N-Alkyl-N-Cyclopropylanilines as Mechanistic Probes in the Nitrosation of N,N-Dialkyl Aromatic Amines

Article abstract of DOI:10.1021/jo991104z

A group of N-cyclopropyl-N-alkylanilines has been synthesized, and their reaction with nitrous acid in aqueous acetic acid at 0°C was examined. All compounds reacted rapidly to produce the corresponding N-alkyl-N-nitrosoaniline by specific cleavage of the cyclopropyl group from the nitrogen. The transformations were unaffected by the nature of the alkyl substituent (Me, Et, ⁱPr, Bn). The reaction of 4-chloro-N-2-phenylcyclopropyl-N-methylaniline with nitrous acid gave 4-chloro-N-methyl-N-nitrosoaniline (76%), cinnamaldehyde (55%), 3-phenyl-5-hydroxyisoxazoline (26%), and 5-(N-4-chlorophenylmethylamino)-3-phenylisoxazoline (8%). Both the selective cleavage of the cyclopropyl group from the aromatic amine nitrogen and nature of the products derived from the cyclopropane ring support a mechanism involving the formation of an amine radical cation. This step is followed by rapid cyclopropyl ring opening to produce an iminium ion with a C-centered radical which either combines with NO or is oxidized.

Full text of DOI:10.1021/jo991104z

96
J . Org. Chem. 2000, 65, 96-103
N-Alk yl-N-Cyclop r op yla n ilin es a s Mech a n istic P r obes in th e
Nitr osa tion of N,N-Dia lk yl Ar om a tic Am in es
Richard N. Loeppky* and Saleh Elomari
Department of Chemistry, University of Missouri, Columbia, Missouri 65211
Received J uly 9, 1999
A group of N-cyclopropyl-N-alkylanilines has been synthesized, and their reaction with nitrous
acid in aqueous acetic acid at 0 °C was examined. All compounds reacted rapidly to produce the
corresponding N-alkyl-N-nitrosoaniline by specific cleavage of the cyclopropyl group from the
i
nitrogen. The transformations were unaffected by the nature of the alkyl substituent (Me, Et, Pr,
Bn). The reaction of 4-chloro-N-2-phenylcyclopropyl-N-methylaniline with nitrous acid gave 4-chloro-
N-methyl-N-nitrosoaniline (76%), cinnamaldehyde (55%), 3-phenyl-5-hydroxyisoxazoline (26%), and
5-(N-4-chlorophenylmethylamino)-3-phenylisoxazoline (8%). Both the selective cleavage of the
cyclopropyl group from the aromatic amine nitrogen and nature of the products derived from the
cyclopropane ring support a mechanism involving the formation of an amine radical cation. This
step is followed by rapid cyclopropyl ring opening to produce an iminium ion with a C-centered
radical which either combines with NO or is oxidized.
Sch em e 1
In tr od u ction
While the reactions of secondary or primary aromatic
amines with nitrous acid are quite well understood, the
same cannot be said for N,N-dialkyl aromatic amines
(exemplified by 1, Scheme 1), whose transformations
have remained perplexing to chemists over much of the
history of organic chemistry. Generally, the formation of
three or four different compounds are observed in these
transformations: nitrosamines and or secondary amines
formed by N-dealkylation reactions, aromatic nitro com-
pounds, and, occasionally, aromatic C-nitroso com-
pounds.1,2 There are both health reasons related to the
potential carcinogenic character of nitrosamines and
practical reasons related to efficient industrial synthesis
for understanding this chemistry.3 Recently, we provided
strong evidence for the existence of at least three linked
competitive transformations which occur when N,N-
dialkyl aromatic amines react with nitrous acid.2 Key to
this mechanistic scheme (Scheme 1) is the notion that a
nitrosammonium ion 2 undergoes reversible homolysis
to form a radical cation intermediate 3. The latter species
gives rise to both a nitrosamine 6 (path B) and a nitro
compound 4 (path C), but the nitrosammonium ion also
generates nitrosamines by competitive NOH elimination
to 5 (path A), as shown.4,5 An important piece of evidence
supporting this hypothesis was the finding that N-alkyl-
N-cyclopropylaromatic amines do not give any nitro
compound but react with cyclopropyl ring opening. This
evidence was taken to support the formation of a radical
cation which was “trapped” by ring opening. The purpose
of the research reported in this paper is to characterize
the products arising from cyclopropyl ring opening and
provide further evidence in support of the hypothesis that
radical cations are involved in these nitrosation (and
nitration) processes.
Resu lts
Syn th esis of Ar yl N-cyclop r op yla m in es. N-Cyclo-
propylanilines 10 were prepared by refluxing the ap-
propriate aniline derivative 7 and an excess of 1-bromo-
1-ethoxycyclopropane 8 in the presence of triethylamine
in dichloromethane (Scheme 2). The resulting N-(1-
ethoxycyclopropyl)aniline derivatives 9 were reduced
with NaBH4 in the presence of BF3‚Et2O.
N-(2-Phenylcyclopropyl)-N-methyl-4-chloroaniline 12
was prepared by cyclopropanation (diethyl zinc and
diiodomethane) of the enamine 11 derived from the
condensation of N-methyl-4-chloroaniline and phenyl-
acetaldehyde (Scheme 3) in 71% overall yield.
Nitr osa tion Rea ction s. A solution of the appropriate
N-cyclopropyl-N-alkylaniline in glacial acetic acid was
nitrosated at 0 °C by the introduction of 2 equiv of an
aqueous NaNO2 solution. The progress of the reaction
was monitored by TLC, and once the starting amine had
been consumed, the mixture was neutralized and ex-
tracted into ether in order to obtain the product mixture.
The reaction was usually complete within several min-
* Corresponding author. E-mail: LoeppkyR@missouri.edu.
(1) Loeppky, R. N.; Tomasik, T. J . Org. Chem. 1983, 48, 2751-2756.
(2) Loeppky, R. N.; Singh, S. P.; Elomari, S.; Hastings, R.; Theiss,
T. E. J . Am. Chem. Soc. 1998, 120, 5193-5202.
(3) Loeppky, R. N.; Bao, Y. T.; Bae, J . Y.; Yu, L.; Shevlin, G. In
Nitrosamines and Related N-Nitroso Compounds: Chemistry and
Biochemistry; Loeppky, R. N., Michejda, C. J ., Eds.; American Chemical
Society: Washington, DC, 1994; p 52-65.
(4) Smith, P. A. S.; Loeppky, R. N. J . Am. Chem. Soc. 1967, 89,
1147-1157.
(5) Gowenlock, B.; Hutcheson, R. J .; Little, J .; Pfab, J . J . Chem. Soc.
(Perkin Trans. 2) 1979, 1110-1114.
10.1021/jo991104z CCC: $19.00 © 2000 American Chemical Society
Published on Web 12/15/1999

Nitrosation of N-Cyclopropyl-N-alkylanilines
J . Org. Chem., Vol. 65, No. 1, 2000 97
Sch em e 2
Sch em e 3
Sch em e 6
16, produced in 8% yield, was assigned the structure of
5-(N-4-chlorophenylmethylamino)-3-phenylisoxazoline.
This compound, having a formula C16H15ClN2O, possesses
an unsaturation index of 10, one more than the starting
compound. Comparison of this formula with that of the
starting material indicates that NO has been added and
a proton lost. Moreover, the 1H and 13C NMR data clearly
show that both aromatic rings have been retained
without modification. Neither the IR spectrum nor the
13C NMR spectrum are indicative of the presence of a
carbonyl, but the presence of a 13C peak at δ 155 and IR
bands in the region 1487-1583 cm-1 are consistent with
the presence of a CdN. In addition to the N-CH3 peak in
both the 1H and 13C NMR spectra, there are peaks
supporting the presence of a CH-CH2 group in which
hydrogens of the methylene are nonequivalent, as they
would be in a ring. On the basis of this information and
mechanistic rationale described below, we have assigned
structure 16 to this compound.
Sch em e 4
Sch em e 5
Compound 15 gave a formula C9H9NO2, consistent with
the addition of NO to cinnamaldehyde followed by the
loss of a proton, and has been assigned the structure of
5-hydroxy-3-phenylisoxazoline. This is a known com-
pound and both the melting point and the spectral
properties of the substance isolated from our reaction are
entirely consistent with those presented in the literature.6
Several control experiments were performed to exam-
ine the stability of the N-bound cyclopropyl group under
the nitrosation conditions utilized by us. The nitrosation
of 4-chloro-cyclopropylaniline (10a ) gave 4-chloro-N-
cyclopropyl-N-nitrosoaniline (17) in excellent yield (84%)
(Scheme 6). N-Cyclopropylbenzylamine (18) also nitro-
sated cleanly to give the corresponding nitrosamine 19.
