Direct synthesis of 3-arylindoles via annulation of aryl hydroxylamines with alkynes

Article abstract of DOI:10.1016/j.tet.2009.03.004

3-Arylindoles are produced in moderate to excellent yields from the reaction between aryl hydroxylamines and alkynes catalyzed by 10 mol % iron(II) phthalocyanine [Fe(Pc)]. Terminal and internal alkynes afford 3-aryl substituted indoles exclusively. Elect

Full text of DOI:10.1016/j.tet.2009.03.004

Tetrahedron 65 (2009) 3829–3833
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Direct synthesis of 3-arylindoles via annulation of aryl hydroxylamines
with alkynes
*
Angus A. Lamar, Kenneth M. Nicholas
Department of Chemistry and Biochemistry, University of Oklahoma, Norman, OK 73019, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 January 2009
Received in revised form 24 February 2009
Accepted 2 March 2009
Available online 6 March 2009
3-Arylindoles are produced in moderate to excellent yields from the reaction between aryl hydroxyl-
amines and alkynes catalyzed by 10 mol % iron(II) phthalocyanine [Fe(Pc)]. Terminal and internal alkynes
afford 3-aryl substituted indoles exclusively. Electron-donating and -withdrawing groups are tolerated
on the aryl hydroxylamine. A few bioactive indoles are synthesized as well as several new indoles using
this one-step intermolecular annulation procedure.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Iron catalysis
Indole
Nitrosoarene
1. Introduction
(i)
Y
Y
(ii)
+
Indoles are an important class of N-heterocycles due to their
frequent occurrence as natural products and bioactive compounds.
Many methods have been developed for their preparation,1 yet new
and improved approaches are still being sought which, employ
more accessible starting materials, milder reaction conditions, are
functional group-tolerant, and achieve improved regioselectivity.
Especially attractive, but relatively rare, are methods, which pro-
duce indoles by annulation of N-aromatic precursors, as in the
Fischer-indole synthesis.2,3 The search for a general and efficient
annulation method has spawned several transition metal-pro-
moted routes to indoles,4 though most of these are cyclizations
(1)
NOa
N
A
Z
(iii)
Z
Scheme 1. (i) a¼2, CO/[CpRu(CO)2]2, A¼H; (ii) a¼1,
A¼OMe.
D
, A¼OH; (iii) a¼1,
D/Me2SO4,
hydroxylamines10 were considered attractive candidates. Since
redox metal-catalyzed allylic aminations of olefins with aryl hy-
droxylamines6,11 involve in situ hydroxylamine oxidation, ene re-
action of the resulting nitrosoarene,12 and reduction of the allyl
hydroxylamine, we envisioned a similar catalytic pathway for al-
kyne indolization by aryl hydroxylamines via nitrosoarene and
N-hydroxyindole intermediates.
requiring
a
prefunctionalized ortho-substituted N-aromatic
substrate.5
Our interest in metal-promoted nitrogenation reactions of hy-
drocarbons6 led to the recent discoveries of indole-forming re-
actions of alkynes with nitro-7 and nitroso8-aromatics (Eq. 1). The
indole skeleton in each of these reactions is formed via a novel
cyclocondensation of a nitrosoarene with the alkyne.9 The in-
tervening N-hydroxyindole can either be trapped as the N-methoxy
indole8b or reduced in situ in a second step to the indole
(Scheme 1).7,8a
2. Results and discussion
Utilizing the conditions reported for the N-hydroxyindole prepa-
ration,8a a survey and initial optimization study (Table 1) were con-
ducted on the reaction of PhNHOH with excess phenyl acetylene in
the presence of various redox-active complexes, including
(dtc)2MoO2, (dipic)MoO2(HMPA), FeCl2/FeCl3, Cu(CH3CN)4PF6, CuCl2$
2H2O, and Fe(Pc)6,11 (dtc¼N,N-diethyl dithiocarbamate, dipic¼
2,6-pyridinedicarboxylate, HMPA¼hexamethyl phosphortriamide,
Pc¼phthalocyanine), and solvents (benzene, dioxane, toluene,
1,2-dichloroethane, EtOH, CH3CN, i-PrOH, t-BuOH, and chloroben-
zene). GC, GC–MS, and TLC analysis indicated the production of
3-phenylindole with several of these systems (Table 1) with the best
In order to develop an efficient one step method to form the
parent (NH) indoles that did not require the use of high pressures of
CO and to broaden the scope of the N-aromatic precursors, aryl
* Corresponding author. Tel.: þ1 405 325 3696; fax: þ1 405 325 6111.
