Br?nsted acid catalyzed monoalkylation of anilines with trichloroacetimidates

Article abstract of DOI:10.1021/jo5027222

Trichloroacetimidates are useful alkylating agents for aromatic amines, requiring only a catalytic amount of a Br?nsted acid to facilitate the reaction. Monoalkylation predominates under these conditions. Electron-poor anilines provide superior yields, with electron-rich anilines sometimes showing competitive Friedel-Crafts alkylation. A single flask protocol with formation of the imidate in situ is demonstrated, providing a convenient method for the direct substitution of alcohols with anilines. Reaction with a chiral imidate favors a mechanism that proceeds through a carbocation intermediate.

Full text of DOI:10.1021/jo5027222

Note
pubs.acs.org/joc
Brønsted Acid Catalyzed Monoalkylation of Anilines with
Trichloroacetimidates
Daniel R. Wallach, Patrick C. Stege, Jigisha P. Shah, and John D. Chisholm*
Department of Chemistry, 1-014 Center for Science and Technology, Syracuse University, Syracuse, New York 13244, United States
S
* Supporting Information
ABSTRACT: Trichloroacetimidates are useful alkylating
agents for aromatic amines, requiring only a catalytic amount
of a Brønsted acid to facilitate the reaction. Monoalkylation
predominates under these conditions. Electron-poor anilines
provide superior yields, with electron-rich anilines sometimes
showing competitive Friedel−Crafts alkylation. A single flask
protocol with formation of the imidate in situ is demonstrated, providing a convenient method for the direct substitution of
alcohols with anilines. Reaction with a chiral imidate favors a mechanism that proceeds through a carbocation intermediate.
ur recent findings on the spontaneous reaction of
methane was reported to provide improved conversions for this
transformation.8 Additionally, allylic trichloroacetimidates have
been used as substrates for transition-metal-catalyzed allylic
amination with aniline nucleophiles. These reactions9 employ
catalysts based on rhodium,10 iridium,11 or palladium.12 Fewer
studies have evaluated protic acids in these N-substitution
reactions, although (PhO)2PO2H was recently used with aniline
and a highly reactive isatin derived trichloroacetimidate13 and
TsOH was evaluated in the alkylation of anilines with tert-butyl-
2,2,2-trichloroacetimidate.8
O
trichloroacetimidates with carboxylic acids1 led us to
speculate about the reactivity of these alkylating agents with
other functional groups, including anilines. Substituted anilines
are a common structural unit often found in natural products
and other bioactive compounds (Figure 1). For example, a
As previous studies have generally focused on specific
imidates, we set out to find more general conditions that could
be applied to a greater variety of reaction partners. Initial
experiments were performed with imidate 514 and 2,5-
dichloroaniline 6 (Table 1). No reaction between the imidate
and the aniline was observed in control experiments performed
without an acid catalyst (entries 1 and 2). The use of BF3·OEt2
as a catalyst provided a 33% yield of monoalkylated aniline 7a.
This reaction also gave a number of side products including
dialkylation of the aniline nitrogen, which made isolation and
purification of the desired monoalkylation product difficult.
Repeating the BF3·OEt2 reaction with an excess of aniline to
suppress dialkylation of the nitrogen did provide an improved
yield, but dialkylation and other products were still apparent in
the crude 1H NMR spectra. These polyalkylation products may
be less problematic with the more sterically hindered tert-butyl-
2,2,2-trichloroacetimidate, but this side product formation
seems to be a significant issue with less encumbered imidates.
The switch was then made to less powerful Brønsted acid
catalysts in the hope of improving the selectivity for
monoalkylation of the aniline nitrogen. The use of diphenyl-
phosphoric acid provided a 31% yield of the desired N-
substituted aniline 7a. Promisingly, only unreacted starting
materials and N-alkylation product 7a were observed in the
Figure 1. Aniline-based pharmaceuticals and natural products.
substituted aniline core is found in the cholesterol lowering
drug ezetimibe (1).2 Biologically active natural products also
commonly contain substituted anilines, like the topoisomerase
inhibitor bicolorine (2),3 the tyrosine kinase inhibitor
lavendustin A (3),4 and the lipoxygenase inhibitor onosmin B
(4).5 Substituted anilines also frequently appear in molecules
used in sensor applications and other synthetic receptors.6
Given the ubiquity of N-alkyl anilines, new methods for their
formation from readily available precursors like trichloroaceti-
midates are in high demand.
A search of the literature revealed that tert-butyl-2,2,2-
trichloroacetimidate has been occasionally used for the
alkylation of anilines, typically with BF3·OEt2 as the catalyst
or promoter.7 More recently, copper(II) triflate in nitro-
Received: December 1, 2014
© XXXX American Chemical Society
A
DOI: 10.1021/jo5027222
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The Journal of Organic Chemistry
Note
addition of molecular sieves and Lewis acids to facilitate imine
formation, yields are often moderate.15 More electron-rich
aniline nucleophiles gave lower isolated yields of monoalkylated
products (like 7h and 7i), and often the crude reaction
mixtures appeared to be contaminated with side products from
Friedel−Crafts reactions that led to difficult purifications
(trichloroacetimidates have been shown to participate in
Friedel−Crafts alkylations16). In some cases where the yields
were moderate (Table 2, entries 4 and 9), heating the reaction
to reflux in toluene provided a higher yield of the desired
product. Sterics also appeared to play a significant role in the
yield of the N-alkylation reaction. While one ortho substituent
was well tolerated on the aniline, the incorporation of two
ortho substituents effectively stopped all alkylation (Table 2,
entry 14). N-Alkyl anilines readily participated in the reaction,
with N-methylaniline and indoline providing good yields of
alkylated products 7n and 7o, respectively. With the alkylation
of the anilines performing well, we attempted to expand the
scope to the more basic alkyl amines using morpholine as the
nucleophile. No N-alkylation products were observed with
morpholine (Table 2, entry 17), even when heated in toluene
with CSA, only unreacted starting materials were observed in
the reaction mixture.
Table 1. Optimization of the Reaction of Imidate 5 with 2,5-
Dichloroaniline 6
entry
1
catalyst
none
% yield
0
a
2
none
0
b
3
4
5
6
7
8
BF3·OEt2
(PhO)2PO2H
(BnO)2PO2H
p-TsOH
33 (68 )
31
0
59
97
83
82
22
( )-CSA
e
DNBSA
c
9
d
( )-CSA
10
( )-CSA
a
b
Heated to reflux in toluene for 24 h. 1.1 equiv of aniline 6 was used.
c
d
e
2.4 equiv of imidate was used. 5 mol % catalyst was used. DNBSA =
2,4-dinitrobenzenesulfonic acid.
Evaluation of the substrate scope with respect to imidate
electrophile was also undertaken (Table 3). Most unhindered
benzylic imidates were effective in the alkylation reaction. Only
the electron-poor 4-cyanobenzyl imidate 14 (entry 4) gave
poor conversion. In this case, the reaction had to be heated to
reflux in toluene to obtain product 15, as no reaction was
observed at room temperature in CH2Cl2. Allylic trichloro-
acetimidates 20 and 22 also provided good yields of product
(Table 3, entries 8 and 9), providing the mono-N-Alkylated
products in excellent yield. The tertiary benzylic imidate 24
gave moderate yield of N-alkyl product 25 as this reaction is
slowed by the steric encumbrance of the hindered imidate. The
tert-butyl-2,2,2-trichloroacetimidate 26 gave only a low yield of
the corresponding tert-butyl aniline 27. Evidently, the Brønsted
acid catalyzed conditions are more mild than the Lewis acid
catalyzed conditions typically employed for this imidate7 and,
combined with the greater steric requirements of 2,5-
dichloroaniline compared to aniline, resulted in a reduced
yield (most reactions with tert-butyl-2,2,2-trichloroacetimidate
26 and aniline also require a large excess (2−5 equiv) of the
imidate for good conversion). These results are consistent with
the recent report on the copper triflate catalyzed alkylation of
anilines with imidate 26 where special conditions and excess
imidate are needed to obtain high yields.8 No alkylation
product was observed in the reaction of the ethyl imidate (entry
12), even under forcing conditions (toluene, reflux, 24 h).
