Synthesis of mono- and 1,3-diaminocalix[4]arenes via ullmann-type amination and amidation of 1,3-bistriflate esters of calix[4]arenes

Article abstract of DOI:10.1021/jo102566e

Practical methods are described for the preparation of monoamines 4 and 1,3-diamines 5, bearing one or two amino group(s) instead of the hydroxy group(s) at the 28-position or at both the 26- and 28-positions of p-tert-butylcalix[4]arene (1a) and p-tert-butylthiacalix[4]arene (1b), via the Ullmann-type amination or amidation. Thus, the copper-catalyzed or mediated amination of the 1,3-bistriflate ester (2a) of 1a with benzylamine affords either mono(benzylamino) triflate 7a or 1,3-bis(benzylamine) 8 in a high yield, depending on the reaction conditions. On the other hand, the 1,3-bistriflate ester (2b) of 1b resists disubstitution and produces, under stoichiometric conditions, mono(benzylamino) triflate 7b. The disubstitution of 2b is achieved by amidation with tosylamide, giving 1,3-bis(tosylamide) 17b. The hydrogenolysis of the benzylamino moiety of 7a, followed by the hydrolysis of the Tf moiety, affords monoamine 4a, while the hydrogenolysis of 8 affords 1,3-diamine 5a. The amino moiety of 7b can be deprotected under acidic conditions to give, after hydrolysis, monoamine 4b. The hydrolysis of 17b affords 1,3-diamine 5b. The overall yields of compounds 4a, 4b, 5a, and 5b are 72%, 45%, 78%, and 24%, respectively, based on commercially available compounds 1 and are much higher than the ones previously reported in the literature.

Full text of DOI:10.1021/jo102566e

ARTICLE
pubs.acs.org/joc
Synthesis of Mono- and 1,3-Diaminocalix[4]arenes via Ullmann-Type
Amination and Amidation of 1,3-Bistriflate Esters of Calix[4]arenes
Yuka Nakamura, Shinya Tanaka, Ryuichi Serizawa, Naoya Morohashi, and Tetsutaro Hattori*
Department of Biomolecular Engineering, Graduate School of Engineering, Tohoku University, 6-6-11 Aramaki-Aoba, Aoba-ku,
Sendai 980-8579, Japan
S Supporting Information
b
ABSTRACT: Practical methods are described for the preparation of
monoamines 4 and 1,3-diamines 5, bearing one or two amino
group(s) instead of the hydroxy group(s) at the 28-position or at
both the 26- and 28-positions of p-tert-butylcalix[4]arene (1a) and
p-tert-butylthiacalix[4]arene (1b), via the Ullmann-type amination
or amidation. Thus, the copper-catalyzed or mediated amination of
the 1,3-bistriflate ester (2a) of 1a with benzylamine affords either
mono(benzylamino) triflate 7a or 1,3-bis(benzylamine) 8 in a high
yield, depending on the reaction conditions. On the other hand, the 1,3-bistriflate ester (2b) of 1b resists disubstitution and
produces, under stoichiometric conditions, mono(benzylamino) triflate 7b. The disubstitution of 2b is achieved by amidation with
tosylamide, giving 1,3-bis(tosylamide) 17b. The hydrogenolysis of the benzylamino moiety of 7a, followed by the hydrolysis of the
Tf moiety, affords monoamine 4a, while the hydrogenolysis of 8 affords 1,3-diamine 5a. The amino moiety of 7b can be deprotected
under acidic conditions to give, after hydrolysis, monoamine 4b. The hydrolysis of 17b affords 1,3-diamine 5b. The overall yields of
compounds 4a, 4b, 5a, and 5b are 72%, 45%, 78%, and 24%, respectively, based on commercially available compounds 1 and are
much higher than the ones previously reported in the literature.
’ INTRODUCTION
donor and an acceptor and ligates to metal ions, similar to the
hydroxy group. (2) Its high basicity and softness are expected to
produce novel or improved properties as host molecules. (3)
With its nitrogen atom, branched structures can be constructed.
Calix[4]arenes (e.g., 1) play an important role in supramole-
cular chemistry as molecular scaffolds for elaborating sophisti-
cated hosts.1,2 A variety of functional groups have been regio- and
stereospecifically introduced on the hydroxy groups of calix-
[4]arenes as recognition sites by linking moieties through
etherification. However, the transformation results in locating
the functional groups apart from the calix skeleton,3 which makes
it difficult for guests to be affected by the steric effects of the calix
skeleton and/or to interact with substituents on it (e.g., with
residual hydroxy groups or linking hetero atoms). This issue will
be addressed by cleaving the aryl-oxygen bonds, thereby repla-
cing the hydroxy groups with different functional groups. How-
ever, such a transformation is quite difficult for calix[4]arenes
because of their steric and electronic environment near the
narrow rims,4 in addition to the poor nucleofugacity of the
phenolic hydroxy group. Although the C-O bond cleavage of
aryl triflates or other esters using a palladium or nickel catalyst,
such as the Suzuki-Miyaura5 and Migita-Kosugi-Stille
couplings,6 is one of the most reliable ways for replacing the
phenolic hydroxy group, such reactions have been applied
unsuccessfully to calix[4]arenes,7 with the exception of a recent
report by Georghiou and co-workers, who reported the Sonoga-
shira coupling of 1,3-bistriflate ester 2a to afford 1,3-
dialkynylcalix[4]arenes.4e Out of many variants that bear func-
tions other than the hydroxy group on their narrow rims, we are
interested in aminocalix[4]arenes (e.g., 3-5) for the following
reasons: (1) The amino group serves as both a hydrogen bond
(4) It can be diazotized, from which plenty of new compounds
can be generated.8 Recently, we succeeded in preparing the
tetraaminated variant (3)9 of thiacalixarene 1b and later on,
mono- (4b) and 1,3-diaminated ones 5b10 via a chelation-
assisted nucleophilic aromatic substitution (SNAr) of stereoi-
somers of tetra-O-methylated sulfinylcalixarene 611 with lithium
benzylamide. In solvent extraction experiments, tetraamine 3
selectively extracted gold and palladium,12 whereas tetraol 1b
extracted a variety of metal ions ranging from soft to
Received: December 24, 2010
Published: March 07, 2011
r
2011 American Chemical Society
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The Journal of Organic Chemistry
ARTICLE
intermediate, depending on the soft/hard nature of the binding
moieties. Biali and co-workers reported the synthesis of mono-
amine 4a via the oxidation of 1a to a spirodienone derivative,
followed by the imination of the carbonyl group with hydrazine,
and the subsequent rearomatization of the resulting Schiff base.4c
Shinkai and co-workers succeeded in the synthesis of 1,3-diamine
5a by the reaction of the 1,3-bis(diethylphosphate) of 1a with
potassium amide in liquid ammonia using HMPA as a
cosolvent.4b However, these methods require many steps and/
or produce low yields. In our previous communication,13 we have
reported an application of the Ullmann condensation to synthe-
size monoamines 4. As a follow-up to the previous communica-
tion, here, we wish to describe in detail the first practical methods
for preparing monoamines 4 and 1,3-diamines 5 via Ullmann-
type reactions,14 that is, the Ullmann condensation of 1,3-
bistriflates 2 with benzylamine15 and the Goldberg-modified
Ullmann condensation of 2 with tosylamide.16
Table 1. Amination of 1,3-Bistriflate 2aa
yield (%)c
2a
73 n.d. 23
entry BnNH2 CuIb additive (equiv)b time (h) 7a
8
b
1
2
2.0
2.4
2.4
4.0
2.4
2.4
4.0
4.0
2.4
2.4
2.4
2.4
2.4
4.0
1.2
0.1
0.1
0.1
0.1
0.1
0.1
1.2
0.1
0.1
0.1
0.1
18
24
24
24
24
24
24
24
6
52 18
25 40
16 42
13 66
14 70
11 74
n.d.
3
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
4
5
EG (1.0)
EG (2.0)
EG (2.0)
EG (3.0)
6
7
8
1
80
9
85 n.d. n.d.
84 n.d.
10
11
12
13
EG (0.2)
EG (1.0)
bpy (1.0)
bpy (1.0)
2
2
10 min 87 n.d. n.d.
1
86 n.d. n.d.
’ RESULTS AND DISCUSSION
24
20 44 n.d.
a Reaction conditions: 2a (1.10 mmol), BnNH2, CuI, K3PO4 (4.0 molar
equiv), additive, toluene (30 mL), 80 °C. b Molar equiv. c Isolated yield,
n.d. = not detected.
Amination of 1,3-Bistriflates 2. Our preliminary studies
revealed that 1,3-bistriflate ester 2a, upon treatment with ben-
zylamine (2.0 molar equiv) in the presence of CuI (4.0 molar
equiv) and K3PO4 (4.0 molar equiv) in toluene at 80 °C, gave
benzylamino ester 7a in 73% yield (Scheme 1 and entry 1 in
Table 1), whereas a similar treatment of sulfur-bridged analogue
2b afforded benzylamino ester 7b up to 43% yield along with a
number of byproducts (vide infra).13 Therefore, we decided to
explore the benzylamination of 2a, starting from these reaction
conditions. We have found that reducing the amount of CuI (1.2
molar equiv) gives not only benzylamino ester 7a but also
bis(benzylamine) 8, the latter of which has not been obtained
under the reaction conditions tested in the preliminary experi-
ments (entry 2). In addition, the reaction proceeded even by
using a catalytic amount (0.1 molar equiv) of CuI (entry 3); the
product distribution between monoamine 7a and diamine 8
shifted toward diamine 8, indicating that a decreased amount of
CuI favors the formation of diamine 8. This suggests that the
amination of benzylamino ester 7a is impeded by an excess of
CuI, with which 7a forms an unfavorable complex for the
subsequent amination (vide infra). Increasing the amount of
benzylamine had no effect on the product distribution (entry 4).
It has been reported that the addition of coordinative additives
often accelerates catalytic Ullmann-type reactions.14 We were
pleased to know that the addition of ethylene glycol (EG)17
facilitated the amination (entry 5). Increasing the molar equiv-
alences of EG and benzylamine improved the yield of bis-
(benzylamine) 8 up to 80% at the expense of benzylamino
Scheme 2a
a Reagents and conditions: (a) BnNH2, CuI, K3PO4, additive, toluene,
80 °C. See Table 2 for details.
ester 7a (entries 6-8). On the other hand, benzylamino ester
7a could also be selectively prepared under both stoichiometric
and catalytic conditions by quenching the reaction immediately
after the disappearance of the substrate spot in the TLC plate
(entries 9-11). This indicates that bistriflate 2a is aminated
much faster than the resulting benzylamino ester 7a. Interest-
ingly, addition of bpy18 afforded benzylamino ester 7a in a
shorter reaction period (entry 12). However, a long reaction
with bpy did not produce bis(benzylamine) 8 in a satisfactory
amount (entry 13), which could be attributed to the migrating
tendency of the ester Tf moieties of calixarenes with the help of
pyridine-type base.19
Scheme 1a
The amination of sulfur-bridge containing 1,3-bistriflate ester
2b was more complex than the methylene-bridged counterpart
2a (Scheme 2 and Table 2). Bistriflate 2b was first aminated under
the best conditions developed in the preliminary experiments,13
using benzylamine (1.2 molar equiv), CuI (2.2 molar equiv),
a Reagents and conditions: (a) BnNH2, CuI, K3PO4, additive, toluene,
80 °C. See Table 1 for detail.
