N-Arylation of protected azamacrocycles

Article abstract of DOI:10.1055/s-0032-1318307

A rapid method for efficient palladium-catalyzed N-arylation of polynitrogenated macrocycles is presented. Its applicability for functionalization of protected azamacrocycles of various sizes with substituted aryl bromides of optional electronic properties is demonstrated. The compatibility of the protocol with common N-protecting schemes as well as the impact of electronic versus steric factors is discussed. Using a commercially available catalytic system and easily available alkoxide or phenoxide base, the method provides moderate to excellent yields of N-arylated azamacrocycles (45-96%). Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1318307

PAPER
▌777
paper
N-Arylation of Protected Azamacrocycles
N-Arylation of Azamacrocycles
Alberte X. Veiga, Sven Arenz, Máté Erdélyi*
Department of Chemistry and Molecular Biology, University of Gothenburg, 412 96 Gothenburg, Sweden
Fax +46(31)7721394 ; E-mail: mate@chem.gu.se
Received: 27.12.2012; Accepted after revision: 02.02.2013
is explainable by the fact that polyamines in general are
recognized as one of the most reluctant substrates in Pd-
catalyzed arylations.16e–g In addition, polyamines easily
form stable transition-metal complexes.1–3 Although use-
Abstract: A rapid method for efficient palladium-catalyzed N-aryl-
ation of polynitrogenated macrocycles is presented. Its applicability
for functionalization of protected azamacrocycles of various sizes
with substituted aryl bromides of optional electronic properties is
demonstrated. The compatibility of the protocol with common N- ful in other contexts,1–10 chelation of transition-metal ions
protecting schemes as well as the impact of electronic versus steric
factors is discussed. Using a commercially available catalytic sys-
tem and easily available alkoxide or phenoxide base, the method
prohibits N-arylation of unprotected polyazamacrocycles
in preparatively useful yields.16e–g
Although microwave-assisted Pd-catalyzed cross cou-
plings,17 including general Buchwald–Hartwig reac-
tions,18 are known, so far no conditions suitable for the N-
arylation of polyazamacrocyclic systems were yet estab-
lished. Herein we report the first rapid, microwave-assist-
ed Buchwald–Hartwig cross coupling protocol of
polyazamacrocycles with aryl bromides. Its scope is dem-
onstrated by efficient monofunctionalization of a range of
partially protected polynitrogenated skeletons with substi-
tuted aryl bromides of varying electronic properties. The
compatibility of the reaction conditions with common ni-
trogen protecting groups is explored.
provides moderate to excellent yields of N-arylated azamacrocycles
(45–96%).
Key words: azamacrocycles, N-arylation, C–N coupling, heterocy-
cles, homogeneous catalysis
Owing to their peculiar complexation properties, azamac-
rocycles has become a coveted class of compounds for a
variety of uses. In the past decade, their applicability as
scaffolds for magnetic resonance imaging (MRI) contrast
agents,1 tagging systems for protein labeling,2 and chemi-
cal probes for selective detection of transition metals3 and
anions4 was demonstrated. They were also shown to be
applicable, for example, in supramolecular chemistry,5
biosensing,6 enantioselective molecular recognition,7 ion
chromatography,8 degradation of β-amyloids9 as well as
in the treatment of viral diseases.10
Optimization studies were performed on tri(N-Boc)-cy-
clen 1, the most common substrate in azamacrocycle
chemistry.16a The nature of the catalyst, base, solvent, re-
action temperature, and time were thoroughly optimized.
Single mode microwave irradiation with careful tempera-
ture, pressure, and irradiation power monitoring was ap-
plied, making the procedure highly reproducible. The
reaction rate of Pd-catalyzed aminations is determined by
the reductive elimination step of the catalytic cycle19 and
thus bulky, electron-rich phosphines were expected to
yield best conversions. Indeed, Pd(OAc)2 catalyst along
with (t-Bu)3P16b in a 5:8 ratio turned out superior for the
cross coupling. Application of modern dialkylbiaryl phos-
phine ligands (RuPhos, DavePhos) did not improve con-
versions. Toluene was chemically compatible with the
transformation, but unfavorable for microwave assisted
reactions because of its low dipole moment. Originating
from its similar chemical properties and excellent micro-
wave absorbance, α,α,α-trifluorotoluene was found to be
the most favorable solvent for the cross coupling. This
solvent was originally introduced by Curran and co-
worker20 for organic reactions and was later successfully
applied in microwave-assisted Buchwald–Hartwig reac-
tions.21 It should be noted here that a 6:1 mixture of tolu-
ene–tert-butyl alcohol gave comparable microwave
absorption and good overall yields, providing a cheap,
easily accessible solvent alternative. The reaction temper-
ature was varied between 60 and 180 °C, with 100 °C giv-
ing optimal enhancements. Careful optimization of the
microwave-assisted protocol allowed shortening of the re-
Among the available polynitrogenated skeletons cyclen,
cyclam, and 1,4,7-triazacyclononane (TACN) are by far
the most suitable for the above applications. The avail-
ability of straightforward synthetic routes for functional-
ization of one of the macrocyclic nitrogens is crucial for
most uses, yet remains a major challenge. So far most syn-
theses have utilized N-alkylations.11 Due to the lack of a
robust and general synthetic approach for corresponding
arylation of polyazamacrocycles, N-aryl derivatives have
scarcely been reported. Nevertheless, the higher rigidity
of N-aryl-substituted derivatives is expected to make them
superior for numerous applications, such as for artificial
receptors,12 for paramagnetic tagging in NMR,13 and for
selective ionophors.14 Whereas procedures for cross-
coupling of mononitrogenated macrocycles have been
successfully developed,15 efficient N-arylation of polyni-
trogenated analogues has not yet been achieved. Common
features of the few available preparation methods of N-ar-
ylated polyazamacrocycles16 are long reaction times
(days), narrow scope, and poor-to-moderate isolated
yields. The particular sluggishness of the transformation
SYNTHESIS 2013, 45, 0777–0784
Advanced online publication: 18.02.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1318307; Art ID: SS-2012-T0998-OP
© Georg Thieme Verlag Stuttgart · New York

