Synthesis of N-Benzylated Anilines from the Reaction of Anilines and Benzyl Chloroformate

Article abstract of DOI:10.1081/SCC-120028366

Reactions of benzyl chloroformate with a series of substituted anilines produced N-carbobenzyloxy "CBZ" products along with the unexpected N-benzylated "Bn" compounds. Reaction of aniline, 1a, gave the CBZ, or 2a, and Bn, or 3a, products in 29% and 14% yi

Full text of DOI:10.1081/SCC-120028366

SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 5, pp. 933–940, 2004
Synthesis of N-Benzylated Anilines from
the Reaction of Anilines and Benzyl
Chloroformate
*
Hari Pati, Paul Weisbruch, Adrienne Lemon, and Moses Lee
Department of Chemistry, Furman University, Greenville,
South Carolina, USA
ABSTRACT
Reactions of benzyl chloroformate with a series of substituted anilines
produced N-carbobenzyloxy “CBZ” products along with the unexpected
N-benzylated “Bn” compounds. Reaction of aniline, 1a, gave the CBZ, or
2a, and Bn, or 3a, products in 29% and 14% yield, respectively. For
2-nitro-, 2-bromo-, and 2-bromo-5-nitroanilines, the N-benzylated com-
pounds were produced exclusively. However, 2-methoxy-, 4-bromo,
4-iodo, and 4-ethylanilines gave mainly CBZ products. Other compounds
reported in this study gave mixtures of the two products. For 4-chloro-3-
nitroaniline, in addition to the Bn and CBZ products (53% and 14% yield,
respectively), a N,N-dibenzylated product was isolated in 27% yield.
Collectively, the results indicated that electron-withdrawing groups,
particularly at the ortho position, directed the formation of Bn com-
pounds, whilst electron-donating groups, especially at the ortho and para
positions, favored the synthesis of CBZ products.
*
Correspondence: Moses Lee, Department of Chemistry, Furman University,
Greenville, SC 29613, USA; E-mail: moses.lee@furman.edu.
933
DOI: 10.1081/SCC-120028366
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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Pati et al.
Key Words: N-Benzylated aniline; CBZ; Freidel–Crafts reaction;
Ortho and Para position.
Synthetic transformations involving amines are important in organic
chemistry. This is partly due to their high nucleophilicity and basicity, as well
as their common occurrence in natural products. Consequently, a wide number
of methods have been developed to selectively protect amino groups.[1] The
carbobenzyloxy carbamate or “CBZ” moiety is an example of such protecting
groups. Owing to its ease in preparation and removal, the CBZ group is widely
used in the synthesis of natural products.[2] Despite its versatility for use with
aliphatic amines, such as protection of the amine functionality in amino acids,
its usage with aromatic amines, anilines, is less common.[1] In July 2003, a
search using SciFinder Scholar for preparation of CBZ protected anilines
produced very few “hits.”[3] In one specific example, the reaction of aniline
(1a) with benzyl chloroformate, conducted in the presence of lithium
hydroxide and aluminum oxide, gave the CBZ protected aniline product (2a)
in 95% yield.[3a]
As part of our on-going studies toward the synthesis of analogs of the
natural products CC-1065[4] and the duocarmycins,[5] we had to protect
aromatic amine functionalities on many occasions. In some cases the N-BOC
(tert-butoxycarbonyl)[6] or N-Bn (benzyl)[7] groups were used, but, there
instances where a CBZ group was preferred. In our hands, the reaction of
aniline (1a) with benzyl chloroformate in refluxing methylene chloride and in
the presence of triethylamine did not give a high yield of the desired CBZ
product 2a (29% isolated yield). Moreover, a significant amount of an
unexpected N-benzyl product 3a was isolated in 14% yield. From this initial
discovery, we undertook a systematic study to evaluate the structure and
reactivity of a series of anilines with benzyl chloroformate. The anilines were
grouped into three categories. They either contained electron-withdrawing
groups at the ortho and/or para position(s), electron-donating groups in
the ortho or para position, and either an electron-donating or electron-
withdrawing group at the meta position. The results obtained from the studies
were interesting because anilines that contained electron-withdrawing groups
at the ortho position gave, in some cases, exclusively the N-benzyl products,
making these reactions synthetically viable. Conversely, anilines containing
electron-donating groups produced mainly N-CBZ compounds, again in high
yields making these reactions synthetically useful.
The general synthetic scheme for the reaction of the substituted anilines
with benzyl chloroformate is given in Sch. 1. For a typical reaction, the aniline
was dissolved in methylene chloride that had been dried over molecular sieves
˚
3 A, and the solution was chilled in an ice bath. To this solution was added

