Synthesis of non-symmetrical 3,5-diamidobenzyl amines, ethers and sulfides

Article abstract of DOI:10.1016/j.tetlet.2008.01.003

A straightforward synthesis of non-symmetrical 3,5-diamidobenzyl amines, ethers and sulfides starting from 3,5-dinitrobenzoic acid is reported. Functionalization of the benzylic position is only achieved after formation of the two amides, otherwise benzylic hydrogenolysis occurs during nitro group reduction.

Full text of DOI:10.1016/j.tetlet.2008.01.003

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Tetrahedron Letters 49 (2008) 1660–1664
Synthesis of non-symmetrical 3,5-diamidobenzyl amines,
ethers and sulfides
David Barker *, Anna L. Lehmann, Anna Mai, Gul S. Khan, Eric Ng
Department of Chemistry, University of Auckland, 23 Symonds Street, Auckland, New Zealand
Received 26 November 2007; revised 19 December 2007; accepted 2 January 2008
Available online 8 January 2008
Abstract
A straightforward synthesis of non-symmetrical 3,5-diamidobenzyl amines, ethers and sulfides starting from 3,5-dinitrobenzoic acid
is reported. Functionalization of the benzylic position is only achieved after formation of the two amides, otherwise benzylic hydro-
genolysis occurs during nitro group reduction.
Ó 2008 Elsevier Ltd. All rights reserved.
meta-Diamidobenzenes are a moiety found in many
compound classes including polybenzamide DNA minor-
groove binding agents and benzamide polymers.1–5 We
wished to synthesize and incorporate non-symmetrical
3,5-diamidobenzylamines into polybenzamide DNA
minor-groove binding agents with the aim of testing what
effect the additional polar amine moieties would have on
DNA binding. Whilst there are numerous examples of sym-
metrical 3,5-diamidobenzenes, generally formed from the
diacylation of 3,5-diaminobenzenes, we were surprised to
find a lack of information on these deceptively simple,
substituted benzene derivatives. Herein, we report the syn-
thesis of a range of non-symmetrical 3,5-diamidobenzyl
amines, ethers and sulfides.
Starting from the commercially available 3,5-dinitro-
benzyl alcohol 2, which can also conveniently be obtained
on a large scale from the borane reduction of 3,5-dinitro-
benzoic acid 1,6 selective reduction of one nitro group using
aqueous ammonium sulfide7 gave amino alcohol 3 (Scheme
1). It should be noted that attempts to selectively mono
reduce N,N-diethyl-3,5-nitrobenzylamine8 using the same
conditions led to the formation of a complex mixture of
products. Attempts to selectively acylate the amino group
HO
HO
HO
X
(ii)
(iii),(iv)
NH2 O2N
O
O2N
N
H
R
O2N
(i)
NO2
1: X = O
2:
3
4a: R = Me
4b:
X = H,H
R = Ph
Scheme 1. Reagents, conditions and yields: (i) BH3–THF, THF, 0 °C to
rt, 18 h, 78%; (ii) 20% aq (NH4)2S, MeOH, reflux, 6 h, then rt 20 h, 86%;
(iii) for 4a, 3 equiv Ac2O, NEt3, DMF, rt, 24 h, 92%, for 4b, 3 equiv BzCl,
NEt3, DCM, rt 3 h, 99%; (iv) 2 equiv NaOH, 4:1 EtOH/H2O, rt, 3 h, 4a
98%, 4b 96%.
of 3 with 1 equiv of either acetic anhydride or benzoyl chlo-
ride gave a mixture of N-, O- and diacylated products. This
problem was circumvented by reacting 3 with either an
excess of acetic anhydride or benzoyl chloride to give the
diacylated product, followed by selective hydrolysis of the
ester using aqueous sodium hydroxide to give acetamide
alcohol 4a9,10 in 90% yield or benzamide alcohol 4b in
95% yield, respectively, over two steps.
