Electrophilic ipso-iodocyclization of N-benzyl-N-(1-naphthyl)propiolamides: Synthesis of complex polycyclic lactams

Article abstract of DOI:10.1039/c3ob42020e

An intramolecular electrophilic ipso-iodocyclization of N-benzyl-N-(1-naphthyl)propiolamides combined with the Friedel-Crafts-type reaction for the synthesis of complex polycyclic lactams is reported. The resulting iodinated cyclization product can provide a very useful handle for further structural manipulation. The Royal Society of Chemistry.

Full text of DOI:10.1039/c3ob42020e

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Electrophilic ipso-iodocyclization of N-benzyl-
N-(1-naphthyl)propiolamides: synthesis of
complex polycyclic lactams†
Cite this: Org. Biomol. Chem., 2014,
12, 643
Li-Jing Wang, Hai-Tao Zhu, Yi-Feng Qiu, Xue-Yuan Liu and Yong-Min Liang*
Received 9th October 2013,
Accepted 18th November 2013
An intramolecular electrophilic ipso-iodocyclization of N-benzyl-N-(1-naphthyl)propiolamides combined
with the Friedel–Crafts-type reaction for the synthesis of complex polycyclic lactams is reported. The
DOI: 10.1039/c3ob42020e
resulting iodinated cyclization product can provide
manipulation.
a very useful handle for further structural
www.rsc.org/obc
give the corresponding products; (ii) para-unactivated aryl-
alkynes through the external nucleophilic attack such as HOAc
Introduction
Electrophilic iodocyclization has emerged as an extremely to produce substituted cyclohexadienes (Scheme 1 type 1).3
active field in the past decade, because it provides a very However, the intramolecular electrophilic ipso-iodocyclization
efficient route to a wide range of useful, functionally substi- of para-unsubstituted aryl compounds combined with the
tuted compounds which can be readily converted to structu- Friedel–Crafts-type reaction to produce iodinated cyclization
rally interesting compounds through transition metal- products has not been reported to date (Scheme 1 type 2).
catalyzed transformations.1,2 However, among the various elec-
Herein, in the context of our ongoing interest in iodocycli-
trophilic iodocyclization reactions discovered, only limited zation chemistry,4 we wish to report an electrophilic ipso-iodo-
ipso-iodocyclization, which can provide synthetically useful cyclization of N-benzyl-N-(1-naphthyl)propiolamide derivatives
spiro or bridged frameworks, has been reported.3 As shown in combined with the Friedel–Crafts-type reaction to produce
Scheme 1, the previous electrophilic ipso-iodocyclization complex iodinated polycyclic lactams.
reports have focused on the following: (i) para-activated
arylalkynes through the elimination of the leaving group (Y) to
Results and discussion
We started our investigations with N-benzyl-N,3-diphenyl-
propiolamide (1aa) (0.2 mmol) and 2 equiv. of I2 in CH3NO2 at
room temperature. Surprisingly, it was found that compound
1aa was not through the ipso-arene attack able to convert into
the desired product 2aa, but through the ortho-arene attack
regioselectively gave the iodocyclization product 3aa, which
was determined by X-ray crystallographic analysis, in a yield of
75% (Scheme 2, path b).5 We envisioned that the failure to get
the desired product 2aa may be the reason why there was not a
stable conjugated system after the ipso-arene attack in this
transformation (Scheme 2, path a) and so it was unfavourable
Scheme 1 Electrophilic ipso-iodocyclization.
to the following Friedel–Crafts-type reaction and had to go
through the ortho-arene attack (Scheme 2).
This interesting observation prompted us to further syn-
State Key Laboratory of Applied Organic Chemistry Lanzhou University, Lanzhou
thesize N-benzyl-N-(1-naphthyl)-3-phenylpropiolamide (1a),
which was subjected to the above reaction conditions. Gratify-
ingly, the desired complex polycyclic lactam 2a was isolated in
730000, China. E-mail: liangym@lzu.edu.cn; Fax: +86-931-8912582;
Tel: +86-931-8912582
†Electronic supplementary information (ESI) available. CCDC 928528 (2a) and
good yield (80%) after 1 h (Table 1, entry 1). The structure
CCDC 928529 (3aa). For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c3ob42020e
of compound 2a was identified unambiguously by X-ray
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Table 2 Intramolecular electrophilic ipso-iodocyclization of fused
arenes 1a–qa
Product 2/3
Entry
Substrate 1 (time)
(Yieldb [%])
1
2
3
4
5
6
7
8
9
1a (40 min): R1 = Ph
2a (93)
2b (94)
2c (50)
2d (93)
2e (96)
2f (89)
2g (65)
2h (89)
2i (94)
1b (35 min): R1 = p-Me-C6H4
1c (35 min): R1 = p-OMe-C6H4
1d (150 min): R1 = o-Br-C6H4
1e (120 min): R1 = o-Cl-C6H4
1f (85 min): R1 = p-Br-C6H4
1g (160 min): R1 = n-pentyl
1h (25 min): R1 = cyclohexen-1-yl
1i (40 min): R1 = cyclopropyl
Scheme 2 Intramolecular electrophilic iodocyclization of 1aa.
Table 1 Optimization of electrophilic ipso-iodocyclization of 1aa
10
11
12
13
1j (60 min): R2 = R3 = R5 = H, R4 = Me
1k (60 min): R2 = R4 = H, R3 = R5 = Me
1l (60 min): R2 = R4 = R5 = H, R3 = OMe
1m (60 min): R2 = R4 = H, R3 = R5 = OMe
2j (96)
2k (90)
2l (88)
2m (76)
Electrophile
(equiv.)
T (°C)/t
(min)
2a
Entry
Solvent
(Yieldb [%])
14
1
2
3
4
5
6
7
8
I2 (2)
I2 (2)
I2 (2)
I2 (2)
I2 (2)
I2 (2)
NIS (2)
IBr (2)
ICl (2)
I2 (1.5)
I2 (2.2)
I2 (2.5)
CH3NO2
DCM
DCE
25/60
25/60
25/60
40/60
60/40
80/25
60/45
60/10
60/10
60/95
60/35
60/35
80
66
61
86
93
72
90
86
83
81
74
88
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
15
9
10
11
12
16
a All reactions were run under the following conditions, unless
otherwise indicated: 0.2 mmol of 1a with 2.0 equiv. of I2 in 4 mL of
CH3NO2 at 60 °C. b Isolated yield; the stereochemistry was determined
by X-ray structure analysis.
diffraction.6 With other solvents such as dichloromethane and
1,2-dichloroethane, no superior results were obtained (Table 1,
entries 2 and 3). To improve the reaction efficiency, the effect
of temperature was then investigated (Table 1, entries 4–6). It
was found that the yield increased to 93% gradually with the
reaction temperature rising to 60 °C. However, further increas-
ing the temperature to 80 °C gave the decreased yield of 72%
(Table 1, entry 6). The reaction was also tested with other elec-
trophiles such as NIS, IBr, and ICl, but no better results were
observed (Table 1, entries 7–9). Furthermore, the iodine
loading was also investigated in this reaction, but it was shown
that either an increase or decrease in the iodine loading was
not able to improve the yield (Table 1, entries 10–12).
