A novel annulation reaction of N-substituted-2-nitrosoanilines with esters of α-isocyano acids. A one-pot, two-step route to 2-benzimidazole- substituted esters of α-amino acids

Article abstract of DOI:10.1016/j.tetlet.2014.04.030

A BF₃-promoted α-addition of isocyanides to both nitrogen atoms of N-aryl-2-nitrosoanilines leads to stable BF₃-complexes of 3-N-hydroxy-(2-alkylimino)benzimidazole derivatives, which, after reduction with Zn in AcOH produce 1-N-aryl-2-alkylaminobenzimidazoles. This two-step annulation proceeds efficiently in a one-pot protocol with isocyanides derived from esters of α-amino acids. The chirality of the latter remains unaffected in the reaction.

Full text of DOI:10.1016/j.tetlet.2014.04.030

Accepted Manuscript
A novel annulation reaction of N-substituted-2-nitrosoanilines with esters of α-
isocyano acids. A one-pot, two-step route to 2-benzimidazole-substituted esters
of α-amino acids
Robert Bujok, Piotr Cmoch, Zbigniew Wróbel
PII:
S0040-4039(14)00629-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.04.030
TETL 44492
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
6 March 2014
1 April 2014
10 April 2014
Please cite this article as: Bujok, R., Cmoch, P., Wróbel, Z., A novel annulation reaction of N-substituted-2-
nitrosoanilines with esters of α-isocyano acids. A one-pot, two-step route to 2-benzimidazole-substituted esters of
α-amino acids, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.04.030
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A novel annulation reaction of N-substituted-2-nitrosoanilines with esters of α-isocyano acids. A one-pot,
two-step route to 2-benzimidazole-substituted esters of α-amino acids
Robert Bujok, Piotr Cmoch, Zbigniew Wróbel*
O
OH
R
N
N
R
H
NAr
.
BF3 Et2O
Zn
CO2Et
N
N
_
CO2Et
R
N
+
N
+
C N
+
_
BF3
H
N
Ar
CH2Cl2
AcOH
CO2Et
X
X
X
Ar
41 - 54%
87 - 99%
one-pot:
51 - 73%
overall yield
X = F, Cl, OMe
Ar = 4-Y-C6H4 Y = H, Cl, OMe, OEt

A novel annulation reaction of N-substituted-2-nitrosoanilines with esters of
α-isocyano acids. A one-pot, two-step route to 2-benzimidazole-substituted
esters of α-amino acids
Robert Bujok, Piotr Cmoch, Zbigniew Wróbel*
Institute of Organic Chemistry, Polish Academy of Sciences, ul. Kasprzaka 44, 01-224 Warszawa 42, Poland.
Fax: +48 22 6326681.
E-mail: wrobel@icho.edu.pl
Abstract: A BF3-promoted α-addition of isocyanides to both nitrogen atoms of N-aryl-2-
nitrosoanilines leads to stable BF3-complexes of 3-N-hydroxy-(2-alkylimino)benzimidazole
derivatives, which, after reduction with Zn in AcOH produce 1-N-aryl-2-
alkylaminobenzimidazoles. This two-step annulation proceeds efficiently in a one-pot
protocol with isocyanides derived from esters of α-amino acids. The chirality of the latter
remains unaffected in the reaction.
Key words: heterocycles, nitroso group, isocyanides, cyclization.
In 2007, we described an easy and convenient synthesis of formerly difficult to access N-aryl-
2-nitrosoanilines.1 The proximity of the nucleophilic amine and strongly electrophilic nitroso
group makes these compounds attractive substrates in various domino processes leading to
important nitrogen heterocyclic scaffolds. The strategies, directed to the synthesis of fused
nitrogen heterocyclic compounds, and applied practically for the annulation of N-aryl-2-
nitrosoanilines, are shown in Scheme 1. Each of them consists of consecutive reactions of an
electrophilic nitroso group with the external nucleophile, and of the amine nitrogen with the
electrophilic function, included in the external reagent, or created in an earlier step of the
reaction. These steps could also proceed in the reverse order.
The cyclization of N-aryl-2-nitrosoanilines leading to phenazines demonstrates the
intramolecular ring-forming reaction of both reactive centres featuring a part of the
conjugated N-aryl ring (path a).1a, 2a According to the strategies involving external linking
reagents, reactions with acidic benzyl sulfones (Nu-LG) furnish 2-aryl substituted
benzimidazoles (path b),2b with acidic esters such as malonates, aryl acetoacetates or
phosphonoacetates (Nu-E) give quinoxalin-2(1H)-ones (path d).2c The latter reactions depend
on both the nature of the nitroso compound and the reaction conditions. They produced

