Activation of the NC-H bond of Baylis-Hillman adducts of N-methylisatin with CAN/ROH

Article abstract of DOI:10.1016/j.tetlet.2006.07.070

A facile method for activation of the NC-H bond of N-methylisatin and Baylis-Hillman adducts of N-methylisatin with cerium ammonium nitrate (CAN) and saturated and unsaturated alcohols is reported. Adducts bearing an ester group at the activated alkene afford functionalized ethers, while those with a nitrile afforded ethers and nitrated aromatic products in good yield.

Full text of DOI:10.1016/j.tetlet.2006.07.070

Tetrahedron Letters 47 (2006) 6851–6855
Activation of the NC–H bond of Baylis–Hillman adducts
of N-methylisatin with CAN/ROH
Ponnusamy Shanmugam,* Vadivel Vaithiyanathan and Baby Viswambharan
Chemical Sciences and Technology Division, Regional Research Laboratory (CSIR), Thiruvananthapuram 695 019, Kerala, India
Received 25 May 2006; revised 6 July 2006; accepted 13 July 2006
Available online 8 August 2006
Dedicated to Professor Dr. Martin F. Semmelhack, Princeton University, NJ, USA, on the occasion of his forthcoming 65th birthday
Abstract—A facile method for activation of the NC–H bond of N-methylisatin and Baylis–Hillman adducts of N-methylisatin with
cerium ammonium nitrate (CAN) and saturated and unsaturated alcohols is reported. Adducts bearing an ester group at the acti-
vated alkene afford functionalized ethers, while those with a nitrile afforded ethers and nitrated aromatic products in good yield.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
HO
CO2Me
Activation of C–H bonds by oxidative processes1 and by
HO
organometallic reagents2 has been of great interest to
O
N
CO2Me
organic chemists in recent years. Cerium(IV) ammo-
nium nitrate (CAN) has emerged as a versatile reagent
for a variety of synthetic transformations, which have
been well documented.3 The synthetic versatility of isa-
tin and its derivatives has led to the extensive use of this
compound in organic synthesis.4 Amongst the various
carbon–carbon bond forming reactions, the Baylis–Hill-
man reaction is an important reaction giving rise to den-
sely functionalized molecules and is considered to be
atom economic.5 In continuation of our research in
the area of novel synthetic applications of Baylis–Hill-
man adducts,6 we were interested to study the C–H acti-
vation of Baylis–Hillman derivatives of N-methylisatin
with CAN as a one electron oxidant and with a number
of alcohols as reagents. The details of this study are the
subject matter of this letter.
Me
CH3OH, CAN (4 equiv.),
RT, 24 h
O
O
60%
2
N
+
O2N
HO
1
CO2Me
O
N
30%
3
Scheme 1. Optimization of the NC–H activation with CAN/MeOH.
adduct 1 was treated with 4 equiv of CAN in the
presence of excess methanol at room temperature to
afford the NC–H oxidized ether derivative 2 in 60%
yield along with the nitrated product 3 in 30% yield
(Table 1, entry 1). The compounds were separated by
column chromatography and characterized by spectral
techniques.
2. Results and discussion
To check the selectivity and effect of the substituents,
various Baylis–Hillman adducts were investigated.
Nitrile bearing adduct 4 afforded the corresponding
ether 5 and the nitrated compound 6 in 50% and 30%
yields, respectively (Table 1, entry 2). The sulfone bear-
ing adduct 7 afforded compounds 8 and 9 in only trace
amounts (Table 1, entry 3). Interestingly, the simple
N-methylisatin 10, under optimized conditions, yielded
only the nitrated product 11 in 15% yield. Other
N-methylisatin derivatives such as the bromo compound
The studies were initiated using the Baylis–Hillman
adduct of N-methylisatin 1 as a starting material. The
preliminary results are outlined in Scheme 1. Thus,
Keywords: CAN; Baylis–Hillman adduct; CH-activation; Isatin; Func-
tionalized ethers.
*
Corresponding author. Tel.: +91 471 2515275; fax: +91 471
2491712; e-mail: shanmu196@rediffmail.com
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.07.070

