Scaffold-divergent synthesis of ring-fused indoles, quinolines, and quinolones via iodonium-induced reaction cascades

Article abstract of DOI:10.1021/jo400125p

N-(2-Iodophenyl)imines A are readily formed from Schiff's base condensation of 2-iodoanilines with carbonyls and ketals. These imines provide useful substrates in scaffold-divergent synthesis through the attachment of an alkyne (Songashira coupling or acyl substitution of a Weinreb amide) followed by an iodonium-induced reaction cascade to give ring-fused indoles B, quinolines C, or quinolones D depending on the reaction conditions employed.

Full text of DOI:10.1021/jo400125p

Article
pubs.acs.org/joc
Scaffold-Divergent Synthesis of Ring-Fused Indoles, Quinolines, and
Quinolones via Iodonium-Induced Reaction Cascades
Rosliana Halim, Luigi Aurelio, Peter J. Scammells, and Bernard L. Flynn*
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville,
Victoria 3052, Australia
S
* Supporting Information
ABSTRACT: N-(2-Iodophenyl)imines A are readily formed
from Schiff’s base condensation of 2-iodoanilines with carbonyls
and ketals. These imines provide useful substrates in scaffold-
divergent synthesis through the attachment of an alkyne
(Songashira coupling or acyl substitution of a Weinreb amide)
followed by an iodonium-induced reaction cascade to give ring-
fused indoles B, quinolines C, or quinolones D depending on the reaction conditions employed.
Scheme 2. Iodocyclization with Nucleophilic Trapping
INTRODUCTION
■
Electrophilic activation of alkynes toward intramolecular
nucleophilic attack has emerged as a highly effective means of
forming a variety of carbocyclic and heterocyclic ring systems.1,2
A particularly useful reaction is the 5- and 6-endo-digonal
iodocyclization of a tethered heteroatomic nucleophile Nu upon
an alkyne using an iodonium source 1 → 2 → 3 (Scheme 1).
Scheme 1. Iodocyclization with Electrofugal (Ef)
Displacement
The electrofuge (Ef) may either be a proton or an alkyl group
that is removed using either a base or nucleophile (usually I−),
respectively. An interesting variation on the use of an electrofuge
is the trapping of the initially formed cyclic cation by another
nucleophile in a reaction cascade. For example, Barluenga and
Larock have demonstrated that iodocyclization of o-alkynylben-
zaldehydes 4 gives a benzopyranium ion 5 that undergoes
subsequent nucleophilic attack to give a highly substituted
4-iodobenzopyran 6 (Scheme 2).3,4 We rationalized that a similar
cascade could be used in a cocyclization strategy to form ring-
fused indoles 9 where readily accessible N-(2-alkynylphenyl)-
imines 7 undergo iodocylization to an imminum ion 8 that can
then be trapped by a nucleophile tethered to the alkynyl group
giving 9 (Path A, Scheme 2). Herein, we report our
investigations into this approach to ring-fused indoles 9.5,6 We
also describe an equivalent cocylization process for the formation
of ring-fused quinolones 13 → 14 → 15. Interestingly, during
our evaluation of different reaction conditions to effect
cocyclizations to give indoles 9, we have identified an alternative
pathway (Path B) involving iodonium activation of the imine
7 (R2 = H, Nu = OH) such that it becomes an electrophile and
undergoes a concerted cocyclization with the tethered alkynol to
give a ring-fused quinolines 7 → 10 → 11 → 12 (Path B). The
ring structures made available through these cocyclization
strategies may provide useful scaffolds exhibiting interesting
Received: January 23, 2013
© XXXX American Chemical Society
A
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biological activities. Examples of related structures that have
exhibited biological activity include the HCV NSB5 polymerase
inhibitor 16,7 the steroid dehydrogenase inhibitor 17,8 the
acetylcholinesterase (AChE) inhibitor 18,9 and the topoisomer-
ase inhibitor 19 (Figure 1).10
Table 1. Synthesis of NH-3-Iodoindoles 23
7
a
entry
R2
R3
R4
method
23 (%, from 21)
1
2
3
4
5
7a
7b
7b
7c
7d
H
NMe2
Ph
Ph
A
23a (78)
23a (70)
23a (87)
23b (94)
23b (0)
Ph
Ph
Ph
H
Ph
B
Ph
Ph
C
Figure 1. Bioactive ring-fused indoles, quinolines, and quinolones.
Ph
nPr
nPr
B
Ph
B/C
a
Method A: I2, CH2Cl2, then K2CO3, MeOH (aq); B: NIS, CH2Cl2; C
RESULTS AND DISCUSSION
For the purpose of our investigation, we first prepared a series
of different N-(2-iodophenyl)imines 21 (eq 1). These could be
■
I2, K2CO3, CH3CN.
alternative activating group to complement these other methods to
NH-3-iodoindoles (Table 1). Sonogashira coupling of 21 with
terminal alkynes gives efficient access to the desired N-(2-
alkynylphenyl)imines 7. Since compounds 7 are prone to proto-
cyclization on silica gel, the crude material was not chromato-
graphed but subjected directly iodocyclization (Table 1). The
dimethylcarboximidate group in 7a (R2 = H, R3 = NMe2) was
effective in promoting iodocyclization using I2 in CH2Cl2 to give
the imminium intermediate 22, which was readily cleaved upon
treatment with K2CO3 in MeOH (methanolysis) to afford the NH-
3-iodoindole 23a (78%, from 21a) (Method A, entry 1, Table 1).
The diphenylimine (R2 = R3 = Ph) also undergoes facile
iodocyclization using either NIS in CH2Cl2 (Method B) or I2
and K2CO3 in CH3CN (Method C) (entries 2−4, Table 1). These
reactions occur with in situ cleavage of the imminium intermediate
to give direct access to NH-3-iodoindoles 23a and 23b in good
yields (70−94%, from 21a). Aldimines (R2 = H, R3 = Ph) failed in
the iodocyclization step, with hydrolysis to form the 2-alkynylaniline
and benzaldehyde being the major byproducts (entry 5, Table 1).
Thus, diphenylimine and dimethylcarboximidate are useful
activating groups for achieving access to NH-3-iodoindoles under
neutral or slightly basic conditions, complementing the earlier
approaches described above.
Of particular interest to us was to explore the use of N-(2-
alkynylphenyl)imines 7 bearing tethered nucleophiles in reaction
cascades, where iodocyclization of 7 gives an imminium ion 8 that
undergoes intramolecular attack by the pendant nucleophile to give
a cocyclized product 9 (Scheme 2). To evaluate this we coupled a
series N-(2-iodophenyl)imines 21 to several terminal alkynes
containing nucleophilic substituents (R4 = alcohol or electron-rich
arene) under Sonogashira conditions to give N-(2-alkynylphenyl)-
imines 7 (Table 2). Again, imines 7 were not able to be purified by
chromatography and so were subjected directly to iodocyclization
(Method B/C, Table 2). Using Method B (NIS in CH2Cl2) most
imines 7 were successfully cyclized to the ring-fused indoles 9 in
moderate to good yields over the two steps from 21 43−94%
(Method B, Table 2). An exception to this was the iodocyclization
of phenylaldimine 7 (R2 = H, R3 = Ph, R4 = CH2OH), which failed
accessed from the corresponding 2-iodoaniline 20 via condensation
reactions and were generally formed in good yields (69−99%).
However, two of these imines, 21f and 21h, were not isolated
because of stability issues but used directly in the subsequent
coupling and iodocyclization steps (vide infra).
Our initial studies focused on the use of imines to act as labile
activating groups for promoting iodocyclization to give simple
NH-indoles (Table 1). The iodocyclization of simple 2-alkynylani-
lines to NH-3-iodoindoles has been previously achieved using a
strong base and a gold salt (KOH, NaAuCl4, I2) or the use of a very
powerful iodonium source (Pyr2I·BF4).2d,j Knight demonstrated
that 2-alkynylanilines bearing electron-withdrawing groups (Boc
and Tosyl) on the nitrogen could be iodocyclized under mildly
basic conditions (K2CO3, I2).2e These activating groups can then be
readily cleaved under acidic (Boc) or basic (Tosyl) conditions to
give the NH-3-iodoindole. Finally, N,N-dialkyl-2-alkynylanilines can
be iodocyclized to N-alkyl-3-iodoindoles under relatively mild
conditions.2a,l,k We have briefly explored the use of imines as
B
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a
Table 2. Synthesis of Ring-Fused Indoles 9 and Quinolines 12
a
b
Unless otherwise stated, the isolated yield of 9 and 12 is calculated from the relevant imine 21. Isolated yield calculated from 2-iodoaniline 20.
to yield cocyclized product 9a, returning the imine hydrolysis
products 2-(propynol)aniline and benzaldehyde (not shown). By
contrast, the related aldimine substrates bearing OH groups on
longer tethers [R4 = (CH2)2OH or (CH2)3OH] were successfully
iodocyclized to the ring-fused 3-iodoindoles: 9c (62%), 9g (41%), 9j
(75%), 9m (73%) and 9n (52%). These results suggest that suitably
distal nucleophiles (OH) can promote iodocyclization avoiding the
competing aldimine hydrolysis seen when either a shorter tether is
used (R4 = CH2OH) or where no nucleophile is present (R4 = nPr).
In addition to R4 = alcohol, cocyclization was also achieved where
R4 = electron-rich arene, 9p (52%) (see also below).
59−80% over two steps from iodoimine 21 and 12e,f 46−48%
over three steps from iodoaniline 20).
