A facile rearrangement of pyrroloindoline derivative to pyrroloquinoline: A new analogues of duocarmycins

Article abstract of DOI:10.1002/jhet.5570450513

(Chemical Equation Presented) Free-radical generated at C-7 position of indole derivative bearing N-(3′-chloroallyl) group prompted a regioselective intramolecular cyclization to furnish pyrroloindoline derivative, through the more favorable 5-exo-trig cyclization mode. The pyrroloindoline compound smoothly rearranged to pyrroloquinoline under mild conditions.

Full text of DOI:10.1002/jhet.5570450513

Sep-Oct 2008
1333
A Facile Rearrangement of Pyrroloindoline derivative to
Pyrroloquinoline: A New Analogues of Duocarmycins
Naim H. Al-Said*, Khaled Q. Shawakfeh and Baha A. Hammad
Department of Applied Chemical Sciences, Jordan University of Science and Technology, P. O. Box 3030, Irbid
22110, Jordan. E-mail: naim@just.edu.jo
Received October 8, 2007
Cl
Cl
Nu
I
N
CO2Et
N
CO2Et
N
CO2Et
a) AIBN, Bu3SnH
b) H2 / Pd (C)
c) Nu
Nu = Cl, CN, OMe
OBn
OH
OH
Free-radical generated at C-7 position of indole derivative bearing N-(3'-chloroallyl) group prompted a
regioselective intramolecular cyclization to furnish pyrroloindoline derivative, through the more favorable
5-exo-trig cyclization mode. The pyrroloindoline compound smoothly rearranged to pyrroloquinoline
under mild conditions.
J. Heterocyclic Chem., 45, 1333 (2008).
INTRODUCTION
It is believed that the stability of these drugs is mainly
due to the conjugation of the electron pair on the nitrogen
atom with cyclopropylindoline moiety. The non-covalent
binding to DNA induces a change in the conformation of
the amide group, disrupts the stabilization and activates
the cyclopropane for nucleophilic attack by adenine-N3
[7,9,10].
Duocarmycins (1-3, Figure 1) [1-3] are natural potent
antitumor antibiotics that afford their biological activity
through selective covalent binding with adenine-N3
within the minor groove of the DNA by its
cyclopropylindole (CPI) unit. It has been shown that
duocarmycins 2 and 3 readily lose HCl to generate the
active cyclopropane-containing drug (1) [4-8].
The synthesis of different analogues of duocarmycins
allows establishing some important molecular
requirements for biological activity [11-16]. Nevertheless,
no attempt was made to prepare conjugated analogs in
which the lone pair on the nitrogen atom has permanent
predetermined orientation.
O
MeO2C
Me
OMe
OMe
OMe
N
H
N
N
H
O
We have previously reported the free radical-promoted
ring closure of indole compound 4 bearing a radical
acceptor (2'-chloroallyl) attached onto the indole nitrogen
to furnish regioselectively the choropyrroloquinoline
derivative 5 through 6-endo-trig cyclization mode [17].
Hydrogenolysis (H2/Pd on C) of the benzyl group in 5 not
only furnished the corresponding phenol derivative 6, but
also small amount of the unexpected dehalogenated
phenol 7.
O
Duocarmycin A (1)
Cl
O
MeO2C
Me
OMe
OMe
OMe
N
H
N
N
HO
O
H
Duocarmycin C2 (2)
Cl
Y
O
Cl
OMe
OMe
OMe
I
MeO2C
Me
N
CO2Et
N
CO2Me
N
CO2Et
N
N
H
N
H
O
HO
OBn
O
OR
Duocarmycin C1 (3)
4
5: R = Bn; Y = Cl
6: R = H; Y = Cl
7: R = H; Y = H
8
Figure 1. Structures of some duocarmycins.