Alternatively, the phthalimidomethyl imidate 30 (entry 13)
gave N-alkylated product 31 in excellent yield. One interesting
facet of these alkylations was the preference for substitution
over elimination in benzylic systems like 7a and 19. In order to
further investigate the preference for substitution, the doubly
unsaturated imidate 32 that is more prone to elimination was
explored as a reaction partner (entry 14). This substitution
provided the desired N-alkyl aniline 33 in 63% yield but
required 72 h to proceed to completion. Some elimination side
products were observed in this reaction, but given the simplicity
of the reaction conditions, the selectivity for substitution over
elimination is impressive. In the cases where some elimination
was observed in the crude NMR (Table 3, entries 6, 7, 10, and
reaction mixture, with no polyalkylation products being
observed. Building on this result, a number of Brønsted acid
catalysts were screened in the N-substitution reaction.
( )-Camphorsulfonic acid (CSA) provided the highest yield
of the monoalkylation product. Interestingly, only a mono-
alkylation product was obtained even when excess imidate was
used (entry 9). Given the selectivity of this protocol for
monoalkylation, these conditions were chosen for evaluation in
further studies.
Next, a number of aniline nucleophiles were evaluated for
their reactivity (Table 2). Electron-poor anilines proved to be
the best substrates for the substitution reaction. This is notable
and quite useful, as electron-deficient anilines are typically
difficult substrates for reductive aminations, and even with the
Table 2. Reaction of Amines with Imidate 5
entry
amine
2,5-dichloroaniline
% yield 7
97 (7a)
1
2
aniline
76 (7b)
89 (7c)
3
4-chloroaniline
a
4
4-bromoaniline
56 (70 ) (7d)
5
2-bromoaniline
70 (7e)
98 (7f)
94 (7g)
70 (7h)
6
3,5-bis(trifluoromethyl)aniline
2-nitroaniline
7
8
4-(methylthio)aniline
4-ethylaniline
a
9
47 (65 ) (7i)
10
11
12
13
14
15
16
17
2-fluoro-4-methylaniline
2-chloro-5-(trifluoromethyl)aniline
2-chloro-4-fluoroaniline
2-chloro-4-methylaniline
2,4,6-tribromoaniline
N-methylaniline
80 (7j)
98 (7k)
99 (7l)
94 (7m)
0
84 (7n)
74 (7o)
0
indoline
morpholine
a
1
Reaction performed in toluene at reflux.
14), the signals for the minor alkene byproducts in the H
B
DOI: 10.1021/jo5027222
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The Journal of Organic Chemistry
Note
alkylating agents for anilines typically requires a transition-
metal catalyst and high temperatures.17 In contrast, a direct
procedure through the imidate intermediate would avoid the
use of transition metals and proceed at room temperature.
Taking the desired alcohol and forming the imidate in
dichloromethane with 10 mol % DBU catalyst, followed by
addition of the aniline and 20 mol % ( )-CSA, proved to be a
useful protocol for the synthesis of substituted anilines (Table
4), with yields for the single flask protocol often surpassing the
Table 3. Reaction of Imidates with 2,5-Dichloroaniline 6
Table 4. Single Flask Synthesis of Monosubstituted Anilines
two-step procedure. In addition to the synthesis of several
alkylated anilines, the synthesis of the natural product onosmin
B 4 was performed using the methodology. This provided the
lipoxygenase inhibitor in 85% yield from the corresponding
alcohol. Additionally, the alkylated piperonal derivative 39 was
synthesized, which represents a formal synthesis of 5,6-
dihydrobicolorine, as this system has been cyclized previously
to the natural product in a single step.18
The propensity of the N-substitution reaction to displace an
enantiomerically enriched imidate was also investigated with
the use of phenethyl imidate (R)-5. The ability to generate a
chiral amine directly from the chiral alcohol via the
trichloroacetimidate would be quite useful, but substitution
reactions of similar enantiomerically pure imidates with oxygen
nucleophiles are challenging and typically provide mixtures of
enantiomers as products.19 Reaction of imidate (R)-5 with 4-
chloroaniline 42 (Scheme 1) provided the substituted aniline
a
b
Reaction performed in toluene at reflux. Reaction performed with
c
BF3·OEt2 (10 mol %) Reaction was performed at room temperature
for 72 h Ar = 2,5-dichlorophenyl.
d
Scheme 1
NMR were contaminated with other impurities that made
quantification difficult. Attempts to isolate and quantify these
side-products were thwarted by the presence of other nonpolar
impurities and the volatility of the alkenes.
A single flask method for the conversion of alcohols to
substituted anilines was then developed. The use of alcohols as
C
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The Journal of Organic Chemistry
Note
recorded in CDCl3, with residual chloroform or TMS used as the
internal reference.
product 7c in excellent conversion. Evaluation of the
enantiomeric purity of the reaction product revealed that
both enantiomers of the aniline 7c were formed in the reaction,
as the product was shown to be a 35:65 mixture of the R and S
enantiomers.
These results and the inability to alkylate ethyl trichlor-
oacetimidate (Table 3, entry 12) are consistent with a
carbocation intermediate in the reaction, which precludes
high levels of stereocontrol (scalemic mixtures often result from
cationic processes due to ion pairing20). A proposed
mechanism is shown in Figure 2 below. Protonation of the
Representative procedures for the aniline substitution reactions:
Representative Procedure A: Reaction of Imidate 5 with 2,5-
Dichloroaniline 6. 1-Phenethyl imidate 5 (0.30 g, 1.13 mmol) and
2,5-dichloroaniline 6 (0.15 g, 0.94 mmol) were added to a flame-dried
round-bottom flask under argon. Dry dichloromethane (4 mL) was
added, followed by camphorsulfonic acid (0.03 g, 0.11 mmol). The
reaction was stirred at room temperature for 24 h. After triethylamine
(0.5 mL) was added, the reaction mixture was preadsorbed on silica
gel and purified by silica gel chromatography using 19% dichloro-
methane/80% hexanes/1% triethylamine to give 0.24 g (97%) of
substituted aniline 7a as a yellow oil.
Representative Procedure B: Single Flask Synthesis of
Monosubstituted Aniline 7a. Phenethyl alcohol 34 (0.33 g, 2.73
mmol) and trichloroacetonitrile (0.33 mL, 3.27 mmol) were added to
a flame-dried round-bottom flask under argon. Dry dichloromethane
(4 mL) was added, followed by 1,8-diazabicyclo[5.4.0]undec-7-ene
(0.04 g, 0.27 mmol). The reaction was stirred at room temperature
and monitored for disappearance of the alcohol by TLC (4 h). 2,5-
Dichloroaniline 6 (0.37 g, 2.28 mmol) was added, followed by
camphorsulfonic acid (0.13 g, 0.54 mmol). The reaction was allowed
to stir at room temperature for 24 h. Triethylamine (0.5 mL) was then
added, and the reaction mixture was preadsorbed on silica gel and
purified by silica gel chromatography using 19% dichloromethane/80%
hexanes/1% triethylamine to provide 0.55 g (90%) of substituted
aniline 7a as a yellow oil.