The iodocyclization used to form indoles 21 and 9 was also
extended to quinolones 25 and 15 (Table 3). Lithiation of the
iodoimines 21 (iodide for lithium exchange) followed by acyl
substitution of the Weinreb amides 24 gave alkynones 13, which
were not isolated but subject directly to iodocyclization to afford
iodoquinolones 15 and/or 25 (see below). Weinreb amides 24
were readily formed from the corresponding terminal alkynes by
deprotonation and acyl substitution of 1-methoxy-1,3,3-trimethylurea
(eq 2).11
For diphenylimines cocyclization of 7 gave the same product
9 under Method C (I2, K2CO3, CH3CN) as Method B (NIS,
CH3Cl2) in, for example, 9b (98%) and 9d (96%). However,
cocyclization of arylaldimines bearing tethered alcohols 7 [R2 =
H, R3 = aryl, R4 = (CH2)2OH, (CH2)3OH] using Method C
gave an alternative product in the form of the furano and
pyrano fused quinolones 12a−f in reasonable yields (12a−d
C
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Table 3. Synthesis of 3-Iodoquinolones 25 and 15
a
13
entry
R2
Ph
R3
X
Y
iodocyc. solvent
product (%, from 21)
1
2
3
4
5
6
7
13a
13b
13c
13d
13e
13f
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
H
H
CH3CN
CH3CN
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
25a (36), 15a (47)
25a (58)
OMe
OMe
OMe
OMe
Ph
H
H
OMe
H
25b (61)
b
OMe
OiPr
OMe
OiPr
15d (85)
OMe
H
15e (90)
15f (59)
15g (95)
13g
Ph
OMe
a
b
This material was not isolated but subject directly to the iodocyclization step to give 15 or 25. Isolated as a 1:1 mixture of regiosiomers (X = OMe,
ortho and para to CR2R3).
We initially investigated the use of imines 13 to promote
iodocyclization to give an NH-3-iodoquinolones 25. The diphenyl-
imine group was not as effective in the cyclization of 13 (R1 = R2 =
Ph) to give NH-3-iodoquinolones 25 as it had been in the cyclization
of 7 (R1 = R2 = Ph) to give NH-3-iodoindoles 23 because of an
increased propensity of unactivated arenes (X = Y = H) to undergo
trapping to give 15. Thus, iodocyclization of 13a using NIS in
CH3CN gave a mixture of NH-3-iodoquinolone 25a and cocyclized
material 15a (entry 1, Table 3). However, the use of the
methylbenzimidate group overcame this issue, allowing alkynones
13b and 13c to be iodocyclized to NH-3-iodoquinolones 25a and
25b in reasonable yield, 58 and 61%, respectively, from 21 (entry 2
and 3, Table 3). When the nucleophilic arene was activated by the
presence of suitable donors (X = electron donor) and the
iodocyclization was performed in anhydrous CH2Cl2, the cocycliza-
tion product 15 dominated and was isolated in moderated to good
yields 59−90% (entries 4−7, Table 3).
First, we were struck by the capacity of the pendant alcohols
[R4 = (CH2)2OH, (CH2)3OH] in 7 to promote cocyclization of
aldimines to give a ring-fused 3-iodoindoles, despite the fact
that iodocyclization of the aldimines 7 (R2 = H) where the OH
is absent (e.g., R4 = nPr) or attached to shorter tether (R4 =
CH2OH) failed to iodocyclize and underwent competitive
imine hydrolysis. This prompted us to propose a mechanism
where the tethered OH group promotes iodocyclization
(cocyclization), possibly by stabilizing the emerging positive
charge on the imine nitrogen during nucleophilic attack on the
alkyne, as in transition state TSA.5 The shorter tether in 7 (R4 =
CH2OH) may prevent access to TSA because of geometric
constraints, preventing overlap between the OH electron lone
pair and π* of the imine (a disfavored 5-endo-trig).12
To get a better understanding of the nature of the alkyne
substituents on cyclization rates, we undertook a reaction rate
study of the diphenylimine systems 7 (R2 = R3 = Ph), and
unlike the aldimines system 7 (R2 = H, R3 = Ph), in these cases
all the iodocyclization products were successfully formed irrespective
of the alkyne substituent (Figure 2). Tracking the extent of convers-
ion as a function of time, we found that the propynol group (R4 =
CH2OH) iodocyclized much more slowly than the other systems 7
[R4 = nPr, (CH2)2OH, (CH2)3OH]; that is, 9b is formed much
more slowly than 21b, 9d, and 9i. Since 7 (R4 = CH2OH) cyclizes
slower than all other substrates, including 7 (R4 = nPr), it is not
necessary to evoke a disfavored 5-endo-trig in TSA to explain the
inability to form 9a. Instead, we attribute the slow cyclization of 7
(R4 = CH2OH) to 9b to an electron-withdrawing inductive effect of
OH upon the alkyne. This inductive effect may significantly reduce
the rate of iodonium attack upon the alkyne and/or impede the
nucleophilic attack of the imine upon iodonium/alkyne complex 26,
which requires the development of a transient positive charge on the
alkyne-carbon proximal to the electron withdrawing CH2OH group.
Presumably, this inductive effect impedes the rate of formation of 9a
to a sufficient degree that competing hydrolysis of the aldimine
becomes the prevailing pathway. However, this does not explain
why the phenylaldimine 7d (R2 = H, R3 = Ph, R4 = nPr) failed to
iodocyclize (entry 5, Table 1) despite the efficient iodo-cocyclization
of many other aldimine substrates bearing pendant OH groups 7
[R2 = H, R3 = aryl, R4 = (CH2)2/3OH] (Method B, Table 3). One
possibility is that diphenylimines do not require the nucleophilic
assistance because of the increased stabilization given to the
On the basis of observations made during this study, we have
made a number of tentative mechanistic proposals (Scheme 3).
Scheme 3. Mechanistic Proposal for Formation of 9 and 12
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Figure 2. Conversion 7 → 21/9 vs time.
imminium ion by the two phenyl groups, favoring a stepwise
mechanism through 27, whereas aldimines do benefit from the
presence of pendant nucleophiles (TSA).
for example, Songashira coupling of 91 gives 31 72% (eq 3). Thus
providing efficient acess to highly substituted polycycles through
functional group tolerant chemistry.
Another interesting feature of the reaction profile of the
aldimine systems 7 (R2 = H) is the capacity to redirect the
cocyclization path from fused indoles 9 toward ring-fused
quinolones 12 (Scheme 2). Reaction of 22 with NIS in CH2Cl2
(Method B) gives indoles 9 (Path A) and with I2 and K2CO3 in
CH3CN (Method C) gives 12 (Path B). The alternation between
these two pathways is effectively complete, with only a specific
cocyclization product 9/12 being observed under each method. It
is proposed that, relative to iodine, NIS in CH2Cl2 acts more
effectively as an electrophilic π-acid complexing the alkyne favoring
reaction through TSA to give 9 (Path A). On the other hand, I2 is
well-known to activate both alkynes and imines to electrophilic
attack, enabling access to both TSA (or 27) and TSB. Presumably
TSB is lower in energy for 7 (R2 = H) than is TSA, favoring
formation of 12.13 For substrates 7 where R2 ≠ H, conformer 28
and TSB are sterically encumbered, favoring cyclization through
26 → 27 → 9 under either conditions method B or C (Path B).
The use of iodonium ions as activating agents in these reaction
cascades has the added advantage of enabling subsequent
elaboration of the product using Pd-mediated coupling techniques;
CONCLUSIONS
■
The reactions described in this study enable ready access to a
range of different polycyclic scaffolds, ring-fused indoles 9,
quinolines 12, and quinolones 15, through minor alterations in
the reaction conditions and/or substrate substitution patterns.
While some imine substrates 21 and intermediates 7 and 13
have proven to be unstable to chromatography, this has not
impeded access to the target products since subsequent
coupling and/or iodocyclization steps can be conducted
without purification of the respective intermediate. Moreover,
the overall yields obtained over the three step process leading
to the target products 23, 9, 12, 25, and 15 have been quite
reasonable, 40−90%. The presence of the iodide functionality
in polycycles 9 and 12 affords excellent opportunity for the
further elaboration of these valuable structural classes.
EXPERIMENTAL SECTION
■
General Methods. All reactions were performed under an inert
atmosphere of anhydrous N2(g) using glassware that was first heated
(heat gun) under reduced pressure, backfilled with N2(g), and allowed
to cool to ambient temperature prior to use (vacuum-gas manifold).
Toluene, tetrahydrofuran (THF), acetonitrile (CH3CN) and dichloro-
methane (CH2Cl2) were dried using a commercial solvent purification
system. Reagents were used as supplied by commercial vendors
without further purifications or drying. Column (flash) chromatog-
raphy was performed on either 40−60 μm silica gel or neutral alumina
(activation grade III), as indicated. IR spectra were obtained on an FT-
IR spectrometer and are reported in terms of frequency of absorption
(cm−1). 1H NMR spectra were recorded at 300 MHz and are reported
E
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as follows: chemical shift (δH) (integration, multiplicity and coupling
constant (Hz)). The following abbreviations were used to explain
multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet, br = broad, dd = doublet of doublets, dt = doublet of triplets.
13C NMR spectra were recorded at 75 MHz and reported in terms of
chemical shift (δC). All chemical shifts were calibrated using residual
nondeuterated solvent as an internal reference and are reported in parts
per million relative to trimethylsilane. High-resolution mass spectra
(HRMS) were recorded on a time-of-flight mass spectrometer fitted with
either an electrospray (ESI) or atmospheric pressure ionization (APCI)
ion source.
N-(Dimethylaminomethylene)-2-iodoaniline (21a). A mixture
of 2-iodoaniline (2.19 g, 10.0 mmol) and N,N-dimethylformamide
dimethylacetal (1.46 mL, 11.0 mmol) in anhydrous DMF (20 mL) was
heated at 80 °C overnight. More N,N-dimethylformamide dimethyl-
acetal (0.66 mL, 5.0 mmol) was added, and the mixture was heated for
another 8 h. After cooling to room temperature, water (30 mL) was
added, and the mixture was extracted with ethyl acetate (3 × 50 mL).