More surprising was the nitrosation of N-cyclopropyl-N-
methylbenzylamine 20, which gave benzylmethyl-
nitrosamine (21) as the exclusive product in 88% yield
at 25 °C.
utes after the addition of NaNO2. In each of these
experiments the only nitrosamine product observed was
the corresponding N-alkyl-N-nitrosoaniline 13 (see Scheme
4 for yields). In each case the cyclopropyl group was
cleaved selectively from the nitrogen atom. No aromatic
nitro products were observed.
To determine the nature of the products derived from
the cyclopropyl ring, we used N-(2-phenylcyclopropyl)-
N-methyl-4-chloroaniline (12). Attachment of the phenyl
group to the cyclopropane ring assured the formation of
products which could be more easily isolated and char-
acterized than those derived from compounds with an
unsubstituted cyclopropane ring. The nitrosation, con-
ducted as described above, produced a mixture of four
products which were separated by flash chromatography
and characterized as follows.
Discu ssion
As indicated in the Introduction, nitrosation of N,N-
dialkyl aromatic amines occurs by three competing
pathways: two of which give the nitrosamine, and the
Two of the compounds, N-nitroso-N-methyl-4-chloro-
aniline (13b) (76% yield; see Scheme 5) and cinnamal-
dehyde 14 (53% yield), are known compounds and were
identified by a comparison of the spectral and chromato-
graphic properties with authentic compounds. Compound
(6) DePuy, C. H.; J ones, H. L.; Gibson, D. H. J . Am. Chem. Soc.
1972, 94, 3924-9.

98 J . Org. Chem., Vol. 65, No. 1, 2000
Loeppky and Elomari
Sch em e 7
third produces an o-nitro compound. In this context, the
data presented here exhibit several remarkable features.
The results presented in Scheme 4 show that, regardless
of the other N-bound substitutent, all compounds give
only the nitrosamine produced by the loss of the cyclo-
propyl group. The yields, determined for the isolated
products, are relatively consistent from compound to
compound and show that the size of the N-alkyl substi-
tutent has little effect on the reaction course. Moreover,
when compared with other tertiary amine nitrosation
reactions,2,4,5 even those of similar compounds, the N-
cyclopropylanilines react very rapidly as evidenced by the
complete consumption of starting material within min-
utes at 0 °C. These data, as well as the nature of the
cyclopropyl ring derived products, are completely consis-
tent with the hypothesis that these tertiary amine
dealkylation reactions are occurring exclusively through
a radical cation (path B of Scheme 1).
Extensive documentation demonstrates that the for-
mation of a radical on an atom to which a cyclopropyl
ring is attached results in the rapid opening of the three-
membered ring.7 The rate of cyclopropyl ring opening has
been independently determined for several systems
where the cyclopropyl group is attached to a carbon
centered radical and serves as a “radical clock” for the
timing of competitive intramolecular processes.8 Rapid
cyclopropyl ring opening also occurs when a radical cation
or radical is centered on an attached N-atom and has
been used extensively to detect amine radical cation
formation in enzymatic amine oxidations9-12 and related
chemical model processes.13,14 We have produced evidence
that N,N-dialkyl aromatic amine nitrosation occurs by
the reversible homolysis of the nitrosammonium ion 2
(Scheme 1) to produce the radical cation 3 and NO.2 In
the case of the N-cyclopropylanilines, however, the open-
ing of the three-membered ring occurs so rapidly as to
preclude either recombination of the radical cation and
NO or its reaction with NO2 to give a nitro compound 4.
Thus, the opening of the cyclopropyl ring is envisioned
to kinetically force the transformation exclusively in one
direction, the regioselective removal of the cyclopropyl
substitutent from the amine nitrogen. In other work in
our laboratory, we have shown that the nature of the
N-alkyl group affects the rate of N,N-dialkylaniline
nitrosation reactions. N-Benzyl and N-isopropyl groups
retard the reaction rate. These observations led us to the
hypothesis that larger N-alkyl groups induced rotation
around the aryl C to N bond through steric hindrance in
such a way as to diminish N-p-π electron donation to the
aromatic ring. Such a phenomenon is not manifested
here, since the reactions are independent of the size of
the N-alkyl substituent.
Sch em e 8
radical cation (23) followed by rapid ring opening to
produce the separated cation radical 24, as shown in
Scheme 7. This reactive intermediate is then consumed
by two competitive pathways. Oxidation of 24 by the
nitrous acid medium results in 27. Nitrous acid is well-
known to consist of a mixture of nitrogen species, the
relative concentrations of which are dependent upon pH,
temperature, [H2O], and the nature of the anion derived
from the acid used to generate the nitrous acid from
sodium nitrite. Several of these nitrogen species (NO+,
NO2, and N2O3) are known to be effective oxidants as well
as electrophiles.2 Under our reaction conditions the most
probable oxidant is N2O3, which reacts with 24 (R•) to
give NO•, NO2-, and the carbocation 27, which is con-
verted into cinnamaldehyde (14) and the secondary
amine 7b by proton loss followed by hydrolysis of the
iminium ion. Nitrosation of the amine coproduct of this
hydrolysis, 7b, forms the nitrosamine 13b. In the other
pathway, the radical center of 24 reacts with NO to
generate 25, which isomerizes to the oximinoiminium ion
26. The main reaction of this oxime involves hydrolysis
to the secondary amine 7b and the isoxazoline 15. A
similar process generates the isoxazoline 16.
The conversion of 23 to 15 and 16 has literature
precedent. DePuy and colleagues6 examined the ther-
molysis and photolysis of a series of cyclopropyl nitrites.
In two cases, where phenyl-substituted cyclopropyl ni-
trites were employed, they observed the formation of
isoxazolines. In one case, as shown in Scheme 8, the
product was 15. In every case examined by them, the
carbon radical produced by the opening of the cyclopro-
pane ring reacted with NO to form a nitrogen containing
product. Another interesting feature of this chemistry,
which parallels our observation, is the unexpectedly rapid
homolytic decomposition of the cyclopropyl nitrites, e.g.
28, at low temperatures (0-5 °C). Simple alkyl nitrites
The nature of the reaction products observed from the
nitrosation of N-(2-phenylcyclopropyl)-N-methyl-4-chlo-
roaniline (12) is also consistent with generation of a
(7) Maeda, Y. a. K. U. I. J . Am. Chem. Soc. 1980, 102, 328-331.
(8) Newcomb, M. Tetrahedron 1993, 49, 1151-1176.
(9) Macdonald, T. L.; Zirvi, K.; Burka, L. T.; Peyman, P.; Guengerich,
F. P. J . Am. Chem. Soc. 1982, 104, 2050-2.
(10) Zhao, Z.; Mabic, S.; Kuttab, S.; Franot, C.; Castagnoli, K.;
Castagnoli, N., J r. Bioorg. Med. Chem. 1998, 6, 2531-2539.
(11) Hanzlik, R. P.; Kishore, V.; Tullman, R. J . Med. Chem. 1979,
22, 759-61.
(12) Silverman, R. B. Acc. Chem. Res. 1995, 28, 335-342.
(13) Franot, C.; Mabic, S.; Castagnoli, N., J r. Bioorg. Med. Chem.
1998, 6, 283-291.
(14) Chen, H.; de Groot, M. J .; Vermeulen, N. P. E.; Hanzlik, R. P.
J . Org. Chem. 1997, 62, 8227-8230.

Nitrosation of N-Cyclopropyl-N-alkylanilines
J . Org. Chem., Vol. 65, No. 1, 2000 99
undergo homolytic scission of the N-O bond above 80
°C at measurable rates. The influence of substituents on
homolytic bond scission remains an intriguing problem.
DePuy et al. attributed the rapid rate of cyclopropyl
nitrite homolysis to a concerted homolysis of the O-N
and C-C bonds. The ability of a remote substitutent to
influence decomposition rates by the synchronous scission
of two or more bonds, however, has been questioned more
recently.15 The high reactivity in this system as well as
ours could be explained by reversible homolytic scission
to generate NO. In systems without cyclopropyl ring
substituents, the recombination with NO occurs. In
systems containing the cyclopropyl ring adjacent to the
radical site, rapid ring opening precludes attack at the
original atom of NO attachment. Despite the inherent
logic of such an argument, it is intuitively difficult to
imagine that normal alkyl nitrites, for example, are
undergoing undetected reversible homolysis at temper-
atures as low as 25 °C.