2,5-Dichloro-N-(1-phenylethyl)aniline (7a).22 Prepared using
procedure A (0.24 g, 97%) from 2,5-dichloroaniline 6 and the
known imidate 514 or procedure B (0.55 g, 90%) from 1-phenethyl
alcohol, purified using silica gel chromatography (4% ethyl acetate/
95% hexanes/1% triethylamine). Yellow oil (0.24 g, 97%); TLC Rf =
0.71 (19% dichloromethane/80% hexanes/1% triethylamine); 1H
NMR (300 MHz, CDCl3) δ 7.35−7.25 (m, 5H), 7.14 (d, J = 8.4 Hz,
1H), 6.54 (dd, J = 8.4, 2.4 Hz, 1H), 6.38 (d, J = 2.4 Hz, 1H), 4.49 (q, J
= 6.6 Hz, 1H), 1.57 (d, J =6.6 Hz, 3H); 13C NMR (300 MHz, CDCl3)
δ 144.0, 133.6, 129.8, 129.1, 128.5, 127.6, 125.9, 117.3, 117.2, 112.4,
53.5, 25.1.
Figure 2. Proposed mechanism.
aniline and imidate is reversible, but protonation of the imidate
eventually leads to the formation of a carbocation and loss of
trichloroacetamide. Capture of the carbocation by the aniline,
followed by proton transfer to another equivalent of aniline,
provides the observed alkylated product and regenerates the
protonated aniline to turnover the catalytic cycle. More basic
amines (like morpholine) are not acidic enough to protonate
the imidate, explaining their low reactivity under these
conditions.
In summary, a method for alkylating anilines using
trichloroacetimidate electrophiles under Brønsted acid cata-
lyzed conditions has been described. Monoalkylation of anilines
is primarily observed under these conditions. While most
anilines react well, electron-rich anilines provide more
moderate yields, often forming side products due to competing
Friedel−Crafts alkylations. The more basic alkylamines fail to
react under these conditions, as the amine salt formed from
their reaction with the catalyst is less acidic and, therefore, not
capable of catalyzing the reaction. A range of imidates proved
compatible, although the structures must be benzylic, allylic, or
tertiary, implicating a mechanism that proceeds through a
carbocation intermediate. This new method appears to favor
substitution over elimination in sensitive systems such as 33. A
one-step protocol where the imidate is formed in situ and then
displaced by the aniline nucleophile was also demonstrated as a
useful method for the alkylation of aromatic amines with
alcohols. The utility of this protocol has been demonstrated in
the synthesis of the lipoxygenase inhibitor onosmin and a
formal synthesis of 5,6-dihydrobicolorine.
N-(1-Phenylethyl)aniline (7b).22 Prepared using procedure A from
aniline and the known imidate 5,14 purified using silica gel
chromatography (95% hexanes/4% ethyl acetate/1% triethylamine).
Yellow oil (0.14 g, 76%); TLC Rf = 0.59 (95% hexanes/4% ethyl
acetate/1% triethylamine); 1H NMR (300 MHz, CDCl3) δ 7.38−7.28
(m, 4H), 7.25−7.24 (m, 1H), 7.12−7.06 (m, 2H), 6.66 (t, J = 7.8 Hz,
1H), 6.54 (d, J = 7.5 Hz, 2H), 4.48 (q, J = 6.9 Hz, 1H), 1.53 (d, J = 6.9
Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 147.5, 145.4, 129.4, 128.9,
127.1, 126.1, 117.5, 113.6, 53.7, 25.3.
4-Chloro-N-(1-phenylethyl)aniline (7c).23 Prepared using proce-
dure A from 4-chloroaniline and the known imidate 5,14 purified using
silica gel chromatography (4% ethyl acetate/95% hexanes/1%
triethylamine). Reddish crystals (0.19 g, 89%); mp = 58−60 °C;
TLC Rf = 0.43 (5% ethyl acetate/95% hexanes); 1H NMR (300 MHz,
CDCl3) δ 7.33−7.19 (m, 5H), 7.00 (dt, J = 9.9, 3.0 Hz, 2H), 6.40 (dt,
J = 10.2, 3.3 Hz, 2H), 4.42 (q, J = 6.9 Hz, 1H), 4.04 (br s, 1H), 1.49
(d, J = 6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 145.8, 144.7,
128.9, 128.7, 127.1, 125.8, 121.9, 114.4, 53.6, 25.0. When (R)-5 (>98:2
er) was used, an 85% yield (0.061 g) of reddish crystals was obtained
as a 35:65 ratio of R:S enantiomers. Chiral HPLC analysis: Chiralcel
OD (heptane/i-PrOH = 95/5, 1.0 mL/min, 254 nm, 25 °C): tminor
7.52 min, tmajor = 9.75 min, 35:65 ratio, 30% ee.
=
4-Bromo-N-(1-phenylethyl)aniline (7d).24 Prepared using proce-
dure A from 4-bromoaniline and the known imidate 5,14 purified using
silica gel chromatography (49% dichloromethane/50% hexanes/1%
triethylamine). Off-white solid (0.18 g, 70%); mp = 68−71 °C; TLC
Rf = 0.71 (49% dichloromethane/50% hexanes/1% triethylamine); 1H
NMR (400 MHz, CDCl3) δ 7.33−7.28 (m, 4H), 7.24−7.21 (m, 1H),
7.14 (dt, J = 9.6, 3.2 Hz, 2H), 6.36 (dt, J = 10.0, 2.4 Hz, 2H), 4.43 (q, J
= 6.8 Hz, 1H), 4.06 (br s, 1H) 1.50 (d, J = 6.4 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 146.3, 144.7, 132.0, 128.9, 127.2, 125.9, 115.0, 109.0,
53.6, 25.1.
EXPERIMENTAL SECTION
■
General. All anhydrous reactions were run under a positive
pressure of argon or nitrogen. Dichloromethane and THF were dried
by passage through an alumina column following the method of
Grubbs.21 Column chromatography was performed using silica gel 60
(230−400 mesh). Melting points are uncorrected. NMR spectra were
D
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Note
2-Bromo-N-(1-phenylethyl)aniline (7e).25 Prepared using proce-
dure A from 2-bromoaniline and the known imidate 5,14 purified using
silica gel (19% dichloromethane/80% hexanes/1% triethylamine).
Clear colorless oil (0.18 g, 70%); TLC Rf = 0.50 (19% dichloro-
methane/80% hexanes/1% triethylamine); 1H NMR (400 MHz,
CDCl3) δ 7.50 (dd, J = 8.0, 1.6 Hz, 1H), 7.44−7.38 (m, 4H), 7.33−
7.29 (m, 1H), 7.07 (ddd, J = 8.0, 7.2 1.2 Hz, 1H), 6.58 (ddd, J = 7.6,
7.2 1.6 Hz, 1H), 6.48 (dd, J = 8.4, 1.2 Hz, 1H), 4.81 (br d, J = 3.6 Hz,
1H), 4.60 (p, J = 6.8 Hz, 1H), 1.65 (d, J = 6.8 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 144.6, 144.1, 132.3, 128.9, 128.4, 127.1, 125.8,
117.9, 112.8, 109.7, 53.6, 25.3.
and the known imidate 5,14 purified using silica gel chromatography
(5% ethyl acetate/94% hexanes/1% triethylamine). Yellow oil (0.28 g,
98%); TLC Rf = 0.57 (5% ethyl acetate/94% hexanes/1% triethyl-
amine); IR (thin film) 3428, 3087, 3066, 3031, 2974, 2930, 2873, 1603
cm−1; 1H NMR (300 MHz, CDCl3) δ 7.34−7.25 (m, 6H), 6.80 (ddd, J
= 8.1, 2.1, 0.6 Hz, 1H), 6.64 (d, J = 1.8 Hz, 1H), 4.55 (q, J = 6.6 Hz,
1H), 1.60 (d, J = 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 143.6,
143.3, 130.1 (q, J = 32.0 Hz), 129.3, 129.0, 127.5, 125.7, 124.0 (q, J =
271.0 Hz), 122.2, 113.7 (q, J = 4.0 Hz), 108.8 (q, J = 4.0 Hz), 53.4,
24.7. Anal. Calcd for C15H13ClF3N: C, 60.11; H, 4.37; N, 4.67. Found:
C, 60.27; H, 4.36; N, 4.55.