1334
N. H. Al-Said, Khaled Q. Shawakfeh and Baha A. Hammad
Vol 45
It was hypothesized that compound 7 is generated from
6, separated in excellent yield (91%) by column
chromatography on silica gel, did not correspond to the
required compound 8. The spectroscopic (1H NMR, 13C
NMR) and physical properties (melting point, Rf) of the
isolated product 6 were identical in all respects with those
of the compound prepared in our laboratory [17]. We
further observed that K2CO3 is not necessary for this
rearrangement. Thus, the phenol derivative 9 was
converted to 6 just by stirring in dry solvent (acetone,
THF) for 24 hrs. It is quite interesting that this
rearrangement actually did occur in a pure solid sample of
9. TLC indicated that pure 9 became contaminated with
the rearranged product 6 after storage for several weeks.
Furthermore, we observed that the benzyloxy derivative
12 was stable under neutral and basic conditions in
different solvents (THF, acetone, DMF).
the reduction of cyclopropane system 8, formed in situ
from 7 after losing HCl [17]. Despite the conversion of 5
to cyclopropylindole 8 proved unsuccessful under various
conditions, the formation of the minor product 7 was
encouraging for the construction of a new DNA alkylating
unit similar to CPI subunit found in duocarmycins.
Now, we wish to report the conclusive chemical
evidence for the ring expansion through an in situ
formation of the biological important cyclopropylindoline
system from suitably functionalized pyrroloindoline
derivatives.
RESULTS AND DISCUSSION
In order to validate the proposal of in-situ formation of
cyclopropane system 8, we have directed our interest to the
construction of the related pyrroloindoline system 9 [18].
Since the expansion of the five-membered ring in
pyrroloindoline into six-membered ring in pyrrolo-quinoline
proceeds through 8 as an intermediate. From retrosynthetic
perspective, we considered the construction of 9 via free
radical cyclization of N-(3'-chloroallyl)-7-iodoindole
derivative 10 (Scheme 1) followed by hydrogenolysis of the
benzyl group. Our synthetic sequence started with the known
7-iodoindole derivative 11 [17], which was smoothly
converted into the required indole compound 10 as a
cis/trans mixture in excellent yield. The cis/trans mixture
was not separated. It was subjected to a free-radical
cyclization using toluene at reflux in the presence of Bu3SnH
and a catalytic amount of AIBN. To our pleasant surprise,
this reaction afforded chloropyrroloindoline 12 in good (75-
85%) yield through the 5-exo-trig cyclization mode. It is
noteworthy that this reaction furnished exclusively the
chloropyrroloindoline 12 and we did not observed formation
of pyrroloquinoline derivative, suggesting that the 5-exo-trig
cyclization mode is preferred over the 6-endo-trig mode. The
opposite appears to be the case with N-allyl and N-(2'-
choroally) indole derivatives. This result clearly suggests that
the strain in the saturated five-membered ring is not the
deterrent factor in the formation of pyrroloindoline
compound. Removal of the benzyl-protecting group from 12
was effected under mild conditions (H2 balloon, Pd/C, 15
min) to afford chloropyrroloindoline 9 in good yield. The
experimental conditions i.e., solvent and time, were crucial
for the formation of 9 as the only product. In fact, conducting
the reaction for 2 h, the known compounds 6 and 7 [17] were
isolated, probably due to the formation of cyclopropyl-
pyrroloindole derivative 8.
Scheme 1
Cl
I
H
N
I
CO2Et
CO2Et
N
b
a
OBn
OBn
11
10
Cl
Cl
CO2Et
N
CO2Et
N
c
+ 7 + 6
OH
OBn
9
12
d
Nu
CO2Et
N
6: Nu = Cl, 13: Nu = CN, 14: Nu = OMe
OH
Reagents and conditions: (a) NaI, K2CO3, DMF, ClCH2CH=
CHCl, 98%; (b) Toluene, Bu3SnH, AIBN, 85%; (c) H2, Pd/C,
hexane-EtOAc (9:1), 15 min, 90%; d) for 6: K2CO3, Acetone, rt,
95%; for 13 KCN, Acetone, rt; 90%; for 14: MeOH, rt.