The combined organic phase was washed with water and dried over
MgSO4. Removal of solvent afforded the title compound (2.73 g, 99%)
as a yellow oil: δH (300 MHz, CDCl3) 3.09 (3H, br s), 3.16 (3 H, br
s), 6.75 (1H, dt, J 3.0, 7.0 Hz), 6.93 (1H, mc), 7.24 (1H, dd, J 2.0, 6.0
Hz), 7.41 (1H, s), 7.81 (3H, dd, J 2.0, 6.0 Hz); δH (300 MHz, CDCl3)
34.5, 40.0, 96.9, 118.8, 123.7, 129.0, 138.6, 152.5, 152.9; HRMS
(APCI) calculated for [C9H12IN2]+ (MH+) m/z 275.0045 found
275.0054.
using petroleum spirit/ethyl acetate (10:1) as eluent to afford the title
compound (1.52 g, 69%) as yellow solid: mp 119−120 °C; δH (300
MHz, CDCl3) 3.82 (3H, s), 3.92 (3H, s), 6.54 (1H, dd, J 1.3, 7.9 Hz),
6.66 (1H, dd, J 1.3, 7.8 Hz), 6.83 (2H, d, J 8.6 Hz), 6.99 (2H, d, J 8.8
Hz), 7.12 (1H, dd, J 1.0, 7.4 Hz), 7.18 (2H, d, J 8.6 Hz), 7.79 (1H, dd, J
1.0, 7.8 Hz), 7.87 (2H, d, J 8.8 Hz); δC (75 MHz, CDCl3) 55.1, 55.4,
92.1, 113.2, 113.5, 120.5, 124.0, 128.2, 128.3, 130.5, 131.4, 131.9, 138.3,
153.2, 159.7, 162.0, 167.6; HRMS (ESI) calculated for [C21H18INO2]+
(MH+) m/z 444.0461 found 444.0463.
N-(4-Methylbenzylidene)-2-iodoaniline (21g). A mixture of 2-
iodoaniline (2.19 g, 10.0 mmol) and p-tolualdehyde (1.18 mL, 10.0
mmol), p-toluenesulfonic acid (cat.) and powdered 5 Å molecular
sieves (10 g) in benzene (50 mL) was stirred at room temperature for
7 days. The mixture was filtered, and the filtrate was concentrated under
reduced pressure. The crude material was suspended in minimum amount
of absolute ethanol (ca. 5 mL), filtered and dried to afford the title
compound (2.81 g, 88%) as pale yellow solid: mp 47−49 °C (lit. mp15
33−35 °C). The 1H NMR of this material is identical to that previously
reported.15
N-(Diphenylmethylene)-4-methyl-2-iodoaniline (21i). A mix-
ture of 4-methyl-2-iodoaniline16 (2.33 g, 10.0 mmol), benzophenone
(1.82 g, 10.0 mmol) and p-toluenesulfonic acid (cat.) in toluene (100
mL) was heated under reflux with the aid of a Dean−Stark apparatus
for 2 days. The mixture was concentrated under reduced pressure, and
the crude residue was taken up in diethyl ether (50 mL), washed with
a saturated solution of sodium bicarbonate (20 mL) and brine. The
organic phase was separated and dried over MgSO4. The crude
mixture was purified by flash chromatography using petroleum spirit/
ethyl acetate (20:1) as eluent to give the title compound (3.14 g, 79%)
as yellow solid: mp 78−80 °C; δH (300 MHz, CDCl3) 2.25 (3H, s,
Me), 6.41 (1H, d, J 8.0 Hz), 6.90 (1H, dd, J 1.0, 8.0 Hz), 7.22−7.27
(2H, m), 7.31−7.36 (3H, m), 7.47−7.56 (3H, m), 7.64 (1H, s), 7.89
(2H, m); δC (75 MHz, CDCl3) 20.1, 91.7, 120.0, 127.9, 128.2, 128.7,
129.1, 129.5, 131.0, 134.2, 136.0, 138.7, 150.0, 168.7; HRMS (ESI)
calculated for [C20H16IN]+ (MH+) m/z 398.0406 found 398.0418.
General Procedure for Sonogashira Coupling to Give N-(2-
Alkynylphenyl)imines 7 (0.5 mmol scale). The N-(2-iodophenyl)-
imine 21 (0.5 mmol) was dissolved in a mixture of THF (4 mL) and
triethylamine (2 mL). To this solution was added the relevant terminal
alkyne (1.2 mmol) and Pd(PPh3)Cl2 (10.5 mg, 15 μmol), and the
solution was deoxygenated by bubbling nitrogen gas through the solution
for 1 min prior to the addition of CuI (7.6 mg, 40 μmol). The resultant
reaction mixture was stirred overnight under nitrogen at room
temperature and then diluted with diethyl ether (25 mL) and transferred
to a separatory funnel. This mixture was washed with saturated NH4Cl aq
(30 mL) and brine (30 mL) and then dried over MgSO4 and
concentrated under a vacuum. The resulting residue, containing mostly
N-(2-alkynylphenyl)imines 7, was used in the subsequent cyclization step
without further purification.
General Procedures for Iodocyclization (0.5 mmol scale).
Method A (I2, CH2Cl2). I2 (190 mg, 0.75 mmol) was added to a solution
of the crude N-(2-alkynylphenyl)imine 7 (∼0.5 mmol, obtained from
the general procedure for Sonogashira coupling, described above) in
dry CH2Cl2 (5 mL) and stirred at room temperature until the
complete disappearance of starting material was observed by TLC
analysis (up to 1 h). The reaction mixture was then transferred to a
separatory funnel and diluted with CH2Cl2 (7 mL). This solution was
then washed with Na2S2O3 10% w/v aq (10 mL), dried over MgSO4,
and then concentrated under reduced pressure. The residue was then
diluted with MeOH (3.0 mL), and K2CO3 (276 mg, 2.0 mmol) was
added. The resultant suspension was then stirred at room temperature
for 24 h. After this time the mixture was diluted with diethyl ether
(15 mL), filtered and concentrated under reduced pressure. The
residue was then subjected by flash chromatography on silica gel or
deactivated alumina (as indicated) to afford the pure product.
Method B (NIS, CH2Cl2). N-Iodosuccinimide (135 mg, 0.6 mmol)
was added to a solution of the crude N-(2-alkynylphenyl)imine 7
(∼0.5 mmol, obtained from the general procedure for Sonogashira
coupling, described above) in dry CH2Cl2 (2.5 mL), and the mixture
was stirred at room temperature for 1 h. The reaction mixture was
N-Benzylidene-2-iodoaniline (21b). This material was prepared
according to a previously described procedure and yielded the title
compound in an 85% yield (1H NMR identical to that previously
reported).14
N-(Diphenylmethylene)-2-iodoaniline (21c). A mixture of
2-iodoaniline (2.19 g, 10.0 mmol), benzophenone (1.82 g, 10.0 mmol)
and p-toluenesulfonic acid (cat.) in toluene (50 mL) was heated under
reflux overnight with the aid of a Dean−Stark apparatus. The mixture
was filtered, and the filtrate was concentrated under reduced pressure.
The residue was redissolved in diethyl ether (50 mL), washed with a
saturated solution of sodium bicarbonate (20 mL), brine (20 mL) and
dried over MgSO4. The resulting dark brown residue was purified by
flash chromatography using petroleum spirit/ethyl acetate (25:1) as
eluent to give the title compound (3.52 g, 92%) as yellow solid: mp
79−82 °C; δH (300 MHz, CDCl3) 6.49 (1H, dd, J 1.2, 7.8 Hz), 6.32
(1H, d, J 7.8 Hz), 7.06 (1H, t, J 7.9 Hz), 7.17−7.29 (4H, m), 7.43−
7.51 (3H, m), 7.74 (1H, d, J 7.9 Hz), 7.85 (2H, d, J 7.2 Hz); δC (75
MHz, CDCl3) 91.6, 120.2, 124.4, 127.9, 128.2, 128.3, 128.6, 128.8,
129.5, 131.0, 135.8, 138.4, 138.7, 152.8, 168.6; HRMS (ESI) calculated
for [C19H14IN]+ (MH+) m/z 384.0249 found 384.0262.
N-(Methoxyphenylmethylene)-2-iodoaniline (21d). A mixture
of 2-iodoaniline (2.19 g, 10.0 mmol), trimethylorthobenzoate (1.9 mL,
11.0 mmol) and p-toluenesulfonic acid (cat.) in toluene (50 mL) was
heated under reflux overnight with the aid of a Dean−Stark apparatus.
The mixture was filtered, and the filtrate was concentrated under
reduced pressure. The residue was redissolved in diethyl ether
(50 mL), washed with a saturated solution of sodium bicarbonate
(20 mL), brine (20 mL) and dried over MgSO4. Flash chromatography
using petroleum spirit/ethyl acetate (25:1) as eluent afforded the title
compound (3.07 g, 91%) as yellow oil and mainly single double bond
isomer (ratio of isomers = 10:1): δH (300 MHz, CDCl3, * denotes
resonances associated with the minor isomer) 3.99* (3H, s), 4.11 (3H, s),
6.59 (1H, d, J 7.9 Hz), 6.73 (1H, t, J 7.6 Hz), 7.15 (1H, t, J 7.6 Hz), 7.26−
7.40 (5H, m), 7.50−7.59 (2H, m), 7.84 (1H, d, J 7.9 Hz), 8.10* (1H, d,
J 8.4 Hz); δC (75 MHz, CDCl3) 54.5, 93.0, 121.2, 124.0, 128.0, 128.3,
128.78, 128.8, 130.1, 131.1, 138.8, 150.0, 159.6; HRMS (ESI) calculated for
[C14H12INO]+ (MH+) m/z 338.0042 found 338.0049.