N-(1-Phenylethyl)-3,5-bis(trifluoromethyl)aniline (7f).26 Prepared
using procedure A (0.29 g, 98%) from 3,5-bis(trifluoromethyl)aniline
and the known imidate 5,14 or procedure B (0.75 g, 99%) from 1-
phenethyl alcohol 34, purified using silica gel chromatography (19%
dichloromethane/80% hexanes/1% triethylamine). White solid (0.29
g, 98%); mp = 56−57 °C; TLC Rf = 0.47 (19% dichloromethane/80%
hexanes/1% triethylamine); 1H NMR (400 MHz, CDCl3) δ 7.39−7.37
(m, 4H), 7.32−7.29 (m, 1H), 7.15 (s, 1H), 6.91 (s, 2H), 4.57 (q, J =
6.8 Hz, 1H), 4.51 (br s, 1H), 1.59 (d, J = 6.8 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 147.9, 143.6, 132.2 (q, J = 33.0 Hz), 129.2, 127.7,
125.6, 123.8 (q, J = 271.0 Hz), 112.6 (q, J = 3.0 Hz), 110.2 (sep, J =
3.0 Hz), 53.6, 24.6.
2-Nitro-N-(1-phenylethyl)aniline (7g). Prepared using procedure A
from 2-nitroaniline and the known imidate 5,14 purified using silica gel
chromatography (49% dichloromethane/50% hexanes/1% triethyl-
amine). Yellow oil (0.24 g, 94%); TLC Rf = 0.31 (50% dichloro-
methane/50% hexanes); IR (thin film) 3380, 3086, 3029, 2972, 2929,
2873, 1618 cm−1; 1H NMR (300 MHz, CDCl3) δ 8.41 (br s, 1H), 8.17
(dd, J = 8.4, 1.5 Hz, 1H), 7.35−7.25 (m, 6H), 6.64−6.57 (m, 2H), 4.69
(p, J = 6.6 Hz, 1H), 1.65 (d, J = 6.9 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 144.6, 143.7, 136.1, 132.3, 129.1, 127.5, 126.8, 125.7, 115.7,
115.3, 53.3, 25.1. Anal. Calcd for C14H14N2O2: C, 69.41; H, 5.82; N,
11.56. Found: C, 69.15; H, 5.90; N, 11.16.
2-Chloro-4-fluoro-N-(1-phenylethyl)aniline (7l). Prepared using
procedure A from 2-chloro-4-fluoroaniline and the known imidate 5,14
purified using silica gel chromatography (19% dichloromethane/80%
hexanes/1% triethylamine). Dark oil (0.27 g, 99%); TLC Rf = 0.52
(19% dichloromethane/80% hexanes/1% triethylamine); IR (thin
1
film) 3424, 3064, 3029, 2971, 2929, 2871, 1599 cm−1; H NMR (300
MHz, CDCl3) δ 7.33−7.28 (m, 4H), 7.25−7.22 (m, 1H), 7.03 (dd, J =
8.4, 3.0 Hz, 1H), 6.69 (ddd, J = 9.0, 8.1, 2.7 Hz, 1H), 6.32 (dd, J = 9.0,
5.7 Hz, 1H), 4.52 (br s, 1H), 4.47 (q, J = 6.9 Hz, 1H), 1.57 (d, J = 6.9
Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 154.4 (d, J = 236.4 Hz)
144.5, 139.9 (d, J = 2.2 Hz), 128.9, 127.2, 125.8, 118.8 (d, J = 10.3
Hz), 116.3 (d, J = 25.8 Hz), 114.3 (d, J = 21.5 Hz), 112.8 (d, J = 8.0
Hz), 53.9, 25.3. Anal. Calcd for C14H13ClFN: C, 67.34; H, 5.25; N,
5.61. Found: C, 67.39; H, 4.97; N, 5.53.
2-Chloro-4-methyl-N-(1-phenylethyl)aniline (7m).29 Prepared
using procedure A from 2-chloro-4-methylaniline and the known
imidate 5,14 purified using silica gel chromatography (5% dichloro-
methane/94% hexanes/1% triethylamine). Yellow oil (0.22 g, 94%);
TLC Rf = 0.56 (5% dichloromethane/94% hexanes/1% triethylamine);
1H NMR (300 MHz, CDCl3) δ 7.35−7.19 (m, 5H), 7.07 (dd, J = 2.1,
0.9 Hz, 1H), 6.76 (dd, J = 8.1, 1.8, 0.6 Hz, 1H), 6.35 (d, J = 8.1 Hz,
1H), 4.51 (q, J = 6.6 Hz, 1H), 2.16 (s, 3H), 1.58 (d, J = 6.6 Hz, 3H);
13C NMR (75 MHz, CDCl3) δ 145.0, 140.8, 129.6, 128.9, 128.4, 127.2,
127.0, 126.0, 119.0, 112.9, 53.8, 25.4, 20.3.
4-(Methylthio)-N-(1-phenylethyl)aniline (7h).27 Prepared using
procedure A from 4-(methylthio)aniline and the known imidate 5,14
purified using silica gel chromatography (5% ethyl acetate/94%
hexanes/1% triethylamine). Orange oil (0.17g, 70%); TLC Rf = 0.31
(5% ethyl acetate/94% hexanes/1% triethylamine); IR (thin film)
3411, 3082, 3061, 3026, 2979, 2919, 2867, 1598 cm−1; 1H NMR (400
MHz, CDCl3) δ 7.36−7.29 (m, 4H), 7.24−7.23 (m, 1H), 7.12 (d, J =
8.4 Hz, 2H), 6.46 (br d, J = 7.6 Hz, 2H), 4.46 (q, J = 6.8 Hz, 1H), 2.36
(s, 3H), 1.51 (d, J = 6.8 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ
146.2, 145.0, 131.4, 128.8, 127.1, 125.9, 124.2, 114.0, 53.6, 25.0, 19.1.
4-Ethyl-N-(1-phenylethyl)aniline (7i).28 Prepared using procedure
A from 4-ethylaniline and the known imidate 5,14 purified using silica
gel chromatography (1% dichloromethane/98% hexanes/1% triethyl-
amine). Orange oil (0.10 g, 47%); TLC Rf = 0.74 (1% dichloro-
methane/98% hexanes/1% triethylamine); 1H NMR (300 MHz,
CDCl3) δ 7.40−7.22 (m, 5H), 6.94−6.92 (m, 2H), 6.47 (dt, J = 9.0,
2.4 Hz, 2H), 4.45 (q, J = 6.9 Hz, 1H), 2.49 (q, J = 7.5 Hz, 2H), 1.51
(d, J = 6.6 Hz, 3H), 1.15 (t, J = 7.5, 3H); 13C NMR (75 MHz, CDCl3)
δ 145.7, 145.5, 133.3, 128.9, 128.7, 127.1, 126.1, 113.6, 54.0, 28.1, 25.3,
16.2.
2-Fluoro-4-methyl-N-(1-phenylethyl)aniline (7j). Prepared using
procedure A from 2-fluoro-4-methylaniline and the known imidate 5,14
purified using silica gel chromatography (5% ethyl acetate/94%
hexanes/1% triethylamine). Clear colorless oil (0.17g, 80%); TLC Rf =
0.59 (5% ethyl acetate/94% hexanes/1% triethylamine); IR (thin film)
3431, 3061, 3031, 2968, 2925, 1658 cm−1; 1H NMR (300 MHz,
CDCl3) δ 7.38−7.28 (m, 4H), 7.25−7.19 (m, 1H), 6.79 (dd, J = 12.3,
1.5 Hz, 1H), 6.64−6.61 (m, 1H), 6.40 (br s, 1H), 4.48 (q, J = 6.6 Hz,
1H), 2.18 (s, 3H), 1.57 (d, J = 6.6 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 151.6 (d, J = 236.6 Hz), 145.2, 133.4 (d, J = 11.8 Hz), 128.9,
127.2, 126.7 (d, J = 6.6 Hz), 126.0, 124.9 (d, J = 3.1 Hz), 115.3 (d, J =
18.2 Hz), 113.5 (d, J = 3.4 Hz), 53.8, 25.3, 20.6 (d, J = 1.1 Hz). Anal.
Calcd for C15H16FN: C, 78.57; H, 7.03; N, 6.11. Found: C, 78.31; H,
7.27; N, 5.76.