quinoxalin-2(1H)-one 4-N-oxides (path c),2d or employed the second molecule of the alkyl
cyanoacetic ester which substituted a hydrogen at an unexpected position on the benzene ring.
In specific cases this product undergoes further intramolecular acylation furnishing tricyclic
fused oxopyrrole derivatives.2e The reaction of N-aryl-2-nitrosoanilines with arylidene
cyanoacetic esters gave, in turn, 4-N-hydroxy-2,3-dihydroquinoxalines (path e), which were
easily reducible to the 1,2,3,4-tetrahydroquinoxaline derivatives. In this case, the reaction
sequence is opposite to that mentioned above. It starts with nucleophilic attack of the amino
function of the N-aryl-2-nitrosoaniline on the arylidene Michael acceptor, followed by capture
of the so-formed carbanion by the nitroso group.2f
AND Enantiomer
OH
EWG
N
EWG
N
Ar'
Ar
N
(R, Ar, LG)
N
N
Ar
N
O
e
Ar
d
a
- H2O
- H2O
O
N
_
(LG)
Nu
E
N H
Ar
electrophilicO
N
c
–
O
N
+
R
O
- LG
NHAr
O
N
Ar
nucleophilic
N
_
Nu LG
N H
Ar
b
N
N
1
Ar
- H2O
- LG
Nu - nucleophilic centre
E
- electrophilic centre
LG - leaving group
EWG - electron-w ithdraw ing group
Ar
Scheme 1. Strategies for the synthesis of nitrogen heterocycles from N-aryl-2-nitrosoanilines
and representative types of final products.
In continuation of our work in this field, we became interested in the use of isocyanoacetic
esters, being derivatives of α-amino acids. Initially, the electrophilic disposition of the nitroso
group of N-substituted-2-nitrosoanilines was designed to form a C-N bond with carbanions of
the isocyanoacetates, regarded as Nu-E components in terms of Scheme 1. The methylene
group of the latter compounds is relatively acidic and could be deprotonated with relatively
weak bases such as DBU, and then add to the nitroso group.3 The expected final products of
such reactions were either quinoxalinone derivatives bearing an isocyanide function, as a

result of elimination of a water molecule from the adduct followed by intramolecular
acylation of the amine nitrogen, or fused heterocyclic ring systems with the N=C bond of the
isocyanide function incorporated into the new ring.4 Unfortunately, in the presence of base,
regardless of the reaction conditions, only intractable mixtures of products were formed.
Thus, we switched our approach, and decided to exploit the most prominent feature of an
isocyanide function, i.e., the ability to link a strong electrophilic group and a nucleophilic
moiety (“intercepting nucleophile”) with the divalent carbon atom of the cyanide function.
This initiative was supported by numerous reports on multicomponent reactions of
isocyanides with various pairs of reagents, following classical Ugi and Passerini reaction
schemes or their modifications.5,6 The in situ generated iminium salts were used most
frequently as electrophilic components in a pair with a carboxylate anion or a primary amine7
as intercepting nucleophiles. When both crucial components were placed in the same
molecule the reaction with isocyanides turned out to be a ring-formation process.7c-f Less
electrophilic imine or carbonyl groups needed activation with a Lewis acid in order to enter
the reaction with isocyanides.7d, 8
The key inspiration for our approach came from a report by Krasavin et al.9 on the BF3·Et2O-
promoted reaction of isocyanides with o-aminobenzophenones, in which the terminal carbon
atom of the isocyanide group, linking the ortho-positioned carbonyl and amino functions,
became an element of the fused five-membered ring. Although the primary products, 2-
amino-3-hydroxy-3-aryl-3H-indoles, were unstable under the reaction conditions and
transformed into final products of different structure, the initial reaction course prompted us
to study whether N-aryl-2-nitrosoanilines would react in such a way, opening a new
possibility for their annulation (Scheme 2). Since both an electrophilic nitroso group and a
nucleophilic amine group are present in N-aryl-2-nitrosoanilines, and located at convenient
positions to form a five-membered ring with the divalent carbon atom of the isocyanide
group, they seem to be perfectly suitable bifunctional components for isocyanide-based ring-
forming reactions.
O
R
OH
N
N
_
C
CO2Et
CO2Et
+
N
N
X1
R
X1
N
Ar
NH
Ar
1
2
3
Scheme 2. A new strategy for the heteroannulation of N-aryl-2-nitrosoanilines.

