Unusual approach to 3-aryl-2-aminopyridines through a radical mechanism: Synthesis and theoretical rationale from quantum mechanical calculations

Article abstract of DOI:10.1021/jo102122h

Tris(trimethylsilyl)silane and azobis(cyclohexanenitrile) promoted the easy intramolecular arylation of aryl bromopyridine carbamates through a radical [1,6] ipso substitution process. These substrates showed a preference for this type of reaction over th

Full text of DOI:10.1021/jo102122h

pubs.acs.org/joc
X by the attacking radical. Since hydrogen is not a feasible
Unusual Approach to 3-Aryl-2-aminopyridines
through a Radical Mechanism: Synthesis and
Theoretical Rationale from Quantum Mechanical
Calculations†
leaving group (X = H), one of the possible methods for the
homolytic process consists of using a good radical leaving
group.1
Despite recent progress concerning the intermolecular
approach,2 the use of intramolecular reactions largely over-
comes the problems of poor regioselectivity obtained in
intermolecular reactions and is therefore much more useful
in synthesis.3 In addition, one of the possible methods for the
intramolecular reaction involves the use of a good radical
leaving group as part of a linker connecting the aryl radical to
the arene under attack. According to previous publications,4
and as shown in Scheme 1, the intramolecular addition of the
aryl radical I can take place at two different carbons. The
reaction at the ortho position (pathway A, Scheme 1) forms
the radical intermediate II, which is converted into the fused
ring III by hydrogen abstraction. Attack at the ipso carbon
(pathway B, Scheme 1) produces the unstable spirocyclodie-
nyl radical intermediate IV. There are several possible reac-
tions for radical IV, but rearomatization by β-scission (ipso
substitution) is generally the fastest alternative if a good
leaving group is present. This reaction sometimes involves
the extrusion of a small, stable fragment and/or molecule to
generate the biaryl derivative, depending on the nature of
substituents W and X.
Marta Camacho-Artacho,‡ Valentina Abet,§
Luis M. Frutos, Federico Gago,*,‡ Julio Alvarez-Builla,§
and Carolina Burgos*,§
‡
§
Departamentos de Farmacologıa, Quımica Organica, and
´
Quımica Fısica, Universidad de Alcala, E-28871 Alcala de
´
ꢀ
´
´
ꢀ
Henares, Madrid, Spain
ꢀ
federico.gago@uah.es; carolina.burgos@uah.es
Received November 4, 2010
In this context, intramolecular arylations, by ipso substi-
tution of suitable sulfonyl,5 phosphinate,6 silyl,7 and benzylic
ether derivatives,8 under reductive conditions, have been
widely reported for the preparation of both biaryls and
arylheterocyclic derivatives.
In a previous paper9 and following on Motherwell’s
work,5 we reported the preparation of 3-aryl-2-aminopyr-
idines 1 through a radical process based on the intramole-
cular heteroarylation of arenesulfonamides in the presence
of tris(trimethylsilyl)silane (TTMSS) and azobis(isobutyro-
nitrile) (AIBN) under thermal conditions. The heteroaryla-
tion process involves the generation of a pyridyl radical, ipso
substitution, and rearomatization through the loss of sulfur
dioxide. However, in all cases the [1,5] ipso substitution
process competes with the alternative [1,6] direct addition,
and the corresponding pyrido[2,3-c][1,2]benzothiazine diox-
ides have been isolated as side products.
Tris(trimethylsilyl)silane and azobis(cyclohexanenitrile)
promoted the easy intramolecular arylation of aryl bro-
mopyridine carbamates through a radical [1,6] ipso sub-
stitution process. These substrates showed a preference
for this type of reaction over the alternative [1,7] addition.
The results were rationalized by making use of quantum
mechanical calculations and computer graphics.
The addition of an aryl radical onto another aromatic
nucleus has become an important tool in organic synthesis,
and consequently, some examples of biaryls and their homo-
logues, such as oligo- and polyaryls, have been prepared
from monoaryl precursors.
Taking the above observations into consideration, and
since the nature, geometry, and number of atoms in the
connecting chain can play an important role in the aromatic
The process can be considered as a substitution procedure
that can be defined as the replacement of a leaving group
(3) Bowman, W. R.; Storey, J. M. D. Chem. Soc. Rev. 2007, 36, 1803–
1822.
