Amino-Claisen versus oxy-claisen rearrangement: Regioselective synthesis of pyrrolocoumarin derivatives

Article abstract of DOI:10.1055/s-2008-1032195

Pyrrolocoumarin and its derivatives have been synthesized regioselectively in excellent yields by the amino-Claisen rearrangement of 3-N- propargylaminocoumarin and 3-N-(aryloxybut-2-ynyl)aminocoumarins. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1032195

PAPER
921
Amino-Claisen versus Oxy-Claisen Rearrangement: Regioselective Synthesis
of Pyrrolocoumarin Derivatives
A
mino-ClaisenRe
r
arrangem
i
ent shna C. Majumdar,* Buddhadeb Chattopadhyay
Department of Chemistry, University of Kalyani, Kalyani 741 235, India
Fax +91(33)25828282; E-mail: kcm_ku@yahoo.co.in
Received 3 December 2007
R
Abstract: Pyrrolocoumarin and its derivatives have been synthe-
sized regioselectively in excellent yields by the amino-Claisen rear-
rangement of 3-N-propargylaminocoumarin and 3-N-(aryloxybut-
2-ynyl)aminocoumarins.
Cl
NH2
O
NH
O
(i)
+
Key words: amino-Claisen rearrangement, oxy-Claisen rearrange-
ment, [3,3]-sigmatropic rearrangement, 3-aminocoumarin, pyrrolo-
coumarin, 5-exo-trig
O
O
R
2a–e
3a–e
1
3a, R = CH2OC6H4(4-OMe), 63%
3b, R = CH2OC6H3(2,4-Cl2), 51%
3c, R = CH2OC6H2(4-Cl-3,5-Me2), 59%
3d, R = CH2OC6H3(3-Me-4-Cl), 55%
3e, R = H, 60%
Coumarins fused with heterocyclic compounds and aza-
analogues of coumarins have received great attention due
to their potential biological activities.1 In particular, those
coumarins fused to pyridines have been reported to have
antialergic,2 antidiabetic,3 and analgesic4 properties. Be-
sides this, 3-aminocoumarin core is an ubiquitous subunit
in many natural products with remarkable biological ac-
tivities. In medicinal chemistry, members of this family
have wide practical applications as antibiotic and antiviral
agents.5,6 For example, novobiocine is a 3-aminocoumarin
derived antibiotic, an ATP competitive inhibitor of gyrase
subunit blocking the negative super cooling of relaxed
DNA.5,6 Recently, Sames et al. reported7 that the various
pyrrolocoumarins may be used as the fluorogenic probes.
Scheme 1 Reagents and conditions: (i) anhyd ethyl methyl ketone,
K2CO3, NaI, reflux, 24–30 h.
Compounds 3a–e were characterized from their elemental
analyses and spectroscopic data. The IR spectrum of 3a
showed an absorption at 3221 cm–1 due to the presence of
1
a NH group. The H NMR spectrum of 3a revealed a
three-proton singlet at d = 3.78 due to the OCH3 and two
sets of two-proton singlets at d = 4.06 and 4.65 due to the
NCH2 and OCH2 respectively. A one-proton singlet ap-
peared at d = 6.44 due to the H-4 of coumarin moiety. The
mass spectrum of the compound 3a showed a molecular
ion peak at m/z = 335 [M+].
We have very recently reported8 3-aminocoumarin-annu-
lated pyrido[2,3-c]coumarin derivatives by palladium-
catalyzed intramolecular Heck reaction. Therefore, in the
interest of synthesizing new coumarin ring systems for
possible evaluation as biologically active compounds or
any other useful compounds such as fluorogenic probes
and laser dyes, we have synthesized a variety of pyrrolo-
coumarin derivatives by the application of the less studied
amino-Claisen rearrangement. Additional interest is de-
rived from our longstanding efforts in the synthesis of
coumarin-annulated heterocycles.8,9
The substrates 3a–e possess two potential reactive sites
for the Claisen rearrangement. The aryloxypropargyl
ether moiety may undergo an oxy-Claisen rearrangement,
while the vinylpropargylamine segment may undergo an
amino-Claisen rearrangement. Thus, these substrates pro-
vide scope for studying the competition between oxy-
Claisen rearrangement and amino-Claisen rearrange-
ments. It is a well-established phenomenon that the
amino-Claisen rearrangement12 requires higher activation
energies compared to the oxy-Claisen rearrangement.
However, the activation energy required for the arylprop-
argyl ether rearrangement is much higher than that of the
propargylvinyl ether rearrangement.13
The starting materials 3-N-(4-aryloxybut-2-ynyl)amino-
coumarins 3a–d and 3-N-propargylaminocoumarin (3e)
were prepared in 51–63% yields by refluxing 3-amino-
coumarin (1), with either the corresponding 1-aryloxy-4-
chlorobut-2-ynes10 2a–d or propargyl bromide (2e) in an-
hydrous ethyl methyl ketone in the presence of anhydrous
potassium carbonate and a small amount of sodium
iodide11 (Scheme 1).