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Table 2. Amination of 1,3-Bistriflate 2ba
yield (%)c
CuIb additive (equiv)b time (h) 7b anti-7b
9
10b
11
sub total 12 13 14b 1b
15
2b
total
b
entry BnNH2
1d
2d
3
1.2
1.2
2.4
4.0
2.4
2.4
2.4
2.2
1.2
1.2
1.2
0.5
0.5
0.5
10
12
6
39
45
43
42
26
17e
23e
6
trace
trace
16
1
3
49
53
67
56
37
17e
31e
12 10
6
8
n.d.
n.d.
n.d.
5
1
83
92
6
1
3
1
1
14
4
9
7
6
3
5
2
3
4
10
12
34
trace
2
90
4
5
4
10
trace trace
2
n.d. trace
78
5
5
2
9
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
7
18
trace n.d.
99
6
bpy (0.5)
EG (0.5)
5
n.d.
n.d.
8e
6e n.d.
3e n.d.
64e 11e n.d.
46e 20e n.d.
n.d.
98e
100e
7
3
n.d.
n.d.
a Reaction conditions: 2b (1.02 mmol), BnNH2, CuI, K3PO4 (4.0 molar equiv), additive, toluene (30 mL), 80 °C. b Molar equiv. Isolated yield
c
otherwise noted. d K3PO4 (2.0 molar equiv) was employed. e Determined by 1H NMR analysis.
and K3PO4 (2.0 molar equiv) (entry 1). The reaction was
quenched as soon as most of the substrate disappeared by
monitoring on TLC, in order to minimize the loss of benzyla-
mino ester 7b by side reactions. Purification of the reaction
mixture by crystallization, combined with chromatography (see
the Experimental Section), allowed us to isolate benzylamino
ester 7b (39%), 1,2-bistriflate 12 (12%), and bis(phenoxathiine)
1520 (5%) in almost the same yields as reported before. The
formation of 1,2-bistriflate 12 is attributed to the intramolecular
rearrangement of 1,3-bistriflate 2b, whereas bis(phenoxathiine)
15 by the Ullmann condensation (Ullmann biaryl ether syn-
thesis).14 It has been reported from our laboratory that the
intramolecular rearrangement of 2b with Hunig’s base in DMSO
at 60 °C proceeded quantitatively to afford 12.19 In addition to
these compounds, we isolated and fully characterized monoami-
nated products anti-7b, 9, 10b, and 11, reduced product 13,
monotriflate 14b, as well as the recovery of substrate 2b; the total
yield of identified products amounted to 83%. Decreasing the
amount of CuI to 1.2 molar equiv somewhat simplified the
reaction system, as evidenced by TLC analysis, and improved the
yield of benzylamino ester 7b to 45% (entry 2). While keeping
the amount of CuI at 1.2 molar equiv, increasing the amount of
benzylamine to 2.4 molar equiv promoted detriflation (entry 3).
However, a shortened reaction time was observed in this case.
We believe that the amination was accelerated and could sup-
press other copper-mediated reactions (i.e., intramolecular ether-
ification and reduction), as well as the intramolecular migration
of a Tf moiety, to improve the subtotal yield of monoaminated
products (67%). Further increase in the amount of benzylamine
lowered the overall yield of products (entry 4), suggesting that an
excess of benzylamine induces the production of unidentified
compounds. The use of a catalytic amount of CuI (0.5 molar
equiv), either by itself or in combination with EG or bpy, resulted
in the preferential formation of monotriflate 14b and tetraol 1b
(entries 5-7). Comparison of the subtotal yield of monoami-
nated compounds with the molar equivalence of CuI employed
reveals that CuI serves as a stoichiometric reagent in the
amination of bistriflate 2b. As mentioned so far, it was difficult
to selectively convert 1,3-bistriflate 2b into benzylamino triflate
7b because of the marked tendency of these thiacalix-based
compounds to cause the migration and elimination of Tf
moieties, in addition to the tendency of 2b to undergo intramo-
lecular cyclization and 7b to undergo debenzylation. However,
we could readily obtain deprotected amino triol 4b in a synthe-
tically useful yield by subjecting the crude reaction mixture to
hydrolysis without purification (vide infra).
Scheme 3a
a Reagents and conditions: (a) BnNH2 (1.2 molar equiv), CuI (2.2
molar equiv), K3PO4 (2.0 molar equiv), H2O (0.5 molar equiv), DMSO,
80 °C; (b) concd HCl, dioxane, 100 °C; (c) NaOH, H2O, THF-EtOH,
reflux.
To gain insights into the reaction mechanism, we attempted
the amination of the 2,4-dimethoxy derivative (16) of 1,3-
bistriflate 2b, with the intention of preventing the intramolecular
side reactions. The reaction carried out under the same condi-
tions as employed in entry 3 with an exception of reaction time
(24 h) resulted in the recovery of starting ester 16 (99%). This
suggests that a hydroxy group adjacent to the TfO moiety that is
to undergo the amination participates in the reaction. Similar
treatment of monotriflate 14b, as well as 1,2-bistriflate 12, did not
afford aminated products; monotriflate 14b was recovered al-
most unchanged (92%), while 1,2-bistriflate 12 was detriflated to
give monotriflate 14b (60%) with the recovery of 12 (29%). This
observation, in combination with the others made in the amida-
tion of varying substrates (vide infra), may indicate that the
amination, as well as the amidation, does not take place in mono-
and bistriflated calixarenes that contain two underived phenolic
hydroxy groups adjacently.
In the amination of bistriflate 2b, the desired 1,3-bis-
(benzylamine) was not obtained. Then, we explored the possi-
bility of further amination of benzylamino ester 7b (Scheme 3).
The treatment of 7b with benzylamine (1.2 molar equiv) in
DMSO in the presence of CuI (2.2 molar equiv) and K3PO4 (2.0
molar equiv) gave a complex mixture, in which deprotected
diamine 5b was detected by TLC analysis by the comparison of
its elution behavior with that of an authentic sample. This implies
the presence of 1,3-bis(benzylamine) and its monodebenzylated
compound; however, they could not be isolated because of the
complexity of the reaction mixture. Therefore, the mixture
was directly subjected to debenzylation (vide infra) without
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The Journal of Organic Chemistry
ARTICLE
purification to obtain diamine 5b (Scheme 3). It should be noted
that the yield of 5b varied with each run carried out under the
same reaction conditions. We found that a trace amount of
incidental water affected the reproducibility of the amination and
that an active addition of water (0.5-1.0 molar equiv) repeatedly
gave 5b in 16-19% yields.21
recovery of starting ester 2b (30%) (Scheme 4 and entry 1 in
Table 3). On the other hand, changing the solvent to DMSO
gave a complex mixture, from which the desired bis(tosylamide)
17b (20%), as well as tosylamino ester 18b (3%), its regioisomer
19 (3%), and compound 20 (11%) generated by the detriflation
of 18b, could be isolated (entry 2). The comparison of the yield
of diamide 17b (20%) with the sum of the yields of monoamides
18b, 19, and 20, which amounts to 17%, indicates that the
displacement of the TfO moiety of tosylamino ester 18b
proceeds rather smoothly. The reaction mixture also contained
bis(phenoxathiine) 15 (24%), together with the reduced product
13 (3%) and monotriflate 14b (1%). The yield of bis-
(tosylamide) 17b was improved to 30% when DMF was used
as a solvent (entry 3). We then examined the amidation in DMF
with varying amounts of tosylamide and CuI. Increasing the
amount of tosylamide to 4.0 molar equiv improved the yield of
tosylamino ester 18b (15%) (entry 4), which was further
increased to 19% when the amount of CuI was increased to 4.0
molar equiv (entry 5). Even after extending the reaction time to
48 h, however, the tosylamino ester 18b could not be converted
into bis(tosylamide) 17b (entry 6). On the other hand, decreas-
ing the amount of CuI to 1.0 molar equiv, with the intention of
using CuI as a catalyst, resulted in increasing the yields of
detriflated products 14b (13%) and 20 (5%), in addition to
producing thiacalixarene 1b (12%), at the expense of the forma-
tion of bis(tosylamide) 17b (13%) and tosylamino ester 18b
(3%) (entry 7). The addition of EG did not affect the product
distribution (entry 8).
Amidation of 1,3-Bistriflates 2. We reasoned that the
displacement of the two TfO moieties of the 1,3-bistriflate ester
(2b) of thiacalixarene 1b might be realized if sulfonamides or
carboxamides were employed as nucleophiles. These nucleo-
philes could avoid the formation of undesired copper complexes
during the course of the second amidation step due to the weaker
coordination ability of amide groups compared to the benzyla-
mino group (vide infra). Another advantage of employing amides
as nucleophiles was the improved stability of amide groups under
the reaction conditions when compared to the benzyl amino
group. In fact, the elimination of the benzyl moiety from
benzylamino ester 7b during the amination increases the com-
plexity of the reaction system (vide supra). The reaction of
bistriflate 2b with tosylamide (2.4 molar equiv), carried out in the
presence of CuI (2.2 molar equiv) and K3PO4 (4.0 molar equiv)
in toluene at 80 °C for 24 h, resulted in the formation of 1,2-
bistriflate 12 (22%) and monotriflate 14b (41%) with the
Scheme 4a
The conditions employed in entry 3 in Table 3 were extended
to other amide reagents in order to explore the effect of
nucleophiles on the formation of diamides. Various amide
reagents successfully used in our study are shown in Scheme 5.
p-Methoxybenzenesulfonamide, containing an electron-donat-
ing methoxy group, afforded the corresponding diamide 21 in the
same yield (30%) as that of bis(tosylamide) 17b (entry 3),
whereas p-nitrobenzenesulfonamide bearing an electron-with-
drawing nitro group afforded diamide 22 in a reduced yield
(20%), presumably due to the decrease in nucleophilicity of the
corresponding amidate. A similar tendency was observed for
alkylsulfonamides; methanesulfonamide afforded diamide 23
(28%), while trifluoromethanesulfonamide did not yield dia-
mide. Benzylamide and trifluoroacetamide, the amidate ions of
which are more nucleophilic than those of sulfonamides, did not
yield amidated products. A plausible explanation for this is that
a Reagents and conditions: (a) TsNH2, CuI, K3PO4, additive, solvent,
80 °C. See Table 3 for details.
Table 3. Amidation of 1,3-Bistriflate 2b with Tosylamidea
yield (%)c
b
entry
TsNH2
CuIb
additive (eq)b
solvent
17b
18b
19
20
12
22
13
14b
15
2b
total
1
2
3
4
5
6d
7
8
2.4
2.4
2.4
4.0
4.0
4.0
2.4
2.4
2.2
2.2
2.2
2.2
4.0
4.0
1.0
1.0
toluene
DMSO
DMF
DMF
DMF
DMF
DMF
DMF
n.d.
20
30
29
31
32
13
12
n.d.
3
n.d.
3
n.d.
11
n.d.
3
41
1
trace
24
30
93
65
82
89
86
83
77e
74e
n.d.
n.d.
n.d.
n.d.
n.d.
trace
trace
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
4
5
2
2
3
36
15
19
13
3
6
n.d.
n.d.
n.d.
5
4
n.d.
1
35
5
7
23
7
8
1
22
8
4
13
7
19
EG (1.0)
1
5
11
4
22
a Reaction conditions: 2b (1.02 mmol), TsNH2, CuI, K3PO4 (4.0 molar equiv), additive, solvent (30 mL), 80 °C, 24 h. b Molar equiv. c Isolated yield.
d The reaction time was extended to 48 h. e 1b (12%) was also isolated.
