Further investigations into the regioselectivity of 6,7-indole aryne cyclo-additions with 2-substituted furans: Remarkable contrasteric preference depends on pyrrole and benzene ring substitution

Article abstract of DOI:10.1055/s-0033-1338911

A series of related 6,7-dibromoindole compounds were prepared to study the effects of pyrrole and benzene ring substitution patterns on the regioselectivity of 6,7-indole aryne cycloadditions with 2-tert-butylfuran. The arynes were generated by our metal-halogen exchange/elimination protocol. The results of this investigation reveal that substitution at the 3-position on the indole ring in particular results in remarkable regiocontrol that favored the contrasteric products. Aromatic conjugation at this site significantly enhanced this effect. However, the presence of most 4- or 5-substituents generally resulted in markedly reduced selectivity. Exceptions in this latter series included the 4-ethyl and 4-iodo cases both of which also gave predominantly contrasteric products even in the absence of a beneficial C-3 substituent. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0033-1338911

PAPER
▌1843
paper
Further Investigations into the Regioselectivity of 6,7-Indole Aryne Cyclo-
additions with 2-Substituted Furans: Remarkable Contrasteric Preference
Depends on Pyrrole and Benzene Ring Substitution
6,7-Indole Aryne Cycloadditions with 2-Substituted Furans
Alok Nerurkar,a Nalin Chandrasoma,a Lincoln Maina,a Allen Brassfield,a Diheng Luo,a Neil Brown,a,b
Keith R. Buszek*a,b
a
Department of Chemistry, University of Missouri, 205 Kenneth A. Spencer Chemical Laboratories, 5100 Rockhill Road, Kansas City,
MO 64110, USA
b
Center of Excellence in Chemical Methodologies and Library Development (KU-CMLD), University of Kansas,
Delbert M. Shankel Structural Biology Center, 2034 Becker Drive, Lawrence, KS 66047, USA
Fax +1(816)2355502; E-mail: buszekk@umkc.edu
Received: 24.04.2013; Accepted after revision: 16.05.2013
This paper is warmly dedicated to Professor Scott Denmark on the occasion of his 60th birthday.
ed polycyclic indole libraries.5 The value of the indole
Abstract: A series of related 6,7-dibromoindole compounds were
aryne chemistry was further validated by numerous subse-
prepared to study the effects of pyrrole and benzene ring substitu-
quent contributions from the Garg6 and Lautens7 laborato-
ries.
tion patterns on the regioselectivity of 6,7-indole aryne cycloaddi-
tions with 2-tert-butylfuran. The arynes were generated by our
metal–halogen exchange/elimination protocol. The results of this
investigation reveal that substitution at the 3-position on the indole
ring in particular results in remarkable regiocontrol that favored the
contrasteric products. Aromatic conjugation at this site significantly
enhanced this effect. However, the presence of most 4- or 5-substit-
uents generally resulted in markedly reduced selectivity. Excep-
tions in this latter series included the 4-ethyl and 4-iodo cases both
of which also gave predominantly contrasteric products even in the
absence of a beneficial C-3 substituent.
During the course of these investigations we found a re-
markable preference in the 6,7-indole aryne cycloaddi-
tions with 2-substituted furans for the more sterically
crowded or contrasteric regioisomer 2 (Table 1). By con-
trast no regiochemical preference was observed for the
other two indole arynes, namely, the 4,5- and 5,6-indole
arynes. An ab initio computational study by Buszek and
Cramer using DFT methods revealed that the 6,7-indole
aryne can be viewed appropriately as a highly polarized
bond in the manner shown (Scheme 1), with the nucleo-
philic center at C-7, and as such, cycloadditions at this site
impart substantial asynchronous electrophilic substitution
character in the initial bond forming step in the cycloaddi-
tion process.2e The calculations predicted, inter alia, that
a similar trend would be observed in the corresponding
benzofuran and benzothiophene aryne systems, and that
prediction has now been confirmed experimentally.3,4
Key words: alkaloids, arynes, cycloaddition, indoles, regioselec-
tivity
Arynes are becoming a main theme and an increasingly
common and versatile functional group in organic synthe-
sis.1 The Buszek laboratories pioneered the discovery, de-
velopment, and application of indole arynes (indolynes),2
benzofuran arynes (benzofuranynes),3 and benzothio-
phene arynes (benzothiophenynes)4 which we began re-
porting in 2007. Since that time we designed the first
general route to all of these arynes associated with the
benzene side of the aromatic nucleus via facile and selec-
tive metal–halogen exchange and elimination of their cor-
responding o-dibromo systems.2a
The original regiochemical preference with 6,7-indole
arynes was made with N-methyl-6,7-dibromo-3-phenylin-
dole (1), which exhibited a remarkable 49:1 preference for
the contrasteric isomer. The decision to use a 3-phenyl
substituent in these studies was fortuitous since it was
subsequently found that in cases in which a 3-substituent
is absent, there is sharply diminished regiocontrol. These
curious and surprising results prompted us to embark on
an empirical study to identify the type and position of var-
ious substituents on the pyrrole and benzene sides of the
indole nucleus responsible for regiocontrol in 6,7-indole
aryne cycloadditions. The results are now presented here-
with.
The practical value of this powerful new methodology is
already evident. One application in particular, namely cy-
cloadditions with 6,7-indole arynes, became a key strate-
gy in the total synthesis of several important 6,7-
benzannulated indole alkaloid natural products, including
the trikentrins and the herbindoles,2b,d,f and represented
the first use of this tactic in natural products total synthe-
sis. Additional efforts that combined 6,7-indole aryne cy-
cloadditions with various cross-coupling reactions in
4,6,7-tribromoindoles culminated in the first benzannulat-
N
N
Me
Me
SYNTHESIS 2013, 45, 1843–1852
Advanced online publication: 06.06.2013
4
5
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1338911; Art ID: SS-2013-C0341-OP
© Georg Thieme Verlag Stuttgart · New York
Scheme 1

1844
A. Nerurkar et al.
PAPER
Table 1 Regioselective 3-Phenyl-6,7-indole Aryne Cycloadditions with 2-Substituted Furansa
O
R
(5 equiv)
Ph
Ph
Ph
n-BuLi (1.2 equiv)
+
R
Et2O, –78 °C to r.t.
Br
N
N
N
Me
Me
Me
O
O
Br
R
1
2
3
Entry
R
2
3
Yield (%)
1
2
3
4
4
5
Me
4
1
1
89
90
88
91
92
83
Et
5.3
15.7
49
i-Pr
t-Bu
Ph
1
1
>99
<1
<1
SO2Ph
>99
a Reference 2e.
We first examined the effect of substituted phenyl and MeOC6H4, Table 2, entry 2). None of the other regioiso-
other groups at the C-3 position. The corresponding in- mer 8 could be detected by NMR analysis. This is a sig-
dole aryne precursors were prepared as described previ- nificant increase over a simple phenyl group. On the other
ously, using the Fischer,2a the Bartoli,8 or the hand, the less electron-rich 4-fluorophenyl case (entry 3)
Leimgruber–Batcho9 indole synthetic routes. The arynes exhibited somewhat lower regiocontrol (15.7:1) versus
were generated via metal–halogen exchange with a slight the phenyl example (49:1). The effect of these or other
excess of n-BuLi in either diethyl ether or toluene at substituents at the ortho and meta positions were not in-
–78 °C in the presence of excess 2-tert-butylfuran.10 The cluded in this study. However, there appears from just
indole aryne is then formed upon warming to about these limited examples a definitive trend by which in-
–35 °C. The reaction mixture was quenched after reaching creasingly electron-rich aryl groups at C-3 gave the great-
room temperature. The results are shown in Table 2.
est degree of regiocontrol.
It can be seen that the more electron-rich 4-methoxyphe- The issue of aromatic conjugation at the C-3 position was
nyl group gave within the limits of our analysis and detec- next examined. Here a benzyl group at that site (entry 4)
tion exclusively (>99:1) the contrasteric product 7 (R = 4- gave a substantially reduced 10:1 ratio of products com-
Table 2 Regioselective 3-Substituted 6,7-Indole Aryne Cycloadditions with 2-tert-Butylfuran
O
t-Bu
(5 equiv)
R
R
R
n-BuLi (2.0 equiv)
+
t-Bu
Br
N
N
N
PhMe, –78 °C to r.t.
Me
Me
t-Bu
Me
O
O
Br
6
7
8
Entry
R
7
8
Yield (%)
1a
2
3
4
5
6
Ph
49
>99
1
91
76
59
58
64
60
4-MeOC6H4
4-FC6H4
CH2Ph
Et
<1
1
15.7
10
1
6.1
3.0
1
H
1
a Reference 2e.
Synthesis 2013, 45, 1843–1852
© Georg Thieme Verlag Stuttgart · New York

PAPER
6,7-Indole Aryne Cycloadditions with 2-Substituted Furans
1845
Table 3 Regioselective 2-Phenyl- and 2,3-Diphenyl-6,7-indole Aryne Cycloadditions with 2-tert-Butylfuran
O
t-Bu
(5 equiv)
R1
R2
R1
R2
R1
R2
n-BuLi (2.0 equiv)
+
t-Bu
PhMe, –78 °C to r.t.