N-Methyl-N-(1-phenylethyl)aniline (7n).30 Prepared using proce-
dure A (0.17 g, 84%) from N-methylaniline and the known imidate
5,14 or procedure B (0.36 g, 82%) from 1-phenethyl alcohol, purified
using silica gel chromatography (4% ethyl acetate/95% hexanes/1%
triethylamine). Yellow oil (0.17 g, 84%); TLC Rf = 0.32 (2% ethyl
acetate/97% hexane/1% triethylamine); 1H NMR (300 MHz, CDCl3)
δ 7.34−7.22 (m, 7H), 6.84 (d, J = 8.1 Hz, 2H), 6.73 (t, J = 7.2 Hz,
1H), 5.13 (q, J = 6.9 Hz, 1H), 2.68 (s, 3H), 1.55 (d, J = 6.9 Hz, 3H);
13C NMR (75 MHz, CDCl3) δ 150.4, 143.0, 129.4, 128.6, 127.1, 127.0,
116.9, 113.3, 56.7, 32.0, 16.5.
1-(1-Phenylethyl)indoline (7o).31 Prepared using procedure A from
indoline and the known imidate 5,14 purified using silica gel
chromatography (5% ethyl acetate/94% hexanes/1% triethylamine).
Dark oil (0.18 g, 74%); TLC Rf = 0.52 (5% ethyl acetate/94%
hexanes/1% triethylamine); 1H NMR (300 MHz, CDCl3) δ 7.42−7.22
(m, 5H), 7.05 (dd, J = 7.2, 0.9 Hz, 1H), 6.98 (t, J = 7.5 Hz, 1H), 6.60
(t, J = 6.9 Hz, 1H), 6.35 (d, J = 7.5 Hz, 1H), 4.71 (q, J = 7.2 Hz, 1H),
3.44−3.28 (m, 2H), 2.94 (t, J = 8.7 Hz, 2H), 1.53 (d, J = 6.9 Hz, 3H);
13C NMR (75 MHz, CDCl3) δ 151.7, 143.2, 130.5, 128.7, 127.5, 127.4,
127.2, 124.7, 117.3, 107.6, 54.9, 48.3, 28.5, 16.9.
N-Benzyl-2,5-dichloroaniline (9). Prepared using procedure A
(0.23 g, 92%) from 2,5-dichloroaniline 6 and the commercially
available benzyl-2,2,2-trichloroacetimidate 8 or procedure B (0.37 g,
64%) from benzyl alcohol, purified using silica gel chromatography
(19% dichloromethane/80% hexanes/1% triethylamine). Clear color-
less oil (0.23 g, 92%); TLC Rf = 0.50 (20% dichloromethane/80%
hexanes); IR (thin film) 3422, 3064, 3030, 2852, 1595 cm−1; 1H NMR
(300 MHz, CDCl3) δ 7.39−7.29 (m, 5H), 7.18−7.15 (m, 1H), 6.62−
6.59 (m, 2H), 4.76 (br s, 1H), 4.36 (s, 2H); 13C NMR (75 MHz,
CDCl3) δ 144.8, 138.1, 133.8, 129.9, 129.1, 127.8, 127.6, 117.5, 117.4,
111.5, 48.0. Anal. Calcd for C13H11Cl2N: C, 61.93; H, 4.40; N, 5.56.
Found: C, 62.26; H, 4.26; N, 5.51.
2-Chloro-N-(1-phenylethyl)-5-(trifluoromethyl)aniline (7k). Pre-
pared using procedure A from 2-chloro-5-(trifluoromethyl)aniline
2,5-Dichloro-N-(4-methoxybenzyl)aniline (11). Prepared using
procedure A from 2,5-dichloroaniline 6 and the commercially available
E
DOI: 10.1021/jo5027222
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
4-methoxybenzyl-2,2,2-trichloroacetimidate 10, purified with silica gel
chromatography (5% ethyl acetate/94% hexanes/1% triethylamine).
Yellow oil (0.22 g, 91%); TLC Rf = 0.42 (2% ethyl acetate/97%
hexanes/1% triethylamine); IR (thin film) 3422, 3071, 3003, 2958,
2836, 1595 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.26 (d, J = 8.4 Hz,
2H), 7.15 (d, J = 8.4 Hz, 1H), 6.89 (d, J = 8.8 Hz, 2H), 6.62−6.58 (m,
2H), 4.66 (br s, 1H), 4.27 (s, 2H), 3.80 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 159.3, 144.9, 133.8, 130.1, 129.9, 128.9, 117.4, 117.2, 114.4,
111.5, 55.5, 47.5. Anal. Calcd for C14H13Cl2NO: C, 59.59; H, 4.64; N,
4.96. Found: C, 59.61; H, 4.94; N, 4.84.
N-((6-Bromobenzo[d][1,3]dioxol-5-yl)methyl)-2,5-dichloroaniline
(13). Prepared using procedure A from 2,5-dichloroaniline 6 and the
known imidate 12,32 purified using silica gel chromatography (19%
dichloromethane/80% hexanes/1% triethylamine). Yellow oil (0.20 g,
80%); TLC Rf = 0.29 (20% dichloromethane/80% hexanes); IR (thin
film) 3436, 3107, 3078, 3010, 2915, 1593 cm−1; 1H NMR (300 MHz,
CDCl3), δ 7.17 (d, J = 8.4 Hz, 1H), 7.04 (s, 1H), 6.82 (s, 1H), 6.62
(dd, J = 8.4, 2.4 Hz, 1H), 6.51 (d, J = 2.1 Hz, 1H), 5.97 (s, 2H), 4.84
(t, J = 5.4 Hz, 1H), 4.33 (d, J = 5.7 Hz, 2H); 13C NMR (100 MHz,
CDCl3), δ 147.82, 147.76, 144.2, 133.7, 130.0, 129.8, 117.5, 117.4,
113.5, 113.0, 111.4, 108.7, 101.9, 47.8. Anal. Calcd for C14H10-
O2NBrCl2: C, 44.83; H, 2.69; N, 3.73. Found: C, 45.10; H, 2.74; N,
3.94.
4-(((2,5-Dichlorophenyl)amino)methyl)benzonitrile (15). Pre-
pared using procedure A from 2,5-dichloroaniline 6 and the known
imidate 14,16 purified using silica gel chromatography (9% ethyl
acetate/90% hexanes/1% triethylamine). White solid (0.11 g, 43%);
mp = 114−115 °C; TLC Rf = 0.59 (50% dichloromethane/50%
hexanes); IR (thin film) 3409, 2916, 2224, 1595, 1567 cm−1; 1H NMR
(400 MHz, CDCl3) δ 7.64 (dd, J = 6.4, 1.6 Hz, 2H), 7.45 (d, J = 8.0
Hz, 2H), 7.18 (d, J = 8.8 Hz, 1H), 6.63 (dd, J = 8.4, 2.0 Hz, 1H), 6.45
(d, J = 2.0 Hz, 1H), 4.92 (t, J = 5.6 Hz, 1H), 4.47 (d, J = 6.0 Hz, 2H);
13C NMR (100 MHz, CDCl3) δ 144.0, 143.7, 133.7, 132.7, 130.0,
129.7, 117.3, 117.0, 116.8, 111.3, 45.9; Anal. Calcd for C9H9Cl2N: C,
53.49; H, 4.49; N, 6.69. Found: C, 53.40; H, 4.89; N, 6.69.
