Synthesis of benzimidazoles by phosphine-mediated reductive cyclisation of ortho-nitro-anilides

Article abstract of DOI:10.1002/hlca.201100123

Heating ortho-nitro-anilides 1-3 and 2-methyl-N-(3-nitropyridin-2-yl) propanamide (5) with 4 equiv. of a phosphine led to the 2-substituted benzimidazoles 6-8 and to the imidazo[4,5-b]pyridine 10, respectively, in yields between 45 and 85%. Heating 1 with (EtO)₃P effected cyclisation and N-ethylation, leading to the 1-ethylbenzimidazole 6b. The slow cyclisation of the N-pivaloylnitroaniline 2b allowed isolation of the intermediate phosphine imide 11 that slowly transformed into the 1H-benzimidazole 7b. The structure of 11 was established by crystal-structure analysis. While the N-methylated ortho-nitroacetanilide 3 cyclised to the 1,2-dimethyl-1H-benzimidazole (8), the 2-methylpropananilide 4 was transformed into 1-methyl-3-(1-methylethyl)-2H- benzimidazol-2-one (9).

Full text of DOI:10.1002/hlca.201100123

Helvetica Chimica Acta – Vol. 94 (2011)
977
Synthesis of Benzimidazoles by Phosphine-Mediated Reductive Cyclisation of
ortho-Nitro-anilides
by Jan Duchek and Andrea Vasella*
Laboratorium fꢀr Organische Chemie, ETH Zꢀrich, Wolfgang-Pauli Strasse 10, CH-8093 Zꢀrich
(e-mail: vasella@org.chem.ethz.ch)
Heating ortho-nitro-anilides 1 – 3 and 2-methyl-N-(3-nitropyridin-2-yl)propanamide (5) with 4
equiv. of a phosphine led to the 2-substituted benzimidazoles 6 – 8 and to the imidazo[4,5-b]pyridine 10,
respectively, in yields between 45 and 85%. Heating 1 with (EtO)3P effected cyclisation and N-
ethylation, leading to the 1-ethylbenzimidazole 6b. The slow cyclisation of the N-pivaloylnitroaniline 2b
allowed isolation of the intermediate phosphine imide 11 that slowly transformed into the 1H-
benzimidazole 7b. The structure of 11 was established by crystal-structure analysis. While the N-
methylated ortho-nitroacetanilide 3 cyclised to the 1,2-dimethyl-1H-benzimidazole (8), the 2-methyl-
propananilide 4 was transformed into 1-methyl-3-(1-methylethyl)-2H-benzimidazol-2-one (9).
Introduction. – The reductive cyclisation of 6-(acylamino)-5-nitrosopyrimidines
using triaryl- or trialkylphosphines leads in high yields to 8-substituted guanines [1][2].
This robust method has, to the best of our knowledge, only be used for the cyclisation of
the above mentioned nitrosopyrimidines [3]. We became interested in the analogous
reductive cyclisation of N-acyl-2-nitroanilines and similar heteroaromatic compounds,
considering the practically limited access to nitroso arenes [4][5] and the much easier
synthesis of N-acyl-2-nitroanilines. The cyclisation is expected to lead to annulated
imidazoles, and would be particularly attractive if phosphites could be used besides
phosphines. We decided to test this reductive cyclisation by transforming a few ortho-
nitro-anilides, notwithstanding the many known methods for the synthesis of
benzimidazoles1) [7]. The first synthesis of a benzimidazole was reported in 1872 by
Hobrecker who treated 4-methyl-2’-nitroacetanilide with Sn/HCl and isolated 2,5-
dimethylbenzimidazole [8]. Since then, ortho-nitro-anilides were transformed to
benzimidazoles in reducing media such as Zn/AcOH and Fe/HCl, by catalytic or
electrochemical reduction, or by treatment with ferrous oxalate. Stepwise procedures,
i.e., cyclisation of intermediate ortho-amino-anilides or reduction of intermediate
benzimidazole N-oxides are also well-known. All of the mentioned methods, as well as
other ones used for the synthesis of benzimidazoles, were thoroughly reviewed [9 – 14].
Results and Discussion. – The starting known ortho-nitro-anilides 1 – 4 [15] were
prepared from the commercially available 2-nitroaniline and N-methyl-2-nitroaniline.
N-(3-Nitropyridin-2-yl)isobutyramide was prepared by acylating the commercially
available 3-nitropyridin-2-amine with isobutyryl chloride in the presence of Hꢀnigꢁs
1
)
For selected recent syntheses, see [6].
ꢂ 2011 Verlag Helvetica Chimica Acta AG, Zꢀrich

978
Helvetica Chimica Acta – Vol. 94 (2011)
base at room temperature that resulted in a mixture of 5 (61%) and the N,N-diacylated
product (35%). The 1H-NMR spectra of the N-methyl anilides 3 and 4 in CDCl3 display
two sets of signals, evidencing a mixture of (E)- and (Z)-rotamers. Due to the
deshielding by the C¼O group, the N-Me group of the (E)-rotamer resonates at
lower field than that of the (Z)-rotamer (Dd ¼ 0.2 ppm). The nitro-anilides 1 and 2 and
the pyridine-derived nitro-anilide 5 in CDCl3 solution are (E)-configured single
rotamers, due to the intramolecular H-bond between NH and the NO2 group, as
evidenced by the chemical shift of the NH signal (d 10.27 – 11.36 for 1 and 2, and
9.82 ppm for 5)2).