778
A. X. Veiga et al.
PAPER
action times from the hitherto reported 24–60 hours16 to 1
hour without any need for application of an increased
amount of palladium catalyst. Longer reaction times or
higher temperatures did not lead to higher yields, but in
increased extent of side reactions, such as the Ullmann ho-
mocoupling of the aromatic moiety.22 In line with previ-
ous studies,23 microwave heating is not a necessity for the
progress of the reaction; it can also be carried out with
conventional heating. However, providing firm control of
reaction time, temperature and pressure,23 heating by mi-
crowave irradiation was preferred in this study. Numerous
bases commonly used in Pd-catalyzed aminations were
tried: DBU, MTBD,24 Cs2CO3, K3PO4, and KF.25 They led
either to slow reaction rates or no reaction at all. Excellent
conversions were obtained using sodium tert-butoxide16c–e
for aryl bromides with para-electron-donating substitu-
ents (Table 1, entries 1–3 and 5) and the electron-poor p-
CF3 substituted analogue (Table 1, entry 8). However, the
reaction failed for reactants with electron-withdrawing
substituents such as nitro, cyano, or ester, due to compet-
ing O-arylation of the base, transesterification and/or sub-
strate decomposition. Similarly, the use of the sterically
unhindered and less basic sodium phenoxide26 resulted in
O-arylation. Further optimization revealed that the bulky
and thereby less nucleophilic sodium 2,4,6-tri-tert-
butylphenolate27a base is favorable for conversion of elec-
tron-poor substrates (Table 1, entries 6 and 7). This soft
base was also compatible with electron-rich reactants (Ta-
ble 1, entries 3 and 4), and provided moderate yields for
aryl bromides bearing substituents with various electronic
properties in meta position (Table 1, entries 9, 10). This
observation demonstrates the key role of the applied base
for the reaction.27 In our hands, sterically hindering ortho
substituents were not compatible with the reaction condi-
tions, and thus 2,4-bromodimethylbenzene and 2,6-bro-
modimethylbenzene yielded complex product mixtures
with only traces of the N-arylated adducts,28 independent-
ly of the choice of base. Utilization of dialkylbiaryl phos-
phine ligands (RuPhos, DavePhos, etc.), which are
commonly applied in modern palladium-mediated cross-
coupling protocols for the sterically hindered ortho- and
meta-substituted reactants did not yield any noticeable
improvement. Nevertheless, coupling of two heterocycles
was successful with any of the above bases (Table 1, en-
tries 11 and 12).
Table 1 Buchwald–Hartwig Coupling of N-Tri-Boc Cyclen with
Functionalized Aryl Bromides
Br
Boc
Boc
Boc
Boc
Boc
Pd(OAc)2 (5 mol%)
N
N
N
N
N
N
N
(t-Bu)3P (8 mol%)
+
base (140 mol%)
α,α,α-trifluorotoluene
1 h, μW
HN
R
Boc
1
2
3
R
Entry
Ra
Baseb
Temp
(°C)
Yield
(%)c
1
p-Me
A
A
A
B
A
B
B
A
B
B
A
100
120
120
120
120
100
100
80
85
83
72
75
82
80
70
84
45
40
40
60
2
p-OMe
3
p-NMe2
p-NMe2
p-SMe
4
5
6
p-CO2Me
p-CHO
p-CF3
7
8
9
m-OMe
100
100
100
100
10
11
12
m-CO2Me
2-pyridyl
6-(2-methylquinolyl)
B
a Relative positions; p denotes relative para, whereas m relative meta
position of bromine and the R substituent.
b Base A: sodium tert-butoxide; base B: sodium 2,4,6-tri-tert-butyl-
phenoxide.
c Isolated yield, following chromatographic purification.
sults being summarized in Table 3. N-Arylation of the
Boc- (Table 1, entry 1) and the CBz-protected cyclenes
(Table 3, entry 1) gave the monoarylated products in high
yields, whereas that of the formyl-protected29 (Table 3,
entry 2) showed potency for preparative applications. As
the trifluoroacetyl group was previously employed for
amine-protection in Pd-catalyzed cross couplings,30 its
compatibility with the reaction conditions was assessed,
however, due to its reactivity under basic conditions,31
with limited success (Table 3, entry 3).
