Synthesis of α-ketoester- and α-hydroxyester-substituted isoindazoles via the thermodynamic coarctate cyclization of ester-terminated azo-ene-yne systems

Article abstract of DOI:10.1021/jo9011283

(Chemical Equation Presented) The synthesis of isoindazoles bearing α-ketoester and R-hydroxyester groups via the coarctate cyclization of ester-terminated azo-ene-yne precursors is described. Whereas previous studies on isoindazole formation have shown t

Full text of DOI:10.1021/jo9011283

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Synthesis of r-Ketoester- and r-Hydroxyester-Substituted Isoindazoles
via the Thermodynamic Coarctate Cyclization of Ester-Terminated
Azo-Ene-Yne Systems
Sean P. McClintock,† Nathan Forster,† Rainer Herges,‡ and Michael M. Haley*,†
†Department of Chemistry, University of Oregon, Eugene, Oregon 97403-1253, and ‡Institut fu€r Organische
Chemie, Universita€t Kiel, 24098 Kiel, Germany
haley@uoregon.edu
Received May 27, 2009
The synthesis of isoindazoles bearing R-ketoester and R-hydroxyester groups via the coarctate
cyclization of ester-terminated azo-ene-yne precursors is described. Whereas previous studies on
isoindazole formation have shown the reaction to proceed through a kinetic coarctate pathway,
functionalization of the terminal acetylene with a methyl ester sufficiently stabilizes the carbene
intermediate to make the coarctate cyclization the thermodynamic pathway. Density functional
theory (DFT) computations reveal ca. 8-9 kcal mol-1 lower energy transition states for the coarctate
pathway compared to the parent system.
Introduction
that possess alternating double-single-double-single-triple
bonds) to prepare a variety of 5-membered aromatic hetero-
cycles.1 Such heterocyclic compounds have found uses as di-
verse as incorporation into organic light emitting devices to
utilization as pharmacaphores in medicinal applications.2-4
Our laboratory has been studying a subset of “ene-ene-
yne” reactions, namely, the coarctate cyclization of azo-ene-
yne5-8 and azo-ene-nitrile9 systems. Our interest began with
the discovery that o-ethynylphenyltriazenes (1) could under-
go two different cyclization pathways by simple modification
of the reaction conditions (Figure 1).5 Treatment of 1 with
Recently there has been considerable interest in the cycl-
ization reactions of “ene-ene-yne” systems (compounds
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Heterocyclic Chemistry; Blackwell: Oxford, UK, 2000. (c) Li, J. J.; Gribble,
G. W. Palladium in Heterocyclic Chemistry; Permamon: Amsterdam, The
Netherlands, 2000. (d) Eicher, T.; Hauptmann, S. The Chemistry of Hetero-
cycles: Structure, Reactions, Syntheses, and Application; Wiley-VCH: Wein-
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Shu, C. F. Appl. Phys. Lett. 2004, 85, 4609–4611. (c) Wu, F.-I.; Su, H.-J.; Shu,
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Chem. 2005, 15, 1035–1042.
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Wissner, A. J. Med. Chem. 2005, 48, 1107–1131. (f) Chauhan, P. M. S.;
Martins, C. J. A.; Horwell, D. C. Bioorg. Med. Chem. 2005, 13, 3513–3518.
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FIGURE 1. Dual cyclization pathways of azo-ene-yne 1.
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Chem. Soc. 2002, 124, 13463–13473. (b) Kimball, D. B.; Herges, R.; Haley,
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DOI: 10.1021/jo9011283
r
Published on Web 07/30/2009
J. Org. Chem. 2009, 74, 6631–6636 6631
2009 American Chemical Society

McClintock et al.
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FIGURE 2. DFT (B3LYP/6-31G*+ZPE) calculated relative energies of reactants, transitions states, and products for the cyclization of the
NMe2 analogue of ester 4 to isoindazole carbenes and the cinnoline zwitterion.
CuCl led to the formation of the isoindazole ring system (2)
via a carbene/carbenoid intermediate whereas thermolysis at
200 °C led to the formation of cinnoline derivatives (3).
