Ring opening reaction of furan with high regio- and diastereo-selectivity via controlled addition of isatin-derived diazoamides

Article abstract of DOI:10.1016/j.tetlet.2011.10.004

Reaction of cyclic diazoamides with furan systems using rhodium(II) acetate as a catalyst afforded a variety of (3Z)-3-[(2E)-4-oxopent-2-en-1-ylidene] indol-2-ones in a regio- and diastereo-selective manner. The diastereoselectivity was based on the flow rate of cyclic diazoamides. The representative products were characterized by single-crystal X-ray analyses.

Full text of DOI:10.1016/j.tetlet.2011.10.004

Tetrahedron Letters 52 (2011) 6732–6735
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Tetrahedron Letters
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Ring opening reaction of furan with high regio- and diastereo-selectivity
via controlled addition of isatin-derived diazoamides
⇑
Sengodagounder Muthusamy , Datshanamoorthy Azhagan
School of Chemistry, Bharathidasan University, Tiruchirappalli 620 024, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Reaction of cyclic diazoamides with furan systems using rhodium(II) acetate as a catalyst afforded a vari-
ety of (3Z)-3-[(2E)-4-oxopent-2-en-1-ylidene]indol-2-ones in a regio- and diastereo-selective manner.
The diastereoselectivity was based on the flow rate of cyclic diazoamides. The representative products
were characterized by single-crystal X-ray analyses.
Received 25 August 2011
Revised 30 September 2011
Accepted 2 October 2011
Available online 15 October 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Copper(I) triflate
Diazoamide
Rhodium(II) acetate
Ring opening reaction
Substituted oxindoles and their derivatives containing carbonyl
group are known to possess a variety of biological activities.1 Reac-
2-en-1-ylidene]indol-2-ones in a regio- and diastereo-selective
manner.
tions of
a-diazocarbonyl compounds continue to be a subject of
The required 3-diazooxindoles9 7 and substituted furans 8
were assembled based on the literature procedure (Fig. 1). The
N-substituted-3-diazooxindoles 7a–e were synthesized by
N-alkylation of 3-diazooxindole 7g using methyl iodide, benzyl
bromide, allyl bromide or propargyl bromide in the presence of
sodium hydride/DMF in 80–95% yield.
considerable interest in organic synthesis as they generate very
attractive transformations.2 Rhodium(II) acetate has been the
superior catalyst for the generation of transient electrophilic rho-
dium-carbenoid from
a-diazocarbonyl compounds. Subsequently,
these undergo an array of reactions which led to a variety of C–C,
C–X bond formations that are important for creation of the basic
skeleton of the organic structure.3 Generally, copper or rhodium
catalyzed reaction of diazocarbonyl compound with olefin is an
efficient method for the preparation of cyclopropane derivatives.4
The intermolecular cyclopropanation reactions are limited5 only
to simple precursors like acyclic diazo ketones or diazo esters. Gen-
erally, transition metal catalyzed reaction of diazo compound with
furan was reported6 to furnish the detectable cyclopropane inter-
mediates 3, 4 which rearranges to a mixture of ring-opened prod-
ucts 5 and ring-enlarged product 6 (Scheme 1). Interestingly, there
is scarcity of report7 available on the reaction of 3-diazopiperidin-
2-one (a cyclic diazoamide) and furan furnishing the correspond-
ing cyclopropane. To the best of our knowledge, there is no report
dealt on cyclic diazoamides for the ring opening reaction of furan
ring system with diastereoselectivity. In continuation of our work8
on the rhodium catalyzed reactions of cyclic diazoamides, we here-
in report the metallo-carbenoid reaction of cyclic diazoamides
with furan systems affording a variety of (3Z)-3-[(2E)-4-oxopent-
Subsequently, we investigated the rhodium(II) acetate cata-
lyzed behavior of cyclic diazoamides 7 with furan 8 in an intermo-
lecular fashion. To the reaction mixture containing furan 8a and
R'COCHN2
+
RO
O
1
2
CuOTf (or) Rh2(OAc)4
O
O
R'
R'
OR
+
+
+
RO
O
O
3
4
H
H O
R'
R'
RO
O
RO
O H
H
O
5
6
⇑
Corresponding author. Tel.: +91 431 2407053; fax: +91 431 2407045.