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ARTICLE
Scheme 5a,b
Table 4. Amidation of 1,3-Bistriflate 2aa
yield (%)c
entry TsNH2 CuIb additive (equiv)b 17a 18a 26 27 14a
b
1
2
3
4
5
6
7
2.4
4.0
4.0
2.4
2.4
2.4
2.4
2.2
2.2
4.0
1.0
0.1
0.1
0.1
33 16 16
38 19 10 13 trace
45 12 11 trace
30 14 10 10 trace
9
trace
4
3
2
4
53 n.d. n.d. 23
50 n.d. n.d. 20
59 n.d. n.d. 11
EG (1.0)
bpy (0.1)
a Reaction conditions: 2a (0.548 mmol), TsNH2, CuI, K3PO4 (4.0
molar equiv), additive, DMF (15 mL), 80 °C, 24 h. b Molar equiv.
c Isolated yield otherwise noted.
a Reagents and conditions: (a) RNH2 (2.4 molar equiv), CuI (2.2 molar
equiv), K3PO4 (4.0 molar equiv), DMF, 80 °C. b Abbreviations: AN = p-
methoxyphenyl; Ns = p-nitrophenylsulfonyl.
Scheme 7a
Scheme 6a
a Reagents and conditions: (a) TsNH2, CuI, K3PO4, DMF, 80 °C. See
Table 4 for details.
We found that methylene-bridged bistriflate 2a was also
diamidated (Scheme 7 and Table 4). Bistriflate 2a, on treatment
with tosylamide under the standard conditions, afforded the
desired bis(tosylamide) 17a (33%), along with tosylamino ester
18a (16%), and its reduced and iodinated compounds 26 (16%)
and 27 (9%) (entry 1).22 The yield of 17a was improved to 45%
by increasing the molar equivalences of tosylamide and CuI (4.0
molar equiv each) (entry 3). On the other hand, decreasing the
amount of CuI (0.1 molar equiv) resulted in the formation of
detriflated compound 14a (entry 5), as observed in the amida-
tion of sulfur-bridged analogue 2b with a reduced amount of CuI
(1.0 molar equiv) (entry 7 in Table 3). In addition to this, it
markedly changed the product ratio between bis(tosylamide)
17a and tosylamino ester 18a in favor of the latter; the compar-
ison of the crop of 18a (53%, 290 μmol) with the amount of CuI
employed (54.8 μmol) indicates that the first amidation of
bistriflate 2a to 18a proceeds catalytically. However, tosylamino
ester 18a could not be converted into bis(tosylamide) 17a even
after adding EG or bpy (entries 6 and 7).
a Reagents and conditions: (a) TsNH2 (2.4 molar equiv), CuI (2.2 molar
equiv), K3PO4 (4.0 molar equiv), DMF, 80 °C.
carboxamides are not acidic enough to be efficiently deproto-
nated under the reaction conditions.
As in the case of amination, the reaction of the 2,4-dimethoxy
derivative (16) of bistriflate 2b with tosylamide, carried out under
the standard conditions, recovered the starting ester, suggesting the
participation of the hydroxy group in the amidation (vide supra).
Under the same conditions, neither monotriflate 14b nor 3-amino
triflate 10b produced amidated compounds; monotriflate 14b was
recovered almost unchanged, while 3-amino triflate 10b underwent
Tf migration, as well as detriflation, to afford 2-amino triflate 11
(48%) and amino triol 4b (42%) (Scheme 6). These results, as
discussed in the amination, suggest that two hydroxy groups, as well
as a hydroxy and an aminogroup, residingadjacently on a substrate,
disturb the displacement of a TfO moiety with a nitrogen
nucleophile (vide supra). In fact, monotriflate 14b, once the
3-hydroxy group was capped with a benzyl moiety, underwent
the amidation to give the corresponding monoamide25 (18%) and
its debenzylated derivative 20 (11%) (Scheme 6).
Mechanistic Consideration. Before discussing the reaction
mechanisms of the amination and amidation carried out in this
study, we would like to briefly mention the stereochemistry of the
products. In calixarene chemistry, it is common knowledge that
the two propyl groups on the phenolic oxygens of 1,3-di-
O-alkylated calix[4]arenes are bulky enough to prevent the
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ARTICLE
interconversion between their conformational isomers originat-
ing from the syn and anti arrangements of the two alkoxy groups
with respect to the mean plane defined by the macrocycle.23 On
the basis of this fact, it is readily conceivable that benzylamino
ester 7a, bis(benzylamine) 8, bis(tosylamide) 17a, and tosyla-
mino ester 18a should have stereoisomers among the products
Scheme 8
1
derived from methylene-bridged bistriflate 2a. In the H NMR
spectrum of a methylene-bridged calix[4]arene, the chemical
shift difference (Δδ) between a pair of geminal methylene
protons is known to vary depending on its stereostructure.24
Above all, the cone isomer of a compound can be readily
differentiated from other isomers as its Δδ values for all the
methylene protons lie within 0.9-0.5 ppm in nonpolar solvents.
The Δδ values of all the methylene protons of the above-
mentioned compounds in CDCl3 fall within the range of
0.76-0.49 ppm, indicating that they adopt cone conformation
(that is, they are syn stereoisomers).25 This means that bistriflate
2a, adopting syn form,7a was stereospecifically converted into
these compounds by the Ullmann-type reactions. On the other
hand, it is difficult to determine the stereochemistry of thiacalix-
[4]arenes because of the lack of NMR structural information
from the bridging moieties. However, based on X-ray crystal-
lography, benzylamino ester 7b and bis(tosylamide) 17b, as well
as staring bistriflate 2b, could be designated as syn stereoisomers
1
(see the Supporting Information). The H NMR spectrum of
anti-7b exhibited three singlets with the integrated intensity
values of 9H, 9H, and 18H, respectively, for the tert-butyl
protons, one singlet for the methylene protons (2H), one
multiplet (5H) for the aryl protons of the benzyl moiety, two
doublets (2H each) and two singlets (2H each) for the aryl
protons of the calixarene skeleton, and one broad signal for the
amino proton; the magnetic equivalence suggests a Cs-symmetric
structure in which the benzylamino and TfO moieties are in the
σ-plane, that is, syn- or anti-1,3-disubstituted compound. This
observation, combined with the fact that the spectrum is different
from that of authentic 7b of syn form, allowed us to assign anti-7a.
The stereochemistry of 1,2-bistriflate 12 was already established
as syn.19 We could not determine the stereochemistry of other
thiacalixarene derivatives, but it did not hinder our goals of
obtaining deprotected amines 4b and 5b.
Scheme 8 illustrates a feasible mechanism for the amination
and amidation. Bistriflate 2 reacts with CuI with the aid of K3PO4
to produce copper phenoxide 28, the formation of which will
assist the otherwise difficult oxidative addition of an Ar-OTf
bond of the calix class compound.14,26 This also explains the
inability of the 2,4-dimethoxy derivative (16) of 1,3-bistriflate 2b
to undergo neither amination nor amidation (vide supra). The
TfO moiety of the resulting putative metallacycle 29 is replaced
with a benzylamide or tosylamidate ion to produce a new
metallacycle 30, which undergoes reductive elimination of the
Ar-N bond to give copper chelate 31. This mechanism can also
explain the difference in reactivity between methylene-bridged
bistriflate 2a and the sulfur-bridged one 2b. As mentioned above,
monotriflate 14b and 3-amino triflate 10b did not undergo
amination and/or amidation. This suggests that once two
adjacent hydroxy groups in compound 14b (hydroxy and amino
group in compound 10b) chelate to a copper ion tightly, the
resulting species has difficultly forming such a copper phenoxide
as 28 with another copper ion, using the residual hydroxy group
adjacent to the TfO moiety. This would be the case with
benzylamino esters 7, as well as tosylamino esters 18. This
means that the displacement of the second TfO moiety of
bistriflate 2 with a nitrogen nucleophile is disturbed by the
formation of such an undesired copper chelate; in other words,
the displacement of the second TfO moiety does not take place
unless copper chelate 31 formed in the first displacement
reaction dissociates in situ to give benzylamino ester 7, as well
as tosylamino ester 18. This is consistent with the observation
that decreasing the amount of CuI and/or adding a coordinative
additive facilitated the formation of diamine 8 in the amination of
methylene-bridged calixarene 2a. It is readily conceivable that the
dissociation of the copper chelate 31 formed from thiacalixarene
2b is more difficult than that of 31 formed from calixarene 2a
because the former copper chelate should adopt a stable five-
membered bischelate structure by the additional coordination of
the sulfur atom interposed between the amino or amide group
and an adjacent hydroxy group. Such a five-membered bischelate
structure is often found in metal complexes of thiacalixarene
1b.27 In the case of the amidation of 2b, the initially introduced
amide group that has a weaker coordination ability than the
amino group will be able to dissociate from copper chelate 31
with the assistance of the polar aprotic solvent, which appears to
be responsible for the realization of the second amidation.
However, in the amidation of methylene-bridged calixarene 2a,
an excess amount of CuI favored diamide 17a. Although the
reason is not clear at present, considering the fact that the
monoamidation of 2a proceeds catalytically, high loading of
CuI seems to have diminished a certain difficulty that arose in
the second amidation, against the likelihood that high loading
will retard the second amidation by stabilizing copper chelate 31.
The syn-stereospecificity of the amination and amidation
agrees with this reaction mechanism as the TfO and RNH
ligands in metallacycles 29 and 30, as well as those in the cor-
responding metallacycles in the second TfO displacement, are
apparently bulky enough to prevent the syn-anti isomerization via
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Scheme 9a
difference in reactivity between the calix- and thiacalixarenes is
not clear at present, we believe that the epithio linkage may assist
the protonation of the amino group in the case of 7b, forming a
hydrogen bond between NH and S.9
The hydrolysis of tosylamides generally requires a strong acid.
We have found that H2SO4 is efficient for the deprotection of
bis(tosylamide) 17b. Upon refluxing with H2SO4 in acetic acid,
diamine 5b was obtained in 94% yield (Scheme 9). On the other
hand, methylene-bridged counterpart 17a resisted hydrolysis
under the conditions and the starting material was recovered
almost unchanged (86%). We then explored the possibility to
reductively remove the tosyl moieties of 17a. It is known that
SmI2 is one of the most efficient reductants for tosyl amides and
the reduction is generally carried out in refluxing THF in the
presence of DMPU or HMPA.28 Recently, Ankner and Hilmers-
son reported that the combination of SmI2 with an amine and
water is powerful in reducing tosyl amides at room
temperature.28b This method could be successfully applied to
bis(tosylamide) 17a, giving diamine 5a in 88% yield (Scheme 9),
whereas a similar treatment of sulfur-bridged counterpart 17b
gave diamine 5b in a poor yield (17%).
a Reagents and conditions: (a) H2, Pd/C, EtOH, 60 °C; (b) NaOH,
H2O, THF-EtOH, reflux; (c) concd HCl, AcOH, reflux; (d) SmI2,
H2O, pyrrolidine, THF, rt; (e) concd H2SO4, H2O, AcOH, reflux.
’ EXPERIMENTAL SECTION
General. Melting points were taken with a micro melting point
apparatus and are uncorrected. 1H and 13C NMR spectra were measured
with tetramethylsilane as an internal standard and CDCl3 as a solvent.
Silica gel (63-200 μm) was used for column chromatography and TLC.
Water- and air-sensitive reactions were routinely carried out under
nitrogen. Toluene was distilled from sodium diphenyl ketyl. DMF,
DMSO, benzylamine, and EG were distilled from calcium hydride.
Acetone was distilled from CaSO4. Bistriflate 2a was prepared according
to the literature procedure.7a
the oxygen-through-the-annulus rotation.23 The exceptional
formation of anti-7b can be rationalized by the detriflation of
benzylamino ester 7b to trisphenol 9, followed by the triflation of
9 at the resulting hydroxy group from the side opposite to the
benzylamino moiety with respect to the mean plane defined by
the macrocycle. Alternatively, it might proceed via the initial
isomerization of bistriflate 2b to the anti isomer by the detrifla-
tion-triflation sequence, followed by benzylamination.
