A method for the selective protection of aromatic amines in the presence of aliphatic amines

Article abstract of DOI:10.1055/s-0028-1083290

A simple and efficient procedure has been developed for the regioselective protection of aromatic amines in the presence of aliphatic amines. The method is general for the preparation of mono-N-Boc, -N-Cbz, -N-Fmoc or -N-Alloc aromatic amines in high yield without affecting the aliphatic amines. This approach is applicable to substituted (aminoalkyl)aniline compounds with different functionalities and was employed to supply gram quantities of the protected aniline product. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0028-1083290

PAPER
283
A Method for the Selective Protection of Aromatic Amines in the Presence of
Aliphatic Amines
S
elective Protectio
a
n
of
A
rom
a
l
tic
A
m
é
ine
s
in the
r
P
resenc
e
i
of
A
li
e
phatic
A
mines Perron, Shaun Abbott, Nancie Moreau, Devin Lee, Christopher Penney, Boulos Zacharie*
ProMetic BioSciences Inc., Suite 150, 500 Cartier Blvd. W., Laval, QC, H7V 5B7, Canada
Fax +1(450)7811403; E-mail: b.zacharie@prometic.com
Received 18 July 2008; revised 18 September 2008
(Boc)2O or CbzCl
or FmocCl
Abstract: A simple and efficient procedure has been developed for
the regioselective protection of aromatic amines in the presence of
H2N
H2N
or AllocCl
aliphatic amines. The method is general for the preparation of
1,4-dioxane
10% AcOH
NH2
NHR
mono-N-Boc, -N-Cbz, -N-Fmoc or -N-Alloc aromatic amines in
high yield without affecting the aliphatic amines. This approach is
applicable to substituted (aminoalkyl)aniline compounds with dif-
ferent functionalities and was employed to supply gram quantities
of the protected aniline product.
1
1a R = Boc
1b R = CBz
1c R = Fmoc
1d R = Alloc
Scheme 1 Selective protection of the aromatic amine of 4-amino-
phenethylamine (1)
Key words: amines, carbamates, protecting groups, protonations,
regioselectivity
in the presence of aliphatic amines. As part of our re-
search, we required ready access to multigram quantities
of mono-N-Boc-protected 4-aminophenethylamine 1a.
Reported herein is an efficient and general procedure for
the selective protection of aromatic amines with a Boc,
Cbz or Fmoc group when they are present with aliphatic
amines (Scheme 1).
Selective protection and deprotection of functional groups
are essential components of modern organic chemistry.
Significant progress has been made in the development of
suitable protecting groups for amines. Although a variety
of these groups is available, little work has been under-
taken on the monoprotection of diamines. These mono-
protected compounds are of considerable synthetic
importance. They are versatile intermediates in the syn-
thesis of polyamines1 and heteromacrocycles,2 or in the
construction of biologically active compounds.3 Also,
they are useful reagents that have found application in
many synthetic procedures.4 Several routes have been re-
ported for the preparation of monoprotected alkanedi-
amines.4,5 For example, Lee and co-workers5e have
described the mono-Boc protection of symmetrical and
unsymmetrical aliphatic diamines by the sequential addi-
tion of one equivalent of hydrogen chloride and one
equivalent of di-tert-butyl dicarbonate (Boc2O); however,
this procedure is not suitable for the selective protection
of an aromatic amine when it is present with an aliphatic
amine. King and co-workers6a,b studied the acetylation of
4-aminobenzylamine in water at specific pH values. Al-
though a good selectivity was obtained at either of the two
nucleophilic sites, the final monoprotected product was
contaminated with the corresponding diacetate deriva-
tive.6b It was also reported6a that this procedure suffers
from one or more drawbacks, including long reaction
time, isolation of the starting materials, variable yields of
the monoprotected aromatic amine and formation of the
corresponding diprotected derivatives. Therefore, there is
still a need for the development of a general and more fac-
ile method for the selective protection of aromatic amines
Our strategy to selectively protect an aromatic amine in
the presence of an aliphatic amine was based on the differ-
ence of the pKa value for each amino group. It has been
reported6 that the pKa value of aromatic amines (aniline)
is 4.25, while for aliphatic benzylamines, it is 9.3. Our ini-
tial experiments were carried out using 4-aminophenethyl-
amine (1) as a model substrate. The reaction between
diamine 1 and di-tert-butyl dicarbonate (Boc2O) was stud-
ied at different pH values and in different solvents at room
temperature in order to produce the corresponding mono-
N-Boc derivative 1a. The effect of the pH on the reaction
was investigated using 1 N phosphate buffer or 1 N citrate
buffer or 10% aqueous acetic acid at different acidic pH
values (3–5.5) in 1,4-dioxane. Best results were obtained
with the use of 10% aqueous acetic acid in 1,4-dioxane
(pH 4.5). Replacement of 1,4-dioxane with tetrahydrofu-
ran, or increasing the concentration of acetic acid, did not
affect the yield of 1a. Similar results were obtained when
the temperature of the reaction was decreased to 0 °C dur-
ing the addition of the Boc reagent.
Encouraged by these results and having established the
optimized procedure, the generality of the method was in-
vestigated by probing an array of structurally diverse
(aminoalkyl)aniline derivatives. The results are summa-
rized in Table 1.
Under the optimized conditions, only aromatic amino
groups react efficiently with Boc2O (Table 1, first yield
column), FmocCl (Table 1, second yield column) or
CbzCl (Table 1, last yield column) to give the correspond-
SYNTHESIS 2009, No. 2, pp 0283–0289
Advanced online publication: 19.12.2008
DOI: 10.1055/s-0028-1083290; Art ID: M03808SS
x
x
.
x
x
.2
0
0
8
© Georg Thieme Verlag Stuttgart · New York

284
V. Perron et al.
PAPER
ing protected aromatic amines in high yields. In the pres-
ence of a weak acid, such as acetic acid, the less reactive
amino group was protected selectively. As expected, (2-
aminoethyl)anilines (entries 1 and 2) and (aminometh-
yl)anilines (entries 3 and 4) showed regioselective protec-
tion of the aromatic amine; moving the amino group of the
aniline portion of these compounds from the 3- to the 4-
position did not alter the selectivity or the yield. The
method is general and does not require heat or an inert at-
mosphere. The reaction conditions are very mild and, as a
result, different functionalities (entries 5–8, 11, 12 and 14)
are unaffected. The method also displays good chemose-
lectivity. In the presence of a hydroxy group, only the pro-
tected aromatic amino product was isolated and no
protection of the oxygen atom was observed, according to
1H NMR spectroscopy (entries 6 and 7). The procedure is
also applicable to the protection of rigid aliphatic amines;
only the aromatic amine was protected in high yield and
not the cyclic primary (entry 10) or secondary (entry 9) al-
iphatic amine. The same result was also obtained when the
substrate contained an acid (entry 12), ester (entry 11) or
amide (entry 14) group; again, the aromatic amines were
selectively protected under the reaction conditions. This
method also constitutes a general approach for other pro-
tecting groups. For example, treatment of diamine 1 with
allyl chloroformate under acidic conditions gave only 1d
in high yield (98%).