E-mail address: muthu@bdu.ac.in (S. Muthusamy).
Scheme 1. Reaction of diazo compounds with furans.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.004

S. Muthusamy, D. Azhagan / Tetrahedron Letters 52 (2011) 6732–6735
6733
Table 1
N2
R4
R3
R2
Diastereoselective synthesis of (3Z)-3-[(2E)-4-oxopent-2-en-1-ylidene]indol-2-ones
9/10
O
R5
S.
No
R1
R2 R3
R4
R5
Time
(min)
Yielda 9/10
N
O
R1
Ratiob
7a R1 = CH3; R2 = H
7b R1 = benzyl; R2 = H
7c R1= allyl; R2 = H
8a R3 = R4 = R5 = H
a
b
c
d
e
f
g
h
i
Me
Bn
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
OMe
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
45
40
45
45
30
30
60
25
91
87
85
88
89
87
60
88
87
85
57
88
99:1
98:2
99:1
99:1
99:1
99:1
99:1
98:2
98:2
98:2
98:2
98:2
8b R3 = CH3; R4 = R5 = H
8c R3 = R4 = CH3; R5 = H
Allyl
Propargyl
Me
Propargyl
H
Me
Me
Me
H
7d R1 = propargyl; R2 = H 8d R3 = CH3; R4 = H; R5 = CH3
7e R1 = CH3; R2 = Cl
7f R1 = H; R2 = Cl
7g R1 = H; R2 = H
8e R3 = OCH3; R4 = R5 = H
8f R3 = NO2; R4 = R5 = H
8g R3 = CN; R4 = R5 = H
8h R3 = CHO; R4 = R5 = H
Me 25
j
k
l
H
H
H
30
60
30
Figure 1. Isatin and furan derivatives.
Cl OMe
Cl OMe
Me
a
Isolated yield refers to compound 9.
Ratio of isomers was determined by crude proton NMR spectra.
rhodium(II) acetate dimer catalyst was added a dry dichlorometh-
ane solution (2 mL) containing 1 equiv of N-methyl-3-diazooxin-
dole (7a) over 8 h via syringe pump under an argon atmosphere
at room temperature. The reaction was monitored by TLC. The
reaction mixture was stirred for 45 min after the syringe pump
addition. Then, the solvent was concentrated in vacuum and chro-
matographic purification of the reaction mixture using flash silica
gel furnished a mixture of diastereomers 9a (91% yield) and 10a
in the ratio of 99:1, respectively (Scheme 2, Table 1). The deep
red coloured major product 9a was purified by crystallization
and confirmed10 by the presence of characteristic peak as a doublet
at d = 9.74 (J = 8 Hz) for aldehyde proton in 1H NMR. A typical
downfield chemical shift for H4-proton appeared at d 8.80 as dd
splitting, H3-proton appeared at d 7.41 as td splitting and H2-pro-
ton at d 6.38 as ddd splitting pattern (Fig. 2). The higher coupling
constant values between these protons indicate that the H-atoms
are present in trans geometry. The presence of aldehyde and amide
carbonyl carbons appeared at d 194.1 and 166.5 ppm in 13C NMR,
respectively. Mass spectrum showed the required mass value 233
[M+Na]+. Further, the stereochemistry of the representative prod-
uct 9b was unequivocally corroborated by single crystal X-ray
analysis (Fig. 3). As a control experiment, the above reaction was
performed at room temperature without using the syringe pump
to yield an inseparable mixture of diastereomers 9a (87% yield)
and 10a in the ratio of 63:37. The attempts to separate the diaste-
reomer 10a were failed. Thus, the structure of the minor isomer
10a was tentatively assigned as shown in Scheme 2.
b
JH2- H1 = 8Hz
JH2- H4 = 0.4Hz
H1
JH2- H3 = 16Hz
H2
H4
O
H3
O
N
Me
Figure 2. Coupling constants in compound 9a.