N
Br
N
N
Me
t-Bu
10
Me
O
Me
O
Br
9
11
Entry
R1
R2
10
11
Yield (%)
1a
2
Ph
H
H
49
1
1
1
1
91
61
62
60
Ph
Ph
H
9.1
6.7
3.0
3
Ph
H
4b
a Reference 2e.
b Table 2, entry 6.
pared to phenyl, indicating that conjugation appears to fa- in both of these cases metal–halogen exchange occurs ex-
vor the contrasteric product to a significant degree. clusively at the C-7 position, as confirmed by low temper-
However, the incorporation of just a simple alkyl group, ature quenching with water.2f Thus, it was possible to
for example, ethyl (entry 5), still gave a reasonable, albeit generate the 6,7-indole aryne without untoward reaction
further diminished, degree of regiocontrol (6.1:1). It is ap- at the remaining C-4 or C-5 bromine. Accordingly, these
parent from these examples that any substitution at the in- examples were chosen to investigate the effects of bro-
dole C-3 position benefits the regiochemistry in 2- mine substitution at C-4 and C-5, with and without elec-
substituted furan cycloadditions. Apparently the overall tronic contributions from a C-3 phenyl group (Table 4).
electron density at this site, either by conjugative or induc-
From this data, it can be seen that having a bromine sub-
tive effects, is the key for imparting regioselectivity. This
stituent at C-4 (entry 1) gave about the same ratio of cy-
point is further supported by entry 6 in which no substitu-
cloaddition products 13:14 as when no other substituent is
tion at C-3 results in the smallest proportion of the contr-
present (cf. Table 2, entry 6), or about 3.4:1 and 3.0:1, re-
asteric isomer, or just 3.0:1.
spectively. The reaction again favored the contrasteric
The effect of phenyl substitution at the other pyrrole posi- product. The presence of a phenyl group at C-3 only
tion, namely C-2, was next examined (Table 3). In this slightly mitigated this effect (entry 2), and gave the regio-
case (Table 3, entry 2) it was found that the regioselectiv- isomer 13 in a modestly improved 4.6:1 distribution.
ity favoring 10 was more than 5 times lower (9.1:1) than However, a much more dramatic effect was seen at the C-
having the same substituent at C-3, and was in fact similar 5 position with the bromine now adjacent to the electro-
to having a nonconjugated substituent at C-3. Interesting- philic site of the indole aryne (entry 3). In this case, virtu-
ly, incorporating conjugated phenyl group at both C-2 and ally no selectivity was observed (1.4:1), and even the
C-3 (entry 3) further diminished the selectivity (6.7:1).
presence of aromatic conjugation at C-3 (entry 4) had no
impact, with the same ratio of isomers again observed.
This observation might be rationalized by reasonably as-
suming that steric hindrance between the two phenyl The synthetic challenges associated with the introduction
groups at the adjacent positions on the pyrrole prevented of a wide variety of substituents at the C-5 position on the
effective conjugation at C-3 and thus reduced any benefi- indole ring are not trivial,11 so the foregoing examples are
cial effect of conjugation at that position. Furthermore, it necessarily limited to bromine for now. However, placing
is likely that the electronic contribution by the C-2 phenyl various groups at C-4, while still a difficult task, is at least
is primarily if not exclusively inductive since planarity synthetically tractable. Thus, a final set of cases to glean
with the pyrrole is almost certainly precluded. However, some further insight into the factors controlling 6,7-indole
even in this case, the overall effect on regiocontrol was aryne regiochemistry from the benzene side of the nucleus
again better than having no substitution at both sites.
was examined (Table 5).
With a reasonable understanding of the electronic contri- An expanded set of halogens was prepared to gauge the
butions to regiocontrol from the C-2 and C-3 sites, we impact of electronegative substituents at C-4. The 4-fluo-
turned our attention to studying substituent effects on the ro example (entry 1) gave the contrasteric isomer 16 in
benzene side of the indole ring. Our previous synthetic only a 2.3:1 ratio, compared to 3.4:1 with bromine. The
work with the trikentrin natural products gave us ready ac- much less electronegative iodine (entry 3), however, re-
cess to 4,6,7- and 5,6,7-tribromoindoles.2b,f We found that sulted in a substantially improved 15.7:1 distribution even
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1843–1852

1846
A. Nerurkar et al.
PAPER
Table 4 Regioselective 4-Bromo-, 5-Bromo-, 3-Phenyl-4-bromo-, and 3-Phenyl-5-bromo-6,7-indole Aryne Cycloadditions with 2-tert-Butylfuran
O
t-Bu
R2
R2
R2
(5 equiv)
n-BuLi (2.0 equiv)
PhMe, –78 °C to r.t.
R3
R1
R3
R1
R3
R1
+
t-Bu
Br
N
N
N
Me
Me
t-Bu
13
Me
O
O
Br
12
14
Entry
R1
R2
R3
13
14
Yield (%)
1a
2
H
Br
Br
H
H
3.4
4.6
1.4
1.4
1
1
1
1
76
76
68
62
Ph
H
H
3b
4
Br
Br
Ph
H
a Reference 5a.
b Reference 2f.
Table 5 Regioselective 4-Substituted 6,7-Indole Aryne Cycloadditions with 2-tert-Butylfuran
O
t-Bu
R
R
R
(5 equiv)
n-BuLi (2.0 equiv)
+
t-Bu
N
N
PhMe, –78 °C to r.t.
Br
N
Me
t-Bu
16
Me
O
O
Me
Br
17
15
Entry
R
16
17
Yield (%)
1
F
2.3
3.4
1
1
1
1
71
76
65
63
2a
3
Br
I
15.7
11.5
4b
Et
a Table 4, entry 1; reference 5a.
b Reference 2b.
without a C-3 phenyl group. Surprisingly, the presumably iodine especially effective in controlling regiochemistry
more inductively electron-rich ethyl alkyl group was less absent even the presence of substituents at C-3.
effective in determining the isomeric outcome (entry 4)
and gave the products 16 and 17 in a reduced but still re-
A further investigation to determine the effect of having
various protecting groups on the indole nitrogen on the
spectable 11.5 distribution. Apparently there is a subtle
course of the 6,7-indole aryne cycloaddition is also under-
but still poorly understood interplay between conjugative
way. However, we previously noted that N-sulfonyl
groups apparently preclude any metal–halogen exchange
and inductive effects at least with the halogens that render
O
t-Bu
(5 equiv)
Ph
+
Ph
Ph
Ph
n-BuLi (2.2 equiv)
t-Bu
Et2O, –78 °C to r.t.
N
N
Br
N
N
H
H
H
O
O
Br
t-Bu
20
18
19
21
(1:5.5)
Scheme 2
Synthesis 2013, 45, 1843–1852
© Georg Thieme Verlag Stuttgart · New York

PAPER
6,7-Indole Aryne Cycloadditions with 2-Substituted Furans
1847
give 6,7-dibromo-3-ethyl-1H-indole as a yellow oil; yield: 273 mg
(48%).
1H NMR: δ = 8.04 (br s, 1 H), 7.34 (d, J = 7.9 Hz, 1 H), 7.22 (d,
J = 7.9 Hz, 1 H), 7.09 (s, 1 H), 2.68 (q, J = 8.2 Hz, 2 H), 1.25 (t,
J = 8.2 Hz, 3 H).
and consequently aryne formation by this method. Curi-
ously, when no protecting group is used, the observed re-
giochemistry is reversed, favoring the opposite
regioisomer to some degree (Scheme 2).
In summary, it has been demonstrated that having a sub-
stituent at either position of the pyrrole ring of the indole
nucleus substantially enhances the regiochemistry in 6,7-
indole aryne cycloadditions with 2-tert-butylfuran and
greatly favors the contrasteric product. However, substi-
tution on the benzene side of the aromatic system results
in most cases in a significant diminution of regiocontrol.
Except in the notable examples of iodine and alkyl group
substitution at C-4, having an additional group at the C-3
site generally does not mitigate the effect of benzene sub-
stitution.
13C NMR: δ = 136.16, 126.92, 123.84, 121.57, 120.36, 119.02,
117.15, 106.98, 18.36, 14.35.
HRMS (EI): m/z calcd for C10H9Br2N: 300.9101; found: 300.9111.
6,7-Dibromo-3-(4-methoxyphenyl)-1H-indole
Obtained as above from the reaction between 2,3-dibromophenyl-
hydrazine and 2-(4-methoxyphenyl)acetaldehyde; yield: 65 mg
(62%); yellow oil.
1H NMR: δ = 8.08 (br s, 1 H), 7.79 (s, 1 H), 7.61 (dd, J = 2.0, 6.8
Hz, 2 H), 7.53 (dd, J = 2.5, 7.2 Hz, 1 H), 7.12 (m, 1 H), 6.92 (dd,
J = 2.0, 6.8 Hz, 2 H), 3.84 (s, 3 H).