Next, we planned to convert the benzylic alcohols into
the desired benzylic amines before reducing the second
aromatic nitro group. Attempts to couple alcohol 4b with
various secondary amines under Mitsunobu conditions
failed, presumably due to the lack of a deprotonatable
functionality ortho to the benzylic position.11 Conversion
of the benzylic alcohol into a more activated leaving group
*
Corresponding author. Tel.: +64 9 373 7599; fax: +64 9 373 7422.
E-mail address: d.barker@auckland.ac.nz (D. Barker).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.01.003

D. Barker et al. / Tetrahedron Letters 49 (2008) 1660–1664
1661
was therefore required. The initial approach was to convert
alcohol 4 into chloride 5. This was achieved using thionyl
chloride in DCM to give chloride 5 in 86% yield. However,
chloride 5 was found to decompose quickly even when
stored at <0 °C and is only useful if used immediately.
We therefore sought a more stable coupling partner; bro-
mide 6 was synthesized in 70% yield using Appel condi-
tions12 but was found to be as unstable as chloride 5,
whilst aldehyde 7, which could be converted to the desired
amines using reductive amination, was synthesized via a
MnO2 oxidation but in a poor 26% yield. We eventually
discovered that benzylic mesylates 8a/b, which can be syn-
thesized easily in near quantitative yield, had sufficient
reactivity and, when stored at <0 °C, are stable for periods
over many months (Scheme 2).
With mesylates 8a/b in hand, we investigated their reac-
tivity with a range of nucleophiles, including amines, thiols,
sodium azide and sodium phenolate. The yields were rea-
sonable to excellent for all the nucleophiles examined
(Table 1).
X
(i),(ii),(iii) or (iv)
O
4a or 4b
O2N
N
H
R
5 : R = Me, X = Cl,H
6 : R =Ph, X = Br,H
7 : R =Me, X = O
8a : R =Me, X = OMs,H
8b: R = Ph, X = OMs,H
Scheme 2. Reagents, conditions and yields: (i) SOCl2, DCM, rt, 3 h, 5
86%; (ii) CBr4, PPh3, DCM, rt, 24 h, 6 70%; (iii) MnO2, DCM, reflux 8 h,
then rt 5 days, 7 26%; (iv) 1.05 equiv MsCl, NEt3, THF, 0 °C to rt, 6 h, 8a
and 8b 100%.
With the benzylic position now substituted as desired,
the next step was to reduce the remaining nitro group.
Unfortunately for tertiary amines 9a/b, 10a/b, 11a/b and
Table 1
Reaction of various nucleophiles with mesylates 8a/b
Entry
Mesylate
Nucleophile, conditions
Product
Yielda (%)
MsO
N
N
HNEt2, THF, 0 °C to rt, 16 h
9a 72
9b 81
8a R = Me
8b R = Ph
1
O
9a R = Me
9b R = Ph
O
O
O2N
N
H
R
O2N
N
H
R
R
10a R = Me
10b R = Ph
2
8a/b
HNiPr2, THF, 0 °C to rt, 10 h
10a 60
10b 70
O2N
N
H
H
N
Ph
O
11a R = Me
11b R = Ph
3
4
8a/b
8a/b
PhCH2NH2, THF, reflux, 18 h
11a 92
11b 95
O2N
O2N
N
H
R
OPh
12a R = Me
12b R = Ph
O
PhONa, DMF, rt, 16 h
12a 42
12b 65
N
H
R
N3
13a R = Me
13b R = Ph
O
O
5
6
8a/b
8a/b
NaN3, DMF, 105 °C, 16 h
13a 82
13b 79
O2N
O2N
N
H
R
R
S
14a R = Me
14b R = Ph
EtSNa, THF, rt, 24 h
14a 91
14b 85
N
H
SPh
15a R = Me
15b R = Ph
O
7
8a/b
PhSNa, DMF, reflux, 1 h
15a 45
15b 70
O2N
N
H
R
a
Isolated yield.