5 11,17,23-Tetra-tert-butyl-26,28-dihydroxy-2,8,14,20-
tetrathiapentacyclo[19.3.1.13,7.19,13.115,19]-octacosa-1(25),
3,5,7(28),9,11,13(27),15,17,19(26),21,23-dodecaene-25,27-
diyl Bis(trifluoromethanesulfonate) (2b). To an ice-cold solu-
tion of thiacalixarene 1b (10.0 g, 13.9 mmol) and pyridine (d = 0.983;
6.7 mL, 83.3 mmol) in dichloromethane (160 mL) was added dropwise
trifluoromethanesulfonic anhydride (d = 1.719; 6.8 mL, 41.4 mmol)
with stirring. The mixture was allowed to warm to room temperature and
stirred for 3 h. The reaction was quenched with 2 M HCl (200 mL) and
the resulting mixture was extracted with chloroform. The extract was
washed with water, dried over MgSO4, and evaporated. The residue was
crystallized from methanol-dichloromethane to give 1,3-bistriflate 2b
(10.1 g). On the other hand, the mother liquid was evaporated and the
residue was purified by column chromatography with hexane-chloro-
form (1:1) as an eluent to give an additional crop of 2b (1.56 g) for a total
yield of 11.7 g (85%) as a colorless powder: mp 296.0-298.0 °C dec; IR
(KBr) 3460, 2966, 1427, 1211, 1138, 1065 cm-1; 1H NMR (400 MHz)
δ 0.92 (s, 18H), 1.34 (s, 18H), 6.12 (s, 2H), 7.16 (s, 4H), 7.74 (s, 4H);
13C NMR (100 MHz) δ 30.7, 31.4, 34.3, 34.5, 121.0, 128.8, 133.4, 134.9,
143.8, 147.7, 151.5, 155.4; MS (FAB) m/z 984 Mþ. Anal. Calcd for
C42H46F6O8S6: C, 51.20; H, 4.71; S, 19.53. Found: C, 51.01; H, 4.71;
S, 19.82.
Deprotection of Benzylamines 7 and 8 and Tosylamides
17 to Mono- and Diamines 4 and 5. In our previous
communication,13 we reported that the benzyl moiety of benzy-
lamino ester 7a, as well as that of 7b, could be removed by a three-
step process,9,10 that is, the initial bromination of a benzylamino-
substituted calixarene with NBS and BPO, followed by sponta-
neous dehydrobromination to the corresponding imine, and
subsequent acid hydrolysis to give the desired deprotected
amine. However, the yields of amino esters 10a and 10b were
moderate (69% and 50%, respectively). We have found that a
simple hydrogenolysis of 7a affords 10a with improved yield
(89%) (Scheme 9). The alkaline hydrolysis of the resulting
amino ester 10a furnished amino triol 4a. Bis(benzylamine) 8
could also be deprotected by hydrogenolysis to afford diamine 5a
quantitatively. On the other hand, the benzyl moiety of sulfur-
bridged benzylamino ester 7b was found to be removed by
simply refluxing in concd HCl and acetic acid (Scheme 9). As the
acid treatment was accompanied by the formation of a small
amount of detriflated amine 4b, the crude mixture was subjected
to alkaline hydrolysis without purification to give 4b in 93% yield.
This process could be advantageously utilized to merge mono-
aminated compounds generated by the amination of bistriflate
2b as 4b (vide supra). Thus, bistriflate 2b was benzylaminated
under the same conditions as those employed in entry 3 in
Table 2 to afford amino triol 4b in 53% yield. In contrast,
methylene-bridged benzylamino ester 7a resisted acid hydrolysis.
The cleavage of an N-C linkage should happen via the proton-
ation of the benzylamino group. Although the reason for the
Typical Procedure for the Amination of 1,3-Bistriflate 2a
(Entry 8 in Table 1). To a suspension of bistriflate 2a (1.00 g, 1.10
mmol), CuI (21.5 mg, 0.113 mmol), and K3PO4 (930 mg, 4.38 mmol) in
toluene (30 mL) were added benzylamine (d = 0.981; 479 μL, 4.39
mmol) and EG (d = 1.11; 183 μL, 3.27 mmol), and the mixture was
stirred at 80 °C for 24 h. After cooling, most of the solvent was
evaporated and the residue was dissolved by the addition of saturated
aqueous NH4Cl and chloroform. After the two layers were separated, the
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ARTICLE
aqueous layer was extracted with chloroform, and the combined organic
layer was washed successively with 2 M HCl and water, dried over
MgSO4, and evaporated. The residue was purified by column chromato-
graphy with chloroform-hexane (3:1) as an eluent to give bis(benzy-
lamine) 8 (728 mg, 80%) and benzylamino ester 7a (13.1 mg, 1%).
The same reaction, carried out at 80 °C for 10 min by using reduced
amounts of benzylamine (287 μL, 2.63 mmol) and EG (61.1 μL, 1.09
mmol), gave benzylamino ester 7a (827 mg, 87%), after chromatographic
purification with chloroform-hexane (2:1) as an eluent (entry 11).
27-Benzylamino-5,11,17,23-tetra-tert-butyl-26,28-dihydro-
xypentacyclo[19.3.1.13,7.19,13.115,19]octacosa-1(25),3,5,7(28),
9,11,13(27),15,17,19(26),21,23-dodecaene-25-yl Trifluoromet-
hanesulfonate (7a): colorless powder, mp 120.0-122.0 °C; IR
(KBr) 3584, 3526, 3329, 2955, 1462, 1396, 1362, 1207, 1138,
Anal. Calcd for C48H54F3NO5S5: C, 61.18; H, 5.78; N, 1.49; S, 17.01.
Found: C, 61.42; H, 5.77; N, 1.48; S, 16.80.
27-Benzylamino-5,11,17,23-tetra-tert-butyl-26,28-dihydro-
xy-2,8,14,20-tetrathiapentacyclo[19.3.1.13,7.19,13.115,19]oct-
acosa-1(25),3,5,7(28),9,11,13(27),15,17,19(26),21,23-dode-
caene-25-yl trifluoromethanesulfonate (anti-7b): colorless
powder, mp 237.0-239.0 °C; IR (KBr) 3442, 2964, 2360, 1457,
1
1412, 1212, 1126, 868, 668 cm-1; H NMR (400 MHz) δ 1.02 (s,
9H), 1.27 (s, 9H), 1.28 (s, 18H), 4.20 (s, 2H), 7.29-7.38 (m, 5H), 7.47
(d, 2H, J = 2.4 Hz), 7.49 (d, 2H, J = 2.4 Hz), 7.50 (s, 2H), 7.64 (s, 2H),
7.82 (br, 1H); 13C NMR (100 MHz) δ 30.7, 30.2, 31.3, 34.2, 34.5, 34.6,
57.1, 120.0, 122.0, 127.8, 128.6, 128.8, 129.1, 129.1, 131.1, 131.8, 133.5,
135.8, 137.8, 143.0, 147.1, 148.8, 149.8, 151.8, 154.5; MS (FAB) m/z
941 Mþ; HRMS (ESI) calcd for C48H54F3NNaO5S5 (M þ Na)þ
964.2455, found 964.2450.
1
1072 cm-1; H NMR (400 MHz) δ 0.89 (s, 9H), 1.06 (s, 9H), 1.27
(s, 18H), 3.45 (d, 2H, J = 13.9 Hz), 3.48 (d, 2H, J = 13.9 Hz), 3.94 (d,
2H, J = 13.9 Hz), 4.13 (s, 2H), 4.24 (d, 2H, J = 13.9 Hz), 6.81 (s, 2H),
6.93 (s, 2H), 7.05 (d, 2H, J = 2.4 Hz), 7.14 (d, 2H, J = 2.4 Hz), 7.29-7.38
(m, 5H); 13C NMR (100 MHz) δ 30.7, 31.0, 31.6, 32.8, 33.9, 34.0, 34.0,
34.8, 56.3, 125.3, 125.7, 125.7, 127.3, 127.3, 127.6, 127.7, 127.8, 128.7,
133.1, 134.6, 138.4, 138.9, 141.5 142.5, 147.7, 150.2, 150.8; MS (FAB)
m/z 869 Mþ. Anal. Calcd for C52H62F3NO5S: C, 71.78; H, 7.18; N,
1.61. Found: C, 71.68; H, 7.15; N, 1.48.
26,28-Bis(benzylamino)-5,11,17,23-tetra-tert-butylpenta-
cyclo[19.3.1.13,7.19,13.115,19]octacosa-1(25),3,5,7(28),9,11,
13(27),15,17,19(26),21,23-dodecaene-25,27-diol (8): color-
less powder, mp 254.0-256.0 °C; IR (KBr) 3267, 2963, 1594, 1480,
1452, 1308, 1208, 872, 696 cm-1; 1H NMR (500 MHz) δ 1.18 (s, 18H),
1.19 (s, 18H), 3.30 (d, 4H, J = 13.3 Hz), 3.96 (d, 4H, J = 13.3 Hz), 4.04
(s, 4H), 6.93 (s, 4H), 7.03 (s, 4H), 7.31-7.39 (m, 10H), 10.75 (s, 4H);
13C NMR (100 MHz) δ 31.6, 31.9, 34.1, 34.5, 35.0, 56.9, 125.5, 126.2,
128.0, 128.2, 129.0, 129.5, 137.4, 137.8, 138.3, 141.9, 148.5, 150.7; MS
(FAB) m/z 827 (M þ H)þ; HRMS (ESI) calcd for C58H70N2NaO2
(M þ Na)þ 849.5335, found 849.5330.
28-Benzylamino-5,11,17,23-tetra-tert-butyl-2,8,14,20-tet-
rathiapentacyclo[19.3.1.13,7.19,13.115,19]octacosa-1(25),3,5,
7(28),9,11,13(27),15,17,19(26),21,23-dodecaene-25,26,27-
triol (9): colorless powder, mp 287.2-288.0 °C; IR (KBr) 3239, 2963,
2905, 2867, 1456, 1260, 1245, 890, 746 cm-1; 1H NMR (400 MHz) δ
1.21 (s, 27H), 1.23 (s, 9H), 4.48 (s, 2H), 7.40-7.43 (m, 1H), 7.46-7.50
(m, 2H), 7.57 (d, 2H, J = 2.5 Hz), 7.61 (s, 2H), 7.63-7.68 (m, 2H), 7.65
(d, 2H, J = 2.5 Hz), 7.73 (s, 2H); 13C NMR (100 MHz) δ 31.0, 31.3,
31.3, 34.1, 34.2, 34.5, 57.7, 120.6, 120.9, 121.0, 128.1, 128.8, 129.2, 130.9,
136.1, 136.1, 136.2, 136.8, 136.9, 143.5, 144.0, 148.1, 150.2, 156.3, 157.3;
MS (FAB) m/z 810 (M þ H)þ; HRMS (ESI) calcd for C47H56NO3S4
(M þ H)þ 810.3143, found 810.3138.