The 6-(acylamino)-5-nitrosopyrimidines had been cyclised to guanines by treat-
ment with 2 equiv. of Ph3P in boiling xylene [1]. The ortho-nitro-anilides 1 – 3 and the
pyridine derivative 5 were unreactive under these conditions, while cyclisation in the
presence of 4 equiv. of Ph3P in boiling decane (1748) effected the desired trans-
formation. The expected 2-substituted benzimidazoles 6 – 8 (Table) and the imidazo-
pyridine 10 were isolated in yields between 45 and 85% (Entries 1, 4, 7, 8, 10, 12, and 14,
in the Table).
A scouting experiment suggested that replacing Ph3P by 1,2-bis(diphenylphosphi-
no)ethane (DPPE) has only a small effect on yields [19].
Replacing xylene by p-cymene, 1,2-dichlorobenzene, ethoxybenzene, or diethylene-
glycol diethyl ether provided the benzimidazoles in similar yields, while treating 5 with
Ph3P in boiling DMF led to a mixture of products. The reaction proceeded faster at the
higher temperature of boiling diethylene glycol diethyl ether (1908), but yields were not
improved (Entries 2 and 5). Microwave heating of solutions in 1,2-dichlorobenzene/
DMF 10 :1 to 2508 in a sealed vessel (Entries 6, 9, and 11) shortened the reaction time
considerably. The cyclisations were completed within 30 min, with yields comparable to
those resulting from conventional heating.
Heating 1 with (EtO)3P in decane (Entry 3) led to cyclisation and to N-ethylation,
yielding 42% of the 1H-benzimidazole 6b. N-Alkylation was also observed when
(BuO)3P was used instead of (EtO)3P. A scouting experiment showed that (PhO)3P
transformed 1 slowly into 6a, as inferred from TLC.
The reaction of the N-pivaloyl-2-nitroaniline (2b) in boiling decane proceeded
more slowly than the one of the less bulky anilides, requiring several days to form 7b.
This allowed identifying an intermediate. Monitoring the reaction by TLC showed the
initial appearance of a less polar compound that was slowly converted to 7b.
Interrupting the reaction after 12 h allowed isolation of the 1H-benzimidazole 7b
(15%) and a less polar intermediate (59%) that was identified as the phosphine imide
11 [34] by crystal-structure analysis3) (Fig. 1).
2
)
A similar H-bond was observed between neighbouring C(O)NH and NO groups [2][16]. Its effect
on the acylation of 2,4-diamino-5-nitrosopyrimidines and 2-amino-4-(methylamino)-5-nitrosopyr-
imidines was discussed [17]. NH of N-(pyridin-2-yl)isobutyramide in CDCl3 solution resonates at d
8.06 ppm [18].
The crystallographic data have been deposited with the Cambridge Crystallographic Data Centre,
with deposition No. CCDC-807072 for 11 and CCDC-807073 for 9. Copies of the data can be
obtained free of charge via http://www.ccdc.cam.ac.uk/data_request/cif.
3
)

Helvetica Chimica Acta – Vol. 94 (2011)
979
Table. Reductive Cyclisation of 2-Nitroanilides 1 – 4 and N-(3-Nitropyridin-2-yl) Amide
5
with
Phosphines or Phosphites
Entry
Starting material
Conditionsa)
Product
Yield [%]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1
1
1
[20][15a]
A (12 h)
B
C
A (12 h)
B
D
A (144 h)
A (12 h)
D
A (12 h)
D
A (12 h)
A (12 h)
A (12 h)
6a
6a
6b
7a
7a
7a
7b
7c
7c
7d
7d
8
[21][6q]
85
70
42
74
70
69
49
62
76
64
53
45
49
63
[22][6z][6aa][7b]
[24][25]
2a
2a
2a
2b
2c
2c
2d
2d
3
[23][15a]
[26][15a]
[28][15b]
[27][6l]
[21][6c]
[29][15b]
[30][6b]
[32][33]
[31][15b]
[15c]
4
5
9
10
a) A: PPh3, decane, reflux (Treflux ¼ 168 – 1788); B: 1,2-bis(diphenylphosphino)ethane (DPPE), dieth-
ylene glycol diethyl ether, reflux (Treflux ¼ 180 – 1908), 2 h; C: P(OEt)3, decane, reflux, 12 h; D: PPh3, 1,2-
dichlorobenzene/DMF, microwave irradiation, 2508, 1 bar, 30 min.
In the solid state of 11, the acylamino group adopts the s-cis-configuration. The
torsion angle C(1)ꢀN(7)ꢀC(8)ꢀO(9) is ꢀ 7.38, with the C¼O group turned away from
to the phosphine imide moiety, the torsion angle C(8)ꢀN(7)ꢀC(1)ꢀC(2) being
ꢀ 175.38. In solution in CDCl3, 11 forms an intramolecular NH ··· N¼P H-bond, as
evidenced by the chemical shift of the NH signal, resonating at 9.70 ppm. Although the
position of the corresponding H-atom in the solid state of 11 could not be determined,

980
Helvetica Chimica Acta – Vol. 94 (2011)
Fig. 1. Crystal structure of the phosphine imide 11
the distance N(7) ··· N(14) is 2.58 ꢃ, with a calculated N(7)H ··· N(14) distance of ca.
