Rapid synthesis of fused N-heterocycles by transition-metal-free electrophilic amination of arene C-H bonds

Article abstract of DOI:10.1002/anie.201309973

We disclose an efficient and operationally simple protocol for the preparation of fused N-heterocycles starting from readily available 2-nitrobiaryls and PhMgBr under mild conditions. More than two dozen N-heterocycles, including two bioactive natural products, have been synthesized using this method. A stepwise electrophilic aromatic cyclization mechanism was proposed by DFT calculations. Controlled fusion: A transition-metal-free, low-temperature, and regioselective intramolecular amination of aromatic C(sp²)-H bonds provides fused N-heterocycles. This reaction is operationally simple and scalable (1-10 mmol) and the scope of substrates is wide (see scheme). Density functional calculations indicate that a stepwise electrophilic aromatic cyclization mechanism may be operative.

Full text of DOI:10.1002/anie.201309973

Angewandte
Chemie
DOI: 10.1002/anie.201309973
Heterocycles
Rapid Synthesis of Fused N-Heterocycles by Transition-Metal-Free
ꢀ
Electrophilic Amination of Arene C H Bonds**
Hongyin Gao, Qing-Long Xu, Muhammed Yousufuddin, Daniel H. Ess,* and Lꢀszlꢁ Kꢂrti*
Abstract: We disclose an efficient and operationally simple
protocol for the preparation of fused N-heterocycles starting
from readily available 2-nitrobiaryls and PhMgBr under mild
conditions. More than two dozen N-heterocycles, including two
bioactive natural products, have been synthesized using this
method. A stepwise electrophilic aromatic cyclization mecha-
nism was proposed by DFT calculations.
Given the tremendous importance of functionalized
carbazoles and their derivatives across many fields, it is not
surprising that during the past 50 years dozens of synthetic
methods have been developed to access this valuable hetero-
cyclic framework with a variety of substitution patterns (see
Figure 2 for representative methods):[2–8] 1) the Fischer–
Borsche synthesis[2a] that relies on the [3,3]-rearrangement
of arylhydrazones derived from cyclic ketones followed by
T
he carbazole ring system appears as a motif in a large
number of biologically active natural products, active phar-
maceutical ingredients (APIs), and novel functional organic
materials (Figure 1).[1]
Figure 1. The carbazole structural motif in biologically active natural
products, pharmaceuticals, and functional materials.
[*] Dr. H. Gao, Dr. Q.-L. Xu, Prof. L. Kꢀrti
Division of Chemistry, Department of Biochemistry
University of Texas Southwestern Medical Center
5323 Harry Hines Boulevard, Dallas, TX 75390 (USA)
E-mail: laszlo.kurti@utsouthwestern.edu
Dr. M. Yousufuddin
Figure 2. Selected methods for the synthesis of structurally diverse
Center for Nanostructured Materials
The University of Texas at Arlington, Arlington, TX 76019 (USA)
carbazoles, including our low-temperature, transition-metal(TM)-free
2
ꢀ
intramolecular amination of aromatic C(sp ) H bonds.
Prof. D. H. Ess
Department of Chemistry and Biochemistry
Brigham Young University, Provo, UT 84602 (USA)
E-mail: dhe@chem.byu.edu
dehydrogenation (Figure 2A); 2) one-pot, Pd-catalyzed
[2b,g,h]
ꢀ
ꢀ
domino N H/C H bond activation
using substituted
[**] Financial support from the UT Southwestern Endowed Scholars in
Biomedical Research Program (W.W. Caruth, Jr., Endowed Scholar-
ship in Biomedical Research), the Robert A. Welch Foundation
(grant I-1764), the ACS-PRF (grant 51707-DNI1), and the American
Cancer Society & Simmons Cancer Center Institutional Research
Grant (ACS-IRG 02-196) is greatly appreciated. D.H.E. thanks BYU
and the Fulton Supercomputing Lab. We also express our gratitute
to Professors E. J. Corey (Harvard University), Arthur J. Catino
(Scranton University), Paul Knochel (LMU Munich), and Fabio
Ragaini (University of Milan) for insightful discussions.