The Claisen rearrangement of the substrates 3a–e was at-
tempted in refluxing chlorobenzene and o-dichloroben-
zene, but without success. However, the substrate 3a,
upon refluxing in N,N-dimethylaniline for eight hours,
gave a solid product 4a in 91% yield. This was character-
ized from its elemental analysis and spectroscopic data.
Compound 4a exhibited IR absorption band at 3229 cm–1
due to the presence of NH group. The 1H NMR spectrum
of 4a displayed two three-proton singlets at d = 2.53 and
3.78 resulting from =CCH3 and OCH3 respectively; a
SYNTHESIS 2008, No. 6, pp 0921–0924
x
x
.
x
x
.2
0
0
8
Advanced online publication: 28.02.2008
DOI: 10.1055/s-2008-1032195; Art ID: Z27807SS
© Georg Thieme Verlag Stuttgart · New York

922
K. C. Majumdar, B. Chattopadhyay
PAPER
R
In conclusion, the occurrence of a [3,3]-sigmatropic rear-
rangement at the propargyl vinyl amine moiety in prefer-
ence to the arylpropargyl ether moiety in the substrates
3a–e studied so far is noteworthy. In our present study, the
amino-Claisen rearrangement leads to the exclusive for-
mation of the pyrrolocoumarins and its derivatives. This
result is interesting in view of an earlier report15 where it
has been shown that the oxy-Claisen rearrangement is fa-
vored over the amino-Claisen rearrangement in sub-
strates, namely, 5-N-(4-aryloxybut-2-ynyl)-N-methyl-
1,3-dimethylpyrimidine-2,4-diones, during the thermal
rearrangement.
R1
R
NH
O
NH
O
(i)
O
O
3a–e
4a–e
4a, R = CH2OC6H4(4-OMe), R1 = Me, 91%
4b, R = CH2OC6H3(2,4-Cl2), R1 = Me,94%
4c, R = CH2OC6H2(4-Cl-3,5-Me2), R1 = Me, 90%
4d, R = CH2OC6H3(3-Me-4-Cl), R1 = Me, 91%
4e, R = H, R1 = H, 90%
Scheme 2 Reagents and conditions: N,N-dimethylaniline, reflux,
6–9 h.
Melting points were determined in open capillaries and are uncor-
rected. IR spectra were recorded on a Perkin-Elmer L120-000A
spectrometer (cm–1) using KBr disks. NMR spectra were recorded
on a Bruker DPX-400 spectrometer in CDCl3 (chemical shifts in d)
with TMS as the internal standard. Silica gel (60–120 mesh) was
used for chromatographic separation. Silica gel G was used for
TLC. Petroleum ether refers to the fraction boiling between 60–
80 °C.
R
R
H
NH
O
NH
O
[3,3]
O
O
3
5
Compounds 3a–e; General Procedure
[1,3] shift
Me
A mixture of 3-aminocoumarin (1; 0.32 mmol, 500 mg), an appro-
priate amount of 2 (0.32 mmol, 1.2 equiv) and anhyd K2CO3 (2.0 g)
in anhyd ethyl methyl ketone (75 mL) was refluxed in the presence
of a pinch of NaI for 30–35 h. The mixture was cooled, filtered, and
the solvent was removed. The residue was then extracted with
CH2Cl2 (3 × 30 mL). The CH2Cl2 layer was washed with H2O
(2 × 50 mL), brine (30 mL), and dried (Na2SO4). Removal of
CH2Cl2 gave a crude product, which was then chromatographed
over silica gel using 10% EtOAc–petroleum ether to give the com-
pounds 3a–e.
R
R
NH2
O
NH
O
5-exo-trig
O
O
6
4
Scheme 3 Probable mechanism of the amino-Claisen rearrange-
ment
3a
two-proton singlet at d = 5.13 resulting from OCH2; a
broad singlet at d = 10.3 due to the NH proton and the re-
maining protons are aromatic in nature. The mass spec-
trum of 4a displayed a molecular ion peak at m/z 335
[M+]. To test the generality of the reaction, the thermal re-
arrangements of four other substrates 3b–e were studied
and all of them were converted under refluxing condition
in N,N-dimethylaniline for about 7–9 hours to give the cy-
clized product through the amino-Claisen rearrangement
instead of the low activation energy needing oxy-Claisen
rearrangement (Scheme 2). It is notable here that out of
the two possibilities14 of the formation of two cyclized
products, that is, either the five-membered pyrrolocou-
marin derivatives or the six-membered pyridocoumarin
derivatives we obtained exclusively the pyrrolocoumarin
derivatives by the regioselective amino-Claisen rear-
rangement.