1662
D. Barker et al. / Tetrahedron Letters 49 (2008) 1660–1664
azide 13a/b, under standard hydrogenation conditions,
using 10% Pd/C, rapid benzylic hydrogenolysis occurred
giving in all cases the 3-amido-5-aminotoluene 16a/b in
near quantitative yield (Scheme 3). Altering the pH to pro-
duce either acidic or basic conditions, or using a less active
palladium source did not alter the outcome.13–15 We then
turned to metal-based reductions that had previously been
reported to work successfully on aromatic nitro com-
pounds bearing a meta benzylic amine or ether. However,
OTBDMS
O
OH
(i)-(ii)
O
H2N
N
H
Me
O2N
N
H
Me
4a
19
(iii)
OTBDMS
O
OMs
(iv)-(v)
O
O
O
reductions with SnCl2,16 Al–NiCl2 and NaBH4–NiCl2
17
18
Ph
N
N
H
Me
Ph
N
N
H
Me
H
resulted in either no reaction or total decomposition whilst
the use of zinc powder in acetic acid19 on amine 9b resulted
in a complex mixture with brightly coloured azo-dimer 17
being the predominant (ꢀ80%) product. Whilst there are
reports of other benzylic amines with a meta nitro group
that have been successfully reduced,16,18,20–22 none have
an additional meta amide functionality. It appears that this
additional group subtly alters the reactivity of these mole-
cules such that benzylic cleavage is highly favoured. Inves-
tigating the hydrogenation of sulfides 14a/b and 15a/b
resulted in the formation of a complex mixture of products;
H
20
21a
OH
OMs
(i)-(v)
O
O
O
O2N
N
H
Ph
p
-NO2C6H4
N
N
H
Ph
H
4b
21b
Scheme 4. Reagents and conditions: (i) TBDMSCl, imidazole, DMF, rt,
2 h, 93%; (ii) H2, 10% Pd/C, MeOH, 3 h, 100%; (iii) benzoyl chloride (4-
nitrobenzoyl chloride for 21b), pyridine, rt, 16 h, 80%; (iv) 4 equiv TBAF,
4 equiv AcOH, THF, rt, 36 h, 81%; (v) 1.05 equiv MsCl, NEt3, THF,
100%.
1
however, H NMR analysis of the crude mixture showed
that toluenes 16a/b were also present in the mixtures.
Hydrogenation of ether 12a, however, proceeded cleanly
to give aniline 18 in quantitative yield.
80% yield. Deprotection of the silyl ether with TBAF was
greatly improved by using 4 equiv of acetic acid to buffer
the pH23 giving a benzylic alcohol, which underwent mesyl-
ation using the previously determined conditions to give
mesylate 21a in 81% yield over two steps.24 Using the same
reaction sequence, alcohol 4b was converted to bis-amide
mesylate 21b in 57% yield over five steps, the only differ-
ence being the use of 4-nitrobenzoyl chloride rather than
benzoyl chloride so as to again have differently substituted
amides.
We then investigated the ability of these bis-amide mesyl-
ates 21a/b to undergo substitution reactions with a range of
nucleophiles.25 The yields were comparable to those
previously obtained when using mesylates 8a/b except for
sulfides 26a/b, which were isolated in significantly lower
yields (Table 2).