(4) Ohno, H.; Iwasaki, H.; Eguchi, T.; Tanaka, T. Chem. Commun. 2004,
2228–2229. and references cited therein.
† Dedicated to Prof. Rafael Suau, “in memoriam”.
(5) (a) da Mata, M. L. E. N.; Motherwell, W. B.; Ujjainwalla, F.
Tetrahedron Lett. 1997, 38, 137–140. (b) da Mata, M. L. E. N.; Motherwell,
W. B.; Ujjainwalla, F. Tetrahedron Lett. 1997, 38, 141–144.
(6) (a) Clive, D.L. J.; Kang, S. J. Org. Chem. 2001, 66, 6083–6091.
(b) Clive, D. L.; Kang, S. Tetrahedron Lett. 2000, 41, 1315–1319.
(7) (a) Studer, A.; Amrein, S.; Matsubara, H.; Schiesser, C. H.; Doi, T.;
Kawamura, T.; Fukuyama, T.; Ryu, I. Chem. Commun. 2003, 1190–1191. (b)
Studer, A.; Bossart, M.; Vasella, T. Org. Lett. 2000, 2, 985–988.
(8) Harrowven, D. C.; Nunn, M. I. T.; Newman, N. A.; Fenwick, D. R.
Tetrahedron Lett. 2001, 42, 961–964.
(1) (a) Studer, A.; Bossart, M. Radicals in Organic Synthesis; Renaud, P.,
Sibi, M. P., Eds.; Wiley-VCH: Weinheim, Germany, 2001; Vol. 2, pp 62-80.
(b) Fossey, J.; Lefort, D.; Sorba, J. Free Radicals in Organic Chemistry;
Wiley: Chichester, U.K., 1995; pp 167-180.
(2) (a) Wetzel, A.; Pratsch, G.; Kolb, R.; Heinrich, M. R. Chem. Eur. J.
2010, 16, 2547–2556. (b) Crich, D.; Grant, D.; Krishnamurthy, V.; Patel, M.
Acc. Chem. Res. 2007, 40, 453–463. (c) Curran, D. P.; Keller, A. I. J. Am.
~
Chem. Soc. 2006, 128, 13706–13707. (d) Nunez, A.; Sanchez, A.; Burgos, C.;
Alvarez-Builla, J. Tetrahedron 2004, 60, 6217–6224. (e) Martinez-Barrasa,
V.; Garcia de Viedma, A.; Burgos, C.; Alvarez-Builla, J. Org. Lett. 2000, 2,
3933–3935.
~
(9) Sanchez, A.; Nunez, A.; Alvarez-Builla, J.; Burgos, C. Tetrahedron
2004, 60, 11843–11850.
1452 J. Org. Chem. 2011, 76, 1452–1455
Published on Web 01/25/2011
DOI: 10.1021/jo102122h
r
2011 American Chemical Society

Camacho-Artacho et al.
JOCNote
SCHEME 1. Intramolecular Addition of Aryl Radicals onto
Arenes
SCHEME 3. Preparation of Starting Materialsa
SCHEME 2. Two Plausible Pathways for the Intramolecular
Arylation of Carbamate Derivatives through a Radical Process
aLegend: (a) aryl chloroformate in dry acetone, room temperature,
10 min; (b) Et3B in EtOH, room temperature, 24 h; (c) NaH in dry DMF,
0-5 °C, 30 min, MeI, room temperature, 1 h; (d) MeI in dry acetone,
room temperature, 36 h; (e) Pt/C, HCO2H, Et3N in MeCN, room
temperature, 4 h; (f) NaH in dry CH2Cl2, aryl chloroformate, reflux
24 h.
TABLE 1. Preparation of Starting Material 3 from N-Aminide 9
product, yield (%)
entry
Ar
method
8
10
3
1
2
3
4
5
6
7
8
9
10
Ph
Ph
A
B
A
A
A
B
A
B
A
B
8a, 98
10a, 29
3a, 39
3b, 60
3c, 67
4-Me-C6H4
4-MeO-C6H4
4-Cl-C6H4
8b, 98
8c, 78
8d, 75
10b, 60
10c, 65
10d, -
4-Cl-C6H4
3d, 60
3e, 71
3f, 65
4-NO2-C6H4
4-NO2-C6H4
1-naphthyl
1-naphthyl
8e, 88
8f, 90
10e, -
10f, 25
Previous studies5 seem to demonstrate that simplistic ideas
related to a kinetically driven pathway and a preference for the
formation of six- over seven-membered rings are invalid.11,12
Thus, to explain the regiochemistry of ring closure, we turned
to quantum mechanical calculations. Prior work in this area
has been communicated by Ganguly and co-workers.12
Our initial work in this field started from the salts 8 (R2 =
pyridinium; Scheme 3), obtained from N-aminide 9 by
reaction with different aryl chloroformates (method A).
