Mechanistic Studies of Periodinane-Mediated Reactions of Anilides and Related Systems

Full text of DOI:10.1002/1521-3773(20010105)40:1<202::AID-ANIE202>3.0.CO;2-3

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[13] The term self-replication is limited to linear structures whose
replication is based on the template chemistry of nucleic acids; the
term self-reproduction is a more general one, valid for all structures
including micelles and vesicles; and the term autopoietic self-
reproduction is for the particular case in which reactions leading to
self-reproduction take place within the boundary of the reproductive
unit (e.g. within the boundary of a vesicle).
labeling, kinetic studies, cyclic voltammetry measurements,
NMR spectroscopic analysis, and designed cascade reactions.
For the IBX-mediated ring closures of anilides and related
systems to N-heterocycles, we had previously proposed a
pathway predicated on single electron transfer (SET) as
shown in Scheme 1 (I !II !III !IV!V).[3] To confirm this
[14] E. Blöchliger, M. Blocher, P. Walde, P. L. Luisi, J. Phys. Chem. B 1998,
102, 10383 ± 10390.
[15] M. Schroeder, Chem. Rev. 1980, 80, 187 ± 213.
[16] M. Minato, K. Yamamoto, J. Tsuji, J. Org. Chem. 1990, 55, 766 ± 768.
[17] W. P. Griffith, A. C. Skapski, K. A. Woode, M. J. Wright, Inorg. Chim.
Acta 1978, 31, L413 ± L414.
[18] H. C. Kolb, M. S. Van Nieuwenhze, K. B. Sharpless, Chem. Rev. 1994,
94, 2483 ± 2547.
[19] H.-L. Kwong, C. Sorato, Y. Ogino, H. Chen, B. K. Sharpless,
Tetrahedron Lett. 1990, 31, 2999 ± 3002.
[20] T. Oberholzer, K. H. Nierhaus, P. L. Luisi, Biochem. Biophys. Res.
Commun. 1999, 261, 238 ± 241.
[21] T. Oberholzer, M. Albrizio, P. L. Luisi, Chem. Biol. 1995, 2, 677 ± 682.
Mechanistic Studies of Periodinane-Mediated
Reactions of Anilides and Related Systems**
K. C. Nicolaou,* Phil S. Baran, Remo Kranich,
Yong-Li Zhong, Kazuyuki Sugita, and Ning Zou
We have recently reported a series of novel synthetic
technologies for the facile construction of complex poly-
cycles,[1] diverse heterocycles,[2] amino-sugars,[3] and a,b-
unsaturated carbonyl compounds[4] induced by hypervalent
iodine reagents (o-iodoxybenzoic acid (1-hydroxy-1,2-benzio-
doxol-3(1H)-one-1-oxide, IBX) and Dess ± Martin periodi-
nate (DMP)). This spate of reactions, which arose from a
discovery made during the total synthesis of the CP mole-
cules,[5] necessitated an in-depth mechanistic investigation to
gain further understanding of the sequence of processes
involved. Herein we present divergent mechanistic pathways
for these IBX- and DMP-mediated reactions based on isotope
[*] Prof. Dr. K. C. Nicolaou, P. S. Baran, Dr. R. Kranich, Dr. Y.-L. Zhong,
Dr. K. Sugita, Dr. N. Zou
Scheme 1. Proposed mechanism of the IBX-mediated ring closure of
anilides and related systems to N-heterocycles (I !V). SETˆ single
electron transfer, IBX ˆ o-iodoxybenzoic acid.