27-Amino-5,11,17,23-tetra-tert-butyl-26,28-dihydroxy-2,-
8,14,20-tetrathiapentacyclo-[19.3.1.13,7.19,13.115,19]octacosa-
1(25),3,5,7(28),9,11,13(27),15,17,19(26),21,23-dodecaene-25-yl
trifluoromethanesulfonate (10b): colorless powder, mp 252.0-
254.0 °C; IR (KBr) 3472, 2963, 1454, 1427, 1204, 1138 cm-1; 1H NMR
(400 MHz) δ 0.72 (s, 9H), 1.09 (s, 9H), 1.32 (s, 18H), 6.95 (s, 2H), 7.38
(s, 2H), 7.67 (d, 2H, J = 2.5 Hz), 7.68 (d, 2H, J = 2.5 Hz); 13C NMR (100
MHz) δ 30.5, 31.0, 31.4, 34.0, 34.2, 34.2, 120.3, 121.0, 121.5, 121.6,
129.9, 132.1, 134.1, 134.5, 135.2, 143.3, 144.4, 147.1, 131.1, 155.3; MS
(FAB) m/z 851 Mþ. Anal. Calcd for C41H48F3NO5S5: C, 57.79; H, 5.68;
N, 1.64. Found: C, 57.68; H, 5.57; N, 1.57.
Typical Procedure for the Amination of 1,3-Bistriflate 2b
(Entry 3 in Table 2). To a suspension of bistriflate 2b (1.00 g, 1.02
mmol), CuI (234 mg, 1.23 mmol), and K3PO4 (863 mg, 4.07 mmol) in
toluene (30 mL) was added benzylamine (d = 0.981; 266 μL, 2.44
mmol), and the mixture was stirred at 80 °C for 6 h and worked up as
before. The resulting mixture was crystallized from methanol-dichlor-
omethane, and the precipitate was collected by filtration and chromato-
graphed on a silica gel column with hexane-chloroform (1:1) as an
eluent to give benzylamino ester 7b (315 mg, 33%) and its detriflated
compound 9 (135 mg, 16%). The filtrate contained a number of
compounds, which could not be separated by column chromatography.
Therefore, one-fifth portion of the filtrate was purified by TLC with
hexane-chloroform (1:1) as a developer, which isolated anti-7b (6.7
mg, 4%), 1,2-bis(triflate) 12 (7.8 mg, 4%), reduced product 13 (11.6 mg,
7%), monotriflate 14b (16.6 mg, 10%), bis(phenoxathiine) 15 (2.4 mg,
2%), and an additional crop of 7b (20 mg, 43% in total); yields (%) are
given as 5-fold values of the crops. Also obtained was a mixture of
debenzylated product 10b (6.0 mg, 3%) and its regioisomer 11 (2.3 mg,
1%), which could be separated into each component by TLC with
hexane-ethyl acetate (6:1) as a developer.
27-Benzylamino-5,11,17,23-tetra-tert-butyl-26,28-dihydro-
xy-2,8,14,20-tetrathiapentacyclo[19.3.1.13,7.19,13.115,19]oct-
acosa-1(25),3,5,7(28),9,11,13(27),15,17,19(26),21,23-dode-
caene-25-yl trifluoromethanesulfonate (7b): colorless powder,
mp 241.0-243.0 °C; IR (KBr) 3425, 3283, 2963, 1450, 1427, 1207,
1134 cm-1; 1H NMR (400 MHz) δ 0.71 (s, 9H), 1.13 (s, 9H), 1.30 (s,
18H), 4.42 (s, 2H), 6.93 (s, 2H), 7.32-7.47 (m, 5H), 7.51 (s, 2H), 7.66
(s, 4H); 13C NMR (100 MHz) δ 30.4, 30.9, 31.4, 34.1, 34.2, 34.3, 57.5,
121.4, 121.4, 127.5, 128.6, 128.6, 129.4, 130.0, 132.3, 134.7, 134.9, 136.1,
138.1, 143.0, 146.9, 148.5, 149.4, 151.2, 156.3; MS (FAB) m/z 941 Mþ.
26-Amino-5,11,17,23-tetra-tert-butyl-27,28-dihydroxy-2,
8,14,20-tetrathiapentacyclo[19.3.1.13,7.19,13.115,19]octacosa-
1(25),3,5,7(28),9,11,13(27),15,17,19(26),21,23-dodecaene-
25-yl trifluoromethanesulfonate (11): colorless powder, mp
244.0-246.0 °C; IR (KBr) 3466, 3427, 3356, 2965, 2870, 1611, 1456,
1425, 1211, 1133, 867 cm-1; 1H NMR (400 MHz) δ 0.88 (s, 9H), 1.12
(s, 9H), 1.26 (s, 9H), 1.30 (s, 9H), 7.15 (d, 1H, J = 2.4 Hz), 7.27 (d, 1H, J
= 2.4 Hz), 7.41 (d, 1H, J = 2.4 Hz), 7.46 (d, 1H, J = 2.4 Hz), 7.62 (d, 1H, J
= 2.3 Hz), 7.65 (d, 1H, J = 2.3 Hz), 7.68 (d, 1H, J = 2.4 Hz), 7.70 (d, 1H, J
= 2.4 Hz); 13C NMR (100 MHz) δ 30.6, 31.1, 31.4, 34.0, 34.1, 34.3, 34.4,
119.7, 120.1, 120.6, 120.6, 120.7, 121.0, 128.5, 129.9, 133.3, 133.9, 134.7,
135.1, 135.1, 135.7, 135.8, 135.9, 141.6, 144.0, 147.8, 147.8, 151.9, 155.4,
155.5; MS (FAB) m/z 852 (M þ H)þ; HRMS (ESI) calcd for
C41H48F3NNaO5S5 (M þ Na)þ 874.1986, found 874.1980.
Compounds 12,19 13,20 14b,20 and 1520 are know compounds. The
NMR spectra of the samples are essentially identical with those reported
in the literature.
5,11,17,23-Tetra-tert-butyl-26,28-dimethoxy-2,8,14,20-
tetrathiapentacyclo[19.3.1.13,7.19,13.115,19]octacosa-1(25),3,
5,7(28),9,11,13(27),15,17,19(26),21,23-dodecaene-25,27-
diyl Bis(trifluoromethanesulfonate) (16). A mixture of 1,3-
bistriflate 2b (1.00 g, 1.02 mmol), iodomethane (d = 2.287; 1.26 mL,
20.3 mmol), and Cs2CO3 (3.30 g, 10.1 mmol) in acetone (30 mL) was
refluxed for 4 h. After most of the solvent was evaporated, the residue
was dissolved by the addition of 2 M HCl and chloroform. After the two
layers were separated, the aqueous layer was extracted with chloroform,
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and the combined organic layer was washed successively with 2 M
Na2SO3 and water, dried over MgSO4, and evaporated. The residue was
purified by column chromatography with hexane-chloroform (1:1) as
an eluent to give dimethyl ether 16 (896 mg, 87%) as a colorless powder,
mp 290.0-292.0 °C; IR (KBr) 2966, 1423, 1204, 1138, 999 cm-1; 1H
NMR (400 MHz) δ 1.01 (br s, 18H), 1.35 (s, 18H), 3.86 (br s, 6H), 7.23
(br s, 4H), 7.77 (br s, 4H); 13C NMR (100 MHz) δ 30.8, 31.2, 34.3, 34.5,
59.2, 114.9, 117.5, 120.0, 122.6, 129.1, 134.0, 134.3, 147.5, 150.3; MS
(FAB) m/z 1012 Mþ. Anal. Calcd for C44H50F6O8S6: C, 52.16; H, 4.97.
Found: C, 52.33; H, 4.99.
NH4Cl and extracted with chloroform. The extract was washed succes-
sively with 2 M HCl and water, dried over MgSO4, and evaporated to
leave a residue, which was suspended in hot methanol. The insoluble
part was collected by filtration and chromatographed on a silica gel
column with chloroform-ethyl acetate (1:0 to 10:1) as an eluent to give
bis(tosylamide) 17b (301 mg, 29%), bis(phenoxathiine) 15 (236 mg,
34%), tosylamino ester 18b (19.2 mg, 2.0%), its regioisomer 19 (4.9 mg,
0.5%), and detriflated tosylamide 20 (20 mg, 2%). On the other hand,
one-fifth portion of the filtrate was purified by TLC with hexane-ethyl
acetate (4:1) as a developer to give reduced product 13 (3.2 mg, 2%),
monotriflate 14b (5.2 mg, 3%), and additional crops of 17b (1.8 mg,
30% in total), 15 (3.2 mg, 36% in total), 18b (5.1 mg, 4% in total), and
19 (9.6 mg, 5% in total).
Amination of Benzylamino Ester 7b and Subsequent
Deprotection to 26,28-Diamino-5,11,17,23-tetra-tert-butyl-
2,8,14,20-tetrathiapentacyclo[19.3.1.13,7.19,13.115,19]octacosa-
1(25),3,5,7(28),9,11,13(27),15,17,19(26),21,23-dodecaene-
25,27-diol (5b). To a suspension of benzylamino ester 7b (49.7 mg,
52.7 μmol), CuI (22.1 mg, 0.116 mmol), and K3PO4 (22.0 mg, 0.104
mmol) in DMSO (3.0 mL) were added benzylamine (d = 0.981; 6.9 μL,
63 μmol) and water (0.5 μL, 28 μmol), and the mixture was stirred at
80 °C for 24 h. After cooling, the solvent was evaporated and the residue
was dissolved by the addition of saturated aqueous NH4Cl and chloro-
form. After the two layers were separated, the water layer was extracted
with chloroform, and the combined organic layer was washed with water,
dried over MgSO4, and evaporated. The residue was treated with concd
HCl (3.0 mL) in dioxane (3.0 mL) at 80 °C for 24 h. After cooling, the
mixture was neutralized with 2 M NaOH and extracted with chloroform.
The extract was washed with water and evaporated to leave a residue,
which was dissolved by the addition of THF (3.0 mL) and ethanol
(1.5 mL). To the solution were added water (1.5 mL) and NaOH (293
mg, 7.33 mmol), and the mixture was refluxed for 24 h. After cooling, the
mixture was poured into 2 M HCl (15 mL) and extracted with chloro-
form. The extract was washed with water, dried over MgSO4, and
evaporated. The residue was purified by TLC with chloroform-ethyl
acetate (30:1) as an eluent to give diamine 5b (7.2 mg, 19%) as a
colorless powder, mp 290.0-292.0 °C; IR (KBr) 3445, 3395, 3360,
2963, 1454, 1269, 1242 cm-1; 1H NMR (400 MHz) δ 1.13 (s, 18H),
1.25 (s, 18H), 7.49 (s, 4H), 7.61 (s, 4H); 13C NMR (100 MHz) δ 31.1,
31.4, 34.0, 34.1, 121.6, 123.9, 134.8, 135.4, 142.9, 145.3, 146.4, 157.2;
MS (FAB) m/z 719 (M þ H)þ; HRMS (ESI) m/z calcd for
C40H50N2NaO2S4 (M þ Na)þ 741.2647, found 741.2644.
N,N0-(5,11,17,23-Tetra-tert-butyl-26,28-dihydroxy-2,8,14,
20-tetrathiapentacyclo[19.3.1.13,7.19,13.115,19]octacosa-1-
(25),3,5,7(28),9,11,13(27),15,17,19(26),21,23-dodecaene-
25,27-diyl)bis(p-toluenesulfonamide) (17b): colorless powder,
mp 326.1-327.8 °C; IR (KBr) 3346, 3258, 2964, 1448, 1168, 1090,
676 cm-1; 1H NMR (400 MHz) δ 0.88 (s, 18H), 1.26 (s, 18H), 2.46 (s,
6H), 7.20 (s, 4H), 7.29 (d, 4H, J = 8.2 Hz), 7.42 (s, 2H), 7.57 (s, 4H),
7.58 (d, 4H, J = 8.2 Hz), 8.22 (s, 2H); 13C NMR (100 MHz) δ 21.9, 30.7,
31.5, 34.3, 34.5, 121.9, 128.1, 130.0, 133.5, 133.7, 134.1, 135.7, 136.9,
143.8, 144.3, 150.9, 155.3; MS (FAB) m/z 1027 (M þ H)þ; HRMS (ESI)
calcd for C54H62N2NaO6S6 (M þ Na)þ 1049.2830, found 1049.2824.