Reduction of the N-N bond furnished the unsubstituted
carbamates 10 (R2 = H), and methylation on the exocyclic
nitrogen provided methyl carbamates 3, which are starting
materials for the radical cyclization process. However, this
pathway only gave satisfactory results in some cases (entries
3 and 4 in Table 1; Ar = 4-Me-C6H4, 4-MeO-C6H4, respec-
tively), and an alternative route (method B) was chosen,
starting from N-aminide 9, to prepare 3 in good yields
through compounds 11 and 12, using a previously described
method.13
substitution,3 we turned our attention to the studies of
Newcomb and co-workers10 concerning carbamate derivatives
•
and the corresponding carbamoyloxyl radicals R2NCO2 .
The authors reported that these kinds of compounds can
afford aminyl radicals by decarboxylation of the initially
•
formed R2NCO2 radicals. In this context, the pyridyl radical
2 (Scheme 2), obtained from the bromopyridine 3, could
evolve through a [1,7] addition (pathway A), to yield 4 and 5.
Alternatively, 2 could be cyclized onto the aryl moiety
through an intramolecular [1,6] process to yield the spiro-
cyclic radical 6. This intermediate could rearomatize by
β-scission and decarboxylation of the initially obtained
carbamoyloxyl radical 7 to produce 1.
(11) For some examples of 7-trig cyclization see: (a) De la Fuente, M. C.;
Dominguez, D. J. Org. Chem. 2007, 72, 8804–8810. and references cited
therein. (b) Ishibashi, H. Chem. Rec. 2006, 6, 23–31.
(12) Ganguly, A. K.; Wang, C. H.; Misiaszek, J.; Chan, T. M.; Pramanik,
B. N.; McPhail, A. T. Tetrahedron Lett. 2004, 45, 8909–8912.
(13) (a) Abet, V.; Nunez, A.; Mendicuti, F.; Burgos, C.; Alvarez-Builla, J.
J. Org. Chem. 2008, 73, 8800–8807. (b) Nunez, A.; Sanchez, A.; Burgos, C.;
Alvarez-Builla, J. Tetrahedron 2007, 63, 6774–6783. (c) Martinez-Barrasa,
V.; Delgado, F.; Burgos, C.; Garcia-Navio, J. L.; Izquierdo, M. L.; Alvarez-
Builla, J. Tetrahedron 2000, 56, 2481–2490.
(10) (a) Newcomb, M.; Marquardt, D. J.; Deeb, T. M. Tetrahedron 1990,
46, 2317–2328. (b) Newcomb, M.; Marquardt, D. J.; Kumar, M. U. Tetra-
hedron 1990, 46, 2345–2352.
J. Org. Chem. Vol. 76, No. 5, 2011 1453

Camacho-Artacho et al.
JOCNote
TABLE 2. Preparation of Biaryls 1 from Carbamates 3
product, yield (%)
entry
Ar
1
5
1
2
3
4
5
7
Ph
1a, 67
1b, 75
1c, 35
1d, 47
1e, 45
1f, 45
5a, traces
5b, traces
5c, -
4-Me-C6H4
4-MeO-C6H4
4-Cl-C6H4
4-NO2-C6H4
1-naphthyl
5d, -
5e, -
5f, -
Therefore compounds 3 were prepared by two alternative
routes: method A, 9 f 8 f 10 f 3; method B, 9 f 11 f 12 f
3. Method A works only for Ar = 4-Me-C6H4 and 4-MeO-
C6H4.
Bearing in mind previous reports from Motherwell5 and
Ganguly,12 and our own previous results,13 the radical reac-
tion was attempted in the presence of TTMSS and azobis-
(cyclohexanenitrile) (ABCN) under thermal conditions.