E-mail address: knicholas@ou.edu (K.M. Nicholas).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.03.004

3830
A.A. Lamar, K.M. Nicholas / Tetrahedron 65 (2009) 3829–3833
Table 1
phenylpropyne (Table 3, entry 10). The 2-Me-3-Ph-indole is iso-
lated exclusively, further demonstrating the 3-aryl regioselectivity
of the reaction. An exploration of the alkyne substrate scope is
summarized in Table 3. A scale-up reaction using 2.0 mmol of
PhNHOH and 10 equiv of 3,4-dimethoxyphenyl acetylene resulted
in a nearly identical yield (55%, entry 12), with w98% of the
unreacted alkyne recovered. The attempt to utilize cyclooctyne as
a substrate in order to generate a precursor to the anti-depressant
iprindole13 resulted in cyclotrimerization14 in the presence of
Fe(Pc) in either refluxing toluene or benzene, with no indole
formed. Owing to the technical ease of isolation of the parent (NH)
indoles using the present one-step procedure, several previously
unused N-aromatic substrates and/or alkynes were utilized in this
study resulting in new indoles 3f, 3f0, 3h, 3h0, 3i, 3l, and 3m. Of
particular interest are indoles 3l and 3m, which both possess in-
teresting bioactivity15 and relatively limited synthetic ap-
proaches.16 It is noteworthy that indole 3m is produced in 72% yield
despite having a potentially N-coordinating alkyne used in large
excess relative to the catalyst.
To address the issue of whether the free nitrosoarene is gener-
ated in the Fe(Pc)-catalyzed reactions, the trapping experiment
shown in Scheme 3 was conducted. When the PhNHOH/PhC^CH
reaction was carried out in the presence of 2,3-dimethyl-1,3-bu-
tadiene (10 equiv of diene, 10 equiv of alkyne), none of the indole
was detected, but rather the hetero Diels–Alder product17 was
formed and verified by 1H NMR and GC–MS. This result strongly
suggests the intermediacy of PhNO in the Fe(Pc)-catalyzed reaction.
Transition metal-catalyzed indolization of phenyl acetylene and N-
phenylhydroxylaminea
Entry
Solvent
Catalystb
Yieldc (%)
1
2
3
4
5
6
7
8
9
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
Dioxane
Toluene
Toluene
Mo(dtc)2O2
(dipic)MoO2(HMPA)
9:1 FeCl2/FeCl3
Cu(CH3CN)4PF6
CuCl2$H2O
Fe(Pc)
Fe(Pc)
Fe(Pc)
Fe(Pc)
51
11
34d
15
19
66
70
84
70e
a
Phenylhydroxylamine (0.5 mmol) added by syringe pump (7–8 h), 10 mmol
phenyl acetylene, Ar, reflux.
b
Cat. (10 mol %).
GC yield using naphthalene as internal standard.
Anhydrous Fe salts or FeXn hydrates.
Fe(Pc) (5 mol %).
c
d
e
results being obtained with commercially available and inexpensive
Fe(Pc) as catalyst. Minor products include azoxybenzene (3–10%),
azobenzene (0–2%), and aniline (0–15%). By slowly adding PhNHOH
(0.5 mmol in toluene, 7–8 h) to a refluxing solution of phenyl acety-
lene (10 mmol) and Fe(Pc) (0.05 mmol) an 84% yield of 3-phenyl-
indole (GC) was achieved.