2,5-Dichloro-N-(cyclohex-2-en-1-yl)aniline (23). Prepared using
procedure A from 2,5-dichloroaniline 6 and the known imidate 22,35
purified using silica gel chromatography (2% ethyl acetate/97%
hexanes/1% triethylamine). Orange oil (0.19 g, 79%); TLC Rf = 0.60
(5% ethyl acetate/95% hexanes); IR (thin film) 3418, 3026, 2938,
2862, 1593 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.14 (d, J = 8.4 Hz,
1H), 6.66 (d, J = 2.4 Hz, 1H), 6.57 (dd, J = 8.4, 2.4 Hz, 1H), 5.94- 5.88
(m, 1H), 5.75−5.70 (m, 1H), 4.36 (br d, J = 7.8 Hz, 1H), 3.98 (br s,
1H), 2.09−2.05 (m, 2H), 1.96−1.89 (m, 1H), 1.77−1.63 (m, 3H); 13C
NMR (100 MHz, CDCl3) δ 143.8, 133.6, 131.2, 129.9, 127.4, 117.3,
116.5, 111.3, 47.7, 28.6, 25.1, 19.5; Anal. Calcd for C12H13Cl2N: C,
59.52; H, 5.41; N, 5.78. Found: C, 59.38; H, 5.27; N, 5.45.
2,5-Dichloro-N-(2-phenylpropan-2-yl)aniline (25). Prepared using
procedure A from 2,5-dichloroaniline 6 and the known imidate 24,36
purified using silica gel chromatography (9% dichloromethane/90%
hexanes/1% triethylamine). Clear colorless oil (0.22 g, 42%); TLC Rf
= 0.58 (10% dichloromethane/90% hexanes); IR (thin film) 3419,
1
3042, 3011, 2857, 1578 cm−1; H NMR (400 MHz, CDCl3) δ 7.45−
7.42 (m, 2H), 7.34 (tt, J = 6.8, 1.6 Hz, 2H), 7.25 (tt, J = 6.8, 1.6 Hz,
1H), 7.12 (d, J = 8.4 Hz, 1H), 6.48 (dd, J = 8.0, 2.4 Hz, 1H), 6.06 (d, J
= 2.4 Hz, 1H), 4.84 (br s, 1H), 1.68 (s, 6H); 13C NMR (100 MHz,
CDCl3) δ 145.9, 142.7, 132.7, 129.6, 128.9, 126.9, 125.4, 118.0, 116.8,
114.4, 56.1, 30.5. Anal. Calcd for C15H15Cl2N: C, 64.30; H, 5.40; N,
5.00. Found: C, 63.95; H, 5.71; N, 4.70.
N-(tert-Butyl)-2,5-dichloroaniline (27). Prepared using procedure
A from 2,5-dichloroaniline 6 and the commercially available tert-butyl
2,2,2-trichloroacetimidate 26, purified using silica gel chromatography
(19% dichloromethane/80% hexanes/1% triethylamine). Clear color-
less oil (0.01 g, 5%); TLC Rf = 0.45 (20% dichloromethane/80%
hexanes); IR (thin film) 3416, 3086, 3060, 2981, 1592, 1504 cm−1; 1H
NMR (300 MHz, CDCl3) δ 7.14 (d, J = 8.4 Hz, 1H), 6.89 (d, J = 2.4
Hz, 1H), 6.56 (dd, J = 8.4, 2.4 Hz, 1H), 4.38 (br s, 1H), 1.40 (s, 9H);
13C NMR (75 MHz, CDCl3) δ 143.6, 132.9, 129.8, 118.6, 116.6, 113.8,
127.6, 118.7, 117.8, 117.5, 111.4, 111.3, 47.2. Anal. Calcd for
C14H10Cl2N2: C, 60.67; H, 3.64; N, 10.11. Found: C, 60.32; H,
3.58; N, 9.80.
51.4, 29.6. Anal. Calcd for C10H13Cl2N: C, 55.06; H, 6.01; N, 6.42.
Found: C, 55.13; H, 6.35; N, 6.13.
N-Benzhydryl-2,5-dichloroaniline (17). Prepared using procedure
A (0.28 g, 87%) from 2,5-dichloroaniline 6 and the known imidate
1633 and procedure B (0.39 g, 88%) from diphenylmethanol, purified
using silica gel chromatography (10% dichloromethane/89% hexanes/
1% triethylamine). Clear colorless oil (0.28 g, 87%); TLC Rf = 0.59
(10% dichloromethane/89% hexanes/1% triethylamine); IR (thin
film) 3417, 3031, 2925, 1656, 1596 cm−1; 1H NMR (300 MHz,
CDCl3) δ 7.34−7.25 (m, 10H), 7.16 (d, J = 8.4 Hz, 1H), 6.59 (dd J =
8.4, 2.4 Hz, 1H), 6.44 (d, J = 2.1 Hz, 1H), 5.52 (s,1H), 4.95 (br s,
1H); 13C NMR (75 MHz, CDCl3) δ 144.1, 141.9, 133.7, 129.9, 129.2,
128.7, 128.0, 127.6 117.7, 112.7, 62.7. Anal. Calcd for C19H15Cl2N: C,
69.52; H, 4.61; N, 4.27. Found: C, 69.75; H, 4.62; N, 4.60.
2-(((2,5-Dichlorophenyl)amino)methyl)isoindoline-1,3-dione
(31). Prepared using procedure A from 2,5-dichloroaniline 6 and the
known imidate 30,37 purified using silica gel chromatography (20%
ethyl acetate/79% hexanes/1% triethylamine). White powder (0.24 g,
74%); mp = 200−201 °C; TLC Rf = 0.83 (20% ethyl acetate/79%
hexanes/1% triethylamine); IR (KBr) 3397, 3067, 1718, 1657 cm−1;
1H NMR (400 MHz, CDCl3) δ 7.88−7.86 (m, 2H), 7.74−7.72 (m,
2H), 7.26 (s, 1H), 7.13 (d, J = 8.4 Hz, 1H), 6.66 (dd, J = 8.4, 2.4 Hz,
1H), 5.47 (t, J = 7.6 Hz, 1H), 5.19 (d, J = 7.6 Hz, 2H); 13C NMR (100
MHz, CDCl3) δ 168.2, 142.0, 134.4, 133.8, 131.8, 130.1, 123.7, 119.0,
118.0, 112.4, 46.6. Anal. Calcd for C15H10Cl2N2O2: C, 56.10; H, 3.14;
N, 8.72. Found: C, 56.06; H, 3.33; N, 8.51.
2,5-Dichloro-N-(1-(p-tolyl)ethyl)aniline (19). Prepared using pro-
cedure A from 2,5-dichloroaniline 6 and the known imidate 18,34
purified using silica gel chromatography (5% ethyl acetate/94%
hexanes/1% triethylamine). Clear colorless oil (0.17 g, 68%); TLC Rf
= 0.81 (5% ethyl acetate/95% hexanes); IR (thin film) 3422, 2968,
2,5-Dichloro-N-(1,4-diphenylbut-3-yn-1-yl)aniline (33). Prepared
using procedure A from 2,5-dichloroaniline 6 and the known imidate
32,38 purified using silica gel chromatography (4% dichloromethane/
95% hexanes/1% triethylamine). Yellow solid (50 mg, 63%); mp =
86−88 °C; TLC Rf = 0.54 (10% ethyl acetate/90% hexanes); IR (KBr)
1
2923, 2867, 1594 cm−1; H NMR (300 MHz, CDCl3) 7.23−7.20 (m,
1
3380, 3114, 2989, 1594, 1504 cm−1; H NMR (400 MHz, CDCl3) δ
2H), 7.16−7.12 (m, 3H), 6.53 (dd, J = 8.4, 2.4 Hz, 1H), 6.40 (d, J =
2.1 Hz, 1H), 4.72 (br s, 1H), 4.46 (q, J = 6.6 Hz, 1H), 2.33 (s, 3H),
1.55 (d, J = 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 143.9, 140.8,
136.9, 133.4, 129.6, 125.6, 117.1, 116.9, 112.2, 53.0, 24.9, 21.1 (one
signal in the aromatic region was not resolved). Anal. Calcd for
C15H15Cl2N: C, 64.30; H, 5.40; N, 5.00. Found: C, 64.52; H, 5.20; N,
4.74.
