Aza-Nazarov cyclization cascades

Article abstract of DOI:10.1016/j.tetlet.2010.11.164

Benzamides with tethered acetal groups undergo reactions in CF ₃SO₃H to give ring-fused isoindolinones by a cyclization cascade. The reaction initially forms an N-acyliminium ion which then gives the isoindolinone by the aza-Nazarov

Full text of DOI:10.1016/j.tetlet.2010.11.164

Tetrahedron Letters 52 (2011) 2195–2198
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Tetrahedron Letters
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Aza-Nazarov cyclization cascades
⇑
Kiran Kumar Solingapuram Sai, Matthew J. O’Connor, Douglas A. Klumpp
Department of Chemistry, Northern Illinois University, DeKalb, IL 60115, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Available online 7 December 2010
Benzamides with tethered acetal groups undergo reactions in CF3SO3H to give ring-fused isoindolinones
by a cyclization cascade. The reaction initially forms an N-acyliminium ion which then gives the isoind-
olinone by the aza-Nazarov reaction. An unusual variant also cyclizes at the allylic position.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Heterocycles
Aza-Nazarov
Superacid
N-Acyliminum ions
Cyclization
The Nazarov reaction is an acid-catalyzed cyclization involving
the divinyl ketones and related compounds.1 This reaction has
been useful in carbocyclic synthesis, including utilization in natu-
ral products and pharmaceutical agent syntheses. The mechanism
EtN
CF3
O
OMe
OMe
H
N
N
N
O
NH
HO
of this conversion generally involves a concerted, 4p-electron
1
2
electrocyclization. Recently, there have been several reports of
aza-Nazarov reactions in which the nitrogen atoms have been
incorporated into the new ring.2 Our own studies showed that
N-acyliminium ions may undergo cyclization in the presence of
superacidic CF3SO3H to give nitrogen heterocycles (Eq. 1).2d We
proposed the involvement of superelectrophilic, dicationic species
in these conversions. In these studies, the requisite N-acyliminium
ions were prepared by the direct acylation of imines using
carboxylic acid chlorides.
OH
O
Me
N
3
F
Scheme 1.
Cl
2 TfO
quinolinones via N-acyliminium ions by the acid-catalyzed
reactions of phenylacetamides having tethered acetal groups.7
Another recent report described an N-acyliminium ion cyclization
cascade done with a ketoamide.8 In the following Letter, we report
a new route to the ring-fused aza-Nazarov products. This chemistry
utilizes acid-promoted reactions of acetals, aldehydes and enamides
to generate the intermediate N-acyliminium ions. Subsequent
cyclizations then give the ring-fused aza-Nazarov products.
Our studies began with the syntheses of a series of acetal
derivatives (4–9, Table 1). The compounds were prepared from
the corresponding carboxylic acid chlorides and 4,4-diethoxy-1-
butanamine. In reactions with CF3SO3H, the heterocyclic products
were obtained in fair to good yields (entries 1–4). In an effort to cy-
clize into olefinic sites, indene and dihydronaphthalene derivatives
(8–9) were also reacted in superacid. However, products (19–20)
were obtained from cyclization at the methyl carbon. We also ex-
plored the option of cyclizing alcohol substrates (entries 7–11).
O
OH
O
Me
Me
Ph
CF3SO3H
56%
N
N
ð1Þ
N
Me
Ph
Ph
The products from our reactions were derivatives of isoindoli-
nones. This class of compounds is well known for a variety of bio-
logical activities. The 5-HT2c agonist (1),3 urotensin-II receptor
antagonist (2),4 and HIV-1 integrase inhibitor (3)5 are representa-
tive examples of the biologically active isoindolinones (Scheme 1).
N-Acyliminium ions may be generated by a number of methods.6
For example, King and coworkers prepared pyrrolo-tetrahydroiso-
⇑
Corresponding author. Tel.: +1 815 753 1959.
