3-Indolylacyl radical cyclizations upon pyridines and tetrahydropyridines: Access to ergoline-related indole [cd]-fused isoquinolines

Article abstract of DOI:10.1021/jo2006279

Cyclizations of selenoester-derived 3-indolylacyl radicals, involving the homolytic acylation of pyridines or the addition to double bonds included in tetrahydropyridine rings, have been used to synthesize indole [cd]-fused isoquinolines related to the natural ergoline system.

Full text of DOI:10.1021/jo2006279

NOTE
pubs.acs.org/joc
3-Indolylacyl Radical Cyclizations upon Pyridines and
Tetrahydropyridines: Access to Ergoline-Related Indole
[cd]-fused Isoquinolines
M.-Lluïsa Bennasar* and Tomꢀas Roca
Laboratory of Organic Chemistry, Faculty of Pharmacy, and Institut de Biomedicina (IBUB), University of Barcelona,
Barcelona 08028, Spain
S Supporting Information
b
ABSTRACT: Cyclizations of selenoester-derived 3-indolylacyl radi-
cals, involving the homolytic acylation of pyridines or the addition to
double bonds included in tetrahydropyridine rings, have been used to
synthesize indole [cd]-fused isoquinolines related to the natural
ergoline system.
n the last years we have been working on the implementation
of a novel indole annulation procedure taking advantage of the
Scheme 1. Synthetic Strategy
I
reactions of selenoester-derived 2-indolylacyl radicals.1,2 We
have shown that these reactive intermediates participate in
cyclizations upon alkenes3ꢀ6 and (hetero)aromatic systems,7ꢀ9
leading to a great variety of polycyclic indolyl ketones of interest
in the synthesis of natural products and related bioactive com-
pounds.10 On the basis of these results, we considered using
the regioisomeric 3-indolylacyl radicals11 in similar reactions
for the construction of indole [cd]-fused isoquinolines I,
which are structurally related to the ergoline system present in
the biologically important ergot alkaloids (for example, lysergic
acid, Scheme 1). We specifically wanted to study if cyclizations of
pyridine- or tetrahydropyridine-containing 3-indolylacyl radicals
of general formula II, involving either aromatic substitution
or alkene addition processes, would serve to close the central
carbocyclic 6-membered ring, thus giving direct access to the
target tetracyclic systems.
Scheme 2. Synthesis of Selenoesters 3
Intramolecular homolytic aromatic substitutions have become
a useful tool for the construction of otherwise inaccessible
polycyclic systems, in particular with the advent and application
of tin-based reagents.12 However, the use of electron-deficient
pyridines as substrates toward nucleophilic acyl radicals, which
represents the umpolung of the FriedelꢀCraft reaction, has been
scarcely studied.8,9,13 Indeed, most reported examples of such
homolytic acylations are conducted in acidic media under
oxidative protocols (Minisci reactions).14
Selenoesters 3a and 3b (Scheme 2), bearing 4- or 3-pyridyl
moieties attached at the indole 4-position, were selected as the
radical precursors to study cyclizations leading to pyrido-fused
systems.15 These compounds were efficiently prepared by Suzuki
coupling of methyl 4-iodo-3-indolecarboxylate 1 with 4- or
3-pyridylboronic acid, followed by hydrolysis of the ester func-
tion and phenylselenation of the resulting carboxylic acid accord-
ing to the Batty and Crich protocol.16
Treatment of selenoester 3a with n-Bu3SnH as the radical
mediator and AIBN as the initiator in refluxing benzene for 20 h
Received: March 24, 2011
Published: April 07, 2011
r
2011 American Chemical Society
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|

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NOTE
Scheme 3. Cyclization of Selenoesters 3
Scheme 5. Synthesis of Selenoesters 9
intermediate cyclized radical (for the 4-pyridyl series, A,
Scheme 4), most probably at the hands of the initiator AIBN,17,18
which is present in stoichiometric amounts. However, formation
of byproduct 5a,b could not be readily explained.
To gain further insight into the mechanistic course of the
above cyclizations, we briefly examined the behavior of sele-
noester 3a under tris(trimethylsilyl)silane (TTMSS)-AIBN
conditions. After 18 h at reflux we obtained a complex crude
reaction mixture, in which the major product was shown by 1H
NMR to be a dihydro derivative of indole 5a, i.e., indoline 6. No
trace of tetracycle 4a was detected. As expected considering its
dihydroaromatic structure, indoline 6 proved to be unstable
during the extractive workup and column chromatography,
mainly undergoing oxidation to 5a. We were nevertheless able
to obtain a pure sample and confirm its highly conjugated enol
structure by 1H NMR. Significantly, it was fully converted into
indoles 4a and 5a (1:3 ratio) after 12 h in the NMR tube
(CD3OD).