2.16 ꢃ. No intermolecular H-bonds are detectable in the solid state of 114).
Surprisingly, heating the N-methylated isobutyramide 4 and Ph3P in boiling decane
(Entry 13) led to a product (49%) that could not be the expected benzimidazole, the
CH group of the isopropyl group resonating at an unexpectedly low field (4.74 ppm),
and the IR spectrum showing a strong (C¼O) band at 1688 cmꢀ1. The structure of the
benzimidazolone 9 was established by crystal structure analysis3) (Fig. 2).
Fig. 2. Crystal structure of the rearrangement product 9
4
)
A considerable number of crystal structure analyses of phosphine imides were found in the
Cambridge Data File, many of them as metal complexes. For representative references, see [35].

Helvetica Chimica Acta – Vol. 94 (2011)
981
The formation of the phosphine imide 11 and, particularly, the contrast between the
formation of the benzimidazole 8 from 3, but of the benzimidazolone 9 from 4, were
surprising. We had expected the reaction mechanism for the cyclisation of the nitro-
anilides 1 – 4 to be similar to the one suggested for the cyclisation of 4-(acylamino)-5-
nitrosopyrimidines [1], i.e., reduction of the NO2 to the NO group, followed by addition
of the phosphine to the NO group, and formation of an aza-Wittig reagent5) via a
nitrene or nitrenoid intermediate. Surprisingly, however, no intermediate phosphine
imide was observed during the formation, under milder reaction conditions, of an 8-
(tert-butyl)guanine from a 4-(pivaloylamino)-5-nitrosopyrimidine [1]. The addition of
a phosphine to the NO2 group6) is thought to occur more slowly than that to the NO
group, due to the different formal negative charge on the O-atoms [39], the relative
stability of NO2 and NO compounds, and – for nitrosopyrimidines – also to the effect of
the electronegative properties of the heteroaromatic ring7). For the anilides 1 and 2,
and for 5, the nucleophilic attack of the phosphine may also occur more readily than
onto the N-alkylated nitro-anilide 3, on account of the intramolecular H-bond. This
difference of reactivity of the nitro-anilides is, however, not expected to affect the
outcome of the reaction, and the lower yields for the cyclisation of 3 to 8 must reflect
the different reactivity of the bona fide NO intermediate, or one of the subsequently
formed reactive intermediates.
A reaction mechanism rationalising the observations is depicted in the Scheme 2.
Starting material (SM) for the discussion of the reaction mechanism are the bona fide
intermediate nitrosoamides. Addition of Ph3P to the nitrosoamides possessing an NH
group is expected to lead to an intermediate 12, which is stabilized by an intramolecular
NH ··· N H-bond. Elimination of Ph3PO then generates the H-bond-stabilised nitrenoid
intermediate 13 [40]. Reaction with Ph3P forms the phosphine imide 14, which is also
stabilized by an intramolecular H-bond. As a consequence of this H-bond, the
phosphine imide moiety and the C¼O group of 14 are too far away from each other to
undergo an intramolecular aza-Wittig reaction8). However, at the high temperature of
the reaction, conformers 14 and 15 will (partially) equilibrate. The ensuing aza-Wittig
reaction of conformer 15 leads to the observed benzimidazoles 6 and 7.
The aza-Wittig reaction of the pivaloyl amide is sufficiently slow to allow isolating
the phosphine imide 11, since addition of the phosphine imide moiety to the C¼O group
generates an intermediate with two adjacent tetrahedral centres.
In the absence of the NH group, elimination of Ph3PO from the addition product 16
may lead to the nitrene 17, as there is no configurational bias by a H-bond.
5
)
For the formation of indoles by intramolecular Wittig reaction, see [36]. For a review about
phosphine imides in the synthesis of heterocycles, see [37].
6
7
8
)
A single-electron transfer (SET) to the NO2 group cannot be excluded on the basis of our
experiments. For a reaction of a phosphite anion that leads to a SET to a shielded NO2 compound
and to a nucleophilic attack on a less shielded analogue, see [38].
The consequence, i.e., the expectation that the cyclisation of ortho-nitro-anilides possessing
acceptor substituents and of heteroaromatic analogues will give the best results, has not yet been
checked.
A similar effect of an intramolecular H-bond stabilizing the starting material was observed for the
intramolecular [4 þ 2] cycloaddition of 6-(dienoylamino)-5-nitrosopyrimidines [2][41] and for the
nitroso-ene reaction of 4-(alkenoylamino)-5-nitrosopyrimidines [16].
)
)

982
Helvetica Chimica Acta – Vol. 94 (2011)
Scheme. Reaction Mechanism Rationalising the Transformation of the Intermediate Nitrosoanilines
(SM ¼ Starting Material) to the Products 6 – 8 of Cyclisation and to the Rearrangement Product 9
Electrocyclisation of 17 forms 18 that may evolve towards the oxaziridine 19.