In an attempt to further explore the scope of the reaction,
the optimized conditions were applied for straightforward
N-arylation of a variety of azamacrocycles (Table 2).
Hence, in addition to the N-arylation of cyclen, good
overall yields were obtained for monofunctionalization of
the six- (piperazine), the seven- (1,4-diazepane), the nine-
(TACN), and the fourteen-membered (cyclam) polynitro-
genated rings, of which the last is famous for being espe-
cially challenging in cross couplings.
Attempts to react cyclenes bearing protecting groups at-
tached via an sp3-carbon gave only traces of the desired
product (Table 3, entries 4–6). This observation reveals
the impact of the nature of the protecting group for the
outcome of metal-catalyzed cross-coupling reactions of
polyazamacrocycles: Protecting groups that delocalize the
nitrogen lone pair into an amide or carbamate allow the
cross-coupling to proceed, whereas those preserving their
amine character do not facilitate the reaction, presumably
through inhibition of the catalyst by strong metal com-
plexation. This suggestion is supported by the recent ap-
The use of protecting groups is inevitable for the selective
functionalization of polyazamacrocycles. Therefore, the
compatibility of the optimized reaction conditions with
common amine-protecting schemes was studied, the re-
plication of
a
protected cyclen as palladium(II)
Synthesis 2013, 45, 777–784
© Georg Thieme Verlag Stuttgart · New York

PAPER
N-Arylation of Azamacrocycles
779
Table 2 Pd-Catalyzed N-Arylation of Polyazamacrocycles with
Table 3 Screening of Protecting Groups Compatible with the Pd-
Functionalized Aryl Bromides
Catalyzed Amination of Polyazamacrocycles
Br
R
R
R
R
R
Boc
N
Pd(OAc)2 (5 mol%)
N
N
N
N
N
N
N
N
(t-Bu)3P (8 mol%)
n
Br
Boc
N
+
Pd(OAc)2 (5 mol%)
base (140 mol%)
α,α,α-trifluorotoluene
100 °C, 1 h, μW
n
(t-Bu)3P (8 mol%)
N
+
R
H
base (140 mol%)
α,α,α-trifluorotoluene
100 °C, 1 h, μW
N
H
7
5
8
Entry
7
Basea
Yield (%)b
4
5
6
1
2
3
4
5
6
Cbz
A
B
B
B
A
86
Entry
4
Basea
B
Yield (%)b
CHO
60
COCF3
CH2CN
allyl
mixture
traces
traces
mixture
1
2
96
89
Boc
N
N
NH
NH
B
B
Boc
CH2CO2t-Bu
A
Boc
a Base A: sodium tert-butoxide; base B: sodium 2,4,6-tri-tert-butyl-
phenoxide.
N
NH
3
95
b Isolated yield, following chromatographic purification.
N
Boc
Boc
Boc
N
N
N
the excellent chelating ability of these macrocycles. The
procedure disclosed here provides isolated yields accept-
able for preparative work for N-arylation of azamacrocy-
cles of optional size, within one hour. It is demonstrated
to be applicable for couplings with a wide range of aryl
bromides and its compatibility with common protecting
schemes is explored. The use of protecting groups that de-
localize those nitrogen lone pair, that are not intended to
react in the cross coupling is shown necessary to achieve
acceptable yields in N-arylation of polyazamacrocycles.
4
5
A
B
85
86
HN
Boc
Boc
Boc
N
N
N
HN
Boc
a Base A: sodium tert-butoxide; base B: sodium 2,4,6-tri-tert-butyl-
phenolate.
b Isolated yield, following chromatographic purification.
All reactions were carried out under inert atmosphere (argon or N2).
Solvents were purified according standard techniques33 or pur-
chased from Sigma Aldrich in Sure/SealTM bottles and used as re-
ceived. Cyclen and TACN were purchased from ABCR, cyclam
was purchased from Sigma Aldrich; they were used without further
purification. Chemicals involved in the Pd-mediated couplings
were purified prior to use and stored in a glove box. Solid reagents
were grinded and dried overnight in a vacuum desiccator (~1 mbar);
liquid reagents were distilled using a Kugelrohr apparatus under ar-
gon atmosphere. t-BuONa was purchased from Sigma-Aldrich and
sublimed in vacuo prior to use. Pd(OAc)2 was purchased from
ABCR and was used as a 0.05 M stock solution in anhyd toluene.