In this context, the results of our “control reactions”
are particularly interesting. Given the known reactivity
of cyclopropane rings toward electrophiles, we considered
that the attack of NO+ (or equivalent) on a cyclopropyl
ring bond to generate a stabilized iminium ion, rather
than initial N-nitrosation, could explain our observations.
The nitrosation of 4-chloro-N-cyclopropylaniline (10a )
under the same conditions used for the tertiary amines
resulted in its smooth conversion to 4-chloro-N-cyclopro-
pyl-N-nitrosoaniline (17). A similar observation was made
for the nitrosation of N-cyclopropylbenzylamine (18). The
nitrosation smoothly produces benzylcyclopropylnitro-
samine (19) in high yield, yet the nitrosation of N-
cyclopropyl-N-methylbenzylamine (20) gives exclusively
benzylmethylnitrosamine (21) at 25 °C. There are several
notable features associated with these observations. The
ability of the N-cyclopropyl secondary amines to be
efficiently converted into their respective nitrosamines
argues against either direct nitrosation of the cyclopropyl
ring or the involvement of radical cations in these
processes. It has been reported that radical cations can
be formed in the nitrosation reactions of both primary
and secondary aromatic amines,16,17 the oxidation poten-
tials of which are certainly less positive than most
aliphatic amines. But initial N-nitrosation must be
followed by rapid proton loss to give the nitrosamine
rather than reversible homolysis to generate a radical
cation and NO, which would certainly lead to cyclopropyl
ring opening.
cations can be involved in these processes as well. This
possibility is being probed by further experimentation.
Finally, although we have shown the fate of the cleaved
cyclopropyl group in the case where it bears a phenyl
substituent (12), it is possible that this substituent
influences the chemistry because it is known to increase
the rate of cyclopropane ring opening in carbon systems.8
Because of their low molecular weight and water solubil-
ity, products derived from the opening of the unsub-
stitued cyclopropyl group are difficult to detect in our
system. It is unlikely, however, that the fundamental
nature of the operative mechanistic process, generation
of the radical cation by the path shown in Scheme 1 and
the subsequent opening of the cyclopropyl group, is
changed by H for phenyl substitution on the three-
membered ring.
Con clu sion
The data presented here strongly support our hypoth-
esis that the nitrosation of N,N-dialkyl aromatic amines
involves the reversible homolysis of a nitrosammonium
ion or an equivalent electron-transfer process. It is
difficult to explain both the regiospecific cleavage of the
cyclopropane ring from the nitrogen atom and the nature
of the products produced from 12 without invoking the
formation of an amine radical cation. The data and
interpretation presented here provide additional support
for the mechanistic hypothesis presented in Scheme 1,
which arose from our prior work.
Exp er im en ta l Section
Th e Syn th esis of Secon dar y N-Alkylan ilin es an d Th eir
Nitr osa m in es. N-Methyl- (7b), N-ethyl- (7c), and N-benzyl-
4-chloroaniline (7d ), as well as ethyl 4-methylaminobenzoate
(7e) and their corresponding nitrosamines (13b-e), are all
known compounds. Amines were prepared by the reduction of
their respective amides with BH3‚THF and the nitrosamine
by acidic nitrosation.
4-Ch lor o-N-cyclop r op yla n ilin e (10a ). N-(1-Ethoxycyclo-
propyl)-4-chloroaniline was obtained by stirring 1 g (7.8 mmol)
of 4-chloroaniline with 2.6 g (15.78 mmol) of 1-bromo-1-
ethoxycyclopropane in the presence of excess triethylamine in
refluxing dichloromethane for 48 h. Workup and chromato-
graphic purification (15% ethyl acetate in hexane) gave the
product as a white solid (mp 46-47 °C) in 51% yield (0.84 g)
which was used directly in the reduction step without ad-
ditional compositional characterization beyond the spectral
1
data listed. H NMR (CDCl3, 500 MHz) δ 7.13 (d, 2H, J ) 8.7
Hz), 6.79 (d, 2H, J ) 8.7 Hz), 4.78 (br s, 1H), 3.54 (q, 2H, J )
7.0 Hz), 1.11 (br t, 5H, J ) 7.0 Hz), 0.85 (dd, 2H, J ) 4.7, 6.6
Hz); 13C NMR (CDCl3, 125.8 MHz) δ 144.06, 128.86, 123.07,
115.29, 68.59, 60.93, 15.29, 14.87.
The most surprising result involves the very rapid
nitrosation of the tertiary amine N-cyclopropyl-N-meth-
ylbenzylamine (20), which results in the exclusive cleav-
age of the cyclopropyl ring from the nitrogen. The
nitrosation of N,N-dimethylbenzylamine occurs only at
a measurable rate at temperatures above 50 °C and
results in cleavage of both methyl and benzyl groups from
N.18 We had thought the latter process to occur exclu-
sively by NOH elimination (see Scheme 1), but the
specific removal of the cyclopropyl ring from 20, coupled
with its very rapid nitrosation, suggests that radical
Using the reduction procedure described in general below,
800 mg (3.78 mmol) of N-(1-ethoxycyclopropyl)-4-chloroaniline
dissolved in 2 mL of dry THF was added dropwise to a stirring
solution of 287 mg (7.58 mmol) of NaBH4 and 1.01 g (7.58
mmol) of BF3‚Et2O in 6 mL of THF at 0 °C under an
atmosphere of nitrogen. After stirring at rt for 38 h, TLC
indicated reaction completion. Workup and chromatographic
purification (10% ethyl acetate in hexanes) afforded the desired
product as a colorless oil in 78% yield (470 mg): 1H NMR
(CDCl3, 500 MHz) δ 7.12 (dt, 2H, J ) 3.3, 8.7 Hz), 6.71 (dt,
2H, J ) 3.3, 8.7 Hz), 4.15 (br s, 1H), 2.40-2.37 (m, 1H), 0.74-
0.71 (m, 2H), 0.51-0.48 (m, 2H); 13C NMR (CDCl3, 125.8 MHz)
δ 147.20, 128.89, 122.31, 114.17, 25.27, 7.40; IR (neat) 3405m
cm-1; MS (70 eV) 169 ((M + 2)+, 24), 168 ((M + 1)+, 30), 167
(M+, 75), 166 (77), 140 (63), 138 (88), 132 (100), 131 (52), 130
(15) Kurhanewicz, J .; J urch, J ., G. R. J . AM. Chem. Soc. 1987, 109,
5038-5039.
(16) Morkovnik, A. S.; Divaeva, L. N.; Okhlobystin, O. Y. J . Gen.
Chem. USSR 1989, 59, 2459-2471.
(17) Koshechko, V. G.; Inozemtsev, A. N. J . Gen. Chem. USSR 1983,
53, 1911-1914.
(90), 111 (50), 77 (31), 75 (52), 51 (23). Anal. Calcd for C9H10
-
NCl: C, 64.48; H, 6.01; N, 8.36. Found C, 64.62; H, 5.89; N,
8.54.
(18) Loeppky, R. N.; Outram, J . R.; Tomasik, W.; Faulconer, J . M.
Tetrahedron Lett. 1983, 24, 4271-4274.

100 J . Org. Chem., Vol. 65, No. 1, 2000
Loeppky and Elomari
N-Cyclop r op ylben zyla m in e (18). To a stirring solution
of 10 g (175 mmol) of cyclopropylamine (purchased from
Aldrich) and 3.2 g (30 mmol) of benzaldehyde and 1.25 g (20
mmol) of NaCNBH3 in 50 mL of methanol was added 30 mL
of 2.25 M HCl in MeOH dropwise at rt. The resulting solution
was allowed to stir for 72 h without monitoring. The reaction
mixture was treated with 15 mL of 3 N NaOH solution and
extracted in 100 mL of ether. The ether layer was dried over
Na2SO4, filtered, and concentrated under reduced pressure on
a rotary evaporator. The resulting colorless oil was further
purified by flash column chromatography using 100% hexanes
as an eluent. The pure product was obtained as a colorless oil
in 78% yield (3.44 g): 1H NMR (CDCl3, 500 MHz) δ 7.37-7.30
(m, 4H), 7.27-7.22 (m, 1H), 3.84 (s, 2H), 2.19-2.13 (m 1H),
1.81 (br s, 1H), 0.46-0.42 (m, 2H), 0.41-0.37 (m, 2H); 13C NMR
(CDCl3, 125.7 MHz) δ 140.56, 128.29, 128.12, 126.76, 53.67,
29.98, 6.41; IR (neat) 3317w, 3276w cm-1; MS (70 eV) 146 (M+,
22), 132 (19), 92 (11), 91 (100), 65 (19). Anal. Calcd for
C10H13N: C, 81.58; H, 8.90; N, 9.51. Found C, 81.70; H, 9.10;
N, 9.23.