E-mail address: dklumpp@niu.edu (D.A. Klumpp).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.164

2196
K. K. S. Sai et al. / Tetrahedron Letters 52 (2011) 2195–2198
Table 1
Products and yields from cyclization cascades
Entry
Substrate
Product
Yield (%)
69
O
O
O
MeO
MeO
MeO
OEt
N
H
N
(1)
OEt
MeO
4
OMe
OMe
OMe
OMe
15a
O
MeO
MeO
OEt
N
N
H
(2)
(3)
76
71
OEt
5
16a
O
O
O
MeO
MeO
MeO
MeO
OEt
OEt
N
N
H
17a
6
O
MeO
MeO
OEt
N
N
(4)
(5)
(6)
66
63
64
H
OEt
7
18a
O
O
OEt
N
N
H
OEt
8
19a
O
O
OEt
N
N
H
OEt
20a
9
O
O
S
S
(CH2)5OH
N
N
(7)
(8)
40c
H
10
21b
O
O
MeO
HO
MeO
MeO
(CH2)5OH
N
N
H
43
OMe
OMe
22b
11
O
O
MeO
MeO
(CH2)5OH
N
N
H
(9)
81
53
OMe
OMe
O
23b
12
O
N
HN (CH2)5OH
(10)
13
24b
O
(CH2)5OH
N
N
H
O
(11)
45
OMe
OH
25b
14
a
b
c
Product from CF3SO3H.
Product from PCC oxidation, followed by reaction with CF3SO3H.
Isolated yields, calculated from conversions of enamides to final products.
These substrates were prepared from the 5-amino-1-pentanol and
the respective acid chlorides. The conversions were accomplished
by initially oxidizing the alcohol substrates with PCC. In all cases,
the intermediate enamides (26–30) were formed and could be iso-
lated. For example, substrate 12 gives the enamide 26 by reaction
with PCC (Eq. 2). Further reaction with CF3SO3H gives the aza-Naz-
arov cyclization products (21–25). In some cases, demethylation of
the ether groups was also observed in the major product (entries 8

K. K. S. Sai et al. / Tetrahedron Letters 52 (2011) 2195–2198
2197
O
O
and 11). With compound 4, demethylation of the para-methoxy
MeO
MeO
H
group also occurs (similar to compound 22), but it is a minor side
reaction. Demethylation could be suppressed by carrying out the
reaction with short reaction time. For the naphthyl systems (13
and 14), two types of cyclization were observed. Compound 13 fa-
vored the cyclization to form the six-member heterocyclic ring
(24), while compound 14 reacted to give the aza-Nazarov product
(25).
N
N
MeO
OMe
OMe
36
TfO
35
ð5Þ
H
OH
N
MeO
O
O
MeO
(CH2)5OH
MeO
PCC
N
N
H
OMe
TfO
37
OMe
OMe
12
26
The reactions of compounds 8 and 9 are quite unusual, giving
products from reaction at the methyl group. It is proposed that
these conversions are the result of equilibria between the N-acyli-
minium ion and an enol tautomer (Eq. 6). For example, compound
8 reacts in the superacid to give the N-acyliminium ion (38). Fur-
ther reaction with the CF3SO3H gives the superelectrophile 39
which then gives the enol-type structure 40. This leads to product
O
O
MeO
MeO
N
S
N
ð2Þ
OMe
27
28
O
formation, either through a concerted 6p-electron electrocycliza-
N
tion or a stepwise electrophilic reaction. DFT calculations at the
B3LYP 6-311G (d,p) level estimate the energy of structure 40 to
be about 20 kcal/mol above the N-acyliminium ion 38 (Fig. 1).9 This
energy difference is similar to other keto-enol tautomeric struc-
tures.10 Regarding the role of the superelectrophile (39), it has been
shown in several recent studies that formation of superelectro-
philes can greatly enhance the acidities of adjacent carbon–hydro-
gen bonds.11 Thus, formation of the superelectrophile may lead to a
relatively low energy barrier between ions 38 and 40.
N
O
OMe
29
30
Although the conversions have not been fully optimized, reac-
tion of compound 5 with 25 equiv of CF3SO3H gives a complete
conversion to the heterocyclic product (16) in just 15 min (isolated
yield 76%). Decreasing amounts of CF3SO3H give successively lower
yields of product. With 1.0 equiv of acid, product 16 is formed in
just 26% yield. Compounds 31–32 did not give the expected aza-
Nazarov cyclization products, but the corresponding enamides
33–34 are major products from reactions in superacid (Eqs. 3 and
4).
O
OH
N
H
N
38
39
40
-H
OH
N
OH
N
O
O
-H
ð6Þ
OEt
OEt
S
CF3SO3H
CHCl3
S
N
H
N
ð3Þ
ð4Þ
31
33
-H
O
O
O
OEt
OEt
CF3SO3H
CHCl3
N
N
N
O
O
H
19
32
34
In summary, the conversions described above demonstrate that
aza-Nazarov products may be prepared by superacid-promoted
reactions involving amides with tethered acetal and aldehyde
groups (which convert into enamides).12,13 These aza-Nazarov
reactions are shown to produce ring-fused isoindolone derivatives.