17
a All reactions were run under the following conditions, unless
otherwise indicated: 0.2 mmol of 1 with 2.0 equiv. of I2 in 4 mL
CH3NO2 at 60 °C. b Isolated yield; the stereochemistry was determined
by X-ray structure analysis.
(1-naphthyl)propiolamide derivatives 1a–q were then sub-
mitted to the above conditions, as depicted in Table 2.
The reactions of substrates 1b and 1d–f bearing an elec-
tron-donating or an electron-withdrawing aromatic R1 group
produced the corresponding complex polycyclic lactams 2b
After a series of detailed investigations, the reaction con-
ditions were eventually optimized as: 1.0 equiv. of 1a and
2.0 equiv. of I2 in nitromethane at 60 °C.
To investigate the generality and the scope of this electro-
philic ipso-iodocyclization, various representative N-benzyl-N-
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and 2d–f in excellent yields (entry 2 and entries 4–6). However,
compound 1c with the p-methoxyphenyl R1 group only gave
the desired complex polycyclic lactam in a yield of 50%
(entry 3). Subsequently, we designed compound 1g having an
aliphatic group at R1, which proceeded to give the desired
complex polycyclic lactam 2g in good yield (entry 7). The reac-
tions also worked well with compounds 1h and 1i with a cyclo-
hexen-1-yl or a cyclopropyl group at R1, which proceeded to
give the desired complex polycyclic lactams 2h and 2i in yields
of 89% and 94%, respectively (entries 8 and 9). We have also
investigated the substrates 1j–m bearing the electron-donating
groups within the N-benzyl residue giving the corresponding
products in good yields (entries 10–13). However, the reaction
of substrate 1p with a chloro group within the N-benzyl
residue only gave the corresponding complex polycyclic lactam
2p in a yield of 39% and along with the ortho-arene attacked
iodocyclization product 3p in a yield of 26%. Compound 1q
with a trifluoromethyl group within the N-benzyl residue did
not give the desired product 2q, but gave the compound 3q in
45% yield regioselectively (entries 16 and 17). These results
suggest that the electron-deficient group within the N-benzyl
residue was unfavourable to the Friedel–Crafts-type reaction,
which was a crucial step for this intramolecular electrophilic
ipso-iodocyclization. Then substrate 1n was tested to give the
corresponding complex polycyclic lactam 2n but only in a yield
of 35% (entry 14). We envisioned that it was conducive to the
result of an unfavourable steric interaction between the two
naphthyl groups in compound 1n. Furthermore, we also tested
the effect of substituents attached to the naphthyl groups.
Similarly, the substrate 1o underwent the ipso-iodocyclization
smoothly to give the corresponding complex polycyclic lactam
2o in a yield of 75% (entry 15).
Scheme 4 Palladium-catalyzed reactions.
(ii) Complex A via the intramolecular ipso-electrophilic cycli-
zation reaction generated intermediate B. (iii) Among the
possible resonance forms of intermediate B, structure C is the
most favourable one. (iv) The Friedel–Crafts-type reaction fol-
lowed by deprotonation gave the complex polycyclic lactam 2p.
Scheme 3 (path b) depicts a possible mechanism for the
ortho-arene attacked iodocyclization reaction. (i) Coordination
of the alkynyl moiety of 1p to an iodide cation gave the
complex A. (ii) The adjacent naphthyl group, which acts as the
nucleophile, attacked the halogenated alkyne group intermedi-
ate (via 6-endo-trig, cyclization), and followed by deprotonation
gave the product 3p.
As depicted in Scheme 3 (path a), we proposed the follow-
ing plausible mechanisms for this intramolecular electrophilic
ipso-iodocyclization reaction. (i) Coordination of the alkynyl
moiety of 1p to an iodide cation gave the complex A.
As shown in Scheme 4, these halogen-promoted aromatic
cyclizations not only construct a highly functionalized carbon
skeleton quickly but also can be used to prepare more complex
compounds. For example, the desired iodocyclization com-
pounds 2a and 2j produced by this strategy can be employed
in palladium-catalyzed reactions, such as the Sonagashira
coupling,7 Heck coupling,8 Suzuki coupling,9 and carboannu-
lation of alkynes,10 to quickly achieve additional molecular
complexity.
Experimental
General methods
Column chromatography was carried out on silica gel. 1H
NMR spectra were recorded on 400 MHz in CDCl3 and 13C
NMR spectra were recorded on 100 MHz in CDCl3. Chemical
shifts (ppm) were recorded with tetramethylsilane (TMS) as
the internal reference standard. Multiplicities are given as: s
(singlet), d (doublet), t (triplet), dd (doublet of doublets) or m
Scheme 3 Possible mechanism for the formation of 2p and 3p from
1p.
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(multiplet). IR spectra were recorded on a FT-IR spectrometer solid, mp 246–248 °C. H NMR (CDCl3, 400 MHz) δ 7.30–7.24
and only major peaks are reported in cm−1. Melting points (m, 3H), 7.22–7.16 (m, 2H), 7.15–7.11 (m, 2H), 7.07 (t, J =
were determined on a microscopic apparatus and were uncor- 5.2 Hz, 1H), 6.94–6.92 (m, 1H), 6.75 (d, J = 8.8 Hz, 2H), 6.48 (d,
rected. All products were further characterized by accurate J = 8.4 Hz, 2H), 6.19 (dd, J = 9.6 Hz, 6.4 Hz, 1H), 6.01 (d, J =
mass (the instrument is maxis 4G and the source type is ESI†); 10 Hz, 1H), 5.39 (d, J = 17.2 Hz, 1H), 4.31 (d, J = 17.2 Hz, 1H),
1
copies of their H NMR and 13C NMR spectra are provided in 3.80 (s, 3H), 3.68 (d, J = 6.4 Hz, 1H). 13C NMR (CDCl3,
the ESI.† Room temperature is 23–25 °C. Commercially avail- 100 MHz) δ 168.8, 166.5, 159.9, 134.9, 134.3, 131.3, 129.2,
able reagents and solvents were used without further purifi- 129.0, 128.8, 128.2, 127.4, 127.2, 127.0, 126.6, 125.9, 124.6,
cation unless otherwise indicated. THF was dried over sodium. 113.3, 95.1, 70.5, 55.1, 40.1, 40.0. IR (neat, cm−1): 3365, 3059,
2924, 2846, 2243, 1692, 1616, 1505, 1446, 1401, 1289, 1248,
General procedure for the preparation of 2 and 3. Synthesis of
2a and 3a
1177, 1108, 1069, 1026, 973, 910, 838, 776, 735, 593, 553.