The ability of the one precursor to undergo different
cyclizations affording two classes of heterocycles in high
yield was very intriguing both synthetically and mechanisti-
cally. Whereas the formation of 3 occurs via a pericyclic
mechanism, the generation of 2 arises from a coarctate
cyclization,5 a relatively rare type of concerted reaction
mechanism that involves the making and breaking of two
bonds at a single atom.10 Coarctate reactions generally entail
the making or breaking of five-membered ring systems along
with the formation of an exocyclic carbene/carbenoid inter-
mediate, which can be trapped in a number of ways.1,11
Computational analysis of the experimental results con-
firmed that azo-ene-yne systems do indeed possess dual
cyclization pathways, and that the pericyclic pathway is the
thermodynamically favored route;5-8 however, the pericyc-
lic pathway is often not observed because of additional, high-
energy reactions needed to furnish isolable products.6-8 On
the basis of the previous works, we theorized that by
internally stabilizing the carbene intermediate, it might be
possible to make the coarctate cyclization the thermody-
namic pathway. To that end, incorporation of a methyl ester
on the terminus of the azo-ene-yne skeleton should allow for
a more facile cyclization reaction and access to functionality
not previously available. Herein we present our computa-
tional and experimental results which corroborate isoinda-
zole formation via a thermodynamically favored coarctate
reaction.
Results and Discussion
Computational Studies. The cyclization of ester 4 was
examined by using the Gaussian 0312 suite of programs at
the B3LYP level of theory13 and the 6-31G* basis set, which
(12) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.;
Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci,
B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada,
M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima,
T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M; Li, X.; Knox, J. E.;
Hratchian, H. P.; Cross, J. B.; Adamo, C.; Jaramillo, J.; Gomperts, R.;
Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.;
Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.;
Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain,
M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.;
Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski,
J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.;
Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.;
Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen,
W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03, Revision B.04;
Gaussian, Inc.: Pittsburgh, PA, 2003.
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R. J. Org. Chem. 2004, 69, 6979–6985.
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Herges, R. J. Am. Chem Soc. 2006, 128, 9711–9721.
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2411–2418.
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6619–6622.
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Herges, R. J. Chem. Inf. Comput. Sci. 1994, 34, 91–102.
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73, 8755–8762.
(13) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648–5652. (b) Lee, C.;
Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785–789.
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FIGURE 3. DFT (B3LYP/6-31G*+ZPE) calculated relative energies of the reactants, transition states, and products for the cyclization of the
NMe2 analogue of 1 to isoindazole carbenes and cinnoline zwitterion.
has been found to be a good balance of computational cost
and accuracy in our previous cyclization studies.5-8 To
reduce the number of conformational degrees of freedom
and to save on computational cost, we replaced the NEt2
group with NMe2. In previous studies, we computationally
examined the cyclizations of NH2-terminated triazenes;
however, with the current system there appeared to be a
hydrogen-bonding interaction between the unsubstituted
NH2 group and the carbene. A NMe2-substituted triazene
eliminated this interaction (Figure 2). To compare this
system to the parent terminal alkyne, the corresponding
cyclization of 1 had to be reevaluated computationally by
using a NMe2-terminated triazene (Figure 3).
As expected, incorporation of the carbomethoxy group
leads to a lower energy pathway for the coarctate cyclization
versus the pericyclic cyclization by stabilizing the carbene
intermediate. The intermediate energies for the syn and anti
products (where syn and anti refer to the orientation of the
ester to the benzene ring) were lowered by 8.4 and 9.7 kcal
mol-1, respectively. A similar change is seen with the transi-
tion states (TS) where the syn and anti TS dropped by 7.3 and
9.3 kcal mol-1, respectively. What is interesting, and un-
expected, was that the pericyclic cyclization rose in energy,
such that both coarctate intermediates are the lowest energy
intermediates between the two pathways; thus, incorpora-
tion of the methyl ester into the ene-ene-yne scaffold creates a
thermodynamic coarctate cyclization. This is achieved in two
ways: (1) by stabilizing the carbene intermediate/TS to give
the lower energy pathway and (2) by destabilizing the
pericyclic pathway. In the case of the pericyclic cyclization,
the relative intermediate energy raises by 5.7 kcal mol-1
while the TS raises slightly by only 2.2 kcal mol-1. This
indicates that we can precisely manipulate the energetics of
the cyclization to favor the coarctate pathway, while at the
same time disfavoring the pericyclic cyclization. Transition
state analysis indicates that the systems are reacting via
“true” coarctate and pericyclic mechanisms (see the Support-
ing Information).