(t-Bu)3P was purchased from Sigma-Aldrich as 1 M stock solution
in toluene and was diluted to 0.25 M stock solution. 1,4,7-Tris(tert-
scavenger,32 and by previous reports on difficulties (low
yields) to perform arylation of nonprotected or alkylated
polyazamacrocycles.16e–g The cross-coupling of the bulky
tri-Boc (Table 1, entry 1) and tri-Cbz-protected (Table 3,
entry 1) cyclenes did not give products in lower yield than
the sterically less hindered, flexible triformyl protected
one (Table 3, entry 2). This observation is significant in
light of the previous suggestion that the bulkiness of nitro-
gen protecting groups may be the rate limiting factor for
the N-arylation of cyclenes.16a The collected data demon-
strate that conjugation of the free electron pairs of the
azacyclic amines is a key element for smooth progress of
the catalytic cycle.
butoxycarbonyl)-1,4,7,10-tetraazacyclododecane
(1),
1,4,7-
tris(benzyloxycarbonyl)-1,4,7,10-tetraazacyclododecane,
1,4,7-
tris(trifluoroacetyl)-1,4,7,10-tetraazacyclododecane, 1,4,7-tris(for-
myl)-1,4,7,10-tetraazacyclododecane, 1,4,7-tris(allyl)-1,4,7,10-tet-
raazacyclododecane,
1,4,7-tris(tert-butoxycarbonylmethyl)-
Previous methods for Buchwald–Hartwig N-arylation of
polyazamacrocycles16 were neither robust, nor general
and suffered from low conversions and long reaction
times greatly limiting their applicability. Preceding at-
tempts for selective N-arylation of unprotected polyaza-
macrocycles gave only low yields,16e–g originating from
1,4,7,10-tetraazacyclododecane, 1,4,8-tris(tert-butoxycarbonyl)-
1,4,8,11-tetraaazacyclotetradodecane, and 1,4-bis(tert-butoxycar-
bonyl)-1,4,7-triaazacyclononane were prepared following literature
procedures.34
Reactions were monitored by LC-MS (ESI) and TLC was carried
out on silica gel (Merck 60 F254) or Al2O3 plates (Merck 60 F254) us-
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 777–784

780
A. X. Veiga et al.
PAPER
ing UV light, ninhydrin and/or Hannesian’s reagent for staining.
Column chromatography was performed using Merck silica gel
(Grade 9385, 230–400 mesh) or Merck Al2O3 90 (Active neutral
70–230 mesh, Activity III). All products were characterized by 1H,
13C NMR, and HRMS. NMR spectra for the synthesized com-
Microwave-Assisted Pd-Mediated Couplings;
General Procedure
All reactions described here can be carried out under dry conditions
on a standard laboratory bench. Motivated by our easy access to a
glove box and its superiority for work under dry conditions, the re-
action mixtures in this study were prepared inside a glove box.
Hence, a flame-dried and N2-purged Biotage® microwave vial was
charged with the alkoxide (t-BuONa or sodium 2,4,6-tri-tert-butyl-
phenolate, 140 mol%). Pd(OAc)2 (5 mol% from a 0.05 M stock so-
lution in toluene) and (t-Bu)3P (8 mol% from a 0.25 M stock
solution in toluene) were added and the mixture was stirred for 5
min. A solution of the amine (100 mol%) and the aromatic bromide
(105 mol%) in α,α,α-trifluorotoluene (0.1 M) was transferred via a
syringe to the microwave vial, which was capped, removed from the
glove box, and irradiated in the microwave reactor until completion
of the reaction. The reaction mixture was diluted with toluene (10
mL), filtered over a plug of Celite, and the solvents were removed
in vacuo. The crude products were purified by column chromatog-
raphy.
1
pounds are provided in the Supporting Information (S4–S39). H
NMR data are reported in δ units, parts per million (ppm), by refer-
encing to the residual solvent signal (CDCl3 7.26 ppm, CD2Cl2 5.32
ppm, or 1,2-dichloroethane-d4 6.00 ppm). 13C NMR spectra are re-
ported in ppm relative to CDCl3 (77.16 ppm), CD2Cl2 (53.84 ppm)
1
or 1,2-dichloroethane-d4 (73.8 ppm) and were obtained with H
broadband decoupling. The NMR data were processed with
MestreNova (Mestrelab Research S.L.). Pd-mediated cross cou-
pling reactions were carried out in a Biotage® Initiator microwave
synthesizer using single mode microwave irradiation with tempera-
ture and pressure control. The reaction temperature was held con-
stant throughout the irradiation.23 LC-MS (ESI/UV) analyses were
performed using a PerkinElmer PE Sciex API 150 EX mass spec-
trometer equipped with a Grace column (Genesis Light C8 4 μm,
length 50 mm, ID 4.6 mm) and MeCN–H2O (95:5) eluent contain-
ing 1% formic acid. The chromatograms were analyzed with Ana-
lyst 1.5.1 software. Melting points were obtained on a Büchi B-545
melting point apparatus. HRMS analyses were performed by
Stenhagen Analys AB, Gothenburg, Sweden.