Th e Syn th esis of N-Cyclop r op yl-N-Alk yla n ilin es. Gen -
er a l P r oced u r e for th e Alk yla tion of An ilin e Der iva tives
w ith 1-Eth oxy-1-br om ocyclop r op a n e.19,20 In an oven-dried
reaction flask equipped with a Teflon-sealed stirring bar and
a reflux condenser with a drying tube (CaCl2), the appropriate
aniline derivative 7, an excess (1.5-2 mmol equiv) of 1-bromo-
1-ethoxycyclopropane 8, and triethylamine (1.5-2 mmol equiv)
were mixed in dichloromethane (2 M solution with respect to
the aniline substrate). The resulting mixture was allowed to
stir at reflux for 24-72 h. The progress of the reaction was
monitored by TLC. When the reaction was completed, the
mixture was diluted with dichloromethane (3-5 mL/mmol of
amine), washed with water (2 × 3 mL/mmol), and washed once
with brine. The aqueous washes were back-extracted with an
equal amount of dichloromethane. The two organic layers were
combined and dried over anhydrous MgSO4 or Na2SO4. Filtra-
tion and removal of the solvent under reduced pressure on a
rotary evaporator followed by flash column chromatographic
purification afforded the desired products. For a representative
example of this procedure, see the alkylation of 4-chloro-N-
methylaniline 7b below.
Gen er a l P r oced u r e for th e Red u ction of N-(1-Eth oxy-
cyclop r op yl)a n ilin es 9. Reduction according to the procedure
of Kang21 proceeded as follows. In an oven-dried reaction flask
equipped with a stirring bar and a rubber septa, the appropri-
ate N-(1-ethoxycyclopropyl)aniline derivative (1 mmol equiv)
dissolved in freshly distilled THF (1 mL/mmol of substrate)
was added dropwise to a stirring mixture of NaBH4 (2 equiv)
and BF3‚Et2O (2 equiv) in dry THF (1 mL/mmol equiv) at 0
°C (the NaBH4-BF3‚Et2O mixture was stirred for 30-45 min
before the addition of the substrate at 0 °C). The resulting
solution was allowed to slowly warm to room temperature with
stirring, and continued the stirring until reaction completion.
The progress of the reaction was monitored by TLC. Once
completed, the reaction mixture was carefully quenched with
water and extracted in diethyl ether (5 mL/mmol) by washing
with 3 × 20 mL of H2O and 1 × 20 mL of brine. The organic
layer was dried over anhydrous MgSO4, filtered, and concen-
trated under reduced pressure. The resulting residues were
purified by flash column chromatography. For a representing
procedural example, see the reduction of 4-chloro-N-(1-ethoxy-
cyclopropyl)-N-methylaniline 9b below.
reflux with stirring for 65 h. The progress of the reaction was
monitored by TLC. The reaction mixture was diluted with 45
mL of dichloromethane and rinsed with 2 × 30 mL of water
and once with 20 mL of saturated aqueous sodium chloride
solution. The aqueous washes were back-extracted with 45 mL
of CH2Cl2. The two organic layers were combined, dried over
anhydrous MgSO4, and filtered. The solvent was removed
under reduced pressure on a rotary evaporator. The resulting
residue was purified by column chromatography on silica gel
(5% ethyl acetate in hexanes) to give 4-chloro-N-(1-ethoxycy-
clopropyl)-N-methylaniline 9b as a colorless oil in 67% yield
(78% corrected): 1H NMR (CDCl3, 500 MHz) δ 7.18 (dt, 2H, J
) 3.3, 9.2 Hz), 6.91 (dt, 2H, J ) 3.3, 9.2 Hz), 3.51 (q, 2H, J )
7.0 Hz), 3.06 (s, 3H), 1.22 (br s, 2H), 1.11 (t, 3H, J ) 7.0 Hz),
0.90 (br d, 2H, J ) 1.9 Hz); 13C NMR (CDCl3, 125 MHz) δ 146.2,
128.48, 122.49, 114.69, 75.09, 62.24, 37.94, 16.42, 15.42.
In an oven-dried reaction flask equipped with a stirring bar
and a rubber septa, 671 mg (17.73 mmol) of NaBH4 was
suspended in 15 mL of dry THF. The solution was cooled to 0
°C and 2.66 g (17.73 mmol) of BF3‚Et2O was added via a
syringe under nitrogen atmosphere. The mixture was stirred
at 0 °C for 45 min, and 2.0 g (8.86 mmol) of N-methyl-N-(1-
ethoxycyclopropyl)-4-chloroaniline 9b, dissolved in 3 mL of dry
THF was added dropwise via a gastight syringe. The reaction
mixture was allowed to slowly warm to room temperature with
stirring and continued to stir at rt for an additional 6 h. TLC,
then, indicated reaction completion. The reaction was carefully
quenched with water and extracted in 40 mL of diethyl ether
by washing with 3 × 20 mL of H2O and 1 × 20 mL of brine.
The organic layer was dried over anhydrous MgSO4, filtered,
and concentrated under reduced pressure. Column chroma-
tography purification (3% ethyl acetate in hexanes) afforded
the desired product 10b as a colorless oil in 89% yield: 1H
NMR (CDCl3, 500 MHz) δ 7.17 (dt, 2H, J ) 3.3, 9.2 Hz), 6.9
(dt, 2H, J ) 3.3, 9.2 Hz), 2.94 (s, 3H), 2.53 (m, 1H), 0.81 (m,
2H), 0.60 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ 149.39,
128.54, 122.19, 114.80, 39.07, 33.30, 9.07; MS (70 eV): 183
((M + 2)+, 30), 182 ((M + 1)+, 36), 181 (M+, 100), 180 (81), 168
(24), 166 (82), 154 (30), 146 (61), 145 (47), 144 (69), 140 (29),
138 (58), 131 (26), 130 (41), 127 (23), 125 (65), 113 (27), 110
(80), 77 (33), 75 (73), 70 (34), 63 (20), 65 (37), 51 (31). Anal.
Calcd for C10H12ClN: C, 66.11; H, 6.66; N, 7.71. Found C,
66.29; H, 6.52; N, 7.52.
4-Ch lor o-N-cyclop r op yl-N-eth yla n ilin e (10c). The in-
termediate N-(1-Ethoxycyclopropyl)-N-ethyl-4-chloroaniline (9c)
was prepared by stirring 1 g (6.42 mmol) of 4-chloro-N-
22
ethylaniline 7c and 2 g (12.12 mmol) of 1-bromo-1-ethoxy-
cylopropane in refluxing CH2Cl2 in the presence of excess Et3N
for 96 h according to the reaction conditions described above.
The crude reaction mixture was purified by column chroma-
tography on silica gel (eluted with 4% ethyl acetate in hexanes)
to give the product as a colorless oil in 63% yield (74%
corrected): 1H NMR (CDCl3, 500 MHz) δ 7.16 (d, 2H, J ) 9.0
Hz), 6.91 (d, 2H, J ) 9.0 Hz), 3.56 (q, 2H, J ) 7.0 Hz), 3.47 (q,
2h, J ) 7.0 Hz), 1.19 (br s, 2H), 1.13 (t, 3H, J ) 7.0 Hz), 1.10
(t, 3H, J ) 7.0 Hz), 0.94 (br d, 2H, J ) 1.8 Hz); 13C NMR
(CDCl3, 125.8 MHz) δ 144.83, 128.53, 122.15, 115.11, 75.06,
61.93, 45.05, 15.41, 13.69.