Experimental Studies. The initially envisioned route for
the cyclization precursors was a modified Sonogashira cross-
coupling between known iodotriazene 5a5c and methyl pro-
piolate (Scheme 1); however, this “straightforward” method
proved problematic. K2CO3 was used as the base to minimize
deleterious 1,4-additions to the alkyne, according to the
procedure of Eckert and Ipaktschi.14 Unfortunately, we
obtained only low (<20%) yields of the desired product
6a. The addition of a few drops of water to solubilize the base
did lead to higher but considerably variable yields; thus, an
alternative route was pursued.
The preferential synthesis of the cyclization precursors is
illustrated in Scheme 2, using commercially available
p-trifluoromethylaniline. Iodination15 followed by triazene
formation furnished arene 5b. Sonogashira cross-coupling
with TMSA gave 7, and subsequent protiodesilation af-
forded azo-ene-yne 8b in 52% overall yield for the four steps.
Analogues 8a,c-h were prepared in a similar manner as
(14) Eckert, T.; Ipaktschi, J. Synth. Commun. 1998, 28, 327–335.
(15) Adimurthy, S.; Ramachandraiah, G.; Ghosh, P. K.; Bedekar, A. V.
Tetrahedron Lett. 2003, 44, 5099–5101.
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McClintock et al.
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SCHEME 1. Modified Sonogashira Cross-Coupling of Iodo-
triazene 5a with Methyl Propiolate
TABLE 1. Yields (%) for Ester 6 and Isoindazoles 9 and 10
entry
R
6
9
10
a
b
c
d
e
f
NO2
CF3
CN
Cl
H
Me
66
68
85
82
75
68
65
65
85
85
92
60
75
88
88
69
95
99
92
95
95
90
95
88
g
h
t-Bu
OMe
SCHEME 4. Cyclization of 6 and Trapping of the Carbene
Intermediate
SCHEME 2. Synthesis of Azo-Ene-Yne 8b and Esters 6a-h
CuCl, excess CuI, excess Cu(OAc)2, excess CuCl2) failed to
give any appreciable amount of 9.
Interestingly, when using [Rh(OAc)2]2 as a catalyst, we did
not obtain R-ketoester 9. The 1H NMR spectrum of the new
material showed two doublets (δ 5.95 and 4.14 ppm for 10a,
J=6.1 Hz) and asymmetric methylene signals of the diethyl-
amino group, the latter result not observed in any of our
prior studies. A strong band in the IR spectrum typical of an
O-H stretch suggested the presence of an alcohol group.
This was corroborated by shaking the NMR sample (in
CDCl3) with D2O, which resulted in collapse of the doublet
at 5.95 ppm to a singlet and the loss of the signal at 4.15 ppm.
Taken as a whole, the data suggested that the carbene/
carbenoid had been trapped with a molecule of water via
an O-H insertion to afford R-hydroxyester 10a, a result
confirmed by X-ray diffraction (see the Supporting
Information). While carbenes are known to undergo O-H
insertion reactions, this product was unexpected as water
was not intentionally added to the reaction. With vigorous
attempts to exclude water (flame-dried glassware, distilled
solvents, etc.), the formation of 10 could be suppressed and
instead 9 was obtained after several days. Whereas the CuCl-
mediated cyclization required excess salt, the [Rh(OAc)2]2
cyclizations occurred with as little as 5 mol % of catalyst.
These reaction conditions were amenable to a range of
substituents, from electron withdrawing to electron donat-
ing, all with very good yields. Overall the yields tended to be
higher with the Rh-catalyzed reaction than in the Cu-
mediated cyclization. Both reactions were very clean, requir-
ing only filtration though a pad of silica to afford pure
compounds.