Since the desired benzylic amines 1 could not be
obtained using the method outlined above but ether 12a
could be reduced without benzylic cleavage, we turned to
the idea that benzylic alcohols 4a/b could be protected as
an ether, the nitro group reduced and converted into the
desired second amido functionality before deprotection of
the ether and then conversion into the desired benzylic
amines via the mesylate. To test the viability of this reac-
tion sequence, alcohol 4a was protected using tert-butyl-
dimethylsilyl chloride to give the silyl ether, which was then
followed by hydrogenation under standard conditions to
give aniline 19 in 93% yield over two steps, with no sign
of benzylic hydrogenolysis (Scheme 4). Acylation of 19
with benzoyl chloride in pyridine gave bis-amide 20 in
Finally, we wished to determine whether the bis-amide
benzylic amines 22a/b, 23a/b and azide 24a/b were as sus-
ceptible to hydrogenolysis as mono-amides 9a/b, 10a/b,
11a/b. We were pleased to find that hydrogenation of
nitrobenzamide 22b under standard conditions for 2 h gave
an 85% yield of amine 27 (Scheme 5). On repeating the
Me
(i)
16a R = Me
16b R = Ph
9a/b, 10a/b,
11a/b, 13a/b
O
H2N
N
H
R
Ph
HN
N
1
O
reaction for 24 h, H NMR analysis of the crude reaction
N
N
(ii)
mixture showed that benzylic cleavage was eventually
occurring with ꢀ15% of toluene 28 being produced; how-
ever, even after three days complete conversion into tolu-
ene 28 had not occurred. Hydrogenation of azide 24a for
1 h also went smoothly giving a 95% yield of benzylamine
29.26
In summary, we have synthesized non-symmetrical 3,5-
diamidobenzyl amines, ethers and sulfides starting from
the readily available 3,5-dinitrobenzyl alcohol. Investiga-
tions into the role of the 3- and 5-substituent on the rate
O
9b
N
NH
Ph
17
OPh
(i)
O
12a
H2N
N
H
Me
18
Scheme 3. Reagents, conditions and yields: (i) H2, 10% Pd/C, MeOH, 2–
3 h, >95% in all cases; (ii) Zn powder, AcOH, reflux, 24 h, ꢀ80%.

D. Barker et al. / Tetrahedron Letters 49 (2008) 1660–1664
1663
Table 2
Reaction of various nucleophiles with mesylates 21a/b
Entry
Mesylate
Nucleophile, conditions
HNEt2, THF, rt, 24 h
Product
Yielda (%)
OMs
N
O
O
R2
N
H
N
H
R1
1
22a 95
22b 89
O
O
R2
N
N
H
R1
21a: R1 = Me, R2 = Ph
H
22a: R1 = Me, R2 = Ph
21b: R1 = Ph, R2 =
p
-NO2C6H4
22b: R1 = Ph, R2 =
p-NO2C6H4
N
O
R2
O
2
3
4
21a/b
HNiPr2, THF, rt, 10 h
23a 68
23b 59
N
H
N
H
R1
23a: R1 = Me, R2 = Ph
23b: R1 = Ph, R2 =
p-NO2C6H4
N3
O
R2
O
N
H
N
H
R1
21a/b
NaN3, DMF, 105 °C, 24 h
24a 77
24b 84
24a: R1 = Me, R2 = Ph
24b: R1 = Ph, R2 =
p-NO2C6H4
OPh
O
R2
O
21a/b
PhONa, DMF, rt, 12 h
25a 55
25b 60
N
H
N
H
R1
25a: R1 = Me, R2 = Ph
25b: R1 = Ph, R2 =
p-NO2C6H4
SPh
O
R2
O
5
21a/b
PhSNa, DMF, reflux, 1 h
26a 20
26b 31
N
H
N
H
R1
26a: R1 = Me, R2 = Ph
26b: R1 = Ph, R2 =
p-NO2C6H4
a
Isolated yield.
of benzylic hydrogenolysis as well as the utilization of this
methodology in the synthesis of DNA minor-groove bind-
ing agents bearing additional polar substituents will be
reported in due course.
N
(i)
O
O
22b
p
-NH2C6H4
N
H
NHBz
NHBz
27
Me
References and notes
1. Yuan, L.; Feng, W.; Yamato, K.; Sanford, A. R.; Xu, D.; Guo, H.;
Gong, B. . J. Am. Chem. Soc. 2004, 126, 11120–11121.
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Polym. Chem. 2005, 43, 1119–1128.
p-NH2C6H4
N
H
28
N3
NH2
3. Fox, K.; Yan, Y.; Gong, B. Anti-Cancer Drug Des. 1999, 14, 219–230.
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5. Bhuvana, S.; Hariharan, R.; Sarojadevi, M. J. Macromol. Sci., Pure
Appl. Chem. 2005, A42, 909–920.