To a stirring solution of NaBH4 (475 mg; 12.5 mmol) and
BF3‚Et2O (1.78 g; 12.5 mmol) in 10 mL of THF at 0 °C was
added dropwise 1.5 g (6.26 mmol) of N-(1-ethoxycyclopropyl)-
N-ethyl-4-chloroaniline 5c dissolved in 3 mL of THF, and the
resulting solution was allowed to stir at rt for 8 h. Standard
aqueous workup and chromatographic purification (4% ethyl
acetate in hexanes) provided the product as a colorless oil in
96% yield (1.17 g): 1H NMR (CDCl3, 250 MHz) δ 7.15 (dt, 2H,
J ) 3.3, 9.1 Hz), 6.88 (dt, 2H, J ) 3.3, 9.1 Hz), 3.43 (q, 2H, J
) 7.0 Hz), 2.42-2.34 (m, 1H), 1.07 (t, 3H, J ) 7.0 Hz), 0.84-
0.79 (m, 2H), 0.59-0.53 (m 2H); 13C NMR (CDCl3, 62.9 MHz)
δ 147.87, 128.62, 121.95, 115.41, 45.39, 30.91, 11.36, 8.90; MS
(70 eV) 197 ((M + 2)+, 19), 196 ((M + 1)+, 16), 195 (M+, 57),
4-Ch lor o-N-cyclop r op yl-N-m eth yla n ilin e (10b). In a
flame-dried reaction flask equipped with a stirring bar and a
reflux condenser with a drying tube, 2.0 g (14.12 mmol) of
N-methyl-4-chloroaniline2 7b, 3.5 g (21.18 mmol) of 1-ethoxy-
1-bromocyclopropane, and 2.14 (21.18 mmol) of triethylamine
were all dissolved in 7 mL of dry dichloromethane under
nitrogen atmosphere. The resulting mixture was allowed to
(19) Gadwood, R. C. Tetrahedron Lett. 1984, 25, 5851.
(20) Gadwood, R. C.; Rubino, M. R.; Nagarajan, S. C.; Michel, S. T.
J . Org. Chem. 1985, 50, 3255-3260.
(21) Kang, J .; Kim, K. S. J . Chem. Soc., Chem. Commun. 1987, 897-
898.
(22) Roberts, R. M.; Vogt, P. J . J . Am. Chem. Soc. 1956, 78, 4778-
4781.

Nitrosation of N-Cyclopropyl-N-alkylanilines
J . Org. Chem., Vol. 65, No. 1, 2000 101
194 (31), 180 (37), 168 (21), 166 (57), 151 (20), 145 (21), 144
(40), 139 (41), 138 (97), 131 (23), 130 (55), 125 (37), 113 (32),
110 (100), 77 (24), 76 (21), 75 (72), 70 (69), 56 (46), 51 (22).
Anal. Calcd for C11H14ClN: C, 67.51; H, 7.21; N, 7.16: Found:
C, 67.27; H, 6.98; N, 6.91.
144 (44), 132 (28), 131 (33), 130 (26), 105 (24), 104 (22), 77
(27), 70 (29), 65 (20), 56 (25). Anal. Calcd for C13H17ClNO2: C,
71.20; H, 7.81; N, 6.39. Found C, 71.13; H, 7.66; N, 6.14.
4-Ch lor o-N-cyclop r op yl-N-isop r op yla n ilin e (10f). To a
stirring solution of 1.1 g (6.56 mmol) of N-cyclopropyl-4-
chloroaniline 10a and 1.9 g (32.8 mmol) of acetone in 10 mL
of methanol were added 630 mg (10 mmol) of NaCNBH3 and
10 mL of 2.25 M of HCl in methanol in succession. The
resulting mixture was allowed to stir at room temperature for
4 days. Workup and extraction in ether followed by chromato-
graphic separation (3% ethyl acetate in hexanes) afforded the
desired product 10f in 24% yield as a colorless oil. The starting
amine was recovered in 47% yield: 1H NMR (CDCl3, 500 MHz)
δ 7.14 (d, 2H, J ) 9.0 Hz), 6.92 (d, 2H, J ) 9.0 Hz), 3.84 (septet,
1H, J ) 6.7 Hz), 2.27-2.23 (m, 1H), 1.24 (d, 6H, J ) 6.7 Hz),
0.77 (m, 2H), 0.48 (m, 2H); 13C NMR (CDCl3, 125.8 MHz) δ
150.11, 128.23, 123.20, 118.85, 54.58, 26.32, 20.76, 9.05; MS
(70 eV) 211 ((M + 2)+, 15), 210 ((M + 1)+, 10), 209 (M+, 54),
196 (30), 194 (87), 180 (23), 166 (52), 153 (38), 152 (34), 151
(34), 140 (37), 139 (21), 138 (100), 131 (27), 130 (49), 125 (48),
113 (27), 110 (80), 84 (49), 75 (53); Anal. Calcd for C12H16ClN:
C, 68.72; H, 7.70; N, 6.68. Found C, 68.70; H, 7.67; N, 6.47.
N-Cyclop r op yl-N-m eth ylben zyla m in e (20). This com-
pound was obtained by reductive amination of formaldehyde
with N-cyclopropylbenzylamine. To a stirring solution of
N-cyclopropylbenzylamine 18 (2.5 g; 16.99 mmol), formalde-
hyde (2.43 g of 37% HCHO in water; 900 mg, 30 mmol HCHO),
and NaCNBH3 (1.07 g, 16.99 mol.) in 30 mL of methanol was
added dropwise 10 mL of 2.25N HCl in MeOH. The resulting
mixture was allowed to stir at rt for 48 h. The reaction mixture
was treated with 10 mL of 3 N NaOH solution and extracted
in 50 mL of ether. The aqueous layer was extracted again with
50 mL of ether, and the two layers were combined and dried
over Na2SO4, filtered, and concentrated under reduced pres-
sure on a rotary evaporator. The resulting oil was purified by
flash column chromatography on silica gel (2% ethyl acetate
in hexanes) to give the desired product 20 as a colorless oil in
68% yield (84% based on recovered starting amine): 1H NMR
(CDCl3, 500 MHz) δ 7.31-7.22 (m, 5H), 3.66 (s, 2H), 2.25 (s,
3H), 1.72-1.68 (m, 1H), 0.48-0.45 (m, 2H), 0.44-0.41 (m, 2H);
13C NMR (CDCl3, 125.8 MHz) δ 138.48, 129.36, 128.04, 126.83,
62.24, 41.91, 38.47, 7.10; MS (70 eV) 161 (M+, 15), 160 (55),
146 (17), 132 (12), 91 (100), 70 (29), 65 (29). Anal. Calcd for
4-Ch lor o-N-ben zyl-N-cyclop r op yla n ilin e (10d ). The in-
termediate N-(1-ethoxycyclopropyl)-N-benzyl-4-chloroaniline
(9d ) was prepared by stirring 2.6 g (11.94 mmol) of 4-chloro-
23
N-benzylaniline
7d and 2.9 g (17.9 mmol) of 1-bromo-1-
ethoxycylopropane in refluxing CH2Cl2 in the presence of
excess Et3N according to the reaction conditions described
above. After stirring at reflux for 96 h, the reaction was
stopped and worked up. The crude reaction mixture was
purified by column chromatography on silica gel (eluted with
5% ethyl acetate in hexanes) to give the product as a white
solid (mp 103-104 °C) in 62% yield (79% corrected): 1H NMR
(CDCl3, 500 MHz) δ 7.27 (t, 2H, J ) 7.2 Hz), 7.20 (t, 1H, J )
7.2 Hz), 7.10 (dt, 2H, J ) 3.3, 9.1 Hz), 7.0 (br d, 2H, J ) 7.2
Hz), 6.86 (dt, 2H, J ) 3.3, 9.1 Hz), 4.82 (br s, 2H), 3.56 (q, 2H,
J ) 7.0 Hz), 1.17 (br s, 2H), 1.14 (t, 3H, J ) 7.0 Hz), 0.95 (br
s, 2H); 13C NMR (CDCl3, 125.8 MHz) δ 145.04, 138.78, 128.73,
128.51, 126.83, 125.25, 122.91, 115.60, 75.29, 62.18, 55.78,
15.42.
Using the same reduction procedure, 1 g (3.31 mmol) of N-(1-
ethoxycyclopropyl)-N-benzyl-4-chloroaniline 9d was reduced
with NaBH4 (250 mg; 6.62 mmol) in the presence of BF3‚Et2O
(884 mg (6.62 mmol) according to the reduction procedure
described earlier. The reaction was completed after stirring
at room temperature for 3 h. Workup and chromatographic
purification on silica gel (3% ethyl acetate in hexanes) gave
the product 10d as a colorless oil in 98% yield: 1H NMR
(CDCl3, 250 MHz) δ 7.31-7.19 (m, 3H), 7.14-7.08 (m, 4H),
6.82 (dt, 2H, J ) 3.3, 9.0 Hz), 4.58 (s, 2H), 2.62-2.54 (m, 1H),
0.86-0.79 (m, 2H), 0.7-0.64 (m, 2H); 13C NMR (CDCl3, 62.9
MHz) δ 148.38, 139.35, 128.61, 128.53, 126.77, 126.29, 122.31,
115.08, 56.15, 32.80, 8.96; MS (70 eV) 259 ((M + 2)+, 34), 258
((M + 1)+, 40), 257 (M+, 100), 256 (69), 228 (27), 166 (41), 138
(38), 132 (72), 110 (24), 91 (97). Anal. Calcd for C16H16ClN: C,
74.56; H, 6.25; N, 5.43. Found C, 74.57; H, 6.10; N, 5.55.