SCHEME 3. Cyclization of 6 Affording Isoindazoles 9 or 10
previously described.5a,c Deprotonation with either LDA
(8a,c) or EtMgBr (8b,d-h) in THF followed by addition of
methyl chloroformate gave esters 6a-h in 65-85% yields
(Table 1).
With the desired precursors in hand, we examined several
different metal salts to mediate the cyclization, and found
that, similar to our previous studies, CuCl proved optimal
for the cyclization of 6 to isoindazole-substituted R-ketoe-
sters 9 in 60-90% yield (Scheme 3, Table 1). As the calcula-
tions suggested, we observed a remarkable decrease in the
reaction time indicative of a lower energy pathway: whereas
1 required heating to 50 °C for 16 h with excess CuCl,5 ester 6
needed only 4 h at 50 °C to cyclize completely to 9. The
reaction could also be carried out overnight (14 h) at room
temperature. All other copper-mediated conditions (e.g., 5%
The fact that we could induce cyclization with known
carbene/carbenoid stabilizers to afford isoindazoles posses-
sing functionality archetypical of reactions involving car-
benes again suggested the presence of such reactive
intermediates. In addition to 9 and 10, we successfully
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trapped the carbene/carbenoid (Scheme 4) via O-H inser-
tion (methanol, 11a), O-D insertion (deuterated water,
11b), and N-H insertion (propylamine, 11c). Attempts to
demonstrate carbene/carbenoid intermediacy via a [2+1]
cycloaddition with tetramethylethylene, as done in our prior
studies, were unsuccessful. This is likely due to the inability of
the sterically crowded carbene to approach the tetrasubstituted
alkene, as can be inferred from the crystal structure of 10a
(see the Supporting Information).
1:1 hexanes:EtOAc and the solvent was removed in vacuo to
afford pure 9.
General Procedure D: [Rh(OAc)2]2-Catalyzed Cyclization.
Ester 6 (1 equiv) and [Rh(OAc)2]2 (5 mol %) were dissolved in
1,2-dichloroethane (0.02 M) and the mixture was stirred at room
temperature open to the air. Upon completion (TLC), the
reaction was filtered through a pad of silica eluting with 1:1
hexanes:EtOAc and the solvent was removed in vacuo to afford
pure 10.
Iodotriazene 5b. 4-(Trifluoromethyl)aniline (3.0 g, 18.8 mmol),
KIO3 (1.40 g, 6.6 mmol), and KI (2.07 g, 12.5 mmol) were
dissolved in water (60 mL) and methanol (10 mL). HCl (1M,
20.5 mL, 20.5 mmol) was added dropwise to the stirred solution
over a period of 45 min. Upon complete addition of the HCl, the
reaction was stirred for3 h, dilutedwithwater, and extracted three
times with CH2Cl2. The combined organics were washed with aq
NaHSO3 (2ꢀ), water (2ꢀ), and brine. The organic layer was dried
(MgSO4) and filtered through a pad of silica then the solvent was
removed in vacuo to yield 2-iodo-4-(trifluoromethyl)aniline as a
tan solid. The product was immediately dissolved in a minimal
amount of MeCN and treated with conc HCl (10 mL, 120 mmol)
with stirring. The reaction was cooled to -10 °C and a solution of
NaNO2 (2.5 g, 36.2 mmol) in water (15 mL) and MeCN (5 mL)
was added slowly such that the internal temperature stayed below
0 °C. Upon completion the mixture was allowed to stir for 45 min
at -10 °C. The diazonium solution was transferred via cannula to
a stirred quench solution of HNEt2 (18.1 mL, 172 mmol) and
K2CO3 (11.9 g, 86.1 mmol) in water (150 mL) and MeCN (50 mL)
cooled to -10 °C. After warming to room temperature overnight,
the reaction was extracted three times with ether. The organic
layer was dried (MgSO4) and filtered through a pad of silica then
solvent was removedinvacuo to yield 5b (6.08 g, 88%) as a red oil.