Oxaziridine intermediates were considered before as intermediates in related reactions
[42]. The NꢀO bond of 19 may open either to generate the N-oxide 20 that will be
deoxygenated by Ph3P, leading to the dimethylbenzimidazole 8, or to the ortho-
diazaquinoid intermediate 21 that will generate the rearranged product 9 either by a
[1,5] sigmatropic rearrangement [43], or by a 1,2 pinacolꢀpinacolone type migration of
the i-Pr group. It is, however, not clear why there should be such a dichotomy in the
opening of the oxaziridine substituted by either a Me, or an i-Pr group, so that one
oxaziridine will react while maintaining the aromatic ring intact, and the other one lead
to dearomatization. It is more likely that the isobutyrylamino group of 16 (R ¼ 1-
methylethyl ¼ isopropyl) is more strongly turned out of the plane of the aromatic ring
than the one of the analogous acetamido derivative, and directly attacked by the
negatively charged N-centre to generate the phosphorane 22 and hence 21, while the
acetamido analogue may evolve via 17 – 20, and result in the benzimidazole 8.
Thus, ortho-nitro-anilides are converted by reaction with phosphines in one pot to
form annulated imidazoles or imidazolones in non-optimized yields between 45 and
85%, with intramolecular H-bonds and conformational aspects strongly influencing the
course of the transformation.

Helvetica Chimica Acta – Vol. 94 (2011)
983
We thank the Syngenta AG, Basel, for generous support, Dr. Bruno Bernet for checking the
experimental data, and Dr. W. Bernd Schweizer for determining the crystal structures.
Experimental Part
General. Solvents were distilled. Commercially available reagents were used as supplied. The
reactions were carried out in oven-dried glassware, under N2 or Ar, unless stated otherwise. Qual. TLC:
precoated silica-gel plates (Merck silica gel 60 F254); detection by UV. Flash chromatography (FC): silica
gel Fluka 60 (0.04 – 0.063 mm) or alumina under slightly elevated pressure (0.1 – 0.4 bar). M.p.:
uncorrected. IR Spectra: ca. 2% soln. in CHCl3; absorptions in cmꢀ1. NMR Spectra: chemical shifts d in
ppm rel. to TMS as external standard or to a solvent peak; multiplicities of 13C-signals determined by
DEPT (distortionless enhancement of polarisation transfer). HR-MS-MALDI: in gentisic acid (¼2,5-
dihydroxybenzoic acid, DHB) or 3-hydroxypicolinic acid (3-HPA) matrix. For elemental analysis,
samples were sublimed or dried for at least 3 d at < 10ꢀ4 Torr.
General Procedure for the Synthesis of Anilides 1 and 2. The acyl chloride (1.5 equiv.) was added over
30 min to a cold (48) orange soln. of 2-nitroaniline (3 – 4 mmol) and DMAP (¼4-(dimethylamino)pyr-
idine; 0.03 equiv.) in a 1:1 mixture of pyridine (12 – 15 equiv.) and CH2Cl2. The mixture was stirred, until
TLC indicated the disappearance of the starting material, diluted with CH2Cl2, washed with 2m HCl, sat.
aq. NaHCO3 soln., and brine, dried (MgSO4), and evaporated. FC afforded the desired anilides.
General Procedure for the Synthesis of Anilides 3 and 4. A dark ocre soln. of N-methyl-2-nitroaniline
(4 – 5 mmol) in an acyl chloride (10 – 20 equiv.) was treated with Hꢀnigꢁs base (1.3 – 1.5 equiv.) at 258. The
mixture was stirred at the indicated temp., until TLC indicated the disappearance of the starting material,
and poured into 10% aq. Na2CO3 soln. The mixture was vigorously stirred for 1 h and extracted with
CH2Cl2. The combined org. layers were washed with brine, dried (MgSO4), and evaporated. FC afforded
the desired anilides.
General Procedure A for the Synthesis of Benzimidazoles. A soln. of an anilide (0.5 mmol) in decane
(5 ml) was treated with Ph3P (4 equiv.). The mixture was heated to reflux, until TLC indicated the
disappearance of the starting material, left to reach 258, diluted with CHCl3, and purified by FC and/or
crystallisation to obtain the desired benzimidazoles.
General Procedure B for the Synthesis of Benzimidazoles. A soln. of an anilide (0.1 mmol) in 1,2-
dichlorobenzene (1.5 ml) and DMF (0.15 ml) was treated with Ph3P (4 equiv.). The mixture was heated
to 2508 at 1 bar in the microwave oven for 30 min. FC afforded the desired benzimidazoles.
Acylation of 3-Nitropyridin-2-amine. According to the general procedure for 3 and 4 at 258. FC
(silica gel, cyclohexane/AcOEt 6 :1 ! 3 :1 ! 1:1) gave 61% of compound 5 and 35% of 2-methyl-N-(2-
methylpropanoyl)-N-(3-nitropyridin-2-yl)propanamide.
2-Methyl-N-(3-nitropyridin-2-yl)propanamide (5). Yellow solid. M.p. 132 – 133.58. Rf (cyclohexane/
AcOEt 1:1) 0.28. 1H-NMR (300 MHz, CDCl3): 9.82 (br. s, exchange with D2O, NH); 8.70 (dd, J ¼ 4.7, 1.7,
HꢀC(6’)); 8.47 (dd, J ¼ 8.2, 1.7, HꢀC(4’)); 7.23 (dd, J ¼ 8.2, 4.7, HꢀC(5’)); 2.78 (sept., J ¼ 6.9, Me2CH);
1.31 (d, J ¼ 6.9, Me2CH). HR-EI-MS: 209.0794 (8, Mþ, C9H11N3O3þ ; calc. 209.0800), 163.0865 (14, [M ꢀ
NO2]þ, C9H11N2Oþ; calc. 163.0871), 70.0331 (69), 43.0575 (100).