HRMS (ESI) Calcd for C27H21INO2: [M + H]+ = 518.0617.
To a solution of N-benzyl-N-(naphthalen-1-yl)-3-phenylpropiol- Found: 518.0617.
amide 1a (0.20 mmol) in CH3NO2 (4.0 mL) was added
(4bS,13bR)-5-(2-Bromophenyl)-6-iodo-9,13b-dihydro-7H-benzo-
2.0 equiv. I2 (0.4 mmol). The resulting mixture was stirred at [c]pyrrolo[2,1-e]phenanthridin-7-one 2d. Eluent: petroleum
60 °C. When the reaction was considered complete as deter- ether–ethyl acetate (8 : 1). Yield 105.1 mg (93%), white solid,
mined by TLC analysis, the reaction mixture was quenched by mp 108–110 °C. 1H NMR (CDCl3, 400 MHz) δ 7.60–7.58 (m,
the addition of saturated aqueous sodium thiosulfate and 1H), 7.27–7.21 (m, 3H), 7.17–7.15 (m, 2H), 7.13–7.10 (m, 2H),
extracted with ethyl acetate (3 × 15 mL), washed with water, 7.07–7.03 (m, 1H), 6.91–6.85 (m, 2H), 6.45 (dd, J = 10 Hz,
saturated brine, dried over Na2SO4 and evaporated under 6.8 Hz, 1H), 5.94 (d, J = 10 Hz, 1H), 5.59 (dd, J = 8 Hz, 1.6 Hz,
reduced pressure. The residue was purified by chromatography 1H), 5.45 (d, J = 17.2 Hz, 1H), 4.42 (d, J = 17.2 Hz, 1H), 4.13 (d,
on silica gel to afford the corresponding iodinated dearomati- J = 6.8 Hz, 1H). 13C NMR (CDCl3, 100 MHz) δ 166.5, 166.2,
zation product 2a or the product 3a.
135.2, 134.8, 133.9, 132.4, 130.7, 129.9, 129.2, 128.8, 128.8,
128.6, 128.3, 127.4, 127.3, 127.1, 126.8, 126.6, 126.3, 125.6,
124.0, 122.0, 98.2, 71.8, 40.4, 39.6. IR (neat, cm−1): 3432, 3058,
Physical data of compounds 2 and 3
(4bS,13bR)-6-Iodo-5-phenyl-9,13b-dihydro-7H-benzo[c]pyrrolo- 2921, 2840, 1698, 1617, 1449, 1396, 1290, 1209, 1105, 1030,
[2,1-e]phenanthridin-7-one 2a. Eluent: petroleum ether–ethyl 911, 776, 736, 596, 557. HRMS (ESI) Calcd for C26H17BrINONa:
acetate (8 : 1). Yield 90.6 mg (93%), white solid, mp [M + Na]+ = 587.9442. Found: 587.9436.
206–208 °C. 1H NMR (CDCl3, 400 MHz) δ 7.35–7.30 (m, 1H),
(4bS,13bR)-5-(2-Chlorophenyl)-6-iodo-9,13b-dihydro-7H-benzo-
7.28–7.17 (m, 6H), 7.12 (dd, J = 6 Hz, 3.2 Hz, 2H), 7.05 (t, J = [c]pyrrolo[2,1-e]phenanthridin-7-one 2e. Eluent: petroleum
4.4 Hz, 1H), 6.90 (d, J = 6.8 Hz, 1H), 6.54 (d, J = 7.6 Hz, 2H), ether–ethyl acetate (8 : 1). Yield 100.0 mg (96%), white solid,
1
6.17 (dd, J = 10 Hz, 6.8 Hz, 1H), 5.94 (d, J = 10 Hz, 1H), 5.40 (d, mp 120–122 °C. H NMR (CDCl3, 400 MHz) δ 7.41 (d, J = 8 Hz,
J = 17.2 Hz, 1H), 4.33 (d, J = 17.2 Hz, 1H), 3.70 (d, J = 6.8 Hz, 1H), 7.29–7.20 (m, 4H), 7.17 (d, J = 6.4 Hz, 1H), 7.12–7.10 (m,
1H). 13C NMR (CDCl3, 100 MHz) δ 168.9, 166.3, 134.8, 134.5, 2H), 7.07–7.04 (m, 1H), 6.88–6.85 (m, 2H), 6.44–6.41 (m, 1H),
134.1, 131.1, 129.2, 128.9, 128.7, 128.5, 128.1, 127.8, 127.3, 5.94 (d, J = 9.6 Hz, 1H), 5.63 (dd, J = 8 Hz, 1.6 Hz, 1H), 5.44 (d,
127.1, 127.0, 126.6, 125.8, 124.4, 95.1, 77.2, 70.6, 40.0, 39.9. IR J = 17.2 Hz, 1H), 4.41 (d, J = 17.2 Hz, 1H), 4.01 (d, J = 6.8 Hz,
(neat, cm−1): 3391, 2921, 2846, 1697, 1593, 1386, 1259, 1149, 1H). 13C NMR (CDCl3, 100 MHz) δ 166.2, 165.5, 134.7, 133.9,
1068, 777, 743, 700, 599. HRMS (ESI) Calcd for C26H19INO: 133.3, 132.0, 130.8, 129.9, 129.2, 128.8, 128.8, 128.6, 128.3,
[M + H]+ = 488.0501. Found: 488.0511.
127.4, 127.4, 127.1, 126.9, 126.6, 125.8, 125.6, 124.0, 97.9, 71.7,
(4bS,13bR)-6-Iodo-5-(p-tolyl)-9,13b-dihydro-7H-benzo[c]pyrrolo- 40.4, 39.7. IR (neat, cm−1): 3389, 3070, 2922, 1698, 1621, 1447,
[2,1-e]phenanthridin-7-one 2b. Eluent: petroleum ether–ethyl 1396, 1287, 1164, 1071, 1040, 911, 776, 736, 598. HRMS (ESI)
acetate (8 : 1). Yield 94.2 mg (94%), white solid, mp Calcd for C26H17ClINONa: [M + Na]+ = 543.9954. Found:
216–218 °C. 1H NMR (CDCl3, 400 MHz) δ 7.27–7.24 (m, 2H), 543.9941.