Yield: 63%; solid; mp 120–121 °C.
IR (KBr): 1725, 3221 cm–1.
1H NMR (CDCl3, 400 MHz): d = 3.78 (s, 3 H, OCH3), 4.02 (s, 2 H,
NCH2), 4.67 (s, 2 H, OCH2), 6.41 (s, 1 H, H-4 of coumarin moiety),
6.83 (d, J = 8.8 Hz, 2 H, ArH), 7.19 (d, J = 8.8 Hz, 2 H, ArH), 7.22–
7.31 (m, 4 H, ArH), 10.00 (s, 1 H, NH).
13C NMR (CDCl3, 100 MHz): d = 76.7, 77.0, 77.3, 80.3, 84.6,
114.4, 114.6, 115.8, 115.9, 116.1, 116.3, 119.2, 124.6, 126.8, 128.8,
141.9, 149.8, 151.3, 154.3, 157.3.
MS: m/z = 335 [M+].
Anal. Calcd for C20H17NO4: C, 71.63; H, 5.11; N, 4.18. Found: C,
71.79; H, 4.99; N, 4.37.
3b
Yield: 51%; solid; mp 165–166 °C.
IR (KBr): 1723, 3227 cm–1.
1H NMR (CDCl3, 400 MHz): d = 4.03 (s, 2 H, NCH2), 4.69 (s, 2 H,
OCH2), 6.43 (s, 1 H, H-4 of coumarin moiety), 6.90 (s, 1 H, ArH),
7.08 (d, J = 8.6 Hz, 2 H, ArH), 7.17–7.29 (m, 4 H, ArH), 10.00 (s,
1 H, NH).
The formation of the products 4 from the substrate 3 may
be rationalized by an initial [3,3]-sigmatropic rearrange-
ment of the propargylamine moiety of the substrate 3 to
give the allene intermediate 5, followed by an imine-
enamine tautomerism to give the tautomerized intermedi-
ate 6 (not isolated). Subsequently, a 5-exo-trig cyclization
occurring in the intermediate 6 gives the corresponding
MS: m/z = 373 [M+].
Anal. Calcd for C19H13Cl2NO3: C, 60.98; H, 3.50; N, 3.74. Found:
C, 61.13; H, 3.61; N, 3.64.
cyclized product pyrrolocoumarin derivatives
(Scheme 3).
4
3c
Yield: 59%; solid; mp 127–128 °C.
Synthesis 2008, No. 6, 921–924 © Thieme Stuttgart · New York

PAPER
Amino-Claisen Rearrangement
923
IR (KBr): 1722, 3230 cm–1.
7.51 (m, 2 H, ArH), 7.89 (d, J = 7.8 Hz, 1 H, ArH), 10.30 (s, 1 H,
NH).
1H NMR (CDCl3, 400 MHz): d = 2.36 (s, 6 H, CH3), 4.03 (s, 2 H,
NCH2), 4.66 (s, 2 H, OCH2), 6.42 (s, 1 H, H-4 of coumarin moiety),
6.72 (s, 2 H, ArH), 7.18–7.27 (m, 4 H, ArH), 10.02 (s, 1 H, NH).
MS: m/z = 373 [M+].
Anal. Calcd for C19H13Cl2NO3: C, 60.98; H, 3.50; N, 3.74. Found:
C, 61.07; H, 3.33; N, 3.89.
MS: m/z = 367 [M+].
Anal. Calcd for C21H18ClNO3: C, 68.57; H, 4.93; N, 3.81. Found: C,
68.71; H, 4.91; N, 4.01.
4c
Yield: 90%; solid; mp 138–139 °C.
3d
IR (KBr): 1719, 3230 cm–1.
Yield: 55%; solid; mp 139–140 °C.
IR (KBr): 1719, 3227 cm–1.
1H NMR (CDCl3, 400 MHz): d = 2.27 (s, 3 H, CH3), 4.02 (s, 2 H,
NCH2), 4.66 (s, 2 H, OCH2), 6.41 (s, 1 H, H-4 of coumarin moiety),
6.68 (dd, J = 6.8, 1.7 Hz, 2 H, ArH), 6.76 (d, J = 1.7 Hz, 1 H, ArH),
7.21–7.31 (m, 4 H, ArH), 9.99 (s, 1 H, NH).
1H NMR (CDCl3, 400 MHz): d = 2.36 (s, 3 H, CH3), 2.57 (s, 3
H, =CCH3), 5.22 (s, 2 H, OCH2), 6.73 (s, 2 H, ArH), 7.28 (d, J = 7.8
Hz, 1 H, ArH), 7.43–7.48 (m, 2 H, ArH), 7.78 (d, J = 7.8 Hz, 1 H,
ArH), 10.30 (s, 1 H, NH).
