1,3-Dipolar cycloaddition of arynes with azomethine imines: synthesis of 1,2-dihydropyrazolo[1,2-a]indazol-3(9H)-ones

Article abstract of DOI:10.1016/j.tetlet.2009.04.102

A [3+2] 1,3-dipolar cycloaddition reaction of arynes with stable azomethine imines has been developed. The reaction rapidly assembles tricyclic pyrazoloindazolone derivatives in moderate yields under mild reaction conditions.

Full text of DOI:10.1016/j.tetlet.2009.04.102

Tetrahedron Letters 50 (2009) 4067–4070
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Tetrahedron Letters
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1,3-Dipolar cycloaddition of arynes with azomethine imines: synthesis
of 1,2-dihydropyrazolo[1,2-a]indazol-3(9H)-ones
Feng Shi a, Raffaella Mancuso b, Richard C. Larock a,
*
a Department of Chemistry, Iowa State University, Ames, IA 50011, USA
b Dipartimento di Chimica, Universitá della Calabria, 87036 Arcavacata di Rende, Cosenza, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
A [3+2] 1,3-dipolar cycloaddition reaction of arynes with stable azomethine imines has been developed.
The reaction rapidly assembles tricyclic pyrazoloindazolone derivatives in moderate yields under mild
reaction conditions.
Received 7 March 2009
Revised 11 April 2009
Accepted 24 April 2009
Available online 3 May 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1,3-Dipolar cycloadditions have been recognized as a powerful
tool for the synthesis of five-membered ring heterocycles.1 In addi-
tion to traditional dipolarophiles, such as alkynes and alkenes, ary-
nes readily undergo 1,3-dipolar cycloadditions to afford various
heterocycles.2–5 Although the initial success with arynes was re-
ported long ago,6 at that time the benzyne was generated using
hazardous diazotized anthranilic acid as the benzyne precursor.
Recent studies have demonstrated that benzynes can be conve-
niently generated from o-(trimethylsilyl)phenyl triflates (1) under
mild, non-hazardous, fluoride-promoted conditions.7 Arynes gen-
erated from these modern aryne precursors have been successfully
applied to 1,3-dipolar cycloaddition reactions of diazo compounds
to generate indazoles,2 azides to generate benzotriazoles,3 and nit-
rones to generate dihydrobenzo[d]isoxazoles.4 With our contin-
uing interest in aryne chemistry, especially aryne annulation
chemistry, we wish to report that azomethine imines (2)8
smoothly react with arynes generated from o-(trimethyl-
silyl)phenyl triflates under mild reaction conditions to furnish
the corresponding 1,2-dihydropyrazolo[1,2-a]indazol-3(9H)-ones
(3).
Azomethine imines (2), easily prepared via condensation of 3-
pyrazolidinone9 with various aldehydes,10 are isolable and stable
compounds. They have been shown to react with a variety of dipol-
arophiles.8,10a,b The reactivity of benzyne with this specific 1,3-di-
pole has been briefly examined using the hazardous benzyne
precursor diazotized anthranilic acid.6,11 This prompted us to re-
investigate the reactivity of this dipole with a more modern ben-
zyne precursor under fluoride-promoted conditions. To our sur-
prise, this approach was intentionally ‘excluded from
consideration’ in the previous investigation,11 because of the belief
that benzynes generated in this way involve the ‘intermediate
ortho-substituted phenyl anion’, which has ‘demonstrated ability’
‘to add to the iminium bond’. Herein, we wish to report our preli-
minary results in the [3+2] dipolar cycloaddition of azomethine
imines 2 with o-(trimethylsilyl)phenyl triflates as the benzyne pre-
cursors under fluoride-promoted conditions (Scheme 1).
We started by optimizing the reaction conditions using an
unsubstituted benzyne precursor (1a, X = H) and an azomethine
imine derived from 4-methoxybenzaldehyde (2a, R = 4-MeOC6H4)
(Table 1). Although this reaction was promising, it was not partic-
ularly clean. Somewhat surprisingly, unlike previous analogous
[3+2] cycloadditions we had examined,2–4 the yield seemed not
to be very dependent on the reaction conditions when 1.0 equiv
of 1a was used (entries 1–3). Regardless of the fluoride source, sol-
vent, and temperature, the desired product 3a (X = H, R = 4-
MeOC6H4) was obtained in moderate yields with incomplete con-
version, and the best result, a 55% yield, was obtained when using
TBAF (tetrabutylammonium fluoride) as the fluoride source (entry
3). In an attempt to drive the reaction to completion, higher load-
ings of the benzyne precursor 1a were employed (entries 4–9).
While we did observe higher conversion, and most reactions were
complete, the yields of the desired product actually dropped (com-
pare entry 4 with entry 3). After examining a number of reaction
conditions, none gave a yield higher than 55%. Crude 1H NMR spec-
tral analysis revealed that the reaction mixture is even dirtier than
those performed using a 1:1 stoichiometry. Varying the tempera-
ture, diluting the reaction mixture, or performing portionwise
addition of 1a (not shown) all resulted in significantly lower yields.
We have conducted a control experiment in which we allowed the
isolated product 3a to react with the benzyne precursor 1a under
the usual reaction conditions. We observed a nearly identical crude
1H NMR spectrum to that obtained in the reaction mixture of 2a
with excess 1a. Clearly, the lower yield employing a higher loading
of 1a was at least in part caused by some reaction of the benzyne
with 3a. Unfortunately, the reaction between 1a and 3a, or excess
1a with 2a, gave such a complex mixture that no useful informa-
tion could be obtained.12
* Corresponding author. Tel.: +1 515 294 4660; fax: +1 515 294 0105.
E-mail address: larock@iastate.edu (R.C. Larock).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.04.102

