Facile Preparation of Λ-Shaped Building Blocks: Hünlich Base Derivatization

Article abstract of DOI:10.1055/s-0036-1588180

Hünlich's base modification has resulted in introducing a series of versatile Λ-shaped building blocks presented in this work. The methods are optimized to provide convenient approaches in the quicker production of these new building blocks in low-cost and low-risk.

Full text of DOI:10.1055/s-0036-1588180

SYNLETT
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5
2
1
4
1
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0
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6
© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–E
letter
A
en
M. Kazem-Rostami
Letter
Synlett
Facile Preparation of Λ-Shaped Building Blocks: Hünlich Base
Derivatization
Masoud Kazem-Rostami*
Department of Chemistry and Biomolecular Sciences,
Macquarie University, North Ryde, NSW 2109, Australia
masoud.kazem-rostami@hdr.mq.edu.au
masoud.kr@gmail.com
Received: 17.03.2017
Accepted after revision: 25.04.2017
Published online: 17.05.2017
nium source in organic solutions25 or ionic liquids.26 For in-
stance; herein, a bistriazene TBA 1 (Table 1) is produced and
converted into its corresponding bisthiophenol derivative 2
to introduce the first TBA-possessing sulfhydryl groups.
This conversion achieved under a method reported in
2012.25 This work not only introduces the first sulfhydryl
and triazene carrying TBAs but also elaborates a quicker
and much safer method of the preparation of bishydroxyl-
and ethano-strapped TBAs using inexpensive materials.
DOI: 10.1055/s-0036-1588180; Art ID: st-2017-b0194-l
Abstract Hünlich’s base modification has resulted in introducing a se-
ries of versatile Λ-shaped building blocks presented in this work. The
methods are optimized to provide convenient approaches in the quick-
er production of these new building blocks in low-cost and low-risk.
Key words amines, bicyclic compounds, azo compounds, diazo com-
pounds, nucleophilic aromatic substitution, phenols, protecting
groups, thiols
Table 1 Synthesis of the Building Blocks
Tröger’s base analogues (TBAs) are tetracyclic boomer-
ang-shaped molecules whose aromatic moieties nearly
stand in a perpendicular dihedral angle to one another. The
bent-shaped chiral core of TBAs is generated by two tertiary
amine groups which flank a diazocine strap. Depending on
which side of the molecule the strap is located, the handed-
ness of TBAs is determined as an SS or RR enantiomer. Vari-
ous TBAs structures have been elucidated by single-crystal
X-ray crystallography.1,2
11
N
12
1
4
10
R
Me
R
2
3
9
8
CH2 n
Me
N
6
7
5
Entry Compda Time (h) R Substituent;b [n]
Yield (%)
1
2
1
2
3.5
2.5
2.5
6
3-benzyl-3-methyl-1-triazene; [1]35
SH; [1]36
60
19
96
92
77
TBAs have played a substantial role as versatile building
blocks employed in the design of Λ-shaped photoswitch-
able molecular hinges,3,4 chiral ligands,5 catalysts,6 recep-
tors,7–9 supermolecules,10 sensors,7,11 polymers,12 molecular
tweezers, and leashes.13 Although numerous methods have
reported the production of TBAs including azide or triazole
carrying ones;2,14 up to the date, no TBA has been produced
carrying triazene or sulfhydryl functional groups which
would be useful in coordination,15 polymer,16,17 surface,18
and organometallic/heterocyclic19 chemistries. Triazene
3
3
OH; [1]37
4
4
tert-butyl carbamate; [1]
tert-butyl carbamate; [2]
5
5
12
6
6
9
12
8
4-hydroxy-3,5-dimethylphenyl diazene; [1] 83
4-butoxy-3,5-dimethylphenyl diazene; [1] 71
4-hydroxy-3,5-dimethylphenyl diazene; [2] 78
4-butoxy-3,5-dimethylphenyl diazene; [2] 22
7
7
8
8
9
9
24
1
10
11
12
13
10
11
12
13
NH2; [2]
96
2.5
18
2.5
OH; [2]
91
group can be converted into functionalized lactams,20 tri-
22
azoles,21 dibenzopyranones, and coumarins,
or be uti-
OH; [0]
trace
92
lized as a substrate for perfluoroalkylation reactions.23 Fur-
thermore, the triazene group can be replaced with many
other functional groups24,25 by being consumed as a diazo-
H; [1]; 1,7: OH; and 4,10: Me
a Compound (racemate).