A nitroso group is rather a strong electrophile, which is able to add alkyl isocyanides under
thermal conditions,10 nevertheless, its activation by a Lewis acid was found to be necessary to
induce the reaction with isocyanoacetates at ambient temperature. Thus, boron trifluoride-
diethyl etherate (BF3·OEt2), known for its efficient activation of the carbonyl group of
aminobenzophenone,9 was used in the reaction of 5-methoxy-2-nitroso-N-(4-tolyl)aniline (1a)
with the ethyl ester of glycine-derived isocyanide 2a in dichloromethane. As a result,
essentially one product was formed in reasonable yield. Its structure, however, could not be
interpreted in a straightforward manner, as we were concerned with the possible subsequent
transformations of the initially formed product. The elemental analysis (C, H and N) of the
isolated product, gave values much lower than those calculated for the expected structure 3 (R
= H, Ar = Tol, X1 = OMe in Scheme 2). Searching for the ‘missing’ mass, the presence of
fluorine was found in the molecule in ca.13.6%. This indicated incorporation of a BF3 moiety
into the product, and this finding led to a satisfactory agreement between the obtained and
calculated values for the product (C19H21BF3N3O4). This also proved the involvement of the
complete molecules of both nitrosoaniline 1a and isocyanate 2a as well as the stoichiometric
contribution of BF3. Taking into consideration all the possible structures with BF3
complexation of one of the heteroatoms, including potential products of further
rearrangements, a detailed NMR study was undertaken.
The formation of the new ring was confirmed in the DEPT 135 spectra by the five positive
signals of the protons of the two aromatic rings, thus the presence of an open-chain imine
proton was excluded. 1H – 15N HMBC as well as 1H – 15N HSQC techniques allowed us to
exclude the presence of protons connected to nitrogen atoms, therefore, the broad signal at
8.81 ppm observed in the 1H NMR spectrum could be attributed to the N-OH proton.
Additionally, the resonance observed at –314 ppm in the nitrogen NMR spectrum was
-
attributed to the positively charged nitrogen atom connected to the BF3 group, while signals
representative of an imine nitrogen were not found (typically -90 - 0 ppm).11 All these
observations confirmed the structure as a complex with boron trifluoride bonded to the
exocyclic imine nitrogen (Figure 1).12
OH
CO2Et
N
+
N
-
BF3
N
MeO
3aa

Figure 1
The complexed product 3aa was found to be relatively stable. In particular, no skeletal
rearrangement under the reaction conditions, resembling that described by Krasavin et al.,9
was observed. Moreover, the product could be isolated and purified by column
chromatography and stored at room temperature for a long period of time without any
noticeable decomposition.
This reaction had opened a simple route to 2-aminoarylbenzimidazole derivatives from easily
available N-aryl-2-nitrosoanilines. Starting from variously substituted compounds 1 and
glycine derivatives 2, several such complexes were isolated and characterized (Table 1).
Although they seem to be interesting examples of rare and stable complexes of imines, and
their possible reactivity as well as application in synthesis is worth investigating, for the
purpose of this work, they were subjected to transformation into aminobenzimidazoles 4. This
was achieved by reduction of compounds 3 with the Zn/AcOH system. It was found that when
crude 3 was reduced without purification, this simpler procedure allowed us to obtain higher
overall yields of the final products.13
[Table 1]
BF3-Complexed aminobenzimidazoles 3 were formed in moderate yields, regardless of the
substituents on the N-aryl-2-nitrosoaniline. The reaction is not restricted to N-phenyl
derivatives as 2-(N-butyl)-1-nitrosonaphthalene reacted well. Searching for more efficient
reaction conditions, a few other Lewis acids such as Cu(BF4)2·4.5 H2O, Yb(OTf)3·H2O,
Mg(ClO4)2, and LiCl were used in place of BF3-diethyl etherate in the one-pot reactions of 1c
with 2a. They were, however, less efficient, and led to the formation of 4ca accompanied with
large amounts of side products.
Benzimidazoles containing an amino acid framework at position 2 exhibit biological activity
including respiratory syncytial virus replicant inhibition,14a rotamase enzyme inhibition,14b
Bacillus subtilis HPr kinase/phosphatase inhibition,14c host-directed inhibition of
myxoviruses,14d antiproliferative activity against breast cancer,14e leukocyte adhesion
mediated by VLA-4 inhibition,14f anti-inflammatory action,14g and others. Therefore,
numerous methods have been presented for their synthesis.14-16
Recently, we described the formation of N-substituted 2-aminobenzimidazoles from 2-
(arylamino)iminophosphoranes and alkyl/aryl isocyanates, in mostly excellent yields.17