To collect more information, some supporting
experiments were conducted. In one experiment, the
reaction was carried out in the presence of KCN in
acetone at room temperature for 0.5 hr. The cyano
derivative 13 was formed and isolated from the reaction
mixture in 90% yield. In another experiment, the reaction
was carried out in methanol to afford the methyl ether
derivative 14 contaminated with inseparable impurities.
A mechanistic rationalization for the formation of 6 can
be made along the following lines (Scheme 2). Once
With a convenient access to 9, we explored the
formation and isolation of the biologically important
cyclopropylpyrroloindole derivative 8. Thus, compound 9
was stirred in mild basic conditions (K2CO3, acetone or
NaH, THF) at room temperature. The starting material
was consumed in short time (45 minutes). We were
surprised to find that the structure of the exclusive product

Sep-Oct 2008
A Facile Rearrangement of Pyrroloindoline derivative to Pyrroloquinoline
1335
1
(100%); ir (KBr): 1715, 1648 and 1605 cm-1; H NMR (400
MHz, CDCl3) ꢀ: 7.30 (m, 7H, Ar-H), 6.28 (d, J = 8.2 Hz, 1H,
Ar-H), 6.08 (m, 1H, CHCl), 5.84 (m, 1H, CH), 5.08 (bs, 2H,
CH2N), 5.11 (s, 2H, -OCH2Ph), 4.28 (q, J = 7.3 Hz, 2H, OCH2),
1.32 (t, J = 7.3 Hz, 3H, -CH3); EIMS m/z: 495.3 (M+).
formed, the phenole derivative 9 can undergo cyclization
to furnish the intermediate 8 or its protonated form 15.
The next step presumably involves nucleophilic attack at
C to regenerate the aromatic system. Cleavage of C-C
bond would eradicate the strain in the cyclopropylindoline
unit and gives a stable six-membered ring. The use of
K2CO3 accelerates the reactions by forming the
corresponding phenoxide anion.
Ethyl 8-benzyloxy-5-(chloromethyl)-4,5-dihydro-1H-
pyrrolo[3,2,1-hi]indoline-2-carboxylate (12). A solution of 10
(0.268 g, 0.602 mmol), Bu3SnH (97%, 0.18 g, 0.600 mmol), and
a catalytic amount of AIBN (93 mg) in 50 mL of toluene was
degassed with nitrogen for 5 min, and heated at reflux. After 30
min, an additional 0.2 g of Bu3SnH was added and refluxed for
10 min. The reaction mixture was cooled to room temperature,
and concentrated. The crude product was purified by column
chromatography eluting with 3% ethyl acetate in hexane to
afford a white solid of 12, 0.176 g (79%), mp 110-112º; ir (KBr
Scheme 2
Cl
Nu
N
CO2Et
CO2Et
N
CO2Et
N
disk): 1710 and 1608 cm-1; H-NMR (400 MHz, CDCl3): ꢀ 7.30
1
-Cl
NuH or
Nu
(m, 6H, Ar-H), 6.90 (d, J = 7.4 Hz, 1H, Ar-H), 6.39 (d, J = 7.6
Hz, 1H, Ar-H), 5.18 (s, 2H, -OCH2), 4.80 (dd, J = 12.1, 8.4 Hz,
1H, -NCHH), 4.55 (dd, J = 12.1, 4.4 Hz, 1H), 4.30 (m, 3H), 3.82
(dd, J = 10.8, 5.6 Hz, 1H), 3.65 (dd, J = 10.8, 8.6 Hz, 1H) 1.33
(t, J = 7.10 Hz, 3H, -CH3); 13C-NMR(100 MHz, CDCl3) ꢀ:
161.8, 153.2, 150.8, 137.1, 128.5, 127.9, 127.4, 126.5, 118.5,
110.6, 109.7, 104.2, 70.8, 60.7, 56.4, 49.4, 46.8, 14.4; EIMS
m/z: 369.6 (M+). Anal. Calcd. for C21H20NClO3: C, 68.20; H,
5.45; N, 3.79. Found: C, 68.54; H, 5.38; N, 3.86.