b R is symmetrically positioned on 3 and 9 positions.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

B
M. Kazem-Rostami
Letter
Synlett
The preparation of dihydroxy TBAs (Scheme 1, iii) has
been performed by using the excess amounts of extremely
hazardous and expensive reagents such as boron tribro-
mide and trifluoroacetic acid (TFA).9,27
The literature also introduces the preparation of dihy-
droxy TBAs by the reduction of benzyl ether carrying ana-
logues in the presence of hydrogen gas, and Pd/C catalyst.27
This method is as costly as the aforementioned ones, in ad-
dition, requires the stream of an explosive gas or special-
ized hydrogenation reactor(s) which are only applicable in
small batches. Although BBr3 has apparently9,27,28 covered
the tedious production of hydroxyl-carrying TBAs, the in-
volved risks and costs cannot be ignored and yet an alterna-
tive method is needed to be found. Therefore, an easier
method (Scheme 1, bottom) on the production of dihy-
droxy TBAs (Table 1, compounds 3, 11, and 13) is described
in this work. Hünlich’s base (Scheme 1, HB) is an affordable
diamino TBA that facilitates the synthesis in the big scale in
much lower costs. Furthermore, additionally introduced
methyl groups significantly increase the hydrophobicity of
3, 11, and 13 products which helps their extraction during
the workup.
HO
O
NH2
BBr3 (excess)
TFA
OH(CH2O)nH
N
CH2Cl2
N
N
N
1–2 d
–78 to 0 °C
Ar atmosphere
7 d
i
ii
iii
O
OH
OH
O
NH2
NH2
6.5% H2SO4(aq)
CH2O(aq)
NaNO2(aq)
2 h
N
N
36 h
NH2
N
N
HB
3
The applied method in the production of 3, 11, and 13 is
known as the decomposition of diazonium salts in aqueous
media16 which is optimized here to result in the facile pro-
duction of the dihydroxy TBAs. This method16 uses a diluted
aqueous solution of sulfuric acid (H2SO4/H2O, v/v 6.5%) in-
stead of an expensive and fuming acid (neat TFA), and a
harmless sodium nitrite solution (NaNO2 in H2O, w/v 3%)
instead of boron tribromide which is violently corrosive,
expensive, problematic to store and handle. Delightfully,
the production of 3, 11, and 13 included none of the afore-
mentioned drawbacks and resulted in the excellent amount
of yields (91–96%).
TBAs structure has been modified by replacing the diaz-
ocine strap as well as changing the substituents.29,30 Such
structural modifications result in the emergence of en-
hanced properties. For instance, replacing the methylene
group of the diazocine bridge by an ethylene group simply
prevents the racemization4 of TBAs in acidic media. Fur-
thermore, such a modification gives new features to these
valuable building blocks such as changing the size of their
Λ-shape void and the dihedral angle (ca. up to 20°) of the
scaffold.29,31
Compounds 6 and 7 are previously introduced as mo-
lecular photoswitches with the potential of being utilized
for various purposes.3 The strap modification can make the
chirality of such compounds resistant to acids and tightens
their scaffold which may be beneficial in molecule recogni-
tion studies. Therefore, the change of strap was herein per-
formed on compound 7 to obtain its ethano-strapped de-
rivative 9. The strap-change operation (Scheme 3, step c)
usually ends up with a mixture of both methano- and etha-
no-strapped TBAs, especially when TBAs carry electron-
withdrawing groups. Despite many attempts, in optimizing
the conversion of 7 into 9, neither the higher ratio of alkyl
halide–TBA nor elongated reaction time did improve the
conversion yield beyond 30%. Also, the separation of these
two is challenging because the butyl groups make the re-
H2N
HO
Scheme 1 The previously reported method on the preparation of di-
hydroxy TBAs (top) and the inexpensive shortcut introduced in this
work (bottom).