This represents a convenient route to a class of compounds known
to possess a broad spectrum of biological activities.12
The cyclizations of the acetal derivatives (4–7) occur through
the formed N-acyliminium ions (Eq. 5). In the case of 5, ionization
of the acetal leads to cyclization at the amide nitrogen and
formation of compound 35. Further ionization leads to the N-
acyliminium ion 36, where protosolvation can then lead to the
superelectrophile (37). As shown in our previous report,2d
formation of the superelectrophile (i.e., 37) significantly lowers
the transition state energy barrier leading to the aza-Nazarov
product. It is also expected that partial protonation of the carbonyl
group could help facilitate the aza-Nazarov cyclization. Analysis of
some product mixtures indicated the presence of minor amounts
of enamides. These are likely formed during the reaction workup
from unreacted N-acyliminium ion. In the reactions of alcohol sub-
strates 10–14, oxidation to the aldehydes leads to the formation of
the enamide-type products (i.e., 26). Upon reaction of the super-
acid, the enamides are protonated and give the N-acyliminium
ions. The resulting N-acyliminium ions then undergo the aza-
Nazarov cyclization.
E+ZPE,
Hartrees
-710.870390
-710.836923
OH
O
N
N
38
40
21.0
Relative Energy,
kcal•mol-1
0.0
Figure 1. Relative energies of ions 38 and 40.

2198
K. K. S. Sai et al. / Tetrahedron Letters 52 (2011) 2195–2198
13. Analytical data: Compound 15, mp 119–122 °C; 1H NMR (500 MHz, CDCl3) d:
Acknowledgments
7.08 (s, 1H), 4.64 (q, 1H, J = 5 Hz), 3.96 (s, 3H), 3.94 (s, 3H), 3.92 (s, 3H), 3.66 (q,
1H, J = 8 Hz), 3.39 (t, 1H, J = 9 Hz), 2.39–2.30 (mult, 3H), 1.26–1.15 (mult, 1H);
13C NMR (500 MHz, CDCl3) d: 171.4, 155.2, 148.4, 144.1, 143.6, 131.8, 129.0,
102.0, 62.6, 61.0, 56.3, 41.8, 29.8, 29.6. Low-resolution mass spectra, EI: 263
(M+), 235, 220, 192. Compound 16, mp 141–143 °C; 1H NMR (500 MHz, CDCl3)
d: 6.88 (s, 1H), 6.57 (s, 1H), 4.60 (q, 1H, J = 5 Hz), 3.85 (s, 3H), 3.83 (s, 3H), 3.66
(q, 1H, J = 8 Hz), 3.40 (t, 1H, J = 7 Hz), 2.37–2.29 (mult, 3H), 1.18–1.14 (mult,
1H); 13C NMR (500 MHz, CDCl3) d: 171.6, 161.9, 155.5, 135.9, 127.6, 102.5, 97.9,
62.7, 55.8, 55.5, 41.7, 29.7, 29.4; Low-resolution mass spectra, EI: 233 (M+),
205, 190, 162. Compound 17, mp 141–143 °C. 1H NMR (500 MHz, CDCl3) d:
6.88 (s, 1H), 6.57 (s, 1H), 4.60 (q, 1H, J = 5 Hz), 3.85 (s, 3H), 3.83 (s, 3H), 3.66 (q,
1H, J = 8 Hz), 3.40 (t, 1H, J = 7 Hz), 2.37–2.29 (mult, 3H), 1.18–1.14 (mult, 1H);
13C NMR (500 MHz, CDCl3) d: 171.6, 161.9, 155.5, 135.9, 127.6, 102.5, 97.9,
62.7, 55.8, 55.5, 41.7, 29.7, 29.4; Low-resolution mass spectra, EI: 233 (M+),
205, 190, 162. Compound 18, mp 120–123 °C. 1H NMR (500 MHz, CDCl3) d:
7.28 (d, 1H, J = 8 Hz), 7.20 (s, 1H), 7.02 (d, 1H, J = 8 Hz), 4.56 (q, 1H, J = 5 Hz),
3.75 (s, 3H), 3.64 (q, 1H, J = 8 Hz), 3.35 (t, 1H, J = 6 Hz), 2.32–2.19 (mult, 3H),
1.20–1.11 (mult, 1H); 13C NMR (500 MHz, CDCl3) d: 171.6, 160.1, 138.7, 134.9,
123.4, 119.7, 106.7, 64.2, 55.5, 41.9, 29.6, 29.2; Low-resolution mass spectra,
EI: 203 (M+), 175, 147, 132. Compound 19, mp 104–106 °C; 1H NMR (500 MHz,
CDCl3) d: 7.43 (d, 1H, J = 7 Hz), 7.40–7.35 (mult, 1H), 7.36–7.29 (mult, 2H),
3.94–3.92 (mult, 1H), 3.78–3.72 (mult, 2H), 3.63–3.56 (mult, 2H), 3.06 (dd, 1H,
J = 12 Hz), 2.54–2.46 (mult, 1H), 2.34–2.29 (mult, 1H), 2.11–2.07 (mult, 1H),
1.89–1.85 (mult, 1H), 1.83–1.77 (mult, 1H); 13C NMR (500 MHz, CDCl3) d:
163.2, 148.6, 145.1, 142.3, 135.7, 127.2, 126.6, 124.6, 120.4, 58.2, 43.8, 35.7,
33.4, 29.6, 23.4; Low-resolution mass spectra, EI: 225 (M+), 156, 128, 70.