O
H
O
H
OH
9
15
A mechanistic rationalization
In conclusion, a free-radical generated at C-7 position
of indole derivative bearing N-(3'-chloroallyl) group has
been demonstrated to furnish pyrroloindoline derivative,
through 5-exo-trig cyclization mode. Furthermore, we
have shown that properly substituted pyrroloindoline
derivative smoothly rearranged to pyrroloquinoline, even
in a solid state, confirming that the conjugation of the lone
pair of electron on the nitrogen atom of the carboxamido
group of duocarmycins is crucial for the stability of the
cyclopropylindoline moiety.
Ethyl 5-(chloromethyl)-8-hydroxy-4,5-dihydro-4H-pyrrolo-
[3,2,1-hi]indoline-2-carboxylate (9). A solution of 12 (0.22 g,
0.959 mmol), and 5.0% Pd/C (100 mg) in ethyl acetate (50 mL)
was degassed by nitrogen gas. The reaction mixture was placed
under an atmosphere of H2 and stirred at 35ºC for 15 min. The
reaction mixture was filtered through celite and washed several
times with ethyl acetate. The combined organic solvent was
removed in vacuo, and the resulting crude product was purified
by chromatography eluting with 5-15% ethyl acetate in hexane
to give the expected phenol 9 as a white solid, 0.150 g (90%),
1
mp 160º; ir (KBr disk): 3300, 1689, 1606 cm-1; H NMR (400
EXPERIMENTAL
MHz, CDCl3) ꢀ: 7.21 (s, 1H), 6.87 (d, J = 7.1 Hz, 1H), 6.31 (d, J
= 7.1 Hz, 1H), 5.28 (bs, 1H), 4.82 (dd, J = 11.9, 8.2 Hz, 1H),
4.56 (dd, J = 11.9, 4.3 Hz, 1H), 4.32 (m, 3H), 3.83 (dd, J =10.9,
5.7 Hz, 1H), 3.56 (dd, J =10.9, 8.6 Hz, 1H), 1.35 (t, J = 7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3): ꢀ 162.2, 150.9, 149.6, 126.8,
119.4, 118.2, 109.7, 108.2, 106.0, 60.8, 56.6, 49.5, 46.8, 14.5;
EIMS m/z: 279.4 (M+). Anal. Calcd. for C14H14NClO3: C, 60.11;
H, 5.04; N, 5.01. Found: C, 60.21; H, 5.13; N, 4.93.
Melting points were measured using an electrothermal digital
melting point apparatus and were uncocorrected. IR spectra were
recorded using a Nicolet-Impact 410 FT-IR spectrophotometer.
1H NMR and 13C NMR spectra were recorded on a Bruker
AVANCE 400S spectrometer. The chemical shifts are given in ꢀ
ppm relative to TMS as the internal standard. Microanalytical
determinations were performed on a Perkin Elmer 2400 Series
PCII apparatus. Analytical thin-layer chromatography (TLC)
was done on silica gel 60 F254 coated aluminum sheets (0.25
mm thickness) with a fluorescent indicator. Visualization was
accomplished with UV light (254 nm). Column chromatography
was done using silica gel 60 (230–400 mesh) from Aldrich.
Ethyl 4-(benzyloxy)-1-(3-chlorallyl)-7-iodo-1H-indole-2-
caboxylate (10). A mixture of indole 11 (0.53 g, 1.26 mmol),
potassium carbonate (0.35 g, 2.53 mmol), sodium iodide (0.15 g,
1.00 mmol) and cis/trans mixture of 1,3-dichloropropene (0.62
g, 5.04 mmol) in DMF (50 ml) was stirred at 50 ºC for 19 h. The
solvent was evaporated under reduced pressure, diluted with
H2O (150 mL), and extracted with ethyl acetate (3 x 60 mL).