Table 1 Selective Protection of Aromatic Amines in the Presence of
Aliphatic Amines
Entry Substrate
Yielda (%) of protected
aromatic amine
Boc
Fmocb Cbz
NH2
NH2
1
75
93
80
93
80
93
81
97
93
H2N
H2N
27a
73
NH2
3
57c
60c
H2N
H2N
NH2
NH2
4
Me
OH
OH
H2N
5
58
60
65
79
88
83
67b
H2N
NH2
77b
60
74
78
OH
In summary, a practical and selective method has been de-
veloped for the protection of aromatic amines with a
mono-N-Boc, -N-Cbz or -N-Fmoc group without affecting
aliphatic amines. The procedure is amenable to scale-up
and in most cases no chromatographic purification of the
product is required. This method is applicable to substitut-
ed (aminoalkyl)aniline compounds with different func-
tionalities. It offers the advantage of a general route with
high yield which can be undertaken at ambient tempera-
ture and in environmentally acceptable conditions.
NH2
H2N
H2N
O
87c
51
85
78
81
98
73
76
NH2
9
50c
71
NH
H2N
107b
NH2
H2N
O
Solvents and reagents were obtained from commercial sources and
used without purification. Melting points were determined on an
Electrothermal melting point apparatus. NMR spectra were record-
ed on a Varian 400 spectrometer operating at 400 MHz for 1H NMR
and 100 MHz for 13C NMR. The purity and identity of all the prod-
ucts were monitored by LC/MS at 210 or 250 nm (Agilent 1100) us-
ing an analytical C18 column (75 × 4.6 mm, 5 microns) with
different gradients of MeCN–H2O containing 0.01% TFA as the
eluent. Compounds 1, 3–5, 9 and 12 are commercially available.
117b
67
80
86
84
77
OMe
OH
NH2
H2N
O
12
53c
NH2
H2N
NH2
4-(2-Aminoethyl)-N-(tert-butoxycarbonyl)phenylamine (1a);
Typical Procedure
137d
58c
94c
87
76
61
To a soln of 4-aminophenethylamine (0.3 g, 2.3 mmol) in 10% aq
AcOH (20 mL) was added a soln of Boc2O (0.5 g, 2.4 mmol) in 1,4-
dioxane (20 mL). After overnight stirring at r.t., H2O (100 mL) was
added and the mixture was washed with Et2O (3 × 50 mL). The
aqueous phase was basicified with 2 N NaOH to pH 14 and extract-
ed with Et2O (3 × 75 mL). The combined extract was washed with
H2O (2 × 40 mL), dried (Na2SO4), filtered and concentrated under
reduced pressure to give the expected product 1a.
H2N
O
NH2
d
147e
–
N
H
H2N
a Isolated yield unless indicated otherwise.
b Isolated as the hydrochloride salt.
c % conversion by HPLC.
White solid; yield: 75% (98% conversion by HPLC); mp 89–91 °C.
d Difficult to isolate.
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Selective Protection of Aromatic Amines in the Presence of Aliphatic Amines
285
1H NMR (400 MHz, CD3OD): d = 7.32 (d, J = 8.4 Hz, 2 H), 7.09 (d,
J = 8.6 Hz, 2 H), 2.80–2.83 (m, 2 H), 2.67 (t, J = 7.4 Hz, 2 H), 1.50
(s, 9 H).
1H NMR (400 MHz, CD3OD): d = 7.43 (s, 1 H), 7.21–7.30 (m, 2 H),
7.00 (d, J = 7.2 Hz, 1 H), 4.58 (t, J = 7.2 Hz, 1 H), 2.77–2.79 (m, 2
H), 1.51 (s, 9 H).
13C NMR (101 MHz, CD3OD): d = 154.24, 137.60, 133.91, 128.88,
118.94, 79.53, 43.00, 38.08, 27.52.
13C NMR (101 MHz, CD3OD): d = 154.14, 143.82, 139.50, 128.63,
120.19, 117.84, 116.40, 79.64, 74.54, 48.78, 27.56.
MS (ESI): m/z = 259 [M + Na+].
MS (ESI): m/z = 253 [M + H+].
This procedure was scaled up using the following amounts: 4-ami-
nophenethylamine (40.4 g, 310 mmol), 10% aq AcOH (2.5 L),
Boc2O (68.0 g, 311 mmol) and 1,4-dioxane (2.5 L). This gave the
expected product 1a in 65% yield.
(1S,2S)-2-Amino-1-[4-(tert-butoxycarbonylamino)phenyl]pro-
pane-1,3-diol (Entry 7)
Pale yellow solid; yield: 60%; mp 138–140 °C.
1H NMR (400 MHz, CD3OD): d = 7.38 (d, J = 8.6 Hz, 2 H), 7.28 (d,
J = 8.6 Hz, 2 H), 4.60 (d, J = 8.8 Hz, 1 H), 3.73 (dd, J = 3.5, 11.9
Hz, 1 H), 3.59–3.65 (m, 1 H), 3.08–3.12 (m, 1 H), 1.50 (s, 9 H).
Protection with Boc (Table 1, First Yield Column)
3-(2-Aminoethyl)-N-(tert-butoxycarbonyl)phenylamine (Entry
2)
13C NMR (101 MHz, CD3OD): d = 154.09, 139.14, 134.18, 126.87,
Yellow oil; yield: 73%.
118.64, 94.59, 80.32, 67.32, 58.21, 27.56.
1H NMR (400 MHz, CD3OD): d = 7.28 (s, 1 H), 7.23 (d, J = 8.2 Hz,
1 H), 7.16 (t, J = 7.4 Hz, 1 H), 6.83 (d, J = 7.4 Hz, 1 H), 2.84 (t,
J = 6.85 Hz, 2 H), 2.69 (t, J = 7.2 Hz, 2 H), 1.50 (s, 9 H).
13C NMR (101 MHz, CD3OD): d = 154.14, 140.35, 139.57, 128.75,
123.00, 118.99, 116.66, 79.60, 42.87, 38.89, 27.60.