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Synthesis of N-Benzylated Anilines
935
Scheme 1. Reaction of anilines 1a–k with benzyl chloroformate.
˚
three mole equivalents of triethylamine, also dried over molecular sieves 3 A.
This solution was placed in an ice bath, and while stirring under a drying tube
(drierite), a solution of 6 mol equivalents of benzyl chloroformate in dry
methylene chloride was added in a dropwise manner. After the addition was
completed, the reaction mixture was warmed to room temperature then heated
to reflux for 2 days. Upon work-up, the organic extract was purified by silica
1
gel chromatography, and the products were characterized by 500 MHz H
NMR, FT-IR and mass spectrometry. A summary of representative spectral
characteristics for the compounds described in this study is given in Table 1.
For the case of aniline, the structures of the N-CBZ and N-benzyl aniline
products were unambiguously determined by comparison of their spectral data
to literature values.[3,8] In all cases, the benzylic CH2 signals for the N-CBZ
and N-Bn compounds resonate at characteristic chemical shifts in the 1H NMR
spectra. For N-CBZ the signal is typically located at about 5.2 ppm, but, for
N-Bn the resonance is situated around 4.3–4.7 ppm.
The results from the coupling of eleven different anilines to benzyl
chloroformate are given in Table 2. The results are divided into three cate-
gories according to the electronic properties and position of the substituent.

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Pati et al.
Table 1. Spectral characteristics for the compounds reported in this article.
Compound
IR C55O (cm21
)
1H NMR (CDCl3) ppma
MS (EI) Mþ
2b
3b
2c
3c
2d
3d
2e
3f
1701
—
5.20
4.68
5.20
4.64
5.21
4.65
5.25
4.56
4.65
4.48
5.21
4.34
4.68
5.21
4.61
4.73
5.20
306
262
353
309
255
211
257
228
262
307
307
263
353
257
213
228
272
1698
—
1702
—
1701
—
3g
3h
2i
—
—
1708
—
3i
4i
—
2j
1709
—
3j
2k
3k
—
1707
aChemical shift of the benzylic protons.
Aniline (1a) was studied as a reference compound, and for comparison to a
literature report.[3] The results indicate that anilines containing an electron-
donating group at either the para or ortho position favor the formation of
N-CBZ products (2b–e), particularly for 2-methoxyaniline, where the product
2e was isolated exclusively in 98% yield. Electron-donating properties
apparently play a role in promoting the synthesis of the N-CBZ product,
presumably by enhancing the electron density on the amino function through
resonance effects. This contention is supported by evidence that reaction of 3-
methoxyaniline (1j), which has limited through resonance effects, with benzyl
chloroformate gave the N-CBZ (2j) and N-Bn (3j) materials in almost equal
proportions.
For anilines (1f–i), which contain electron-withdrawing groups, the
results were generally opposite to those observed for reactants 1a–e. There
was a preponderance amount of N-benzyl products, and in several cases
(1f–h), no N-CBZ products was isolated. It is worthy to note that reactions of
1f–h gave the corresponding N-Bn compounds (3f–h) in 58–91% yields.
Reaction of 4-chloro-2-nitroaniline (1i) gave mainly N-benzyl products,
which was expected. But, in addition to the N-Bn product (3i), a N,N-DiBn
(dibenzylated) compound (4i) was isolated and characterized. In the final
entry, 3-nitroaniline also reacted to give the N-Bn product 3k, but the main