6852
P. Shanmugam et al. / Tetrahedron Letters 47 (2006) 6851–6855
Table 1. Optimization of CH-activation reactions of isatin derivativesa
Entry
Substrate
Products
Yield (%)
C–H activated (A)
Nitrate (B)
(A)
60
(B)
30
HO
O2N
HO
HO
N
CO2Me
CO2Me
CO2Me
1
O
N
O
O
N
3
1
O
2
HO
CN
O2N
HO
N
HO
N
CN
CN
2
3
50
30
O
N
O
O
4
6
O
5
HO
HO
N
O2N
HO
N
SO2Ph
SO2Ph
SO2Ph
Trace
Trace
O
N
O
O
7
9
O
8
O2N
O
O
4
5
6
7
—
—
—
—
—
—
—
—
15
—
—
—
O
O
N
N
10
11
MeO2C
Br
—
—
—
O
N
12
CO2Me
O
N
13
N
OH
O
N
14
a Reagents and conditions; CAN (4 equiv), MeOH, rt, 24 h.
12, N-methyl-3-spirocyclopropyl-2-indolone 13 and oxime
derivative 14 did not yield any NC–H activated ether
product or nitrated product.
NC–H activated ether 15 in moderate yield. In order
to functionalize the N-methyl group with unsaturated
systems, the reaction of adduct 1 with propargyl
alcohol and homopropargyl alcohol afforded highly
functionalized NC–H activated ethers 16 and 17 in
good yields (Table 2, entries 2 and 3). The reaction of
When acetonitrile was used as a solvent, with 4 equivs of
alcohol and 4 equiv of CAN, higher yields were obtained
than when methanol was used in excess as reagent and
solvent. Hence, we chose acetonitrile as the solvent in
the rest of our studies. Thus, according to preliminary
experiments, only Baylis–Hillman adducts bearing nitrile
and ester groups underwent the desired NC–H activation
reaction under the optimized reaction conditions. All the
new compounds were characterized by spectroscopic
(IR, 1H and 13C NMR) and HRMS data.
HO
Z
HO
O
Z
N
ROH (4 equiv.), CAN (4 equiv.),
CH3CN (1 mL), RT, 24 h
R
51-67%
25-65%
O
+
HO
O
O2N
N
Z
Encouraged by these results, we were interested to dem-
onstrate the generality of the reaction of Baylis–Hillman
adducts of N-methylisatin 1 with various alcohols
(Scheme 2). Thus, the reaction of the Baylis–Hillman
adduct 1 with ethanol (Table 2, entry 1) afforded
Z = CO2CH3, CN
O
R=CH3, C2H5, propargyl, homopropargyl, ethane-1,2-diol,
propane-1,2-diol, benzyl, isopropanol, -butanol
N
t
Scheme 2. Generality of the NC–H activation with various alcohols.

P. Shanmugam et al. / Tetrahedron Letters 47 (2006) 6851–6855
Table 2. Generality of the C–H activation with various alcoholsa
6853
Entry
Substrate
Alcoholb
Products
Nitrate (B)
Yield (%)
Ether (A)
A
B
HO
HO
N
CO2Me
CO2Me
1
EtOH
O
—
52
—
N
O
O
1
15
HO
N
HO
CO2Me
CO2Me
2
3
Propargyl alcohol
—
51
58
—
25
O
N
O
O
16
1
1
HO
O2N
HO
N
HO
N
CO2Me
CO2Me
CO2Me
Homopropargyl alcohol
O
N
O
O
O
3
17
HO
HO
N
CO2Me
CO2Me
4
Ethane-1,2-diol
—
55
—
O
N
OH
O
O
1
1
18
HO
N
HO
N
CO2Me
CO2Me
O
5
Propane-1,3-diol
—
67
—
O
O
OH
19
HO
HO
N
CO2Me
CO2Me
6
Benzyl alcohol
O
—
59
—
N
O
Ph
O
1
20
HO
N
O2N
HO
HO
N
CN
CN
CN
O
7
8
9
MeOH
50
53
57
30
27
35
O
O
N
O
4
6
6
6
5
HO
O2N
HO
HO
N
CN
CN
CN
EtOH
O
N
O
O
N
O
4
21
HO
N
O2N
HO
HO
N
CN
CN
CN
Propargyl alcohol
O
O
O
N
O
4
22
(continued on next page)