Department of Chemistry
and The Skaggs Institute for Chemical Biology
The Scripps Research Institute
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
Fax : (‡ 1)858-784-2469
and
hypothesis it was critical to first determine whether the
hydrogen atom which must quench the proposed radical that
would result from cyclization (IV!V, Scheme 1) originated
from the substrate itself, IBX, or the solvent. Thus, when the
reaction of 1a (Scheme 2) with IBX was performed in
[D8]THF/[D6]DMSO (10/1), deuterium was detected
(NMR) in product [D]-2a at the carbon atom as predicted
from the proposed mechanism. Carrying out the reaction of
1a in THF/[D6]DMSO (10/1) or of [D]-1a (see Scheme 2) in
THF/DMSO (10/1) led to 2a containing no deuterium. When
the experiment was carried out without a hydrogen-donating
solvent (such as THF or dioxane) present (for example, in
neat DMSO), no reaction was observed.[6] This peculiar
solvent dependence led us to conclude that the solvent
actually plays a role in this reaction, besides being a source of
Department of Chemistry and Biochemistry
University of California San Diego
9500 Gilman Drive, La Jolla, CA 92093 (USA)
E-mail: kcn@scripps.edu
[**] Professors M. G. Finn, A. Eschenmoser, and M. E. Newcomb are
gratefully acknowledged for valuable discussions and suggestions. We
thank Dr. D. H. Huang and Dr. G. Siuzdak for NMR spectroscopic
and mass spectrometric assistance, respectively. We would also like to
thank Dr. G. Vasilikogiannakis for helpful discussions and an
anonymous referee for critical suggestions. Financial support for this
work was provided by The Skaggs Institute for Chemical Biology, the
National Institutes of Health (USA), a predoctoral fellowship from
the National Science Foundation (P.B.), postdoctoral fellowships from
ArrayBiopharma (N.Z.) and Bayer AG (R.K.), and grants from
Abbott, Amgen, ArrayBiopharma, Boehringer± Ingelheim, Glaxo,
Hoffmann ± LaRoche, DuPont, Merck, Novartis, Pfizer, and Schering
Plough.
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a. IBX
[D8]THF/[D6]DMSO (10/1)
90 °C
D
CO2Me
O
CO2Me
O
CO2Me
CO2Me
O
HN
1a
HN
1a
HN
+
N
1b: X = OMe
1c: X = Et
1d: X = F
O
1e: X = Cl
[D]-2a
1f: X = C(O)Me
X
1b-f
d. IBX
THF/DMSO
(10/1)
c. IBX
DMSO
90 °C
b. IBX
THF/[D6]DMSO (10/1)
90 °C
[1a/1b-f = 1/1]
a. IBX (2.0 equiv)
THF/DMSO (10/1)
90 °C
80 °C, 10 min
e. IBX
THF/DMSO (10/1)
90 °C
CO2Me
O
CO2Me
CO2Me
CO2Me
+
DN
N
N
N
O
O
O
X
2a
2b-f
[D]-1a
2a
Scheme 3. Competition reactions of equimolar mixtures of 1a and 1b ± f.
Reagents and conditions: a) IBX (2.0 equiv), THF/DMSO (10/1), 808C,
10 min.
Scheme 2. The role of THF as a hydrogen atom donor in the IBX-
mediated cyclization of anilides. Reagents and conditions: a) IBX
(4.0 equiv), [D8]THF/[D6]DMSO (10/1), 908C, 24 h, 24%; b) IBX
(1.0 equiv), THF/[D6]DMSO (10/1), 808C, 10 min, 15% conversion
(NMR); c) IBX (4.0 equiv), DMSO, 908C, 24 h; d) and e) IBX (4.0 equiv),
THF/DMSO (10/1), 908C, 24 h, 40% (2a).
The Hammett plot,[8] based on the ratio of the reaction rate
‡
constants (ks/ku) and sp parameters,[9] gave a linear graph with
a negative slope (1 ˆ ꢀ1.4, R2 ˆ 0.97; Figure 1).[10] This
1 value is typical for a radical reaction[8] and indicates a lower
electron density in the transition state relative to the initial
hydrogen as shown in Scheme 1B. A viable scenario might
involve coordination of THF to IBX, which would lead to
intermediate A (Scheme 1B). This intermediate would act as
an extraordinary oxidant which could then initiate the
cyclization by SET to furnish intermediates II (Scheme 1A)
and B (Scheme 1B). Rearrangement of B to C followed by
hydrogen abstraction by IV would lead to product V in
addition to D, which should rapidly lead to IBA and 3-butenal.