anilines and halogenated arenes (Figure 2B); 3) oxidative
cyclization (i.e., dehydrogenative cross-coupling) of substi-
tuted N,N-diarylamines[3] to form an aryl–aryl bond (Fig-
ure 2C); 4) Pd-catalyzed double amination[4] of 2,2’-dihalo-
1,1’-biaryls (Figure 2D); 5) insertion of transition metal
2
(TM)-nitrenoids[5] into aromatic C(sp ) H bonds at elevated
ꢀ
2
ꢀ
temperatures (Figure 2E); 6) oxidative aromatic C(sp ) H
bond amination of 2-aminobiaryls[6] (Figure 2F); 7) Cadogan
cyclization[7] of 2-nitrobiaryls at very high temperatures (150–
2208C) using either excess arylphosphines (e.g., PPh3,
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201309973.
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DPPE), excess trialkylphosphites [e.g., P(OMe)3], or catalytic
amounts of transition metal complexes[7b] (e.g., Pd, Ru, and
Mo) in the presence of pressurized (5–60 bars) carbon
monoxide (Figure 2G); 8) reaction of arynes with nitroso-
arenes,[2i] and 9) iron-mediated synthesis of carbazoles.[8]
Recently we have developed a regioselective, TM-free,
scalable direct aryl–aryl bond-forming process for the syn-
thesis of halogenated 2-amino-2’-hydroxy-1,1’-biaryls
(Scheme 1A).[9] This transformation requires the presence
of this transition-metal-free intramolecular amination reac-
tion for ortho-arylated nitroarene substrates. We find that the
reactions have a wide substrate scope and the cyclization is
highly regioselective. We also present density functional
calculations that probe possible cyclization mechanisms
under reducing conditions.
Since we obtained 6 in a synthetically useful yield (68%),
we decided to examine the transformation of 5!6 more
closely and determine if it can be extended to other 2-
nitrobiaryl systems. Among the different solvents we tried
(THF, DME, Et2O and toluene), THF gave the best results
between ꢀ40 and 08C, both in terms of the highest yield (33–
68%) of 6 and the lowest yield (21–31%) of the hydroxyl-
amine side product (7). Thus we chose THF as the preferred
solvent as we began our studies by conducting a thorough
screen of reaction conditions such as the optimum temper-
ature and the number of equivalents of phenylmagnesium
bromide (Table 1). It was clear from these experiments that in
order to consume all the starting material (5), three equiv-
alents of PhMgBr had to be used at 08C (Table 1, entry 7). At
lower temperatures (Table 1, entries 1–5), either substantial
amounts of 5 was recovered or the ratio of 6 to 7 was too low
to be useful.
Scheme 1. Remarkable difference in reactivity of 2-substituted nitro-
arenes.
Table 1: Optimization of the reaction conditions for the conversion of 5
to 6.[a]
of a halogen substituent in the ortho position of the nitroarene
substrate (1) and likely involves the formation of a N,O-
biarylhydroxylamine intermediate (2) that then undergoes
[3,3]-sigmatropic rearrangement to afford the corresponding
biaryl product (4) upon re-aromatization of intermediate 3.
During these studies, we tested a number of different
substituents (alkyl, alkoxy, azido, etc.) in the 2-position of
nitroarenes under our optimized reaction conditions
[PhMgBr (3 equiv), THF, 08C] and found dramatically differ-
ent reactivities. For example, 2-nitrobiphenyl (5) did not
afford the expected functionalized biaryl (8), but furnished
68% isolated yield of NH-carbazole (6) and 21% yield of
hydroxylamine 7 (Scheme 1B). Even more interesting was
the observation that exposing 5 to vinylmagnesium bromide
(3 equiv) at 08C (i.e., Bartoli indole synthesis) led to an
approximately 1:1 mixture of 6 and 7-phenyl indole (9) in
a combined 66% yield.