1H NMR (CDCl3) δ 8.06 (d, J=1.2 Hz, 1H), 7.51 (dd, J=8.5,
1.2 Hz, 1H), 7.41 (d, J=8.5 Hz, 1H), 3.83 (q, J=7.4 Hz, 4H), 1.37
(t, J=7.2 Hz, 3H), 1.32 (t, J=7.2 Hz, 3H). 13C NMR (CDCl3) δ
136.2, 136.1, 136.0, 125.7, 125.6, 117.0, 95.7, 49.6, 42.6, 14.4, 10.8.
Conclusion
In summary, functionalization of 1 with a terminal methyl
ester moiety results in stabilization of the carbene intermediate
and thus leads to a thermodynamic coarctate cyclization.
Computations indicate ca. 8-9 kcal mol-1 lower TS barrier
and experimental evidence corroborates the lower energy
pathway. By using ether CuCl or [Rh(OAc)2]2 to induce
cyclizations, we were able to trap the isoindazole carbene with
molecular oxygen to give R-ketoesters 9a-h or water to afford
R-hydroxyesters 10a-h in good to excellent yields. Work on
transforming 9 into non-natural amino acids is ongoing.
Experimental Section
General Methods. These have been described previously in
ref 5.
General Procedure A: Ester Formation with EtMgBr. Alkyne
8 (1 equiv) was dissolved in freshly distilled THF (0.1 M) under
an Ar atmosphere. EtMgBr (0.98 equiv, 1 M in THF) was
added dropwise and the reaction was allowed to stir at room
temperature until the evolution of ethane ceased (∼2 h). The
reaction was then cooled to -78 °C and methyl chloroformate
(1.5 equiv) was added dropwise. The reaction was allowed to
stir at -78 °C for 1 h before slowly warming to room
temperature. The reaction was quenched with aq saturated
NaHCO3 solution then diluted with EtOAc and the layers
were separated. The organic layer was then washed with water
twice and then brine. The organic layer was dried (MgSO4)
and filtered through a short pad of silica. The solvent was
removed in vacuo and the residue was purified via column
chromatography.
General Procedure B: Ester Formation with LDA. A solution
of i-Pr2NH (1.15 equiv) in freshly distilled THF (1 M based on
i-Pr2NH) was cooled to -78 °C under an Ar atmosphere. BuLi
(1.1 equiv, 2.5 M in hexanes) was added slowly and the mixture
was stirred at -78 °C for 1 h. In a second flask, alkyne 8 (1 equiv)
was dissolved in freshly distilled THF (0.1 M based on 8) and
cooled to -78 °C under Ar. The LDA solution was transferred
via cannula into the solution of 8 and the reaction was stirred at
-78 °C for 2 h. With continued cooling at -78 °C, methyl
chloroformate (1.5 equiv) was added and the reaction was
stirred at -78 °C for 1 h before slowly warming to room
temperature. The reaction was quenched with aq saturated
NaHCO3 solution then diluted with EtOAc and the layers were
separated. The organic layer was then washed with water twice
and then brine. The organic layer was dried (MgSO4) and
filtered through a short pad of silica. The solvent was removed
in vacuo and the residue was purified via column chromatogra-
phy.
IR (NaCl) ν 2977, 2936, 2875, 1317, 1254, 1121, 1074 cm-1
.
HRMS (EIþ) for C11H13N3F3I: calcd 371.01066, found
371.01190.
Ester 6a via Modified Sonogashira Cross-Coupling. Iodotria-
zene 5a (92 mg, 0.26 mmol), Pd(PPh3)2Cl2 (4 mg, 0.005 mmol,
2 mol %), CuI (2 mg, 0.01 mmol, 4 mol %), and K2CO3 (144 mg,
1.04 mmol) were dissolved in freshly distilled THF (2 mL) and
water (5 drops) in a screw-top reaction vessel. The solution
was purged with Ar for 45 min, then methyl propiolate (0.1 mL,
1.04 mmol) was added. The sealed vessel was heated to 65 °C
overnight. Upon cooling, the carbonate was filtered and the
solvent was removed in vacuo. The crude material was dissolved
in ether and the solution was filtered through a pad of silica and
then concetrated. The residue was purified by preparative TLC
(CH2Cl2) to yield 6a (50 mg, 61%) as a yellow solid. 1H NMR
(CDCl3) δ 8.42 (d, J=2.7 Hz, 1H), 8.18 (dd, J=9.2, 2.7 Hz, 1H),
7.58 (d, J=9.2 Hz, 1H), 3.90 (q, J=7.2 Hz, 4H), 3.84 (s, 3H), 1.40
(t, J=7.2 Hz, 3H), 1.32 (t, J=7.2 Hz, 3H). 13C NMR (CDCl3) δ
158.6, 154.2, 143.5, 129.6, 126.2, 117.0, 114.6, 85.1, 83.0, 52.7,
50.2, 43.2, 14.2, 10.6. IR (NaCl) ν 2979, 2225, 1713, 1575, 1516,
1320, 1253, 1083 cm-1. HRMS (EIþ) for C14H16N4O4: calcd
304.11715, found 304.11908.