MS (ESI): m/z = 283 [M + H+].
3-(2-Aminoethoxy)-N-(tert-butoxycarbonyl)phenylamine (En-
try 8)
Pale yellow solid; yield: 51%; mp 88–90 °C.
MS (ESI): m/z = 259 [M + Na+].
1H NMR (400 MHz, CD3OD): d = 7.10–7.14 (m, 2 H), 6.91 (dd,
J = 0.8, 1.8 Hz, 1 H), 6.89 (dd, J = 0.8, 1.8 Hz, 1 H), 3.96 (t, J = 5.3
Hz, 2 H), 2.96 (t, J = 5.1 Hz, 2 H), 1.50 (s, 9 H).
4-(Aminomethyl)-N-(tert-butoxycarbonyl)phenylamine (Entry
3)
13C NMR (101 MHz, CD3OD): d = 159.63, 153.99, 140.65, 129.31,
111.03, 108.54, 104.94, 79.64, 69.21, 40.73, 27.52.
Conversion by HPLC: 57%.
A portion of this material was isolated and characterized: pale yel-
low solid; mp 86–90 °C.
MS (ESI): m/z = 253 [M + H+].
1H NMR (400 MHz, CD3OD): d = 7.35 (d, J = 8.4 Hz, 2 H), 7.18–
7.22 (m, 2 H), 3.69 (s, 2 H), 1.50 (s, 9 H).
7-(tert-Butoxycarbonylamino)-1,2,3,4-tetrahydroisoquinoline
(Entry 9)
Conversion by HPLC: 50%.
13C NMR (101 MHz, CD3OD): d = 154.15, 138.26, 136.56, 128.30,
127.74, 118.72, 79.57, 45.00, 27.54.
A portion of this material was isolated and characterized: pale yel-
low solid; mp 186–189 °C.
1H NMR (400 MHz, CD3OD): d = 7.10–7.12 (m, 2 H), 6.97 (d,
J = 8.0 Hz, 1 H), 3.87 (s, 2 H), 3.03 (t, J = 6.1 Hz, 2 H), 2.74 (t,
J = 5.9 Hz, 2 H), 1.50 (s, 9 H).
MS (ESI): m/z = 245 [M + Na+].
3-(Aminomethyl)-N-(tert-butoxycarbonyl)phenylamine (Entry
4)
Conversion by HPLC: 60%.
13C NMR (101 MHz, CD3OD): d = 154.21, 137.12, 135.28, 129.23,
A portion of this material was isolated and characterized: pale yel-
low solid; mp 130–134 °C.
1H NMR (400 MHz, CD3OD): d = 7.34 (s, 1 H), 7.27 (d, J = 8.0 Hz,
1 H), 7.20 (t, J = 7.6 Hz, 1 H), 6.97 (d, J = 7.4 Hz, 1 H), 3.73 (s, 2
H), 1.51 (s, 9 H).
128.73, 117.09, 116.26, 79.51, 47.52, 43.38, 27.54.
MS (ESI): m/z = 249 [M + H+].
5-(tert-Butoxycarbonylamino)indan-2-amine (Entry 10)
Pale yellow oil; yield: 71%.
13C NMR (101 MHz, CD3OD): d = 154.15, 143.18, 139.54, 128.77,
1H NMR (400 MHz, CD3OD): d = 7.28 (br s, 1 H), 7.12–7.14 (m, 1
H), 7.04–7.07 (m, 1 H), 3.71–3.74 (m, 1 H), 3.10 (m, 2 H), 2.81 (m,
1 H), 2.78 (m, 1 H), 1.50 (s, 9 H).
13C NMR (101 MHz, CD3OD): d = 152.69, 140.86, 136.45, 134.48,
122.96, 115.86, 113.75, 77.86, 59.08, 51.37, 39.36, 37.90, 26.02.
121.49, 117.60, 117.21, 79.62, 45.55, 27.52.
MS (ESI): m/z = 445 [M2 + H+].
(RS)-3-(1-Aminoethyl)-N-(tert-butoxycarbonyl)phenylamine
(Entry 5)
Clear oil; yield: 58%.
MS (ESI): m/z = 249 [M + H+].
1H NMR (400 MHz, CD3OD): d = 7.36 (s, 1 H), 7.25–7.27 (dd,
J = 1.9, 8.2 Hz, 1 H), 7.15–7.22 (m, 1 H), 6.98 (dd, J = 1.4, 7.6 Hz,
1 H), 3.96 (q, J = 6.6 Hz, 1 H), 1.51 (s, 9 H), 1.35 (d, J = 6.7 Hz, 3
H).
13C NMR (101 MHz, CD3OD): d = 154.16, 147.22, 139.56, 128.82,
120.00, 117.40, 116.23, 79.66, 51.12, 27.59, 23.75.
Methyl (S)-2-Amino-3-[4-(tert-butoxycarbonylamino)phe-
nyl]propionate (Entry 11)
White solid; yield: 67%; mp 108–110 °C.
1H NMR (400 MHz, CD3OD): d = 7.36 (d, J = 8.6 Hz, 2 H), 7.11 (d,
J = 8.6 Hz, 2 H), 3.98 (t, J = 6.8 Hz, 1 H), 3.73 (s, 3 H), 3.07 (dd,
J = 6.1, 13.9 Hz, 1 H), 2.99 (dd, J = 7.0, 13.9 Hz, 1 H), 1.50 (s, 9 H).
MS (ESI): m/z = 237 [M + H+].
13C NMR (101 MHz, CD3OD): d = 170.92, 152.49, 137.07, 128.10,
127.95, 117.30, 78.06, 53.22, 50.16, 36.34, 25.92.
(RS)-2-Amino-1-[3-(tert-butoxycarbonylamino)phenyl]ethanol
(Entry 6)
MS (ESI): m/z = 295 [M + H+].
White solid; yield: 60%; mp 42–45 °C.
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286
V. Perron et al.
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(S)-2-Amino-3-[4-(tert-butoxycarbonylamino)phenyl]propion-
ic Acid (Entry 12)
(m, 8 H), 4.48 (d, J = 6.7 Hz, 2 H), 4.29 (t, J = 6.7 Hz, 1 H), 3.91 (s,
2 H).
Conversion by HPLC: 53%.
13C NMR (101 MHz, DMSO-d6): d = 154.10, 144.44, 141.50,
139.91, 130.36, 128.60, 128.40, 127.83, 125.89, 120.94, 118.81,
66.33, 47.27, 42.40.