5,11,17,23-Tetra-tert-butyl-26,28-dihydroxy-2,8,14,20-tet-
rathia-27-(p-toluenesulfonylamino)pentacyclo[19.3.1.13,7
9,13.115,19]octacosa-1(25),3,5,7(28),9,11,13(27),15,17,19(26),-
.
1
21,23-dodecaene-25-yl trifluoromethanesulfonate (18b):
colorless powder, mp 283.5-285.2 °C; IR (KBr) 3386, 3262, 2965,
1420, 1207, 1169, 1128, 866, 685, 618 cm-1; 1H NMR (400 MHz) δ
0.75 (s, 9H), 0.95 (s, 9H), 1.31 (s, 18H), 2.45 (s, 3H), 6.69 (br s, 2H),
6.93 (s, 2H), 7.24 (s, 2H), 7.25-7.29 (m, 2H), 7.53 (d, 2H, J = 8.3 Hz),
7.65 (d, 2H, J = 2.5 Hz), 7.67 (d, 2H, J = 2.5 Hz), 8.04 (br s, 1H); 13C
NMR (100 MHz) δ 21.7, 30.5, 30.7, 31.4, 31.2, 34.3, 34.4, 120.9, 122.6,
128.0, 129.2, 129.8, 132.4, 133.3, 133.6, 134.3, 134.5, 135.5, 136.8, 143.7,
144.2, 147.0, 150.9, 151.2, 155.1. Anal. Calcd for C48H54F3NO7S6: C,
57.29; H, 5.41; N, 1.39. Found: C, 57.32; H, 5.40; N, 1.35.
5,11,17,23-Tetra-tert-butyl-27,28-dihydroxy-2,8,14,20-
tetrathia-26-(p-toluenesulfonylamino)pentacyclo[19.3.1.13,7
.
19,13.115,19]octacosa-1(25),3,5,7(28),9,11,13(27),15,17,19(26),-
21,23-dodecaene-25-yl trifluoromethanesulfonate (19):
colorless powder, mp 263.0-265.0 °C; IR (KBr) 3377, 2964, 1449,
1430, 1207, 1168, 860, 676, 616 cm-1; 1H NMR (400 MHz) δ 1.01 (s,
9H), 1.10 (s, 9H), 1.19 (s, 9H), 1.21 (s, 9H), 2.45(s, 3H), 7.28 (m, 2H),
7.32 (d, 1H, J = 2.3 Hz), 7.36 (d, 1H, J = 2.3 Hz), 7.48 (d, 1H, J = 2.5 Hz),
7.51 (d, 1H, J = 2.5 Hz), 7.52 (d, 1H, J = 2.5 Hz), 7.54 (m, 3H), 7.55
(d, 2H, J = 6.1 Hz), 7.73 (s, 1H), 8.09 (s, 1H), 8.17 (s, 1H); 13C NMR
(100 MHz) δ 21.7, 30.8, 30.9, 31.2, 31.3, 34.2, 34.5, 34.7, 117.1, 119.8,
120.0, 120.1, 121.9, 128.1, 129.6, 129.8, 131.1, 133.7, 134.2, 134.3, 135.2,
135.2, 135.4, 135.6, 135.6, 135.8, 135.9, 136.6, 143.8, 143.9, 144.1, 148.4,
150.9, 152.0, 155.4, 155.8; MS (FAB) m/z 1006 Mþ; HRMS (ESI) calcd
for C48H54F3NNaO7S6 (M þ Na)þ 1028.2074, found 1028.2069.
N-(5,11,17,23-Tetra-tert-butyl-26,27,28-trihydroxy-2,8,14,
20-tetrathiapentacyclo-19.3.1.13,7.19,13.115,19]octacosa-1(25),
3,5,7(28),9,11,13(27),15,17,19(26),21,23-dodecaene-25-yl-
p-toluenesulfonamide (20): colorless powder, mp 316.0-
27-Benzyloxy-5,11,17,23-tetra-tert-butyl-26,28-dihydroxy-
2,8,14,20-tetrathiapentacyclo[19.3.1.13,7.19,13.115,19]octacosa-
1(25),3,5,7(28),9,11,13(27),15,17,19(26),21,23-dodecaene-
25-yl Trifluoromethanesulfonate (24). A mixture of monotriflate
14b (200 mg, 0.234 mmol), Na2CO3 (249 mg, 2.35 mmol), (bromo-
methyl)benzene (d = 1.44; 279 μL, 2.35 mmol), and acetone (10 mL)
was refluxed for 6 h. After cooling, the mixture was quenched with 2 M
HCl (10 mL) and extracted with chloroform. The extract was washed
with water, dried over MgSO4, and evaporated. The residue was
chromatographed on a silica gel column with hexane-chloroform
(1:1) as an eluent to give benzyl ether 24 (167 mg, 76%) as a colorless
powder, mp 238.2-239.6 °C; IR (KBr) 3394, 2964, 1451, 1424, 1206,
1138, 1067, 911, 875 cm-1; 1H NMR (500 MHz) δ 0.58 (s, 9H), 1.13 (s,
9H), 1.31 (s, 18H), 5.26 (s, 2H), 6.75 (s, 2H), 7.40-7.47 (m, 3H), 7.49
(s, 2H), 7.55 (s, 2H), 7.55-7.58 (m, 2H), 7.62 (d, 2H, J = 2.4 Hz), 7.70
(d, 2H, J = 2.4 Hz); 13C NMR (125 MHz) δ 30.4, 30.9, 31.4, 33.9, 34.2,
34.6, 81.3, 120.1, 120.2, 122.6, 127.7, 129.0, 129.1, 129.2, 130.8, 131.3,
133.3, 134.4, 135.5, 136.1, 142.8, 147.0, 149.7, 150.2, 156.0, 156.0; MS
(FAB) m/z 943 (M þ H)þ. Anal. Calcd for C48H53F3O6S5: C, 61.12; H,
5.66. Found: C, 60.91; H, 5.63.
1
318.0 °C; IR (KBr) 3320, 2963, 1451, 1167, 1091, 886 cm-1; H
NMR (400 MHz) δ 1.15 (s, 9H), 1.20 (s, 18H), 1.22 (s, 9H), 2.45 (s,
3H), 7.30 (d, 2H, J = 8.1 Hz), 7.55 (d, 2H, J = 2.5 Hz), 7.62 (m, 6H), 7.64
(s, 2H), 9.03 (s, 1H), 9.20 (s, 2H), 9.73 (s, 1H); 13C NMR (100 MHz) δ
21.7, 30.8, 31.2, 31.3, 34.1, 34.2, 34.6, 119.1, 120.5, 121.5, 128.1, 129.8,
133.5, 135.4, 135.6, 136.0, 136.1, 136.4, 137.8, 144.3, 144.3, 144.4, 151.8,
155.9, 156.0; MS (FAB) m/z 874 (M þ H)þ; HRMS (ESI) calcd for
C47H55NNaO5S5 (M þ Na)þ 896.2581, found 896.2576.
Typical Procedure for the Amidation of 1,3-Bistriflate 2b
(Entry 3 in Table 3). A suspension of bistriflate 2b (1.00 g, 1.02
mmol), tosylamide (417 mg, 2.44 mmol), CuI (426 mg, 2.24 mmol),
and K3PO4 (862 mg, 4.06 mmol) in DMF (30 mL) was stirred at 80 °C
for 24 h. After cooling, the mixture was poured into saturated aqueous
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The following compounds were also obtained by this procedure with
a different substrate or amide reagents.
hexane-ethyl acetate (4:1) as an eluent to give bis(tosylamide) 17a
(479 mg, 46%).
N,N0-(5,11,17,23-Tetra-tert-butyl-26,28-dihydroxy-2,8,14,
20-tetrathiapentacyclo[19.3.1.13,7.19,13.115,19]octacosa-1(25),
3,5,7(28),9,11,13(27),15,17,19(26),21,23-dodecaene-25,27-
diyl)bis(p-methoxybenzenesulfonamide) (21): colorless pow-
der, mp 335.0-337.0 °C; IR (KBr) 3350, 3262, 2964, 1597, 1497, 1437,
N,N0-(5,11,17,23-Tetra-tert-butyl-26,28-dihydroxypentac-
yclo[19.3.1.13,7.19,13.115,19]octacosa-1(25),3,5,7(28),9,11,13-
(27),15,17,19(26),21,23-dodecaene-25,27-diyl)bis(p-toluen-
esulfonamide) (17a): colorless powder, mp 337.0-339.0 °C; IR
(KBr) 3104, 2956, 1598, 1449, 1165, 1092 cm-1; 1H NMR (500 MHz)
δ 1.10 (s, 18H), 1.17 (s, 18H), 2.47 (s, 6H), 3.16 (d, 4H, J = 14.1 Hz),
3.91 (d, 4H, J = 14.1 Hz), 6.92 (s, 4H), 6.98 (s, 4H), 7.31 (d, 4H, J = 8.2
Hz), 7.64 (d, 4H, J = 8.2 Hz), 8.62 (s, 2H), 9.42 (s, 2H); 13C NMR (125
MHz) δ 21.7, 30.9, 31.5, 33.8, 33.9, 34.3, 125.4, 126.2, 126.5, 127.1,
127.9, 129.8, 135.1, 138.4, 143.4, 144.5, 148.5, 150.7; MS (FAB) m/z
955 (M þ H)þ; HRMS (ESI) calcd for C58H70N2NaO6S2 (M þ Na)þ
977.4573, found 977.4568.
1
1261, 1161, 1094, 1026, 679 cm-1; H NMR (400 MHz) δ 0.89 (s,
18H), 1.26 (s, 18H), 3.89 (s, 6H), 6.96 (d, 4H, J = 8.9 Hz), 7.21 (s, 4H),
7.47 (s, 2H), 7.57 (s, 4H), 7.64 (d, 4H, J = 8.9 Hz), 8.23 (s, 2H); 13C
NMR (100 MHz) δ 30.8, 31.5, 34.3, 34.5, 55.8, 114.5, 121.9, 130.3,
133.5, 133.8, 134.2, 137.0, 143.8, 150.9, 155.3, 163.6; HRMS (ESI) calcd
for C54H62N2NaO8S6 (M þ Na)þ 1081.2728, found 1081.2723.
N,N0-(5,11,17,23-Tetra-tert-butyl-26,28-dihydroxy-2,8,14,
20-tetrathiapentacyclo[19.3.1.13,7.19,13.115,19]octacosa-1(25),
3,5,7(28),9,11,13(27),15,17,19(26),21,23-dodecaene-25,27-diyl)-
bis(p-nitrobenzenesulfonamide) (22): colorless powder, mp
342.0-343.0 °C; IR (KBr) 3370, 3249, 2964, 1533, 1348, 1173, 1089,
854, 739 cm-1; 1H NMR (400 MHz) δ 0.90 (s, 18H), 1.26 (s, 18H),
7.21 (s, 4H), 7.38 (s, 2H), 7.57 (s, 4H), 7.89 (d, 4H, J = 8.9 Hz), 8.35 (d,
4H, J = 8.9 Hz), 8.48 (s, 2H); 13C NMR (100 MHz) δ 30.7, 31.5, 34.4,
34.6, 121.6, 124.6, 129.5, 133.6, 134.0, 134.4, 136.0, 144.0, 144.5, 150.6,
151.8, 154.8; HRMS (ESI) calcd for C52H56N4NaO10S6 (M þ Na)þ
1111.2218, found 1111.2213.