Unfortunately, to date, we have not found conditions suitable for the reactions of isocyanates
derived from amino acids. The method presented here complements those previously
described in this important field.
For the significance of the presented method for contemporary organic synthesis, it was
important to find out whether the reaction was suitable for derivatives of chiral amino acids
whilst preserving their chirality in the final products. For this purpose, two chiral amino
esters, S-alanine and S-phenylalanine, were converted into the corresponding chiral
isocyanides following the described procedures.18 The enantiomeric purities of products 4
were determined as their salts with Mosher’s acid according to 1H NMR spectroscopy19 in
which only one enantiomer could be detected. The suitability of the method was verified by
1H NMR spectroscopy of 4ac, obtained from the reaction of racemised isocyanide ester 2b
(Table 1, entry 11), in which diagnostic signals of both enantiomers could be clearly
recognized.
Contrary to the derivatives of amino acids described here, simple alkyl isocyanides
participated in this reaction much less effectively. Taking into account the repulsive odour of
volatile alkyl isocyanides and low yields of the products, our previously described method for
the synthesis of 2-(alkylamino)imidazoles from 2-nitrosoanilines via 2-
(arylamino)aryliminophosphoranes, and their condensation with alkyl isocyanates seems more
appropriate in these cases.17
In conclusion, a novel strategy for the heteroannulation of N-substituted 2-nitrosoanilines
leading to 2-aminobenzimidazole derivatives is described. The BF3·OEt2 promoted reaction
with isocyanides derived from amino acids, comprises α-addition of the divalent carbon atom
of the isocyanide group to the nitrogen atoms of the ortho positioned nitroso and amino
functions of the substrate, and after one-pot reduction with Zn/AcOH, furnishes 2-
benzimidazole-substituted esters of α-amino acids. The mild reaction conditions allow the
chirality of the starting isocyanide to be preserved, and the simplicity of the one-step process
makes the method useful for the synthesis of valuable 2-aminobenzimidazole derivatives.
Supplementary data
Supplementary data (general procedures, physical and spectral data of all compounds)
associated with this article can be found, in the online version, at ...

References and notes.
1. (a) Wróbel, Z.; Kwast, A. Synlett 2007, 1525-1528, (b) Wróbel, Z.; Kwast, A.
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2. (a) Kwast, A.; Stachowska, K.; Trawczyński, A.; Wróbel, Z. Tetrahedron Lett. 2011,
6484; (b) Wróbel,Z.; Stachowska,K.; Grudzień, K.; Kwast, A. Synlett 2011, 1439; (c)
Wróbel, Z.; Stachowska, K.; Kwast, A.; Gościk, A.; Królikiewicz, M.; Pawłowski, R.;
Turska, I. Helv. Chim. Acta 2013, 96, 956; (d) Wróbel, Z.; Królikiewicz, M. J.
Heterocycl. Chem. 2014, 51, 123; (e) Królikiewicz, M.; Cmoch, P.; Wróbel, Z. Synlett
2013, 24, 973; (f) Królikiewicz, M.; Błaziak, K.; Danikiewicz,W.; Wróbel, Z. Synlett
2013, 24, 1945.
3. The only example of the addition of a tert-butyl isocyanoacetate anion to a nitroso
group with subsequent elimination of water was described by: Dell'Erba, C.; Novi, M.;
Petrillo, G.; Tavani, C. Tetrahedron, 1997, 53, 2125.
4. For example, formation of a seven-membered ring could be expected in a process
analogous to the reported contribution of the isocyanide function in imidazoline
formation: (a) Elders, N.; Schmitz, R. F.; de Kanter, F. J. J.; Ruijter, E.; Groen, M. B.;
Orru, R. V. A. J. Org. Chem. 2007, 72, 6135; (b) Bon, R. S.; van Vliet, B.; Sprenkels,
N. E.; Schmitz, R. F.; de Kanter, F. J. J.; Stevens, C. V.; Swart, M.; Bickelhaupt, F.
M.; Groen, M. B.; Orru, R. V. A. J. Org. Chem. 2005, 70, 3542; (c) van Leusen, A.
M.; Wildeman, J.; Oldenziel, O. H. J. Org. Chem. 1977, 42, 1153.
5. For the latest reviews covering the topic, see: (a) Nenajdenko, V. G., Ed.; Isocyanide
Chemistry: Application in Synthesis and Materials Science; Wiley-VCH: Weinheim,
2012; (b) Gulevich, A. V; Zhdanko, A. G.; Orru, R. V. A.; Nenajdenko, V. G. Chem.
Rev. 2010, 110, 5235; (c) Dömling, A. Chem. Rev. 2006, 106, 17; (d) Banfi, L.; Riva,
R. The Passerini Reaction In Organic Reactions; Chapatte, A. B., Ed.; Wiley: New
York, 2005; Vol. 65, p 1; (e) Zhu, J., Bienayme, H., Eds. Multicomponent Reactions;
Wiley: Weinheim, Germany, 2005.
6. For various reactivity profiles of isocyanoacetic acid derivatives, see for example: (a)
Lalli, C.; Bouma, M. J.; Bonne, D.; Masson, G.; Zhu, J. Chem. Eur. J. 2011, 17, 880;
(b) Elders, N.; Ruijter, E.; de Kanter, F. J. J.; Groen, M. B.; Orru, R. V. A. Chem. Eur.
J. 2008, 14, 4961.