N-[Bis(4-methoxyphenyl)methylene]-2-iodoaniline (21e). A
mixture of 2-iodoaniline (1.09 g, 5.0 mmol), bis-(4-methoxyphenyl)-
methanone (1.21 g, 5.0 mmol) and p-toluenesulfonic acid (cat.) in
toluene was heated under reflux for two days with the aid of a Dean−
Stark apparatus. The mixture was concentrated under reduced pressure,
and the residue was redissolved in dichloromethane and passed through
a pad of Celite. The crude mixture was purified by flash chromatography
F
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then transferred to a separatory funnel and diluted with CH2Cl2
(7 mL). This solution was then washed with Na2S2O3 10% w/v aq
(10 mL), dried over MgSO4, and then concentrated under reduced
pressure. The residue was then subjected to flash chromatography on
silica gel or deactivated alumina (as indicated) to afford the pure
product.
(CD3)2SO) 3.00−3.07 (2H, m), 3.95−4.12 (2H, m), 6.53 (1H, d, J 8.2
Hz), 6.77 (1H, s), 6.91 (1H, t, J 7.4 Hz), 7.07 (1H, t, J 7.3 Hz), 7.23−
7.31 (3H, m), 7.38−7.43 (3H, m); δC (75 MHz, (CD3)2SO) 24.8,
57.4, 60.9, 86.1, 111.0, 119.4, 120.5, 121.5, 127.5, 128.6, 129.5, 134.3,
136.2, 137.7; HRMS (APCI) calculated for [C17H14INO]+ (MH+) m/z
376.0198 found 376.0202.
Method C (I2, K2CO3, CH3CN). I2 (190 mg, 0.75 mmol) was added
to a suspension of K2CO3 (104 mg, 0.75 mmol) and N-(2-
alkynylphenyl)imine 7 (∼0.5 mmol, obtained from the general
procedure for Sonogashira coupling, described above) in dry
CH3CN (5 mL). The resultant solution was stirred at room
temperature for 2 h (TLC analysis indicated complete consumption
of starting material). After this time, Na2S2O3 10% w/v aq (10 mL)
was added, and the mixture was transferred to a separatory funnel and
extracted with diethyl ether (2 × 10 mL). The organic phases were
combined, dried over MgSO4, and concentrated under reduced
pressure. The residue was then subjected to flash chromatography on
silica gel or deactivated alumina (as indicated) to afford the pure
product.
3-Iodo-2-phenyl-1H-indole (23a). N-(Dimethylaminomethy-
lene)-2-iodoaniline (21a) (137 mg, 0.5 mmol) was coupled to
phenylacetylene (55 μL, 0.7 mmol) using the general method for
Sonogashira coupling described above, and the resultant product 7a
was subjected to iodocyclization using Method A (above). The
product was purified using flash chromatography on deactivated
alumina(III) using petroleum spirit and ethyl acetate (10:1) as eluent
giving 23a as pale yellow solid (123 mg, 78%): mp 79−81 °C (lit.17
mp 71−80 °C); δH (300 MHz, (CD3)2CO) 7.20−7.25 (2H, m),
7.42−7.53 (5H, m), 7.88−7.91 (2H, m), 10.95 (1H, br); δC (75 MHz,
(CD3)2CO) 57.3, 112.6, 121.5, 121.9, 124.0, 129.3, 129.5, 132.8, 133.4,
138.1, 139.2; HRMS (ESI) calculated for [C14H9IN]+ (M-H+) m/z
317.9780 found 317.9782.
5-Iodo-1,1-diphenyl-3,4-dihydro-1H-[1,3]oxazino[3,4-a]-
indole (9d). Iodoimine 21c (195 mg, 0.51 mmol) and 3-butyn-1-ol
(46 μL, 0.6 mmol) were coupled using the general method for
Sonogashira coupling described above, and the resultant product was
subjected to iodocyclization using Method B (above). Column
chromatography on silica gel using petroleum spirit/ethyl acetate (10:1)
afforded 9d as pale yellow solid (216 mg, 94%): mp 176.5−177 °C; IR
(cm−1) 2953, 1544, 1489, 1445; δH (300 MHz, CDCl3) 3.21 (2H, t, J 6.1
Hz), 4.03 (2H, t, J 6.1 Hz), 6.34 (1H, d, J 8.4 Hz), 6.89 (1H, t, J 8.3 Hz),
7.14 (1H, t, J 8.3 Hz), 7.27−7.50 (11H, m); δC (75 MHz, CDCl3) 25.5,
58.6, 59.6, 94.7, 113.0, 120.1, 120.5, 122.0, 128.3, 128.8, 129.2, 129.7,
135.8, 136.4, 140.3; HRMS (APCI) calculated for [C23H18INO]+ (MH+)
m/z 452.0511 found 452.0513.
Iodocyclization using Method C gave the same product in 98%
yield.
5-Iodo-7-methyl-1,1-diphenyl-3,4-dihydro-1H-[1,3]oxazino-
[3,4-a]indole (9e). Iodoimine 21i (100 mg, 0.25 mmol) and 3-butyn-
1-ol (23 μL, 0.3 mmol) were coupled using the general method for
Sonogashira coupling described above, and the resultant product was
subjected to iodocyclization using Method B (above). The reaction
mixture was purified by column chromatography on deactivated
alumina(III) using petroleum spirit/ethyl acetate (25:1 then 10:1)
afforded 9e as pale yellow solid (81 mg, 70%): mp 167−167.5 °C; δH
(300 MHz, (CD3)2SO) 2.30 (3H, s), 3.08 (2H, t, J 6.0 Hz), 3.85 (2H,
t, J 6.0 Hz), 6.09 (1H, d, J 8.5 Hz), 6.61 (1H, d, J 8.5 Hz), 7.06−7.13
(5H, m), 7.35−7.45 (6H, m); δC (75 MHz, (CD3)2SO) 20.7, 24.7,
58.2, 59.0, 93.9, 112.2, 119.1, 123.3. 128.3, 129.2, 129.3, 134.1, 136.1,
139.9; HRMS (APCI) calculated for [C24H20INO]+ (MH+) m/z
466.0668 found 466.0663.
1-Ethoxy-5-iodo-3,4-dihydro-1H-[1,3]oxazino[3,4-a]indole
(9f). A solution of 2-iodoaniline (101.0 mg, 0.5 mmol) and
p-toluenesulfonic acid (2 mg) in triethylorthoformate (2 mL) was
heated under reflux overnight. After the solvent was removed, the
crude mixture was taken up in diethyl ether (10 mL) and washed with
NaHCO3 aq 5% w/v (10 mL), water (10 mL) and brine (10 mL). The
organic phase was dried over MgSO4 and concentrated under reduced
pressure to afford 21h, which was unstable and used in the next step
without further purification. This crude form of 21h and 4-butyn-1-ol
(46 μL, 0.6 mmol) were coupled using the general method for
Sonogashira coupling described above, and the resultant product was
subjected to iodocyclization using Method B (above). Column
chromatography on deactivated alumina(III) using petroleum spirit/
ethyl acetate (50:1) afforded 9f as pale yellow solid (87.5 mg, 51%): mp
71−72 °C; IR (cm−1) 2979, 1706, 1454, 1336; δH (300 MHz,
(CD3)2CO) 1.26 (3H, t, J 7.1 Hz), 2.90−3.01 (2H, m), 3.80−3.90
(2H, m), 4.08 (1H, m, ddd, J 2.9, 5.9, 11.0 Hz), 4.34 (1H, dt, J 4.4, 11.0
Hz), 6.52 (1H, s), 7.17−7.22 (2H, m), 7.32−7.36 (1H, m), 7.38−7.42
(1H, m); δC (75 MHz, (CD3)2CO) 15.4, 25.6, 57.2, 58.0, 62.4, 99.8,
111.5, 120.5, 122.0, 123.2, 130.8, 135.7; HRMS (APCI) calculated for
[C13H14INO2]+ (MH+) m/z 344.0148 found 344.0155.
5-Iodo-1-(4-methoxyphenyl)-3,4-dihydro-1H-[1,3]oxazino-
[3,4-a]indole (9g). A mixture of 2-iodoaniline 20 (R1 = H) (359.1
mg, 1.64 mmol), 4-methoxybenzaldehyde (0.2 mL, 1.64 mmol),
p-toluenesulfonic acid (cat.) and powdered 5 Å molecular sieves (1.64 g)
in benzene (10 mL) was stirred at room temperature for 3 days. The
mixture was filtered, and the filtrate was concentrated under reduced
pressure to afford 21f (crude product). This crude product and 3-
butyn-1-ol (0.13 mL, 2.0 mmol) were coupled using the general
method for Sonogashira coupling described above, and the resultant
product was subjected to iodocyclization using Method B (above).
Column chromatography on deactivated alumina(III) using petroleum
spirit/ethyl acetate (20:1) afforded 9g as yellow oil (286.0 mg, 43%):
δH (300 MHz, (CD3)2SO) 2.98−3.07 (2H, m), 3.76 (3H, s), 3.93−
4.01 (1H, m), 4.08−4.15 (1H, m), 6.52 (1H, d, J 8.2 Hz), 6.69 (1H, s),
The same product (23a) was formed when 21a was substituted for
21b, and the crude product resulting from Songashara Coupling (7b)
was subjected to iodocyclization using either Method B or C, giving
23a in 70 and 87% yield, respectively (see Table 1).
3-Iodo-2-propy-1H-indole (23b). Iodoimine 21b (191 mg, 0.5
mmol) was coupled to 1-pentyne (58 μL, 0.6 mmol) using the general
method for Sonogashira coupling described above, and the resultant
product 7c was subjected to iodocyclization using Method B (above).
The product was purified using flash chromatography on deactivated
alumina(III) using petroleum spirit and ethyl acetate (10:1) as eluent,
giving 23b as a tan oil (133 mg, 94%): δH (300 MHz, (CD3)2CO) 0.98
(3H, t, J 7.4 Hz), 1.78 (2H, sextet, J 7.4 Hz), 2.82 (2H, t, J 7.4 Hz),
7.08−7.13 (2H, m), 7.27−7.34 (2H, m), 10.5 (1H, br); δC (75 MHz,
(CD3)2CO) 13.6, 22.9, 30.6, 57.6, 111.6, 120.2, 120.4, 122.4, 131.2,
137.1, 141.3; HRMS (APCI) calculated for [C11H12IN]+ (MH+) m/z
285.0014 found 285.0018.