Notably, treatment of THF with only IBX at 908C for 24 h led
to the isolation of 2-iodobenzoic acid along with polymeric
material and compounds containing aldehyde residues, as
judged by 1H NMR spectroscopy. In addition, when IBA was
employed in the cyclization (I !V) no reaction was observed.
Further support of the proposed mechanism (Scheme 1)
was gained upon a systematic evaluation of the kinetics of the
reaction with substrates designed to probe the electronic
effects of aromatic substituents on the rates of the entire
process (I !V) and of step III !IV (see below). Thus, by
synthesizing a series of aromatic amides differing in substitu-
tion at the para position (1b ± f, Scheme 3)[7] the stage was set
to compare the different overall reaction rates and to arrive at
a Hammett plot. Competing equimolar mixtures of 1a and 1b,
1c, 1d, 1e, or 1 f were heated with two equivalents of IBX in
THF/DMSO (10/1) at 808C for 10 min (Scheme 3). The ratios
between the unsubstituted product 2a and the para-substi-
Figure 1. Hammett plot for the reaction shown in Scheme 3 (1 !2). See
ref. [9] for more details.
ground state of the substrate. It supports the assumption that
the first step of the reaction involves SET from the aromatic
ring of the amide to IBX to form a radical anion/radical cation
pair as shown in Scheme 1. After loss of a proton, radical
cation II is converted into radical III as shown in Scheme 1.
The latter amidyl radical (III) then cyclizes onto the double
bond in a 5-exo-trig fashion, to furnish carbon-centered
radical species IV which is quenched by the transfer of a
hydrogen radical from THF (see above).
Based on the pioneering work of Newcomb and co-workers
in the area of amide-centered radicals,[11±13] we were able to
use N-(phenylthio)amides[12] 4a ± c derived from 3a ± c[7]
(Scheme 4) to deduce whether the rate-limiting step of the
reaction was I !II or III !IV. Three reactions for each amide
1
tuted products 2b ± f were determined by H NMR spectros-
copy. Electron-donating substituents [namely, X ˆ OMe (1b)
and Et (1c)] resulted in an increase in the rate of the
cyclization, whereas electron-withdrawing substituents caused
a decrease in the reaction rate [namely, X ˆ Cl (1e) and
C(O)Me (1 f)] or had no significant effect on the rate [X ˆ F
(1d)] relative to that of the unsubstituted substrate. For
amides of type 1 with X ˆ NO2 or CF3, no reaction occurred
under the conditions described in Scheme 3.
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solutions, the p-substituted anilides were determined to be
more difficult to oxidize than ferrocene by the following
amounts: 1.20 V (3a), 0.82 V (3b), 1.23 V (3c), 1.48 V (3d),
and ꢁ1.57 V (3e).[14] A direct correlation of the measured
oxidation potentials with the observed relative rates of the
reactions (see above) was immediately apparent. Thus,
anilides with lower oxidation potentials (3a ± c) proceeded
rapidly while anilides with higher oxidation potentials pro-
ceeded only sluggishly (3d) or not at all (3e).[15]
Scheme 5 illustrates a number of unexplained failures of
this IBX reaction previously encountered in our laboratories
which can now be rationalized in light of these new findings.
The need for an open position ortho to the nitrogen atom is
evident since substrates 6a and 6b do not undergo reaction.
This could be explained by an increase in the oxidation
H
O
O
b.
O
HN
PhSN
N
H
a. NaH;
nBu3SnH
+ 3a-c
then PhSCl
[0.2-1.0 M]
AIBN (cat.)
R
R
R
4a: R = H
4b: R = OMe
4c: R = F
3a: R = H
3b: R = OMe
3c: R = F
3d: R = C(O)Me
3e: R = CF3
5a: R = H
5b: R = OMe
5c: R = F
Scheme 4. Synthesis of N-(phenylthio)amides 4a ± c and their tin hydride-
mediated conversion into cyclized (5a ± c) and uncyclized (3a ± c) amides.