Entry
X
T [8C] t [min] Recov. of
5 [%]
Yield[b] of
6 [%]
Yield[b] of
7 [%]
[equiv]
1
2
3
4
5
6
7
8
9
3
3
2.5
3
3
2.5
3
3
ꢀ40
ꢀ20
ꢀ20
ꢀ10
ꢀ10
0
30
20
20
20
15
15
15
20
15
42
15
18
0
0
6
28
37
38
57
46
63
68
58
57
12
19
21
26
31
22
21
21
23
0
0
0
0
3
20
0
[a] Reactions were performed on 1 mmol scale (0.1m solution) under Ar
atmosphere for the indicated amount of time. [b] Yield of isolated
product after column chromatography.
With these optimized reaction conditions in hand, we
initiated an extensive study to determine the scope of
substrates. First, both electron-rich and electron-poor 2-
substituted carbazoles were prepared (11a–f, Scheme 2) and
there was little difference in yields, except when the
substituent was CF3 (11 f). To our surprise, despite the
presence of excess PhMgBr, the CO2Me group was well-
tolerated; presumably the reduction of the nitro group is
significantly faster than addition to the ester functionality
(11g). The substrate containing a nitrile group (CN), how-
ever, furnished the product (11h) only in fair yield. We found
These findings were surprising since an intramolecular
2
ꢀ
amination of an aromatic C(sp ) H bond has taken place in
a preparatively useful manner and under very mild conditions
in order to form 6. In general, aromatic C(sp ) H bonds are
much harder to functionalize than alkenyl C(sp ) H bonds;
2
ꢀ
2
[7b]
ꢀ
indeed, a literature search after this discovery revealed
a single report describing the reductive cyclization of 2-
alkenyl nitroarenes to the corresponding indoles at low
temperature (ꢀ408C).[10] The analogous low-temperature
transformation of ortho-arylated nitroarenes to carbazoles
has never been studied systematically. This transformation
(5!6) is also surprising because the amination reaction
proceeds by a formal electrophilic nitrene insertion under
highly reducing conditions. Here we present the development
ꢀ
that the C N bond formation was regiospecific when 10j was
subjected to the reaction conditions: only 3-methoxycarba-
zole (11j) was formed and not even traces of the regioiso-
meric 1-methoxy carbazole product were detected. Using this
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thiophenyl (12p), and 3,3’-disubstituted (R)-BINOL (12q)
were subjected to our low-temperature intramolecular C-
2
ꢀ
(sp ) H amination protocol. ortho-(2-Naphthyl)nitroarenes
(12a–j) underwent regiospecific cyclization to the corre-
sponding 11H-benzo[a]carbazoles[12] (13a–j); not even trace
amounts of the possible regioisomeric 5H-benzo[b]carbazoles
2
ꢀ
were detected. Clearly the more hindered C(sp ) H bond
(i.e., the 1-position of naphthalene) is specifically and
invariably aminated in all 10 cases (13a–j). This regiochem-
ical outcome is complementary to that of fused carbazoles
obtained using other methods[13,6d] in which invariably the less
2
2
ꢀ
ꢀ
hindered C(sp ) H bonds undergo amination. C(sp ) H
bonds that are part of fused heteroaromatic systems also
underwent amination readily, yielding complex fused N-
heterocycles such as the benzofuro-carbazole[14] (13k),
indolo-quinoline (13l), benzofuro-indole (13m), dihydroin-
dolo-indole (13n), dihydropyrrolo-carbazole[15] (13o), thieno-
indole (13p, and dimeric benzo[a]carbazole[16] (13q). The
only substrate that led to a 7:1 mixture of regioisomers was 5-
(2-nitrophenyl)-N-methylindole 12o; o-nitrobiaryls 12l and
12p gave rise to 13l and 13p, respectively, as single
regioisomers.