A portion of this material was isolated and characterized: white sol-
id; mp 198–200 °C.
1H NMR (400 MHz, CD3OD): d = 7.36 (d, J = 8.4 Hz, 2 H), 7.20 (d,
J = 8.6 Hz, 2 H), 3.71–3.74 (m, 1 H), 3.25 (dd, J = 4.1, 14.5 Hz, 1
H), 2.94 (dd, J = 8.8, 14.7 Hz, 1 H), 1.50 (s, 9 H).
13C NMR (101 MHz, CD3OD): d = 172.83, 154.18, 138.63, 130.13,
129.58, 119.12, 79.66, 56.38, 36.52, 27.48.
MS (ESI): m/z = 367 [M + Na+].
3-(Aminomethyl)-N-(9-fluorenylmethoxycarbonyl)phenyl-
amine Hydrochloride (Entry 4)
White solid; yield: 80%; mp 223–225 °C.
1H NMR (400 MHz, CD3OD): d = 7.83 (d, J = 7.4 Hz, 2 H), 7.71 (d,
J = 7.6 Hz, 2 H), 7.68 (m, 1 H), 7.32–7.44 (m, 6 H), 7.12–7.14 (m,
1 H), 4.53 (d, J = 6.5 Hz, 2 H), 4.30 (t, J = 6.5 Hz, 1 H), 4.08 (s, 2
H).
13C NMR (101 MHz, CD3OD): d = 154.58, 144.03, 141.49, 139.89,
133.97, 129.58, 127.69, 127.02, 124.97, 124.88, 123.10, 119.89,
119.78, 119.37, 66.55, 43.23.
MS (ESI): m/z = 281 [M + H+].
4¢-(Aminomethyl)-N-(tert-butoxycarbonyl)-1,1¢-biphenyl-4-
ylamine (Entry 13)
Conversion by HPLC: 58%.
A portion of this material was isolated and characterized: yellow
solid; mp 75–78 °C.
1H NMR (400 MHz, CD3OD): d = 7.45–7.55 (m, 6 H), 7.36 (d,
J = 8.4 Hz, 2 H), 3.80 (s, 2 H), 1.50 (s, 9 H).
13C NMR (101 MHz, CD3OD): d = 154.07, 140.59, 139.51, 138.79,
135.13, 127.81, 126.95, 126.51, 118.90, 79.72, 45.10, 27.60.
MS (ESI): m/z = 345 [M + H+].
(RS)-3-(1-Aminoethyl)-N-(9-fluorenylmethoxycarbonyl)phe-
nylamine Hydrochloride (Entry 5)
Pale yellow solid; yield: 65%; mp 170–172 °C.
1H NMR (400 MHz, CD3OD): d = 7.80 (d, J = 7.6 Hz, 2 H), 7.66–
7.70 (m, 3 H), 7.30–7.42 (m, 6 H), 7.10–7.13 (m, 1 H), 4.51 (d,
J = 6.5 Hz, 2 H), 4.39 (q, J = 6.7 Hz, 1 H), 4.28 (t, J = 6.4 Hz, 1 H),
1.61 (d, J = 6.8 Hz, 3 H).
LRMS (ESI): m/z = 282 [M + H+ – NH3].
4-(2-Aminoethyl)-N-(9-fluorenylmethoxycarbonyl)phenyl-
amine Hydrochloride (1b); Typical Procedure
To a soln of 4-aminophenethylamine (0.3 g, 2.3 mmol) in 10% aq
AcOH (20 mL) was added FmocCl (0.6 g, 2.4 mmol) dissolved in
1,4-dioxane (20 mL). After overnight stirring at r.t., Et2O (2 × 30
mL) was added to the reaction mixture to extract the nonpolar im-
purities. The reaction mixture was then acidified with 2 N HCl to
pH 1. The precipitate was collected by filtration, washed with Et2O
(15 mL) and dried under reduced pressure overnight.
13C NMR (101 MHz, CD3OD): d = 154.57, 144.02, 141.46, 139.89,
139.16, 129.68, 127.71, 127.05, 125.02, 120.81, 119.90, 119.80,
116.98, 66.60, 51.20, 47.14, 19.51.
MS (ESI): m/z = 359 [M + H+].
(RS)-2-Amino-1-[3-(9-fluorenylmethoxycarbonylamino)phe-
nyl]ethanol Hydrochloride (Entry 6)
White solid; yield: 79%; mp 138–140 °C.
White solid; yield: 93% (99% conversion by HPLC); mp 207–
209 °C.
1H NMR (400 MHz, DMSO-d6): d = 9.68 (br s, 1 H), 7.92–8.05 (m,
2 H), 7.89 (d, J = 7.6 Hz, 2 H), 7.73 (d, J = 7.4 Hz, 2 H), 7.31–7.43
(m, 4 H), 7.13 (d, J = 8.2 Hz, 2 H), 4.45 (d, J = 6.7 Hz, 2 H), 4.28
(t, J = 6.5 Hz, 1 H), 2.93–2.97 (m, 2 H), 2.78–2.82 (m, 2 H).
13C NMR (101 MHz, DMSO-d6): d = 154.23, 144.35, 141.42,
138.21, 131.99, 129.70, 128.44, 127.85, 125.80, 119.36, 66.24,
47.24, 40.81, 32.89.
1H NMR (400 MHz, CD3OD): d = 7.78 (d, J = 7.6 Hz, 2 H), 7.68 (d,
J = 7.6 Hz, 2 H), 7.60 (br s, 1 H), 7.26–7.40 (m, 6 H), 7.10 (d,
J = 7.6 Hz, 1 H), 4.85 (t, J = 7.2 Hz, 1 H), 4.45 (d, J = 6.8 Hz, 2 H),
4.24 (t, J = 6.8 Hz, 1 H), 3.14 (dd, J = 3.6, 13.0 Hz, 1 H), 2.99 (dd,
J = 9.6, 12.4 Hz, 1 H).
13C NMR (101 MHz, CD3OD): d = 154.68, 144.05, 142.13, 141.46,
139.40, 129.08, 127.67, 127.02, 124.97, 120.41, 119.82, 118.65,
116.30, 69.68, 66.58, 48.50, 46.14.
MS (ESI): m/z = 359 [M + H+].
MS (ESI): m/z = 375 [M + H+].
Protection with Fmoc (Table 1, Second Yield Column)
3-(2-Aminoethyl)-N-(9-fluorenylmethoxycarbonyl)phenyl-
amine Hydrochloride (Entry 2)
(1S,2S)-2-Amino-1-[4-(9-fluorenylmethoxycarbonylamino)phe-
nyl]propane-1,3-diol Hydrochloride (Entry 7)
White solid; yield: 74%; mp >246 °C (dec).