Using the optimized conditions, a series of substituted N-aryl
hydroxylamines were tested with phenyl acetylene in the indoli-
zation reaction (Scheme 2, Table 2). Both electron-donating and
-withdrawing groups are tolerated on the aryl hydroxylamine. In
terms of regioselectivity of the alkyne cycloaddition, 3-aryl isomers
are solely detected in all examples. From meta-substituted N-aryl
hydroxylamine substrates (entries 6–8), mixtures of 4- and 6-
substituted indoles were obtained, with the 4-substituted indole
slightly favored in each case. 3-Phenyl-benz[g]indole (entry 9) was
also produced regioselectively from the annulation of alkyne with
1-hydroxylamino-naphthalene. Yields of indoles from the current
one-step procedure are comparable (3–15% lower) to those pro-
duced by the two-step N-hydroxyindole preparation and its re-
duction (H2/10% Pd/C) to the free indole.8b
Table 3
Fe(Pc)-catalyzed preparationa of indoles from aryl alkynes and 1a (N-phenyl-
hydroxylamine) (Scheme 2)
Entry
10
Alkyne
Major product
% Isolated yield
Ph
Ph
Me
25
Me
N
H
2b
3j
OMe
(Y)
Ph
MeO
X
Y
X
Y
Ph
H
11
88
10% Fe(Pc)
+
(2)
2c
N
H
NHOH
N
H
3k
H
Z
1
Z
MeO
2
3
OMe
OMe
Scheme 2.
57 (55)b
MeO
12
Representative terminal and internal aryl alkynes were effective
partners with good to excellent yields produced from terminal al-
2d
N
H
3l
kynes (Table 2, entry 1) and
a moderate yield from 3-
N
N
13c
72
Table 2
Fe(Pc)-catalyzed preparation of indoles from phenyl acetylene and N-aryl hydroxyl-
2e
aminesa (Scheme 2)
N
H
Entry
1
X
Y
Z
3
% Isolated yield
3m
1
2
3b
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
H
H
H
H
H
H
H
H
H
Me
H
H
3a
3b
3c
3d
81
55
55
38
Me
CN
Cl
H
H
H
14d
>50
H
3e
45
Me
CF3
Cl
3f, f0
3g, g0
3h, h0
3i
47 (4-Me/6-Me¼27:20)
65 (4-CF3/6-CF3¼34:31)
55 (4,5-Cl/5,6-Cl¼34:21)
37
4
Cl
H
H
5
–C4H4–
a
Fe(Pc) (10 mol %), refluxing toluene, 7–8 h addition of 1a.
Scale-up reaction: 10 equiv alkyne, 32 h addition of 1a.
Alkyne (17 equiv), reaction run in dark.
No indole detected.
a
b
c
Fe(Pc) (10 mol %), refluxing toluene, 7–8 h addition of aryl hydroxylamine
(procedure in Experimental section).
b
d
Dioxane used as solvent.

A.A. Lamar, K.M. Nicholas / Tetrahedron 65 (2009) 3829–3833
3831
appropriate 1H and 13C NMR data as reported.14b Toluene, benzene,
and dioxane were distilled prior to use over Na/benzophenone. All
other solvents including those used in chromatography were used
without any purification. Visualization of the developed chro-
matogram was performed under UV light or I2 stain. 1H NMR
spectra were obtained at 300 MHz and 13C NMR spectra at 60 MHz;
NMR spectra were internally referenced to residual protio solvent
signals. Data for 1H NMR data are reported as follows: chemical
Ph
Ph
Fe(Pc)
N
H
+
Ph
NHOH
N
O
5
Scheme 3.
shift
(
d
ppm), multiplicity (br¼broad, s¼singlet, d¼doublet,
t¼triplet, m¼multiplet, dd¼doublet of doublets), coupling constant
The catalytic reaction pathway is thus suggested to proceed via
PhNHOH oxidation by a FeIII(Pc) species18 to PhNO, nitroso/alkyne
cyclocondensation to the N-hydroxyindole, and reduction of the
latter to the indole by FeII(Pc) (Scheme 4).
(Hz), integration, and assignment. Data for 13C NMR are reported in
terms of chemical shift (d ppm). Mass spectra were acquired in
methanol or acetonitrile solution by ESI. Naphthalene was used as
an internal standard for GC yield determinations.