2-Methyl-N-(2-methylpropanoyl)-N-(3-nitropyridin-2-yl)propanamide. Ocre solid. M.p. 67.5 – 69.58.
Rf (cyclohexane/AcOEt 1:1) 0.53. 1H-NMR (300 MHz, CDCl3): 8.79 (dd, J ¼ 4.8, 1.7, HꢀC(6’)); 8.46 (dd,
J ¼ 8.2, 1.7, HꢀC(4’)); 7.59 (dd, J ¼ 8.2, 4.8, HꢀC(5’)); 2.91 (sept., J ¼ 6.7, 2 Me2CH); 1.20 (d, J ¼ 6.7,
2 Me2CH). HR-EI-MS: 279.1214 (0.27, Mþ, C13H17N3O4þ ; calc. 279.1219), 236.0668 (4, [M ꢀ C3H7]þ,
C10H10N3Oþ4 ; calc. 236.0671), 71.0487 (63), 43.0722 (100).
2-(1-Methylethyl)-3H-imidazo[4,5-b]pyridine (10). General procedure A (12 h at reflux). FC (silica
gel; cyclohexane/AcOEt/MeOH 1:1:0 ! 1:3 :0 ! 1:3 :0.05), followed by FC (CHCl3/AcOEt 2 :1 !
1:4), gave 10 (63%). Colourless solid. M.p. 149 – 151.58 (sublimed). Rf (AcOEt) 0.21. IR (CHCl3):
3451w, 3223m, 3154m, 3089s, 2972s, 2876m, 2776m, 2747m, 1924w, 1887w, 1851w, 1729w, 1615m, 1598m,
1520m, 1485w, 1460m, 1432s, 1418s, 1391m, 1305m, 1280m, 1264s, 1161w, 1115w, 1093m, 1066w, 1050w,
1
980w, 917w. H-NMR (300 MHz, CDCl3): 13.87 (br. s, exchange with D2O, NH); 8.36 (dd, J ¼ 5.0, 1.4,
HꢀC(5)); 8.07 (br. d, J ¼ 7.9, HꢀC(7)); 7.26 (dd, J ¼ 8.0, 5.0, HꢀC(6)); 3.39 (sept., J ¼ 7.0, Me2CH); 1.58

984
Helvetica Chimica Acta – Vol. 94 (2011)
(d, J ¼ 7.0, Me2CH). 13C-NMR (300 MHz, CDCl3): 162.50 (s, C(2)); 149.38 (s, C(3a)); 141.85 (d, C(5));
136.30 (s, C(7a)); 127.35 (d, C(7)); 117.90 (d, C(6)); 29.87 (d, Me2CH); 21.48 (q, Me2CH). HR-EI-MS:
161.0946 (40, Mþ, C9H11N3þ ; calc. 161.0953), 160.0870 (25, [M ꢀ H]þ, C9H10Nþ3 ; calc. 160.0875), 146.0708
(100, [M ꢀ Me]þ, C8H8Nþ3 ; calc. 146.0718). LR-ESI-MS: 213.2 (100, [M þ Na]þ). Anal. calc. for C9H11N3
(161.20): C 67.06, H 6.88, N 26.07; found: C 67.16, H 6.76, N 26.08.
1,3-Dihydro-1-methyl-3-(1-methylethyl)-2H-benzimidazol-2-one (9). General procedure A. FC
(cyclohexane/AcOEt 1:1) gave 9 (49%). Colourless solid. M.p. 104 – 1068. Rf (cyclohexane/AcOEt
2 :1) 0.32. IR (CHCl3): 3067w, 3031w, 3007m, 2983m, 2938w, 2881w, 1916w, 1866w, 1812w, 1688s, 1620w,
1606w, 1496s, 1458w, 1436m, 1398m, 1390m, 1372w, 1362w, 1324w, 1218w, 1161w, 1129w, 1093w, 1084w,
1
1048w, 1021w, 951w, 910w. H-NMR (300 MHz, CDCl3): 7.16 – 6.94 (m, 4 arom. H); 4.74 (sept., J ¼ 7.0,
Me2CH); 3.40 (s, MeN); 1.53 (d, J ¼ 7.0, Me2CH). 13C-NMR (300 MHz, CDCl3): 154.05 (s, C¼O); 130.43,
128.39 (2s, C(3a), C(7a)); 120.98, 120.81 (2d, C(5), C(6)); 109.02, 107.56 (2d, C(4), C(7)); 45.18 (d,
Me2CH); 27.12 (q, MeN); 20.45 (q, Me2CH). HR-EI-MS: 190.1097 (58, Mþ, C11H14N2Oþ; calc. 190.1106),
175.0858 (27, [M ꢀ Me]þ, C10H11N2Oþ; calc. 175.0871), 148.0630 (100, [M ꢀ C3H6]þ, C8H8N2Oþ; calc.
148.0637). LR-ESI-MS: 213.2 (100, [M þ Na]þ). Anal. calc. for C11H14N2O · 1/8 H2O (192.49): C 68.63, H
7.46, N 14.55; found: C 68.69, H 7.44, N 14.35.