7. (a) McFarland, D. B.; Cai, Z.; Xu, R.; Isbell, J. J. Comb. Chem. 2002, 4, 600; (b)
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(e) Krasavin, M.; Parchinsky, V. Synlett 2008, 645; (f) Heravi, M. M.; Baghernejad,
B.; Oskooie, H. A. Tetrahedron Lett. 2009, 50, 767, disproved [contradicted] later by
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F. J. Org. Chem. 1969, 34, 2269.
11. Witanowski, M.; Stefaniak, L.; Webb, G. A. Annu. Rep. NMR Spectrosc. 1986, 18, 1;
1993, 25, 1.
12. Physical and spectral data for compound 3aa: Pale brown solid, mp 143 °C; Rf
(50% EtOAc/hexane) = 0.37; IR (KBr): νmax 3334, 2989, 1750, 1660, 1624, 1531,
1495, 1370, 1330, 1227, 1131, 1077, 954 cm−1; 1H NMR (500 MHz, DMSO-d6): δ
1.16 (3 H, t, J = 7.1 Hz, OCH2CH3), 2.46 (3 H, s, CH3-Ar), 3.70 (3 H, s, OCH3), 4.09
(2 H, q, J = 7.1 Hz, OCH2CH3), 4.24 (2 H, s, N-CH2COOEt), 6.44 (1 H, d, J = 2.1
Hz), 7.00 (1 H, dd, J = 8.8, 2.1 Hz), 7.43 (1 H, d, J = 8.8 Hz), 7.52 (4 H, br s), 8.18 (1
H, br s, OH); 13C NMR (125 MHz, DMSO-d6): δ 13.9, 20.8, 43.4, 55.9, 61.0, 94.8,
111.7, 111.8, 122.8, 127.9, 128.3, 128.4, 131.2, 140.7, 145.6, 156.9, 169.1; 19F NMR
(470 MHz, DMSO-d6): δ -150.7 to -150.6 (m, BF3), 1H– 15N HMBC (600 MHz, 60
MHz, DMSO-d6): -314.5 (N–BF3), -251.7, -208.3, 11B NMR (192 MHz, DMSO-d6): δ
0.4; MS (ESI, MeOH): 378 [M -BF3 +Na]+; HRMS (ESI, MeOH): calcd for
C19H21N3O4Na [M -BF3 +Na]+: 378.1430; found 378.1426. Anal. Calcd for:
C19H21N3O4F3B: C, 53.92; H, 5.00; N, 9.93; F, 13.47. Found: C, 54.06; H, 5.18; N,
10.01; F, 13.58.
13. General procedure for the one-pot synthesis of 4: To a solution of 2-nitrosoaniline
1 (1.0 mmol) in CH2Cl2 (5 mL), isocyanide 2 (1.15 mmol) and BF3·Et2O (0.145 g; 1.0
mmol) were added sequentially (a dark-red colour formed immediately). The solution