1H NMR (400 MHz, CD3OD): d = 7.80 (d, J = 7.4 Hz, 2 H), 7.69 (d,
J = 7.4 Hz, 2 H), 7.44 (m, 2 H), 7.34–7.39 (m, 2 H), 7.31 (m, 4 H),
4.69 (d, J = 9.0 Hz, 1 H), 4.48 (d, J = 6.7 Hz, 2 H), 4.27 (t, J = 6.5
Hz, 1 H), 3.54 (dd, J = 3.7, 11.7 Hz, 1 H), 3.39–3.43 (m, 1 H), 3.29–
3.31 (m, 1 H).
White solid; yield: 80%; mp 183–184 °C.
1H NMR (400 MHz, CD3OD): d = 7.79 (d, J = 7.6 Hz, 2 H), 7.68 (t,
J = 7.6 Hz, 2 H), 7.44 (br s, 1 H), 7.22–7.40 (m, 6 H), 6.95 (d,
J = 6.8 Hz, 1 H), 4.46 (d, J = 6.8 Hz, 2 H), 4.24 (t, J = 6.8 Hz, 1 H),
3.15 (t, J = 8.0 Hz, 2 H), 2.92 (t, J = 8.0 Hz, 2 H).
13C NMR (101 MHz, CD3OD): d = 154.69, 144.05, 141.47, 139.54,
137.48, 129.31, 127.67, 127.02, 124.96, 123.29, 119.83, 119.07,
117.73, 66.55, 48.48, 40.70, 33.44.
13C NMR (101 MHz, CD3OD): d = 153.05, 142.49, 139.90, 137.75,
133.63, 126.10, 125.68, 125.45, 123.39, 118.27, 118.19, 117.31,
69.04, 64.99, 57.02, 45.59.
MS (ESI): m/z = 359 [M + H+].
MS (ESI): m/z = 405 [M + H+].
4-(Aminomethyl)-N-(9-fluorenylmethoxycarbonyl)phenyl-
amine Hydrochloride (Entry 3)
White solid; yield: 93%; mp >255 °C (dec).
1H NMR (400 MHz, DMSO-d6): d = 9.80 (br s, 1 H), 8.29 (br s, 2
H), 7.89 (d, J = 7.4 Hz, 2 H), 7.73 (d, J = 7.2 Hz, 2 H), 7.28–7.45
3-(2-Aminoethoxy)-N-(9-fluorenylmethoxycarbonyl)phenyl-
amine Hydrochloride (Entry 8)
White solid; yield: 85%; mp 184–186 °C.
1H NMR (400 MHz, CD3OD): d = 7.80 (d, J = 7.4 Hz, 2 H), 7.68 (d,
J = 7.4 Hz, 2 H), 7.37–7.41 (m, 2 H), 7.31–7.33 (m, 3 H), 7.19 (t,
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Selective Protection of Aromatic Amines in the Presence of Aliphatic Amines
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J = 8.2 Hz, 1 H), 6.93–6.96 (m, 1 H), 6.66–6.69 (m, 1 H), 4.46 (d,
J = 6.8 Hz, 2 H), 4.26 (t, J = 6.8 Hz, 1 H), 4.19 (t, J = 4.9 Hz, 2 H),
3.34 (t, J = 5.1 Hz, 2 H).
13C NMR (101 MHz, CD3OD): d = 157.17, 152.97, 142.47, 139.88,
138.79, 128.01, 126.10, 125.45, 123.39, 118.26, 110.40, 107.36,
103.71, 64.99, 62.44, 45.57, 37.56.
4¢-(Aminomethyl)-N-(9-fluorenylmethoxycarbonyl)-1,1¢-biphe-
nyl-4-ylamine Hydrochloride (Entry 13)
Conversion by HPLC: 94%; a portion of this material was isolated
and characterized: pale yellow solid; mp >240 °C (dec).
1H NMR (400 MHz, DMSO-d6): d = 9.89 (br s, 1 H), 8.59 (br s, 2
H), 7.89 (d, J = 7.4 Hz, 2 H), 7.75 (d, J = 7.2 Hz, 2 H), 7.64 (d,
J = 7.6 Hz, 2 H), 7.54–7.59 (m, 6 H), 7.41 (t, J = 7.2 Hz, 2 H), 7.33
(t, J = 7.2 Hz, 2 H), 4.48 (d, J = 6.3 Hz, 2 H), 4.30 (t, J = 6.7 Hz, 1
H), 4.01 (br s, 2 H).
13C NMR (101 MHz, DMSO-d6): d = 154.10, 144.45, 141.50,
140.40, 139.47, 134.15, 133.39, 130.27, 128.40, 127.84, 127.67,
126.89, 125.86, 120.90, 119.34, 66.31, 47.30, 42.50.
MS (ESI): m/z = 375 [M + H+].
7-(9-Fluorenylmethoxycarbonylamino)-1,2,3,4-tetrahydroiso-
quinoline Hydrochloride (Entry 9)
Pale yellow solid; yield: 78%; mp >270 °C (dec).
1H NMR (400 MHz, CD3OD): d = 7.79 (d, J = 7.6 Hz, 2 H), 7.68 (d,
J = 7.4 Hz, 2 H), 7.39 (t, J = 7.4 Hz, 3 H), 7.28–7.33 (m, 3 H), 7.13
(d, J = 8.4 Hz, 1 H), 4.47 (br s, 2 H), 4.23–4.28 (m, 3 H), 3.46 (td,
J = 3.3, 6.5 Hz, 2 H), 3.04 (t, J = 6.3 Hz, 2 H).
13C NMR (101 MHz, CD3OD): d = 154.54, 144.04, 141.47, 138.07,
129.39, 128.39, 127.67, 127.02, 125.73, 124.93, 119.83, 118.73,
116.32, 66.51, 44.71, 41.84, 24.29.
LRMS (ESI): m/z = 404 [M + H+– NH3].
N-(2-Aminoethyl)-4-(9-fluorenylmethoxycarbonylamino)benz-
amide Hydrochloride (Entry 14)
White solid; yield: 87%; mp 231–233 °C.