Crystal Structure of 9. C11H14N2O (190.246), Monoclinic P21/n, a ¼ 9.0169 (10) ꢃ, b ¼ 9.9103 (12),
c ¼ 12.030 (2) ꢃ, b ¼ 105.013 (7)8, V¼ 1038.3 (2) ꢃ3, Z ¼ 4, Dcalc ¼ 1.217 Mg/m3, F(000) ¼ 408.0. The
reflexions were measured on a Bruker Nonius Kappa CCD diffractometer with MoKa radiation l ¼
0.71073 at 223 K, q range ¼ 2.753 – 24.1088. Refinement on F2 (full-matrix least-squares refinement),
R(all) ¼ 0.0809, R(gt) ¼ 0.0563. All the calculations were performed using maXus. The programme
SHELXS-97 was used to solve the structure, and the programme SHELXL-97 was used to refine the
structure.
2,2-Dimethyl-N-{2-[(triphenylphosphoranylidene)amino]phenyl}propanamide (11). General proce-
dure A (12 h at reflux). FC (alumina B, act. III; cyclohexane/AcOEt 5 :1 ! 3 :1); gave 11 (59%) and 7b
(15%).
Data of 11. Colourless solid. M.p. 180 – 181.58 (Et2O/hexane). Rf (cyclohexane/AcOEt 2 :1) 0.45. IR
(CHCl3): 3336w, 3079w, 3061w, 3007m, 2965w, 2870w, 1983w, 1963w, 1916w, 1895w, 1818w, 1775w, 1655m,
1592m, 1574m, 1517s, 1483m, 1469m, 1446s, 1437s, 1398w, 1345s, 1309s, 1257w, 1162w, 1116s, 1050w,
1020m, 999w, 923w. 1H-NMR (300 MHz, CDCl3): 9.70 (br. s, exchange with CD3OD, NH); 8.45 (ddd, J ¼
8.0, 2.7, 1.8, HꢀC(6)); 7.79 – 6.69 (m, 6 arom. H); 7.60 – 7.42 (m, 9 arom. H); 6.69 (td, J ¼ 7.6, 1.3), 6.59 (td,
J ¼ 7.6, 1.8) (HꢀC(4), HꢀC(5)); 6.42 (dt, J ꢁ 7.8, 1.3, HꢀC(3)); 1.32 (s, t-Bu). 13C-NMR (CDCl3,
75 MHz): 176.35 (s, C¼O); 139.73 (s, C(2)); 133.25 (d, 3J(C,P) ¼ 19.8, C(1)); 132.60 (dd, 2J(C,P) ¼ 9.7, 3
4
1
C(2’) and 3 C(6’)); 132.14 (dd, J(C,P) ¼ 2.7, 3 C(4’)); 130.60 (d, J(C,P) ¼ 100.1, 3 C(1’)); 128.86 (dd,
3J(C,P) ¼ 12.1, 3 C(3’) and 3 C(5’)); 122.54 (d, C(5)); 119.34 (dd, 4J(C,P) ¼ 9.4, C(6)); 118.08 (dd,
4
3J(C,P) ꢁ J(C,P) ꢁ 2.6, C(3) and C(4)); 40.09 (s, Me3C); 28.06 (q, Me3C). HR-MALDI-MS: 453.2097
(100, [M þ H]þ, C29H30N2OPþ; calc. 453.2096). Anal. calc. for C29H30N2OP (752.53): C 76.80, H 6.67, N
6.18, P 6.83; found: C 76.54, H 6.63, N 6.24, P 6.81.
Crystal Structure of 11. C29H29N2OP (452.538), Monoclinic P21/c, a ¼ 9.0471 (2), b ¼ 14.3479 (4), c ¼
19.6929 (5) ꢃ, b ¼ 102.671 (2)8, V¼ 2494.02 (11) ꢃ3, Z ¼ 4, Dcalc ¼ 1.205 Mg/m3, F(000) ¼ 960.0. The
reflexions were measured on a Bruker Nonius Kappa CCD diffractometer with MoKa radiation l ¼
0.71073 at 298 K, q range ¼ 2.425 – 27.485 8. Refinement on F2 (full-matrix least-squares refinement),
R(all) ¼ 0.1318, R(gt) ¼ 0.0848. All calculations were performed using maXus. The programme SIR97
was used to solve the structure, and the programme SHELXL-97 was used to refine the structure.
REFERENCES
[1] M. Xu, F. De Giacomo, D. E. Paterson, T. G. George, A. Vasella, Chem. Commun. 2003, 1452.
[2] T. Steinlin, A. Vasella, Helv. Chim. Acta 2008, 91, 435.
´
[3] T. G. George, P. Szolcsanyi, S. G. Koenig, D. E. Paterson, Y. Isshiki, A. Vasella, Helv. Chim. Acta
2004, 87, 1287.
[4] B. G. Gowenlock, G. B. Richter-Addo, Chem. Rev. 2004, 104, 3315.

Helvetica Chimica Acta – Vol. 94 (2011)
985
[5] B. C. Challis, R. J. Higgins, A. J. Lawson, J. Chem. Soc., Perkin Trans. 2 1972, 1831.
[6] a) K. Bahrami, M. M. Khodaei, A. Nejati, Green Chem. 2010, 12, 1237; b) M. A. Chari, D. Shobha,
E.-R. Kenawy, S. S. Al-Deyab, B. V. S. Reddy, Tetrahedron Lett. 2010, 51, 5195; c) S. Gupta, P. K.