7.42−7.27 (m, 10H), 7.15 (d, J = 8.4 Hz, 1H), 6.57 (dd, J = 8.4, 2.4
Hz, 1H), 6.40 (d, J = 2.0 Hz, 1H), 5.33 (d, J = 5.2 Hz, 1H), 4.61 (q, J
= 5.6 Hz, 1H), 3.05 (dd, J = 16.8, 5.2 Hz, 1H), 2.91 (dd, J = 16.8, 6.4
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 143.8, 141.1, 133.4, 131.6,
129.7, 128.9, 128.3, 128.1, 127.9, 126.2, 123.0, 117.7, 117.5, 112.6,
84.8, 84.2, 56.5, 29.3. Anal. Calcd for C22H17Cl2N: C, 72.14; H, 4.68;
N, 3.82. Found: C, 72.35; H, 4.63; N, 3.82.
N-Allyl-2,5-dichloroaniline (21). Prepared using procedure A from
2,5-dichloroaniline 6 and the commercially available O-allyl 2,2,2-
trichloroacetimidate 20, purified using silica gel chromatography (4%
dichloromethane/94% hexanes/1% triethylamine). Clear colorless oil
(0.19 g, 77%); TLC Rf = 0.24 (5% dichloromethane/95% hexanes);
IR(thin film) 3426, 3086, 3013, 2985, 2926, 2850, 1645, 1595 cm−1;
1H NMR (300 MHz, CDCl3) δ 7.16−7.13 (m, 1H), 6.61−6.58 (m,
2H), 5.94−5.87 (m, 1H), 5.32−5.20 (m, 2H), 4.52 (br s, 1H), 3.82 (d,
J = 8.4 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 144.6, 134.0, 133.6,
N-((6-Bromobenzo[d][1,3]dioxol-5-yl)methyl)-N-methylaniline
(39). Prepared using procedure B from the known 6-bromo-1,3-
benzodioxole-5-methanol 3839 and N-methylaniline 36, purified using
silica gel chromatography (49% dichloromethane/50% hexanes/1%
triethylamine). Yellow solid (0.81 g, 81%); mp = 72−74 °C; TLC Rf =
0.37 (50% dichloromethane/50% hexanes); IR (KBr) 3436, 3093,
1
3064, 2893, 2827, 2565, 1597 cm−1; H NMR (400 MHz, CDCl3) δ
7.24−7.20 (m, 2H), 7.04 (s, 1H), 6.73 (dt, J = 7.2, 0.8 Hz, 1H), 6.73−
F
DOI: 10.1021/jo5027222
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
6.65 (m, 3H), 5.93 (s, 2H), 4.44 (s, 2H), 3.07 (s, 3H); 13C NMR (75
MHz, CDCl3) 149.2, 147.8, 147.3, 131.0, 129.3, 116.8, 113.0, 112.6,
112.1, 108.0, 101.7, 57.4, 38.8. Anal. Calcd for C15H14O2NBr: C,
56.27; H, 4.41; N, 4.37. Found: C, 56.43; H, 4.28; N, 4.36.
Onosmin B (4).5 Prepared using procedure B with 4-methylbenzyl
alcohol 40 and 2-aminomethylbenzoate 41, purified using silica gel
chromatography (29% dichloromethane/70% hexanes/1% triethyl-
amine). Clear colorless oil (0.26 g, 85%); TLC Rf = 0.55 (10% ethyl
acetate/90% hexanes); IR (thin film) 3368, 3078, 3020, 2949, 2921,
2847, 1681 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.14 (br s, 1H), 7.92
(dd, J = 8.0, 1.6 Hz, 1H), 7.29 (ddd, J = 8.5, 7.2, 1.6 Hz, 1H), 7.26−
7.23 (m, 2H), 7.14 (d, J = 7.6 Hz, 2H), 6.65 (dd, J = 8.0, 0.8 Hz, 1H),
6.59 (ddd, J = 8.0, 7.2, 1.2 Hz, 1H), 4.41 (s, 2H), 3.86, (s, 3H), 2.33 (s,
3H); 13C NMR (100 MHz, CDCl3) 169.1, 150.9, 136.8, 135.7, 134.6,
131.6, 129.4, 127.1, 114.8, 111.7, 110.2, 51.5, 46.8, 21.1. Anal. Calcd
for C16H17O2N: C, 75.27; H, 6.71; N, 5.49. Found: C, 75.54; H, 6.67;
N, 5.83.
Lett. 2005, 7, 3817. (d) Watanabe, T.; Oishi, S.; Fujii, N.; Ohno, H.
Org. Lett. 2008, 10, 1759. (e) Rousseaux, S.; Davi, M.; Sofack-Kreutzer,
J.; Pierre, C.; Kefalidis, C. E.; Clot, E.; Fagnou, K.; Baudoin, O. J. Am.
Chem. Soc. 2010, 132, 10706. (f) Pierre, C.; Baudoin, O. Org. Lett.
2011, 13, 1816.
(8) Cran, J. W.; Vidhani, D. V.; Krafft, M. E. Synlett 2014, 25, 1550.
(9) Arnold, J. S.; Zhang, Q.; Nguyen, H. M. Eur. J. Org. Chem. 2014,
4925.
(10) (a) Arnold, J. S.; Stone, R. F.; Nguyen, H. M. Org. Lett. 2010,
12, 4580. (b) Arnold, J. S.; Cizio, G. T.; Nguyen, H. M. Org. Lett.
2011, 13, 5576. (c) Arnold, J. S.; Nguyen, H. M. J. Am. Chem. Soc.
2012, 134, 8380. (d) Arnold, J. S.; Cizio, G. T.; Heitz, D. R.; Nguyen,
H. M. Chem. Commun. 2012, 48, 11531. (e) Arnold, J. S.; Nguyen, H.
M. Synthesis 2013, 45, 2101. (f) Arnold, J. S.; Mwenda, E. T.; Nguyen,
H. M. Angew. Chem., Int. Ed. 2014, 53, 3688.
(11) Brawn, R. A.; Guimaraes, C. R. W.; McClure, K. F.; Liras, S. Org.
Lett. 2012, 14, 4802.
(12) (a) Cumpstey, I.; Ramstadius, C.; Borbas, K. E. Synlett 2011,
1701. (b) Cumpstey, I.; Frigell, J.; Pershagen, E.; Akhtar, T.; Moreno-
Clavijo, E.; Robina, I.; Alonzi, D. S.; Butters, T. D. Beilstein J. Org.
Chem. 2011, 7, 1115.
ASSOCIATED CONTENT
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S
* Supporting Information
1
Copies of H NMR and 13C NMR spectra of new compounds
(13) Piemontesi, C.; Wang, Q.; Zhu, J. Org. Biomol. Chem. 2013, 11,
1533.
(14) Cramer, F.; Pawelzik, K.; Baldauf, H. J. Chem. Ber. 1958, 91,
1049.
as well as chiral HPLC data for compounds 5 and 7c. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(15) (a) Baxter, E. W.; Reitz, A. B. Org. React. 2002, 59, 1. (b) Abdel-
Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.; Shah, R.
D. J. Org. Chem. 1996, 61, 3849.
AUTHOR INFORMATION
Corresponding Author
*E-mail: jdchisho@syr.edu (J.D.C.).
■
(16) Zhang, J.; Schmidt, R. R. Synlett 2006, 1729.
(17) (a) Fujita, K.-i.; Enoki, Y.; Yamaguchi, R. Tetrahedron 2008, 64,
1943. (b) Martinez-Asencio, A.; Yus, M.; Ramon, D. J. Synthesis 2011,
3730. (c) Wang, D.; Guo, X.-Q.; Wang, C.-X.; Wang, Y.-N.; Zhong, R.;
Zhu, X.-H.; Cai, L.-H.; Gao, Z.-W.; Hou, X.-F. Adv. Synth. Catal. 2013,
355, 1117. (d) Banerjee, D.; Junge, K.; Beller, M. Angew. Chem., Int.