1,4,7-Tris(tert-butoxycarbonyl)-10-(4-methylphenyl)-1,4,7,10-
tetraazacyclododecane (Table 1, entry 1)
Following the general procedure, a mixture of 1,4,7-tris(tert-bu-
toxycarbonyl)-1,4,7,10-tetraazacyclododecane (1; 102 mg, 0.216
mmol), 4-bromotoluene (39 mg, 0.226 mmol), t-BuONa (30 mg,
0.302 mmol), Pd(OAc)2 (214 μL, 1.07 × 10–2 mmol), and (t-Bu)3P
(69 μL, 1.72 × 10–2 mmol) in α,α,α-trifluorotoluene (1.8 mL) was
heated to 100 °C for 1 h. The crude product was purified by flash
chromatography (SiO2, CH2Cl2–i-PrOH, 80:1 to 60:1) to provide
the title compound as a colorless solid (104 mg, 85%); mp 156–158
°C.
Note: Due to the flexibility of the cyclenes, most reported NMR
spectra contain multiplets belonging to more than one conformer.
The presence of conformers was confirmed using variable temper-
ature NMR of selected examples (see Supporting Information, Fig-
ures S23, S38, and S39).
1,4,7-Tris(cyanomethyl)-1,4,7,10-tetraazacyclododecane
(Table 3, entry 4)
1H NMR (400 MHz, CD2Cl2): δ = 7.04 (AA′XX′, 2 H), 6.67
(AA′XX′, 2 H), 3.63–3.03 (3 br m, 16 H), 2.24 (s, 3 H), 1.46 (s, 18
H), 1.42 (s, 9 H).
13C NMR (101 MHz, CD2Cl2): δ = 156.6, 156.0, 147.8, 130.1,
128.3, 116.4, 79.9, 79.6, 51.1, 50.3, 49.7, 28.74, 28.67, 20.4.
HRMS (ESI): m/z calcd for C30H51N4O6: 563.3803 [M + H]+; found:
563.3809.
A flame-dried and N2-purged round-bottomed flask was charged
with cyclen (250 mg, 1.45 mmol) and Et3N (627 μL, 4.50 mmol).
The mixture was dissolved in anhyd CH2Cl2 (14 mL) and the flask
was immersed in an ice/salt bath (–15 °C). A solution of bromoace-
tonitrile (307 μL, 4.43 mmol) in anhyd CH2Cl2 (16 mL) was added
using a syringe pump (0.3 mL/min). Upon completion of the addi-
tion, the reaction mixture was allowed to warm slowly to r.t. and
was stirred overnight. Phosphate buffer (pH 7, 30 mL) was added
and the aqueous phase was extracted with CH2Cl2 (3 × 10 mL). The
combined organic phases where dried (Na2SO4), filtered, and the or-
ganic solvent was removed in vacuo. The crude product was puri-
fied by flash chromatography (SiO2, CH2Cl2–MeOH, 4:1) to
provide the title compound as a colorless foam (147 mg, 35%).
1,4,7-Tris(tert-butoxycarbonyl)-10-(4-methoxyphenyl)-
1,4,7,10-tetraazacyclododecane (Table 1, entry 2)
Following the general procedure, a mixture of 1 (100 mg, 0.211
mmol), 4-bromoanisole (41 mg, 0.222 mmol), t-BuONa (28 mg,
0.296 mmol), Pd(OAc)2 (210 μL, 1.05 × 10–2 mmol), and (t-Bu)3P
(68 μL, 1.69 × 10–2 mmol) in α,α,α-trifluorotoluene (1.8 mL) was
heated to 120 °C for 1 h. The crude product was purified by flash
chromatography (SiO2, CH2Cl2–i-PrOH, 60:1 to 40:1) to provide
the title compound as a slightly orange solid (101 mg, 83%); mp: a
dark gel formed at 78 °C.
1H NMR (400 MHz, CD2Cl2–CD3CN): δ = 9.42 (br s, 2 H), 7.43 (br
s, 1 H), 3.68 (s, 4 H), 3.60 (s, 2 H), 3.11–2.51 (m, 16 H).
13C NMR (101 MHz, CD2Cl2–CD3CN): δ = 115.9, 114.0, 50.6,
50.1, 48.4, 45.9, 44.4.
HRMS (ESI): m/z calcd for C14H23N7: 290.2088 [M + H]+; found:
290.2093.
1H NMR (400 MHz, CD2Cl2): δ = 6.82 (AA′XX′, 2H), 6.78
(AA′XX′, 2 H), 3.74 (s, 3 H), 3.33 (br m, 16 H), 1.47 (s, 18 H), 1.43
(s, 9 H).
Sodium 2,4,6-Tri-tert-butylphenolate27a
13C NMR (101 MHz, CD2Cl2): δ = 156.5, 155.9, 153.8, 144.1,
A flame-dried and argon-purged round-bottomed flask was charged
with 2,4,6-tri-tert-butylphenol (2 g, 7.62 mmol) and anhyd THF (40
mL). Fine-cut pieces of Na (175 mg, 7.62 mmol) and a small crystal
of I2 was added. A reflux condenser was fitted to the neck of the
flask and the system was slowly brought to reflux and kept refluxing
overnight. The reaction mixture was cooled to r.t. and the solvent
was removed in vacuo (using a rotary evaporator placed inside a
glove box). The resulting white precipitate was filtered, washed
with small amounts of anhyd THF, and further dried overnight un-
der vacuum (~1 mbar) at 100 °C yielding a greenish solid (1.62 g,
75%). 1H NMR spectra showed the presence of the alkoxide without
coordinated THF molecules, in contrast to the previous report.