FeII(Pc)
4.2. General procedure for the preparation
of 3-arylindoles (3)
X
X
NHOH
Ar
A mixture of 0.05 mmol of Fe(Pc),10 mmol of alkyne, and15 mL of
toluene was stirred at reflux under argon and to this was added
0.50 mmol of the N-aryl hydroxylamine in 5–6 mL of toluene by sy-
ringe pump (7–8 h). After the addition was complete, reflux was
continued overnight (8–12 h). After cooling, the mixture was evap-
orated to a solid under vacuum. Flash chromatography of the residue
over silica gel (20% EtOAc/hexane eluant) afforded the indole prod-
ucts, typically as solids. All new compounds were spectroscopically
pure (>95%) and exhibited appropriate 1H and 13C NMR spectra and
MS data (provided in Supplementary data). Previously characterized
indoles 3a,8a 3b,7b,15d 3d,8a 3e,24 3g,8a 3g0,8a 3j,8a and 3k25 displayed
1H NMR spectra and MS data that matched those reported in the
respective literature (available in Supplementary data).
NO
N
FeIII(Pc)
Ar
X
Ar
X
FeII(Pc)
N
H
OH
Scheme 4.
3. Conclusions
Insummary, we havedevelopedanewmetal-catalyzedprocedure
to produce 3-arylindoles in moderate to excellent yields. Electron-
donating and -withdrawing N-aryl hydroxylamines are both suitable
substrates, as well as a variety of aryl alkynes, including one with N-
coordinating ability. Terminal and internal alkynes can be applied
with exceptional regioselectivity to 3-aryl products. Advantages of
the system include the production of the parent (NH) indole in a one-
step, one-pot reaction that doesn’t require high pressures of CO, and
the use of inexpensive and commercially available Fe(Pc) as catalyst.
The N-aryl hydroxylamines used are conveniently prepared in one
step via reduction of nitroaromatics, and purified by recrystallization.
In contrast, the nitrosoaromatics utilized in our previous method are
formed inone step viaoxidationofamineswithpurificationgenerally
by column chromatography. In this intermolecular annulation, the
system does not require a ortho-substituted or activated N-aromatic
substrates scaffold, resulting in a highly convergent indole synthesis.
Efforts to further demonstrate the synthetic utility of this new direct
indolization reaction are currently underway.
4.2.1. 5-Cyano-3-phenylindole (3c)
Prepared according to the general procedure from 4-cyano-N-
phenylhydroxylamine (72 mg, 0.5 mmol) dissolved in 6 mL di-
oxane, Fe(Pc) (28 mg, 0.05 mmol), phenyl acetylene (1.1 mL,
10 mmol), and dioxane (15 mL) to provide the title compound
(60.1 mg, 0.276 mmol) in 55% yield: 1H and ESI/MS data for 3c
matched those reported in the literature.8a
4.2.2. 4-Methyl-3-phenylindole (3f) and 6-methyl-3-phenyl-
indole (3f0)
Prepared according to the general procedure from 3-methyl-N-
phenylhydroxylamine (61.5 mg, 0.5 mmol) dissolved in 6 mL tolu-
ene, Fe(Pc) (28 mg, 0.05 mmol), phenyl acetylene (1.1 mL, 10 mmol),
and toluene (15 mL) to provide 3f as an oily tan solid (28 mg,
0.135 mmol) in 27% yield: 1H NMR (CDCl3, 300 MHz)
d 8.13 (br s, 1H,
NH), 7.84 (d, J¼11.4 Hz, 1H), 7.68 (dd, J¼8.1 and 0.9 Hz, 2H), 7.45 (t,
J¼6.6 Hz, 2H), 7.29 (m, 3H), 7.05 (dd, J¼8.4 and 1.2 Hz, 1H), 2.50 (s,
3H); 13C NMR (CDCl3, 300 MHz)
d 137.3, 135.9, 132.5, 128.9, 127.6,
4. Experimental
4.1. General
126.1, 123.8, 122.3, 121.3, 119.7, 118.4, 111.5, 21.9; HRMS (ESI) calcu-
lated for C15NH13 (MþHþ) requires m/z 208.1126, found m/z 208.1186.