13C NMR: δ = 158.41, 136.34, 128.74, 128.62, 126.94, 124.78,
The results from the previous 6,7-dehydrobenzofuran cy-
cloaddition studies3 in which a high degree of regiocontrol
is seen favoring the corresponding contrasteric product
(e.g., 11.5:1 for 2-tert-butylfuran; >99:1 for 2-phenylfu-
ran), even without having substitution anywhere else on
its aromatic nucleus, suggests that the indole system has
unique electronic properties that are highly sensitive to
aromatic substitution patterns. The origin of these differ-
ences is currently being investigated both computationally
and experimentally by this laboratory and will be reported
in due course.
122.73, 122.04, 119.88, 117.56, 114.32, 113.89, 55.34.
HRMS (EI): m/z calcd for C15H11Br2NO: 378.9207; found:
378.9205.
6,7-Dibromo-3-(4-fluorophenyl)-1H-indole
Obtained as above from the reaction between 2,3-dibromophenyl-
hydrazine and 4-fluorophenylacetaldehyde as an orange oil; yield:
263 mg (38%).
1H NMR: δ = 8.46 (br s, 1 H), 7.65 (dd, J = 0.7, 8.4 Hz, 1 H), 7.55
(dd, J = 5.5, 8.9 Hz, 2 H), 7.41 (d, J = 8.4 Hz, 1 H), 7.36 (d, J = 2.7
Hz, 1 H), 7.16 (app t, J = 8.9 Hz, 2 H).
13C NMR: δ = 162.98, 160.53, 130.49 (d, J = 3.7 Hz), 129.07 (d,
J = 8.1 Hz), 125.41, 125.10, 122.43, 119.71, 119.01, 117.87, 115.91
(d, J = 22.1 Hz), 107.52.
1H NMR (400 MHz) and 13C NMR (100 MHz) were performed in
CDCl3 unless otherwise noted with reference to residual solvent at
δ = 7.26 and 77.0, respectively. Melting points when reported are
uncorrected. Unless otherwise noted all commercially available
starting materials were used as received. Alkyllithiums were titrated
against butan-2-ol in anhyd THF with 1,10-phenanthroline as an in-
dicator prior to use. THF was distilled from sodium and benzophe-
none under N2 prior to use. Toluene was distilled from CaH2 under
N2 prior to use. Temperatures of –78 °C were obtained through the
use of a dry ice/acetone cold bath. All reactions were carried out un-
der an inert atmosphere unless otherwise noted.
HRMS (EI): m/z calcd for C14H8FBr2N: 366.9007; found: 366.9000.
3-Benzyl-6,7-dibromo-1H-indole
Obtained as above from the reaction between 2,3-dibromophenyl-
hydrazine and 2-phenylpropionaldehyde as a brown oil; yield: 281
mg (40%).
1H NMR: δ = 8.12 (br s, 1 H), 7.32–7.20 (m, 7 H), 6.94 (s, 1 H), 4.06
(s, 2 H).
13C NMR: δ = 140.37, 136.21, 128.48, 128.40, 127.06, 126.08,
124.13, 123.39, 119.34, 117.33, 117.23, 107.07, 31.43.
N-Methyl-6,7-dibromo-3-phenylindole (1) and Its Benzannulat-
ed Cycloaddducts 2 and 3
HRMS (EI): m/z calcd for C15H11Br2N: 362.9258; found: 362.9261.
The preparation of the aryne precursor N-methyl-6,7-dibromo-3-
phenylindole (1) and the methods for its aryne generation via
metal–halogen exchange have been reported.2a The physical and
spectral data for the cycloadducts 2 and 3 have likewise appeared
previously.2e
6,7-Dibromo-1H-indole
Prepared via the Bartoli indole synthesis as follows: In a 250 mL
flame-dried round-bottom flask under argon was dissolved 1,2-di-
bromo-3-nitrobenzene (489 mg, 1.74 mmol) in THF (20 mL) and
the solution cooled to –40 °C. To this stirred solution was added in
one portion vinylmagnesium bromide (10.4 mL, 1 M, 10.4 equiv).
The reaction mixture was stirred at –40 °C for 1 h, then quenched
with aq NH4Cl (100 mL) and the flask warmed to r.t. The mixture
was extracted with Et2O (3 × 50 mL) and the combined organic lay-
ers washed with H2O (1 × 50 mL) and brine (1 × 25 mL), then dried
(MgSO4). The solution was filtered and concentrated under reduced
pressure. The residue was purified via flash chromatography on sil-
ica gel using 10% EtOAc in hexanes to afford a white solid; mp
93.6–94.3 °C; yield: 230 mg (47%).
3-Substituted 6,7-Dibromoindoles; 6,7-Dibromo-3-ethyl-1H-in-
dole; Typical Procedure
The 3-substituted 6,7-dibromoindoles were generally prepared via
the Fischer indole route. In a tube was added 2,3-dibromophenylhy-
drazine (500 mg 1.88 mmol). This was dissolved in EtOH (20 mL).
To the stirred solution was added butyraldehyde (0.20 mL, 2.26
mmol, 1.20 equiv). The tube was sealed and the mixture was heated
to 100 °C for 3 h, then cooled to r.t. and the contents were concen-
trated under reduced pressure. The residue was diluted with tert-bu-
tyl methyl ether (TBME, 25 mL) and the organic layer was washed
with aq NaHCO3 (10 mL), H2O (10 mL), and brine (10 mL). The
organic layer was dried (MgSO4), filtered, and concentrated under
reduced pressure. The residue was purified via flash column chro-
matography on silica gel using 20% TBME in hexanes as eluent to
1H NMR: δ = 8.36 (br s, 1 H), 7.45 (d, J = 8.3 Hz, 1 H), 7.34 (d,
J = 8.3 Hz, 1 H), 7.24 (app t, J = 2.8 Hz, 1 H), 6.62 (dd, J = 2.0, 3.2
Hz, 1 H).
13C NMR: δ = 135.78, 127.43, 125.26, 124.64, 120.78, 117.27,
107.07, 104.14.
HRMS (EI): m/z calcd for C8H5Br2N: 272.8789; found: 272.8790.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1843–1852

1848
A. Nerurkar et al.
PAPER
N-Methylated Indoles; 6,7-Dibromo-3-(4-methoxyphenyl)-1-
methyl-1H-indole (6; R = 4-MeOC6H4); Typical Procedure
In a 50 mL flame-dried round-bottomed flask under argon was add-
ed 6,7-dibromo-3-(4-methoxyphenyl)-1H-indole (300 mg, 0.79
mmol). This was dissolved in anhyd THF (20 mL) and to this solu-
tion was added dry NaH (38 mg, 1.56 mmol, 2.0 equiv). The solu-
tion was stirred at r.t. for 30 min, and then MeI (0.10 mL, 1.56
mmol, 2.0 equiv) was added via syringe. The resulting solution was
stirred for 1 h, and then quenched by dropwise addition of aq NH4Cl
(25 mL). The aqueous mixture was extracted with Et2O (3 × 25
mL). The combined organic layers were dried (MgSO4), filtered,
and concentrated under reduced pressure. The residue was purified
via flash column chromatography on silica gel using 20% TBME in
hexanes as eluent to give 6,7-dibromo-3-(4-methoxyphenyl)-1-
methyl-1H-indole as a yellow oil; yield: 268 mg (86%).
Indole Aryne Generation from o-Dibromoindoles and Trapping
with 2-Substituted Furans; 9-(tert-Butyl)-3-ethyl-1-methyl-6,9-
dihydro-1H-6,9-epoxybenzo[g]indole (7) (Table 2, Entry 5);
Typical Procedure
A flame-dried 50 mL round-bottomed flask was charged with anhyd
toluene (20 mL), 6,7-dibromo-3-ethyl-1-methyl-1H-indole (109
mg, 0.35 mmol), and 2-tert-butylfuran (0.25 mL, 1.75 mmol, 5
equiv) under an atmosphere of argon, and the resulting mixture was
cooled to –78 °C. To this cold solution was added n-BuLi (16 μL,
2.6 M, 0.42 mmol, 1.2 equiv) in toluene dropwise, and the solution
was stirred at –78 °C for 30 min. The cold bath was removed and
the solution was allowed to warm slowly to r.t. over 1 h. The reac-
tion was quenched with aq NH4Cl (25 mL) and the aqueous layer
was extracted with Et2O (3 × 25 mL). The combined organic layers
were dried (MgSO4), filtered, and concentrated under reduced pres-
sure. The residue was purified by flash column chromatography on
silica gel using 20% TBME in hexanes as eluent; yield: 53 mg
(55%); yellow oil. All purified products were obtained as solids, or
clear to slightly colored oils or foams (Table 2).
1H NMR: δ = 7.60 (d, J = 8.6 Hz, 1 H), 7.45 (d, J = 8.4 Hz, 2 H),
7.36 (d, J = 8.6 Hz, 1 H), 7.05 (s, 1 H), 6.99 (d, J = 8.4 Hz, 2 H),
4.19 (s, 3 H), 3.86 (s, 3 H).