119.0, 115.0, 79.9, 79.5, 55.9, 49.9, 49.3, 28.7, 28.6.
HRMS (ESI): m/z calcd for C30H51N4O7: 579.3752 [M + H]+; found:
579.3752.
1,4,7-Tris(tert-butoxycarbonyl)-10-(4-dimethylaminophenyl)-
1,4,7,10-tetraazacyclododecane (Table 1, entry 3)
Following the general procedure, a mixture of 1 (103 mg, 0.218
mmol), 4-bromodimethylaniline (46 mg, 0.229 mmol), t-BuONa
(29 mg, 0.305 mmol), Pd(OAc)2 (216 μL, 1.08 × 10–2 mmol), and
(t-Bu)3P (70 μL, 1.74 × 10–2 mmol) in α,α,α-trifluorotoluene (1.8
mL) was heated to 120 °C for 1 h. The crude product was purified
by flash chromatography (SiO2, CH2Cl2–i-PrOH, 50:1) to provide
the title compound as a slightly brown solid (93 mg, 72%); mp: a
thick, black gel formed at 82 °C.
1H NMR (400 MHz, CD2Cl2): δ = 7.10 (s, 2 H), 1.45 (s, 18 H), 1.25
(s, 9 H).
Synthesis 2013, 45, 777–784
© Georg Thieme Verlag Stuttgart · New York

PAPER
N-Arylation of Azamacrocycles
781
1H NMR (400 MHz, CD2Cl2): δ = 6.88 (AA′XX′, 2 H), 6.73
(AA′XX′, 2 H), 3.34 (s, 8 H), 3.28 (s, 8 H), 2.86 (s, 6 H), 1.47 (s, 18
H), 1.44 (s, 9 H).
13C NMR (101 MHz, CD2Cl2): δ = 156.3, 155.8, 145.6, 141.5,
120.1, 114.6, 79.9, 79.4, 50.7, 49.6, 41.7, 28.7, 28.6.
HRMS (ESI): m/z calcd for C31H54N5O6: 592.4069 [M + H]+; found:
592.4074.
tri-tert-butylphenolate (88 mg, 0.310 mmol), Pd(OAc)2 (222 μL,
1.11 × 10–2 mmol), and (t-Bu)3P (71 μL, 1.77 × 10–2 mmol) in
α,α,α-trifluorotoluene (1.8 mL) was heated to 100 °C for 1 h. The
crude product was purified by flash chromatography (SiO2,
CH2Cl2–MeOH, 50:1 to 40:1) to provide the title compound as a
white foam (90 mg, 70%).
1H NMR (400 MHz, CD2Cl2): δ = 9.71 (s, 1 H), 7.70 (AA′XX′, 2
H), 6.73 (AA′XX′, 1 H), 3.64 (br s, 4 H), 3.44 (br s, 8 H), 3.33 (br
m, 4 H), 1.45 (s, 9 H), 1.41 (s, 18 H).
1,4,7-Tris(tert-butoxycarbonyl)-10-(4-dimethylaminophenyl)-
1,4,7,10-tetraazacyclododecane (Table 1, entry 4)
13C NMR (101 MHz, CD2Cl2): δ = 190.1, 157.4, 156.5, 153.2,
Following the general procedure, a mixture of 1 (101 mg, 0.214
mmol), 4-bromodimethylaniline (45 mg, 0.224 mmol), sodium
2,4,6-tri-tert-butylphenolate (85 mg, 0.299 mmol), Pd(OAc)2 (212
μL, 1.06 × 10–2 mmol), and (t-Bu)3P (68 μL, 1.70 × 10–2 mmol) in
α,α,α-trifluorotoluene (1.8 mL) was heated to 120 °C for 1 h. The
crude product was purified by flash chromatography (SiO2,
CH2Cl2–i-PrOH, 50:1) to provide the title compound as a slightly
brown solid (94 mg, 75%); mp: a thick, black gel formed at 82 °C.
1H NMR (400 MHz, CD2Cl2): δ = 6.88 (AA′XX′, 2 H), 6.73
(AA′XX′, 2 H), 3.34 (s, 8 H), 3.28 (s, 8 H), 2.86 (s, 6 H), 1.47 (s, 18
H), 1.44 (s, 9 H).
13C NMR (101 MHz, CD2Cl2): δ = 156.3, 155.8, 145.6, 141.5,
120.1, 114.6, 79.9, 79.4, 50.7, 49.6, 49.0, 41.7, 28.7, 28.6.
HRMS (ESI): m/z calcd for C31H54N5O6: 592.4069 [M + H]+; found:
592.4074.