Compound 3f0 was obtained as an orange solid (21 mg,
0.101 mmol) in 20% yield: 1H NMR (CDCl3, 300 MHz)
d
8.19 (br s,1H,
NH), 7.47–7.23 (m, 6H), 7.14 (t, J¼4.8 Hz, 2H), 6.89 (dd, J¼6.9 and
0.9 Hz, 1H), 2.28 (s, 3H); 13C NMR (CDCl3, 300 MHz)
137.2, 136.4,
Commercial reagents were purchased from Sigma Aldrich, Alfa
Aesar, or GFS. Nitroaromatics used in reduction to N-aryl hydroxyl-
amines were used without any purification. N-Aryl hydroxylamines
1a,10 1e,10 1f,10 1g,19a 1h,19b and 1i19c were prepared using literature
procedure (Ref. 10b), compounds 1b,10 1c,19d and 1d10 were pre-
pared by literature procedure (Ref. 10d), and each compound was
determined to be pure by comparison to individual known data. All
N-aryl hydroxylamines were stored under argon and kept below
0 ꢀC. Purchased alkynes were purified by distillation before use, and
alkynes 2b,20 2d,21 2e,22 and 423 were all prepared according to
their literature procedures, and each compound exhibited appro-
priate 1H and/or 13C NMR data. Cyclooctyne trimer 5 exhibited
d
131.5, 130.9, 127.8, 126.6, 125.4, 123.1, 122.6, 121.8, 119.9, 109.2, 21.0;
LRMS (EI) m/z 207.
4.2.3. 4,5-Dichloro-3-phenylindole (3h) and 5,6-dichloro-3-
phenylindole (3h0)
Prepared according to the general procedure from 3,4-dichloro-
N-phenylhydroxylamine (89 mg, 0.5 mmol) dissolved in 6 mL tol-
uene, Fe(Pc) (28 mg, 0.05 mmol), phenyl acetylene (1.1 mL,
10 mmol), and toluene (15 mL) to provide the title compound as
a beige solid (44.3 mg, 0.169 mmol) in 34% yield: 1H NMR (CDCl3,

3832
A.A. Lamar, K.M. Nicholas / Tetrahedron 65 (2009) 3829–3833
300 MHz)
d
8.23 (br s, 1H, NH), 7.40 (dd, J¼7.8 and 1.8 Hz, 2H), 7.34–
stirred at reflux under argon and to this was added 0.50 mmol of
the N-aryl hydroxylamine in 5–6 mL benzene by syringe pump (7–
8 h). After the addition was complete, reflux was continued over-
night (8–12 h). After cooling, the mixture was evaporated to a solid
under vacuum. No indole was detected by GC or by isolation. 4,5-
Dimethyl-2-phenyl-3,6-dihydro-2H-1,2-oxazine (5) was isolated
and the 1H NMR spectrum matched with that reported in the
literature.17b
7.27 (m, 3H), 7.23–7.16 (m, 2H), 7.11 (d, J¼2.7 Hz, 1H); 13C NMR
(CDCl3, 300 MHz)
d 135.6, 134.8, 131.2, 127.6, 126.9, 125.6, 124.9,
124.7, 124.6, 124.1, 119.7, 110.9; HRMS (ESI) calculated for C14NCl2H9
(MþNaþ) requires m/z 284.0010, found m/z 284.0034, mp¼90 ꢀC.
Compound 3h0 was isolated as
a white solid (28 mg,
0.107 mmol) in 21% yield: 1H NMR (CDCl3, 300 MHz)
d 8.26 (br s,1H,
NH), 7.99 (s, 1H), 7.61 (dd, J¼8.3 and 1.2 Hz, 2H), 7.55 (s, 1H), 7.47
(t, J¼7.2 Hz, 2H), 7.40 (d, J¼2.7 Hz, 1H), 7.33 (t, J¼7.2 Hz, 1H); 13C
NMR (CDCl3, 300 MHz)
d 135.5, 134.5, 129.2, 127.6, 126.8, 126.5,
Acknowledgements
125.8, 124.7, 123.6, 121.1, 118.5, 113.0; LRMS (EI) m/z 261, 263.