The combined organic layer was washed with brine solution,
dried over anhydrous sodium sulfate and concentrated under
reduced pressure. The resultant crude product was purified by
column chromatography eluting with 2.5% ethyl acetate in
hexane to afforded 10 as a mixture of E and Z isomers, 0.62 g
Ethyl 5-chloro-9-hydroxy-5,6-dihydro-4H-pyrrolo[3,2,1-hj]-
quinoline-2-carboxylate (6).
Method A. A solution of compound 12 (10 mg, 35.8 μmol),
potassium carbonate (20 mg, 144.7 μmol), in acetone (10 mL),
was stirred for 45 minutes. The solvent was then evaporated
under reduced pressure. The residue was purified by
chromatography (5-15% ethyl acetate in hexane) to afford
phenol 6 as a white solid 9.1 mg (91%), mp 244º; ir (KBr disk),
1
3275, 1671, 1606 cm-1; H-NMR (400 MHz, CDCl3): ꢀ 7.25 (s,
1H, Pyr-H), 6.84 (d, J = 7.5 Hz, 1H, Ar-H), 6.38 (d, J = 7.4 Hz,
Ar-H), 6.38 (d, J = 7.4 Hz, 1H, Ar-H), 5.02 (bs, 1H, -OH), 4.81
(dd, J = 14.0, 3.3 Hz, 1H, -NCHH-), 4.60 (m, 3H, CHCl and
NCHH), 4.32 (q, J = 7.2, 2H, -OCH2), 3.36 (dd, J = 16.2, 8.2 Hz,
1H, CHH-), 3.14 (dd, J = 16.2, 5.4 Hz, 1H, CH), 1.35 (t, J = 7.2
Hz, 3H, CH3); 13C-NMR(100 MHz, CDCl3) ꢀ: 161.9, 152.9,
139.3, 127.4, 123.4, 114.1, 111.5, 106.5, 104.7, 60.5, 52.2, 50.9,

1336
N. H. Al-Said, Khaled Q. Shawakfeh and Baha A. Hammad
Vol 45
34.4, 14.2. m/z 279.1 (M+). Anal. Calcd. for C14H14NClO3: C,
60.11; H, 5.04; N, 5.01. Found: C, 60.50; H, 5.11; N, 5.12.
Method B. A solution of compound 12 (10 mg, 35.8, μmol),
and sodium hydride washed with THF (2.0 mg, 160 μmol), was
dissolved in THF (10 mL), and stirred for 30 minutes. The
solvent was then evaporated under reduced pressure. The residue
was purified by chromatograph (5-15% ethyl acetate in hexane)
to afford the phenol 6 as a white solid 9.5 mg (95%).
[2] Ichimura, M; Ogawa, T.; Takahashi, K.; Kobayashi, E.,
Kawamoto, I.; Yasuzawa, T.; Takahashi, I.; Nakano, H. J. Antibiot.,
1990, 43, 1037.
[3] Yasuzawa, T.; Muroi, K.; Ichimura, M.; Takahashi, I.;
Ogawa, T.; Takahashi, K.; Sano, H.; Saitoh, Y. Chem. Pharm. Bull.,
1995, 43, 378.
[4] Li, L. H.; Kelly, R. C.; M. Warpehoski, A.; McGovern, J. P.;.
Gebhard, I.; DeKoning, T. F. Invest. New Drugs, 1991, 9, 137.
[5] Warpehoski, M. Advances in DNA Sequence Specific Agents,
L. H. Hurley, Ed., JAI: Greenwich, Vol. 1, 1992, pp 217-245.
[6] Boger, D. L.; Garbaccio, R. M. Acc. Chem. Res., 1999, 32,
1043.