Encouraged with these results, we generalized by performing
the reaction of substituted furans 8a–h with 3-diazooxindoles
7a–e using syringe pump addition as described above. The N-
substituted diazoamides 7a–e with furans 8a–e furnished good
Figure 3. ORTEP view of compound 9b.
Table 2
Diazoamide 7a with other metal catalysts
S. No
Catalyst
Isolated yield
Ratio 9a/10a
N2
R4
R3
R2
1
2
3
4
5
6
Rhodium(II) acetate dimer
Rhodium(II) heptafluroacetate
CuOTf
Cu(OTf)2
RhCl3
91
87
86
—
—
—
99:1
97:3
97:3
—
—
—
O
+
R5
N
O
R1
Slow addition of 7
8
BF3 etherate
Rh2(OAc)4 Dry DCM
yield when compared8b to the corresponding unsubstituted ana-
logs 7f–g (Table 1). The crude 1H NMR spectra indicated that the
presence of minor regioisomer in all the reactions even with the
flow rate of 0.25 mL/h. The absence of minor isomer was not com-
pletely achieved even at slower flow rate of 0.17 mL/h. However,
faster flow rate of diazoamide furnished the ring opened products
of furan without much selectivity. Interestingly, the structure 9 is
related11 to the natural product, soulieotine alkaloid.
O
R4
R3
R3
O
R5
R5
R4
E
Z
Z
R2
R2
Z
H
+
H
O
O
N
N
R1
R1
9 (2E, 4Z)
10 (2Z, 4Z)
The representative reaction was examined using different metal
catalysts (Table 2) under similar reaction conditions. We found that
Scheme 2. Synthesis of products 9/10.

6734
S. Muthusamy, D. Azhagan / Tetrahedron Letters 52 (2011) 6732–6735
Supplementary data
N2
Rh2(OAc)4
O
Rh2(OAc)4
-N2
O
Experimental procedures, characterization data, proton and car-
bon spectra for selected compounds and X-ray crystallographic
data (CCDC-838515 and CCDC-838516) for compounds 9f and 9i.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.10.004.
N
R
N
R
7
11
- Rh2(OAc)4
8
O
References and notes
O
H
H
H
O
O
R
H
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N
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9
12
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Scheme 3. Plausible mechanism.
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7. Hutchinson, I. S.; Matlin, S. A.; Mete, A. Tetrahedron 2002, 58, 3137–3143.
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Soc., Chem. Commun. 2002, 824–825; (b) Muthusamy, S.; Gunanathan, C. Synlett
2002, 1783–1786; (c) Muthusamy, S.; Gunanathan, C. J. Chem. Soc., Chem.
Commun. 2003, 440; (d) Muthusamy, S.; Srinivasan, P. Tetrahedron Lett. 2005,
46, 1063–1066; (e) Muthusamy, S.; Srinivasan, P. Tetrahedron Lett. 2009, 50,
3794–3797; (f) Muthusamy, S.; Azhagan, D.; Gnanaprakasam, B.; Suresh, E.
Tetrahedron Lett. 2010, 51, 5662–5665; (g) Muthusamy, S.; Ramkumar, R.;
Mishra, A. K. Tetrahedron Lett. 2011, 52, 148–150; (h) Muthusamy, S.; Karikalan,
T.; Suresh, E. Tetrahedron Lett. 2011, 52, 1934–1937; (i) Muthusamy, S.;