Ed. 2014, 53, 13049. (e) Hamid, M. H. S. A.; Slatford, P. A.; Williams,
J. M. J. Adv. Synth. Catal. 2007, 349, 1555. (f) Hamid, M. H. S. A.;
Allen, C. L.; Lamb, G. W.; Maxwell, A. C.; Maytum, H. C.; Watson, A.
J. A.; Williams, J. M. J. J. Am. Chem. Soc. 2009, 131, 1766. (g) Watson,
A. J. A.; Maxwell, A. C.; Williams, J. M. J. J. Org. Chem. 2011, 76, 2328.
(h) Ma, W. M. J.; James, T. D.; Williams, J. M. J. Org. Lett. 2013, 15,
4850. (i) Cano, R.; Ramon, D. J.; Yus, M. J. Org. Chem. 2011, 76, 5547.
(18) (a) De, S.; Ghosh, S.; Bhunia, S.; Sheikh, J. A.; Bisai, A. Org. Lett.
2012, 14, 4466. (b) De, S.; Mishra, S.; Kakde, B. N.; Dey, D.; Bisai, A.
J. Org. Chem. 2013, 78, 7823.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Acknowledgement is made to the Donors of the American
Chemical Society Petroleum Research Fund for a recent New
Directions award (54823-ND1). We also thank the Syracuse
University Lewis Stokes Alliances for Minority Participation for
a summer fellowship for P.C.S. in 2013. Support for the
Syracuse University NMR facility was provided by the National
Science Foundation (CHE-1229345), which is gratefully
acknowledged.
REFERENCES
■
(19) Kuethe, J. T.; Marcoux, J.-F.; Wong, A.; Wu, J.; Hillier, M. C.;
Dormer, P. G.; Davies, I. W.; Hughes, D. L. J. Org. Chem. 2006, 71,
7378.
(20) Raber, D. J.; Harris, J. M.; Schleyer, P. v. R. In Ions and Ion Pairs
in Organic Reactions; Szwarc, M., Ed.; Wiley: New York, 1974; Vol. 2, p
247.
(1) (a) Adhikari, A. A.; Shah, J. P.; Howard, K. T.; Russo, C. M.;
Wallach, D. R.; Linaburg, M. R.; Chisholm, J. D. Synlett 2014, 283.
(b) Shah, J. P.; Russo, C. M.; Howard, K. T.; Chisholm, J. D.
Tetrahedron Lett. 2014, 55, 1740.
(2) (a) Clader, J. W. J. Med. Chem. 2004, 47, 1. (b) Earl, J.;
Kirkpatrick, P. Nat. Rev. Drug Discovery 2003, 2, 97. (c) Rosenblum, S.
B.; Huynh, T.; Afonso, A.; Davis, H. R., Jr.; Yumibe, N.; Clader, J. W.;
Burnett, D. A. J. Med. Chem. 1998, 41, 973.
(21) Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.;
Timmers, F. J. Organometallics 1996, 15, 1518.
(22) Li, L.; Huang, G.; Chen, Z.; Liu, W.; Wang, X.; Chen, Y.; Yang,
L.; Li, W.; Li, Y. Eur. J. Org. Chem. 2012, 2012, 5564.
(23) Liu, X.-Y.; Che, C.-M. Org. Lett. 2009, 11, 4204.
(24) Zhu, S.-F.; Xie, J.-B.; Zhang, Y.-Z.; Li, S.; Zhou, Q.-L. J. Am.
Chem. Soc. 2006, 128, 12886.
(25) Ciana, C.-L.; Phipps, R. J.; Brandt, J. R.; Meyer, F.-M.; Gaunt,
M. J. Angew. Chem., Int. Ed. 2011, 50, 458.
(26) Kaspar, L. T.; Fingerhut, B.; Ackermann, L. Angew. Chem., Int.
Ed. 2005, 44, 5972.
(27) Johns, A. M.; Utsunomiya, M.; Incarvito, C. D.; Hartwig, J. F. J.
(3) Baechler, S. A.; Fehr, M.; Habermeyer, M.; Hofmann, A.; Merz,
K.-H.; Fiebig, H.-H.; Marko, D.; Eisenbrand, G. Bioorg. Med. Chem.
2013, 21, 814.
(4) Onoda, T.; Iinuma, H.; Sasaki, Y.; Hamada, M.; Isshiki, K.;
Naganawa, H.; Takeuchi, T.; Tatsuta, K.; Umezawa, K. J. Nat. Prod.
1989, 52, 1252.
(5) Ahmad, I.; Nawaz, S. A.; Afza, N.; Malik, A.; Fatima, I.; Khan, S.
B.; Ahmad, M.; Choudhary, M. I. Chem. Pharm. Bull. 2005, 53, 907.
(6) (a) Frazer, A.; Morales Alma, R.; Woodward Adam, W.; Tongwa,
P.; Timofeeva, T.; Belfield Kevin, D. J. Fluoresc. 2014, 24, 239.
(b) Ramachandram, B.; Sankaran, N. B.; Samanta, A. Res. Chem.
Intermed. 1999, 25, 843. (c) Wehner, M.; Janssen, D.; Schaefer, G.;
Schrader, T. Eur. J. Org. Chem. 2005, 138.
Am. Chem. Soc. 2006, 128, 1828.
(28) Pan, W.; Deng, Y.; He, J.-B.; Bai, B.; Zhu, H.-J. Tetrahedron
2013, 69, 7253.
(29) Menche, D.; Hassfeld, J.; Li, J.; Menche, G.; Ritter, A.; Rudolph,
S. Org. Lett. 2006, 8, 741.
(30) Baeza, A.; Pfaltz, A. Chem.Eur. J. 2009, 15, 2266.
(7) (a) Dvolaitzky, M.; Chiarelli, R.; Rassat, A. Angew. Chem. 1992,
104, 180. (b) Anderson, J. C.; Cran, J. W.; King, N. P. Tetrahedron
Lett. 2002, 43, 3849. (c) Bacque, E.; El Qacemi, M.; Zard, S. Z. Org.
G
DOI: 10.1021/jo5027222
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(31) Shahane, S.; Louafi, F.; Moreau, J.; Hurvois, J.-P.; Renaud, J.-L.;
van de Weghe, P.; Roisnel, T. Eur. J. Org. Chem. 2008, 4622.
(32) Angle, S. R.; Choi, I.; Tham, F. S. J. Org. Chem. 2008, 73, 6268.
(33) Ali, I. A. I.; El Ashry, E. S. H.; Schmidt, R. R. Eur. J. Org. Chem.
2003, 4121.
(34) Onyeozili, E. N.; Mori-Quiroz, L. M.; Maleczka, R. E.
Tetrahedron 2013, 69, 849.
(35) Bachi, M. D.; Korshin, E. E.; Hoos, R.; Szpilman, A. M.;
Ploypradith, P.; Xie, S.; Shapiro, T. A.; Posner, G. H. J. Med. Chem.
2003, 46, 2516.
(36) Yue, C.; Thierry, J.; Potier, P. Tetrahedron Lett. 1993, 34, 323.
(37) Ali, I. A. I.; Abdel-Rahman, A. A. H.; El Ashry, H. E. S.; Schmidt,
R. R. Synthesis 2003, 1065.
(38) Kang, J.-E.; Kim, H.-B.; Lee, J.-W.; Shin, S. Org. Lett. 2006, 8,
3537.
(39) Rigby, J. H.; Cavezza, A.; Heeg, M. J. J. Am. Chem. Soc. 1998,
120, 3664.
H
DOI: 10.1021/jo5027222
J. Org. Chem. XXXX, XXX, XXX−XXX