132.2, 126.2, 112.0, 80.4, 80.3, 54.0, 50.6, 50.5, 49.5, 28.6, 28.5.
HRMS (ESI): m/z calcd for C30H49N4O7: 577.3596 [M + H]+; found:
577.3601.
1,4,7-Tris(tert-butoxycarbonyl)-10-(4-trifluoromethylphenyl)-
1,4,7,10-tetraazacyclododecane (Table 1, entry 8)
Following the general procedure, a mixture of 1 (102 mg, 0.216
mmol), 4-bromotrifluoromethylbenzene (51 mg, 0.226 mmol), t-
BuONa (29 mg, 0.302 mmol), Pd(OAc)2 (214 μL, 1.07 × 10–2
mmol), and (t-Bu)3P (69 μL, 1.72 × 10–2 mmol) in α,α,α-trifluoro-
toluene (1.8 mL) was heated to 80 °C for 1 h. The crude product was
purified by flash chromatography (SiO2, CH2Cl2–i-PrOH, 80:1 to
50:1) to provide the title compound as a slightly yellow foam (112
mg, 84%).
1H NMR (400 MHz, CD2Cl2): δ = 7.44 (AA′XX′, 2 H), 6.69
(AA′XX′, 2 H), 3.58 (t, J = 5.3 Hz, 4 H), 3.41 (d, J = 3.3 Hz, 8 H),
3.29 (s, 4 H), 1.45 (s, 9 H), 1.43 (s, 18 H).
13C NMR (101 MHz, CD2Cl2): δ = 156.7, 156.1, 150.9, 126.3
(J = 3.8 Hz), 125.1 (J = 269.9 Hz), 117.8, 112.0, 79.8, 50.2, 49.0,
28.2, 28.1
1,4,7-Tris(tert-butoxycarbonyl)-10-(4-methylthiophenyl)-
1,4,7,10-tetraazacyclododecane (Table 1, entry 5)
Following the general procedure, a mixture of 1 (100 mg, 0.211
mmol), 4-bromothioanisole (45 mg, 0.222 mmol), t-BuONa (28 mg,
0.296 mmol), Pd(OAc)2 (210 μL, 1.05 × 10–2 mmol), and (t-Bu)3P
(68 μL, 1.69 × 10–2 mmol) in α,α,α-trifluorotoluene (1.8 mL) was
heated to 120 °C for 1 h. The crude product was purified by flash
chromatography (SiO2, CH2Cl2–i-PrOH, 60:1 to 40:1) to provide
the title compound as a slightly yellow solid (104 mg, 82%); mp: a
thick, dark gel formed at 73 °C.
HRMS (ESI): m/z calcd for C30H48F3N4O6: 617.3520 [M + H]+;
found: 617.3526.
1,4,7-Tris(tert-butoxycarbonyl)-10-(3-methoxyphenyl)-
1,4,7,10-tetraazacyclododecane (Table 1, entry 9)
Following the general procedure, a mixture of 1 (89 mg, 0.188
mmol), 3-bromoanisole (37 mg, 0.198 mmol), sodium 2,4,6-tri-tert-
butylphenolate (75 mg, 0.264 mmol), Pd(OAc)2 (188 μL, 9.40 × 10–3
mmol), and (t-Bu)3P (60 μL, 1.50 × 10–2 mmol) in α,α,α-trifluoro-
toluene (1.6 mL) was heated to 100 °C for 1 h. The crude product
was purified by flash chromatography (SiO2, hexane–EtOAc, 5:1)
to provide the title compound as a colorless foam (50 mg, 45%). To
confirm the presence of rotamers variable temperature NMR (VT-
NMR) was run and the spectra are provided in the Supporting Infor-
mation.
1H NMR (400 MHz, CD2Cl2): δ = 7.23 (AA′XX′, 2 H), 6.68
(AA′XX′, 2 H), 3.47 (m, 4 H), 3.36 (m, 8 H), 3.24 (br m, 4 H), 2.40
(s, 3 H), 1.45 (s, 18 H), 1.43 (s, 9 H).
13C NMR (101 MHz, CD2Cl2): δ = 156.5, 148.1, 130.9, 125.6,
115.8, 80.0, 79.8, 50.5, 49.6, 28.7, 28.6, 18.7.
HRMS (ESI): m/z calcd for C30H51N4O6S: 595.3524 [M + H]+;
found: 595.3529.
1,4,7-Tris(tert-butoxycarbonyl)-10-[4-(methoxycarbonyl)phe-
nyl]-1,4,7,10-tetraazacyclododecane (Table 1, entry 6)
Following the general procedure, a mixture of 1 (104 mg, 0.220
mmol), methyl 4-bromobenzoate (50 mg, 0.231 mmol), sodium
2,4,6-tri-tert-butylphenolate (88 mg, 0.308 mmol), Pd(OAc)2 (220
μL, 1.10 × 10–2 mmol), and (t-Bu)3P (70 μL, 1.76 × 10–2 mmol) in
α,α,α-trifluorotoluene (1.8 mL) was heated to 100 °C for 1 h. The
crude product was purified by flash chromatography (SiO2,
CH2Cl2–MeOH, 50:1 to 40:1) to provide the title compound as a
white foam (107 mg, 80%).