MS: m/z = 367 [M+].
Anal. Calcd for C21H18ClNO3: C, 68.57; H, 4.93; N, 3.81. Found: C,
68.77; H, 5.15; N, 3.98.
MS: m/z = 353 [M+].
Anal. Calcd for C20H16ClNO3: C, 67.90; H, 4.56; N, 3.96. Found: C,
68.14; H, 4.37; N, 4.03.
4d
Yield: 91%; solid; mp 152–153 °C.
3e
IR (KBr): 1721, 3228 cm–1.
Yield: 60%; solid; mp 85–86 °C.
IR (KBr): 1724, 3225 cm–1.
1H NMR (CDCl3, 400 MHz): d = 2.02 (s, 1 H, ≡CH), 4.01 (s, 2 H,
NCH2), 6.40 (s, 1 H, H-4 of coumarin moiety), 7.17–7.26 (m, 4 H,
ArH), 10.00 (s, 1 H, NH).
1H NMR (CDCl3, 400 MHz): d = 2.27 (s, 3 H, CH3), 2.53 (s, 3
H, =CCH3), 5.23 (s, 2 H, OCH2), 6.77 (dd, J = 7.2, 1.7 Hz, 1 H,
ArH), 6.84 (d, J = 1.7 Hz, 1 H, ArH), 7.18 (d, J = 7.6 Hz, 1 H, ArH),
7.21–7.32 (m, 4 H, ArH), 10.31 (s, 1 H, NH).
MS: m/z = 353 [M+].
MS: m/z = 199 [M+].
Anal. Calcd for C20H16ClNO3: C, 67.90; H, 4.56; N, 3.96. Found: C,
68.11; H, 4.66; N, 3.86.
Anal. Calcd for C12H9NO2: C, 72.35; H, 4.55; N, 7.03. Found: C,
72.35; H, 4.55; N, 7.03.
4e
Yield: 90%; solid; mp 101–102 °C.
IR (KBr): 1718, 3231 cm–1.
1H NMR (CDCl3, 400 MHz): d = 2.52 (s, 3 H, =CCH3), 6.47 (s, 1
H, =CH), 7.28 (t, J = 7.0 Hz, 1 H, ArH), 7.35–7.43 (m, 2 H, ArH),
7.74 (d, J = 6.9 Hz, 1 H, ArH), 10.10 (s, 1 H, NH).
Compounds 4a–e; General Procedure
The respective compound 3a–e (0.2 g) was refluxed in N,N-dimeth-
ylaniline (5 mL) for 6–8 h. The mixture was cooled, poured into ice-
cold aq HCl solution (1:1) and kept aside for overnight. The mixture
was then extracted with EtOAc (3 × 25 mL). The combined organic
layers were washed with dil. HCl (3 × 20 mL), brine (20 mL), and
dried (Na2SO4). EtOAc was distilled off and the residual mass was
chromatographed over silica gel using 15% EtOAc–petroleum ether
to give products 4a–e.
MS: m/z = 199 [M+].
Anal. Calcd for C12H9NO2: C, 72.35; H, 4.55; N, 7.03. Found: C,
72.10; H, 4.72; N, 6.91.
4a
Yield: 91%; solid; mp 141–142 °C.
IR (KBr): 1717, 3229 cm–1.
1H NMR (CDCl3, 400 MHz): d = 2.53 (s, 3 H, =CCH3), 3.78 (s, 3
H, OCH3), 5.13 (s, 2 H, OCH2), 6.85 (d, J = 7.6 Hz, 2 H, ArH), 6.93
(d, J = 7.6 Hz, 2 H, ArH), 7.28–7.30 (m, 1 H, ArH), 7.45–7.48 (m,
2 H, ArH), 7.87 (d, J = 7.6 Hz, 1 H, ArH), 10.31 (s, 1 H, NH).
Acknowledgment
We thank the CSIR (New Delhi) for financial assistance. One of us
(B.C.) is grateful to the CSIR (New Delhi) for a junior research fel-
lowship. We also thank the DST (New Delhi) for providing a FT-IR
Spectrometer under DST-FIST program.
13C NMR (CDCl3, 100 MHz): d = 12.5, 55.7, 61.3, 113.9, 114.9,
116.3, 116.4, 117.5, 124.7, 124.9, 129.6, 133.1, 136.5, 151.9, 152.4,
152.5, 154.7, 160.2.
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K. C. Majumdar, B. Chattopadhyay
PAPER
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Synthesis 2008, No. 6, 921–924 © Thieme Stuttgart · New York