However, in the course of our experiments to improve the
initial yields, we were able to detect only traces of compounds
5 (if at all) and only biaryl derivatives 1 could be isolated in
moderate yields (see Table 2).
FIGURE 1. Free energy profile for the intramolecular cyclization
reaction leading from the starting radical (2) to the cyclic radicals 6
and 4 by way of transition states TS1 and TS2, respectively. Note
that conformation 21 leads to TS1 and conformation 22 leads to TS2
and also that an additional barrier of ∼13-14 kcal mol-1 separates
the more stable trans conformation of 2 from the reactive cis
conformation shown here (Supporting Information, Figure S1).
the free energy of activation for each optimized structure
at 298.15 K, their relative equilibrium population being
given by
In order to shed some light on this striking result, the
optimized geometries and electronic structures of radicals 2,
4, and 6 (R1 = Me), as well as those of the corresponding
transition states (TS1 and TS2), were calculated by means of
the unrestricted density functional theory (DFT) method
B3LYP and a 6-31G(d) basis set, as implemented in Gauss-
ian 03.14 Vibrational frequencies were computed on the
stationary points to identify them as a TS (one imaginary
frequency corresponding to the intramolecular bond to be
created) or an energy minimum (all frequencies positive) on
the potential energy surface. TS were located using the
synchronous transit-guided quasi-Newton (STQN) method,
and IRC (intrinsic reaction coordinate) calculations in both
directions were also performed using 30 steps of 0.1 amu1/2
Bohr increments along the reaction pathway. Molden 4.715
was used to visualize molecular structures and orbitals. To
compare the relative accessibility of each TS, we computed
pTS
1
- ΔΔGq=RT
µ e
p
TS2
where p is the equilibrium population and ΔΔGq is the
difference in the free energy of activation. It is important
to realize that, for cyclization to take place, the amide bond
of radical 2 must adopt a cis conformation and also that the
reactive conformation leading to TS2 (236.66i cm-1) and 4 is
achieved only after visiting that leading to TS1 (284.01i
cm-1) and 6 upon rotation of the pyridine ring relative to
the phenyl ring (Figure 1). Furthermore, TS1 turns out to be
∼2.6 kcal mol-1 more stable than TS2, which translates into
an expected ratio for both species of 96% and 4%, respec-
tively, in good agreement with the experimental findings, and
radical 6 is stabilized through hyperconjugation due to
delocalization of the spin density on the phenyl ring
(Scheme 2 and Figure 1; see also Figure S2 in the Supporting
Information).
With regard to the molecular orbital (MO) containing the
electron that will pair up with that present in the SOMO
(#72) to form the new bond, we focused on the HOMO (#71)
and HOMO-1 (#70), each of which lodges a pair of electrons
(one in orbital R and the other in orbital β). The HOMO
contributions in 2 emanate from atoms that are not directly
involved in the reaction mechanism but instead participate in
the π cloud of the pyridine ring and are conjugated with the
lone pairs of the heteroatoms that form the carbamate amide
bond. In contrast, representation of the HOMO-1, in both 2
and TS1, showed the important contribution to this orbital of
the atoms involved in the formation of the new bond
(Supporting Information, Figure S3). A succinct graphical
overview of the frontier orbital energy levels for the starting
radical, for the reactive conformation (2) TS1, and for the
(14) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Montgomery, Jr., J. A.; Vreven, T.; Kudin, K. N.;
Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci,
B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada,
M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima,
T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.;
Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.;
Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;
Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.;
Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels,
A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari,
K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski,
J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin,
R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.;
Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.;
Gonzalez, C.; and Pople, J. A. Gaussian 03, Revision B.04; Gaussian, Inc.,
Wallingford, CT, 2004.
(15) Schaftenaar, G.; Noordik, J. H. Molden: a pre- and post-processing
program for molecular and electronic structures. J. Comput.-Aided Mol.
Design 2000, 14, 123–134. (http://www.cmbi.ru.nl/molden/).
1454 J. Org. Chem. Vol. 76, No. 5, 2011

Camacho-Artacho et al.
JOCNote
temperature was maintained at <5 °C (vigorous stirring is
required to keep the suspension fluid). Upon complete addition,
the suspension was stirred vigorously for an additional 20 min
while the temperature was maintained below 5 °C, and then
methyl iodide (1.15 mmol) was added dropwise. After it was
stirred for 30 min, the reaction mixture was brought to room
temperature over a 1 h period, before water (0.5 mL) was added.