Reagents and conditions: a) NaH (1.3 equiv), THF, reflux, 4 h; then PhSCl
(ca. 1 equiv, added until yellow color of PhSCl persists), ꢀ788C, 1 h, 74 ±
86%; b) nBu3SnH (0.2 ± 1.0m), toluene, 658C, 2 ± 5 h, 85 ± 92% total yield
of cyclized and uncyclized anilide.
O
O
R
R
H
N
IBX
were conducted at 658C in toluene in the presence of excess
nBu3SnH at concentrations ranging from 0.2 to 1.0m. The
relative yields of cyclized product (C, 5a ± c) and acyclic
amide (A, 3a ± c) were determined by HPLC. From the ratio
of C:A and by assuming that the rate of trapping of tin
hydride is the same for all of the radicals[11±13] the relative rate
constants for cyclization of the amide centered radicals could
be inferred. The relative rates of cyclization were determined
to be (0.66 Æ 0.1), (0.30 Æ 0.1), and (0.40 Æ 0.1)m for 4a, 4b,
and 4c, respectively. Since the opposite trend is observed
when the overall rate (see above) is evaluated, and because
the amidyl radical cyclization is quite rapid in all cases (4a ±
c), we conclude that SET from the aromatic nucleus of the
anilide to IBX/THF (I !II) is the rate-determining step of the
reaction.
O
N
R
O
R
THF/DMSO (10/1)
6a: R = Cl
R = Cl, Me
6b: R = Me
O
O
H
N
IBX
O
CO2Et
N
O
7
CO2Et
THF/DMSO (10/1)
H
N
R
X
X
IBX
N
8a: R = SO2Ph, X = O
8b: R = Bn, X = H,H
8c: R = Bn, X = O
8d: R = Ph, X = H,H
8e: R = Boc X = H,H
R
THF/DMSO (10/1)
Me
Since the first SET step (I !II) is likely irreversible, we
gauged the oxidation potentials of a series of anilides (3a ± e,
Scheme 4). By performing cyclic voltammetry on CH2Cl2
Scheme 5. Nonparticipating substrates for the IBX-mediated cyclization
which supports the proposed mechanism of Scheme 1.
H
N
IBX
O
Ph
N
O
N
10
11
9
O
IBX
SET [O]
O
I
HO
O
O
a. IBX
(48%)
N
12
O
- H
Scheme 6. Cascade cyclization of 9
to 15. Reagents and conditions:
a) IBX (4.0 equiv every 24 h),
rearomatization
N
N
N
13
THF/DMSO (10/1), 908C, 48 h,
48%.
14
15
O
O
O
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potential caused by deconjugation
of the lone pair on the nitrogen
atom from the arene ring,[16]
a
decreased rate of 5-exo-trig cycliza-
tion, or simply a lack of deprotona-
tion of the radical cation (II !III).
The mildly electrophilic nature of
the nitrogen-centered radical[11, 13] is
evident since a,b-unsaturated ester
7 failed to react (Scheme 5). The
notion that only anilides can react
with IBX in this manner is support-
ed by the fact that substrates 8a, 8c,
and 8e are unresponsive to the
conditions, while 8b and 8d lead
rapidly only to decomposition prod-
ucts.