Scheme 2. Preparation of mono- and disubstituted carbazoles includ-
ing the bioactive alkaloids 11k and 11l. Reactions were performed on
a 1 mmol scale (0.1m solution) under Ar atmosphere. Structures,
compound numbers, and yields of isolated products are given.
method, two bioactive carbazole alkaloids, clausine V[11]
(11k) and glycoborine (11l), were also obtained in prepara-
tively useful quantities.
Next, we conducted an in-depth investigation (Table 3 was
reformatted as Scheme 3) to determine the regioselectivity of
the method; ortho-nitrobiaryls featuring fused aromatic rings
such as 2-naphthyl (12a–j), 1-dibenzofuranyl (12k), 3-quino-
linyl (12l), 2-benzofuranyl (12m), 3- and 5-indolyl (12n,o), 3-
Naturally, we were eager to explore the possibility of
forming indolines as well as six- or seven-membered N-
heterocycles using our method. None of the nitroarenes (14–
20) shown in Figure 3 undergo cyclization to form the
Figure 3. Substrates that failed to undergo cyclization to five-, six-, or
seven-membered N-heterocycles.
expected indoline or larger N-containing rings; complex
reaction mixtures were obtained that contained varying
amounts of N,N-diaryl hydroxylamine products. These results
are in good agreement with the performance of current
intramolecular arene-amination methods[2a,c–f,h–i,3a,f] as these
furnish only products with five-membered rings.
An initial examination of likely mechanisms for this
transformation was carried out using unrestricted M06-2X/6-
31 + G(d,p) density functional calculations in Gaussian 09
with the SMD solvent model for THF.[17] Explicit THF solvent
was also examined.[18] Open-shell singlet energies were spin-
projected.[19] At the outset we examined the possibility that
carbazole 6 results from electrocyclization of nitroso inter-
mediate 21 (Scheme 4). Pathway I is reasonable to consider
given that a nitroso intermediate has been proposed in the
Bartoli indole synthesis and low barriers have been reported
for similar cyclizations.[20] However, the computed DH° for
21!22 is 32.4 kcalmolꢀ1, which is too high to be consistent
with the facile formation of carbazole 6 at the experimental
temperature of 08C. In addition, not even trace amounts of N-
Scheme 3. Highly regioselective preparation of substituted fused carb-
azoles. Reactions were performed on a 1 mmol scale (0.1m solution)
under Ar atmosphere. Structures, compound numbers, and yields of
isolated products are given.
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27 is exothermic by ꢀ24.6 kcalmolꢀ1, and therefore the 26!
27 step is irreversible. Small barriers were found for hydrogen
migration as well as tautomerization mediated by MgBr-
coordinated phenoxide. Our calculations also rule out the
possibility that phenoxide anion or [MgBr]+ dissociates from
ꢀ
2 prior to cyclization or that cyclization occurs prior to N O
bond cleavage. Concerted conversion of 26 to 6 was not
considered since Li and others have shown that this type of
transition state is significantly higher in energy than a stepwise
pathway.[24]
Pathway II also accounts for the lack of reactivity for
3
ꢀ
C(sp ) H bonds. For example, 14 lacks an arene p system
needed for cyclization. The computed DH° for the cyclization
of 14 via an open-shell singlet TS (hS2i = 0.7) is roughly
27 kcalmolꢀ1. For compounds 16–20 there is a p system, but
cyclization is more difficult since a larger ring would be
formed. For example, DH° for cyclization of 18 is 19.8 kcal
molꢀ1. Lastly, our proposed mechanism can also account for
the observed regioselectivity preference in carbazole forma-
tion. Calculations show a 3.0 kcalmolꢀ1 DDH° between para-
TS2 and ortho-TS2 for cyclization of compound 10j.
Scheme 4. Possible mechanistic pathways (energies in kcalmolꢀ1).
hydroxyindole 23 were detected or isolated. It is also unlikely
that 22 or 23 are readily transformed into carbazole 6.
