. Chem. Soc. 2006, 128,
15552 – 15553.
[25] N. A. Petasis, K. A. Teets, J. Am. Chem. Soc. 1992, 114, 10328 –
10334.
[26] M. Curini, F. Epifano, S. Genovese, Tetrahedron Lett. 2006, 47,
4697 – 4700.
[27] Using the same reaction conditions, but quenching with excess
[D4]MeOH, resulted in the formation of a mixture of tetra-,
penta-, hexa-, and septa-deuterated products of 15, which is
indicative of an equilibration between (2E)-aryl-3-methoxy-but-
2-en-1-one 15 and [D4]MeOH, with hydrogen and deuterium
scrambling at both the a-carbonyl C-H and g-methyl sites.
[28] The observation that g-proton abstraction and cumulenolate
formation is obligatory in these reactions is further corroborated
by the failure to obtain a chromone product upon treatment of
2-(3-phenylpropioloyl)phenyl diethyl O-carbamate under LTMP
reaction conditions.
Angew. Chem. Int. Ed. 2008, 47, 2097 –2101
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
2101