1H NMR (400 MHz, DMSO-d6): d = 10.01 (br s, 1 H), 8.68 (t,
J = 5.6 Hz, 1 H), 8.11 (br s, 2 H), 7.98 (d, J = 7.2 Hz, 2 H), 7.85 (d,
J = 8.8 Hz, 2 H), 7.74 (d, J = 7.6 Hz, 2 H), 7.51 (br s, 2 H), 7.31–
7.43 (m, 5 H), 4.49 (d, J = 6.8 Hz, 2 H), 4.30 (t, J = 6.4 Hz, 1 H),
3.47–3.51 (m, 2 H), 2.93–2.97 (m, 2 H).
13C NMR (101 MHz, DMSO-d6): d = 166.90, 153.99, 144.39,
142.62, 141.50, 129.05, 128.41, 127.84, 125.82, 120.91, 117.91,
66.43, 47.24, 39.33, 37.74.
MS (ESI): m/z = 371 [M + H+].
5-(9-Fluorenylmethoxycarbonylamino)indan-2-amine Hydro-
chloride (Entry 10)
White solid; yield: 81%; mp 208–210 °C.
1H NMR (400 MHz, CD3OD): d = 7.81 (d, J = 7.4 Hz, 2 H), 7.69 (d,
J = 7.4 Hz, 2 H), 7.42–7.52 (m, 1 H), 7.40 (t, J = 7.4 Hz, 2 H), 7.28–
7.34 (m, 2 H), 7.15–7.23 (m, 2 H), 4.48–4.52 (m, 2 H), 4.27 (t,
J = 6.5 Hz, 1 H), 4.04–4.10 (m, 1 H), 3.34–3.39 (m, 2 H), 2.92–3.01
(m, 2 H).
13C NMR (101 MHz, CD3OD): d = 153.15, 142.49, 139.87, 138.33,
136.90, 132.07, 126.11, 125.46, 123.41, 123.33, 118.28, 116.82,
113.78, 64.95, 50.12, 45.58, 36.13, 35.41.
MS (ESI): m/z = 402 [M + H+].
4-(2-Aminoethyl)-N-(benzyloxycarbonyl)phenylamine (1c);
Typical Procedure
To a soln of 4-aminophenethylamine (0.32 g, 2.33 mmol) in 10% aq
AcOH (20 mL) was added CbzCl (0.42 g, 2.44 mmol) dissolved in
1,4-dioxane (20 mL). The mixture was stirred overnight at r.t. H2O
(100 mL) was added and the mixture was washed with Et2O (3 × 50
mL). The aqueous phase was made basic with 2 N NaOH to pH 14
and extracted with Et2O (3 × 75 mL). The combined extract was
washed with H2O (2 × 40 mL), dried (Na2SO4), filtered and concen-
trated under reduced pressure to give the expected product 1c.
MS (ESI): m/z = 371 [M + H+].
Methyl (S)-2-Amino-3-[4-(9-fluorenylmethoxycarbonylami-
no)phenyl]propionate Hydrochloride (Entry 11)
White solid; yield: 80%; mp 203–205 °C.
1H NMR (400 MHz, CD3OD): d = 7.79 (d, J = 7.4 Hz, 2 H), 7.68 (d,
J = 7.4 Hz, 2 H), 7.37–7.46 (m, 4 H), 7.29–7.33 (m, 2 H), 7.15 (d,
J = 8.4 Hz, 2 H), 4.48 (d, J = 6.5 Hz, 2 H), 4.24–4.29 (m, 2 H), 3.80
(s, 3 H), 3.21 (dd, J = 6.1, 14.5 Hz, 1 H), 3.11 (dd, J = 7.4, 14.5 Hz,
1 H).
13C NMR (101 MHz, CD3OD): d = 169.30, 154.63, 144.06, 141.47,
138.82, 129.72, 128.36, 127.67, 127.02, 125.00, 119.87, 119.76,
119.31, 66.53, 54.02, 52.50, 35.56.
Pale yellow solid; yield: 93% (98% conversion by HPLC); mp 151–
153 °C.
1H NMR (400 MHz, CD3OD): d = 7.30–7.42 (m, 7 H), 7.13 (d,
J = 8.6 Hz, 2 H), 5.16 (s, 2 H), 2.87 (t, J = 6.8 Hz, 2 H), 2.72 (t,
J = 7.0 Hz, 2 H).
13C NMR (101 MHz, DMSO-d6): d = 166.71, 154.08, 137.38,
135.37, 129.66, 129.12, 128.75, 118.85, 66.30, 53.28, 36.77, 29.42.
MS (ESI): m/z = 271 [M + H+].
MS (ESI): m/z = 417 [M + H+].
Protection with Cbz (Table 1, Last Yield Column)
3-(2-Aminoethyl)-N-(benzyloxycarbonyl)phenylamine (Entry
2)
(S)-2-Amino-3-[4-(9-fluorenylmethoxycarbonylamino)phe-
nyl]propionic Acid Hydrochloride (Entry 12)
White solid; yield: 86%; mp 216–218 °C.
1H NMR (400 MHz, DMSO-d6): d = 9.69 (br s, 1 H), 7.88 (d, J = 7.4
Hz, 2 H), 7.72 (d, J = 7.4 Hz, 2 H), 7.27–7.42 (m, 6 H), 7.15 (d,
J = 8.4 Hz, 2 H), 4.44 (d, J = 6.8 Hz, 2 H), 4.26–4.29 (m, 1 H),
3.54–3.59 (m, 1 H), 3.07 (dd, J = 4.9, 14.3 Hz, 1 H), 2.89 (dd,
J = 7.4, 14.3 Hz, 1 H).
White solid; yield: 81%; mp 79–81 °C.
1H NMR (400 MHz, CDCl3): d = 7.33–7.40 (m, 5 H), 7.21–7.26 (m,
3 H), 6.87–6.90 (m, 1 H), 5.18 (s, 2 H), 2.94 (br s, 2 H), 2.70 (t,
J = 6.8 Hz, 2 H).
13C NMR (101 MHz, CDCl3): d = 153.70, 141.11, 138.34, 136.37,
129.34, 128.85, 128.57, 128.52, 124.17, 119.30, 116.81, 67.15,
43.56, 40.21.
13C NMR (101 MHz, DMSO-d6): d = 170.87, 154.11, 144.45,
141.47, 138.36, 131.26, 130.46, 128.38, 127.81, 125.88, 120.93,
119.02, 66.17, 55.44, 47.30, 36.45.
MS (ESI): m/z = 271 [M + H+].
MS (ESI): m/z = 403 [M + H+].
4-(Aminomethyl)-N-(benzyloxycarbonyl)phenylamine (Entry
3)
White solid; yield: 97%.
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V. Perron et al.