13C NMR: δ = 158.34, 130.05, 129.68, 128.82, 128.09, 126.67,
124.81, 119.88, 119.82, 116.40, 114.28, 106.79, 55.32, 37.77.
1H NMR: δ = 7.30 (d, J = 7.4 Hz, 1 H), 7.19 (m, 2 H), 7.10 (d,
J = 5.5 Hz, 1 H), 6.75 (s, 1 H), 5.79 (d, J = 1.5 Hz, 1 H), 3.94 (s, 3
H), 2.78 (q, J = 7.8 Hz, 2 H), 1.53 (s, 9 H), 1.38 (t, J = 7.8 Hz, 3H).
HRMS (EI): m/z calcd for C16H13Br2NO: 392.9364; found:
392.9366.
13C NMR: δ = 147.83, 145.80, 142.62, 134.66, 133.93, 130.75,
129.74, 118.16, 115.55, 112.66, 104.41, 81.83, 39.41, 33.33, 29.43,
18.14, 13.94.
6,7-Dibromo-3-(4-fluorophenyl)-1-methyl-1H-indole (6; R = 4-
FC6H4)
Obtained as above from 6,7-dibromo-3-(4-fluorophenyl)-1H-indole
as a colorless oil; yield: 42 mg (92%).
HRMS (EI): m/z calcd for C19H23NO: 281.1781; found: 281.1788.
6-(tert-Butyl)-3-ethyl-1-methyl-6,9-dihydro-1H-6,9-epoxyben-
zo[g]indole (8) (Table 2, Entry 5)
1H NMR: δ = 7.56 (d, J = 8.6 Hz, 1 H), 7.49 (m, 2 H), 7.38 (d, J =
8.6 Hz, 1 H), 7.14 (app t, J = 8.6 Hz, 2 H), 7.09 (s, 1 H), 4.21 (s, 3 H).
13C NMR: δ = 162.85, 160.41, 134.98, 130.02 (d, J = 3.7 Hz),
129.14 (d, J = 8.1 Hz), 128.24, 127.85, 125.05, 120.01, 119.63,
115.71 (d, J = 21.4 Hz), 106.92, 37.85.
Yield: 9 mg (9%); yellow oil.
1H NMR: δ = 7.29 (d, J = 7.9 Hz, 1 H), 7.18 (d, J = 7.9 Hz, 1 H),
7.08 (m, 2 H), 6.71 (s, 1 H), 6.21 (d, J = 1.6 Hz, 1 H), 3.84 (s, 3 H),
2.71 (q, J = 7.5 Hz, 2 H), 1.34 (s, 9 H), 1.28 (t, J = 7.5 Hz, 3 H).
HRMS (EI): m/z calcd for C15H10FBr2N: 380.9164; found:
380.9169.
13C NMR: δ = 144.53, 144.31, 143.67, 134.28, 131.94, 127.67,
126.91, 117.49, 114.45, 113.84, 100.02, 79.82, 34.55, 32.58, 26.81,
18.30, 14.50.
6,7-Dibromo-1-methyl-3-benzyl-1H-indole (6; R = CH2Ph)
Obtained as above as an orange solid; yield: 394 mg (98%); mp 78–
81 °C.
1H NMR: δ = 7.35–7.24 (m, 7 H), 6.67 (s, 1 H), 4.03 (s, 2 H), 4.00
HRMS (EI): m/z calcd for C19H23NO: 281.1781; found: 281.1786.
9-(tert-Butyl)-3-(4-methoxyphenyl)-1-methyl-6,9-dihydro-1H-
6,9-epoxybenzo[g]indole (7) (Table 2, Entry 2)
Yield: 34 mg (76%); off-white solid; mp 133–135 °C.
1H NMR: δ = 7.50–7.47 (m, 4 H), 7.15 (dd, J = 2.2, 5.5 Hz, 2 H),
7.05 (d, J = 5.5 Hz, 1 H), 7.00 (m, 1 H), 6.97 (d, J = 2.2 Hz, 1 H),
5.72 (d, J = 1.8 Hz, 1 H), 4.00 (s, 3 H), 3.86 (s, 3 H), 1.47 (s, 9 H).
(s, 3 H).
13C NMR: δ = 140.37, 134.59, 130.77, 129.26, 128.40, 128.27,
125.95, 123.87, 119.33, 119.14, 113.85, 106.38, 37.15, 30.94.
HRMS (EI): m/z calcd for C16H13Br2N: 376.9415; found: 376.9418.
13C NMR: δ = 158.11, 148.32, 146.01, 142.62, 134.61, 134.32,
130.41, 129.31, 129.10, 127.57, 117.58, 116.64, 114.08, 113.52,
104.66, 81.84, 55.31, 39.71, 33.39, 29.46.
6,7-Dibromo-3-ethyl-1-methyl-1H-indole (6; R = Et)
Obtained as above from 6,7-dibromo-3-ethyl-1H-indole as a yellow
oil; yield: 343 mg (82%).
HRMS (EI): m/z calcd for C24H25NO: 359.1887; found: 359.1880.
1H NMR: δ = 7.35 (d, J = 8.2 Hz, 1 H), 7.31 (d, J = 8.2 Hz, 1 H),
6.76 (s, 1 H), 4.09 (s, 3 H), 2.71 (q, J = 7.4 Hz, 2 H), 1.31 (t, J = 7.4
Hz, 3 H).
9-(tert-Butyl)-3-(4-fluorophenyl)-1-methyl-6,9-dihydro-1H-6,9-
epoxybenzo[g]indole (7) (Table 2, Entry 3)
Yield: 21 mg (42%); pale yellow oil.
13C NMR: δ = 134.63, 129.41, 129.19, 123.65, 119.24, 118.97,
1H NMR: δ = 7.53–7.47 (m, 3 H), 7.19–7.11 (m, 4 H), 7.07 (d, J =
5.6 Hz, 1 H), 7.00 (s, 1 H), 5.75 (d, J = 1.8 Hz, 1 H), 4.01 (s, 3 H),
1.48 (s, 9 H).
116.98, 106.38, 37.21, 17.77, 14.30.
HRMS (EI): m/z calcd for C11H11Br2N: 314.9258; found: 314.9264.
6,7-Dibromo-1-methyl-1H-indole (6; R = H)
Obtained as above from 6,7-dibromo-1H-indole as a yellow oil;
yield: 173 mg (72%).
1H NMR: δ = 7.38 (d, J = 8.4 Hz, 1 H), 7.31 (d, J = 8.4 Hz, 1 H),
6.98 (d, J = 3.2 Hz, 1 H), 6.40 (d, J = 3.2 Hz, 1 H), 4.15 (s, 3 H).
13C NMR: δ = 162.73, 160.30, 148.58, 146.04, 142.59, 134.56 (d,
J = 5.9 Hz), 131.08 (d, J = 3.7 Hz), 130.74, 129.42 (d, J = 8.1 Hz),
129.044, 116.98, 116.43, 115.48 (d, J = 21.4 Hz), 113.72, 104.71,
81.83, 39.73, 33.39, 29.47.
HRMS (EI): m/z calcd for C23H22FNO: 347.1687; found: 347.1680.
13C NMR: δ = 134.43, 132.54, 130.14, 124.58, 121.03, 119.37,
6-(tert-Butyl)-3-(4-fluorophenyl)-1-methyl-6,9-dihydro-1H-6,9-
epoxybenzo[g]indole (8) (Table 2, Entry 3)
Yield: 3 mg (3%); green oil.
106.57, 101.18, 37.73.
HRMS (EI): m/z calcd for C9H7Br2N: 286.8945; found: 286.8950.
Synthesis 2013, 45, 1843–1852
© Georg Thieme Verlag Stuttgart · New York

PAPER
6,7-Indole Aryne Cycloadditions with 2-Substituted Furans
1849
1H NMR: δ = 8.04 (d, J = 8.2 Hz, 1 H), 7.82 (d, J = 8.2 Hz, 1 H),
7.56 (m, 3 H), 7.32 (m, 1 H), 7.22-7.14 (m, 3 H), 6.42 (d, J = 9.4 Hz,
1 H), 3.89 (s, 3 H), 1.35 (s, 9 H).
13C NMR: δ = 162.54, 149.22, 145.10, 142.11, 136.63, 136.50,
131.11, 130.32, 127.65, 126.64, 126.30, 117.88, 117.86, 116.10,
104.89, 80.71, 37.02, 37.11, 26.67.
(3 × 25 mL). The combined organic layers were neutralized with aq
2 M NaOH, and washed with H2O (20 mL) and brine (20 mL). The
organic layer was dried (MgSO4), filtered, and concentrated under
reduced pressure. The residue was purified by flash column chro-
matography on silica gel using 20% TBME in hexanes as eluent to
give 6,7-dibromo-2-phenyl-1H-indole as a yellow foam; yield: 271
mg (41%).
HRMS (EI): m/z calcd for C23H22FNO: 347.1687; found: 347.1685.