Scheme 4. Likely Mechanism (4-Pyridyl Series)
The formation of indoline 6 can be rationalized by considering
that, after cyclization of the initially formed 3-indolylacyl radical
upon the pyridine ring, the resulting highly delocalized azacy-
clohexadienyl radical A, or its tautomeric form B, is intercepted
by 2-cyano-2-propyl radicals coming from the breakdown of
AIBN19 (Scheme 4). It is likely that this route is also operative
under n-Bu3SnH conditions, which would easily explain the
isolation of the minor byproduct 5a.20 On the other hand,
the major product 4a might be generated by elimination of
2-methylpropanenitrile from 6,21 which would constitute an
alternative route to the direct hydrogen atom abstraction from
radical A. A similar mechanistic rationale can account for the
formation of products 4b and 5b in the 3-pyridyl series (not
depicted).
We then focus our attention on the assembly of indole [cd]-
fused isoquinolines by intramolecular addition of 3-indolyla-
cyl radicals to double bonds included in tetrahydropyridine
rings under reductive conditions. To this end, we selected
selenoesters 9a and 9b (Scheme 5), from which the central
carbocyclic ring of the target system would be closed by
6-endo cyclization upon 1,2,5,6-tetrahydro-4- or -3-pyridyl
moieties, respectively. These compounds were easily pre-
pared from esters 2a or 2b by quaternization with methyl
iodide, reduction of the resulting pyridinium salts with NaBH4,
and subsequent phenylselenation of the tetrahydropyridine
esters 8a or 8b through the corresponding carboxylic acid as in
the above series.
led to the target indolo[4,3-fg]isoquinoline 4a (40% yield,
Scheme 3) along with minor amounts of tetracycle 5a (5%),
which additionally incorporated the 2-cyano-2-propyl moiety of
the initiator at the indole 2-position. Significant amounts (25%)
of unreacted selenoester, indicative of a poor chain, were
recovered, but no trace of aldehyde coming from the premature
reduction of the initially formed acyl radical was observed. An
entirely parallel cyclization course was observed in the 3-pyridyl
series, as selenoester 3b led to the indolo[3,4-gh]isoquinoline 4b
(35%) on exposure to the above conditions, with minor amounts
(5%) of the corresponding 2-(2-cyano-2-propyl)indole 5b also
being formed. It should be noted that the cyclization took place
regioselectively at the 4-position of the pyridine ring and no trace
of the product coming from the alternative attack at the 2-posi-
tion, i.e., the natural ergoline 7, was detected.
We were pleased to find that cyclization of selenoester 9a
smoothly took place under the standard n-Bu3SnH condi-
tions, using AIBN as the initiator in refluxing benzene. The
reaction was completed in 4 h and did not require slow
addition techniques, leading to the expected tetracycle 10a in
At this stage of the work, we assumed that tetracycles 4a,b
were the result of a hydrogen atom abstraction from the
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NOTE
Scheme 6. Cyclization of Selenoesters 9
’ EXPERIMENTAL SECTION
Methyl 4-Iodo-1-methyl-3-indolecarboxylate (1). A solu-
tion of methyl 4-iodo-3-indolecarboxylate23 (1.30 g, 4.32 mmol) in
anhydrous THF (17 mL) was added dropwise under Ar to an ice-cooled
suspension of NaH (5.18 mmol) in anhydrous THF (10 mL). After the
solution was stirred 1 h at 0 °C, iodomethane (1.20 mL, 19.44 mmol)
was added dropwise and the mixture was allowed to warm to rt for 4 h.
The mixture was poured into H2O, acidified with 1 M aqueous HCl, and
extracted with CH2Cl2. The organic extracts were dried and concen-
trated to give 1 (1.35 g, 99%) as an oil, which crystallized on standing. An
analytical sample was obtained by crystallization from MeOH: mp
80ꢀ2 °C; 1H NMR (CD3OD, 300 MHz) δ 3.79 (s, 3H), 3.87
(s, 3H), 6.95 (t, J = 7.8 Hz, 1H), 7.43 (dd, J = 8.1, 0.9 Hz, 1H), 7.76
(dd, J = 7.8, 0.9 Hz, 1H), 7.88 (s, 1H); 13C NMR (CD3OD, 75.4 MHz) δ
33.6 (CH3), 51.5 (CH3), 85.1 (C), 109.1 (C), 111.4 (CH), 124.8 (CH),
129.6 (C), 135.7 (CH), 138.1 (CH), 139.2 (C), 166.2 (C); ESI-HRMS
[M þ H]þ calcd for C11H11INO2 315.9829, found 315.9827.
Pyridines 2a,b. A mixture of iodoindole 1 (0.53 g, 1.68 mmol), the
respective pyridylboronic acid (90%, 0.28 g, 2.03 mmol), Pd(PPh3)4 (78
mg, 0.067 mmol), and 1 M aqueous Na2CO3 (3.9 mL) in DME (16 mL)
was stirred at reflux temperature for 24 (1a) or 4 h (1b). The reaction
mixture was partitioned between AcOEt and H2O. The organic layer was
concentrated to dryness and the crude product was chromatographed
(SiO2, AcOEt) to give the pure product.