Additional evidence pointing to a
radical-based mechanism for this
process is provided by the designed
cascade reaction depicted in
Scheme 6. Thus, when cyclopropyl-
anilide 9[11] was treated with IBX in
Scheme 7. Proposed mechanistic aspects of the DMP-cascade reaction of anilides (VI) to polycycles
(XI).
the usual manner[2] for 48 h the novel tetracycle 15 was
obtained in 48% yield. This striking transformation can
be explained by invoking a radical mechanism involving
formation of species 10, as predicted by Scheme 1, and
which initiates rupture of the adjacent cyclopropyl ring
to give the benzylic radical 11. Oxidation of this radical (11)
leads to cation 12 which is then followed by cationic
cyclization to 14 via resonance structure 13. Finally, re-
aromatization and loss of a proton leads to the observed
product 15 (Table 1).
signals, whereas TLC analysis revealed only starting materials
and minor decomposition products, which indicate the
formation of a transient intermediate (presumably a complex
of type VII, Scheme 7). Furthermore, the participation of two
periodinane species (DMP and Ac-IBX) as postulated in the
proposed mechanism was supported by the observation that
no product was formed in the presence of 1 ± 3 equivalents of
DMP alone (strictly anhydrous conditions) or Ac-IBX alone
(freshly prepared).[17] Recognition of the key synergy between
DMP and Ac-IBX in this cascade led to the proposition that
enough water was needed to convert half of the DMP to Ac-
IBX, and prompted the use of pyridine as a facilitator of the
reaction. These mechanistic insights inspired further modifi-
cations of the reaction conditions leading to a refined process
requiring room temperature, dichloromethane as solvent, and
a minimum of 2.0 equivalents of DMP (optimally 4.0 equiv-
alents), 1.0 equivalent of H2O (optimally 2.0 equivalents), and
1.0 equivalent of pyridine, the latter accelerating the reaction
but not essential.[18]
Our present investigation into the mechanism of the DMP-
induced cyclization of anilides and related substrates to N,O-
heterocycles led us to revise our original proposals[1] to the
one depicted in Scheme 7. Indeed, upon addition of freshly
prepared DMP to a solution of N-phenylacetamide in CDCl3
1
a dark brown coloration appeared along with new H NMR
Table 1. Selected data for compounds 15 and 19.
15: Rf ˆ 0.42 [silica gel, ethyl acetate:hexane (1:2)]; IR (film): nÄmax ˆ 2966,
2923, 2869, 1695, 1609, 1512, 1453, 1394, 1362, 1292, 1217, 1131, 1104,
836 cmꢀ1; 1H NMR (500 MHz, CDCl3): d ˆ 7.49 (d, J ˆ 8.5 Hz, 2H), 7.27 ±
7.24 (m, 3H), 7.21 ± 7.18 (m, 2H), 7.11 (d, J ˆ 8.5 Hz, 2H), 5.88 (d, J ˆ
4.6 Hz, 1H), 5.22 (d, J ˆ 8.1 Hz, 1H), 2.75 ± 2.66 (m, 3H), 2.58 (q, J ˆ
7.5 Hz, 2H), 2.51 ± 2.42 (m, 1H), 2.23 (m, 2H), 1.99 (brt, J ˆ 10.6 Hz,
1H), 1.18 (t, J ˆ 7.5, 3H); 13C NMR (100 MHz, CDCl3): d ˆ 174.9, 137.2,
133.7, 132.7, 129.0, 128.1 (2C), 128.0 (2C), 127.3 (2C), 126.6 (2C), 121.9,
120.7, 60.5, 31.2, 28.2, 28.0, 25.8, 22.7, 15.5; HR-MS (matrix-assisted laser
Further compelling evidence of the participation of Ac-IBX
in the process as a nucleophile that attacks intermediate VII
(Scheme 7) was gathered by preparing Ac-IBX-18O (DMP ‡
H218O) and employing it in the reaction of substrate 16
(Scheme 8). Thus, treatment of anilide derivative 16 with
DMP and Ac-IBX-18O (1.0 equivalent of each) in dichloro-
methane at 258C led to 18O-labeled polycycle 18 (44% yield)
as confirmed by mass spectrometric analysis. This observation
supports the notion that the newly installed oxygen atom
arises from Ac-IBX, rather than from H2O, air, or the
substrate itself. Initial attempts to intercept the postulated o-
azaquinone intermediate 17 were unsuccessful; however, we
were able to isolate and characterize a minor product in this
reaction, the p-quinone structure 19 (Table 1) containing two
18O atoms (mass spectrometry analysis). This intriguing
observation and the understanding of the relation between
the fleeting o-azaquinone 17 and quinone 19 led to the design of
‡
desorption/ionization (MALDI)-FTMS): calcd for C22H23NONa [M‡H ]:
318.1858, found: 318.1857.