We are grateful for financial support provided by the National
Science Foundation (CHE-0552114).
4.2.4. 3-Phenyl-benz[g]indole (3i)
Prepared according to the general procedure from N-1-naph-
thyl-hydroxylamine (79.5 mg, 0.5 mmol) dissolved in 6 mL toluene,
Fe(Pc) (28 mg, 0.05 mmol), phenyl acetylene (1.1 mL,10 mmol), and
toluene (15 mL) to provide the title compound as a gray solid
Supplementary data
1H NMR spectra and MS data of all previously reported indoles,
as well as 1H and 13C NMR spectra and MS data of all new com-
pounds. Supplementary data associated with this article can be
found in the online version, at doi:10.1016/j.tet.2009.03.004.
(45 mg, 0.185 mmol) in 37% yield: 1H NMR (CDCl3, 300 MHz)
d 8.97
(br s, 1H, NH), 8.06–7.96 (m, 3H), 7.74 (d, J¼8.4 Hz, 2H), 7.60–7.44
(m, 6H), 7.34 (t, J¼7.8 Hz, 1H); 13C NMR (CDCl3, 300 MHz)
d 135.5,
131.3, 130.5, 128.9, 128.8, 127.8, 126.2, 125.6, 124.2, 121.8, 121.6,
121.2, 120.3, 119.8, 119.6, 119.3; HRMS (ESI) calculated for C18NH13
(MþNaþ) requires m/z 266.0946, found m/z 266.0996, mp¼236 ꢀC.
References and notes
1. Sundberg, R. J. Indoles; Academic: London, UK, 1996.
2. Robinson, B. The Fischer Indole Synthesis; John Wiley and Sons: New York, NY,
1982; Ref. 1, p 54–70.
4.2.5. 3-(3,4-Dimethoxyphenyl)indole (3l)
Prepared according to the general procedure from N-phenyl-
hydroxylamine (30 mg, 0.27 mmol) dissolved in 5 mL toluene,
Fe(Pc) (17 mg, 0.03 mmol), 3,4-dimethoxyphenylacetylene (0.972 g,
6 mmol), and toluene (10 mL) to provide the title compound as
a yellow solid (38.6 mg, 0.153 mmol) in 57% yield: 1H NMR (CDCl3,
3. (a) Gassman, P. G.; van Bergen, T. J.; Gilbert, D. P.; Cue, B. W., Jr. J. Am. Chem. Soc.
1974, 96, 5495; (b) Sugasawa, T.; Adachi, M.; Sasakura, K.; Kitagawa, A. J. Org.
Chem. 1979, 44, 578; (c) Bartoli, G.; Bosco, M.; Dalpozzo, R.; Palmeri, G.; Mar-
cantoni, E. J. Chem. Soc., Perkin Trans. 11991, 2757; (d) Hwu, J. R.; Patel, H. V.; Lin,
R. J.; Gray, M. O. J. Org. Chem. 1994, 59, 1577.
4. (a) Hegedus, L. S. Angew. Chem., Int. Ed. Engl. 1988, 27, 1113; (b) Li, J. J. In Alka-
loids: Chemical and Biological Perspectives; Pelletier, S. W., Ed.; Wiley: New York,
NY, 1999; Vol. 14, p 437.
5. (a) Larock, R. C.; Yum, E. K.; Refvik, M. D. J. Org. Chem. 1998, 63, 7652; (b) Larock,
R. C.; Yum, E. K. J. Am. Chem. Soc. 1991, 113, 6689; (c) Arcadi, A.; Cacchi, S.;
Marinelli, F. Tetrahedron Lett. 1992, 33, 3915; (d) Cacchi, S.; Fabrizzi, G.; Ma-
rinelli, F.; Moro, L.; Pace, P. Synlett 1997, 1363; (e) Soderberg, B. C.; Shriver, J. A. J.
Org. Chem. 1997, 62, 5838; (f) Tollari, S.; Cenini, S.; Crotti, C.; Gianella, E. J. Mol.