Agarwal, B. Kundu, Tetrahedron Lett. 2010, 51, 1887; d) Y. Shiraishi, Y. Sugano, S. Tanaka, T. Hirai,
Angew. Chem., Int. Ed. 2010, 49, 1656; e) A. J. Blacker, M. M. Farah, M. I. Hall, S. P. Marsden, O.
Saidi, J. M. J. Williams, Org. Lett. 2009, 11, 2039; f) H. Z. Boeini, K. H. Najafabadi, Eur. J. Org.
Chem. 2009, 4926; g) E. C. Creencia, M. Kosaka, T. Muramatsu, M. Kobayashi, T. Iizuka, T.
Horaguchi, J. Heterocycl. Chem. 2009, 46, 1309; h) X. Deng, H. McAllister, N. S. Mani, J. Org. Chem.
2009, 74, 5742; i) J. She, Z. Jiang, Y. Wang, Synlett 2009, 2023; j) Q. Xiao, W.-H. Wang, G. Liu, F.-K.
Meng, J.-H. Chen, Z. Yang, Z.-J. Shi, Chem.–Eur. J. 2009, 15, 7292; k) O. Algul, A. Kaessler, Y.
Apcin, A. Yilmaz, J. Jose, Molecules 2008, 13, 736; l) G. Brasche, S. L. Buchwald, Angew. Chem., Int.
Ed. 2008, 47, 1932; m) B. Das, B. S. Kanth, K. R. Reddy, A. S. Kumar, J. Heterocycl. Chem. 2008, 45,
1499; n) J. C. Lewis, A. M. Berman, R. G. Bergman, J. A. Ellman, J. Am. Chem. Soc. 2008, 130, 2493;
o) W. Shen, T. Kohn, Z. Fu, X. Jiao, S. Lai, M. Schmitt, Tetrahedron Lett. 2008, 49, 7284; p) Y.
Yamamoto, T. Tsuritani, T. Mase, Tetrahedron Lett. 2008, 49, 876; q) D. Yang, H. Fu, L. Hu, Y. Jiang,
Y. Zhao, J. Org. Chem. 2008, 73, 7841; r) J. W. Hubbart, A. M. Piegols, B. C. G. Sçderberg,
Tetrahedron 2007, 63, 7077; s) J. C. Lewis, J. Y. Wu, R. G. Bergman, J. A. Ellman, Angew. Chem., Int.
Ed. 2006, 45, 1589; t) H. Ma, Y. Wang, A. Wang, Heterocycles 2006, 68, 1669; u) P. Sun, Z. Hu, J.
Heterocycl. Chem. 2006, 43, 773; v) J. Charton, S. Girault-Mizzi, C. Sergheraert, Chem. Pharm. Bull.
2005, 53, 492; w) Z.-X. Wang, H.-L. Qin, J. Heterocycl. Chem. 2005, 42, 1001; x) D. Yang, D. Fokas, J.
Li, L. Yu, C. M. Baldino, Synthesis 2005, 47; y) M. Curini, F. Epifano, F. Montanari, O. Rosati, S.
Taccone, Synlett 2004, 1832; z) T. Itoh, K. Nagata, H. Ishikawa, A. Ohsawa, Heterocycles 2004, 63,
2769; aa) V. K. Tandon, M. Kumar, Tetrahedron Lett. 2004, 45, 4185.
[7] a) A. B. Alloum, K. Bougrin, M. Soufiaoui, Tetrahedron Lett. 2003, 44, 5935; b) C. T. Brain, J. T.
Steer, J. Org. Chem. 2003, 68, 6814; c) C. T. Brain, S. A. Brunton, Tetrahedron Lett. 2002, 43, 1893;
˜
d) T. Fonseca, B. Gigante, T. L. Gilchrist, Tetrahedron 2001, 57, 1793; e) A. Navarro-Ocana, L. F.
´
´
Olguꢄn, H. Luna, M. Jimenez-Estrada, E. Barzana, J. Chem. Soc., Perkin Trans. 1 2001, 2754.
[8] F. Hobrecker, Ber. Dtsch. Chem. Ges. 1872, 5, 920.
[9] M. R. Grimmett, ꢅImidazole and Benzimidazole Synthesisꢁ, Academic Press, San Diego, 1997.
[10] J. B. Wright, Chem. Rev. 1951, 48, 397.
[11] P. N. Preston, Chem. Rev. 1974, 74, 279.
[12] A. F. Pozharskii, A. D. Garnovskii, A. M. Simonov, Russ. Chem. Rev. (Engl. Transl.) 1966, 35, 122.
[13] P. N. Preston, G. Tennant, Chem. Rev. 1972, 72, 627.
[14] R. Rastogi, S. Sharma, Synthesis 1983, 861.
[15] a) M. Miyashita, I. Shiina, T. Mukaiyama, Bull. Chem. Soc. Jpn. 1994, 67, 210; b) S. Darvesh, R. S.
McDonald, K. V. Darvesh, D. Mataija, S. Mothana, H. Cook, K. M. Carneiro, N. Richard, R. Walsh,
E. Martin, Bioorg. Med. Chem. 2006, 14, 4586; c) J. A. Murphy, S. J. Roome, J. Chem. Soc., Perkin
Trans. 1 1995, 1349.
[16] F.-L. Zhang, W. B. Schweizer, M. Xu, A. Vasella, Helv. Chim. Acta 2007, 90, 521.