Ethyl 5-cyano-9-hydroxy-5,6-dihydro-4H-pyrrolo[3,2,1-
hj]quinoline-2-carboxylate (13). A solution of compound 12 (10
mg, 35.8 μmol), potassium cyanide (10 mg, 210 μmol), in acetone
(10 mL), was stirred for 30 minuets. The solvent was evaporated
under reduced pressure, and residue was purified by chromato-
graph (5-15% ethyl acetate in hexane) to afford phenol 13 as a
white solid 9.0 mg (90%), mp 264º; ir (KBr) 3284, 2245, 1673,
[7] Boger, D. L.; Johnson, D. S. Angew. Chem., Int. Ed. Engl.,
1996, 35, 1438.
[8] Boger, D. L. Acc. Chem. Res., 1995, 28, 20.
[9] Boger, D. L.; Goldberg, J.; McKie, J. A. Bioorg. Med. Chem.
Lett., 1996, 6, 1955.
1
1602 cm-1; H NMR (400 MHz, CDCl3): ꢀ 7.24 (s, 1H, pyr-H),
6.88 (d, J = 7.2 Hz, 1H, Ar-H), 6.39 (d, J = 7.4 Hz, 1H, Ar-H),
4.85 (dd, J = 13.1, 3.9 Hz, 1H, NCHH)), 5.25 (bs, 1H, OH), 4.60
(dd, J = 13.3, 7.3 Hz, 1H, NCHH), 4.35 (q, J = 7.2 Hz, 1H,
OCH2), 3.35 (m, 1H, CHCN), 3.24 (dd, J =15.9, 4.4 Hz, 1H,
CHH), 3.17 (dd, J =15.9, 8.5 Hz, 1H, CHH), 1.35 (t, J = 7.2 Hz,
3H, CH3), 13C NMR (100 MHz, CDCl3): ꢀ 161.3, 152.1, 139.9,
127.3, 123.7, 118.2, 113.9, 111.0, 104.5, 106.1, 61.1, 50.8, 34.3,
30.2, 14.4; EIMS: m/z 270.2 (M+). Anal. Calcd. for C15H14N2O3: C,
66.66; H, 5.22; N, 10.36. Found: C, 66.59; H, 5.36; N, 10.46.
[10] Boger, D. L.; Mesini, P. ; Tarby, C. M. J. Am. Chem. Soc.,
1994, 116, 6461.
[11] Baraldi, P. G.; Cacciari, B.; Pineda de Las, M. J.; Romagnoli,
R.; Spalluto, G.; Cozzi, Mongelli, N. Anti-Cancer Drug Des., 1997, 12,
67.
[12] Baraldi, P. G.; Cacciari, B.; Romagnoli, R.; Spalluto, G.;
Gambari, R.; Bianchi, N.; Passadore, M.; Ambrosino, P.; Mongelli, N.;
Cozzi, P.; Geroni, C. Anti-Cancer Drug Design, 1997, 12, 555.
[13] Baraldi, P. G.; Cacciari, B.; Guiotto, A.; Romagnoli, R.;
Spalluto, G.; Zaid, A.N.; Capolongo, L.;. Cozzi, P.;. Geroni, C;
Mongelli, N. Il Farmaco, 1997, 52, 717.
Acknowledgement. We thank the Deanship of Research at
Jordan University of Science and Technology for financial
support, Grant No 135/2005.
[14] Boger, D.L.; Garbaccio, R.M. Bioorg. Med. Chem., 1997, 5,
263.
[15] Boger, D. L.; Turnbull, P. J. Org. Chem., 1998, 63, 8004.
[16] Boger, D.L.; Garbaccia, R.M. J. Org. Chem., 1999, 64, 8350.
[17] Al-Said, N. H., Shawakfeh, K. Q., Abdullah, W. N.
Molecules, 2005, 10, 1446.
REFERENCES AND NOTES
[1] Takahashi, I.; Takahashi, K.; Ichimura, M.; Morimoto, M.,
Asano, K.; Kawamoto, I.; Tomita, F.; Nakano, H. J. Antibiot., 1988, 41,
1915.
[18] For the unsubstituted pyrrolo[3,2,1-hi]indole see: Rapoport,
H; Tretter, J. R. J. Am. Chem. Soc., 1958, 80, 5574.