9-Iodo-3,3-diphenyl-1,3-dihydrooxazolo[3,4-a]indole (9b).
Iodoimine 21c (161 mg, 0.42 mmol) and 2-propyn-1-ol (35 μL, 0.6
mmol) were coupled using the general method for Sonogashira
coupling described above, and the resultant product was subjected to
iodocyclization using Method B (above). The reaction mixture was
purified by column chromatography on silica gel using petroleum
spirit/ethyl acetate (10:1) as eluent afforded 9b as yellow-orange solid
(116.0 mg, 63%): mp 139.5−140.5 °C; δH (300 MHz, CDCl3) 5.18
(2H, s), 6.87 (1H, d, J 8.2 Hz), 7.11 (1H, t, J 7.9 Hz), 7.23 (1H, t, J 7.9
Hz), 7.41−7.51 (11H, m); δC (75 MHz, CDCl3) 45.2, 65.6, 99.4,
110.6, 120.6, 121.0, 122.5, 127.8, 128.3, 129.3, 132.4, 135.0, 139.2,
142.5; HRMS (APCI) calculated for [C22H16INO]+ (MH+) m/z
438.0355 found 438.0358.
Iodocyclization using Method C gave the same product in 98%
yield.
5-Iodo-1-phenyl-3,4-dihydro-1H-[1,3]oxazino[3,4-a]indole
(9c). Iodoimine 21b (147 mg, 0.48 mmol) and 3-butyn-1-ol (46 μL,
0.6 mmol) were coupled using the general method for Sonogashira
coupling described above, and the resultant product was subjected to
iodocyclization using Method B (above). Column chromatography on
deactivated alumina(III) using petroleum spirit/ethyl acetate (20:1)
afforded 9c as pale yellow oil (112.0 mg, 62%): δH (300 MHz,
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6.92−6.97 (3H, m), 7.06 (1H, t, J 7.2 Hz), 7.19 (2H, d, J 8.7 Hz), 7.27
(1H, d, J 7.8 Hz); δC (75 MHz, (CD3)2SO) 24.8, 55.1, 57.3, 60.9, 86.0,
111.1, 113.9, 119.3, 120.4, 121.5, 128.9, 129.5, 129.8, 134.3, 136.4,
160.0; HRMS (APCI) calculated for [C18H16INO2]+ (MH+) m/z
406.0304 found 406.0288.
21.1, 26.9, 27.6, 61.2, 62.5, 98.0, 114.2, 120.5, 123.4, 128.1, 128.3,
128.6, 128.8, 128.9, 129.7, 130.1, 131.0, 136.4, 140.5, 143.0; HRMS
(APCI) calculated for [C25H22INO]+ (MH+) m/z 480.0824 found
480.0822.
6-Iodo-1-(p-tolyl)-1,3,4,5-tetrahydro-[1,3]oxazepino[3,4-a]-
indole (9m). Iodoimine 21g (83.1 mg, 0.26 mmol) and 4-pentyn-1-ol
(28 μL, 0.3 mmol) were coupled using the general method for
Sonogashira coupling described above, and the resultant product was
subjected to iodocyclization using Method B (above). Column
chromatography on deactivated alumina(III) using petroleum spirit/
ethyl acetate (100:0 then 20:1) afforded 9m as colorless oil (76.0 mg,
73%): δH (300 MHz, (CD3)2SO) 1.74−1.90 (2H, m), 2.30 (3H, s),
2.75−2.87 (1H, m), 3.17−3.25 (1H, m), 3.89−3.96 (2H, m), 6.93
(2H, d, J 8.0 Hz), 7.02−7.14 (3H, m), 7.21 (2H, d. J 8.0 Hz), 7.25−
7.28 (2H, m); δC (75 MHz, (CD3)2SO) 20.3, 26.7, 28.0, 60.9, 66.1,
86.0, 110.3, 120.2, 120.4, 122.2, 126.7, 129.3, 129.5, 133.7, 136.7,
138.1, 141.9; HRMS (APCI) calculated for [C19H18INO]+ (MH+) m/
z 404.0511 found 404.0512.
6-Iodo-1-(4-methoxyphenyl)-1,3,4,5-tetrahydro-[1,3]-
oxazepino[3,4-a]indole (9n). This material was prepared from 2-
iodoaniline (180.1 mg, 0.83 mmol), 4-methoxybenzaldehyde (0.1 mL,
0.83 mmol) and 4-pentyn-1-ol (0.1 mL, 1.07 mmol) using an identical
reaction sequence and purification procedure as that described for 9g.
This afforded the product 9n as yellow oil (181.3 mg, 52%): δH (300
MHz, CDCl3) 1.61−2.00 (2H, m), 2.89−3.00 (1H, m), 3.31−3.40
(1H, dt, J 4.2, 15.2 Hz), 3.86 (3H, s), 3.96−4.03 (1H, m), 4.08−4.15
(1H, m), 6.92−6.96 (2H, m), 7.02−7.08 (3H, m), 7.21−7.27 (3H, m),
7.49 (1H, d, J 7.2 Hz); δC (75 MHz, CDCl3) 21.2, 28.5, 55.3, 60.9,
66.2, 86.6, 109.6, 114.3, 120.7, 121.1, 122.6, 128.4, 128.6, 130.2, 137.1,
141.7, 160.0; HRMS (APCI) calculated for [C19H18INO2]+ (MH+)
m/z 420.0461 found 420.0460.
1-Ethoxy-6-iodo-1,3,4,5-tetrahydro-[1,3]oxazepino[3,4-a]-
indole (9o). This product was prepared using an identical method to
that described for 9f (above) except that 4-pentyn-1-ol was used in
place of 3-butyn-1-ol. Column chromatography on deactivated
alumina(III) using petroleum spirit/ethyl acetate (50:1) afforded 9o
as pale yellow oil (110.0 mg, 62%): δH (300 MHz, CDCl3) 1.37 (3H, t,
J 7.1 Hz), 2.03−2.09 (2H, m), 3.21−3.35 (2H, m), 3.65−3.87 (2H,
m), 4.00 (1H, td, J 4.3, 12.0 Hz), 4.34−4.43 (1H, m), 6.64 (1H, s),
7.27−7.39 (3H, m), 7.47 (1H, dd, J 2.0, 7.0 Hz); δC (75 MHz, CDCl3)
14.7, 27.2, 28.3, 61.8, 62.7, 63.7, 100.2, 109.0, 120.8, 121.1, 122.7,
130.1, 136.6, 140.7; HRMS (APCI) calculated for [C14H16INO2]+
(MH+) m/z 358.0304 found 358.0302.
11-Iodo-9-isopropoxy-8-methoxy-6,6-diphenyl-6H-
isoindolo[2,1-a]indole (9p). Iodoimine 21c (186.9 mg, 0.49 mmol)
and 5-ethynyl-1-isopropoxy-2-methoxybenzene18 (115 mg, 0.6 mmol)
were coupled using the general method for Sonogashira coupling
described above, and the resultant product was subjected to
iodocyclization using Method B (above). Column chromatography
on silica gel using petroleum spirit/ethyl acetate (20:1) afforded 9p as
light green solid (145.5 mg, 52% over two steps): mp 152−153 °C; δH
(300 MHz, (CD3)2CO) 1.39 (6H, d, J 6.1 Hz), 3.79 (3H, s), 4.69 (1H,
setptet, J 6.1 Hz), 7.01−7.02 (2H, m), 7.07−7.13 (1H, m), 7.19 (1H,
s), 7.25−7.42 (11H, m), 7.79 (1H, s); δC (75 MHz, (CD3)2CO) 21.2,
44.2, 55.5, 71.4, 76.2, 107.4, 108.6, 110.7, 120.0, 120.6, 122.1, 122.6,
127.7, 127.9, 128.2, 133.7, 134.7, 140.6, 145.3, 147.8, 151.8; HRMS
(APCI) calculated for [C31H26INO2]+ (MH+) m/z 572.1087 found
572.1091.
5-Iodo-1,1-bis(4-methoxyphenyl)-3,4-dihydro-1H-[1,3]-
oxazino[3,4-a]indole (9h). Iodoimine 21e (211.8 mg, 0.48 mmol)
and 3-butyn-1-ol (46 μL, 0.6 mmol) were coupled using the general
method for Sonogashira coupling described above, and the resultant
product was subjected to iodocyclization using Method B (above).
Column chromatography on silica gel using petroleum spirit/ethyl
acetate (20:1) afforded 9h as colorless oil (132.1 mg, 54%): δH (300
MHz, (CD3)2CO) 3.12 (2H, t, J 6.1 Hz), 3.81 (6H, s), 3.93 (2H, t, J
6.1 Hz), 6.37 (1H, d, J 8.4 Hz), 6.80 (1H, dt, J 1.0, 7.8 Hz), 6.89−6.94
(4H, m), 7.02−7.12 (5H, m), 7.34 (1H, d, J 7.8 Hz); δC (75 MHz,
(CD3)2CO) 24.9, 54.4, 57.1, 58.5, 94.0, 112.7, 113.0, 119.3, 120.0,
121.4, 129.3, 129.7, 132.4, 136.1, 159.9, 204.8; HRMS (APCI)
calculated for [C25H22INO3]+ (MH+) m/z 512.0723 found 512.0727.