Ester 6a via General Procedure B. Triazene 8a was reacted
according to General Procedure B. Purification as above aff-
orded 6a (0.054 g, 66%) as a yellow solid whose spectral data
were identical with those given above.
General Procedure C: CuCl-Mediated Cyclization. 1,2-Di-
chloroethane (0.02 M) was bubbled with O2 for 30 min, after
which ester 6 (1 equiv) and CuCl (10 equiv) were added. The
sealed flask was heated to 50 °C until TLC indicated the
complete consumption of 6 (ca. 4 h). Upon completion, the
cooled reaction was filtered through a pad of silica eluting with
Triazene 7. A stirred solution of 5b (6.08 g, 16.4 mmol), CuI
(125 mg, 0.6 mmol, 4 mol %), and Pd(PPh3)2Cl2 (220 mg,
0.3 mmol, 2 mol %) in freshly distilled THF (80 mL) and
i-Pr2NH (80 mL) was purged with Ar for 45 min. TMSA
(9.3 mL, 65.5 mmol) was added and the reaction was stirred at
room temperature until TLC indicated completion. The solvent
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was then removed in vacuo and the crude solid was dissolved in
9:1 hexanes:CH2Cl2. The mixture was filtered through a pad of
silica eluting with 4:1 hexanes:CH2Cl2 and the solvent was
removed in vacuo. The crude product was purified by flash
chromatography (9:1 hexanes:CH2Cl2) to yield 7 (4.60 g, 82%)
as a dark oil. 1H NMR (CDCl3) δ 7.73 (d, J=1.8 Hz, 1H), 7.50
(d, J=9.0 Hz, 1H), 7.45 (dd, J=9.0, 1.8 Hz, 1H), 3.82 (q, J=
7.5 Hz, 4H), 1.33 (m, 6H), 0.25 (s, 9H). 13C NMR (CDCl3) δ
155.1, 130.4, 126.4, 126.0, 125.6, 122.3, 118.2, 116.9, 102.0, 99.4,
49.5, 42.2, 14.4, 10.9, -0.08. IR (NaCl) ν 2965, 2938, 2901, 2160,
2068, 1607, 1456, 1422, 1190 cm-1. HRMS (EIþ) for
C16H22N3F3Si: calcd 341.15351, found 341.15484.
Ethynyltriazene 8b. A solution of 7 (1.4 g, 4.2 mmol) and
K2CO3 (5.8 g, 42.3 mmol) in distilled THF (50 mL) and MeOH
(10 mL) was stirred at room temperature for 3 h. The excess
carbonate was filtered and the solvent was removed in vacuo.
The crude material was dissolved in EtOAc and the organic
layer was washed with aq NH4Cl solution (2ꢀ), water (3ꢀ), and
brine (2ꢀ). The organic layer was dried (MgSO4) and filtered
through a pad of silica then the solvent was removed in vacuo to
afford 8b (0.811 g, 72%) as a yellow oil, which was used without
further purification. 1H NMR (CDCl3) δ 7.74 (s, 1H), 7.49 (m,
2H), 3.83 (q, J=8.1 Hz, 4H), 3.30 (s, 1H), 1.31 (m, 6H). 13C
NMR (CDCl3) δ 155.4, 130.6, 126.4, 125.9, 125.8, 122.2, 117.1,
81.9, 80.7, 49.4, 42.1, 14.3, 10.6. IR (NaCl) ν 3309, 2979, 2938,
2876, 2111, 1652, 1327, 1253, 1102 1072 cm-1. HRMS (EIþ) for
C13H14N3F3: calcd 269.11398, found 269.11376.