7.20–7.15 (m, 2H), 7.12–7.10 (m, 2H), 7.06–7.00 (m, 3H),
(4bS,13bR)-5-(4-Bromophenyl)-6-iodo-9,13b-dihydro-7H-benzo-
6.92–6.90 (m, 1H), 6.43 (d, J = 8 Hz, 2H), 6.17 (dd, J = 9.6 Hz, [c]pyrrolo[2,1-e]phenanthridin-7-one 2f. Eluent: petroleum
6.8 Hz, 1H), 5.96 (d, J = 9.6 Hz, 1H), 5.39 (d, J = 17.2 Hz, 1H), ether–ethyl acetate (8 : 1). Yield 100.6 mg (89%), white solid.
1
4.31 (d, J = 17.2 Hz, 1H), 3.68 (d, J = 6.4 Hz). 13C NMR (CDCl3, mp 224–226 °C. H NMR (CDCl3, 400 MHz) δ 7.35 (d, J = 8 Hz,
100 MHz) δ 169.1, 166.4, 138.6, 134.8, 134.2, 1314, 131.2, 2H), 7.28–7.21 (m, 2H), 7.18–7.11 (m, 4H), 7.06 (d, J = 4.4 Hz,
129.1, 128.9, 128.6, 128.6, 128.1, 127.3, 127.3, 127.2, 127.2, 1H), 6.92 (d, J = 8 Hz, 1H), 6.41 (d, J = 8.4 Hz, 2H), 6.20 (dd, J =
126.9, 126.5, 125.8, 124.4, 95.0, 70.5, 39.9, 39.9, 21.4. IR (neat, 9.6 Hz, 6.8 Hz, 1H), 6.00 (d, J = 10 Hz, 1H), 5.39 (d, J = 17.2 Hz,
cm−1): 3434, 3026, 2921, 2242, 1696, 1610, 1489, 1403, 1290, 1H), 4.32 (d, J = 17.2 Hz, 1H), 3.66 (d, J = 6.4 Hz, 1H). 13C NMR
1210, 1105, 1026, 910, 818, 732, 600, 498. HRMS (ESI) Calcd (CDCl3, 100 MHz) δ 167.6, 166.1, 134.6, 133.8, 133.4, 131.2,
for C27H21INO: [M + H]+ = 502.0657. Found: 502.0668.
131.0, 129.3, 129.1, 129.0, 128.3, 128.1, 127.5, 127.4, 127.3,
(4bS,13bR)-6-Iodo-5-(4-methoxyphenyl)-9,13b-dihydro-7H- 127.0, 126.7, 125.8, 124.4, 123.2, 95.7, 70.5, 40.0, 40.0. IR (neat,
benzo[c]pyrrolo[2,1-e]phenanthridin-7-one 2c. Eluent: petro- cm−1): 3436, 3064, 2922, 2835, 2243, 1697, 1618, 1485, 1400,
leum ether–ethyl acetate (8 : 1). Yield 51.7 mg (50%), white 1293, 1209, 1070, 1015, 910, 823, 780, 734, 599, 552. HRMS
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(ESI) Calcd for C26H17BrINONa: [M + Na]+ = 587.9442. Found: 124.4, 95.1, 70.6, 39.8, 21.1. IR (neat, cm−1): 3387, 3047, 2921,
587.9436.
2840, 2243, 1697, 1585, 1447, 1402, 1270, 1072, 974, 910, 786,
(4bS,13bR)-6-Iodo-5-pentyl-9,13b-dihydro-7H-benzo[c]pyrrolo- 732, 648, 471. HRMS (ESI) Calcd for C27H21INO: [M + H]+
[2,1-e]phenanthridin-7-one 2g. Eluent: petroleum ether–ethyl 502.0657. Found: 502.0668.
=
acetate (8 : 1). Yield 62.5 mg (65%), white solid, mp
(4bS,13bR)-6-Iodo-11,13-dimethyl-5-phenyl-9,13b-dihydro-7H-
176–178 °C. 1H NMR (CDCl3, 400 MHz) δ 7.29–7.26 (m, 1H), benzo[c]pyrrolo[2,1-e]phenanthridin-7-one 2k. Eluent: petro-
7.23–7.18 (m, 2H), 7.16–7.07 (m, 3H), 7.03 (d, J = 7.2 Hz, 1H), leum ether–ethyl acetate (8 : 1). Yield 92.7 mg (90%), white
1
6.97 (d, J = 6.8 Hz, 1H), 6.17 (dd, J = 10 Hz, 6.8 Hz, 1H), 6.61 solid, mp 225–227 °C. H NMR (CDCl3, 400 MHz) δ 7.34 (t, J =
(d, J = 9.6 Hz, 1H), 5.30 (d, J = 17.2 Hz, 1H), 4.30 (d, J = 7.2 Hz, 1H), 7.30–7.19 (m, 5H), 6.99–6.97 (m, 1H), 6.82 (d, J =
17.2 Hz, 1H), 3.59 (d, J = 6 Hz, 1H), 2.49–2.42 (m, 1H), 7.6 Hz, 3H), 6.77 (s, 1H), 6.05 (d, J = 10 Hz, 1H), 5.88 (dd, J =
2.32–2.25 (m, 1H), 1.32–1.26 (m, 1H), 1.22 (d, J = 6 Hz, 4H), 10 Hz, 5.2 Hz, 1H), 5.02 (d, J = 16.4 Hz, 1H), 4.15 (d, J = 16 Hz,
1.11–1.08 (m, 1H), 0.83 (t, J = 6.4 Hz, 3H). 13C NMR (CDCl3, 1H), 4.03 (d, J = 5.2 Hz, 1H), 2.23 (s, 3H), 2.20 (s, 3H). 13C NMR
100 MHz) δ 170.7, 166.7, 134.2, 133.6, 131.3, 130.0, 129.0, (CDCl3, 100 MHz) δ 168.4, 166.8, 136.0, 135.6, 133.6, 133.6,
129.0, 128.9, 127.8, 127.6, 127.2, 126.9, 126.5, 125.9, 124.5, 133.4, 131.1, 129.9, 129.1, 129.0, 128.9, 128.2, 127.7, 127.2,
93.0, 69.2, 39.8, 39.5, 31.9, 30.7, 28.0, 22.0, 13.9. IR (neat, 125.7, 125.5, 124.9, 94.6, 70.5, 40.9, 39.7, 21.2, 20.6. IR (neat,
cm−1): 3388, 2924, 2846, 1696, 1603, 1446, 1392, 1265, 1155, cm−1): 3389, 2921, 2854, 2244, 1697, 1615, 1444, 1409, 1281,
1069, 880, 745, 661. HRMS (ESI) Calcd for C25H25INO: [M + H]+ = 1067, 1030, 910, 850, 731, 699, 648, 543. HRMS (ESI) Calcd for
482.0969. Found: 482.0981.
C28H23INO: [M + H]+ = 516.0813. Found: 516.0824.