6-Iodo-1,1-diphenyl-1,3,4,5-tetrahydro-[1,3]oxazepino[3,4-a]-
indole (9i). Iodoimine 21c (190.1 mg, 0.5 mmol) and 4-pentyn-1-ol
(56 μL, 0.6 mmol) were coupled using the general method for
Sonogashira coupling described above, and the resultant product was
subjected to iodocyclization using Method B (above). Column
chromatography on deactivated alumina(III) using petroleum spirit/
ethyl acetate (20:1) afforded 9i as colorless solid (160.0 mg, 69%): mp
127−128 °C; δH (300 MHz, (CD3)2CO) 1.87−1.91 (2H, m), 3.26−
3.31 (2H, m), 3.89 (2H, t, J 6.6 Hz), 6.17 (1H, d, J 8.5 Hz), 6.70 (1H,
t, J 8.2 Hz), 6.97 (1H, t, J 7.3 Hz), 7.24−7.29 (5H, m), 7.36−7.42
(6H, m); δC (75 MHz, CDCl3) 26.7, 27.4, 62.9, 65.3, 98.0, 114.4,
120.2, 120.7, 121.7, 128.0, 128.2, 128.7, 130.0, 130.8, 137.9, 140.2,
142.9; HRMS (APCI) calculated for [C24H20INO]+ (MH+) m/z
466.0668 found 466.0662.
6-Iodo-1-phenyl-1,3,4,5-tetrahydro-[1,3]oxazepino[3,4-a]-
indole (9j). Iodoimine 21b (80.0 mg, 0.26 mmol) and 4-pentyn-1-ol
(28 μL, 0.3 mmol) were coupled using the general method for
Sonogashira coupling described above, and the resultant product was
subjected to iodocyclization using Method B (above). Column
chromatography on deactivated alumina(III) using petroleum spirit/
ethyl acetate (20:1) afforded 9j as pale yellow solid (76.1 mg, 75%):
mp 96−100 °C; δH (300 MHz, (CD3)2SO) 1.78−1.86 (2H, m), 2.78−
2.86 (1H, m), 3.19−3.27 (1H, m), 3.99−4.13 (2H, m), 7.03−7.13
(5H, m), 7.26−744 (5H, m); δC (75 MHz, (CD3)2SO) 26.7, 28.1,
61.1, 63.3, 66.3, 86.1, 110.3, 120.3, 120.4, 122.3, 126.8, 128.7, 128.8,
129.5, 136.68, 136.72, 142.0; HRMS (APCI) calculated for
[C18H16INO]+ (MH+) m/z 390.0355 found 390.0357.
6-Iodo-1,1-bis(4-methoxyphenyl)-1,3,4,5-tetrahydro-[1,3]-
oxazepino[3,4-a]indole (9k). Iodoimine 21e (207.8 mg, 0.47
mmol) and 4-pentyn-1-ol (56 μL, 0.6 mmol) were coupled using
the general method for Sonogashira coupling described above, and the
resultant product was subjected to iodocyclization using Method B
(above). Column chromatography on deactivated alumina using
petroleum spirit/ethyl acetate (10:1 then 3:2) afforded 9k as colorless
solid (151.1 mg, 61%): mp 113−114 °C; δH (300 MHz, (CD3)2CO)
1.84−1.88 (2H, m), 3.24−3.29 (2H, m), 3.79 (6H, s), 3.84 (2H, t, J
6.6 Hz), 6.24 (1H, d, J 8.5 Hz), 6.71 (1H, t, J 7.8 Hz), 6.88−6.99 (5H,
m), 7.13−7.18 (4H, m), 7.25 (1H, d, J 7.8 Hz); δC (75 MHz,
(CD3)2CO) 27.5, 28.3, 55.7, 62.8, 65.5, 98.9, 114.1, 115.6, 121.0,
121.3, 122.5, 131.0, 131.9, 133.7, 138.9, 144.1, 160.9; HRMS (APCI)
calculated for [C26H24INO3]+ (MH+) m/z 526.0879 found 526.0868.
6-Iodo-8-methyl-1,1-diphenyl-1,3,4,5-tetrahydro-[1,3]-
oxazepino[3,4-a]indole (9l). Iodoimine 21i (100.5 mg, 0.25 mmol)
and 4-pentyn-1-ol (28 μL, 0.3 mmol) were coupled using the general
method for Sonogashira coupling described above, and the resultant
product was subjected to iodocyclization using Method B (above).
Column chromatography on deactivated alumina(III) using petroleum
spirit/ethyl acetate (25:1 then 10:1) afforded 9l as colorless solid (83.7
mg, 70%): mp 172−173 °C; IR (cm−1) 2945, 1445, 1300; δH (300
MHz, (CD3)2CO) 1.85−1.90 (2H, m), 2.29 (3H, s), 3.23−3.27 (2H,
m), 3.88 (2H, t, J 6.5 Hz), 6.02 (1H, d, J 8.6 Hz), 6.52 (1H, dd, J 1.1,
8.6 Hz), 7.04 (1H, s), 7.23−7.40 (10H, m); δC (75 MHz, CDCl3)
4-Phenyl-2,3-dihydrofurano[3,2-c]quinoline (12a). Iodoimine
21c (192.0 mg, 0.5 mmol) and 3-butyn-1-ol (46 μL, 0.6 mmol) were
coupled using the general method for Sonogashira coupling described
above, and the resultant product was subjected to iodocyclization using
Method C (above). Column chromatography on silica gel using
petroleum spirit/ethyl acetate (10:1) afforded the 12a as pale yellow
solid (99.1 mg, 80%): mp 60.5−61 °C; δH (300 MHz, CDCl3) 3.61
(2H, t, J 8.9 Hz), 4.91 (2H, t, J 8.9 Hz), 7.48−7.59 (4H, m), 7.69−
7.75 (1H, m), 7.95−8.03 (3H, m), 8.18 (1H, d, J 8.6 Hz); δC (75
MHz, CDCl3) 30.0, 73.0, 115.0, 115.9, 121.3, 125.2, 128.2, 128.4,
128.7, 129.2, 129.5, 139.8, 149.1, 155.4, 164.2; HRMS (ESI) calculated
for [C17H13NO]+ (MH+) m/z 248.1075 found 248.1072.
H
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5-Phenyl-3,4-dihydro-2H-pyrano[3,2-c]quinoline (12b). Io-
doimine 21c (183.0 mg, 0.48 mmol) and 4-pentyn-1-ol (56 μL, 0.6
mmol) were coupled using the general method for Sonogashira
coupling described above, and the resultant product was subjected to
iodocyclization using Method C (above). Column chromatography on
silica gel using petroleum spirit/ethyl acetate (10:1) afforded the 12b
as pale yellow oil (76.3 mg, 61%): IR (cm−1) 2933, 1618, 1578, 1491; δH
(300 MHz, CDCl3) 2.08 (2H, m), 2.82 (2H, t, J 6.3 Hz), 4.51 (2H, t, J
5.2 Hz), 7.47−7.74 (6H, m), 8.11 (1H, d, J 8.2 Hz), 8.20 (1H, d, J 8.2
Hz); δC (75 MHz, CDCl3) 21.9, 23.7, 67.0, 110.5, 121.1, 125.2, 128.1,
128.2, 128.7, 129.0, 129.1, 140.5, 147.3, 157.3, 160.9; HRMS (ESI)
calculated for [C18H15NO]+ (MH+) m/z 262.1232 found 262.1229.
4-(4-Methylphenyl)-2,3-dihydrofurano[3,2-c]quinoline (12c).
Iodoimine 21g (157.1 mg, 0.49 mmol) and 3-butyn-1-ol (46 μL, 0.6
mmol) were coupled using the general method for Sonogashira
coupling described above, and the resultant product was subjected to
iodocyclization using Method C (above). Column chromatography
deactivated alumina(III) using petroleum spirit/ethyl acetate (10:1) afforded
12c as yellow solid (92.1 mg, 72%): mp 133−135 °C; δH (300 MHz,
CDCl3) 2.43 (3H, s), 3.58 (2H, t, J 8.9 Hz), 4.88 (2H, t, J 8.9 Hz), 7.31
(2H, d, J 7.9 Hz), 7.45 (1H, t, J 7.9 Hz), 7.66 (1H, t, J 8.5 Hz), 7.82 (2H, d,
J 8.1 Hz), 7.94 (1H, d, J 8.2 Hz), 8.14 (1H, d, J 8.6 Hz); δC (75 MHz,
CDCl3) 21.4, 30.0, 73.5, 115.2, 115.7, 120.3, 121.4, 121.9, 125.6, 127.5,
128.2, 128.5, 129.3, 130.3, 135.6, 139.5, 147.9, 155.0, 165.1; HRMS (ESI)
calculated for [C18H15NO]+ (MH+) m/z 262.1232 found 262.1227.
5-(4-Methylphenyl)-3,4-dihydro-2H-pyrano[3,2-c]quinoline
(12d). Iodoimine 21g (83.0 mg, 0.26 mmol) and 4-pentyn-1-ol (28 μL,
0.3 mmol) were coupled using the general method for Sonogashira
coupling described above, and the resultant product was subjected to
iodocyclization using Method C (above). Column chromatography on
deactivated alumina(III) using petroleum spirit/ethyl acetate (9:1 then
5:1) afforded 12d as colorless solid (42.0 mg, 59%): mp 97−99 °C; IR
(cm−1) 2921, 1616, 1588, 1491; δH (300 MHz, CDCl3) 2.05−2.13
(2H, m), 2.48 (3H, s), 2.83 (2H, t, J 6.2 Hz), 4.51 (2H, t, J 5.1 Hz),
7.34 (2H, d, J 8.0 Hz), 7.49−7.57 (3H, m), 7.70 (1H, dt, J 1.2, 8.3 Hz),
8.12 (1H, d, J 8.4 Hz), 8.19 (1H, d, J 8.2 Hz); δC (75 MHz, CDCl3)
21.2, 21.9, 23.8, 67.0, 110.6, 119.9, 121.1, 125.2, 128.7, 128.8, 129.0,
137.5, 138.0, 147.2, 157.3, 160.8; HRMS (ESI) calculated for
[C19H17NO]+ (MH+) m/z 276.1388 found 276.1382.