1H NMR: δ = 8.47 (br s, 1 H), 7.71 (d, J = 9.7 Hz, 1 H), 7.51–7.34
(m, 6 H), 6.87 (s, 1 H).
13C NMR: δ = 139.13, 136.58, 131.33, 129.14, 128.72, 128.40,
125.33, 125.05, 120.59, 117.29, 106.88, 101.03.
3-Benzyl-9-(tert-butyl)-1-methyl-6,9-dihydro-1H-6,9-epoxy-
benzo[g]indole (7) (Table 2, Entry 4)
Yield: 48 mg (53%); pink oil.
1H NMR: δ = 7.28 (m, 5 H), 7.17 (d, J = 7.4 Hz, 1 H), 7.12 (dd,
J = 1.9, 5.9 Hz, 1 H), 7.07 (d, J = 7.4 Hz, 1 H), 7.01 (d, J = 5.9 Hz,
1 H), 6.54 (s, 1 H), 5.69 (d, J = 2.0 Hz, 1 H), 4.01 (s, 2 H), 3.86 (s,
3 H), 1.43 (s, 9 H).
13C NMR: δ = 148.07, 145.92, 142.56, 140.67, 134.62, 133.95,
131.53, 130.72, 128.70, 128.30, 125.88, 115.92, 115.39, 112.83,
104.49, 81.89, 39.49, 33.34, 31.45, 29.44.
HRMS (EI): m/z calcd for C14H9Br2N: 348.9102; found: 348.9106.
6,7-Dibromo-2,3-diphenyl-1H-indole
Obtained as above from the reaction of 2,3-dibromophenylhydra-
zine and deoxybenzoin as a light yellow foam; yield: 312 mg (39%).
1H NMR: δ = 8.46 (br s, 1 H), 7.45 (m, 4 H), 7.38–7.29 (m, 8 H).
13C NMR: δ = 137.88, 135.98, 133.85, 132.86, 130.46, 129.34,
128.75, 128.58, 128.30, 127.23, 126.04, 125.29, 121.70, 121.15,
116.52, 111.33.
HRMS (EI): m/z calcd for C24H25NO: 343.1938; found: 343.1944.
3-Benzyl-6-(tert-butyl)-1-methyl-6,9-dihydro-1H-6,9-epoxy-
benzo[g]indole (8) (Table 2, Entry 4)
Yield: 5 mg (6%); pink oil.
1H NMR: δ = 7.26 (m, 5 H), 7.09 (m, 4 H), 6.56 (s, 1 H), 6.20 (d,
J = 1.6 Hz, 1 H), 4.02 (s, 2 H), 3.83 (s, 3 H), 1.32 (s, 9 H).
13C NMR: δ = 144.54, 144.27, 143.85, 141.13, 134.28, 132.01,
128.68, 128.41, 128.30, 127.60, 125.81, 114.65, 114.52, 114.15,
99.97, 79.86, 34.68, 32.55, 31.58, 26.79.
HRMS (EI): m/z calcd for C20H13Br2N: 424.9415; found: 424.9406.
6,7-Dibromo-1-methyl-3-phenyl-1H-indole (9; R1 = Ph, R2 = H)
For preparation, see reference 2e.
6,7-Dibromo-1-methyl-2-phenyl-1H-indole (9; R1 = H, R2 = Ph)
Obtained as above by methylation of 6,7-dibromo-2-phenyl-1H-in-
dole as yellow foam; yield: 327 mg (79%).
1H NMR: δ = 7.41–7.20 (m, 7 H), 6.42 (s, 1 H), 3.93 (s, 3 H).
13C NMR: δ = 144.69, 136.69, 132.05, 129.75, 129.59, 128.56,
128.38, 125.20, 120.56, 119.65, 107.00, 102.62, 35.49.
HRMS (EI): m/z calcd for C24H25NO: 343.1938; found: 343.1937.
9-(tert-Butyl)-1-methyl-6,9-dihydro-1H-6,9-epoxybenzo[g]in-
dole (7) (Table 2, Entry 6)
Yield: 39 mg (45%); yellow oil.
HRMS (EI): m/z calcd for C15H11Br2N: 362.9258; found: 362.9266.
1H NMR: δ = 7.28 (d, J = 2.9 Hz, 1 H), 7.15 (dd, J = 1.8, 5.6 Hz, 1
H), 7.11 (d, J = 7.3 Hz, 1 H), 7.04 (d, J = 5.6 Hz, 1 H), 6.91 (d,
J = 3.1 Hz, 1 H), 6.48 (d, J = 3.1 Hz, 1 H), 5.71 (d, J = 1.5 Hz, 1 H),
3.97 (s, 3 H), 1.46 (s, 9 H).
13C NMR (CD3CN): δ = 149.54, 147.00, 143.74, 135.41, 134.99,
134.34, 118.44, 118.38, 114.18, 105.59, 103.16, 82.65, 40.24,
34.17, 29.80.
6,7-Dibromo-1-methyl-2,3-diphenyl-1H-indole (9; R1 = R2 = Ph)
Obtained as above by methylation of from 6,7-dibromo-2,3-diphe-
nyl-1H-indole as light yellow foam; yield: 323 mg (78%).
1H NMR: δ = 7.52 (d, J = 8.6 Hz, 1 H), 7.49 (d, J = 8.6 Hz, 1 H),
7.37 (m, 4 H), 7.29–7.24 (m, 4 H), 7.19 (m, 3 H), 4.01 (s, 3 H).
13C NMR: δ = 140.72, 135.78, 133.93, 131.19, 131.16, 129.91,
128.45, 128.43, 128.41, 128.25, 126.09, 125.28, 120.15, 119.65,
115.82, 106.95, 35.24.
HRMS (EI): m/z calcd for C17H19NO: 253.1468; found: 253.1466.
HRMS (EI): m/z calcd for C21H15Br2N: 438.9572; found: 438.9568.
6-(tert-Butyl)-1-methyl-6,9-dihydro-1H-6,9-epoxybenzo[g]in-
dole (8) (Table 2, Entry 6)
9-(tert-Butyl)-1-methyl-2-phenyl-6,9-dihydro-1H-6,9-epoxy-
benzo[g]indole (10) (Table 3, Entry 2)
Yield: 37 mg (55%); pale yellow foam.
1H NMR: δ = 7.56–7.08 (m, 9 H), 6.62 (s, 1 H), 5.71 (d, J = 1.6 Hz,
3 H), 3.56 (s, 3 H), 1.45 (s, 9 H).
13C NMR: δ = 147.97, 147.46, 146.19, 142.01, 139.72, 135.66,
132.61, 130.96, 128.80, 128.55, 127.91, 117.12, 114.33, 104.68,
103.79, 81.45, 39.55, 33.97, 29.14.
Yield: 14 mg (16%); yellow oil.
1H NMR: δ = 7.31 (d, J = 7.9 Hz, 1 H), 7.21 (d, J = 7.9 Hz, 1 H),
7.09 (d, J = 5.6 Hz, 1 H), 7.07 (dd, J = 1.8, 5.6 Hz, 1 H), 6.93 (d,
J = 3.2 Hz, 1 H), 6.39 (d, J = 3.2 Hz, 1 H), 6.22 (d, J = 1.8 Hz, 1 H),
3.90 (s, 3 H), 1.34 (s, 9 H).
13C NMR: δ = 144.53, 144.41, 143.80, 134.40, 131.52, 130.42,
128.11, 116.30, 114.65, 101.17, 100.05, 79.89, 34.92, 32.56, 26.79.
HRMS (EI): m/z calcd for C17H19NO: 253.1468; found: 253.1470.
HRMS (EI): m/z calcd for C23H23NO: 329.1781; found: 329.1788.
6,7-Dibromo-2-phenylindole and 6,7-Dibromo-2,3-diphenylin-
dole via Fischer Indole Synthesis; 6,7-Dibromo-2-phenyl-1H-in-
dole; Typical Procedure
6-(tert-Butyl)-1-methyl-2-phenyl-6,9-dihydro-1H-6,9-epoxy-
benzo[g]indole (11) (Table 3, Entry 2)
Yield: 4 mg (6%); pale yellow foam.
In a 50 mL round-bottomed flask under argon was added 2,3-dibro-
mophenylhydrazine (500 mg, 1.88 mmol). This was dissolved in
EtOH (5 mL). To this were added acetophenone (0.22 mL, 1.88
mmol, 1.0 equiv) and a few drops of glacial AcOH. The reaction
mixture was heated to reflux for 2 h, then cooled to r.t. and concen-
trated under reduced pressure to obtain the hydrazone intermediate.
The hydrazone was added to polyphosphoric acid (5 g) and heated
to 120 °C for 2 h. The reaction mixture was then cooled to r.t. and
poured over ice. The aqueous mixture was extracted with CH2Cl2
1H NMR: δ = 8.09–7.22 (m, 9 H), 6.49 (s, 1 H), 6.31 (d, J = 0.8 Hz,
1 H), 3.84 (s, 3 H), 1.36 (s, 9 H).
13C NMR: δ = 147.87, 144.54, 144.32, 142.94, 136.13, 128.79,
128.75, 128.45, 127.44, 125.63, 121.34, 115.92, 115.13, 102.09,
100.40, 80.07, 39.13, 33.10, 32.14, 39.55.