(4bS,13bR)-5-(Cyclohex-1-en-1-yl)-6-iodo-9,13b-dihydro-7H-
(4bS,13bR)-6-Iodo-11-methoxy-5-phenyl-9,13b-dihydro-7H-
benzo[c]pyrrolo[2,1-e]phenanthridin-7-one 2h. Eluent: petro- benzo[c]pyrrolo[2,1-e]phenanthridin-7-one 2l. Eluent: petro-
leum ether–ethyl acetate (8 : 1). Yield 87.4 mg (89%), white leum ether–ethyl acetate (8 : 1). Yield 91.0 mg (88%), white
1
1
solid, mp 200–202 °C. H NMR (CDCl3, 400 MHz) δ 7.26–7.25 solid, mp 96–98 °C. H NMR (CDCl3, 400 MHz) δ 7.35 (t, J =
(m, 1H), 7.21–7.09 (m, 4H), 7.03–6.99 (m, 3H), 6.57 (dd, J = 7.6 Hz, 1H), 7.29–7.22 (m, 5H), 7.16–7.09 (m, 2H), 6.93–6.91
10 Hz, 6.4 Hz, 1H), 6.47 (d, J = 9.6 Hz, 1H), 5.32 (d, J = 17.2 Hz, (m, 1H), 6.72–6.67 (m, 4H), 6.37 (dd, J = 10 Hz, 6 Hz, 1H), 5.88
1H), 4.66 (s, 1H), 4.26 (d, J = 16.8 Hz, 1H), 3.58 (d, J = 6.4 Hz, (d, J = 10 Hz, 1H), 5.18 (d, J = 16.8 Hz, 1H), 4.20 (d, J = 16.8 Hz,
1H), 1.96–1.78 (m, 4H), 1.63–1.52 (m, 4H). 13C NMR (CDCl3, 1H), 3.99 (d, J = 5.6 Hz, 1H), 3.79 (s, 3H). 13C NMR (CDCl3,
100 MHz) δ 171.5, 166.6, 134.5, 134.2, 131.6, 131.2, 129.2, 100 MHz) δ 169.2, 166.0, 157.3, 134.6, 133.9, 133.9, 129.2,
128.8, 128.7, 128.4, 128.0, 127.6, 127.2, 127.0, 126.9, 126.5, 128.9, 128.7, 128.4, 128.3, 128.0, 127.6, 127.5, 127.0, 125.1,
125.8, 124.2, 92.3, 70.1, 39.8, 39.8, 27.6, 25.0, 22.5, 21.3. IR 124.8, 123.1, 118.7, 109.3, 94.4, 70.0, 55.2, 39.8, 38.6. IR (neat,
(neat, cm−1): 3435, 3029, 2926, 2855, 2241, 1695, 1590, 1488, cm−1): 3437, 2921, 2846, 1697, 1638, 1586, 1458, 1385, 1258,
1402, 1265, 1200, 1071, 979, 913, 735, 599, 551. HRMS (ESI) 1060, 1029, 877, 773, 700, 574. HRMS (ESI) Calcd for
Calcd for C26H23INO: [M + H]+ = 492.0814. Found: 492.0824.
C27H21INO2: [M + H]+ = 518.0617. Found: 518.0617.
(4bS,13bR)-5-Cyclopropyl-6-iodo-9,13b-dihydro-7H-benzo-
(4bS,13bR)-6-Iodo-11,13-dimethoxy-5-phenyl-9,13b-dihydro-7H-
[c]-pyrrolo[2,1-e]phenanthridin-7-one 2i. Eluent: petroleum benzo[c]pyrrolo[2,1-e]phenanthridin-7-one 2m. Eluent: pet-
ether–ethyl acetate (8 : 1). Yield 84.8 mg (94%), white solid. mp roleum ether–ethyl acetate (8 : 1). Yield 83.1 mg (76%), white
196–198 °C. 1H NMR (CDCl3, 400 MHz) δ 7.30–6.95 (m, 8H), solid, mp 91–93 °C. 1H NMR (CDCl3, 400 MHz) δ 7.34 (t, J = 7.2
6.69 (dd, J = 9.6 Hz, 6.4 Hz, 1H), 6.57 (d, J = 9.6 Hz, 1H), 5.27 Hz, 1H), 7.28–7.21 (m, 3H), 7.15–7.13 (m, 1H), 6.93–6.91 (m,
(d, J = 17.2 Hz, 1H), 4.18 (d, J = 16.8 Hz, 1H), 3.68 (d, J = 1H), 6.66 (d, J = 7.2 Hz, 2H), 6.33 (dd, J = 10 Hz, 6 Hz, 1H), 6.27
6.4 Hz, 1H), 1.66–1.59 (m, 1H), 1.15–1.09 (m, 1H), 0.95–0.88 (d, J = 2 Hz, 1H), 6.20 (d, J = 2 Hz, 1H), 5.86 (d, J = 10 Hz, 1H),
(m, 1H), 0.73–0.67 (m, 1H), 0.63–0.56 (m, 1H). 13C NMR 5.14 (d, J = 16.8 Hz, 1H), 4.18 (d, J = 16.8 Hz, 1H), 3.90 (d, J =
(CDCl3, 100 MHz) δ 168.5, 166.9, 134.6, 133.9, 131.3, 130.7, 5.6 Hz, 1H), 3.75 (s, 3H), 3.71 (s, 3H). 13C NMR (CDCl3,
129.1, 128.8, 128.8, 127.6, 127.6, 127.4, 126.9, 126.4, 125.8, 100 MHz) δ 169.1, 166.0, 159.1, 158.2, 134.6, 134.3, 133.8,
124.4, 86.4, 70.2, 40.2, 39.6, 11.2, 7.9, 7.3. IR (neat, cm−1): 129.2, 128.8, 128.6, 128.5, 128.2, 127.9, 127.5, 126.9, 124.7,
3389, 2922, 2852, 1694, 1603, 1488, 1409, 1293, 1214, 1074, 115.4, 101.4, 97.9, 94.2, 70.1, 55.2, 55.2, 40.1, 38.0. IR (neat,
1030, 911, 846, 739, 657, 560, 526. HRMS (ESI) Calcd for cm−1): 3389, 3059, 2934, 2843, 2244, 1697, 1608, 1457, 1351,
C23H19INO: [M + H]+ = 452.0511. Found: 452.0511.