Eth yl 4-(N-Cyclopr opyl-N-m eth yl)am in oben zoate (10e).
The intermediate ethyl 4-N-(1-ethoxycyclopropyl)methylami-
nobenzoate 9e was prepared by stirring 1 g (5.5 mmol) of ethyl
4-methylaminobenzoate24 7e and 1.8 g (10.9 mmol) of 1-bromo-
1-ethoxycylopropane in refluxing CH2Cl2 in the presence of
excess Et3N. The reaction was stopped after refluxing for 88
h. Workup and purification by column chromatography on
silica gel (eluted with 5% ethyl acetate in hexanes) afforded
the product as a colorless oil (solidifies in the freezer) in 59%
yield (66% corrected): 1H NMR (CDCl3, 125 MHz) δ 7.93 (dt,
2H, J ) 2.6, 9.0 Hz), 6.99 (dt, 2H, J ) 2.6, 9.0 Hz), 4.32 (q,
2H, J ) 7.1 Hz), 3.52 (q, 2H, J ) 7.0 Hz), 3.16 (s, 3H), 1.36 (t,
3H, J ) 7.1 Hz), 1.26 (br s, 2H), 1.11 (t, 3H, J ) 7.0 Hz), 0.94
(br d, 2H, J ) 1.8 Hz); 13C NMR (CDCl3, 62.9 MHz) δ 166.86,
151.35, 130.67, 119.33, 112.74, 75.00, 62.35, 60.10, 37.89,
15.34, 14.39.
C
11H15N: C, 81.94; H, 9.38; N, 8.68. Found C, 81.73; H, 9.29;
N, 8.54.
Th e Syn t h esis of 4-Ch lor o-N-((E)-2-p h en ylcyclo-
p r op yl)-N-m eth yla n ilin e (12). In an oven-dried 25-mL
volume reaction flask equipped with a stirring bar, 1.4 g (9.98
mmol) of 4-chloro-N-methylaniline and 1.1 g (9.2 mmol) of
freshly distilled phenylacetaldehyde were dissolved in 10 mL
of dry benzene.25 A condenser mounted on a Dean-Stark trap
was affixed to the flask and the reaction was heated at reflux
with stirring for approximately 3 h or until the formation of
water was no longer noticeable as observed in the trap. Then
a small aliquot was drawn with a syringe and the solvent was
1
removed. The H NMR of the remaining residue indicated the
Eth yl 4-N-cyclop r op yl-N-m eth yla m in oben zoa te (10e)
was prepared by subjecting 500 mg (1.9 mmol) of 4-N-(1-
ethoxycyclopropyl)methylaminobenzoate 9e to the reduction
procedure described above (43 h) using NaBH4 (3.8 mmol) in
the presence of BF3‚Et2O (3.8 mmol). Purification of the
resulting residue on silica gel (column chromatography; 15%
ethyl acetate in hexanes) afforded the desired product 10e as
a white solid (mp 27-28 °C) in 64% yield (271 mg): 1H NMR
(CDCl3, 250 MHz) δ 7.92 (dt, 2H, J ) 2.8, 9.0 Hz), 6.90 (dt,
2H, J ) 2.8, 9.0 Hz), 4.32 (q, 2H, J ) 7.1 Hz), 3.03 (s, 3H),
2.56 (s, 2H), 2.62-2.54 (m, 1H), 1.36 (t, 3H, J ) 7.1 Hz), 0.91-
0.84 (m, 2H), 0.68-0.62 (m, 2H); 13C NMR (CDCl3, 62.9 MHz)
δ 167.01, 153.95, 130.84, 118.54, 112.28, 60.11, 38.37, 33.04,
formation of the desired enamine and appeared to be very
pure. The reaction mixture was cooled and the solvent was
removed under pressure to give the product as a pale yellow
solid. GC and GC-MS spectrometry showed that the enamine
was more than 97% pure. The enamine was not purified any
further and was used directly for the next reaction: 1H NMR
(CDCl3, 250 MHz) δ 7.31-7.23 (m, 7H), 7.13-7.07 (m, 1H),
6.98 (d, 2H, J ) 9.0 Hz), 5.7 (d, 1H, J ) 14 Hz), 3.27 (s, 3H);
13C NMR (CDCl3, 62.9 MHz) δ 146.23, 138.53, 133.56, 129.23,
128.66, 126.34, 124.73, 124.44, 118.87, 104.62, 35.64; MS (70
eV): 245 ((M + 2)+, 35), 244 ((M + 1)+, 22), 243 ((M+, 100),
242 (15), 207 (18), 107 (23), 106 (10), 105 (21), 11 (12), 91 (47),
88 (12), 77 (20), 75 (17), 65 (13), 51 (15).
14.45, 9.22; IR (thin film) 1696s, 1606s, 1277s, 1181s cm-1
;
MS (70 eV) 220 ((M + 1)+, 13), 219 (M+, 100), 218 (64), 204
The enamine was subjected to cyclopropanation by using a
(43), 190 (42), 176 (17), 174 (56), 149 (25), 146 (57), 145 (24),
modification of the Simmons-Smith reaction.26,27 In an oven-
(23) Pohloudek-Fabini, R.; Schulz, D. Arch. Pharm. (Weinheim, Ger.
1964, 297, 649-660.
(24) Sekiya, M.; Ito, K. Chem. Pharm. Bull. 1966, 14, 1007-1009.
(25) Hickmott, P. W. Tetrahedron 1982, 38, 1975.
(26) Kuehne, M. E., King, J . C. J . Org. Chem. 1973, 38, 304.
(27) Denmark, S. E.; Edwards, J . P. J . Org. Chem. 1991, 56, 6974.

102 J . Org. Chem., Vol. 65, No. 1, 2000
Loeppky and Elomari
dried two-neck reaction flask equipped with a stirring bar and
a rubber septa (at one neck) and an addition funnel (at the
second neck), 4 g (16.4 mmol) of enamine 11 was dissolved in
30 mL of dry benzene. The solution was cooled to 0 °C, and 25
mL of diethyl zinc solution in hexane (2.53 g; 20.5 mmol of
Et2Zn) was added via a syringe under nitrogen. To the stirring
mixture, 5.35 g (20.5 mmol) of diiodomethane (CH2I2) was
added dropwise (by means of the addition funnel) under
nitrogen atmosphere over a period of 30 min. The resulting
dark yellow solution was gradually warmed to room temper-
ature and then was allowed to further stir for 2 h. The reaction
mixture was diluted with 50 mL of ether, transferred to a
separatory funnel, and carefully washed twice with 45 mL of
10% aqueous NH4OH solution, twice with 50 mL of water, and
once with brine. All aqueous washes were back-extracted with
50 mL of ether. The organic layers were combined and dried
over anhydrous MgSO4, filtered, and concentrated under
reduced pressure. The resulting yellow oil was purified by
distillation under reduced pressure to give a clear yellow oil
in 69% yield (2.9 g): 1H NMR (CDCl3, 250 MHz) δ 7.40-7.15
(m, 7H), 6.82 (d, 2H, J ) 9.0 Hz), 3.05 (s, 3H), 2.64-2.58 (m,
1H), 2.14-2.07 (m, 1H), 1.40-1.32 (m, 2H); 13C NMR (CDCl3,
62.9 MHz) δ 148.86, 140.76, 128.68, 128.49, 126.06, 125.74,
122.49, 114.93, 44.00, 38.60, 27.42, 18.61. Anal. Calcd for
trosation of 4-chloro-N-cyclopropylaniline 10a (65 mg, 0.39
mmol) under the same reaction conditions described in the
general nitrosation procedure (NaNO2, HOAc, H2O, 0 °C, 15
min) followed by workup and chromatographic purification
(eluted with 5% ethyl acetate in hexanes) gave the product as
a yellow oil in 84% yield. The structure was confirmed by
spectral data analysis: 1H NMR (CDCl3, 500 MHz) δ 7.53-
7.47 (m, 2H), 7.43-7.40 (m, 2H), 2.92 (m, 1H), 1.21-1.10 (m,
2H), 0.58-0.54 (m, 2H); 13C NMR (CDCl3, 126 MHz) δ 139.84,
132.59, 129.21, 121.70, 26.70, 8.17; IR (neat) 1494s, 1487s,
1467s (sh) cm-1. Anal. Calcd for C9H9 ClN2O: C, 54.93; H, 4.58;
N, 14.24. Found C, 54.69; H, 4.44; N, 14.05.