HRMS (EI): m/z calcd for C23H23NO: 329.1781; found: 329.1789.
Synthesis 2013, 45, 1843–1852
© Georg Thieme Verlag Stuttgart · New York

1850
A. Nerurkar et al.
PAPER
9-(tert-Butyl)-1-methyl-2,3-diphenyl-6,9-dihydro-1H-6,9-ep-
oxybenzo[g]indole (10) (Table 3, Entry 3)
Yield: 54 mg (53%); yellow foam.
1H NMR: δ = 7.33–7.27 (m, 11 H), 7.15 (m, 2 H), 7.07 (d, J = 5.5
Hz, 1 H), 5.71 (d, J = 1.6, 1 H), 3.53 (s, 3 H), 1.46 (s, 9 H).
13C NMR: δ = 148.43, 146.22, 142.95, 142.18, 138.24, 135.69,
135.07, 131.80, 130.94, 130.74, 130.02, 128.29, 128.21, 127.80,
125.98, 117.78, 116.29, 114.28, 104.03, 81.46, 39.25, 34.04, 29.28.
HRMS (EI): m/z calcd for C17H18BrNO: 331.0572; found:
331.0575.
4-Bromo-6-(tert-butyl)-1-methyl-6,9-dihydro-1H-6,9-epoxy-
benzo[g]indole (14) (Table 4, Entry 1)
Yield: 11 mg (17%); yellow oil.
1H NMR: δ = 7.46 (s, 1 H), 7.07 (m, 2 H), 6.95 (d, J = 3.1 Hz, 1 H),
6.42 (d, J = 3.1 Hz, 1 H), 6.18 (m, 1 H), 3.98 (s, 3 H), 1.30 (s, 9 H).
13C NMR: δ = 145.60, 144.61, 144.23, 134.17, 131.00, 128.17,
HRMS (EI): m/z calcd for C29H27NO: 405.2094; found: 405.2099.
122.95, 117.93, 109.88, 101.66, 100.07, 79.77, 35.14, 29.72, 26.73.
6-(tert-Butyl)-1-methyl-2,3-diphenyl-6,9-dihydro-1H-6,9-ep-
oxybenzo[g]indole (11) (Table 3, Entry 3)
Yield: 9 mg (9%); yellow foam.
1H NMR: δ = 7.31 (m, 2 H), 7.23–7.17 (m, 10 H), 7.09 (m, 2 H),
6.32 (d, J = 0.9 Hz, 1 H), 3.77 (s, 3 H), 1.37 (s, 9 H).
13C NMR: δ = 144.70, 146.56, 142.32, 139.02, 135.14, 134.67,
132.36, 131.54, 131.10, 129.84, 128.38, 128.11, 126.51, 125.56,
117.84, 115.29, 115.15, 100.33, 100.06, 80.25, 32.83, 32.56, 29.66.
HRMS (EI): m/z calcd for C17H18BrNO: 331.0572; found:
331.0577.
4-Bromo-9-(tert-butyl)-1-methyl-3-phenyl-6,9-dihydro-1H-6,9-
epoxybenzo[g]indole (13) (Table 4, Entry 2)
Yield: 46 mg (62%); off-white solid; mp 154–156 °C.
1H NMR: δ = 7.40 (m, 3 H), 7.35(m, 3 H), 7.30 (s, 1 H), 7.12 (dd,
J = 1.8, 2.3 Hz, 1 H), 7.05 (d, J = 5.5 Hz, 1 H), 5.67 (d, J = 1.8 Hz,
1 H), 3.96 (s, 3 H), 1.45 (s, 9 H).
HRMS (EI): m/z calcd for C29H27NO: 405.2094; found: 405.2090.
13C NMR: δ = 149.47, 145.78, 142.54, 135.46, 135.05, 134.22,
133.76, 131.41, 127.05, 126.62, 126.46, 119.06, 118.69, 110.77,
104.94, 81.32, 39.71, 33.60, 29.52.
5,6,7-Tribromoindoles via Leimgruber–Batcho Indole Synthe-
sis
These compounds were prepared according to references 2f and 5a.
HRMS (EI): m/z calcd for C23H22BrNO: 407.0886; found:
407.0890.
5,6,7-Tribromo-1H-indole
For preparation, see reference 2f.
4-Bromo-6-(tert-butyl)-1-methyl-3-phenyl-6,9-dihydro-1H-6,9-
epoxybenzo[g]indole (14) (Table 4, Entry 2)
Yield: 10 mg (14%); off-white solid; mp 185–187 °C.
1H NMR: δ = 7.49 (s, 1 H), 7.40 (m, 2 H), 7.35 (m, 3 H), 7.09 (m, 2
H), 6.94 (s, 1 H), 6.24 (d, J = 1.8 Hz, 1 H), 3.92 (s, 3 H), 1.33 (s, 9
4,6,7-Tribromo-1-methyl-1H-indole (12; R1 = R3 = H; R2 = Br)
For preparation see, reference 5a.
4,6,7-Tribromo-1-methyl-3-phenyl-1H-indole (12; R1 = Ph, R2 =
Br; R3 = H)
Yield: 132 mg (84%); yellow oil.
1H NMR: δ = 7.54 (s, 1 H), 7.41–7.26 (m, 5 H), 6.99 (s, 1 H), 4.2 (s,
3 H).
13C NMR: δ = 134.75, 133.69, 133.06, 131.45, 130.03, 128.41,
127.22, 126.97, 119.46, 118.12, 114.01, 106.26, 38.22.
H).
13C NMR: δ = 145.71, 144.66, 144.16, 134.71, 134.42, 132.34,
131.39, 131.09, 127.12, 126.52, 124.03, 119.96, 118.22, 109.74,
100.05, 79.99, 35.13, 32.52, 26.72.
HRMS (EI): m/z calcd for C23H22BrNO: 407.0886; found:
407.0889.
HRMS (EI): m/z calcd for C15H10Br3N: 440.8363; found: 440.8370.
5-Bromo-9-(tert-butyl)-1-methyl-6,9-dihydro-1H-6,9-epoxy-
benzo[g]indole (13) (Table 4, Entry 3)
5,6,7-Tribromo-1-methyl-1H-indole (12; R1 = R2 = H, R3 = Br)
Yield: 338 mg (82%); white solid; mp 147–149 °C.
1H NMR: δ = 7.87 (s, 1 H), 7.04 (d, J = 3.1 Hz, 1 H), 6.65 (d, J = 3.1
Hz, 1 H), 3.76 (s, 3 H).
13C NMR: δ = 136.21, 131.70, 126.61, 123.98, 120.85, 120.63,
109.77, 99.13, 35.70.
Yield: 34 mg (39%); yellow oil.
1H NMR: δ = 7.36 (s, 1 H), 7.19 (dd, J = 1.8, 5.5 Hz, 1 H), 7.04 (d,
J = 5.5 Hz, 1 H), 6.91 (d, J = 3.3 Hz, 1 H), 6.39 (d, J = 3.3 Hz, 1 H),
5.91 (d, J = 1.9 Hz, 1 H), 3.94 (s, 3 H), 1.43 (s, 9 H).
13C NMR: δ = 147.09, 145.69, 142.95, 139.86, 136.93, 134.28,
133.31, 120.37, 107.27, 105.91, 102.05, 82.44, 39.77, 33.43, 29.41.
HRMS (EI): m/z calcd for C9H6Br3N: 364.8050; found: 364.8051.
HRMS (EI): m/z calcd for C17H18BrNO: 331.0572; found:
331.0580.
5,6,7-Tribromo-1-methyl-3-phenyl-1H-indole (12; R1 = Ph, R2 =
H, R3 = Br )
Yield: 334 mg (81%); yellow solid; mp 144–146 °C.
1H NMR: δ = 8.06 (s, 1 H), 7.55–7.26 (m, 5 H), 7.13 (s, 1 H), 4.15
(s, 1 H).
13C NMR: δ = 134.13, 133.55, 131.24, 128.92, 128.62, 127.61,
126.62, 123.12, 121.57, 116.11, 115.79, 107.88, 37.84.
5-Bromo-6-(tert-butyl)-1-methyl-6,9-dihydro-1H-6,9-epoxy-
benzo[g]indole (14) (Table 4, Entry 3)
Yield: 25 mg (29%); brown oil.
1H NMR: δ = 7.43 (s, 1 H), 7.04 (m, 2 H), 6.94 (d, J = 3.1, 1 H), 6.31
(d, J = 3.3 Hz, 1 H), 6.24 (d, J = 1.6 Hz, 1 H), 3.88 (s, 3 H), 1.46 (s,
9 H).
13C NMR: δ = 144.38, 144.15, 143.61, 137.69, 132.50, 130.82,
HRMS (EI): m/z calcd for C15H10Br3N: 440.8363; found: 440.8365.
130.59, 122.26, 106.96, 103.28, 100.11, 79.15, 35.23, 32.65, 29.81.