4-(4-Methoxyphenyl)-2,3-dihydrofurano[3,2-c]quinoline
(12e). This material was prepared from 2-iodoaniline (126.2 mg, 0.58
mmol), 4-methoxybenzaldehyde (0.07 mL, 0.6 mmol) and 3-butyn-1-
ol (0.07 mL, 1.1 mmol) using as the same procedure as that described
for 9g, except that the iodocyclization was conducted using Method C.
Column chromatography on deactivated alumina using petroleum
spirit/ethyl acetate (9:1) afforded the 12e as a colorless solid (77.1 mg,
48%): mp 136−136.5 °C; δH (300 MHz, CDCl3) 3.62 (2H, t, J 8.9
Hz), 3.93 (3H, s), 4.91 (2H, t, J 8.9 Hz), 7.08 (2H, d, J 8.8 Hz), 7.49
(1H, dt, J 0.9, 8.0 Hz), 7.71 (1H, dt, J 1.2 Hz, 8.3 Hz,), 7.94−8.01 (3H,
m), 8.15 (1H, d, J 8.6 Hz); δC (75 MHz, CDCl3) 30.4, 55.4, 73.0,
114.0, 114.7, 115.9, 121.4, 125.1, 129.2, 129.6, 129.7, 132.7, 149.3,
155.1, 160.3, 164.2; HRMS (ESI) calculated for [C18H15NO2]+ (MH+)
m/z 278.1181 found 278.1177.
5-(4-Methoxyphenyl)-3,4-dihydro-2H-pyrano[3,2-c]-
quinoline (12f). This material was prepared from 2-iodoaniline
(138.1 mg, 0.64 mmol), 4-methoxybenzaldehyde (0.08 mL, 0.64 mmol)
and 4-pentyn-1-ol (0.07 mL, 1.1 mmol) using as the same procedure as
that described for 9g, except that the iodocyclization was conducted using
Method C. Column chromatography on deactivated alumina(III) using
petroleum spirit/ethyl acetate (9:1) afforded 12f as pale yellow solid (85.4
mg, 46%): mp 118−119 °C; IR (cm−1) 2929, 1632, 1606, 1500; δH (300
MHz, CDCl3) 2.06−2.14 (2H, m), 2.85 (2H, t, J 6.3 Hz), 3.93 (3H, s),
4.52 (2H, t, J 5.1 Hz), 7.04−7.08 (2H, m), 7.48−7.72 (5H, m), 8.08 (1H,
d, J 8.4 Hz), 8.17 (1H, d, J 8.3 Hz); δC (75 MHz, CDCl3) 22.0, 24.0, 55.4,
67.0, 110.6, 113.7, 120.0, 121.2, 125.1, 128.96, 129.0, 130.2, 133.1, 134.8,
147.3, 157.3, 159.7, 160.5; HRMS (ESI) calculated for [C19H17NO2]+
(MH+) m/z 292.1338 found 292.1333.
1,3-dimethoxy-1,3-dimethylurea. n-BuLi (11 mmol, 2 M in hexanes)
was added to a solution of arylethyne (10 mmol) in dry THF (15 mL)
at −78 °C. The mixture was stirred at 0 °C for 1 h and then recooled
to −78 °C. A solution of 1-methoxy-1,3,3-trimethylurea (13 mmol) in dry
THF (6 mL) was added dropwise over 5 min. The mixture was then
warmed to 0 °C and stirred for a further 1 h. A saturated solution of
NH4Cl aq (5 mL) was added, and the mixture was extracted with diethyl
ether (3 × 20 mL). The combined organic phase was washed with water
(10 mL), brine (10 mL) and dried over MgSO4. The solvent was
evaporated, and the residue was purified by flash chromatography using
petroleum spirit and ethyl acetate (3:2) as eluent.
N-Methoxy-N-methyl-3-phenylpropiolamide (24a). Prepared
according to the general procedure for the preparation of Weinreb
amides (above) using phenylacteylene (1.10 mL, 10 mmol), giving the
product 24a as a tan oil (1.285 g, 68%). The 1H NMR of this material
was identical to that previously reported.11a
N-Methoxy-3-(4-methoxyphenyl)-N-methylpropiolamide
(24b). Prepared according to the general procedure for the
preparation of Weinreb amides (above) using 4-ethynyl-1-methoxy-
benzene (1.32 g, 10 mmol), giving the product 24b as a tan oil (1.91 g,
87%): δH (300 MHz, CDCl3) 3.31 (3H, br), 3.84 (6H, s), 6.88 (2H, d,
J 8.7 Hz), 7.51 (2H, d, J 8.7 Hz); δC (75 MHz, CDCl3) *32.4, 55.3,
*61.9, 80.1, 90.9, *112.0, 114.1, 134.3, *154.8, 161.2 (* these peaks
show broadening due to conformational effects); HRMS (APCI)
calculated for [C12H14NO3]+ (MH+) m/z 220.0974 found 220.0972.
N-Methoxy-3-(3-methoxyphenyl)-N-methylpropiolamide
(24c). Prepared according to the general procedure for the preparation
of Weinreb amides (above) using 3-ethynyl-1-methoxybenzene (660
mg, 5.0 mmol), giving the product 24c as a tan oil (438 mg, 40%): δH
(300 MHz, CDCl3) 3.32 (3H, br), 3.81 (3H, s), 3.84 (3H, s), 6.96−
7.00 (1H, m), 7.09 (1H, s), 7.16 (1H, J 7.5 Hz), 7.25−7.30 (1H, m); δC
(75 MHz, CDCl3) *32.3, 55.2, *62.1, 80.4, *90.1, 116.7, 117.2, *121.2,
124.9, 129.6, *154.4, 159.2 (* these peaks show broadening due to
conformational effects); HRMS (APCI) calculated for [C12H14NO3]+
(MH+) m/z [C12H14NO3]+ (MH+) m/z 220.0974 found 220.0972.
N-Methoxy-3-(4-isopropoxy-3-methoxyphenyl)-N-methyl-
propiolamide (24d). Prepared according to the general procedure
for the preparation of Weinreb amides (above) using 5-ethynyl-1-
isopropoxy-2-methoxybenzene (1.90 g, 10 mmol),18 giving the
product 24d as a tan oil (1.61 g, 58%): IR (cm−1) 2975, 2202,
1633, 1598, 1506; δH (300 MHz, CDCl3) 1.43 (6H, d, J 6.1 Hz), 3.38
(3H, br), 3.90 (3H, s), 3.94 (3H, s), 4.58 (1H, quintet, J 6.1 Hz), 6.90
(1H, d, J 8.4 Hz), 7.14 (1H, d, J 1.7 Hz), 7.23 (1H, dd, J 1.8, 8.4 Hz);
δC (75 MHz, CDCl3) 21.9, *32.5, 55.9, *62.1, 71.6, 79.9, *91.3, 111.6,
*112.1, 119.4, 126.8, 147.0, 152.5, *154.9 (* these peaks show
broadening due to conformational effects); HRMS (APCI) calculated
for [C15H20NO4]+ (MH+) m/z 278.1392 found 278.1386.
General Procedure for the Formation of Ketones 13 and
Their Iodocyclization to 25 or 15 (0.5 mmol scale). n-BuLi
(0.55 mmol, 2 M in hexanes) was added to a solution of iodoimine 21
(0.5 mmol) in dry THF (2 mL) at −78 °C, and the reaction mixture
was stirred for 10 min at this temperature. A solution of Weinreb amide
24 (0.6 mmol) in dry THF (2 mL) was then added dropwise over 5 min,
followed by stirring at −78 °C for a further 1 h. A saturated solution of
NH4Cl aq (3 mL) was then added, and the mixture was warmed to room
temperature, extracted with diethyl ether (3 × 10 mL), dried over MgSO4
and concentrated under reduced pressure. The resultant crude product 13
was dissolved in solvent (4 mL of either CH3CN or CH2Cl2; see specific
examples below). To this N-iodosuccinimide (0.6 mmol) was added, and
the reaction mixture was stirred overnight. The reaction was quenched by
addition of Na2S2O3 10% w/v (3 mL), and the mixture was extracted with
diethyl ether (3 × 7 mL). The organic extracts were combined, washed
with brine, and dried over MgSO4. The solvent was evaporated, and the
crude mixture was purified by flash chromatography.
6-Iodo-8-methoxy-11,11-diphenylisoindolo[2,1-a]quinolin-
5(11H)-one (15a) and 3-Iodo-2-phenylquinolin-4(1H)-one (25a)
(Table 3, entries 1 and 2). Iodoimine 21c (187 mg, 0.5 mmol) and
Weinreb amide 24a (113 mg, 0.6 mmol) were coupled and
iodocyclized using the general procedure for the formation of ketones
13 and their iodocyclization to 15 and 25 (above), using CH3CN in
General Procedure for the Preparation of Weinreb Amides
24a−d. This method has been adapted from that described by
Whipple and Reich,11 using 1-methoxy-1,3,3-trimethylurea in place of
I
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the iodocyclization step (Table 3, entry 1). Flash chromatography on
deactivated alumina(III) using petroleum spirit/ethyl acetate (4:1)
yielded 15a as a brown resin (120 mg, 47%) and 25a as tan solid
(63 mg, 36%). 15a: δH (300 MHz, (CD3)2SO) 7.18 (1H, d, J 8.2 Hz),
7.31−7.40 (12H, m), 7.61−7.70 (3H, m), 8.25 (1H, d, J 7.7 Hz), 9.32
(1H, d, J 7.6 Hz); δC (75 MHz, (CD3)2SO) 80.5, 80.8, 119.4, 122.0, 124.5,
124.6, 126.4, 127.6, 128.5, 128.6, 128.8, 129.4, 131.3, 131.9, 133.2, 137.7,
138.1, 150.0, 152.7, 174.2; HRMS (APCI) calculated for [C28H19INO]+
(MH+) m/z 512.0506 found 512.0481. 25a: The 1H and 13C NMR of this
material were identical to those previously reported.19
Compound 25a was selectively prepared by reacting iodoimine 21d
(169 mg, 0.5 mmol) with Weinreb amide 24a (113 mg, 0.6 mmol)
using the general procedure for the formation of ketones 13 and their
iodocyclization to 15 and 25 (above), using CH3CN in the
iodocyclization step (Table 3, entry 2). Flash chromatography on
deactivated alumina(III) using petroleum spirit/ethyl acetate gave
25a19 as tan solid (100 mg, 58%).