19: yellow needles; Rf ˆ 0.61 [silica gel, ethyl acetate:hexane (1:2)]
m.p. 77 ± 798C (CHCl3); IR (film) nÄmax ˆ 3330, 2934, 1710, 1692, 1665,
1644, 1609, 1503, 1464, 1454, 1328, 1174, 1096, 898, 723cmꢀ1 1H NMR
;
(CDCl3, 250 MHz): d ˆ 8.03 (brs, 1H), 7.55 (s, 1H), 6.54 (t, J ˆ 1.5 Hz, 1H),
5.84 ± 5.80 (m, 1H), 5.70 ± 5.65 (m, 1H), 3.25 ± 3.12 (m, 1H), 2.57 ± 2.31 (m,
6H), 2.25 ± 2.08 (m, 1H), 1.60 ± 1.41 (m, 1H), 1.13 (t, J ˆ 7.5 Hz, 3H);
13C NMR (CDCl3, 125 MHz): d ˆ 187.9, 183.2, 171.5, 153.2, 137.8, 133.0,
132.3, 128.2, 114.9, 43.9, 42.1, 31.8, 29.5, 22.3, 11.6; HR-MS (MALDI) calcd
‡
for C15H17NO(18O)2 [M‡H ]: 264.1366, found: 264.1487.
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p. 230. For a discussion of Hammett plots, see T. H. Lowry, S. K.
Richardson, Mechanism and Theory in Organic Chemistry, 3rd ed.,
Harper & Row, New York, 1987.
[9] ku: Rate constant of the reaction 1a !2a, ks: rate constants of the
‡
reactions 1b ± f !2b ± f. Since the sp parameter for the acetate
group was not defined in ref. [8], substrate 1 f was not plotted.
For the determination of 1 the following expression[8] was used:
ks/ku ˆ log[1 ꢀ sr/st]/log [1 ꢀ ur/ut]. 1 ˆ reaction constant; ur and sr ˆ
mmols of anilide 1a and p-substituted anilides 1b ± e, respectively, that
reacted, or by analogy, mmols of products 2a and 2b ± e formed; ut and
st ˆ initial mmols of anilide 1a and p-substituted anilides 1b ± e,
respectively.
[10] R. Higgins, C. S. Foote, H. Cheng, ACS Symp. Ser. 1968, 77, 102.
[11] J. H. Horner, O. M. Musa, A. Bouvier, M. Newcomb, J. Am. Chem.
Soc. 1998, 120, 7738; M. Newcomb, N. Tanaka, A. Bouvier, C. Tronche,
J. Horner, O. M. Musa, F. N. Martinez, J. Am. Chem. Soc. 1996, 118,
8505; M. Newcomb Tetrahedron 1993, 49, 1151, and references
therein.
[12] J. L. Esker, M. Newcomb, Tetrahedron Lett. 1993, 34, 6877.
[13] J. L. Esker, M. Newcomb in Advances in Heterocyclic Chemistry,
Vol. 58 (Ed.: A. R. Katritzky), Academic Press, New York, 1993, p. 1.
[14] Anodic peak potentials, 0.2m nBu4NBF4 in CH2Cl2, Pt disk electrode,
Scheme 8. 18O-labeling studies with the DMP-cascade reaction. Isolation
of labeled polycycle 18 and quinone 19 from anilide 16. Reagents and
conditions: a) H218O (2.0 equiv), CH2Cl2, 258C, ultrasound, 1 min; then
258C, 10 min; b) solution of Ac-IBX-18O/DMP, 16 (1.0 equiv), CH2Cl2,
258C, 4 h.