5,11,17,23-Tetra-tert-butyl-26,28-dihydroxy-27-(p-toluen-
esulfonylamino)pentacyclo[19.3.1.13,7.19,13.115,19]octacosa-
1(25),3,5,7(28),9,11,13(27),15,17,19(26),21,23-dodecaene-
25-yl trifluoromethanesulfonate (18a): colorless powder, mp
147.0-148.0 °C; IR (KBr) 3261, 2963, 1486, 1208, 1166, 875 cm-1; 1H
NMR (400 MHz) δ 0.81 (s, 9H), 0.96 (s, 9H), 1.29 (s, 18H), 2.45 (s,
3H), 3.07 (d, 2H, J = 14.5 Hz), 3.47 (d, 2H, J = 14.1 Hz), 3.80 (d, 2H, J =
14.5 Hz), 4.20 (d, 2H, J = 14.1 Hz), 5.26 (s, 2H), 6.70 (s, 2H), 6.79 (s,
2H), 7.04 (d, 2H, J = 2.0 Hz), 7.11 (d, 2H, J = 2.0 Hz), 7.25 (d, 2H, J = 7.9
Hz), 7.55 (d, 2H, J = 7.9 Hz), 7.76 (s, 1H); 13C NMR (100 MHz) δ 21.8,
30.7, 30.9, 31.7, 31.8, 32.0, 33.9, 34.1, 34.2, 34.2, 125.6, 125.6, 125.9,
127.2, 127.6, 127.9, 128.0, 128.0, 129.8, 132.6, 135.6, 137.4, 141.4, 143.6,
144.4, 149.6, 150.5, 150.7; MS (FAB) m/z 934 (M þ H)þ; HRMS (ESI)
calcd for C52H62F3NNaO7S2 (M þ Na)þ 956.3817, found 956.3812.
N-(5,11,17,23-Tetra-tert-butyl-26,28-dihydroxypentacyclo-
[19.3.1.13,7.19,13.115,19]octacosa-1(25),3,5,7(28),9,11,13(27),
15,17,19(26),21,23-dodecaene-25-yl)-p-toluenesulfonamide
(26): colorless powder, mp 228.0-230.0 °C; IR (KBr) 3483, 2962,
1486, 1158 cm-1; 1H NMR (400 MHz) δ 1.64 (s, 9H), 1.22 (s, 9H),
1.25 (s, 18H), 2.44 (s, 3H), 3.23 (d, 2H, J = 14.3 Hz), 3.65 (d, 2H, J =
14.3 Hz), 3.82 (d, 2H, J = 14.3 Hz), 3.95 (d, 2H, J = 14.3 Hz), 5.60 (s,
2H), 6.93 (br, 1H), 7.00 (d, 2H, J = 2.3 Hz), 7.02 (d, 2H, J = 2.3 Hz), 7.05
(br s, 2H), 7.06 (s, 2H), 7.25 (d, 2H, J = 8.1 Hz), 7.54 (d, 2H, J = 8.1 Hz),
7.86 (s, 1H); 13C NMR (100 MHz) δ 21.7, 31.0, 31.3, 31.5, 34.0, 34.3,
34.5, 34.7, 37.9, 123.8, 124.9, 125.6, 126.0, 126.3, 127.1, 127.3, 127.8,
128.3, 129.7, 135.9, 138.8, 140.8, 143.5, 144.2, 149.4, 151.2, 151.6;
MS (FAB) m/z 786 (M þ H)þ; HRMS (ESI) calcd for C51H63NNaO4S
(M þ Na)þ 808.4375, found 808.4370.
N,N0-(5,11,17,23-Tetra-tert-butyl-26,28-dihydroxy-2,8,14,
20-tetrathiapentacyclo[19.3.1.13,7.19,13.115,19]octacosa-1(25),
3,5,7(28),9,11,13(27),15,17,19(26),21,23-dodecaene-25,27-
diyl)bis(methanesulfonamide) (23): colorless powder, mp 313.0-
316.0 °C; IR (KBr) 3360, 3254, 2963, 1448, 1337, 1161, 970, 880 cm-1
;
1H NMR (400 MHz) δ 0.95 (s, 18H), 1.31 (s, 18H), 3.24 (s, 6H), 7.34 (s,
4H), 7.59 (s, 2H), 7.69 (s, 4H), 8.47 (s, 2H); 13CNMR(100MHz)δ30.8,
31.5, 34.4, 34.6, 40.8, 121.7, 132.9, 134.3, 134.5, 137.3, 144.4, 151.3, 155.2;
MS (FAB) m/z 875 (M þ H)þ; HRMS (ESI) calcd for C42H54N2
NaO6S6 (M þ Na)þ 897.2204, found 897.2198.
N-(27-Benzyloxy-5,11,17,23-tetra-tert-butyl-26,28-dihy-
droxy-2,8,14,20-tetrathiapentacyclo[19.3.1.13,7.19,13.115,19]oct-
acosa-1(25),3,5,7(28),9,11,13(27),15,17,19(26),21,23-dode-
caene-25-yl)-p-toluenesulfonamide (25):. colorless powder, mp
257.0-259.0 °C; IR (KBr) 3385, 2963, 1449, 1261, 1167, 1090,
882 cm-1; 1H NMR (400 MHz) δ 0.77 (s, 9H), 1.09 (s, 9H), 1.26 (s,
18H), 2.43 (s, 3H), 5.28 (s, 2H), 7.01 (s, 2H), 7.24 (d, 2H, J = 8.6 Hz),
7.45 (s, 2H), 7.48-7.57 (m, 5H), 7.58 (d, 2H, J = 2.5 Hz), 7.59 (d, 2H, J
= 2.5 Hz), 7.69 (s, 1H), 7.71 (d, 2H, J = 8.6 Hz), 7.86 (s, 2H); 13C NMR
(100 MHz) δ 21.9, 30.7, 31.1, 31.5, 34.2, 34.3, 34.6, 120.1, 123.1, 128.0,
128.2, 129.1, 129.2, 129.5, 129.7, 132.5, 134.0, 135.1, 135.2, 135.3, 136.0,
136.3, 136.5, 143.0, 143.7, 149.6, 150.1, 156.3, 156.8; MS (FAB) m/z
964 (M þ H)þ; HRMS (ESI) calcd for C54H61NNaO5S5 (M þ Na)þ
986.3051, found 986.3045.
N-(5,11,17,23-Tetra-tert-butyl-26,28-dihydroxy-27-iodo-
pentacyclo[19.3.1.13,7.19,13.115,19]octacosa-1(25),3,5,7(28),9,
11,13(27),15,17,19(26),21,23-dodecaene-25-yl)-p-toluene-
sulfonamide (27): colorless powder, mp 256.0-258.0 °C; IR (KBr)
3516, 2963, 1487, 1364, 1168, 874, 816 cm-1; 1H NMR (400 MHz) δ
0.73 (s, 9H), 0.96 (s, 9H), 1.32 (s, 18H), 2.44 (s, 3H), 3.02 (d, 2H, J =
14.5 Hz), 3.72 (d, 2H, J = 14.1 Hz), 3.79 (d, 2H, J = 14.5 Hz), 4.39 (d,
2H, J = 14.1 Hz), 5.19 (s, 2H), 6.56 (s, 2H), 6.78 (s, 2H), 7.03 (d, 2H, J =
2.4 Hz), 7.11 (d, 2H, J = 2.4 Hz), 7.24 (d, 2H, J = 8.0 Hz), 7.53 (d, 2H, J =
8.3 Hz), 7.63 (s, 1H); 13C NMR (100 MHz) δ 21.7, 30.5, 30.8, 31.7,
33.6, 33.8, 34.0, 34.1, 41.2, 104.0, 125.2, 125.7, 126.1, 126.1, 127.8, 127.9,
128.1, 128.6, 129.7, 135.9, 137.6, 142.9, 142.9, 144.0, 150.0, 150.2, 150.3;
MS (FAB) m/z 912 (M þ H)þ; HRMS (ESI) calcd for C51H62IN-
NaO4S (M þ Na)þ 934.3342, found 934.3336.
Typical Procedure for the Amidation of 1,3-Bistriflate 2a
(Entry 3 in Table 4). A suspension of bistriflate 2a (501 mg, 0.549
mmol), tosylamide (376 mg, 2.20 mmol), CuI (418 mg, 2.19 mmol),
and K3PO4 (465 mg, 2.19 mmol) in DMF (15 mL) was stirred at 80 °C
for 24 h. After cooling, the mixture was poured into saturated aqueous
NH4Cl and extracted with chloroform. The extract was washed succes-
sively with 2 M HCl and water, dried over MgSO4, and evaporated to
leave a residue, one-tenth portion of which was purified by TLC with
hexane-ethyl acetate (4:1) as a developer to give bis(tosylamide) 17a
(23.7 mg, 45%), tosylamino ester 18a (6.2 mg, 12%), reduced amide 26
(4.7 mg, 11%), and iodinated amide 27 (2.1 mg, 4%).
Bis(tosylamide) 17a could be isolated on a preparative scale by
column chromatography. Thus, the same reaction was carried out in
2-fold scale, using bistriflate 2a (1.00 g, 1.10 mmol). After workup, the
mixture was suspended in hot methanol and the insoluble part was
collected by filtration and chromatographed on a silica gel column with
Monotriflate 14a is a known compound. The NMR spectra of the
sample are identical with those reported in the literature.7a
27-Amino-5,11,17,23-tetra-tert-butyl-26,28-dihydroxypen-
tacyclo[19.3.1.13,7.19,13.115,19]octacosa-1(25),3,5,7(28),9,11,
13(27),15,17,19(26),21,23-dodecaene-25-yl Trifluorometha-
nesulfonate (10a). To a solution of benzylamino ester 7a (201 mg,
0.231 mmol) in degassed ethanol (10 mL) was added palladium on
carbon (5 w/w %, 20.0 mg), and the mixture was stirred at 60 °C under a
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The Journal of Organic Chemistry
ARTICLE
hydrogen atmosphere for 24 h. After the catalyst was filtered off, the
filtrate was evaporated to leave a residue, which was crystallized from
methanol-dichloromethane to give amino ester 10a (100 mg). The
mother liquid was evaporated and the residue was purified by TLC with
hexane-ethyl acetate (4:1) as an eluent to give an additional crop of 10a
(59.6 mg) for a total yield of 160 mg (89%) as crystals, mp 141.0-
143.0 °C; IR (KBr) 3522, 3418, 2963, 1485, 1420, 1396, 1362, 1208,
1138, 1072 cm-1; 1H NMR (400 MHz) δ 0.88 (br s, 9H), 1.05 (s, 9H),
1.33 (s, 18H), 3.51 (d, 2H, J = 14.7 Hz), 3.55 (d, 2H, J = 14.8 Hz), 4.01
(br d, 2H, J = 14.0 Hz), 4.24 (d, 2H, J = 14.2 Hz), 6.79 (br s, 2H), 6.90 (s,
2H), 7.13 (d, 2H, J = 2.3 Hz), 7.17 (d, 2H, J = 2.3 Hz); 13C NMR (100
MHz) δ 30.7, 31.1, 31.6, 33.1, 33.9, 34.0, 34.0, 35.1, 113.9, 117.1, 120.3,
125.5, 125.5, 125.8, 127.3, 127.7, 128.3, 131.0, 133.0, 142.3, 143.0, 150.0,
150.6; MS (FAB) m/z 780 (M þ H)þ. Anal. Calcd for C45H56F3NO5S:
C, 69.29; H, 7.24; N, 1.80. Found: C, 69.40; H, 7.17; N, 1.75.