6854
P. Shanmugam et al. / Tetrahedron Letters 47 (2006) 6851–6855
Table 2 (continued)
Entry
Substrate
Alcoholb
Products
Nitrate (B)
Yield (%)
Ether (A)
—
A
B
O2N
HO
N
HO
CO2Me
CO2Me
10
iso-Propanol
—
54
O
O
N
1
3
O2N
HO
N
HO
CO2Me
CO2Me
11
t-Butanol
—
—
65
O
O
N
1
3
a Reagents and conditions; CAN (4 equiv), ROH, rt, 24 h.
b 4 equiv.
ethane-1,2-diol and propane-1,3-diol afforded alcoholic
ethers 18 and 19 in good yields (Table 2, entries 4 and 5).
with the alcohol provides the observed products. The
aromatic nitration mechanism with CAN is well known
in the literature.8
Benzyl alcohol also reacted with N-methylisatin adduct
1 under these conditions and afforded a good yield of
the desired product 20 (Table 2, entry 6).
3. Conclusion
Repeating the experiments with nitrile bearing Baylis–
Hillman adduct 4 with methanol, ethanol and propargyl
alcohol afforded functionalized ethers 5, 21 and 22 along
with the corresponding nitrated product 6 in excellent
combined yields (Table 2, entries 7–9). To our surprise,
the reaction of 2° and 3°-alcohols (iso-propanol and
t-butanol) with Baylis–Hillman adduct 1 did not yield
any NC–H activated product, only the nitrated product
was obtained in good yields (Table 2, entries 10 and 11).
All new compounds were characterized by spectral (IR,
1H and 13C NMR) and HRMS data. The results are
summarized in Table 2.
In conclusion, we have demonstrated a novel NC–H
activation of Baylis–Hillman adducts of N-methylisatin
with various alcohols using CAN as a single electron
oxidizing agent. It is noteworthy that the compounds
obtained here are highly functionalized and can be used
for further modification. Further work using these com-
pounds for the synthesis of natural products is under
progress in our laboratory.
4. General experimental procedure
A mixture of Baylis–Hillman adduct (1 mmol), 4 equiv
of cerium ammonium nitrate (4 mmol) and 4 equiv of
ROH (4 mmol) in CH3CN (1 mL) was allowed to stir
at rt for 24 h. The progress of the reaction was moni-
tored by TLC. After completion of the reaction, the sol-
vent was removed under reduced pressure. The crude
reaction mixture was extracted with dichloromethane
and washed with water and brine. The organic layer
was separated and dried (Na2SO4) and concentrated in
vacuo. The crude mixture was purified by silica gel
column chromatography using gradient elution with
hexane and EtOAc to afford pure functionalized ethers
and aromatic nitrated products.
A plausible mechanism for the formation of the ether
products is shown in Scheme 3. The cation radical7 A
of the alcohol, believed to be generated by oxidation
with CAN, oxidizes N-methylisatin to the N-methyl rad-
ical B. Further one electron oxidation of B with CAN
generates the methyl cation C, which upon trapping
O
Ce(IV)
Ce(III)
HO
ROH +
HO
+
R
H
A
CO2Me
CO2Me
O
+
+ R OH2
R
H
O
O
A
4.1. Spectral data for selected compounds
N
N
B
CH3
CH2
4.1.1. Methyl 2-(1-(ethoxymethyl)-3-hydroxy-2-oxoindo-
lin-3-yl) acrylate 15. IR (CH2Cl2): 3382, 1716, 1089,
Ce(IV)
HO
1053 cmÀ1 1H NMR (CDCl3/TMS, 300.1 MHz): d
;
HO
CO2Me
CO2Me
O
1.20 (t, J = 6.9 Hz, 3H), 2.67 (br s, 1H), 3.65 (m, 5H),
5.17 (d, J = 11.1 Hz, 1H), 5.22 (d, J = 11.1 Hz, 1H),
6.43 (s, 1H), 6.58 (s, 1H), 7.05–7.13 (m, 2H), 7.20 (d,
J = 7.2 Hz, 1H), 7.35 (t, J = 7.2 Hz, 1H); 13C NMR
(CDCl3/TMS, 75.3 MHz): d 15.10, 52.26, 64.58, 70.56,
76.66, 110.43, 123.60, 124.09, 128.04, 128.98, 130.63,
ROH
O
R
N
N
C
O
CH2
Scheme 3. A plausible mechanism for ether formation.