was stirred at r.t. for 3 h. The solvent was evaporated and AcOH (6 mL) was added to
the residue. Zn powder (0.48 g, 7 mmol) was added and the mixture was stirred at 50
°C for 24 h. The mixture was poured into H2O (30 ml) and solid K2CO3 was added
portionwise until pH = 8. The mixture was extracted with EtOAc (2 x 30 mL), and the
combined extracts were dried (Na2SO4) and the solvent evaporated. The crude
products were purified by column chromatography (SiO2, hexane/ EtOAc). Physical
and spectral data for compound 4aa: Pale brown oil; Rf (33% EtOAc /hexane) =
0.10; IR νmax (film): 3399, 3217, 2984, 2936, 1746, 1610, 1567, 1518, 1483, 1381,
1276, 1205, 1134, 1046, 1023, 820, 517 cm−1; 1H NMR (600 MHz, DMSO-d6): δ 1.19
(3 H, t, J = 7.1 Hz, OCH2CH3), 2.42 (3 H, s, CH3-Ar), 3.66 (3 H, s, OCH3), 4.02 (2 H,
d, J = 6.2 Hz, NH-CH2COOEt), 4.10 (2 H, q, J = 7.1 Hz, OCH2CH3), 6.42 – 6.44 (2 H,
m, Harom + NH), 6.64 (1 H, dd, J = 8.5, 2.4 Hz), 7.17 (1 H, d, J = 8.5 Hz), 7.37–7.39
and 7.44–7.46 (4 H, AA’XX’); 13C NMR (150 MHz, DMSO-d6): δ 14.1, 20.7, 44.2,
55.5, 60.3, 93.5, 108.3, 115.8, 126.5, 130.8, 131.8, 135.7, 136.4, 138.0, 153.4, 153.9,
170.7; 1H– 15N HMBC (600 MHz, 60 MHz, DMSO-d6): δ -323.4 (d, J = 91 Hz, NH), -
242.4, -188.9; MS (ESI, MeOH): m/z 340 [M+H]+; HRMS (ESI, MeOH): calcd for
C19H22N3O3 [M+H]+: 340.1661; found 340.1660.
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2011, 54, 4339.
17. Łukasik, E.; Wróbel, Z. Synlett, 2014, 25, 217.
18. (a) Kamer, P. C. J.; Cleij, M. C.; Nolte, R. J. M.; Harada, T.; Hezemans, A. M. F.;
Drenth, W. J. Am. Chem. Soc. 1988, 110, 1581; (b) Chancellor, T.; Morton, C.
Synthesis 1994, 1023.
19. (a) Navratilova, H. Chirality, 2001, 13, 731-735; (b) Eichard, A.; Jurczak, J.;
Bańkowski, K. Bull. Acad. Pol. Sci.; Ser. Sci. Chim. 1971, 19, 731; (c) Wenzel, T. J.
Discrimination of Chiral Compounds Using NMR Spectroscopy,: John Wiley & Sons,
Hoboken, New Jersey, 2007, p. 29.

Table 1. Synthesis of 2-aminobenzimidazoles 3 and 4 in the reaction of 2-nitrosoanilines 1
with ethyl isocyanoacetate derivatives 2
O
X2
X2
OH
R
N
R
H
N
X2
_
C N
.
1.0 eq. BF3 Et2O
CO2Et
R
CO2Et
N
N
CO2Et
N
Zn/AcOH
+
+
N
N
H
+
_
BF3
X1
X1
N
CH2Cl2, RT, 3 h
Y
X1
1
2
3
4
Y
Y
Yield,a %
Entry
1
X1
X2
Y
2
R
3, 4
1 -> 3
52
41
47
39
46
48
54
-
3 -> 4
1 -> 4b
71
1
2
a
b
c
d
e
f
OMe
Cl
H
Cl
H
H
H
Me
CN
Cl
a
a
a
a
a
a
a
a
b
c
H
H
aa
ba
ca
da
ea
fa
98
-
-
3
Cl
H
92
87
90
88
99
-
51
4
Cl
OMe
Me
H
50
5
F
H
65
6
Cl
OMe
OEt
H
-
7
g
h
a
a
g
e
a
e
N-butyl-1-nitroso-2-naphthylamine
H
ga
ha
ab
ac
gc
ed
ad
ec
73
8
F
H
H
H
Cl
H
Mec
59
9
OMe
OMe
Me
Me
53
-
-
51c
60d
75e
64e
56e
62e
10
11
12
13
14
(S)-Med
(S)-Med
(S)-Bnf
(S)-Bnf
(S)-Med
-
N-butyl-1-nitroso-2-naphthylamine
c
-
-
F
OMe
F
H
H
H
Cl
d
d
c
-
-
Me
Me
-
-
-
-
a
Isolated yield.
b Without isolation and purification of intermediate 3.
c Racemic.
d Ee = 80%
e The second enantiomer was not detected in the 1H NMR spectrum.
f Optically pure.