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7-(Benzyloxycarbonylamino)-1,2,3,4-tetrahydroisoquinoline
1H NMR (400 MHz, CD3OD): d = 7.25–7.42 (m, 7 H), 7.20 (d,
J = 8.4 Hz, 2 H), 5.13 (s, 2 H), 3.67 (s, 2 H).
(Entry 9)
Pale brown solid; yield: 73%; mp 171–173 °C.
13C NMR (101 MHz, CD3OD): d = 154.62, 137.88, 136.94, 128.43,
128.37, 127.95, 127.84, 118.75, 66.33, 54.24, 45.00.
1H NMR (400 MHz, CD3OD): d = 7.28–7.41 (m, 5 H), 7.14–7.17
(m, 2 H), 6.99 (d, J = 8.2 Hz, 1 H), 5.15 (s, 2 H), 3.89 (s, 2 H), 3.04
(t, J = 6.1 Hz, 2 H), 2.75 (t, J = 6.1 Hz, 2 H).
MS (ESI): m/z = 257 [M + H+].
3-(Aminomethyl)-N-(benzyloxycarbonyl)phenylamine (Entry
13C NMR (101 MHz, CD3OD): d = 153.09, 135.40, 135.20, 133.82,
127.83, 127.76, 126.77, 126.35, 126.24, 115.54, 114.73, 64.70,
45.90, 41.75, 26.05.
4)
Pale yellow solid; yield: 93%; mp 113–115 °C.
1H NMR (400 MHz, CD3OD): d = 7.28–7.42 (m, 7 H), 7.23 (t,
J = 7.6 Hz, 1 H), 7.00 (m, 1 H), 5.17 (s, 2 H), 3.73 (s, 2 H).
MS (ESI): m/z = 283 [M + H+].
5-(Benzyloxycarbonylamino)indan-2-amine (Entry 10)
Pale yellow solid; yield: 76%; mp 87–90 °C.
1H NMR (400 MHz, CD3OD): d = 7.27–7.41 (m, 6 H), 7.16 (d,
J = 8.0 Hz, 1 H), 7.09 (d, J = 8.0 Hz, 1 H), 5.15 (s, 2 H), 3.74–3.80
(m, 1 H), 3.10–3.17 (m, 2 H), 2.65–2.73 (m, 2 H).
13C NMR (101 MHz, CD3OD): d = 154.63, 143.28, 139.19, 136.94,
128.91, 128.38, 127.97, 127.87, 121.86, 117.67, 117.28, 66.37,
45.53.
MS (ESI): m/z = 257 [M + H+].
(RS)-3-(1-Aminoethyl)-N-(benzyloxycarbonyl)phenylamine
(Entry 5)
Colorless oil; yield: 88%.
13C NMR (101 MHz, CD3OD): d = 153.20, 140.50, 136.13, 135.43,
134.41, 126.77, 126.34, 126.23, 123.06, 116.01, 113.79, 64.70,
51.23, 39.82, 39.06.
1H NMR (400 MHz, CD3OD): d = 7.28–7.42 (m, 7 H), 7.23 (t,
J = 7.8 Hz, 1 H), 7.03 (d, J = 7.6 Hz, 1 H), 5.17 (s, 2 H), 3.98 (q,
J = 6.7 Hz, 1 H), 1.36 (d, J = 6.8 Hz, 3 H).
13C NMR (101 MHz, CD3OD): d = 153.09, 146.25, 137.60, 135.38,
127.35, 126.82, 126.41, 126.30, 118.80, 115.77, 114.69, 64.80,
49.56, 22.44.
MS (ESI): m/z = 283 [M + H+].
Methyl (S)-2-Amino-3-[4-(benzyloxycarbonylamino)phe-
nyl]propionate (Entry 11)8a
White solid; yield: 84%; mp 81–83 °C.
1H NMR (400 MHz, CD3OD): d = 7.30–7.41 (m, 7 H), 7.13 (d,
J = 8.6 Hz, 2 H), 5.16 (s, 2 H), 3.93 (t, J = 7.0 Hz, 1 H), 3.72 (s, 3
H), 3.06 (dd, J = 6.1, 13.9 Hz, 1 H), 2.97 (dd, J = 7.0, 13.9 Hz, 1 H).
MS (ESI): m/z = 271 [M + H+].
(RS)-2-Amino-1-[3-(benzyloxycarbonylamino)phenyl]ethanol
(Entry 6)
White solid; yield: 83%; mp 33–36 °C.
13C NMR (101 MHz, CD3OD): d = 171.85, 154.62, 138.40, 136.90,
129.80, 129.70, 128.38, 127.98, 127.84, 119.02, 66.39, 54.55,
51.83, 37.42.
1H NMR (400 MHz, CD3OD): d = 7.47 (s, 1 H), 7.23–7.41 (m, 7 H),
7.03 (d, J = 7.6 Hz, 1 H), 5.16 (s, 2 H), 4.52 (t, J = 5.6 Hz, 1 H),
2.70–2.83 (m, 2 H).
13C NMR (101 MHz, CD3OD): d = 154.65, 144.06, 139.12, 136.94,
128.71, 128.35, 127.94, 127.83, 120.58, 117.85, 116.44, 74.71,
66.34.
MS (ESI): m/z = 329 [M + H+].
(S)-2-Amino-3-[4-(benzyloxycarbonylamino)phenyl]propionic
Acid (Entry 12)8b
White solid; yield: 77%; mp 258–260 °C.
1H NMR (400 MHz, DMSO-d6): d = 9.67 (br s, 1 H), 7.30–7.41 (m,
7 H), 7.13 (d, J = 8.6 Hz, 2 H), 5.12 (s, 2 H), 3.05 (dd, J = 4.3, 14.3
Hz, 1 H), 2.76 (dd, J = 8.4, 14.5 Hz, 1 H).
MS (ESI): m/z = 287 [M + H+].
(1S,2S)-2-Amino-1-[4-(benzyloxycarbonylamino)phenyl]pro-
pane-1,3-diol (Entry 7)
Colorless oil; yield: 78%.
13C NMR (101 MHz, DMSO-d6): d = 170.02, 154.06, 138.20,
137.34, 132.05, 130.36, 129.15, 128.76, 118.91, 66.32, 56.22,
36.89.
1H NMR (400 MHz, CD3OD): d = 7.26–7.45 (m, 9 H), 5.15 (s, 2 H),
4.50 (d, J = 6.8 Hz, 1 H), 3.44 (dd, J = 4.3, 10.8 Hz, 1 H), 3.29–3.33
(m, 1 H), 2.85–2.93 (m, 1 H).