The production of iii is time-consuming and requires
several days to complete the trogeration (Scheme1, the con-
version of i into ii) and the demethylation steps (the con-
version of ii into iii).27 Furthermore, due to the low solubili-
ty of the produced dihydroxy TBA iii in organic solvents,
the separation of the product is problematic. In fact, every
slight increase or decrease of pH value can easily transform
the product into phenoxy form or quaternary amine salt,
respectively (Scheme 2); which both tend to remain in the
aqueous layer and hence the extraction becomes trouble-
some.27 To display the pH-sensitive features of such mole-
cules, the UV-vis spectra of 3 was obtained in the presence
of strong protonating and deprotonating reagents (p. 46,
Supporting Information). Compound 3 experienced a tre-
mendous bathochromic shift upon deprotonation and
turned red in color; however, the protonation led to a nor-
mal hypsochromic shift.
HO
HO
O
H
pH
pH
N
N
N
Scheme 2 The pH-sensitive nature of typical dihydroxy TBAs, e.g. 3
The attempts on demethylation of ii under harsh and
acidic conditions, HCl–AcOH (1:1, 110 °C, 48 h) instead of
using BBr3, only gave a mixture of iii and its asymmetrically
methylated derivative which carries a hydroxyl group as
well as an intact methoxy.9
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

C
M. Kazem-Rostami
Letter
Synlett
tardation factors of 7 and 9 very close to one another.
Hence, the separation of product 9 from the starting mate-
rial 7 was a challenge for common liquid chromatography.
Also, modifying a compound like 7 only gives a specialized
product with specific properties which cannot be consid-
ered as a versatile building block. Therefore, as the ultimate
goal of this project, a versatile and affordable building block
had to be found, for example, a modified diamino TBA.
unprotection of 4 and 5 is fast and easy32 and releases the
corresponding diamino-TBAs which can be easily converted
into the other desired compounds as described.
The generality of the applied methodologies are well
documented in the literature, and rescaling the reactions
up to tenfold showed not a considerable change of the
yields percentage.
To conclude, a group of novel TBAs is safely prepared out
of inexpensive materials. The illustrated structural modifi-
cations in this work can be considered as the reincarnation
of this hundred-year-old compound. These novel products
can be utilized as Λ-shape building blocks in the design of
photonic crystals,33 chiral ligands, receptors, catalysts, mo-
lecular machines, porous, and conductive16,34 polymers.
N
a
N
N
N
HB
N
N
N
NH2
N
N
6
7
9
N
N
N
N
N
N
d
e
OH
b
O
N
4
5
N
O
O
H
Funding Information
O
N
N
OC4H9
The author wholeheartedly appreciates the Australian Government
for providing him with a Research Training Program Scholarship
(IPRS-2014004) and Macquarie University for the provided facilities,
N
N
c
H
f
g
HDR43010477 grant and PGRF2016R2-1672525 fund.
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v
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m
e
nt
Reseacrh
Tranin
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g
P
orgra
m
S
choalrsh
p
i
P
I(RS-2
0
1
4
0
0
4
M)
a
c
q
u
aeri
U
nveitrsi
y
H(D
R
4
3
0
1
0
4
7
7
M)
a
c
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Unvieytrsi
P(
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R
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2
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6
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10
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NH2
OC4H9
Acknowledgment
Scheme 3 Due to the symmetry of the products, they are presented
as half. (a) (i) H2SO4/NaNO2, (ii) 2, 6-dimethylphenol/Na2CO3; (b)
C4H9Br/K2CO3; (c) C2H4Br2/Li2CO3; (d) Boc(anhyd)/I2; (e) C2H4Br2/Li2CO3; (f)
(i) H2SO4/NaNO2, (ii) 2,6-dimethylphenol/Na2CO3, (iii) C4H9Br/K2CO3;
(g) H2SO4; (h) Na2S2O6.
Dr Andrew Piggott and respected Jamie family are thanked for the
provided lab space, and partial access to the departmental facilities.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1588180. Detailed procedures and
Although the reduction of 8 or 9 gives the desired etha-
no-strapped diamino building block 10 (Scheme 3, step h),
such conversion is not convenient due to multiple steps and
instability of 10. A modified building block needs to be eas-
ily produced, stored, and be readily available for straightfor-
ward applications.
the NMR, MS, IR, and UV/Vis spectra are included.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
References and Notes
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fact, the N-Boc-protected groups moderately activate the
substrate compound 4 during the strap-change operation
and also prevent the unwanted N-alkylation reactions.