O
O
O
O
(ii)
Ph
N
H
N
H
Me
Ph
N
H
N
H
Me
29
24a
6. Campbell, R. F.; Fitzpatrick, K.; Inghardt, T.; Karlsson, O.; Nilsson,
K.; Reilly, J. E.; Yet, L. Tetrahedron Lett. 2003, 44, 5477–5481.
Scheme 5. Reagents, conditions and yields: (i) H2, 10% Pd/C, MeOH, 2 h,
85%; (ii) H2, 10% Pd/C, MeOH, 1 h, 95%.

1664
D. Barker et al. / Tetrahedron Letters 49 (2008) 1660–1664
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Tetrahedron Lett. 2005, 46, 7523–7526.
24. Data for 21a: dH (300 MHz, CDCl3) 2.04 (3H, s, NHCOCH3), 2.96
(3H, s, SO2CH3), 5.06 (2H, s, ArCH2O), 7.32 (1H, br s, Ar-H), 7.38–
7.43 (2H, m, Ar-H), 7.48–7.50 (2H, m, Ar-H), 7.80–7.83 (2H, m,
Ar-H), 7.93 (1H, s, Ar-H), 8.27 (1H, s, NH) and 8.59 (1H, s, NH). dC
(75 MHz, CDCl3) 24.3 (CH3, NHCOCH3), 38.1 (CH3, OSO2CH3),
71.21 (CH2, ArCH2O), 112.6 (CH, Ar-C), 115.6 (CH, Ar-C), 115.9
(CH, Ar-C), 127.2 (CH, Ar-C), 128.7 (CH, Ar-C), 132.0 (CH, Ar-C),
134.4 (quat. Ar-C), 134.9 (quat. Ar-C), 139.0 (quat. Ar-C), 139.2
(quat. Ar-C), 166.4 (C@O, NHBz) and 169.3 (C@O, NHAc). Found
M+ 362.09371, C17H18N2O5S requires 362.09364.
25. General procedure for the displacement reaction of benzylic mesylates:
To a solution of mesylate (1 mmol) in dry DMF (2 ml) or dry THF
(3 ml) was added the appropriate nucleophile (3 mmol) and the
mixture stirred at room temperature until no starting material was
visible on the tlc. Ethyl acetate was added (20 ml) and the mixture
washed with water (2 Â 20 ml) and brine (20 ml), dried (NaSO4),
filtered and the solvent removed in vacuo to afford the crude product,
which was purified by flash silica chromatography to afford the
desired benzylic amine, ether or sulfide.
26. Data for 29: dH (400 MHz, CD3OD) 2.11 (3H, s, NHCOCH3), 3.74
(2H, s, ArCH2NH2), 7.32 (1H, br s, Ar-H), 7.36 (1H, br s, Ar-H),
7.46–7.50 (2H, m, Ar-H), 7.54–7.58 (1H, m, Ar-H) and 7.89–7.91 (3H,
m, Ar-H). dC (100 MHz, CD3OD) 23.9 (CH3, NHCOCH3), 46.6
(CH2, ArCH2NH2), 112.8 (CH, Ar-C), 116.4 (CH, Ar-C), 116.9 (CH,
Ar-C), 128.6 (CH, Ar-C), 129.6 (Ch, Ar-C), 132.9 (CH, Ar-C), 136.2
(quat. Ar-C), 140.3 (quat. Ar-C), 140.4 (quat. Ar-C), 144.7 (quat.
Ar-C), 168.8 (C@O, NHBz) and 171.7 (C@O, NHAc). Found MH+
284.13958, C16H18N3O2 requires 284.13990.
22. Chhikara, B. S.; Kumar, N.; Tandon, V.; Mishra, A. K. Bioorg. Med.
Chem. 2005, 13, 4713–4720.