P. Shanmugam et al. / Tetrahedron Letters 47 (2006) 6851–6855
6855
139.24, 143.27, 165.24, 176.97.; HRMS: calcd for
C15H17NO5: 291.1107. Found: 291.1088.
thanks Dr. Vijay Nair, CSIR-Emeritus Scientist, and
the reviewer of this manuscript for suggesting the mech-
anism. Financial support (SR/S1/OC-38/2005) from the
DST (New Delhi) is gratefully acknowledged. V.V. and
B.V. thank CSIR (New Delhi) for the award of a SRF
and a JRF, respectively. Thanks are due to Mrs. Viji
for providing HRMS data.
4.1.2. Methyl 2-(1-[(but-3-ynyloxy)methyl]-3-hydroxy-2-
oxoindolin-3-yl) acrylate 17. IR (CH2Cl2): 3406, 1716,
1614, 1089, 1050 cmÀ1
;
1H NMR (CDCl3/TMS,
300.1 MHz): d 1.80 (br s, OH, 1H), 1.95 (t, J = 2.4 Hz,
1H), 2.46 (td, J = 6.6, 2.4 Hz, 2H), 3.63 (s, 3H), 3.66
(t, J = 6.6 Hz, 2H), 5.20 (d, J = 11.1 Hz, 1H), 5.28 (d,
J = 11.1 Hz, 1H), 6.46 (s, 1H), 6.59 (s, 1H), 7.05–7.20
(m, 3H), 7.35 (t, J = 7.8 Hz, 1H); 13C NMR (CDCl3/
TMS, 75.3 MHz): d 19.84, 30.38, 52.31, 66.90, 69.55,
70.64, 81.34, 110.51, 123.73, 124.12, 126.24, 127.89,
130.71, 139.19, 143.10, 165.22, 176.95. HRMS: calcd
for C17H17NO5: 315.1107. Found: 315.1101.
References and notes
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1
1716, 1613, 1086, 1055 cmÀ1; H NMR (CDCl3/TMS,
300.1 MHz): d 1.73 (quintet, J = 7.2 Hz, 2H), 3.11 (br
s, 2OH), 3.48–3.80 (m, 7H), 5.14 (d, J = 11.4 Hz, 1H),
5.21 (d, J = 11.4 Hz, 1H), 6.55 (s, 1H), 6.60 (s, 1H),
7.03–7.16 (m, 3H), 7.33 (t, J = 7.5 Hz, 1H); 13C NMR
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70.49, 76.35, 110.14, 123.66, 123.98, 128.37, 129.41,
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1
1614, 1073 cmÀ1; H NMR (CDCl3/TMS, 300.1 MHz):
d 1.80 (br s, OH, 1H), 2.48 (t, J = 2.4 Hz, 1H), 4.21 (d,
J = 2.4 Hz, 2H), 5.24 (d, J = 11.1 Hz, 1H), 5.36 (d,
J = 11.1 Hz, 1H), 6.21 (s, 1H), 6.37 (s, 1H), 7.10–7.29
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The authors thank Professor Dr. T. K. Chandrashekar,
Director, for providing infrastructure facilities. P.S.