Methyl 1-methyl-4-(4-pyridyl)-3-indolecarboxylate (2a):
1
0.39 g (87%); mp 134ꢀ6 °C; H NMR (acetone-d6, 300 MHz) δ
3.28 (s, 3H), 3.96 (s, 3H), 7.14 (dd, J = 6.9, 0.9 Hz, 1H), 7.28 (d, J = 6.3
Hz, 2H), 7.38 (dd, J = 8.1, 7.2 Hz, 1H), 7.58 (dd, J = 8.1, 0.9 Hz, 1H),
8.01 (s, 1H), 8.56 (d, J = 6 Hz, 2H); 13C NMR (acetone-d6, 75.4
MHz) δ 33.7 (CH3), 50.4 (CH3), 108.0 (C), 111.4 (CH), 123.4
(CH), 123.6 (C), 124.2 (CH), 124.4 (CH), 134.1 (C), 137.9 (CH),
139.2 (C), 149.6 (CH), 151.3 (C), 164.6 (C); ESI-HRMS [M þ H]þ
calcd for C16H15N2O2 267.1128, found 267.1132. Anal. Calcd for
C16H14N2O2: C, 72.16; H, 5.30; N, 10.52. Found: C, 72.38; H, 5.42;
N, 10.43.
high yield (84%) as a 1.2:1 mixture of transꢀcis stereoisomers
(Scheme 6). Its formation was consistent with the pre-
dicted 6-endo attack of the initially formed acyl radical at
the 3-position of the tetrahydropyridine ring and the subse-
quent reduction of the resulting tetracyclic radical C by
nonstereoselective hydrogen abstraction from the tin hydride.
Similarly, selenoester 9b on exposure to the above conditions
led to tetracycle 10b in 86% yield (1.5:1 mixture of transꢀcis
stereoisomers).
With the aim of improving the above stereoselectivity, we
decided to switch from AIBN initiation to Et3B, which allows
n-Bu3SnH-mediated reactions to be performed at room (or
lower) temperatures.22 However, when 9a was subjected to
this new radical protocol, tetracycle 11, which retained the
original double bond, was isolated in 65% yield. Minor
amounts (10%) of byproduct coming from adventitious
nucleophilic addition (phenylselenolate, H2O) to the enone
moiety were also formed. The formation of 11 was striking
since it indicated that the nucleophilic benzyl-type radical C
resulting from the 6-endo cyclization, instead of being inter-
cepted by the tin hydride, underwent oxidation by loss of a
hydrogen atom, for instance at the hands of ethyl radicals from
the initiator.
In summary, we have shown that selenoester-derived 3-in-
dolylacyl radicals undergo cyclization upon pyridine rings at-
tached at the indole 4-position under n-Bu3SnH-AIBN condi-
tions to give indole [cd]-fused isoquinolines in moderate
yields. There is evidence to suggest that reaction of 2-cyano-
propyl radicals with the initially formed cyclized radical and
subsequent elimination could be a contributory mechanism
for the homolytic aromatic substitution process. From the
synthetic standpoint, the best yields of the target tetracyclic
systems are obtained by 6-endo radical cyclizations upon
tetrahydropyridine double bonds.
Methyl 1-methyl-4-(3-pyridyl)-3-indolecarboxylate (2b):