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F. Shi et al. / Tetrahedron Letters 50 (2009) 4067–4070
Table 2
O
O
Reaction scope of different benzyne precursorsa
F-
TMS
OTf
N
O
N
X
+
O
3
X
N
N
2
1
TMS
OTf
4
TBAT
N
N
+
X
R
R
X
N
MeCN
N
5
1
3
2
Ar
Ar
Scheme 1. General reaction of benzynes with azomethine imines.
1
3
2a
Ar = 4-MeOC6H4
Entry
X
Product
Yieldb (%)
Table 1
Reaction optimization (Scheme 1, X = H, R = 4-MeOC6H4)a
O
Entry
1a:2a
Fluoride/equiv
Conditions
Yieldb (%)
Me
Me
N
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
1:1
1:1
1:1
CsF/2.0
CsF/3.5
MeCN, rt, 1 d
THF, 70 °C, 1 d
MeCN, rt, 1 d
MeCN, rt, 1 d
THF, rt, 1 d
46
49
55
52
41
36
48
50
48
37
49
51
51
53
72
1
4,5-Me2 1b
36
N
TBAF/2.0
TBAF/3.0
TBAF/3.0
TBAF/3.0
TBAF/3.0
TBAF/3.0
TBAF/3.0
TBAF/3.0
TBAF/2.0
TBAF/1.75
TBAF/1.5
TBAF/1.25
TBAT/1.25
Ar
1.8:1
1.8:1
1.8:1
1.8:1
1.8:1
1.8:1
2.0:1
1.75:1
1.5:1
1.25:1
1.05:1
1.05:1
3b
DME, rt, 1 d
DCE, rt, 1 d
O
DCM, rt, 1 d
Acetone, rt, 1 d
MeCN, rt, 6 h
MeCN, rt, 6 h
MeCN, rt, 6 h
MeCN, rt, 6 h
MeCN, rt, 6 h
MeCN, rt, 1 d
MeO
N
2
4,5-(MeO)2 1c
50
N
MeO
Ar
3d
O
a
Reaction conditions: 0.35 mmol of 2a, 3.5 mL of solvent.
Isolated yield.
b
N
55c
N
3
3-MeO 1d
Ar
OMe
Understanding this unanticipated event, we performed a series
3e
of reactions with various loadings of 1a (entries 10–14). As the
loading of 1a decreased, the conversion of 2a also decreased, but
the yield of 3a actually increased, and the reaction got increasingly
cleaner. The best result, a 53% yield, was obtained at a near 1:1 ra-
tio of 1a:2a (entry 14), which was comparable to the result re-
a
Reaction conditions: 0.35 mmol of 2a, 1.05 equiv of 1, 1.25 equiv of TBAT, MeCN
(3.5 mL), rt, 2 d.
b
Isolated yield.
c
The product is a ꢀ19:1 regioisomeric mixture with the major isomer shown in
ported in entry 3. In
a
final attempt, we used TBAT
the table.
(tetrabutylammonium difluorotriphenylsilicate) as an alternative,
soluble fluoride source,13 and, to our pleasure, 3a was obtained
in a much improved 72% yield (entry 15).14 We therefore used this
fluoride and procedure as our standard conditions for further
studies.15
A couple of different benzyne precursors were next screened in
the reaction with azomethine imine 2a using these standard condi-
tions (Table 2). It was observed that electron-rich benzynes were
generated somewhat more slowly and longer reaction times were
needed. Even after 2 days, the crude 1H NMR spectra of these reac-
tions still showed unreacted benzyne precursors. Nonetheless, the
substituted benzynes still reacted with the azomethine imines
smoothly to afford the desired products in moderate yields. An
unsymmetrical 3-methoxybenzyne, generated from precursor 1d
(entry 3), showed good regioselectivity in this cycloaddition,
although related cycloadditions with other dipoles have given
exclusively one regioisomer.2,3
Additional azomethine imines have been tested using benzyne
precursor 1a under the standard reaction conditions (Table 3).
The reaction tolerates a broad range of functional groups, includ-
ing a halide (entry 2), an ester (entry 3), and an acetal (entry 4).
Substitution in the ortho position did not affect the cycloaddition
(entry 4). A variety of azomethine imines derived from heterocy-
clic aldehydes also worked in this cycloaddition, including pyridyl
(entry 5), furyl (entry 6), and pyrrolyl (entry 7). Azomethine imi-
nes derived from aliphatic aldehydes, such as cyclohexanecarbox-
aldehyde (entry 8) and 1-cyclohexene-1-carboxaldehyde (entry
9), proceeded as well, giving the desired adduct in 70% and 55%
yields, respectively. In most cases, the reaction afforded the tricy-
clic adduct in moderate yields.16 However, the yields of the prod-
uct significantly dropped as the solubility of the azomethine
imines in MeCN decreased (entries 4, 6, and 7). In these cases,
running the same reaction in DCM may give a marginal improve-
ment in the yield.17 A gem-dimethyl group on the pyrazolidinone
moiety was found to significantly improve the yield of the reac-
tion (entries 10–12). For instance, azomethine imine 2g derived
from 5-methylfurfuraldehyde without the gem-dimethyl afforded
product 3j in only a 29% yield (entry 6). However, azomethine
imine 2l derived from the same aldehyde, but bearing the gem-
dimethyl moiety, resulted in a dramatic increase in yield to 71%
(entry 11). We believe that the improved yields in these cases
(also compare entry 12 with entry 8) due to the gem-dimethyl
group largely arise from the increased solubility of these azome-
thine imines in the solvent.
In conclusion, we have developed a method for the [3+2] dipo-
lar cycloaddition of arynes using modern aryne precursors with
stable azomethine imines under mild reaction conditions. The
reaction provides tricyclic 1,2-dihydropyrazolo[1,2-a]indazol-
3(9H)-ones in moderate to good yields. More applications of arynes
in dipolar cycloaddition reactions are currently underway in our
laboratory.