Gunanathan, C.; Nethaji, M. Synlett 2004, 639; (j) Muthusamy, S.; Gunanathan,
C. Synlett 2003, 1599.
9. Cava, M. P.; Little, R. L.; Naipier, D. R. J. Am. Chem. Soc. 1958, 80, 2257–2263.
10. All new compounds exhibited spectral data consistent with their structures.
Selected spectral data: Synthesis of compound 9a; In an oven-dried flask, a
solution containing furan 8a (43 mg, 0.63 mmol) and rhodium(II) acetate
dimer (2.5 mg, 1 mol %) in 10 mL of dry dichloromethane (dried over
phosphorous pentoxide) was degasified under an argon atmosphere. To this
reaction mixture, 2 mL solution of 7a (100 mg, 0.57 mmol) in dry
dichloromethane was added for the duration of 8 h via syringe pump under
an argon atmosphere at room temperature. The reaction mixture was further
allowed to stir at room temperature and followed by TLC till the disappearance
of the starting material. The solvent was removed under reduced pressure and
chromatographic purification of (Hexane/EtOAc, 75:25) the residue afforded
113 mg (91%) of 9a. Further recrystallization was also performed to purify the
rhodium(II) heptafluroacetate and CuOTf catalysts were also effec-
tive to furnish the ring opened products 9/10 of furan. Other cata-
lysts such as Cu(OTf)2, RhCl3 and BF3-etherate were inactive to
decompose the diazo functionality. There are many reports12 known
for the isomerization of double bond using iodine or Lewis acid. The
isomerization reaction of 9a/10a having different ratio of isomers
(63:37 or 99:1) was performed using iodine or boron trifluoride or
aluminium trichloride. But these substrates failed to isomerize irre-
spective of the ratio of the diastereomers. No reaction was observed
when the electron withdrawing substituents (NO2 or CN) were pres-
ent on furan ring (8f or 8g). It is interesting to mention that carbonyl
ylide was observed13 instead of the ring opening product when fur-
fural (8h) was used. The reaction of 7a with furan as solvent was per-
formed to yield cyclopropane7 but in vain. Typically, the quantity of
rhodium(II) acetate catalyst was maintained at 1 mol % for perform-
ing the above experiments. All the above reactions afforded the ring-
opened products with high diastereoselectivity. We have not ob-
tained any other side products resulting from cyclopropanation8f
(when R1 = allyl, propargyl) or C–H insertion8a,8b of the rhodium
carbenoids.
Mechanistically, the reaction of cyclic diazoamides 7 with furan 8
in the presence of rhodium(II) acetate may be proposed as given in
Scheme 3. The initially formed transient rhodium(II) carbenoid 11
may have undergone cyclopropanation8f intermediate 12 with furan
moiety 8. Further, the stereoselective ring opening might afford the
product9 with diastereoselectivity. Reaction ofcarbenoid 11usually
occurs onto the less substituted double bond of furan to produce a
labile intermediate that rearranges to ring-opened products in
which a diene is located between two carbonyl groups during the
intermolecular reactions. However, the cyclopropane intermediate
might form on either side of furan moiety having substituted double
bond, for example 2,5-dimethylfuran, affording the corresponding
ring opened products 9i/10i. In all the above reactions, we could
not isolate the proposed cyclopropane intermediate 12.
major diastereomer. Deep red solid; mp 91–93 °C;
mmax(neat) 3018, 2927,
2800, 1674, 1605, 1554, 1487, 1469, 1374, 1163, 1037, 997, 784 cmÀ1; dH
(400 MHz, CDCl3) 9.74 (d, 1H, CHO, J = 8 Hz), 8.80 (dd, 1H, H3, J1 = 16,
J2 = 12 Hz), 7.41 (d, 1H, J = 8 Hz), 7.28 (td, 1H, J1 = 8, J2 = 0.8 Hz), 7.18 (dd, 1H,
H4, J1 = 12, J2 = 0.4 Hz), 6.98 (td, 1H, J1 = 8, J2 = 0.8 Hz), 6.75 (d, 1H, J = 8 Hz),
6.38 (ddd, 1H, H2, J1 = 16, J2 = 8, J3 = 0.4 Hz), 3.18 (s, 3H, CH3); d C (100 MHz,
CDCl3) 194.0 (CHO), 166.5 (C@O), 144.7 (@CH), 144.0 (CAr), 137.8 (@CH), 137.1
(CAr), 131.3 (@CH), 130.6 (@CH), 122.5 (@CH), 122.1 (@C), 120.9 (@CH), 108.4
(@CH), 25.9 (NCH3); HRMS (ESI) calcd for C13H11NO2Na [M+Na]+: 236.0687
found 236.0675. Synthesis of compound 9b; A solution containing furan 8a
(30 mg, 0.44 mmol) and rhodium(II) acetate dimer (2 mg, 1 mol %) in 10 mL of
dry dichloromethane. To this reaction mixture, 2 mL solution of 7b (100 mg,
0.40 mmol) in dry dichloromethane was added via syringe pump and then the
procedure was followed as described above to afford 101 mg (87%) of 9b. Deep
In conclusion, we have demonstrated the synthesis of (3Z)-3-
[(2E)-4-oxopent-2-en-1-ylidene]indol-2-ones from isatin derived
diazoamides and symmetrical as well as unsymmetrical furans in
the presence of rhodium(II) acetate catalyst. Interestingly, the above
products were obtained with high diastereoselectivity under mild
reaction conditions via the controlled addition of diazoamides.