1
0.43 g (96%); mp 114ꢀ6 °C; H NMR (CDCl3, 300 MHz) δ 3.37
(s, 3H), 3.89 (s, 3H), 7.16 (dd, J = 6.3, 1.8 Hz, 1H), 7.34 (ddd, J = 7.8,
5.1, 0.9 Hz, 1H), 7.40 (m, 2H), 7.73 (td, J = 7.2, 1.8 Hz, 1H), 7.87 (s,
1H), 8.59 (dd, J = 5.1, 1.8 Hz, 1H), 8.65 (d, J = 2.1, 1H); 13C NMR
(CDCl3, 75.4 MHz) δ 33.5 (CH3), 50.9 (CH3), 107.5 (C), 109.6 (CH),
122.3 (CH), 122.7 (CH), 123.4 (C), 124.3 (CH), 132.4 (C), 135.5
(CH), 136.8 (CH), 138.0 (C), 138.4 (C), 147.5 (CH), 149.5 (CH),
164.4 (C); ESI-HRMS [M þ H]þ calcd for C16H15N2O2 267.1128,
found 267.1132. Anal. Calcd for C16H14N2O2: C, 72.16; H, 5.30; N,
10.52. Found: C, 71;81 H, 5.29; N, 10.08.
Phenyl Selenoesters 3a,b. A solution of the respective carboxylic
ester 2a or 2b (0.27 g, 1.0 mmol) in a 1:1:1 mixture of 2 N aqueous
KOHꢀMeOHꢀdioxane (5 mL) was heated at reflux for 24 h. MeOH
was evaporated and 1 N aqueous HCl was added until pH 7. The
precipitated carboxylic acid was collected by filtration, washed with
H2O, and dried over P4O10. A suspension of this material in a 1:1
mixture of CH2Cl2ꢀMeOH (8 mL) was treated with Et3N (0.24 mL,
1.70 mmol). After 30 min at rt, the mixture was concentrated under
reduced pressure to give the respective triethylammonium salt. In
another flask, tributylphosphine (0.52 mL, 2.12 mmol) was added under
Ar to a solution of PhSeCl (0.41 g, 2.12 mmol) in anhydrous THF
(4 mL), and the mixture was stirred at rt for 10 min. The resulting yellow
solution was added to a suspension of the above triethylammonium salt
in THF (4 mL) and the resulting mixture was stirred at rt overnight. The
reaction mixture was partitioned between CH2Cl2 and H2O, and
extracted with CH2Cl2. The solvent was removed and the crude product
was purified as indicated below.
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1
Phenyl 1-methyl-4-(4-pyridyl)-3-indolecarboselenoate (3a):
0.28 g (71%, after crystallization on standing in the fridge and washing with
Et2O); mp 192ꢀ4 °C; 1H NMR (CDCl3, 500 MHz) δ 3.92 (s, 3H), 7.23
(dd, J = 5.5, 3 Hz, 1H), 7.32 (m, 5H), 7.44 (m, 4H), 8.03 (s, 1H), 8.60 (d,
J = 5.5 Hz, 2H); 13C NMR (CDCl3, 125.7 MHz) δ 33.9 (CH3), 110.3
(CH), 117.8 (C), 121.3 (C), 123.7 (CH), 124.0 (CH), 124.4 (CH), 126.9
(C), 128.5 (CH), 129.1 (CH), 133.3 (C), 135.6 (CH), 136.6 (CH), 138.6
(C), 148.1 (CH), 149.7 (C), 182.5 (C); ESI-HRMS [M þ H]þ calcd for
C21H17N2OSe 393.0500, found 393.0503. Anal. Calcd for C21H16N2OSe:
C, 64.45; H, 4.12; N, 7.16. Found: C, 63.99; H, 4.20; N, 6.97.
Indoline 6: H NMR (CD3OD, 300 MHz) δ 1.32 (s, 3H), 1.65
(s, 3H), 3.34 (s, 3H), 5.25 (s, 1H), 6.92 (d, J = 7.5 Hz, 1H), 7.61 (dd, J =
8.4, 7.5 Hz, 1H), 7.96 (d, J = 8.4 Hz, 1H), 8.77 (d, J = 6.6 Hz, 1H), 9.03
(d, J = 6.6 Hz, 1H), 9.80 (s, 1H).
Tetrahydropyridines 8a,b. Iodomethane (0.70 mL, 11.80 mmol)
was added to a solution of the respective pyridines 2a or 2b (0.31 g, 1.16
mmol) in anhydrous acetone (7 mL) and anhydrous C6H6 (0.7 mL).
After the mixture was stirred at rt for 24 h, the corresponding pyridinium
salt was collected by filtration. NaBH4 (0.11 g, 2.91 mmol) was added in
three portions to an ice-cooled suspension of the pyridinium salt in
MeOH (10 mL). After the soluton was stirred at rt for 7 h, the solvent
was removed and the resulting residue was partitioned between CH2Cl2
and a saturated aqueous Na2CO3 solution, and extracted with CH2Cl2.
The organic extracts were dried and concentrated and the crude product
was chromatographed (SiO2, 95:5:1 CH2Cl2ꢀMeOHꢀdiethylamine)
to give the pure product.
Methyl 1-methyl-4-(1-methyl-1,2,5,6-tetrahydro-4-pyridyl)-
3-indolecarboxylate (8a): 0.32 g (97%); 1H NMR (CDCl3, 300 MHz)
δ 2.46 (s, 3H), 2.51 (m, 2H), 2.78 (t, J = 5.7 Hz, 2H), 3.17 (q, J = 2.7 Hz,
2H), 3.81 (s, 3H), 3.83 (s, 3H), 5.64 (m, 1H), 7.09 (m, 1H), 7.25 (m, 2H),
7.78 (s, 1H); 13C NMR (CDCl3, 75.4 MHz) δ 31.4 (CH2), 33.1 (CH3),
45.8 (CH3), 51.0 (CH3), 51.9 (CH2), 54.5 (CH2), 107.0 (C), 108.4 (CH),
120.9 (CH), 122.4 (CH), 122.5 (CH), 123.0 (C), 135.8 (CH), 137.2 (C),
137.6 (C), 138.2 (C), 164.1 (C); ESI-HRMS [M þ H]þ calcd for
C17H21N2O2 285.1598, found 285.1597.