Pt wire auxiliary and pseudo-reference electrodes, 238C, 200 mVsꢀ1
,
referenced to internal ferrocene at ‡0.30 V; irreversible and rapid
fouling of the electrode was observed and, therefore, measured
potentials are on the first scan only (reproducible on several
independent runs). Professor M. G. Finn is gratefully acknowledged
for his assistance in these measurements. For a systematic study of the
ꢀ
bond dissociation energies of the N H bonds in anilines, and their
oxidation potentials, see F. G. Bordwell, X.-M. Zhang, J.-P. Cheng, J.
Org. Chem. 1993, 58, 6410.
a series of new reactions which will be described in the
following communication.[19]
[15] The recognition that IBX behaves as a general SETreagent suggests a
SET-based mechanism (rather than the initially proposed ionic
mechanism) for the reaction described in ref. [4]. Furthermore, a
new IBX-mediated benzylic oxidation reaction based on a SET
rationale was devised, and will be reported in due course.
[16] For an insightful study of steric inhibition of resonance, see S. Böhm,
O. Exner, Chem. Eur. J. 2000, 6, 3391, and references therein.
[17] a) For the first report of Ac-IBX, see D. B. Dess, J. C. Martin, J. Am.
Chem. Soc. 1991, 113, 7277; b) water-induced acceleration of the DMP
reagent (leading to Ac-IBX) was also observed in the context of
alcohol oxidation: S. D. Meyer, S. L. Schreiber, J. Org. Chem. 1994, 59,
7549; c) see also: S. D. Munari, M. Frigerio, M. Santagostino J. Org.
Chem. 1996, 61, 9272.
In conclusion, through this study we have provided
supporting evidence for a mechanistic rationale of the
previously reported unique interactions[1±4] of periodinane
reagents (DMP, IBX, and Ac-IBX) with anilide and related
substrates. The mechanistic understanding of these intriguing
processes is expected to lead to the design of new reactions for
the construction of novel molecular diversity and to enrich the
enabling technologies for combinatorial chemistry, chemical
biology, and medicine.
[18] Complete details of this optimization will be given in the full account
of this work.
[19] K. C. Nicolaou, K. Sugita, P. S. Baran, Y.-L. Zhong, Angew. Chem.
2001, 113, 213; Angew. Chem. Int. Ed. 2001, 40, 207.
Received: August 14, 2000
Revised: November 2, 2000 [Z15628]
[1] K. C. Nicolaou, Y.-L. Zhong, P. S. Baran, Angew. Chem. 2000, 112,
636; Angew. Chem. Int. Ed. 2000, 39, 622.
[2] K. C. Nicolaou, Y.-L. Zhong, P. S. Baran, Angew. Chem. 2000, 112,
639; Angew. Chem. Int. Ed. 2000, 39, 625.
[3] K. C. Nicolaou, P. S. Baran, Y.-L. Zhong, J. A. Vega, Angew. Chem.
2000, 112, 2625; Angew. Chem. Int. Ed. 2000, 39, 2525.
[4] K. C. Nicolaou, Y.-L. Zhong, P. S. Baran, J. Am. Chem. Soc. 2000, 122,
7596.
[5] a) K. C. Nicolaou, P. S. Baran, Y.-L. Zhong, H.-S. Choi, W. H. Yoon, Y.
He, K. C. Fong, Angew. Chem. 1999, 111, 1774; Angew. Chem. Int. Ed.
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[6] A reddish-brown color was formed immediately; however, repeated
attempts to isolate a new compound failed. 1H and 13C NMR
spectroscopic analysis of the crude mixture showed the major
component to be starting material. In most cases, starting material
could be recovered in >75% yield.
[7] Synthesized by
a 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
(EDC)-mediated coupling of the corresponding (commercially avail-
able, Aldrich) carboxylic acid and substituted anilines.
‡
[8] For sp values, see P. Zuman, R. C. Patel, Techniques in Organic
Reaction Kinetics, Krieger Publishing Company, Malabar, FL, 1992,
206
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