4-Bromo-9-(tert-butyl)-1-methyl-6,9-dihydro-1H-6,9-epoxy-
benzo[g]indole (13) (Table 4, Entry 1)
Yield: 37 mg (59%); yellow oil.
HRMS (EI): m/z calcd for C17H18BrNO: 331.0572; found:
331.0579.
1H NMR: δ = 7.27 (s, 1 H), 7.10 (dd, J = 1.8, 5.5 Hz, 1 H), 7.01 (d,
J = 5.5 Hz, 1 H), 6.96 (d, J = 3.5 Hz, 1 H), 6.54 (d, J = 3.5 Hz, 1 H),
5.66 (d, J = 1.8 Hz, 1 H), 3.96 (s, 3 H), 1.42 (s, 9 H).
13C NMR: δ = 149.63, 145.81, 142.66, 133.84, 133.42, 130.60,
116.63, 111.13, 104.99, 104.69, 103.02, 81.57, 39.80, 33.26, 29.38.
5-Bromo-9-(tert-butyl)-1-methyl-3-phenyl-6,9-dihydro-1H-6,9-
epoxybenzo[g]indole (13) (Table 4, Entry 4)
Yield: 24 mg (36%); yellow oil.
1H NMR: δ = 7.62 (s, 1 H), 7.50 (m, 2 H), 7.42 (m, 2 H), 7.29 (m, 1
H), 7.18 (dd, J = 1.8, 5.5 Hz, 1 H), 7.06 (d, J = 5.5 Hz, 1 H), 7.01 (s,
1 H), 5.93 (d, J = 1.8 Hz, 1 H), 3.99 (s, 3 H), δ 1.45 (s, 9 H).
Synthesis 2013, 45, 1843–1852
© Georg Thieme Verlag Stuttgart · New York

PAPER
6,7-Indole Aryne Cycloadditions with 2-Substituted Furans
1851
13C NMR: δ = 145.34, 144.67, 138.60, 136.02, 135.95, 133.47,
128.50, 128.30, 127.07, 126.30, 123.65, 118.85, 117.01, 114.27,
100.76, 79.70, 39.37, 36.75, 26.67.
6,7-Dibromo-4-iodo-1-methyl-1H-indole (15; R = I)
Yield: 100 mg (79%); purple oil.
1H NMR: δ = 7.51 (s, 1 H), 7.03 (d, J = 3.3 Hz, 1 H), 6.48 (d, J = 3.3
Hz, 1 H), 4.15 (s, 1 H).
HRMS (EI): m/z calcd for C23H22BrNO: 407.0886; found:
13C NMR: δ = 134.07, 133.00, 130.56, 126.68, 119.11, 114.33,
407.0895.
106.10, 101.94, 37.98.
5-Bromo-6-(tert-butyl)-1-methyl-3-phenyl-6,9-dihydro-1H-6,9-
epoxybenzo[g]indole (14) (Table 4, Entry 4)
Yield: 17 mg (26%); brown oil.
1H NMR: δ = 7.66 (s, 1 H), 7.48 (m, 2 H), 7.35 (m, 2 H), 7.21 (m, 1
H), 7.04 (s, 1 H), 6.99 (m, 2 H), 6.21 (d, J = 1.8 Hz, 1 H), 3.86 (s, 3
H), 1.48 (s, 9 H).
13C NMR: δ = 146.88, 145.43, 136.78, 136.73, 134.62, 133.90,
128.50, 128.12, 127.10, 126.94, 126.30, 118.78, 116.33, 100.41,
100.34, 80.11, 37.85, 37.07, 26.82.
HRMS (EI): m/z calcd for C9H6IBr2N: 412.7912; found: 412.7915.
6,7-Dibromo-4-ethyl-1-methyl-1H-indole (15; R = Et)
Yield: 140 mg (89%); yellow oil.
1H NMR: δ = 7.21 (s, 1 H), 6.96 (d, J = 3.1 Hz, 1 H), 6.44 (d, J = 3.1
Hz, 1 H), 4.14 (s, 1 H), 2.83 (q, J = 7.6 Hz, 2 H), 1.31 (t, J = 7.6 Hz,
3 H).
13C NMR: δ = 136.85, 132.05, 131.79, 129.37, 123.10, 119.44,
103.81, 99.39, 37.71, 25.51, 14.35.
HRMS (EI): m/z calcd for C23H22BrNO: 407.0886; found:
407.0890.
HRMS (EI): m/z calcd for C8H4FBr2N: 314.9258; found: 314.9260.
9-(tert-Butyl)-4-fluoro-1-methyl-6,9-dihydro-1H-6,9-epoxyben-
zo[g]indole (16) (Table 5, Entry 1)
4- Substituted 6,7-Dibromoindoles via Bartoli Indole Synthesis;
6,7-Dibromo-4-fluoro-1H-indole; Typical Procedure
Yield: 39 mg (49%); yellow oil.
In a 250 mL flame-dried round-bottomed flask under argon was dis-
solved 1,2-dibromo-5-fluoro-3-nitrobenzene (0.50 g, 3.35 mmol) in
THF (20 mL) and cooled to –40 °C. To this stirred solution was
added a solution of vinylmagnesium bromide in THF (1 M, 11.7
mmol) at –40 °C. The reaction mixture was stirred at –40 °C for 1
h, then quenched with aq NH4Cl (100 mL), and allowed to warm to
r.t. The mixture was extracted with Et2O (3 × 50 mL), the combined
organic layers washed with H2O (1 × 50 mL), brine (25 mL), and
dried (MgSO4). The solution was filtered and concentrated under
reduced pressure. The crude mixture was purified by column chro-
matography on silica gel using 10% EtOAc in hexanes to give 6,7-
dibromo-4-fluoro-1H-indole as an off-white solid; yield: 150 mg
(31%); mp 84–86 °C.
1H NMR: δ = 7.12 (dd, J = 1.7, 1.7 Hz, 1 H), 7.03 (d, J = 5.5 Hz, 1
H), 6.84 (d, J = 3.5 Hz, 1 H), 6.82 (d, J = 8.0 Hz, 1 H), 6.52 (d,
J = 3.3 Hz, 1 H), 5.65 (d, J = 1.7 Hz, 1 H), 3.96 (s, 3 H), 1.43 (s, 9
H).
13C NMR: δ = 154.55, 152.10, 149.95 (d, J = 7.3 Hz), 145.66,
143.17, 132.36, 129.73, 104.62, 100.38, 99.85 (d, J = 21.2 Hz),
98.15, 81.86, 39.61, 33.20, 29.39.
HRMS (EI): m/z calcd for C17H18FNO: 271.1373; found: 271.1380.
6-(tert-Butyl)-4-fluoro-1-methyl-6,9-dihydro-1H-6,9-epoxyben-
zo[g]indole (17) (Table 5, Entry 1)
Yield: 17 mg (22%); pale yellow solid; mp 118–120 °C.
1H NMR: δ = 7.08 (d, J = 1.2 Hz, 1 H), 7.03 (d, J = 0.6 Hz, 1 H),
7.01 (d, J = 0.6 Hz, 1 H), 6.89 (d, J = 3.1 Hz, 1 H), 6.44 (d, J = 3.1
Hz, 1 H), 6.19 (d, J = 0.8 Hz, 1 H), 3.88 (s, 3 H), 1.31 (s, 9 H).
13C NMR: δ = 154.17, 151.73, 145.55 (d, J = 7.4 Hz), 145.04,
144.18, 133.26, 130.02, 115.80 (d, J = 23.4 Hz), 101.60 (d, J = 22.7
Hz), 100.31 (d, J = 27.1 Hz), 97.35, 79.82, 34.99, 32.50, 26.67.
1H NMR: δ = 8.46 (br s, 1 H), 7.23 (m, 1 H), 7.10 (d, J = 9.4 Hz, 1
H), 6.71 (dd, J = 2.1, 3.3 Hz, 1 H).
13C NMR: δ = 156.26, 153.75, 125.05, 116.91 (d, J = 24.0 Hz),
116.38 (d, J = 9.6 Hz), 110.32 (d, J = 24.2 Hz), 102.12, 100.58.
HRMS (EI): m/z calcd for C8H4FBr2N: 290.8694; found: 290.8690.
4,6,7-Tribromo-1H-indole
For preparation, see reference 5a.
HRMS (EI): m/z calcd for C17H18FNO: 271.1373; found: 271.1372.
9-(tert-Butyl)-4-iodo-1-methyl-6,9-dihydro-1H-6,9-epoxyben-
zo[g]indole (16) (Table 5, Entry 3)
6,7-Dibromo-4-iodo-1H-indole
Yield: 330 mg (33%); purple solid; mp 91–93 °C.
Yield: 50 mg (61%); purple solid; mp 99–101 °C.
1H NMR: δ = 8.50 (br s, 1 H), 7.55 (s, 1 H), 7.30 (dd, J = 2.5, 3.3
Hz, 1 H), 6.66 (dd, J = 2.3, 3.3 Hz, 1 H).