Debenzylation of Bis(benzylamine) 8 to 26,28-Diamino-
5,11,17,23-tetra-tert-butylpentacyclo[19.3.1.13,7.19,13.115,19]-
octacosa-1(25),3,5,7(28),9,11,13(27),15,17,19(26),21,23-do-
decaene-25,27-diol (5a). The procedure employed for the prepara-
tion of compound 10a was applied. Thus, bis(benzylamine) 8 (201 mg,
0.243 mmol) was treated with palladium on carbon (5 w/w %, 21.0 mg)
in ethanol (10 mL) under a hydrogen atmosphere at 60 °C for 16 h.
Crystallization of the worked-up mixture from methanol-dichloro-
methane gave diamine 5a (123 mg). An additional crop of 5a (33.7
mg) was obtained by the TLC of the mother liquid with hexane-ethyl
acetate (2:1) as an eluent for a total yield of 157 mg (100%) as a colorless
powder, mp 269.0-270.0 °C (lit.4b mp 277.5-278.5 °C); IR (KBr)
3342, 2961, 1482, 1363, 1203, 870 cm-1; 1H NMR (400 MHz) δ 1.20
(s, 18H), 1.21 (s, 18H), 3.88 (br, 8H), 7.02 (s, 4H), 7.06 (s, 4H); 13C
NMR (100 MHz) δ 31.4, 31.7, 34.0, 34.3, 35.1, 125.5, 128.4, 133.5,
135.8, 142.2, 147.2, 150.3. The 1H NMR spectrum is essentially identical
with that reported in the literature.4b
28-Amino-5,11,17,23-tetra-tert-butylpentacyclo[19.3.1.13,7
.
1
9,13.115,19]octacosa-1(25),3,5,7(28),9,11,13(27),15,17,19(26),
21,23-dodecaene-25,26,27-triol (4a). Amino ester 10a (150 mg,
0.192 mmol) was boiled with 2 M NaOH (5.0 mL) in a mixture of THF
(3.0 mL) and ethanol (3.0 mL) for 4 h. After cooling, the mixture was
quenched with 2 M HCl (20 mL) and extracted with chloroform. The
extract was washed with water, dried over MgSO4, and evaporated.
Crystallization of the residue from methanol-dichloromethane gave
amino triol 4a (120 mg, 96%) as crystals, mp 306.0-307.0 °C (lit.4c mp
296-297 °C); IR (KBr) 3342, 3221, 2960, 1482, 1363, 1305, 1202, 871,
782 cm-1; 1H NMR (400 MHz) δ 1.19 (s, 9H), 1.21 (s, 18H), 1.23 (s,
9H), 3.48 (br, 4H), 4.23 (br, 4H), 7.00 (d, 2H, J = 2.5 Hz), 7.06 (s, 2H),
7.07 (d, 2H, J = 2.5 Hz), 7.08 (s, 2H); 13C NMR (100 MHz) δ 31.2, 31.4,
33.1, 33.9, 34.0, 34.2, 34.7, 125.6, 125.7, 125.7, 125.8, 127.6, 128.3, 128.3,
131.8, 135.2, 143.3, 143.7, 147.6, 147.9, 148.4. The NMR spectra are
essentially identical with those reported in the literature.4c
Reduction of Bis(tosylamide) 17a to Diamine 5a. A mixture
of bis(tosylamide) 17a (50.3 mg, 52.7 μmol), 0.1 M SmI2 in THF
(15.7 mL, 1.57 mmol), pyrrolidine (d = 0.866; 258 μL, 3.14 mmol), and
water (84.8 μL, 4.71 mmol) was stirred at room temperature for 12 h.
The mixture was quenched by the addition of 2 M HCl (10 mL) and
extracted with chloroform. The extract was dried over MgSO4 and
evaporated to leave a residue, which was purified by TLC with hexane-
ethyl acetate (2:1) as an eluent to give diamine 5a (30.0 mg, 88%).
Hydrolysis of Bis(tosylamide) 17b to Diamine 5b. Bis-
(tosylamide) 17b (50.5 mg, 49.1 μmol) was boiled with concd H2SO4
(1.0 mL) and water (0.2 mL) in acetic acid (6.0 mL) for 8 h. To the
cooled mixture was added water (6 mL) and the mixture was neutralized
in an ice bath by adding dropwise satuared aqueous NaOH. The mixture
was extracted with chloroform, and the extract was dried over MgSO4
and evaporated. The residue was purified by TLC with hexane-ethyl
acetate (4:1) as an eluent to give diamine 5b (33.0 mg, 94%).
Reduction of Bis(tosylamide) 17b to Diamine 5b. The
procedure employed for the reduction of bis(tosylamide) 17a was
applied. Thus, a mixture of bis(tosylamide) 17b (50.2 mg, 48.9 μmol),
0.1 M SmI2 in THF (14.6 mL, 1.46 mmol), pyrrolidine (d = 0.866; 240
μL, 2.92 mmol), and water (78.6 μL, 4.38 mmol) was stirred at room
temperature for 8 h. After the workup, the crude product was purified by
TLC with hexane-ethyl acetate (4:1) as an eluent to give diamine 5b
(6.0 mg, 17%).
X-ray Crystallographic Analyses of Compounds 2b, 7b,
and 17b. Single-crystal X-ray diffraction data were collected with a
CCD diffractometer using Mo KR radiation (λ = 0.71073 Å), employing
a monochromator and a fine-focus rotating anode as radiation source.
Data integration and reduction were performed with SAINT and
XPREP software and the absorption correction was performed by the
semiempirical method with SADABS.29 The structure was solved by the
direct method using SHELXS-97 and refined by using least-squares
methods on F2 with SHELXL-97.30 X-ray analysis was undertaken using
the free GUI software of Yadokari-XG 2009.31
28-Amino-5,11,17,23-tetra-tert-butyl-2,8,14,20-tetrathia-
pentacyclo[19.3.1.13,7.19,13.115,19]octacosa-1(25),3,5,7(28),9,
11,13(27),15,17,19(26),21,23-dodecaene-25,26,27-triol (4b).
Benzylamino ester 7b (201 mg, 0.213 mmol) was boiled with concd HCl
(6 mL) in acetic acid (10 mL) for 3 d. After cooling, most of the acetic
acid was evaporated and the residue was suspended by the addition of
water. The suspension was neutralized with 2 M NaOH and extracted
with chloroform. The extract was dried over MgSO4 and evaporated to
leave a residue, which was dissolved by the addition of THF (6.0 mL)
and ethanol (3.0 mL). To the solution was added a solution of NaOH
(860 mg, 21.5 mmol) in water (3.0 mL), and the mixture was refluxed for
12 h. After cooling, the mixture was acidified with 2 M HCl and the
resulting mixture was extracted with chloroform. The extract was washed
with water, dried over MgSO4, and evaporated. The residue was purified
by column chromatography with chloroform-ethyl acetate (20:1) as an
eluent to give amino triol 4b (143 mg, 93%) as a colorless powder, mp
282.0-284.0 °C dec; IR (KBr) 3356, 3302, 2963, 1458, 1265, 1242 cm-1
1H NMR (400 MHz) δ 1.20 (s, 9H), 1.23 (s, 9H), 1.23 (s, 18H), 7.60 (d,
2H, J = 2.5 Hz), 7.63 (s, 2H), 7.65 (s, 2H), 7.66 (d, 2H, J = 2.5 Hz); 13
;
C
NMR (100 MHz) δ 31.1, 31.3, 31.3, 34.1, 34.2, 34.3, 120.8, 121.0, 121.4,
126.0, 135.9, 136.2, 136.2, 143.9, 144.3, 145.5, 147.1, 153.4, 156.3, 156.8;
MS (FAB) m/z 719 Mþ. Anal. Calcd for C40H49NO3S4: C, 66.72; H,
6.86; N, 1.95. Found: C, 66.70; H, 6.80; N, 1.78.
Data for compound 2b: C42.5H48F6O8.5S6, fw =1001.17, mono-
clinic, P21/c, a = 20.749(4) Å, b = 20.042(4) Å, c = 11.915(2) Å, β =
95.042(2)°, V = 4935.6(15) Å3, Z = 4, T = 100(2) K, 27403 reflections
measured, 11120 independent reflections, 7930 reflections were ob-
served (I > 2σ(I)), R1 = 0.0690, wR2 = 0.1682 (observed), R1 = 0.984,
wR2 = 0.1902 (all data).
Data for compound 7b: C48H54F3NO5S5, fw = 942.22, triclinic,
P1, a = 10.3827(17) Å, b = 13.578(2) Å, c = 18.340(3) Å, R =
86.422(2)°, β = 87.024(2)°, γ = 74.012(2)°, V = 2479.0(7) Å3, Z = 2,
T = 173(2) K, 27260 reflections measured, 10968 independent reflec-
tions, 7928 reflections were observed (I > 2σ(I)), R1 = 0.0601, wR2 =
0.1452 (observed), R1 = 0.0877, wR2 = 0.1685 (all data).
Compound 4b was obtained in an improved yield based on bistriflate 2b
by subjecting the crude reaction mixture of the amination to this deprotec-
tion process. Thus, the amination of 2b (1.00 g, 1.02 mmol) was carried out
under the same conditions as mentioned in the typical procedure (vide
supra) and the worked-up mixture was boiled with concd HCl (30 mL) in
acetic acid (50 mL) for 3 d. After the workup, the mixture was dissolved by
the addition of THF (30 mL) and ethanol (15 mL), and boiled with a
solution of NaOH (3.00 g, 75.0 mmol) in water (15 mL) for 12 h. After the
workup, the mixture was purified by column chromatography with chloro-
form-hexane (3:1) as an eluent to give 4b (385 mg, 53%).
2178
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The Journal of Organic Chemistry
ARTICLE
Data for compound 17b: C60H76N2O6S6, fw =1113.59, mono-
clinic, C2/c, a = 14.710(3) Å, b = 23.366(3) Å, c = 18.063(4) Å, β =
106.207(2)°, V = 5962.0(17) Å3, Z = 4, T = 173(2) K, 33189 reflections
measured, 6800 independent reflections, 5945 reflections were observed
(I > 2σ(I)), R1 = 0.0414, wR2 = 0.1125 (observed), R1 = 0.0483, wR2 =
0.1196 (all data).
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’ ASSOCIATED CONTENT
(10) Tanaka, S.; Katagiri, H.; Morohashi, N.; Hattori, T.; Miyano, S.
Tetrahedron Lett. 2007, 48, 5293.
(11) For stereoisomers of sulfinylcalix[4]arene, see: Morohashi, N.;
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S
Supporting Information. CIF files for compounds 2b,
b
7b, and 17b and NMR spectral charts for the compounds
synthesized. This material is available free of charge via the
Internet at http://pubs.acs.org.
(12) Katagiri, H.; Iki, N.; Matsunaga, Y.; Kabuto, C.; Miyano, S.
Chem. Commun. 2002, 2080.
’ AUTHOR INFORMATION
(13) Tanaka, S.; Serizawa, R.; Morohashi, N.; Hattori, T. Tetrahe-
dron Lett. 2007, 48, 7660.
(14) Reviews: (a) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed.
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Corresponding Author
*E-mail: hattori@orgsynth.che.tohoku.ac.jp.
’ ACKNOWLEDGMENT
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This study was supported in part by Grants-in-Aid for
Scientific Research (Nos. 19550100 and 22750028) from the
Ministry of Education, Culture, Sports, Science and
Technology, Japan.
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