1273, 1202, 1145, 1097, 1056, 910, 832, 730, 647, 519. HRMS
(4bS,13bR)-6-Iodo-12-methyl-5-phenyl-9,13b-dihydro-7H- (ESI) Calcd for C28H23INO3: [M + H]+ = 548.0724. Found:
benzo-[c]pyrrolo[2,1-e]phenanthridin-7-one 2j. Eluent: pet- 548.0722.
roleum ether–ethyl acetate (8 : 1). Yield 96.2 mg (96%), white
solid, mp 228–230 °C. H NMR (CDCl3, 400 MHz) δ 7.33 (t, J = pyrrolo[2,1-e]phenanthridin-7-one 2n. Eluent: petroleum
(4bS,15bR)-6-Iodo-5-phenyl-9,15b-dihydro-7H-dibenzo[c,i]-
1
7.2 Hz, 1H), 7.29–7.16 (m, 6H), 6.99–6.88 (m, 4H), 6.53 (d, J = ether–ethyl acetate (8 : 1). Yield 37.6 mg (35%), white solid, mp
1
7.2 Hz, 2H), 6.16 (dd, J = 9.6 Hz, 6.4 Hz, 1H), 5.93 (d, J = 10 Hz, 220–222 °C. H NMR (CDCl3, 400 MHz) δ 7.89 (d, J = 8.4 Hz,
1H), 5.36 (d, J = 16.8 Hz, 1H), 4.28 (d, J = 16.8 Hz, 1H), 3.66 (d, 1H), 7.75 (d, J = 8 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.54–7.44
J = 6.4 Hz, 1H), 2.23 (s, 3H). 13C NMR (CDCl3, 100 MHz) δ (m, 2H), 7.38–7.27 (m, 2H), 7.23 (t, J = 3.6 Hz, 5H), 6.89 (d, J =
168.9, 166.3, 136.4, 134.7, 134.5, 133.8, 129.1, 128.8, 128.6, 7.2 Hz, 1H), 6.58 (d, J = 8.4 Hz, 2H), 6.24 (dd, J = 9.6 Hz,
128.5, 128.2, 128.1, 127.8, 127.7, 127.5, 127.3, 127.0, 125.6, 6.8 Hz, 1H), 5.99 (d, J = 9.6 Hz, 1H), 5.84 (d, J = 17.2 Hz, 1H),
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4.64 (d, J = 17.2 Hz, 1H), 3.86 (d, J = 6.8 Hz, 1H). 13C NMR 126.0, 125.9, 125.1, 125.0, 124.3, 123.0, 119.4, 100.2, 57.1. IR
(CDCl3, 100 MHz) δ 169.0, 166.5, 134.6, 134.5, 131.8, 131.0, (neat, cm−1): 3437, 3059, 2920, 2852, 1633, 1529, 1463, 1419,
129.5, 129.2, 129.1, 128.8, 128.6, 128.3, 127.9, 127.6, 127.5, 1383, 1330, 1111, 1021, 914, 820, 732, 648, 594, 528. HRMS
127.4, 126.8, 126.3, 126.0, 124.9, 124.4, 122.2, 95.2, 70.4, 40.2, (ESI) Calcd for C27H18F3INO: [M + H]+ = 556.0399. Found:
38.6. IR (neat, cm−1): 3434, 2921, 2857, 2359, 1697, 1624, 1455, 556.0385.
1384, 1262, 1066, 1020, 756, 667, 588. HRMS (ESI) Calcd for
C30H20INONa: [M + Na]+ = 560.0494. Found: 560.0488.
1-Benzyl-3-iodo-4-phenylquinolin-2(1H)-one
3aa. Eluent:
petroleum ether–ethyl acetate (10 : 1). Yield 74.3 mg (85%),
(4bS,13bR)-15-Bromo-6-iodo-5-phenyl-9,13b-dihydro-7H-benzo[c]- white solid, mp 76–78 °C. 1H NMR (CDCl3, 400 MHz) δ 7.53
pyrrolo[2,1-e]phenanthridin-7-one
2o. Eluent:
petroleum (dd, J = 10.4 Hz, 7.2 Hz, 3H), 7.47–7.42 (m, 1H), 7.36 (d, J =
ether–ethyl acetate (8 : 1). Yield 84.9 mg (75%), white solid, mp 8.4 Hz, 1H), 7.32 (d, J = 3.6 Hz, 4H), 7.26–7.25 (m, 3H), 7.14
230–232 °C. 1H NMR (CDCl3, 400 MHz) δ 7.44–7.42 (m, 1H), (dd, J = 8 Hz, 0.8 Hz, 1H), 7.02 (t, J = 7.2 Hz, 1H), 5.70 (s, 2H).
7.37–7.35 (m, 2H), 7.30–7.26 (m, 3H), 7.18–7.15 (m, 4H), 7.08 13C NMR (CDCl3, 100 MHz) δ 159.2, 156.8, 141.1, 138.9, 136.0,
(t, J = 4.8 Hz, 1H), 6.57 (t, J = 7.6 Hz, 3H), 5.40 (d, J = 16.9 Hz, 131.0, 128.9, 128.8, 128.7, 128.6, 128.3, 127.4, 126.8, 122.4,
1H), 4.33 (d, J = 16.9 Hz, 1H), 3.73 (d, J = 7.2 Hz, 1H). 13C NMR 121.6, 115.0, 101.2, 48.2. IR (neat, cm−1): 3432, 3064, 2922,
(CDCl3, 100 MHz) δ 168.3, 166.4, 134.2, 133.8, 132.6, 131.0, 2840, 1639, 1597, 1544, 1490, 1446, 1382, 1303, 1154, 1068,
130.2, 129.9, 129.7, 129.4, 129.0, 128.3, 128.3, 127.4, 127.2, 909, 755, 730, 699, 600, 540. HRMS (ESI) Calcd for C22H17INO:
127.1, 127.0, 125.9, 124.3, 122.2, 95.5, 70.4, 42.3, 40.2. IR (neat, [M + H]+ = 438.0344. Found: 438.0355.
cm−1): 3437, 3064, 2922, 2831, 2243, 1697, 1623, 1485, 1400,
Synthesis and characterization data of 4a, 5a, 6a and 7j
1293, 1202, 1070, 1015, 905, 826, 780, 734, 605, 551. HRMS
(ESI) Calcd for C26H17BrINONa: [M + Na]+ = 587.9442. Found:
587.9436.