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Synthesis of N-Benzylated Anilines
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Table 2. Percent yields from the reaction of eleven different anilines with benzyl
chloroformate. The yields are reported for products that had been purified by silica gel
column chromatography.
“CBZ”
compounds 2 compounds 3 compounds 4
“Bn”
“Di-Bn”
Anilines 1
a, R1 ¼ R2 ¼ R3 ¼ R4 ¼ H
Electron donating groups
29
14
0
b, R1 ¼ R2 ¼ R4 ¼ H, R3 ¼ Br
c, R1 ¼ R2 ¼ R4 ¼ H, R3 ¼ I
d, R1 ¼ R2 ¼ R4 ¼ H, R3 ¼ Et
e, R2 ¼ R3 ¼ R4 ¼ H, R1 ¼ OCH3
48
38
25
93
1
2
0
0
0
0
0
0
Electron withdrawing groups
f, R2 ¼ R3 ¼ R4 ¼ H, R1 ¼ NO2
g, R2 ¼ R3 ¼ R4 ¼ H, R1 ¼ Br
h, R2 ¼ R3 ¼ H, R1 ¼ Br, R4 ¼ NO2
i, R2 ¼ R4 ¼ H, R3 ¼ Cl, R1 ¼ NO2
0
0
91
70
58
53
0
0
0
14
0
27
Meta-substituted anilines
j, R1 ¼ R3 ¼ R4 ¼ H, R2 ¼ OCH3
42
39
38
12
0
0
k, R1 ¼ R3 ¼ R4 ¼ H, R2 ¼ NO2
product was N-CBZ 2k. From these experiments, the data suggest that
electron-withdrawing moieties at positions ortho and para to the amino group
promote N-benzylation, presumably through resonance effects.
Since the synthesis of N-benzyl products from reactions of anilines and
benzyl chloroformate is unprecedented, further studies were conducted to
explain their formation. In an attempt to investigate whether the N-Bn com-
pounds were produced from rearrangement and decarboxylation of the CBZ
compounds, a solution of N-CBZ aniline 2a in methylene chloride and
triethylamine was heated to reflux and monitored for 5 days. At the end of the
reaction the N-CBZ compound 2a remained unchanged, thus indicating that
the formation of the N-Bn compound 3a did not come from 2a. Based on the
available information, it is reasonable to suggest that formation of the N-Bn
compounds might be a result of Freidel–Crafts acylation, followed by
rearrangement and a concomitant loss of carbon dioxide. As indicated in
Sch. 2, an electron-withdrawing group would pull electron density away from
the amino group. That, in turn, would reduce the nucleophilicity of the amine,
increase the electron density in the phenyl moiety, and facilitate the Freidel–
Crafts reaction. The resulting imine intermediate would rearrange and
eliminates carbon dioxide to produce the N-Bn compound 3a.

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Pati et al.
Scheme 2. A proposed mechanism for the formation of the N-Bn compounds.
In conclusion, this article describes an unexpected discovery of sub-
stitutent effects on the reaction of anilines with benzyl chloroformate.
Depending on the electronic properties of the substituent(s), either the N-CBZ
or N-Bn products could be produced in high chemical yields.
EXPERIMENTAL
A Representative Procedure for the Reaction of Aniline with
Benzyl Chloroformate
A solution of aniline 1a (500 mg, 5.34 mmol) in dry CH2Cl2 (15 mL) and
containing dry triethylamine (2.2 mL, 16 mmol) was chilled in an ice-bath.
While the solution was stirred, a solution of benzyl chloroformate (4.6 mL,
32 mmol) in dry CH2Cl2 (15 mL) was added dropwise through a self-
equalizing funnel, which had an attached drying tube containing drierite. After
15 min, the reaction mixture was warmed to room temperature, the dropping
funnel was replaced with a reflux condenser, and the solution was heated to
reflux for 2 days. The reaction mixture was cooled to room temperature then
poured into 1 M HCl, and the organic materials were extracted with CH2Cl2
(50 mL), then washed with saturated Na2CO3 and dried over Na2SO4.
Removal of the drying agent and solvent gave a semi solid that was purified by
silica gel column chromatography, using 5% EtOAc-petroleum ether as a
solvent. The less polar N-Bn product (3a) was isolated as a viscous colorless
oil (137 mg, 14%), and the N-CBZ compound was isolated as a white solid