13C NMR (101 MHz, CD3OD): d = 153.02, 137.19, 135.33, 133.10,
126.82, 126.42, 126.30, 125.39, 117.15, 93.21, 78.67, 65.74, 56.66.
MS (ESI): m/z = 315 [M + H+].
4¢-(Aminomethyl)-N-(benzyloxycarbonyl)-1,1¢-biphenyl-4-
ylamine (Entry 13)
Beige solid; yield: 76%; mp 157–160 °C.
1H NMR (400 MHz, DMSO-d6): d = 9.85 (br s, 1 H), 7.50–7.58 (m,
6 H), 7.27–7.44 (m, 7 H), 5.14 (s, 2 H), 3.37 (br s, 2 H).
MS (ESI): m/z = 317 [M + H+].
3-(2-Aminoethoxy)-N-(benzyloxycarbonyl)phenylamine (Entry
8)
White solid; yield: 98%; mp 111–113 °C.
13C NMR (101 MHz, DMSO-d6): d = 154.03, 139.02, 138.39,
137.27, 134.87, 129.15, 128.84, 128.76, 128.29, 127.49, 126.58,
119.16, 66.47, 45.92, 43.00.
1H NMR (400 MHz, CD3OD): d = 7.30–7.42 (m, 5 H), 7.13–7.17
(m, 2 H), 6.94–6.96 (m, 1 H), 6.61 (dd, J = 0.8, 2.5 Hz, 1 H), 5.16
(s, 2 H), 3.97 (t, J = 5.3 Hz, 2 H), 2.97 (t, J = 5.3 Hz, 2 H).
13C NMR (101 MHz, CD3OD): d = 159.64, 154.52, 140.26, 136.90,
129.47, 128.37, 127.97, 127.84, 111.17, 108.87, 105.08, 69.03,
66.34, 40.65.
LRMS (ESI): m/z = 316 [M + H+ – NH3].
N-(2-Aminoethyl)-4-(benzyloxycarbonylamino)benzamide
(Entry 14)
White solid; yield: 61%; mp 154–156 °C.
1H NMR (400 MHz, CD3OD): d = 7.79 (dd, J = 4.8, 2.0 Hz, 2 H),
7.55 (d, J = 8.8 Hz, 2 H), 7.31–7.43 (m, 5 H), 5.19 (s, 2 H), 3.46 (t,
J = 6.4 Hz, 2 H), 2.86 (t, J = 6.0 Hz, 2 H).
MS (ESI): m/z = 287 [M + H+].
13C NMR (101 MHz, CD3OD): d = 168.91, 154.25, 142.54, 136.76,
128.36, 128.21, 128.13, 127.89, 117.66, 66.52, 48.52, 41.80, 40.77.
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289
MS (ESI): m/z = 314 [M + H+].
(5) (a) Zhang, Z.; Yin, Z.; Meanwell, N. A.; Kadow, J. F.;
Wang, T. Org. Lett. 2003, 5, 3399; and references cited
therein. (b) Krapcho, A. P.; Kuell, C. S. Synth. Commun.
N-(Allyloxycarbonyl)-4-(2-aminoethyl)phenylamine (1d)
White solid; yield: 98%; mp 81–83 °C.
1990, 20, 2559. (c) Kovács, L.; Szegezdi, J. poster presented
at Advancing Library Design and Organic Synthesis
conference, La Jolla, California, USA, 2003. (d)Herges, R.;
Dikmans, A.; Jana, U.; Köhler, F.; Jones, P. G.; Dix, I.;
Fricke, T.; König, B. Eur. J. Org. Chem. 2002, 3004.
(e) Lee, D. W.; Ha, H.-J.; Lee, W. K. Synth. Commun. 2007,
37, 737. (f) Oganesyan, A.; Cruz, I. A.; Amador, R. B.;
Sorto, N. A.; Lozano, J.; Godinez, C. E.; Anguiano, J.; Pace,
H.; Sabih, G.; Gutierrez, C. G. Org. Lett. 2007, 9, 4967.
(6) (a) King, J. F.; Rathore, R.; Lam, J. Y. L.; Guo, Z. R.;
Klassen, D. F. J. Am. Chem. Soc. 1992, 114, 3028.
(b) King, J. F.; Guo, Z. R.; Klassen, D. F. J. Org. Chem.
1994, 59, 1095. (c) CRC Handbook of Chemistry and
Physics; Lide, D. R., Ed.; CRC Press: Boca Raton, FL, 1993,
8.
1H NMR (400 MHz, CD3OD): d = 7.35 (d, J = 8.4 Hz, 2 H), 7.13 (d,
J = 8.6 Hz, 2 H), 5.94–6.03 (m, 1 H), 5.35 (dd, J = 1.6, 17.2 Hz, 1
H), 5.21 (dd, J = 1.4, 10.6 Hz, 1 H), 4.61 (d, J = 5.5 Hz, 2 H), 2.84
(t, J = 7.6 Hz, 2 H), 2.70 (t, J = 7.4 Hz, 2 H).
13C NMR (101 MHz, CD3OD): d = 154.60, 137.30, 134.18, 133.12,
129.01, 119.01, 116.70, 65.23, 42.88, 37.84.
LRMS (ESI): m/z = 221 [M + H+].
Acknowledgment
We thank Ms L. Marcil for the skillful preparation of this manu-
script.
(7) (a) Substrate prepared according to the published procedure;
see: Hah, J.-M.; Martásek, P.; Roman, L. J.; Silverman, R. B.
J. Med. Chem. 2003, 46, 1661. (b) Substrate prepared by
reduction of the corresponding nitrobenzene. (c) Substrate
prepared by alkylation of 3-aminophenol. (d) Substrate
prepared by reduction of the corresponding cyanobenzene.
(e) Substrate prepared by EDC-mediated coupling of 4-
aminobenzoic acid with mono-N-Boc-ethylenediamine,
followed by deprotection. Gutkowska, B.; Biniecki, S. Acta
Poloniae Pharmaceutica 1962, 19, 243.
References
(1) Benoist, E.; Loussouarn, A.; Remaud, P.; Chatal, J.-F.;
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Ustynyuk, Y. A. Synthesis 2007, 1169.
(3) Hah, J.-M.; Martásek, P.; Roman, L. J.; Silverman, R.
J. Med. Chem. 2003, 46, 1661.
(4) Lee, J. W.; Jun, S. I.; Kim, K. Tetrahedron Lett. 2001, 42,
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(8) (a) Cheng, S.; Corner, D. D.; Myers, P. L.; Saunders, J.
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Synthesis 2009, No. 2, 283–289 © Thieme Stuttgart · New York