Methyl 1-methyl-4-(1-methyl-1,2,5,6-tetrahydro-3-pyridyl)-
3-indolecarboxylate (8b): 0.29 g (89%); 1HNMR(CDCl3, 300 MHz)
δ 2.41 (s, 3H), 2.38 (m, 2H), 2.68 (t, J = 5.7 Hz, 2H), 3.22 (q, J = 2.7 Hz,
2H), 3.81 (s, 3H), 3.84 (s, 3H), 5.65 (m, 1H), 7.09 (m, 1H), 7.26 (m, 2H),
7.76 (s, 1H); 13C NMR (CDCl3, 75.4 MHz) δ 26.0 (CH2), 33.2 (CH3),
45.6 (CH3), 51.1 (CH2 and CH3), 58.6 (CH2), 107.4 (C), 108.4 (CH),
121.3 (CH), 122.4 (CH), 122.6 (CH), 123.4 (C), 135.7 (CH and C),
137.6 (C), 138.0 (C), 164.5 (C); ESI-HRMS [M þ H]þ calcd for
C17H21N2O2 285.1598, found 285.1595.
Phenyl 1-Methyl-4-(1-methyl-1,2,5,6-tetrahydro-4-pyridyl)-
3-indolecarboselenoate (9a). Methyl ester 8a (0.31 g, 1.09 mmol)
was subjected to the protocol described for the preparation of 3a,b. The
crude oily residue crystallized on standing in the fridge. After washing
with Et2O, the resulting white solid (selenoester 9a hydrochloride, mp
192ꢀ4 °C) was partitioned between 2 N aqueous Na2CO3 and CH2Cl2
and extracted with CH2Cl2. The organic extracts were dried and con-
centrated to give selenoester 9a: 0.33 g (75%); 1H NMR (CDCl3, 400
MHz) δ2.48(s, 3H), 2.55 (m, 2H), 2.80 (t, J = 5.6Hz, 2H), 3.20 (m, 2H),
3.77 (s, 3H), 5.66 (broad s, 1H), 7.16 (d, J = 6.8 Hz, 1H), 7.24 (d, J = 8.8
Hz, 1H), 7.32 (t, J = 8 Hz, 1H), 7.43 (m, 3H), 7.67 (m, 2H), 7.98 (s, 1H);
13C NMR (CDCl3, 100.6 MHz) δ 30.7 (CH2), 33.4 (CH3), 45.4 (CH3),
51.4 (CH2), 54.2 (CH2), 108.5 (CH), 117.4 (C), 121.5 (C), 121.9 (CH),
122.7 (CH), 123.4 (CH), 127.4 (C), 128.2 (CH), 128.9 (CH), 135.8
(CH), 136.0 (CH), 136.6 (C), 137.3 (C), 138.1 (C), 182.3 (C); ESI-
HRMS [M þ H]þ calcd for C22H23N2OSe 411.0970, found 411.0971.
For 9a HCl: Anal. Calcd for C22H22N2OSe HCl 3/2H2O: C, 55.88; H,
Phenyl 1-methyl-4-(3-pyridyl)-3-indolecarboselenoate (3b):
0.25 g (64%, after flash chromatography, SiO2, hexanes and 4:6 hexanesꢀ
AcOEt); 1H NMR (CDCl3, 300 MHz) δ 3.93 (s, 3H), 7.22 (dd, J = 6, 2.7
Hz, 1H), 7.30 (m, 4H), 7.45 (m, 4H), 7.67 (ddd, J = 8.1, 2.4, 1.8 Hz, 1H),
8.04 (s, 1H), 8.56 (dd, J = 5.1, 1.8 Hz, 1H), 8.74 (dd, J = 2.1, 0.9 Hz, 1H);
13C NMR (CDCl3, 100.6 MHz) δ 33.7 (CH3), 109.6 (CH), 117.7 (C),
121.8 (C), 122.4 (CH), 123.6 (CH), 124.7 (CH), 127.1 (C), 128.3 (CH),
128.9 (CH), 132.6 (C), 135.7 (CH), 135.8 (CH), 136.6 (CH), 136.8 (C),
138.4 (C), 147.9 (CH), 149.5 (CH), 182.4 (C); ESI-HRMS [M þ H]þ
calcd for C21H17N2OSe 393.0500, found 393.0502. Anal. Calcd for
C21H16N2OSe: C, 64.45; H, 4.12; N, 7.16. Found: C, 64.20; H, 4.21; N, 7.01.
Radical Cyclization of Selenoesters 3. A solution of n-Bu3SnH
(0.14 mL, 0.52 mmol) and AIBN (84 mg, 0.52 mmol) in C6H6 (2 mL)
was added over a period of 20 h to a heated (reflux) suspension of the
respective selenoester 3a or 3b (0.10 g, 0.26 mmol) in C6H6 (10 mL).
After an additional 2 h at reflux, the reaction mixture was concentrated,
the resulting residue was partitioned between hexanes (15 mL) and
acetonitrile (15 mL), and the polar layer was washed with hexanes. The
solvent was removed, and the crude mixture was chromatographed
(SiO2, AcOEt and 98:2 AcOEtꢀMeOH) to give the pure products.