Therefore, strap-change operation of 4 accomplished in
good yields (up to 96% converted based on the crude’s NMR,
77% isolated by chromatography). The obtained ethano-
strapped TBA 5 can be readily unprotected and be convert-
ed into other functional groups as earlier performed on the
methano-strapped analogues.
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HB (Scheme 1), to air and light quickly decomposes them.
This can be detected by the fast change of colour from
white to brown. To prevent the decomposition, Boc protec-
tion of the amine groups was performed which significant-
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(35) Synthesis and Characterization of Compound 1
Hünlich’s base (0.56 g, 2.0 mmol, 1.0 equiv) solution in H2SO4
(6.5%, 30 mL) was cooled down to –5 °C. A NaNO2 solution (0.30
g, 4.4 mmol, 2.2 equiv in 5 mL cold H2O) was dropped into the
reaction flask and stirred for 30 min. The resulting yellowish
solution was poured into a solution consisting N-benzylmethyl-
amine (3 mL, excess), Na2CO3 (4.5 g), H2O (60 mL), and MeCN
(30 mL) chilled at –10 °C. The stirring was continued for 3 h
meanwhile the temperature was gradually raised to r.t.; after-
ward, a beige precipitate was extracted from the aqueous
mixture by CH2Cl2 (3 × 50 mL). The CH2Cl2 layers were com-
bined, dried over Na2SO4, and filtered. The evaporation of the
CH2Cl2 gave the crude product which was then purified by chro-
matography to furnish the purified bistriazene compound 1 as a
light-yellow solid. Yield 0.65 g (1.2 mmol, 60%); Rf = 0.3 (silica
gel; MeOH–CH2Cl2, 2% v/v). IR (neat): 3027, 2941, 2893, 2844,
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1610, 1486, 1441, 1341, 1173, 1047, 921, 697 cm–1 1H NMR
.
(400 MHz, CDCl3): δ = 7.28–7.38 (m, 12 H, CH), 6.74 (s, 2 H, CH),
4.91–5.02 (q, J = 16.1 Hz, 4 H, NCH2), 4.66–4.70 (d, J = 16.6 Hz, 2
H, CH2), 4.36 (s, 2 H, NCH2N), 4.22–4.26 (d, J = 16.8 Hz, 2 H, CH2),
3.15 (b, 6 H, NCH3), 2.30 (s, 6 H, CH3). 13C NMR (100 MHz,
CDCl3): δ = 147.9, 146.3, 137.1, 129.0, 128.7, 128.6, 128.0, 127.7,
125.1, 112.7, 67.3, 58.8, 34.4, 17.2. MS (ESI+; i-PrOH): m/z [M +
H]+ calcd for [C33H37N8]+: 545.31; found: 545.2. UV-vis: (EtOAc):
λ (lg ε) = 297 (4.465) nm. Anal. Calcd for C33H36N8: C, 72.77; H,
6.66; N, 20.57. Found: C, 72.56; H, 6.85; N, 20.18.
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The bistriazene compound 1 (0.54 g, 1.0 mmol, 1.0 equiv) was
poured into a 50 mL round-bottom flask containing CH2Cl2 (20
mL). A solution of trichloroacetic acid (5.0 g, 30 mmol, excess, in
CH2Cl2 (20 mL)) was added and stirred for 2 min. Afterward,
Na2S (0.70 g, 9 mmol, excess) was slowly added to the reaction
flask, as shown in the following figure, and remained sealed
when stirred for 2 hours at r.t. The volume of the resulting yel-
lowish suspension was then reduced to half by nitrogen gas
flow and then refluxed for 30 min. The reaction mixture cooled
down to r.t. and diluted with CH2Cl2 (100 mL), and filtered. The
CH2Cl2 layer was rinsed with cold H2O (5 × 100 mL), dried over
Mg2SO4, and filtered. The CH2Cl2 was removed, and the residue
was purified by column chromatography to obtain a pale-lemon
substance with a mild rotten-egg odour which was then stored
under argon in darkness. Yield 0.06 g (0.19 mmol, 19%); Rf = 0.2
(silica gel, MeOH–CH2Cl2, 4% v/v). IR (neat): 2896, 2847, 2560,
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(27) Malik, Q. M.; Ijaz, S.; Craig, D. C.; Try, A. C. Tetrahedron 2011, 67,
5798.