Th e Nit r osa t ion of 4-Ch lor o-N-cyclop r op yl-N-et h yl-
a n ilin e (10c). The nitrosation of 280 mg (1.43 mmol) of
4-chloro-N-cyclopropyl-N-ethylaniline (10c) according to the
general nitrosation procedure gave N-ethyl-N-nitroso-4-chlo-
roaniline1 (13c) in 66% yield (isolated yield) as a yellowish
crystalline substance. No other nitrosation products were
observed: 1H NMR (CDCl3, 250 MHz) δ 7.50-7.41 (m, 4H),
4.04 (q, 2H, J ) 7.15 Hz), 1.16 (t, 3H, J ) 7.15 Hz); 13C NMR
(CDCl3, 63 MHz) δ 139.94, 132.85, 129.59, 120.45, 38.87, 11.59.
Th e Nitr osa tion of 4-Ch lor o-N-ben zyl-N-cyclop r op yl-
a n ilin e (10d ). The nitrosation of 4-chloro-N-benzyl-N-cyclo-
propylaniline (10d ) (350 mg, 1.36 mmol) and chromatographic
purification (eluted with 10% ethyl acetate in hexanes) gave
4-chloro-N-benzyl-N-nitrosoaniline1,28 (13d ) as a yellow solid
(mp 56 °C) in 69% yield (isolated): 1H NMR (CDCl3, 250 MHz)
δ 7.49-7.35 (m, 4H), 7.33-7.20 (m, 3H), 7.07-7.03 (m, 2H),
5.21 (s, 2H); 13C NMR (CDCl3, 62.9 MHz) δ 140.28, 133.96,
132.97, 129.59, 128.91, 127.76, 126.97, 120.58, 46.93.
Th e Nitr osa tion of N-Cyclop r op yl-N-isop r op yl-4-ch lo-
r oa n ilin e (10f). The nitrosation of N-cyclopropyl-N-isopropyl-
4-chloroaniline (10f) (175 mg, 0.83 mmol) followed by chro-
matographic purification on silica gel (eluted with 8% ethyl
acetate in hexanes) gave N-isopropyl-N-nitroso-4-chloro-
aniline29 (13f) as a yellow oil in 62% yield (isolated yield). The
product was obtained as an inseparable mixture of two isomers
in a ratio of 1.6:1: 1H NMR (CDCl3, 250 MHz; the spectral
data for the isomeric mixture) δ 7.48 (m, includes two protons
for each of the two isomers; 4H), 7.28 (dt, 2H, J ) 2.8, 8.8 Hz;
major isomer), 6.90 (dt, 2H, J ) 2.0, 8.7 Hz; minor isomer),
1.53 (septet, 1H, J ) 6.9 Hz; major isomer), 5.05 (septet, 1H,
J ) 6.8 Hz; minor isomer), 1.46 (d, 6H, J ) 6.8 Hz; minor
isomer), 1.18 (d, 6H, J ) 6.9 Hz; major isomer); 13C NMR
(CDCl3, 62.9 MHz; the spectral data for both isomers), δ
138.08, 135.28, 134.86, 134.68, 129.65, 129.32, 129.06, 127.00,
56.01, 46.23, 22.00, 19.69; IR (neat; both isomers) 1494s, 1448s
cm-1. Anal. Calcd for C9H11ClN2O: C, 54.41; H, 5.58; N, 14.10.
Found C, 54.23; H, 5.71; N, 13.93.
C
16H16ClN: C, 74.55; H, 6.26; N, 5.43. Found C, 74.57; H, 6.19;
N, 5.52.
Gen er a l P r oced u r e for t h e Nit r osa t ion of N-Cyclo-
p r op yl-N-a lk yla n ilin es. To a stirring solution of N-cyclopro-
pyl-N-alkylaniline derivative in glacial acetic acid (3 mL of
HOAc/mmol of substrate) at 0 °C was added dropwise NaNO2
(2 mmol of NaNO2/mmol of substrate) dissolved in H2O (2 mL/
mmol) via a syringe. Once the addition began, the reaction
mixture became yellow and the intensity of the color increased
with the progress of the reaction. The progress of the reaction
was monitored by thin layer liquid chromatography. The
reaction is usually complete within several minutes after the
addition of NaNO2. Once completed, the reaction mixture was
carefully neutralized with a saturated aqueous solution of K2-
CO3 or Na2CO3. After neutralization, the resulting solution was
extracted in diethyl ether (10 mL/mmol). The ether layer was
washed three times with water and once with saturated
aqueous solution of sodium chloride. The aqueous washes were
back-extracted with ether. The two ether layers were combined
and dried over anhydrous MgSO4 or Na2SO4. The solvent was
removed under reduced pressure on a rotary evaporator. The
resulting residues were purified by flash column chromatog-
raphy on silica gel (for a detailed example, see the nitrosation
of 4-chloro-N-cyclopropyl-N-methylaniline, 10b).
Th e Nitr osa tion of 4-Ch lor o-N-cyclop r op yl-N-m eth yl-
a n ilin e (10b). In a reaction flask equipped with a stirring bar,
500 mg (2.75 mmol) of 4-chloro-N-cyclopropyl-N-methylaniline
(10b) was dissolved in 6 mL of glacial acetic acid. The solution
was cooled to 0 °C, and 380 mg (5.51 mmol) of NaNO2 dissolved
in 2 mL of H2O was added dropwise over a period of 10 min
while the reaction stirred. The resulting yellow solution was
stirred at 0 °C for approximately 25 min. TLC showed reaction
completion. Then, the reaction mixture was carefully neutral-
ized (dropwise) with saturated aqueous Na2CO3 solution. The
resulting mixture was diluted with 30 mL of ether and
transferred to a separatory funnel. The aqueous layer was
discarded and the remaining organic layer was washed once
with saturated aqueous Na2CO3 solution (10 mL), 3 × 20 mL
of H2O, and once with brine. The aqueous washes were back-
extracted with 30 mL of ether. The organic layers were
combined and dried over anhydrous Na2SO4, filtered, and
concentrated. The resulting reddish residue was purified by
flash column chromatography (10% ethyl acetate in hexanes)
to give a yellow crystalline substance in 68% yield as the sole
product (97% by HPLC analysis). Spectral data analysis
indicated that the product is 4-chloro-N-methyl-N-nitrosoa-
niline2 (13b): 1H NMR (CDCl3, 500 MHz) δ 7.50 (dt, 2H, J )
2.4, 8.9 Hz), 7.45 (dt, 2H, J ) 2.4, 8.9 Hz), 3.43 (s, 3H); 13C
NMR (CDCl3, 125 MHz) δ 140.82, 132.88, 129.57, 120.10,
31.18.
Th e Nitr osa tion of Eth yl 4-N-Cyclop r op yl-N-m eth yl-
a m in ob en zoa t e (10e). The nitrosation of ethyl 4-N-cyclo-
propyl-N-methylaminobenzoate 10e (150 mg, 0.76 mmol)
followed by chromatographic purification (eluted with 15%
ethyl acetate in hexanes) resulted in ethyl 4-methylnitrosami-
nobenzoate2 (13e) in 76% yield: 1H NMR (CDCl3, 500 MHz) δ
8.16 (d, 2H, J ) 8.8 Hz), 7.64 (d, 2H, J ) 8.8 Hz), 4.41 (q, 2H,
J ) 7.2 Hz), 3.46 (s, 3H), 1.42 (t, 3H, J ) 7.2 Hz); 13C NMR
(CDCl3, 126 MHz) δ 165.69, 145.52, 130.94, 128.82, 117.77,
61.16, 30.49, 14.27.