red solid; mp 98–100 °C; mmax(neat) 3013, 1706, 1677, 1604, 1468, 1356, 1187,
1174, 696, 663 cmÀ1; dH (400 MHz, CDCl3) 10.44 (d, H, CHO, J = 8 Hz), 8.07 (dd,
1H, H4, J1 = 14, J2 = 1.2 Hz), 7.76 (dd, 1H, H3, J1 = 14, J2 = 12 Hz), 7.24 (dd, 1H,
J1 = 6, J2 = 1.2 Hz), 7.58 (d, 1H, J = 7.6 Hz), 7.23–7.15 (m, 7H, CH), 6.96 (t, 1H, CH,
J = 7.6 Hz), 6.67 (d, 1H, J = 8), 6.23 (ddd, 1H, H2, J1 = 12, J2 = 8, J3 = 0.4 Hz), 4.89
(s, 2H, CH2); dC (100 MHz, CDCl3) 189.8 (CHO), 167.7 (C@O), 144.2 (CAr), 138.7
(@CH), 135.5 (CAr), 134.3 (@CH), 132.1 (CAr), 131.0 (@CH), 128.8 (@CH), 127.7
(@CH), 127.2 (@CH), 126.3 (@CH), 124.9 (@CH), 122.6 (@CH), 121.0 (@C), 109.7
(@CH), 43.8 (NCH2); HRMS (ESI) calcd for C19H15NO2Na [M+Na]+: 312.1000
found 312.1009.
Acknowledgments
This research was supported by the Department of Science and
Technology (DST), New Delhi. We thank DST, New Delhi, for pro-
viding 400 MHz NMR and XRD facility under FIST program.

S. Muthusamy, D. Azhagan / Tetrahedron Letters 52 (2011) 6732–6735
6735
Crystal data for compound 9b: C19H15NO2, M = 289.32, 0.27 Â 0.18 Â 0.12 mm,
monoclinic, space group 21/a with a = 10.015 (3) Å, b = 9.102 (11) Å,
= 90.00°, b = 99.97(2)°,
= 90.00°, V = 1485.5(19) Å3,
1 = 0.0486, wR2 = 0.0679 on observed data, z = 4,
F(000) = 608, Absorption coefficient = 0.084 mmÀ1
been deposited (CCDC 838514) with the Cambridge Crystallographic Data
Centre. Copy of the data can be obtained free of charge on application to 12,
Union Road, Cambridge CB21EZ, UK (fax: (+44) 1223 336 033; e-mail:
deposit@ccdc.cam.ac.uk).
P
c = 16.546(4) Å,
T = 293(2) K,
a
c
R
Dcalcd = 1.294 mg cmÀ3
,
,
11. Zhou, L.; Yang, J.-S.; Wu, X.; Zou, J.-H.; Xu, X.-D.; Tu, G.-Z. Heterocycles 2005, 65,
1409–1414.
k = 0.71073 Å, 2606 reflections were collected on a smart apex CCD single
crystal diffractometer 1929 observed reflections (I ꢀ 2
r
(I)). The largest
respectively. The
12. Doyle, M. P.; Chapman, B. J.; Hu, W.; Peterson, C. S. Org. Lett. 1999, 1, 1327–
1329.
13. Muthusamy, S.; Gunanathan, C.; Nethaji, M. J. Org. Chem. 2004, 69, 5631–5637.
difference peak and hole = 0.225 and À0.226 e ÅÀ3
,
structure was solved by direct methods and refined by full-matrix least
squares on F2 using SHELXL–97 software. Crystallographic data for 9b have