(4bS,13bR)-5-Phenyl-6-(phenylethynyl)-9,13b-dihydro-7H-benzo[c]-
pyrrolo[2,1-e]phenanthridin-7-one 4a. To a solution of 2a
(4bS,13bR)-12-Chloro-6-iodo-5-phenyl-9,13b-dihydro-7H-benzo[c]- (97.4 mg, 0.20 mmol) in anhydrous CH3CN (2 mL) was added
pyrrolo[2,1-e]phenanthridin-7-one 2p. Eluent: petroleum PdCl2(PPh3)2 (5.6 mg, 4 mol%), CuI (0.76 mg, 2 mol%) and
ether–ethyl acetate (8 : 1). Yield 40.6 mg (39%), white solid, mp K2CO3 (55.2 mg, 2.0 equiv.). The reaction vial was flushed with
236–238 °C. 1H NMR (CDCl3, 400 MHz) δ 7.36–7.18 (m, 7H), Ar and the reaction mixture was stirred for 5 minutes at room
7.11–7.09 (m, 1H), 7.00 (d, J = 8 Hz, 1H), 6.94–6.92 (m, 1H), temperature.
A
solution of ethynylbenzene (30.6 mg,
6.52 (d, J = 7.2 Hz, 2H), 6.11 (d, J = 9.6 Hz, 6.8 Hz, 1H), 5.97 (d, 1.5 equiv.) in anhydrous CH3CN (2 mL) was then added
J = 9.6 Hz, 1H), 5.37 (d, J = 17.2 Hz, 1H), 4.28 (d, J = 17.6 Hz, dropwise through a syringe. The resulting solution was stirred at
1H), 3.63 (d, J = 6.4 Hz, 1H). 13C NMR (CDCl3, 100 MHz) room temperature for 36 h. When the reaction was considered
δ 168.7, 166.4, 136.0, 134.6, 134.3, 132.6, 129.6, 129.4, 129.1, complete as determined by TLC analysis, the mixture was
128.8, 128.3, 127.9, 127.8, 127.5, 127.4, 127.3, 127.2, 127.1, quenched by the addition of saturated aqueous ammonium
126.9, 124.4, 95.1, 70.3, 39.7, 39.6. IR (neat, cm−1): 3389, 3055, chloride (5 mL) and extracted with ethyl ether (3 × 20 mL). The
2923, 2846, 2244, 1697, 1596, 1485, 1402, 1266, 1099, 909, 863, combined organic layers were washed with water and brine,
781, 730, 648, 559. HRMS (ESI) Calcd for C26H17ClINONa: dried over Na2SO4, and concentrated under reduced pressure.
[M + Na]+ = 543.9954. Found: 543.9941.
The crude material was purified by flash column chromato-
1-(4-Chlorobenzyl)-3-iodo-4-phenylbenzo[h]quinolin-2(1H)- graphy to give 4a (yield 65%) as a white solid: mp 202–204 °C.
one 3p. Eluent: petroleum ether–ethyl acetate (10 : 1). Yield 1H NMR (CDCl3, 400 MHz) δ 7.35–7.19 (m, 12H), 7.14–7.07 (m,
27.1 mg (26%), white solid, mp 190–192 °C 1H NMR (CDCl3, 3H), 6.99–6.96 (m, 1H), 6.82–6.80 (m, 2H), 6.18 (dd, J = 9.6 Hz,
400 MHz) δ 8.19 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8 Hz, 1H), 6.4 Hz, 1H), 6.07 (d, J = 9.6 Hz, 1H), 5.38 (d, J = 16.8 Hz, 1H),
7.61–7.54 (m, 4H), 7.46 (d, J = 8.8 Hz, 1H), 7.42 (d, J = 8.4 Hz, 4.25 (d, J = 9.6 Hz, 1H), 3.76 (d, J = 6.4 Hz, 1H). 13C NMR
2H), 7.34 (t, J = 8 Hz, 3H), 7.29–7.26 (m, 3H), 7.15 (d, J = (CDCl3, 100 MHz) δ 166.7, 166.2, 134.9, 134.8, 133.0, 131.9,
8.8 Hz, 1H), 5.73 (s, 2H). 13C NMR (CDCl3, 100 MHz) δ 161.5, 131.5, 129.2, 129.2, 129.0, 128.8, 128.6, 128.3, 128.1, 128.0,
157.4, 141.5, 139.5, 135.9, 135.3, 132.9, 131.1, 129.1, 128.9, 127.6, 127.5, 127.3, 127.3, 127.0, 126.5, 126.0, 125.0, 122.5,
128.7, 128.3, 127.8, 127.5, 125.8, 125.4, 125.0, 124.2, 123.1, 117.2, 97.1, 80.6, 67.3, 40.6, 39.4. IR (neat, cm−1): 3391, 3057,
119.3, 100.3, 56.8. IR (neat, cm−1): 3390, 2921, 2852, 1643, 2923, 2846, 1696, 1488, 1412, 1349, 1265, 1149, 1068, 987, 911,
1464, 1428, 1385, 1290, 1096, 1025, 912, 809, 733, 655, 599, 732, 695, 521. HRMS (ESI) Calcd for C34H24NO: [M + H]+