Catal. 1994, 87, 203; (g) Akazome, M.; Kondo, T.; Watanabe, Y. Chem. Lett. 1992,
769; (h) Yamaguchi, M.; Arisawa, M.; Hirama, M. Chem. Commun. 1998, 1399.
6. (a) Srivastava, A.; Ma, Y.; Pankayatselvan, R.; Dinges, W.; Nicholas, K. M. J. Chem.
Soc., Chem. Commun. 1992, 853; (b) Srivastava, R. S.; Nicholas, K. M. Tetrahedron
Lett. 1994, 8739; (c) Srivastava, R. S.; Nicholas, K. M. J. Org. Chem. 1994, 59, 5365;
(d) Srivastava, R. S.; Khan, M. A.; Nicholas, K. M. J. Am. Chem. Soc. 1996, 118,
3311; (e) Srivastava, R. S.; Nicholas, K. M. Chem. Commun. 1996, 2335; (f) Sri-
vastava, R. S.; Nicholas, K. M. J. Am. Chem. Soc. 1997, 119, 3302; (g) Srivastava, R.
S.; Nicholas, K. M. Chem. Commun. 1998, 2705; (h) Kolel-Veetil, M. K.; Khan, M.
A.; Nicholas, K. M. Organometallics 2000, 19, 3754; (i) O’Dell, D. K.; Nicholas, K.
M. J. Org. Chem. 2003, 68, 6427.
300 MHz)
1H), 7.34 (d, J¼2.4 Hz, 1H), 7.30–7.18 (m, 4H), 6.99 (d, J¼8.1 Hz, 1H),
3.97 (s, 3H), 3.95 (s, 3H); 13C NMR (CDCl3, 300 MHz)
149.3, 147.7,
d
8.23 (br s,1H, NH), 7.92 (d, J¼7.8 Hz,1H), 7.45 (d, J¼7.5 Hz,
d
136.8, 128.6, 126.1, 122.6, 121.5, 120.4, 119.9, 119.8, 118.4, 111.8, 111.6,
111.3, 56.2, 56.1; HRMS (ESI) calculated for C16O2NH15 (MþNaþ)
requires m/z 276.1000, found m/z 276.0898, mp¼150–154 ꢀC.
4.2.6. Scale-up reaction of indole (3l)
Prepared by four sequential 7–8 h additions (w30 h total) of N-
phenylhydroxylamine (four portions of 50 mg, 0.45 mmol, 200 mg,
and 1.8 mmol total) dissolved in 6 mL of toluene each, Fe(Pc)
(113 mg, 0.2 mmol), 3,4-dimethoxyphenylacetylene (3.24 g,
20 mmol), and toluene (35 mL) followed by an additional 8 h reflux
to provide the title compound as
a yellow solid (249 mg,
7. (a) Penoni, A.; Nicholas, K. M. Chem. Commun. 2002, 484; (b) Ragaini, F.; Rapetti,
A.; Visentin, E.; Monzani, M.; Caselli, A.; Cenini, S. J. Org. Chem. 2006, 71, 3748.
8. (a) Penoni, A.; Volkmann, J.; Nicholas, K. M. Org. Lett. 2002, 4, 699; (b) Penoni,
A.; Palmisano, G.; Broggini, G.; Kadowaki, A.; Nicholas, K. M. J. Org. Chem. 2006,
71, 823.
0.984 mmol) in 55% yield. Unreacted alkyne (3.09 g, 19.0 mmol)
was recovered from column chromatography isolation.