From 3a: 4-Methylindolo[4,3-fg]isoquinolin-6-one (4a): 24
mg (40%); 1H NMR (DMSO-d6, 300 MHz) δ 4.07 (s, 3H), 7.57 (t, J =
7.8 Hz, 1H), 7.90 (d, J = 8.4 Hz, 1H), 8.29 (d J = 7.5 Hz, 1H), 8.39 (d, J =
5.1 Hz, 1H), 8.57 (s, 1H), 8.84 (d, J = 5.4 Hz, 1H), 9.43 (s, 1H); 13C
NMR (DMSO-d6, 100.6 MHz) δ 34.2 (CH3), 112.7 (C), 114.8 (CH),
117.9 (CH), 119.1 (CH), 120.6 (C), 124.2 (CH), 126.7 (C), 128.2 (C),
135.2 (C), 136.1 (CH), 142.3 (C), 149.8 (CH), 151.9 (CH), 177.1 (C);
ESI-HRMS [M þ H]þ calcd for C15H11N2O 235.0866, found 235.0866.
5-(2-Cyano-2-propyl)-4-methylindolo[4,3-fg]isoquinolin-6-one (5a):
4 mg (5%); 1H NMR (CDCl3, 500 MHz) δ 2.29 (s, 6H), 4.39
(s, 3H), 7.61 (dd, J = 8, 7 Hz, 1H), 7.68 (d, J = 8.5 Hz, 1H), 8.12 (d
J = 7 Hz, 1H), 8.17 (d, J = 5 Hz, 1H), 8.85 (broad s, 1H), 9.68 (s, 1H);
13C NMR (CDCl3, 125.7 MHz) δ 26.7 (CH3), 33.9 (CH3), 34.2 (C),
111.2 (C), 113.8 (CH), 117.1 (CH), 119.3 (CH), 120.9 (C), 123.3 (C),
124.6 (CH), 126.5 (C), 129.5 (C), 135.6 (C), 147.6 (C), 149.7 (2 CH),
176.9 (C), one quaternary C not observed; ESI-HRMS [M þ H]þ calcd
for C19H16N3O 302.1288, found 302.1289.
From 3b: 4-Methylindolo[3,4-gh]isoquinolin-6-one (4b):
1
21 mg (35%); mp 246ꢀ8 °C; H NMR (CDCl3, 500 MHz) δ 4.07
(s, 3H), 7.55 (m, 2H), 8.12 (m, 1H), 8.13 (s, 1H), 8.31 (d, J = 5 Hz, 1H),
8.80 (d, J = 5 Hz, 1H), 9.65 (s, 1H); 13C NMR (CDCl3, 125.7 MHz) δ
34.4 (CH3), 111.8 (CH), 113.7 (C), 117.3 (CH), 120.6 (CH), 121.8 (C),
124.5 (CH), 126.3 (C), 129.8 (C), 134.2 (CH), 135.1 (C), 139.7 (C),
146.6 (CH), 148.7 (CH), 177.8 (C); ESI-HRMS [M þ H]þ calcd for
3
3
3
5.54; N, 5.92. Found: C, 55.62; H, 5.36; N, 5.75.
Phenyl 1-Methyl-4-(1-methyl-1,2,5,6-tetrahydro-3-pyridyl)-
3-indolecarboselenoate (9b). A solution of methyl ester 8b (0.25 g,
0.93 mmol) in a 1:1:1 mixture of 2 N aqueous KOHꢀMeOHꢀdioxane
(6 mL) was heated at reflux for 24 h. The reaction mixture was con-
centrated, acidified with 1 N aqueous HCl until pH 4, and concentrated to
dryness. The resulting residue was digested with anhydrous MeOH. The
methanolic solution was concentrated to give the crude carboxylic acid
hydrochloride. A suspension of this material in CH2Cl2 (4 mL) was treated
with Et3N (0.26 mL, 1.86 mmol) and the resulting triethylammonium salt
was allowed to react with tributylphosphine (0.46 mL, 1.86 mmol) and
PhSeCl (0.36 g, 1.86 mmol) as described for the preparation of selenoesters
3a,b. After workup, the crude residue was chromatographed (SiO2, CH2Cl2
C15H11N2O 235.0866, found 235.0865. Anal. Calcd for C15H10N2O H2O:
3
C, 71.41; H, 4.79; N, 11.10. Found: C, 71.30; H, 4.36; N, 10.75. 5-(2-
Cyano-2-propyl)-4-methylindolo[3,4-gh]isoquinolin-6-one (5b): 4 mg
(5%); mp 236ꢀ8 °C; 1H NMR (CDCl3, 500 MHz) δ 2.28 (s, 6H), 4.38
(s, 3H), 7.58 (m, 2H), 8.16 (m, 1H), 8.28 (d, J = 5 Hz, 1H), 8.80 (d, J = 5
Hz, 1H), 9.65 (s, 1H); 13C NMR (CDCl3, 125.7 MHz) δ 26.7 (CH3), 33.8
(CH3), 34.2 (C), 111.0 (C), 111.8 (CH), 117.8 (CH), 120.8 (CH), 121.5
(C), 123.4 (C), 124.8 (CH), 125.1 (C), 129.0 (C), 135.5 (C), 139.9 (C),
146.4 (CH), 147.3 (C), 148.7 (CH), 177.0 (C); ESI-HRMS [M þ H]þ
calcd for C19H16N3O 302.1288, found 302.1293.