r-Ketoester 9a. Ester 6a was cyclized according to General
Procedure C to give 9a (19 mg, 85%) as a yellow solid. 1H NMR
(CDCl3) δ 9.18 (d, J=2.1 Hz, 1H), 8.27 (dd, J=9.3, 2.1 Hz, 1H),
7.91 (d, J=9.3 Hz, 1H), 4.00 (s, 3H), 3.33 (q, J=7.2 Hz, 4H), 0.96
(t, J=7.2 Hz, 6H). 13C NMR (CDCl3) δ 177.1, 163.7, 147.4,
146.4, 131.7, 121.8, 120.1, 119.8, 119.7, 52.7, 52.3, 11.1. IR
(NaCl) ν 3111, 2982, 2926, 2873, 1741, 1663, 1575, 1522, 1456,
1344, 1266, 1038, 1029 cm-1. HRMS (EIþ) for C14H16N4O5:
calcd 320.11206, found 320.11071.
r-Hydroxyester 10a. Ester 6a was cyclized according to Gen-
eral Procedure D to give 10a (20 mg, 95%) as a tan solid. 1H NMR
(CDCl3) δ 8.67 (d, J=2.4 Hz, 1H), 8.14 (dd, J=9.9, 2.4 Hz, 1H),
7.73 (d, J=9.9 Hz, 1H), 5.95 (d, J=6.0 Hz, 1H), 4.14 (d, J=6.0 Hz,
1H), 3.80 (s, 3H), 3.51-3.22 (m, 4H), 0.93 (br t, 6H). 13C NMR
(CDCl3) δ 171.8, 147.2, 143.3, 135.9, 120.8, 118.8, 118.7, 116.0,
64.6, 53.5, 52.5, 52.4, 11.8. IR (NaCl) ν 3477 (br), 3103, 2978, 2922,
2852, 1749, 1627, 1569, 1516, 1334, 1216, 1116, 1080 cm-1. HRMS
(EIþ) for C14H18N4O5: calcd 322.12771, found 322.12795.
Computational Methods. All computations were calculated
with use of the Gaussian 0312 suite of programs at the B3LYP/6-
31G* level of theory.13 All stationary points were confirmed by
harmonic frequency analysis and checked for stability for triplet
and SCF convergence. The energies of the stationary points
were determined, including zero-point energies, at the same level
of theory. ACID calculations were performed (see the Support-
ing Information) by using the previously reported method of
Herges et al.16 with the ACID scalar fields interpreted as the
density of delocalized electrons.
Acknowledgment. We thank the National Science Foun-
dation (CHE-0718242) for support of this research. S.P.M.
acknowledges the NSF for an IGERT fellowship (DGE-
0549503). N.F. acknowledges the NSF for a summer under-
graduate STEP (UCORE) fellowship (DUE-0622620). We
thank Dr. Lev Zakharov for obtaining the X-ray structure of
10a. This publication was made possible, in part, by the Mass
Spectrometry Facilities and Services Core of the Environ-
mental Health Sciences Center, Oregon State University,
grant no. P30 ES00210, National Institute of Environmental
Health Sciences, National Institutes of Health.
Supporting Information Available: All computational de-
tails including Cartesian coordinates, total energies, and ima-
ginary frequencies for all computed structures as well as
transition state analysis; experimental details for 9b-h, 10b-
h, and 11a-c; copies of 1H and 13C NMR spectra for 5b, 6a-h,
7, 8, 9a-h, 10a-h, 11a-c; X-ray cif file for 10a. This material is
available free of charge via the Internet at http://pubs.acs.org.
(16) (a) Herges, R.; Geuenich, D. J. Phys. Chem. A 2001, 105, 3214–3220.
(b) Geuenich, D.; Hess, K.; Kohler, F.; Herges, R. Chem. Rev. 2005, 105,
3758–3772.
6636 J. Org. Chem. Vol. 74, No. 17, 2009