3-Iodo-2-(4-methoxyphenyl)quinolin-4-(1H)-one (25b)
(Table 3, entry 3). Iodoimine 21d (92.1 mg, 0.27 mmol) and
Weinreb amide 24b (66.0 mg, 0.30 mmol) were coupled and
iodocyclized using the general procedure for the formation of ketones
13 and their iodocyclization to 15 and 25 (above), using CH3CN in the
iodocyclization step. Flash chromatography on deactivated alumina(III)
using petroleum spirit/ethyl acetate (4:1) yielded 25b as a tan solid (62
mg, 61%). The 1H and 13C NMR of this material were identical to those
previously reported.19
6-Iodo-8,11(and 10,11)-dimethyoxy-11-phenylisoindolo-
[2,1-a]quinolin-5(11H)-one (15d) (Table 3, entry 4). Iodoimine
21d (57.0 mg, 0.17 mmol) and Weinreb amide 24c (44.1 mg, 0.2 mmol)
were coupled and iodocyclized using the general procedure for the
formation of ketones 13 and their iodocyclization to 15 and 25
(above), using CH2Cl2 in the iodocyclization step. Flash chromatog-
raphy on deactivated alumina(III) using petroleum spirit/ethyl acetate
(4:1) yielded 15d as a red solid (72.1 mg, 85%), comprising of a 1:1
mixture of 8/10-methoxy regioisomers. Spectra performed on
regiosiomeric mixture: δH (300 MHz, CDCl3) 3.03 (3H, s, OMe),
3.11 (3H, s), 3.81 (3H, s), 4.0 (3H, s), 7.06−7.45 (17H, m,), 7.58−
7.67 (3H, m), 8.51 (2H, m), 8.94 (1H, s), 9.03 (1H, d, J 8.0 Hz); δC
(75 MHz, CDCl3) 51.0, 51.4, 55.9, 56.0, 80.8, 80.9, 100.4, 101.2, 110.8,
114.5, 117.6, 117.7, 119.0, 119.4, 121.9, 122.0, 124.4, 124.4, 124.5, 125.1,
126.4, 127.3, 127.4, 127.8, 127.9, 128.2, 128.5, 128.8, 128.9, 129.2, 129.9,
131.4, 132.2, 132.4, 134.1, 134.4, 136.0, 137.3, 137.5, 138.2, 139.7, 148.9,
154.8, 160.6, 175.5, 175.6; HRMS (APCI) calculated for [C24H19INO3]+
(MH+) m/z 496.0404 found 496.0385. Subsequent chromatography of
the isomeric mixture 15d on silica gel provided a pure sample of the 8-
methoxy regioisomer: δH (300 MHz, (CD3)2CO) 3.03 (3H, s), 3.97 (3H,
s), 7.24 (1H, dd, J 8.5, 2.2 Hz), 7.30−7.37 (7H, m), 7.39 (1H, dt, J 8.5,
2.4 Hz), 7.50 (1H, dd, J 8.5, 2.4 Hz), 8.33 (1H, dd, J 6.7, 2.2 Hz), 8.91
(1H, d, J 2.2 Hz).
6-Iodo-8-isopropoxy-9,11-dimethoxy-11-phenylisoindolo-
[2,1-a]quinolin-5(11H)-one (15e) (Table 3, entry 5). Iodoimine
21d (41.0 mg, 0.12 mmol) and Weinreb amide 24d (42.0 mg, 0.15
mmol) were coupled and iodocyclized using the general procedure for
the formation of ketones 13 and their iodocyclization to 15 and 25
(above), using CH2Cl2 in the iodocyclization step. Flash chromatog-
raphy on deactivated alumina(III) using petroleum spirit/ethyl acetate
(4:1) yielded 15e as a pale yellow oil (57 mg, 90%): δH (300 MHz,
(CD3)2CO) 1.42 (6H, d, J 5.5 Hz), 3.05 (3H, s), 3.85 (3H, s), 4.72
(1H, quintet, J 6.0 Hz), 6.98 (1H, s,), 7.27−7.58 (9H, m), 8.32 (1H,
dd, J 1.2, 8.0 Hz), 8.91 (1H, s); δC (75 MHz, (CD3)2CO) 21.8, 21.9,
51.0, 56.3, 72.2, 79.0, 100.7, 106.6, 112.4, 117.8, 121.9, 124.2, 125.1,
125.6, 127.7, 127.8, 128.7, 129.2, 129.5, 129.6, 132.4, 138.2, 138.3,
140.5, 148.8, 150.0, 155.1, 174.7; HRMS (APCI) calculated for
[C27H25INO4]+ (MH+) m/z 554.0823 found 554.0833.
using petroleum spirit/ethyl acetate (10:1) yielded 15f as a pink solid
(67.0 mg, 59%): mp 281−284 °C; IR (cm−1) 3063, 1686, 1591, 1536,
1482; δH (300 MHz, (CD3)2SO + CH2Cl2) 3.88 (3H, s), 7.15−7.24
(2H, m), 7.28−7.39 (12H, m), 7.51 (1H, d, J 8.7 Hz), 8.25 (1H, d, J 7.6
Hz), 8.87 (1H, d, J 1.7 Hz); δC (75 MHz, (CD3)2SO + CH2Cl2) 55.6,
79.7, 80.5, 110.4, 118.8, 119.2, 121.4, 124.1, 124.9, 127.1, 128.0, 128.1,
128.8, 131.4, 132.1, 137.2, 137.8, 144.7, 149.1, 158.5, 173.6; HRMS (APCI)
calculated for [C29H21INO2]+ (MH+) m/z 542.0612 found 542.0611.
6-Iodo-8-isopropoxy-9-methoxy-11,11-diphenylisoindolo-
[2,1-a]quinolin-5(11H)-one (15g) (Table, entry 7). Iodoimine 21c
(69.0 mg, 0.18 mmol) and Weinreb amide 24d (64.1 mg, 0.22 mmol)
were coupled and iodocyclized using the general procedure for the
formation of ketones 13 and their iodocyclization to 15 and 25
(above), using CH2Cl2 in the iodocyclization step. Flash chromatog-
raphy on silica gel using petroleum spirit/ethyl acetate (4:1) yielded
15g as a pale yellow solid (102.4 mg, 95%): mp 228−231 °C; δH (300
MHz, (CD3)2SO) 1.37 (6H, d, J 6.0 Hz), 3.72 (3H, s), 4.62 (1H,
quintet, J 6.0 Hz), 7.06 (1H, s), 7.12 (1H, d, J 8.4 Hz), 7.26−7.44
(12H, m), 8.22 (1H, dd, J 1.4, 7.9 Hz), 8.86 (1H, s); δC (75 MHz,
(CD3)2SO) 21.6, 55.3, 71.2, 79.7, 106.3, 110.7, 118.5, 121.1, 122.7,
123.7, 127.0, 128.1, 128.2, 131.1, 137.3, 137.7, 146.3, 149.8, 153.8,
173.4; HRMS (APCI) calculated for [C32H27INO3]+ (MH+) m/z
600.1030 found 600.1034.
4-(8-Methyl-1,1-diphenyl-1,3,4,5-tetrahydro-[1,3]oxazepino-
[3,4-a]indol-6-yl)but-3-yn-1-ol (31). A mixture of iodoindole 9l (80
mg, 0.17 mmol), 3-butyn-1-ol (0.015 mL, 0.2 mmol) and Pd(PPh3)Cl2
(3.4 mg, 5.1 μmol) in a mixture of THF and triethylamine (3 mL, 2:1)
was deoxygenated by bubbling nitrogen through for 10 min.
Copper(I) iodide (2.6 mg, 14 μmol) was then added, and the mixture
was stirred overnight at room temperature under a nitrogen
atmosphere. After this time, NH4Cl aq (sat.) (3 mL) was added to
the reaction mixture, and the mixture was extracted with diethyl ether
(3 × 5 mL). The combined organic extracts were washed with brine
and dried over MgSO4, and the solvent was removed under reduced
pressure. Column chromatography on deactivated alumina(III) using
petroleum spirit/ethyl acetate (2:1) afforded 31 as pale yellow solid
(52 mg, 72%): mp 69−71 °C; IR (cm−1) 2947, 1448, 1398, 1318; δH (300
MHz, (CD3)2SO) 1.80 (2H, m), 2.25 (3H, s), 2.67 (2H, t, J 6.8 Hz),
3.20−3.24 (2H, m), 3.66 (2H, q, J 6.5 Hz), 3.79 (2H, t, J 7.02 Hz), 4.88
(1H, t, J 5.7 Hz), 5.91 (1H, d, J 8.5 Hz), 6.49 (1H, d, J 9.2 Hz), 7.14−7.18
(5H, m), 7.39−7.42 (6H, m); δC (75 MHz, (CD3)2CO) 21.1, 25.0, 25.3,
28.5, 62.1, 62.2, 66.0, 75.6, 91.9, 98.5, 98.6, 114.9, 119.5, 123.7, 128.9, 129.1,
129.5, 129.7, 129.8, 130.7, 136.0, 141.5, 147.3; HRMS (APCI) calculated
for [C29H28NO2]+ (MH+) m/z 422.2120 found 422.2109.
ASSOCIATED CONTENT
■
S
* Supporting Information
Spectra (1H and 13C NMR) of all new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: bernard.flynn@monash.edu.
■
Notes
The authors declare no competing financial interest.
REFERENCES
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