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NOTE
and 96:4 CH2Cl2ꢀMeOH). The resulting pale yellow oil (selenoester 9b
hydrochloride) was partitioned between 2 N aqueous Na2CO3 and CH2Cl2
and extracted with CH2Cl2. The organic extracts were dried and concen-
trated to give selenoester 9b: 0.22 g (58%); 1H NMR(CDCl3, 400 MHz) δ
2.45 (s, 3H), 2.38 (m, 2H), 2.69 (t, J = 6 Hz, 2H), 3.29 (q, J = 2.4 Hz, 2H),
3.81 (s, 3H), 5.68 (m, 1H), 7.16 (dd, J = 7.2, 1.2 Hz, 1H), 7.25 (dd, J = 8.4,
1.2 Hz, 1H), 7.32 (dd, J= 8.4, 7.2 Hz, 1H), 7.41 (m, 3H), 7.65 (m, 2H), 7.93
(s, 1H); 13C NMR (CDCl3, 100.6 MHz) δ 26.1 (CH2), 33.5 (CH3), 45.7
(CH3), 50.7 (CH2), 58.2 (CH2), 108.5 (CH), 118.0 (C), 122.2 (C), 122.5
(CH), 123.3 (CH), 123.4 (CH), 127.7 (C), 128.4 (CH), 129.0 (CH),
135.7 (CH), 135.8 (CH), 135.9 (C), 136.1 (C), 138.3 (C), 182.5 (C); ESI-
HRMS [M þ H]þ calcd for C22H23N2OSe 411.0970, found 411.0977.
Anal. Calcd for C22H22N2OSe: C, 64.54; H, 5.42; N, 6.84. Found: C, 64.10;
H, 5.42; N, 6.84.
(s, 3H, 4-Me), 7.39 (dd, J = 7.8, 7.2 Hz, 1H, 2-H), 7.48 (d, J = 7.8 Hz, 1H,
3-H), 7.54 (d, J = 7.2 Hz, 1H, 1-H), 7.96 (s, 1H, 5-H); 13C NMR
(CDCl3ꢀCD3OD, 125.7 MHz, HSQC, HMBC) δ 25.7 (C-10), 34.0 (4-
Me), 45.6 (8-Me), 51.1 (C-9), 53.1 (C-7), 112.3 (C-3), 113.9 (C-5a),
119.4 (C-1), 123.8 (C-2), 124.4 (C-10b), 125.3 (C-10c), 134.3 (C-3a,
C-6a), 135.4 (C-5), 141.0 (C-10a), 179.4 (C-6); ESI-HRMS [M þ H]þ
calcd for C16H17N2O 253.1335, found 253.1338.
’ ASSOCIATED CONTENT
1
Supporting Information. Copies of H and 13C NMR
S
b
spectra of new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
Tetracycles 10a,b. A solution of the respective phenyl selenoester
9a or 9b (0.16 g, 0.39 mmol), n-Bu3SnH (0.21 mL, 0.78 mmol), and
AIBN(12 mg, 0.08 mmol) inC6H6 (11mL) under Arwas heatedatreflux
for 4 h. The reaction mixture was concentrated, the resulting residue was
partitioned between hexanes (15 mL) and acetonitrile (15 mL), and the
polar layer was washed with hexanes. The solvent was removed and the crude
product was chromatographed (SiO2, CH2Cl2, 98:2 CH2Cl2ꢀMeOH, and
97:2:1 CH2Cl2ꢀMeOHꢀdiethylamine) to give the pure product.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: bennasar@ub.edu.
’ ACKNOWLEDGMENT
We thank the Ministerio de Ciencia e Innovaciꢁon, Spain, for
financial support (project CTQ2009-07175).
4,8-Dimethyl-6a,7,8,9,10,10a-hexahydroindolo[4,3-fg]-
isoquinolin-6-one (10a): 83 mg (84%, 1.2:1 mixture of transꢀcis
stereoisomers); 1H NMR (CDCl3, 400 MHz, HSQC, HMBC, major trans
isomer) δ 1.92 (qd, J = 12.4, 3.6 Hz, 1H, 10-H), 2.07 (t, J = 11.2 Hz, 1H,
7-H), 2.10 (td, J = 12, 2.8 Hz, 1H, 9-H), 2.42 (s, 3H, 8-Me), 2.52 (dm J =
12.8 Hz, 1H, 10-H), 2.79 (td, J = 11.6, 3.6 Hz, 1H, 6a-H), 3.02 (td, J = 11.6,
3.6 Hz, 1H, 10a-H), 3.08 (m, 1H, 9-H), 3.63 (dm, J = 11.6 Hz, 1H, 7-H),
3.85 (s, 3H, 4-Me), 7.10 (d, J = 7.2 Hz, 1H, 1-H), 7.22 (m, 1H, 3-H), 7.25
(m, 1H, 2-H), 7.55 (s, 1H, 5-H); 13C NMR (CDCl3, 100.6 MHz, HSQC,
HMBC, major trans isomer) δ 28.5 (C-10), 33.6 (4-Me), 41.4 (C-10a),
46.4 (8-Me), 52.0 (C-6a), 55.4 and 55.5 (C-7,9), 108.0 (C-3), 113.2
(C-5a), 115.5 (C-1), 123.8 (C-2), 127.6 (C-5), 129.0 (C-10c), 132.4
(C-10b), 134.8 (C-3a), 192.6 (C-6); ESI-HRMS [M þ H]þ calcd for
C16H19N2O 255.1492, found 255.1491.