F. Shi et al. / Tetrahedron Letters 50 (2009) 4067–4070
4069
Table 3
Table 3 (continued)
Reaction scope of different azomethine iminesa
Yieldb (%)
O
Entry
R/Z
Product
O
TMS
TBAT
O
N
N
+
Z
N
Z
MeCN
N
OTf
1a
Z
N
Z
R
N
R
7c
R = N-methylpyrrolyl
Z = H
20
70
55
81
3
2
Me
N
2h
Entry
R/Z
Product
Yieldb (%)
O
3k
N
N
O
N
1
R = 3-MeOC6H4
Z = H
2b
57
N
8
R = Cy
Z = H
2i
MeO
3e
O
3l
N
N
O
2
R = 4-ClC6H4
Z = H
2c
63
N
N
9
R = 1-cyclohexenyl
Z = H
2j
Cl
3f
O
3m
N
O
N
3
R = 4-(MeO2C)C6H4
Z = H
2d
62
N
Me
Me
N
10
R = 3-MeOC6H4
Z = Me
2k
CO2Me
3g
OMe
O
3n
O
N
N
4
R = 2,3-OCH2O
Z = H
2e
38
O
O
N
Me
Me
N
11
R = 5-methylfuryl
71
Z = Me
2l
3h
O
O
Me
3o
N
N
ꢀ50d
O
N
5
R = 3-pyridyl
Z = H
2f
Me
Me
N
N
3i
12
R = Cy
Z = Me
2m
85
O
3p
N
N
6c
R = 5-methylfuryl
29
a
Reaction conditions: 0.50 mmol of 2, 1.05 equiv of 1a, 1.25 equiv of TBAT, MeCN
Z = H
2g
(5 mL), rt, 1 d.
O
b
c
Isolated yield.
This reaction was performed in DCM.
Me
d
The product is contaminated with tetrabutylammonium salt. The yield is based
3j
on the weight and the 1H NMR spectroscopic ratio of the product and the ammo-
nium salt.