4.2.7. 3-(4-Pyridyl)indole (3m)
9. Penoni, A.; Palmisano, G.; Zhao, Y.-L.; Houk, K. N.; Volkman, J.; Nicholas, K. M.
J. Am. Chem. Soc. 2009, 131, 653.
Prepared according to the general procedure for 3 (with pro-
tection from light during reaction) from N-phenylhydroxylamine
(33 mg, 0.3 mmol) dissolved in 5 mL toluene, Fe(Pc) (17 mg,
0.03 mmol), 4-ethynylpyridine (525 mg, 5.1 mmol), and toluene
(10 mL) to provide the title compound as a greenish-white solid
(41.8 mg, 0.215 mmol) in 72% yield (isolated from preparatory TLC
10. Representative preparative examples: (a) Entwistle, I. D.; Gilkerson, T.; John-
stone, R. A. W.; Telford, R. P. Tetrahedron 1978, 34, 213; (b) Sandler, S. R. Organic
Functional Group Preparations; Academic: New York, NY, 1983; Vol. 12, p 416; (c)
Yanada, K.; Yamaguchi, H.; Meguri, H.; Uchida, S. J. Chem. Soc., Chem. Commun.
1986, 1655; (d) Uchida, S.; Yanada, K.; Yamaguchi, H.; Meguri, H. Chem. Lett.
1986, 1069.
11. (a) Johannsen, M.; Jorgensen, K. A. J. Org. Chem. 1994, 59, 214; (b) Johannsen, M.;
Jorgensen, K. A. J. Org. Chem. 1995, 60, 5979; (c) Johannsen, M.; Jorgenson, K. A.
Chem. Rev. 1998, 98, 1689; (d) Ho, C.-M.; Lau, T.-C. New J. Chem. 2000, 24, 859;
(e) Hogan, G. A.; Gallo, A. A.; Nicholas, K. M.; Srivastava, R. S. Tetrahedron Lett.
2002, 43, 9505; (f) Srivastava, R. S.; Khan, M. A.; Nicholas, K. M. J. Am. Chem. Soc.
2005, 127, 7278; (g) Srivastava, R. S.; Tarver, N. R.; Nicholas, K. M. J. Am. Chem.
Soc. 2007, 129, 15250.
using EtOAc): 1H NMR (CDCl3, 300 MHz)
d 8.72 (br s, 1H, NH), 8.64
(d, J¼5.1 Hz, 2H), 8.01 (d, J¼7.5 Hz, 1H), 7.63–7.58 (m, 3H), 7.48 (d,
J¼7.8 Hz,1H), 7.34–7.24 (m, 2H); 13C NMR (CDCl3, 300 MHz)
d 150.2,
143.8, 137.1, 125.3, 123.8, 123.2, 121.8, 121.3, 119.8, 115.6, 112.0;
HRMS (ESI) calculated for C13N2H10 (MþHþ) requires m/z 195.0922,
found m/z 195.0902, HRMS (ESI) calculated for C13N2H10 (MþNaþ)
requires m/z 217.0742, found m/z 217.0727.
12. Adam, W.; Krebs, O. Chem. Rev. 2003, 103, 4131.
13. Maxwell, R. Drug Dev. Res. 1983, 3, 203.
14. (a) Bennett, M.; Donaldson, P. Inorg. Chem. 1978, 17, 1995 and references
therein; (b) Parlier, A.; Rudler, H.; Platzer, N.; Fontanille, M.; Soum, A. J. Chem.
Soc., Dalton Trans. 1987, 1041.
15. (a) Dekker, W.; Selling, H.; Overeem, J. J. Agric. Food Chem. 1975, 23, 785; (b)
Yarrow, J.; Totsukawa, G.; Charras, G.; Mitchison, T. Chem. Biol. 2005, 12, 385; (c)
Ibrahim, P.; Bremer, R.; Gillette, S.; Cho, H.; Nespi, M.; Mamo, S.; Zhang, C.; Artis,
D.; Lee, B.; Zuckerman, R. PCT Int. Appl. WO 2006026754A, 2006; (d) Beevers,
4.3. Nitrosoarene trapping experiment
A mixture of 0.05 mmol Fe(Pc), 5 mmol phenyl acetylene,
5 mmol 2,3-dimethyl-1,3-butadiene, and 15 mL benzene was

A.A. Lamar, K.M. Nicholas / Tetrahedron 65 (2009) 3829–3833
3833
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Cawkill, E.; Clark, N. J. Chem. Soc., Perkin Trans.11980, 244; (c) Gupta, V.; Tandon, S.
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18. FeIII(Pc) could form initially via sacrificial reduction of some ArNHOH by FeII(Pc).
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