’ REFERENCES
(1) For a review on the chemistry of acyl radicals, see: Chatgilialoglu,
C.; Crich, D.; Komatsu, M.; Ryu, I. Chem. Rev. 1999, 99, 1991–2069.
(2) Bennasar, M.-L.; Roca, T.; Griera, R.; Bosch, J. Org. Lett. 2001,
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(3) Bennasar, M.-L.; Roca, T.; Ferrando, F. Org. Lett. 2004,
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4,9-Dimethyl-6a,7,8,9,10,10a-hexahydroindolo[3,4-gh]-
isoquinolin-6-one (10b): 85 mg (86%, 1.5:1 mixture of trans-cis
isomers) [pure trans stereoisomer was obtained by digestion with Et2O];
1H NMR (CDCl3, 300 MHz, HSQC, HMBC) δ 1.77 (m, 1H, 7-H), 2.01
(td, J = 12.4, 2.8 Hz, 1H, 8-H), 2.23 (t, J = 10.8 Hz, 1H, 10-H), 2.39
(m, 2H, 6a-H, 7-H), 2.45 (s, 3H, 9-Me), 3.09 (dm J = 11.2 Hz, 1H, 8-H),
3.41 (td, J = 11.2, 3.6 Hz, 1H, 10a-H), 3.71 (m, 1H, 10-H), 3.88 (s, 3H,
4-Me), 7.06 (d, J = 7.2 Hz, 1H, 1-H), 7.24 (m, 1H, 3-H), 7.28 (m, 1H,
2-H), 7.57 (s, 1H, 5-H); 13C NMR (CDCl3, 100.6 MHz, HSQC, HMBC)
δ 25.4 (C-7), 33.7 (4-Me), 42.3 (C-10a), 46.3 (8-Me), 51.5 (C-6a), 55.8
(C-8), 58.4 (C-10), 108.1 (C-3), 113.3 (C-5a), 115.2 (C-1), 123.7 (C-2),
127.6 (C-5), 129.2 (C-10c), 131.0 (C-10b), 134.7 (C-3a), 193.3 (C-6);
ESI-HRMS [M þ H]þ calcd for C16H19N2O 255.1492, found 255.1493.
4,8-Dimethyl-7,8,9,10-tetrahydroindolo[4,3-fg]isoquinolin-
6-one (11). n-Bu3SnH (0.31 mL, 1.16 mmol) and Et3B (1 M in hexanes,
1.16 mmol) were added to a solution of phenyl selenoester 9a (0.19 g, 0.46
mmol), previously dried azeotropically with anhydrous C6H6, in anhy-
drous C6H6 (16 mL). The reaction mixture was stirred atrt for 5 h with dry
air constantly supplied by passing compressed air through a short tube
of Drierite. n-Bu3SnH (0.31 mL, 1.16 mmol) and Et3B (1 M in hexanes,
1.16 mmol) were again added, and the reaction mixture was stirred at rt
for 5 h. The solution was concentrated and the resulting residue was
partitioned between hexanes (10 mL) and acetonitrile (10 mL), and the
polar layer was washed with hexanes. The solvent was removed and
the resulting residue was chromatographed (SiO2, CH2Cl2, and 97:2:1
CH2Cl2ꢀMeOHꢀDEA) to give tetracycle 11: 76 mg (65%); 1H NMR
(CDCl3, 300 MHz, HSQC and HMBC) δ 2.54 (s, 3H, 8-Me), 2.75 (t, J =
6 Hz, 2H, 9-H), 3.13 (m, 2H, 10-H), 3.57 (t, J = 1.8 Hz, 2H, 7-H), 3.99
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4217
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NOTE
Tetrahedron 2004, 60, 8065–8071. (c) Bowman, W. R.; Fletcher, A. J.;
Pedersen, J. M.; Lovell, P. J.; Elsegood, M. R. J.; Hernꢁandez Lꢁopez, E.;
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refs 9 and 11.
(20) However, as pointed out by one of the reviewers, simple
addition of 2-cyano-2-propyl radicals to the 2-position of the 3-acylin-
dole moiety of 4a cannot be ruled out under n-Bu3SnH conditions.
(21) Elimination from 6 would be less favored when using the less
basic silicon hydride with respect to the tin hydride.
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