The mixture was then diluted with water (2 mL) and Et2O
(10 mL). The organic layer was separated and extracted with water,
0.1 M HCl, saturated aqueous NaHCO3 solution, and brine,
before being dried and concentrated. The resulting residue was
then purified by chromatography (silica gel, hexane/ethyl ace-
tate (80/20)), furnishing products 3b,c.
General Procedure for the Preparation of N-Methylcarba-
mates 3a,d-f: Method B. To a suspension of 12 (1 mmol) and
NaH (2 mmol) in anhydrous CH2Cl2 (6 mL) was added the
corresponding chloroformate (1.1 mmol), and the reaction
mixture was heated to reflux. Stirring was maintained at the
same temperature for a further 24 h. The reaction mixture was
brought to room temperature, and water (1 mL) was added.
The mixture was then diluted with water (2 mL) and CH2Cl2
(10 mL). The organic layer was separated, washed with water,
dried, and concentrated. The resulting residue was then purified
by chromatography (hexane/ethyl acetate (90/10)).
General Procedure for the Preparation of N-Methylamines
1a-f. A solution of TTMSS (248 mg, 1 mmol) and ABCN (164
mg, 1 mmol) in m-xylene (10 mL) was added dropwise by syringe
pump, over 13 h, to a stirred solution of the corresponding
N-methylcarbamate 3 (0.5 mmol) in m-xylene (2 mL) at 80 °C
(bath temperature). After the mixture was stirred for a further 12 h,
the same amount of ABCN and TTMSS was added dropwise by
syringe pump, over 13 h. Stirring was maintained at the same
temperature for a further 12 h. The solution was concentrated and
the crude mixture separated by flash chromatography on silica gel
(hexane/ethyl acetate).
FIGURE 2. Simplified molecular orbital correlation diagram show-
ing the occupation and energies of the frontier orbitals (SOMO [72R]
and SUMO [72β], HOMO [71R and 71β] and HOMO-1 [70R and
70β]) of (from left to right) the “reactant” (starting radical, 2), the
major TS (TS1), and the “product” (cyclic radical, 6). Orbital num-
bering is referred to product 6. The dotted lines show the evolution of
the SOMO, with radical character in 2 to HOMO-1 corresponding to
a σ bond in 6, as well as the evolution of HOMO-1 with π character in
2 to radical character in 6.
cyclic radical 6 (Figure 2) shows the closeness (and even
overlap) of the energy levels of the SOMO, HOMO, and
HOMO-1 in 2, and also how far they are from the SUMO. In
summary, the single electron in the low-energy SOMO pairs
with one of the electrons in HOMO-1 to create a new
bonding orbital, which is very low in energy, and the new
radical 6, which contains the unpaired electron in a SOMO
higher in energy than in the original radical species. This
radical evolves, through the loss of a CO2 molecule, toward
the final major product 1.
Acknowledgment. We acknowledge support of this work
ꢀ
from the Ministerio de Ciencia e Innovacion (projects
CTQ2008-05027, CTQ2009-07120, and SAF2006-12713-
C02-02), Comunidad de Madrid (S-BIO/0214/2006), and
ꢀ
the Instituto de Salud Carlos III (Red de Investigacion
Renal, REDinREN, RD06/0016/0016). V.A. is grateful to
ꢀ
the Ministerio de Educacion y Ciencia for a research fellow-
ship and L.M.F. for a “Ramon y Cajal” contract.
Experimental Section
General Procedure for the Preparation of N-Methylcarba-
mates 3b,c: Method A. The corresponding compound 10 (see
the Supporting Information) (1.0 mmol) was dissolved in anhy-
drous DMF (3 mL), and the solution was cooled to 0 °C in an
ice/water bath. Sodium hydride (50 mg, 60% suspension in oil,
1.25 mmol) was added in portions such that the internal
Supporting Information Available: Text, tables, and figures
giving (1) supplementary graphics, (2) experimental details and
characterization data, (3) copies of 1H and 13C spectra, (4) tables
of atom coordinates, and (5) absolute energies for TS1 and TS2.
This material is available free of charge via the Internet at http://
pubs.acs.org.
J. Org. Chem. Vol. 76, No. 5, 2011 1455