Compound 20, 1H NMR (300 MHz): d 1.70–1.95 (m, 2H), 2.05–2.15 (m, 1H),
2.27–2.36 (m, 1H), 2.41–2.57 (m, 2H), 2.67–2.97 (m, 4H), 3.51–3.62 (m, 1H),
3.67–3.85 (m, 2H), 7.20–7.32 (m, 4H); 13C NMR (DEPT results in parentheses;
300 MHz, CDCl3): d 21.6 (CH2), 23.1 (CH2), 28.0 (CH2), 31.1 (CH2), 33.7 (CH2),
44.4 (CH2), 55.9 (CH), 123.3 (CH), 126.5 (CH), 127.8 (CH), 128.6 (CH), 129.1 (C),
133.8 (C), 137.5 (C), 138.6 (C), 164.6 (C); Low-resolution mass spectrum, EI:
239 [M+], 238, 170, 141, 115. HRMS C16H16ON (MꢁH) calcd, 238.12319, found
238.12258. Compound 21, MP 119–124 °C; 1H NMR (300 MHz, CDCl3): d 1.44–
1.57 (m, 1H), 1.62–1.78 (m, 2H), 1.81–1.90 (m, 1H), 1.98–2.08 (m, 1H), 2.53–
2.59 (m, 1H), 3.00–3.10 (m, 1H), 4.43–4.50 (m, 2H), 7.42–7.48 (m, 2H); 13C
NMR (300 MHz, CDCl3): d 23.4, 25.8, 31.8, 40.3, 58.2, 122.2, 124.5, 125.0, 126.0,
132.4, 146.1, 150.2, 162.9; Low-resolution mass spectrum, EI: 243 [M+], 214,
186, 160. HRMS C14H13ONS calcd, 243.07179, found 243.07083. Compound 22,
mp 171–179 °C; 1H NMR (500 MHz, CDCl3) d, 1.07 (m, 1H), 1.36–1.44 (m, 1H),
1.64–1.67 (m, 1H), 1.75–1.84 (m, 1H), 1.92–2.03 (m, 1H), 2.51–2.58 (m, 1H),
2.96 (dt, J = 13, 3.5 Hz, 1H), 3.93 (s, 3H), 3.98 (s, 3H), 4.28–4.32 (m, 1H), 4.43–
4.46 (m, 1H), 7.14 (s, 1H); 13C NMR (500 MHz, CDCl3) d, 23.7, 25.4, 31.4, 39.9,
56.6, 57.7, 60.4, 100.9, 123.7, 131.3, 141.3, 141.8, 148.5, 166.2; Low-resolution
mass spectrum, EI: 263 [M+], 262, 232, 206, 165. HRMS C14H17O4N calcd,
263.11576, found 263.11501. Compound 23, mp 121–124 °C. 1H NMR
(500 MHz, CDCl3) d, 6.71 (s, 1H), 6.33 (s, 1H), 4.24 (d, 1H, J = 10 Hz), 3.99 (d,
1H, J = 10 Hz), 3.63 (s, 3H), 3.59 (s, 3H), 2.75 (t, 1H, J = 10 Hz), 2.36 (d, 1H,
J = 10 Hz), 1.73 (d, 1H, J = 12 Hz), 1.59 (d, 1H, J = 12 Hz), 1.42 (q, 1H, J = 13 Hz),
1.15 (q, 1H, J = 10 Hz), 0.78 (q, 1H, J = 10 Hz); 13C NMR (500 MHz, CDCl3) d,
165.6, 161.4, 155.3, 134.6, 126.3, 101.7, 97.9, 57.4, 55.5, 55.1, 39.5, 30.9, 25.4,
23.3; Low-resolution mass spectra (EI): 247 (M+), 216, 191, 114. Compound 24,
1H NMR (300 MHz, CDCl3): d, 1.58–1.72 (m, 2H), 1.72–1.86 (m, 2H), 1.93–2.14
(m, 2H), 2.71 (dt, J = 12.6, 2.7 Hz, 1H), 4.84 (d, J = 11.7 Hz, 1H), 5.07–5.12 (m,
1H), 7.30 (d, J = 7.2 Hz, 1H), 7.45–7.59 (m, 2H), 7.74–7.77 (d, J = 8.4 Hz, 1H),
7.91–7.94 (m, 1H), 8.35 (dd, J = 7.2, 0.9 Hz, 1H); 13C NMR (300 MHz, CDCl3): d,
25.6, 25.9, 39.2, 44.0, 61.2, 122.8, 124.3, 126.0, 126.1, 126.3, 126.3, 127.3,
131.2, 132.4, 133.0, 161.4; Low-resolution mass spectrum, EI: 237 [M+], 236,
208, 182, 153. HRMS C16H15ON calcd, 237.11537, found 237.11414. Compound