(28) Kiehne, U.; Lützen, A. Synthesis 2004, 1687.
1608, 1492, 1474, 1205, 1091, 1010, 811 cm–1 1H NMR (400
.
MHz, CDCl3): δ = 7.62 (br, 2 H, SH), 6.65 (s, 2 H, CH), 6.17 (s, 2 H,
CH), 4.56–4.60 (d, J = 16.7 Hz, 2 H), 4.28 (s, 2 H, NCH2N), 4.17–
4.13 (d, J = 16.8 Hz, 2 H), 2.10 (s, 6 H, 2CH3). 13C NMR (100 MHz,
CDCl3): δ = 143.8, 134.5, 128.6, 127.4, 126.8, 124.7, 67.1, 58.4,
20.9. MS (ESI+; i-PrOH–EtOAc–H2O/0.5% HCO2Na = 90:5:5): m/z
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

E
M. Kazem-Rostami
Letter
Synlett
[M + Na]+ calcd for [C17H18N2S2Na]+: 337.08; found: 337.0. MS
(ESI–): m/z [M – H]– calcd for [C17H17N2S2]–: 313.09; found:
313.1. MS (ESI+; MeCN/Δ): m/z [M + 2MeCN + H]+ calcd for
[C21H25N4S2]+: 397.14; found: 397.1. UV-vis: (EtOAc): λ (lg
ε) = 277 (3.583) nm. Anal. Calcd for C17H18N2S2: C, 64.93; H,
5.77; N, 8.91; S, 20.39. Found: C, 65.08; H, 5.83; N, 9.22.
30 mL), the organic layers were combined, dried over Na2SO4,
and evaporated to dryness to obtain the product as a light-grey
powder. Yield 0.54 g (1.9 mmol, 96%). Rf = 0.3 (silica gel, MeOH–
CH2Cl2, 8% v/v). IR (neat): 3649, 3549, 3012, 2948, 2904, 2857,
1620, 1508, 1368, 1081, 910 cm−1 1H NMR (400 MHz, DMSO-
.
d6): δ = 9.06 (s, 2 H, OH), 6.56 (s, 2 H, CH), 6.45 (s, 2 H, CH), 4.39–
4.43 (d, J = 16.4 Hz, 2 H, CH2), 4.07 (s, 2 H, NCH2N), 3.81–3.85 (d,
J = 16.4 Hz, 2 H, CH2), 1.97 (s, 6 H, CH3). 13C NMR (100 MHz,
DMSO-d6): δ = 154.1, 146.5, 128.2, 119.9, 117.9, 110.0, 66.5,
57.8, 15.5. MS (ESI+; EtOH–EtOAc–H2O, 90:5:5): m/z [M + H]+
calcd for [C17H19N2O2]+: 283.14; found: 283.1. MS (ESI–): m/z [M
– H]– calcd for [C17H17N2O2]–: 281.14; found: 281.1. UV-vis:
(EtOAc): λ (lg ε) = 292 (3.643) nm. Anal. Calcd for C17H18N2O2: C,
72.32; H, 6.43; N, 9.92; O, 11.33. Found: C, 72.21; H, 6.61; N,
9.74.
(37) Synthesis and Characterization of Compound 3
Hünlich’s base (0.56 g, 2.0 mmol, 1.0 equiv) was dissolved in
H2SO4 (6.5%, 90 mL), then cooled down to –5 °C. A NaNO2 solu-
tion (0.30 g, 4.4 mmol, 2.2 equiv) in cold H2O (10 mL) was
dropped into the reaction flask and stirred for 30 min. After-
ward, the solution’s temperature was gradually raised to boil,
over 2 h (attention: this step releases nitrogen gas; hence, rapid
heating and sealing the container may lead to explosion). The
reaction mixture was cooled down to r.t., its pH was adjusted to
5 (by adding Na2CO3 sat. solution) and extracted with EtOAc (5 ×
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E