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Synthesis of N-Benzylated Anilines
939
(352 mg, 29%). N-Bn (3a): IR (neat) 3087, 3018 2910, 1597, 1503, 1449,
1356, 1201, 748, 729, 695; 1H-NMR (CDCl3) 7.33 (t, 8.0, 2H), 7.26 (m, 3H),
7.17 (t, 8.0, 2H), 6.75 (d, 8.0, 2H), 6.70 (t, 8.0, 1H), 4.66 (s, 2H); MS (EI) 183
(Mþ, 25%). N-CBZ (2a): M.p. 688C; IR (neat) 3323, 3146, 3058, 3028, 2950,
1709, 1601, 1538, 1445, 1314, 1220, 1054, 754, 695; 1H NMR (CDCl3) 7.20–
7.45 (m, 9H), 7.08 (t, 8.0, 1H), 6.76 (s br, 1H), 5.25 (s, 2H); MS (EI) 223 (Mþ,
35%).
ACKNOWLEDGMENTS
The authors thank the NSF-REU, NIH (RR16461-10) from the BRIN
Program, and Furman University for support.
REFERENCES
1. Greene, T.W.; Wuts, P.G.M. Protecting Groups in Organic Synthesis,
2nd Ed.; Wiley-Interscience: New York, 1991.
2. Overman, L.; Sharp, M.J. Enantioselective total synthesis of the
aumiliotoxin A alkaloids via reductive iminium ion-alkyne cyclizations.
Tetrahedron Lett. 1988, 29, 901–905.
3. (a) Srinath, S.; Madhavan, S.; Sambasivam, G. Modified alumina catalyst,
its preparation for protection of functional intermediates and nucleophilic
substitutions. PCT Int. Appl., 0324591, March 27, 2003; (b) Kawada, K.;
Watanabe, M.; Okamoto, K.; Sugihara, H.; Hirata, T.; Maki, Y.; Imada, I.;
Sanno, Y. Spirocyclopropane compounds. III. Synthesis of
spiro[benzofuran-2(3H), 10-cyclopropan]-3-ones for evaluation as gastric
antisecretory and antiulcer agents. Chem. Pharm. Bull. 1984, 32,
3532–3520; (c) Yoshikawa, M.; Yamada, Y.M.A.; Das, J.; Sasai, H.;
Shibasaki, M. Direct catalytic asymmetric aldol reaction. J. Am. Chem.
Soc. 1999, 121, 4168–4178.
4. Hanka, L.J.; Dietz, A.; Gerpheide, S.A.; Kuentzel, S.L.; Martin, D.G.
CC-1065 (NSC-298223), a new antitumor antibiotic. Production in-vivo
biological activity, microbiological assays, and taxonomy of the
producing microorganism. J. Antibiot. 1978, 31, 1211–1217.
5. Ichimura, M.; Ogawa, T.; Takahashi, K.; Kobayashi, E.E.; Kawamoto, I.;
Yasuzawa, T.; Takahashi, I.; Nakano, H. A new antibiotic from
Streptomyces sp. J. Antibiot. 1990, 43, 1037–1038.
6. (a) Boger, D.L.; Han, N.; Tarby, C.M.; Boyce, C.W.; Cai, H.; Jin, Q.;
Kitos, P.A. Synthesis, chemical properties, and preliminary evalua-
tion of substituted CBI analogs of CC-1065 and the duocarmycins

ORDER
REPRINTS
940
Pati et al.
incorporating the 7-cyano-1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-
4-one alkylation subunit: hammett quantitation of the magnitude of
electronic effects on functional reactivity. J. Org. Chem. 1996, 61,
4894–4912; (b) Howard, T.T.; Lingerfelt, B.M.; Purnell, B.L.;
Scott, A.E.; Price, C.A.; Townes, H.M.; McNulty, L.; Handl, H.L.;
Summerville, K.; Hudson, S.J.; Bowen, J.P.; Kiakos, K.; Hartley, J.A.;
Lee, M. Novel Furano analogs of duocarmycin C1 and C2: design,
synthesis and biological evaluation of seco-iso-cyclopropylfurano[e]
indoline (seco-iso-CFI) and the unexpected seco-cyclopropyltetrahydro-
furano[f]quinoline (seco-CFQ) analogs. Bioorg. Med. Chem. 2002, 10,
2941–2952.
7. Aristoff, P.A.; Johnson, P.D. Synthesis of CBI-PDE-I dimer, the
benzannelated analogue of CC-1065. J. Org. Chem. 1992, 75,
6234–6239.
8. Aldrich Handbook for Fine Chemicals and Laboratory Equipment; Lane,
C. President, Sigma-Aldrich: Milwaukee, WI, 2003; Catalog number for
N-benzylaniline is 12,893-7.
Received in the USA October 16, 2003

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