25, mp 149–151 °C; 1H NMR (500 MHz, CDCl3): d, 1.54–1.61 (m, 1H), 1.84–1.92
(m, 2H), 1.97–2.20 (m, 1H), 2.28–2.34 (m, 1H), 2.87 (dt, J = 13.5, 4.0 Hz, 1H),
3.95–3.98 (m, 1H), 4.61–4.64 (m, 1H), 5.30 (dd, J = 10, 4 Hz, 1H), 7.30 (s, 1H),
7.40–7.43 (m, 1H), 7.52–7.55 (m, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.92 (d, J = 8.5,
1H), 8.57 (s, 1H); 13C NMR (500 MHz, CDCl3): d, 21.4, 23.7, 31.7, 41.6, 85.9,
111.4, 118.2, 124.8, 126.7, 128.5, 129.2, 129.5, 129.8, 136.6, 152.7, 163.1; Low-
resolution mass spectrum, EI: 253 [M+], 170, 142, 114, 83. HRMS C16H15O2N
calcd, 253.11028, found 253.10933. Compound 26, mp 166–169 °C. 1H NMR
(500 MHz, CDCl3) d: 7.00 (s, 1H), 4.61 (q, 1H, J = 10 Hz), 3.89 (s, 3H), 3.79 (s,
3H), 3.56 (q, 1H, J = 8 Hz), 3.31 (t, 1H, J = 9 Hz), 2.32–2.22 (mult, 3H), 1.19–1.12
(mult, 1H); 13C NMR (500 MHz, CDCl3) d: 172.0, 149.0, 141.9, 132.2, 124.4, 62.7,
60.3, 56.5, 41.8, 29.8, 29.5, 29.1; Low-resolution mass spectra, EI: 249 (M+),
221, 206, 178.
We gratefully acknowledge the support of the National Science
Foundation (CHE-0749907) and the NIH–National Institutes of
General Medical Sciences (GM085736-01A1). We also thank Ms.
Anila Kethe for assistance in preparing this manuscript.
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11. Olah, G. A.; Klumpp, G. A. Superelectrophiles and their Chemistry; Wiley & Sons:
New York, 2008. pp 126–127.
12. Typical synthetic procedure: The 4-aminobutyraldehyde diethyl acetal
(1.0 mmol) was dissolved in 10 mL of dry dichloromethane, followed by the
addition of 2.0 equiv of NEt3 at 0 °C. To this cold reaction mixture, the acid
chloride (1.1 equiv dissolved in 4 mL of dry dichloromethane) was slowly
added through an addition funnel. The reaction mixture was stirred for 4 h at
25 °C and then quenched using 10 g of ice. The solution was extracted twice
with dichloromethane, washed twice with saturated NH4Cl, thrice with brine
solution, and then dried over anhydrous sodium sulfate. The tethered acetals
were isolated by column chromatography and characterized by NMR analysis.
The tethered acetal (4–9, 0.4 mmol) or the enamide (from alcohols 10–14,
0.4 mmol) is dissolved in 2 mL of CHCl3 to which is added triflic acid (2 mL,
22 mmol). The mixture is stirred for 5 h at 25 °C and then poured over 10 g of
ice. The solution is extracted with chloroform (3 ꢀ 20 mL) and the organic
solution is washed successively with water and brine. The solution is dried
(Na2SO4) and the product is isolated using column chromatography (hexanes/
Et2O).