Th e Nit r osa t ion of N-Cyclop r op y-N-m et h ylb en zyl-
a m in e (20). The nitrosation of N-cyclopropy-N-methylbenzyl-
amine (20) (70 mg, 0.43 mmol) according to the general
nitrosation procedure (NaNO2-H2O/glacial HOAc) at room
temperature followed by workedup in ether (usual aqueous
workup as described in the general nitrosation procedure) and
purification on silica gel (column chromatography; 10% ethyl
acetate in hexanes) gave benzylmethylnitrosamine (21) as a
yellow oil in 88% yield. The product was obtained as an
inseparable mixture of Z and E isomers in a 3:1 ratio, and no
other products were observed. The reaction was complete in
about 55-65 min at room temperature. When the nitrosation
(28) Carter, P.; Stevens, T. S. J . Chem. Soc. 1961, 1743-1748.
(29) El-Sebai, A. I.; Rida, S.; Soliman, R. Egypt. J . Pharm. Sci. 1973,
14, 75-80.
4-Ch lor o-N-cyclop r op yl-N-n itr osoa n ilin e (17). The ni-

Nitrosation of N-Cyclopropyl-N-alkylanilines
J . Org. Chem., Vol. 65, No. 1, 2000 103
was carried at 60 °C, it was completed in 15 min, giving similar
results (86% yield in a 3:1 ratio). The spectral data were
consistent with benzylmethylnitrosamine: 1H NMR for the
mixture (CDCl3, 500 MHz) δ 7.40-7.30 (m, includes three
protons for the major isomer and three protons for the minor
isomer), 7.26 [(d, 2H (major isomer), J ) 7.0 Hz)], 7.12 [(d, 2H
(minor isomer), J ) 7.0 Hz)], 5.29 (s, 2H, benzylic protons of
the major isomer), 4.80 (s, 2H, benzylic proton of the minor
isomer), 3.68 (s, 3H, methyl group of the minor isomer), 2.93
(s, 3H, methyl group of the major isomer); 13C NMR for both
isomers (CDCl3, 125.8 MHz) δ 134.19, 133.65, 128.90, 128.74,
128.39, 128.19, 127.90, 127.80, 57.39, 47.57, 38.26, 30.56; IR
(neat; both isomers) 1449s cm-1; MS (70 eV) 150 (M+, 16), 91
(100), 65 (13). Anal. Calcd for C8H10N2O: C, 65.73; H, 6.89;
N, 19.16. Found: C, 65.61; H, 6.88; N, 18.93.
Th e Nitr osa tion of 4-Ch lor o-N-(2-p h en ylcyclop r op yl)-
N-m eth yla n ilin e (12). 4-chloro-N-(2-phenylcyclopropyl)-N-
methylaniline (12) was nitrosated (NaNO2-HOAc, 0 °C)
according to the general nitrosation procedure described
earlier. The reaction was complete in 15-20 min. Workup
followed by chromatographic purification on silica gel (eluted
with gradient: 2.5%, 3%, 5%, 15%, 15%, 20% and 25% ethyl
acetate in hexanes) yielded 4-chloro-N-methyl-N-nitrosoaniline
(13b) in 76%, cinnamaldehyde in 53%, compound 16 in 8%,
and compound 15 in 26%.
Com p ou n d 16: 5-(N-4-ch lor op h en ylm eth yla m in o)-3-
p h en ylisoxa zolin e. This product was obtained in 8% yield
as a white solid substance (mp 191-192 °C) from the nitro-
sation of N-(2-phenylcyclopropyl)-N-methyl-4-chloroaniline
(12): 1H NMR (CDCl3, 250 MHz) δ 7.71-7.67 (m, 2H), 7.43-
7.40 (m, 3H), 7.23 (d, 2H, J ) 9.0 Hz), 6.98 (d, 2H, J ) 9.0
Hz), 6.24 (dd, 1H, J ) 4.8, 10.0 Hz), 3.51 (dd, 1H, J ) 10.0,
17.8 Hz), 3.28 (dd, 1H, J ) 4.8, 17.8 Hz), 2.78 (s, 3H); 13C NMR
(62.9 MHz) δ 155.34, 148.02, 130.17, 129.46, 129.09, 128.81,
126.52, 126.42, 119.78, 93.43, 37.01; IR (KBr pellet) 3075w,
3063w, 2958w, 2939w, 2921w, 2830w, 1593m, 1565w, 1487s,
1446m, 1432w, 1358s, 1312s, 1283w, 1255m, 1249m, 1193w,
1188m, 1112m, 1075w, 1007w, 976m, 930m, 914s, 887m, 832s,
802w, 758s, 749s, 692s, 672s, 656m, 537m, 520m cm-1; MS
(70 eV) 288 ((M + 2)+, 10), 286 (M+, 27), 187 (12), 186 (19),
143 (32), 142 (15), 141 (100), 140 (25), 118 (14), 77 (25), 51
(11). Anal. Calcd for C16H15ClN2O: C, 67.02; H, 5.27; N, 9.77.
Found: C, 67.12; H, 5.10; N, 9.63.
N-(2-phenylcyclopropyl)-N-methyl-4-chloroaniline (7): 1H NMR
(CDCl3, 250 MHz) δ 7.70-7.61 (m, 2H), 7.43-7.33 (m, 3H),
6.03 (dd, 1H, J ) 1.8, 6.5 Hz), 4.11 (br d, 1H, J ) 2.3 Hz), 3.40
(dd, 1H, J ) 6.5, 17.5 Hz), 3.23 (dd, 2H, J ) 1.8, 17.5 Hz); 13
C
NMR (CDCl3, 62.9 MHz) δ 156.87, 130.38, 128.96, 128.72,
126.91, 98.00, 42.45; IR (KBr bellet) 2944m, 2865w, 1599m,
1571m, 1499m, 1449s, 1404s, 1359s, 1333s, 1319w, 1294w,
1274s, 1243s, 1189w, 1181s, 1102w, 1084s, 1024w, 1000w,
931s, 905s, 974s, 841s, 800m, 761s, 689s, 672m, 552m, 515m
cm-1; MS (70 eV) 163 (M+, 40), 135 (44), 134 (54), 119 (12),
117 (14), 106 (17), 103 (43), 91 (26), 89 (10), 78 (10), 77 (100),
64 (16), 63 (17), 51 (52). Anal. Calcd for C9H9NO2: C, 66.25;
H, 5.56; N, 8.58. Found: C, 66.35; H, 5.37; N, 8.50.
Cyclop r op ylben zyln itr osa m in e (19). Nitrosation of N-
cyclopropylbenzylamine (18) (42 mg, 0.28 mmol) under the
same reaction conditions discussed earlier (NaNO2, HOAc,
H2O, 0 °C, 15-20 min) and chromatographic purification (12%
ethyl acetate in hexanes) gave the product as a yellow oil in
86% yield. The product was obtained as an inseparable mixture
of two geometric isomers in a ratio of 3.2:1. The product was
identified by spectral data analysis: 1H NMR (CDCl3, 500
MHz) δ 7.38-7.25 (m, includes 5H for the minor isomer and
3H for the major isomer), 7.16 (d, 2H, J ) 7.0 Hz, major
isomer), 5.25 (s, 2H, benzylic proton of the minor isomer), 4.80
(s, 2H, benzylic protons of the major isomer), 3.22 (m, 1H, the
methine proton in the cyclopropane ring of the major isomer),
2.69 (m, 1H, the methine proton of the cyclopropane ring of
the minor isomer), 1.17-1.03 (m, 2H, a methylene group
protons of the cyclopropane ring in the major isomer), 1.01-
0.92 (m, 2H, the second methylene group protons of the
cyclopropane ring of the major isomer), 0.89-0.82 (m, 2H, a
methylene group protons of the cyclopropane ring of the minor
isomer), 0.68-0.59 (m, 2H, the second methylene group
protons of the cyclopropane ring in the minor isomer); 13C NMR
(CDCl3, 126 MHz) δ 135.69, 134.40, 128.82, 128.66, 128.27,
128.15, 127.68, 127.55, 55.39, 48.70, 33.64, 27.37, 5,87, 5.74;
IR (neat) 1496m, 1454s, 1443s, 1419m cm-1; low resolution
mass spectrometry gave a parent ion peak at 176: MS (70 eV)
146 (9), 133 (9), 91 (100), 65 (14). Anal. Calcd for C10H12N2O:
C, 68.16; H, 6.86; N, 15.90. Found: C, 68.31; H, 6.78; N, 16.11.
Ack n ow led gm en t. The support of this research by
a grant (R37 CA26914) from the National Cancer
Institute NIH is gratefully acknowledged.
Com p ou n d 15: 5-Hyd r oxy-3-p h en ylisoxa zolin e. This
compound6 was produced in 26% yield as a white solid
substance (mp 117-118 °C) from the nitrosation reaction of
J O991104Z