We next examined whether discrete nitrene intermediates
are involved (Pathway II, Scheme 4). Aryl nitrene intermedi-
ates have been suggested in the case of the Cadogan
cyclization[7a,c–g] and also in the case of Knochelꢀs reductive
indole/benzimidazole synthesis.[10] We were skeptical about
In summary, we have developed a low-temperature,
transition-metal-free, rapid, and highly regioselective intra-
2
ꢀ
molecular amination of arene C(sp ) H bonds, starting from
readily available 2-nitrobiaryls. This transformation has
a wide scope as demonstrated by the preparation of a total
of 30 fused N-heterocycles, including the two bioactive
carbazole alkaloids 11k and 11l. A preliminary examination
of the mechanism using DFT suggests that a stepwise electro-
philic aromatic cyclization mechanism may be operative. We
anticipate that this transformation may serve as a prototype
for related powerful transformations that build molecular
complexity rapidly, under mild conditions with exceptional
step economy and in an environmentally friendly fashion.
the involvement of a discrete nitrene species since 14 and 15
3
ꢀ
failed to give the corresponding C(sp ) H aminated products.
In addition, no azo compounds resulting from nitrene
dimerization or products derived from azirines were
observed. Although prior extensive computational work by
Tsao et al. showed that the barriers for conversion of ortho-
biphenylnitrene 24 into carbazole 6 is small,[21] the thermody-
namics for formation of singlet 24 from intermediate 2
through loss of Mg(OPh)Br suggests that this pathway is
prohibitively high in energy.[22] Explicit THF solvation and
loss of Mg(OPh)(THF)Br does not change this thermody-
namic penalty.
Experimental Section
Alternative to Pathways I and II, there is the possibility
PhMgBr (0.92m in THF solution) (33 mL, 30 mmol) was slowly
(3 mLminꢀ1) added to the mixture of 2-methoxy-6-(2-nitrophenyl)-
naphthalene (12b) (2.79 g, 10 mmol) and dry THF (100 mL) at 08C in
10 min. During this time the internal temperature was closely
monitored and maintained below 38C. Then the mixture was stirred
at 08C for 5 min followed by the slow and careful addition of
saturated NH4Cl aqueous solution (5 mL). The internal temperature
was maintained below 58C. Then 200 mL water was added and the
resulting mixture was extracted with ethyl acetate (3 ꢁ 100 mL). The
combined organic layers were washed with brine (200 mL), dried over
anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude
product was purified by column chromatography to give 3-methoxy-
11H-benzo[a]carbazole (13b) (1.98 g, 80%) as a white solid. 13b:
Rf = 0.35 (hexanes/ethyl acetate = 5:1); 1H NMR (400 MHz,
[D6]DMSO): d = 12.08 (br s, 1H), 8.44 (d, J = 9.2 Hz, 1H), 8.15–8.08
(m, 2H), 7.61 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.47 (d, J =
2.4 Hz, 1H), 7.37 (t, J = 7.2 Hz, 1H), 7.30 (dd, J = 8.8, 2.4 Hz, 1H),
7.19 (t, J = 7.2 Hz, 1H), 3.90 ppm (s, 3H); 13C NMR (100 MHz,
[D6]DMSO): d = 157.4, 139.0, 136.1, 133.9, 124.5, 123.89, 123.85,
120.4, 119.8, 119.5, 118.9, 117.5, 116.6, 116.3, 111.6, 108.3, 55.6 ppm.
that 2, which presumably arises from O-addition of PhMgBr
ꢀ
to 21, undergoes MgBr-mediated N O bond cleavage (via
TS1)[6] to give nitrenoid[23] 26 followed by aromatic addition/
pseudo-electro-cyclization[24] to give 27 (via TS2) and then
hydrogen migration or tautomerization to give carbazole 6
(Pathway III, Scheme 4). Figure 4 shows TS1 and TS2, which
have DH° values of 15.7 and 17.1 kcalmolꢀ1, respectively,
relative to 2. Inclusion of an explicit THF solvent molecule
does not significantly alter DH°. The resulting intermediate
Received: November 17, 2013
Figure 4. TS1 and TS2. Bond lengths reported in ꢁ.
Published online: January 30, 2014
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