[17] T. Steinlin, A. Vasella, Helv. Chim. Acta 2009, 92, 588.
[18] M. L. H. Mantel, A. T. Lindhardt, D. Lupp, T. Skrydstrup, Chem.–Eur. J. 2010, 16, 5437.
[19] I. A. OꢁNeil, S. Thompson, C. L. Murray, S. B. Kalindjian, Tetrahedron Lett. 1998, 39, 7787.
[20] W. Koerner, Gazz. Chim. Ital. 1874, 4, 305.
[21] H. Hꢀbner, Justus Liebigs Ann. Chem. 1881, 209, 339.
[22] A. Hempel, J. Prakt. Chem. 1890, 41, 161.
[23] E. Hayashi, Y. Miura, Yakugaku Zasshi 1967, 87, 648.
[24] O. Hinsberg, F. Funcke, Ber. Dtsch. Chem. Ges. 1893, 26, 3092.
[25] K. N. Zelenin, I. V. Ukraintsev, V. V. Alekseev, Chem. Heterocycl. Compd. 1998, 34, 329.
[26] M. Miyashita, I. Shiina, T. Mukaiyama, Chem. Lett. 1993, 1053.
[27] M. T. Davies, P. Mamalis, V. Petrow, B. Sturgeon, J. Pharm. Pharmacol. 1951, 3, 420.
[28] H. Hꢀbner, Justus Liebigs Ann. Chem. 1881, 208, 278.
[29] G. Tennant, J. Chem. Soc. 1964, 2666.
[30] R. Walther, T. von Pulawski, J. Prakt. Chem. 1899, 59, 249.

986
Helvetica Chimica Acta – Vol. 94 (2011)
[31] M. A. Phillips, J. Chem. Soc. 1929, 2820.
[32] O. Fischer, Ber. Dtsch. Chem. Ges. 1892, 25, 2826.
[33] A. Gazit, K. Yee, A. Uecker, F. D. Bçhmer, T. Sjçblom, A. ꢆstman, J. Waltenberger, G. Golomb, S.
Banai, M. C. Heinrich, A. Levitzki, Bioorg. Med. Chem. 2003, 11, 2007.
[34] A. W. Johnson, ꢅIminophosphoranes and Related Compoundsꢁ, in ꢅYlides and Imines of
Phosphorousꢁ, John Wiley & Sons, New York, 1993, p. 403 – 483.
[35] a) A. L. Llamas-Saiz, C. Foces-Foces, J. Elguero, P. Molina, M. Alajarꢄn, A. Vidal, J. Chem. Soc.,
Perkin Trans. 2 1991, 1667; b) A. L. Llamas-Saiz, C. Foces-Foces, J. Elguero, P. Molina, M. Alajarꢄn,
A. Vidal, Acta Crystallogr., Sect. C 1992, 48, 1940; c) S. Eguchi, K. Yamashita, Y. Matsushita, A.
´
Kakehi, J. Org. Chem. 1995, 60, 4006; d) P. Molina, A. Tarraga, D. Curiel, Tetrahedron 1997, 53,
15895; e) G. C. Welch, W. E. Piers, M. Parvez, R. McDonald, Organometallics 2004, 23, 1811; f) J. D.
Masuda, D. M. Walsh, P. Wei, D. W. Stephan, Organometallics 2004, 23, 1819; g) K. D. Conroy, W. E.
Piers, M. Parvez, J. Organomet. Chem. 2008, 693, 834.
[36] M. Le Corre, A. Hercouet, H. Le Baron, J. Chem. Soc., Chem. Commun. 1981, 14.
[37] E. Zbiral, ꢅTransformations via Phosphorous-stabilized Anions 4: Heterocyclic Synthesis via
Alkylidenephosphoranes, Iminophosphoranes, and Vinylphosphonium Saltsꢁ, in ꢅOrganophospho-
rous Reagents in Organic Synthesisꢁ, Ed. J. I. G. Cadogan, Academic Press, London, 1979, p. 223 –
268.
[38] R. Meuwly, A. Vasella, Helv. Chim. Acta 1985, 68, 997.
`
[39] G. H. Wagniere, ꢅTheoretical Aspects of the CꢀNO and CꢀNO2 Bondsꢁ, in ꢅThe Chemistry of the
Nitro and Nitroso Groupsꢁ, Ed. S. Patai, Interscience Publishers, New York, 1969, p. 1 – 77.
[40] J. I. G. Cadogan, Synthesis 1969, 11; J. H. Boyer, ꢅDeoxygenation of Nitro and Nitroso Groupsꢁ, in
ꢅNitrenesꢁ, Ed. W. Lwowski, John Wiley & Sons, New York, 1971, p. 163 – 184.
[41] M. Xu, A. Vasella, Helv. Chim. Acta 2006, 89, 1140.
[42] J. I. G. Cadogan, ꢅDeoxygenation via Phosphorous (III) Reagents 1: Heterocyclic Synthesis using
Aromatic Nitro Compoundsꢁ, in ꢅOrganophosphorous Reagents in Organic Synthesisꢁ, Ed. J. I. G.
Cadogan, Academic Press, London, 1979, p. 269 – 294 and refs. cit. therein.
[43] C. W. Spangler, Chem. Rev. 1976, 76, 187.
Received March 22, 2011