=
535. HRMS (ESI) Calcd for C26H17ClINONa: [M + Na]+
543.9954. Found: 543.9941.
=
462.1857. Found: 462.1858.
(4bS,13bR)-5-Phenyl-6-((E)-styryl)-9,13b-dihydro-7H-benzo[c]-
3-Iodo-4-phenyl-1-(4-(trifluoromethyl)benzyl)benzo[h]quinolin- pyrrolo[2,1-e]phenanthridin-7-one 5a. To a solution of 2a
2(1H)-one 3q. Eluent: petroleum ether–ethyl acetate (10 : 1). (97.4 mg, 0.20 mmol) in DMF (2 mL) was added K2CO3
Yield 50.0 mg (45%), white solid, mp 228–230 °C. 1H NMR (138.0 mg, 5.0 equiv.), tetrabutylammonium bromide
(CDCl3, 400 MHz) δ 8.13 (d, J = 8.8 Hz, 1H), 7.85 (d, J = 8 Hz, (128.8 mg, 2.0 equiv.), Pd(OAc)2 (1.34 mg, 3 mol%). The reac-
1H), 7.71 (d, J = 8 Hz, 2H), 7.61–7.53 (m, 6H), 7.48 (d, J = tion vial was flushed with Ar and the reaction mixture was
9.2 Hz, 1H), 7.33–7.25 (m, 3H), 7.17 (d, J = 8.8 Hz, 1H), 5.80 (s, stirred for 5 minutes at room temperature. A solution of
2H). 13C NMR (CDCl3, 100 MHz) δ 161.5, 157.5, 141.6, 141.4, styrene (208 mg, 10 equiv.) in DMF (2 mL) was then added
139.4, 135.4, 129.0, 128.9, 128.7, 128.3, 127.8, 126.3, 126.0, drop wise through a syringe. The resulting solution was stirred
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at 100 °C for 12 h. When the reaction was considered complete 150–152 °C. H NMR (CDCl3, 400 MHz) δ 8.24 (d, J = 7.6 Hz,
as determined by TLC analysis, the mixture was quenched 1H), 7.64–7.61 (m, 1H), 7.47–7.41 (m, 2H), 7.39–7.08 (m, 12H),
slowly by the addition of aqueous 1 M HCl (5 mL) and 7.04–6.97 (m, 4H), 6.90 (d, J = 7.6 Hz, 1H), 6.72 (dd, J = 9.6 Hz,
extracted with ethyl ether (3 × 20 mL). The combined organic 0.8 Hz, 1H), 6.40 (dd, J = 10 Hz, 5.2 Hz, 1H), 5.06 (d, J = 16 Hz,
layers were washed with water, brine, dried over Na2SO4, and 1H), 4.37 (d, J = 4.8 Hz, 1H), 3.90 (d, J = 16 Hz, 1H). 13C NMR
concentrated under reduced pressure. The crude material was (CDCl3, 100 MHz) δ 166.8, 152.6, 140.8, 138.1, 136.9, 136.8,
purified by flash column chromatography to give 5a (yield 136.0, 135.3, 135.1, 132.8, 132.5, 131.1, 131.1, 131.0, 130.5,
99%) as a white solid: mp 112–114 °C. 1H NMR (CDCl3, 130.2, 128.8, 128.5, 127.6, 127.6, 127.5, 127.5, 127.0, 126.9,
400 MHz) δ 8.05 (d, J = 16.4 Hz, 1H), 7.33 (dd, J = 7.2 Hz, 126.9, 126.8, 126.7, 126.6, 126.5, 125.2, 124.7, 63.5, 43.7, 21.2.
4.8 Hz, 3H), 7.27–7.15 (m, 10H), 7.13–7.10 (m, 3H), 6.90–6.88 IR (neat, cm−1): 3438, 3021, 2920, 2852, 1698, 1607, 1495,
(m, 1H), 6.60 (d, J = 6.4 Hz, 2H), 6.49 (d, J = 16.4 Hz, 1H), 6.16 1437, 1387, 1275, 1158, 1030, 916, 805, 757, 700, 600, 544.
(dd, J = 9.6 Hz, 6.8 Hz, 1H), 5.95 (d, J = 9.6 Hz, 1H), 5.42 (d, J = HRMS (ESI) Calcd for C41H30NO: [M + H]+ = 552.2344. Found:
17.2 Hz, 1H), 4.29 (d, J = 17.2 Hz, 1H), 3.72 (d, J = 6.8 Hz, 1H). 552.2327.
13C NMR (CDCl3, 100 MHz) δ 168.6, 159.2, 137.4, 135.0, 134.9,
134.5, 133.2, 131.5, 129.8, 128.8, 127.9, 127.7, 127.3, 127.1,
127.1, 126.8, 126.6, 126.4, 125.9, 124.5, 118.0, 66.4, 40.2, 39.0. Conclusion
IR (neat, cm−1): 3437, 3059, 2923, 2246, 1952, 1686, 1633,
In summary, we have developed the first protocol involving a
1489, 1417, 1301, 1159, 1070, 980, 742, 698, 563. HRMS (ESI)
Friedel–Crafts-type reaction subsequent to the intramolecular
Calcd for C34H26NO: [M + H]+ = 464.2014. Found: 464.2014.
electrophilic ipso-iodocyclization of the para-unsubstituted aryl
(4bS,13bR)-6-(4-Methoxyphenyl)-5-phenyl-9,13b-dihydro-7H-
compounds. We find that both a stable conjugated system
benzo[c]pyrrolo[2,1-e]phenanthridin-7-one 6a. To a solution of
2a (97.4 mg, 0.20 mmol) in DMF–H2O (1 mL : 0.25 mL) was
added (4-methoxyphenyl)boronic acid (39.5 mg, 1.3 equiv.),
Na2CO3 (63.6 mg, 3.0 equiv.), and Pd(OAc)2 (0.90 mg, 2 mol%).
after the ipso-arene attack and electron-rich groups within the
N-benzyl residue are conducive to the Friedel–Crafts reaction
as a crucial step for this intramolecular electrophilic ipso-iodo-
cyclization. The resulting iodinated polycyclic lactams can
The reaction vial was flushed with Ar and the reaction mixture
provide a very useful handle for further structural manipu-
was stirred for 20 h at 40 °C. When the reaction was con-
lation. Further studies on various types of iodocyclizations are
sidered complete as determined by TLC analysis, the mixture
in progress in our laboratory.
was quenched slowly by the addition of aqueous 1 M HCl
(5 mL) and extracted with ethyl ether (3 × 20 mL). The com-
bined organic layers were washed with water, brine, dried over
Na2SO4, and concentrated under reduced pressure. The crude
Acknowledgements
material was purified by flash column chromatography to give
We thank the National Science Foundation (NSF-21072080)
and the National Basic Research Program of China (973
Program) 2010CB8-33203 for financial support. We also
acknowledge support from the “111” Project and Program for
Changjiang Scholars and innovative Research Team in Univer-
sity (IRT1138).
6a (yield 60%) as a white solid: mp 96–98 °C. 1H NMR (CDCl3,
400 MHz) δ 7.35 (d, J = 8.8 Hz, 2H), 7.29–7.22 (m, 6H),
7.15–7.11 (m, 5H), 6.92–6.90 (m, 1H), 6.70 (d, J = 9.2 Hz, 2H),
6.57 (d, J = 8.8 Hz, 2H), 6.15 (dd, J = 10 Hz, 6.8 Hz, 1H), 5.93
(d, J = 10 Hz, 1H), 5.44 (d, J = 17.2 Hz, 1H), 4.30 (d, J = 16.8 Hz,
1H), 3.81 (d, J = 6.8 Hz, 1H), 3.72 (s, 3H). 13C NMR (CDCl3,
100 MHz) δ 169.0, 159.1, 158.3, 135.3, 135.2, 134.2, 131.7,
130.8, 130.1, 128.8, 128.7, 128.7, 128.6, 128.5, 127.9, 127.9,
127.4, 127.2, 126.9, 126.4, 126.0, 124.6, 123.2, 113.3, 66.5, 55.1,
Notes and references
40.2, 39.4. IR (neat, cm−1): 3397, 3057, 2923, 2846, 1685, 1605,
1512, 1446, 1414, 1294, 1252, 1177, 1031, 836, 782, 734, 703,
528. HRMS (ESI) Calcd for C33H26NO2: [M + H]+ = 468.1964.
Found: 468.1963.
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