13C NMR: δ = 135.36, 128.69, 126.69, 125.76, 117.16, 114.08,
1H NMR: δ = 7.28 (s, 1 H), 7.11 (dd, J = 1.8, 5.5 Hz, 1 H), 7.01 (d,
J = 5.5 Hz, 1 H), 6.96 (d, J = 3.3 Hz, 1 H), 6.54 (d, J = 3.3 Hz, 1 H),
5.66 (d, J = 1.8 Hz, 1 H), 3.96 (s, 3 H), 1.42 (s, 9 H).
13C NMR: δ = 149.61, 145.80, 142.65, 133.89, 133.83, 133.42,
130.58, 116.61, 111.12, 104.68, 102.99, 81.55, 39.80, 33.25, 29.73.
106.46, 104.70.
HRMS (EI): m/z calcd for C8H4IBr2N: 398.7755; found: 398.7766.
6,7-Dibromo-4-ethyl-1H-indole
HRMS (EI): m/z calcd for C17H18INO: 379.0434; found: 379.0444.
For preparation, see reference 2b.
6-(tert-Butyl)-4-iodo-1-methyl-6,9-dihydro-1H-6,9-epoxyben-
zo[g]indole (17) (Table 5, Entry 3)
Yield: 9 mg (4%); purple solid; mp 136–138 °C.
6,7-Dibromo-4-fluoro-1-methyl-1H-indole (15; R = F)
Yield: 102 mg (77%); brown solid; mp 69–71 °C.
1H NMR: δ = 7.07 (d, J = 9.0 Hz, 1 H), 6.95 (d, J = 3.1 Hz, 1 H),
6.51 (d, J = 3.1 Hz, 1 H), 4.15 (s, 1 H).
1H NMR: δ = 7.46 (s, 1 H), 7.07 (m, 2 H), 6.99 (d, J = 3.3 Hz, 1 H),
6.42 (d, J = 3.3 Hz, 1 H), 6.18 (m, 1 H), 3.88 (s, 3 H), 1.32 (s, 9 H).
13C NMR: δ = 156.03, 153.54, 132.30, 119.43 (d, J = 24.9 Hz),
118.17 (d, J = 11.9 Hz), 110.10 (d, J = 22.5 Hz), 101.73, 97.37,
37.59.
13C NMR: δ = 145.58, 144.61, 144.21, 134.15, 131.46, 131.01,
128.15, 118.82, 117.91, 109.87, 101.65, 79.76, 35.13, 29.69, 26.72.
HRMS (EI): m/z calcd for C17H18INO: 379.0434; found: 379.0450.
HRMS (EI): m/z calcd for C9H6FBr2N: 304.8851; found: 304.8852.
9-(tert-Butyl)-4-ethyl-1-methyl-6,9-dihydro-1H-6,9-epoxyben-
zo[g]indole (16) (Table 5, Entry 4)
Yield: 50 mg (58%); yellow oil.
4,6,7-Tribromo-1-methyl-1H-indole (15; R = H)
For preparation, see reference 5a.
1H NMR: δ = 7.15 (dd, J = 1.8, 1.8 Hz, 1 H), 7.05 (d, J = 5.7 Hz, 1
H), 7.02 (s, 1 H), 6.92 (d, J = 3.5 Hz, 1 H), 6.53 (d, J = 3.3 Hz, 1 H),
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1843–1852

1852
A. Nerurkar et al.
PAPER
Perchellet, E. M.; Thornton, P. D.; Brown, N.; Hill, D.;
Neuenswander, B.; Lushington, G. H.; Santini, C.;
Chandrasoma, N.; Buszek, K. R. Anticancer Res. 2012, 32,
4671.
5.71 (d, J = 1.8 Hz, 1 H), 3.97 (s, 3 H), 2.89 (q, J = 7.6 Hz, 2 H),
1.47 (s, 9 H), 1.34 (t, J = 7.6 Hz, 3 H).
13C NMR: δ = 148.39, 145.76, 142.84, 133.67, 133.23, 132.17,
131.35, 129.41, 112.45, 104.54, 100.65, 81.96, 39.64, 33.27, 29.40,
25.67, 14.51.
(6) (a) Bronner, S. M.; Bahnck, K. B.; Garg, N. K. Org. Lett.
2009, 11, 1007. (b) Tian, X.; Huters, A. D.; Douglas, C. J.;
Garg, N. K. Org. Lett. 2009, 11, 2349. (c) Bronner, S. M.;
Garg, N. K. J. Org. Chem. 2009, 74, 8842. (d) Cheong, P.
H.-Y.; Paton, R. S.; Bronner, S. M.; Im, G.-T. J.; Garg, N.
K.; Houk, K. N. J. Am. Chem. Soc. 2010, 132, 1267. (e) Im,
G-Y. J.; Bronner, S. M.; Goetz, A. E.; Paton, R. S.; Cheong,
P. H.-Y.; Houk, K. N.; Garg, N. K. J. Am. Chem. Soc. 2010,
132, 17933. (f) Bronner, S. M.; Goetz, A. E.; Garg, N. K.
J. Am. Chem. Soc. 2011, 133, 3832. (g) Huters, A. D.;
Quasdorf, K. W.; Styduhar, E. D.; Garg, N. K. J. Am. Chem.
Soc. 2011, 133, 15797. (h) Goetz, A. E.; Bronner, S. M.;
Cisneros, J. D.; Melamed, J. M.; Paton, R. S.; Houk, K. N.;
Garg, N. K. Angew. Chem. Int. Ed. 2012, 51, 2758.
(i) Quasdorf, K. W.; Huters, A. D.; Lodewyk, M. W.;
Tantillo, D. J.; Garg, N. K. J. Am. Chem. Soc. 2012, 134,
1396.
HRMS (EI): m/z calcd for C19H23NO: 281.1781; found: 281.1787.
6-(tert-Butyl)-4-ethyl-1-methyl-6,9-dihydro-1H-6,9-epoxyben-
zo[g]indole (17) (Table 5, Entry 4)
Yield: 4 mg (5%); dark yellow oil.
1H NMR: δ = 7.14 (s, 1 H), 7.07 (m, 2 H), 6.92 (d, J = 3.3 Hz, 1 H),
6.41 (d, J = 3.3 Hz, 1 H), 6.20 (d, J = 1.6 Hz, 1 H), 3.88 (s, 3 H),
2.86 (q, J = 7.6 Hz, 2 H), 1.34 (s, 9 H), 1.29 (t, J = 7.6 Hz, 3 H).
13C NMR: δ = 144.79, 144.26, 132.35, 132.02, 131.39, 129.63,
113.88, 105.00, 100.10, 99.60, 89.10, 79.90, 34.96, 32.58, 29.69,
26.69, 15.19.
HRMS (EI): m/z calcd for C19H23NO: 281.1781; found: 281.1783.
Acknowledgment
(7) (a) Nguyen, T. D.; Webster, R.; Lautens, M. Org. Lett. 2011,
13, 1370. (b) Candito, D. A.; Dobrovolsky, D.; Lautens, M.
J. Am. Chem. Soc. 2012, 134, 15572.
We acknowledge support of this work by the National Institutes of
Health, Grant R01 GM069711 (KRB). We also acknowledge addi-
tional support of this work by the National Institutes of Health, The
University of Kansas Chemical Methodologies, and Library Deve-
lopment Center of Excellence (KU-CMLD), NIGMS, Grant P50
GM069663.
(8) Bartoli indole synthesis: (a) Bartoli, G.; Palmieri, G.; Bosco,
M.; Dalpozzo, R. Tetrahedron Lett. 1989, 30, 2129.
(b) Bartoli, G.; Bosco, M.; Dalpozzo, R.; Palmieri, G.;
Marcantoni, E. J. Chem. Soc., Perkin Trans. 1 1991, 2757.
(c) Bosco, M.; Dalpozzo, R.; Bartoli, G.; Palmieri, G.;
Petrini, M. J. Chem. Soc., Perkin Trans. 2 1991, 657.
(d) Dalpozzo, R.; Bartoli, G. Curr. Org. Chem. 2005, 9, 163.
(9) Leimgruber–Batcho indole synthesis: (a) Lloyd, D. H.;
Nichols, D. E. J. Org. Chem. 1986, 51, 4294. (b) Mayer, J.
P.; Cassady, J. M.; Nichols, D. E. Heterocycles 1990, 31,
1035. (c) Leze, M.-P.; Palusczak, A.; Hartmann, R. W.; Le
Borgne, M. Bioorg. Med. Chem. Lett. 2008, 18, 4713.
(10) No solvent dependence on regiochemical selectivity was
observed with Et2O, THF, or toluene. The chemical yields
are somewhat higher in toluene, as side reactions tend to be
fewer. Toluene is a more practical solvent and is known to
promote metal–halogen exchange over any competing acid-
base processes: Coe, J. W.; Wirtz, M. C.; Bashore, C. G.;
Candler, J. Org. Lett. 2004, 6, 1589.
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Synthesis 2013, 45, 1843–1852
© Georg Thieme Verlag Stuttgart · New York