4070
F. Shi et al. / Tetrahedron Letters 50 (2009) 4067–4070
11. Taylor, E. C.; Sobieray, D. M. Tetrahedron 1991, 47, 9599–9620.
Acknowledgments
12. We have observed that different side-products were obtained under different
reaction conditions.
We thank the National Institute of General Medical Sciences
(GM070620 and GM079593) and the National Institutes of Health
Kansas University Center of Excellence in Chemical Methodology
and Library Development (P50 GM069663) for their generous
financial support. We also thank Mr. Donald C. Rogness for his help
in preparation of the aryne precursors.
13. (a) Pilcher, A. S.; DeShong, P. J. Org. Chem. 1996, 61, 6901–6905; For other
examples utilizing TBAT as the fluoride source in benzyne chemistry, see: (b)
Gilmore, C. D.; Allan, K. M.; Stoltz, B. M. J. Am. Chem. Soc. 2008, 130, 1558–1559;
(c) Hayes, M. E.; Shinokubo, H.; Danheiser, R. L. Org. Lett. 2005, 7, 3917–3920.
14. Representative procedure (entry 15, Table 1): An oven-dried one-dram vial
equipped with a stirrer bar was charged with 110 mg of 1a (1.05 equiv) and
72 mg of 2a (0.35 mmol), followed by 3.5 mL of dry MeCN. The mixture was
briefly stirred and 235 mg of TBAT (1.25 equiv) was added in one portion. The
vial was sealed, wrapped with ParafilmÒ and stirred at room temperature for
1 day. The resultant mixture was poured into an aqueous solution of NaHCO3
and extracted three times with DCM. The combined DCM extracts were dried
over MgSO4, evaporated, and the residue was purified by column
chromatography (1:1–1:1.5 hexanes/EtOAc) to afford 71 mg of product 3a
(72%) as a slightly yellow solid; mp 154–156 °C; 1H NMR (400 MHz, CDCl3) d
7.62 (d, J = 7.8 Hz, 1H), 7.33 (d, J = 8.6 Hz, 2H), 7.30 (t, J = 7.7 Hz, 1H), 7.05 (t,
J = 7.5 Hz, 1H), 6.94 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 7.5 Hz, 1H), 5.10 (s, 1H), 3.83
(s, 3H), 3.55–3.60 (m, 1H), 3.02–3.18 (m, 2H), 2.79–2.85 (m, 1H); 13C NMR
(100 MHz, CDCl3) d 162.5, 159.8, 135.3, 133.7, 130.2, 129.6, 128.6, 124.8, 123.7,
114.2, 112.7, 74.0, 55.3, 52.0, 36.7; HRMS (EI): calcd for C17H16N2O2 280.1212,
found 280.1216. Note: Most products exhibit air-sensitivity presumably
through oxidation of the methine C–H bond in the central five-membered
ring. Solid samples can be stored well, but most samples in solution readily
decompose. All of the work-up, purification, and characterization should be
performed as quickly as possible, and storing samples as solutions should be
avoided.
References and notes
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15. At least in the case of TBAT, running the reaction with a higher loading of 1a for
a shortened reaction time did not improve the yield.
16. It should be pointed out that the azomethine imine derived from N-methyl 3-
indolecarboxaldehyde reacted with 1a to afford exclusively a 1:2 adduct in
quantitative yield. We have not yet been able to unambiguously assign the
structure of this product.
17. Most azomethine imines are more soluble in DCM than in acetonitrile.
Reactions in DCM are cleaner, but slower. After 1 d of reaction time, the
benzyne precursors were not generally fully consumed. These reactions were
not further optimized in terms of reaction time and mixed solvents.
6. Huisgen, R.; Knorr, R. Naturwissenschaften 1962, 48, 716.
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