1H NMR (400 MHz, CD2Cl2): δ = 7.85 (AA′XX′, 2 H), 6.66
(AA′XX′, 2 H), 3.81 (s, 3 H), 3.61 (br s, 4 H), 3.42 (br s, 8 H), 3.32
(br s, 4 H), 1.44 (s, 9 H), 1.42 (s, 18 H).
13C NMR (101 MHz, CD2Cl2): δ = 167.4, 157.1, 156.6, 152.3,
131.6, 118.1, 111.9, 80.2, 51.7, 50.6, 49.6, 28.6, 28.5.
1H NMR (500 MHz, CD2ClCD2Cl, 30 °C): δ = 7.12 (t, J = 8.2 Hz,
1 H), 6.34 (td, J = 8.2, 2.1 Hz, 2 H), 6.28 (t, J = 2.1 Hz, 1 H), 3.76
(s, 3 H), 3.56–3.42 (m, 4 H), 3.42–3.32 (m, 8 H), 3.25 (br m, 4 H),
1.46 (s, 18 H), 1.44 (s, 9 H).
13C NMR (126 MHz, CD2ClCD2Cl): δ = 159.6, 156.5, 154.8, 154.5,
150.8, 129.4, 108.7, 101.7, 101.1, 79.3, 78.9, 78.6, 57.7, 54.6, 51.9,
50.53, 50.46, 49.9, 27.7, 27.6.
HRMS (ESI): m/z calcd for C30H51N4O7: 579.3752 [M + H]+; found:
579.3758.
1,4,7-Tris(tert-butoxycarbonyl)-10-[3-(methoxycarbonyl)phe-
nyl]-1,4,7,10-tetraazacyclododecane (Table 1, entry 10)
Following the general procedure, a mixture of 1 (94 mg, 0.199
mmol), methyl-3-bromomethylbenzoate (45 mg, 0.209 mmol), so-
dium 2,4,6-tri-tert-butylphenolate (80 mg, 0.278 mmol), Pd(OAc)2
(198 μL, 9.90 × 10–3 mmol), and (t-Bu)3P (64 μL, 1.59 × 10–2
mmol) in α,α,α-trifluorotoluene (1.7 mL) was heated to 100 °C for
1 h. The crude product was purified by flash chromatography (SiO2,
hexane–EtOAc, 5:1) to provide the title compound as a colorless
foam (49 mg, 40%).
HRMS (ESI): m/z calcd for C31H52N4O8: 607.3701 [M + H]+; found:
607.3707.
1,4,7-Tris(tert-butoxycarbonyl)-10-[(4-formyl)phenyl]-1,4,7,10-
tetraazacyclododecane (Table 1, entry 7)
Following the general procedure, a mixture of 1 (105 mg, 0.222
mmol), 4-bromobenzaldehyde (43 mg, 0.233 mmol), sodium 2,4,6-
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 777–784

782
A. X. Veiga et al.
PAPER
1H NMR (500 MHz, CD2ClCD2Cl, 65 °C): δ = 7.45 (d, J = 7.6 Hz,
1 H), 7.39 (s, 1 H), 7.32 (dd, J = 7.9 Hz, 1 H), 6.94 (dd, J = 8.2, 1.9
Hz, 1 H), 3.91 (s, 3 H), 3.56 (t, J = 8.2, 4.6 Hz, 4 H), 3.44 (m, 8 H),
3.31 (br m, 4 H), 1.48 (m, 27 H).
13C NMR (126 MHz, CD2ClCD2Cl, 105 °C): δ = 167.1, 156.05,
155.97, 149.1, 131.1, 129.1, 119.15, 119.0, 114.7, 79.8, 79.6, 53.2,
51.6, 50.2, 49.8, 49.1, 29.4, 28.4, 28.37.
pound as a hygroscopic white solid (67 mg, 89%); mp: not
determined (Lit.36 mp: not reported).
1H NMR (400 MHz, CD2Cl2): δ = 7.00 (AA′XX′, 2 H), 6.61
(AA′XX′, 2 H), 3.51 (m, 6 H), 3.26 (t, J = 5.9 Hz, 1 H), 3.18 (t,
J = 5.9 Hz, 1 H), 2.21 (s, 3 H), 1.94 (m, 2 H), 1.41 (s, 5 H), 1.33 (s,
4 H).
The analytical data were in agreement with those reported in the lit-
erature.36
HRMS (ESI): m/z calcd for C31H51N4O8: 607.3701 [M + H]+; found:
607.3707.
1,4-Bis(tert-butoxycarbonyl)-7-(4-methylphenyl)-1,4,7-tri-
azacyclononane (Table 2, entry 3)
1,4,7-Tris(tert-butoxycarbonyl)-10-(2-pyridinyl)-1,4,7,10-tetra-
azacyclododecane (Table 1, entry 11)
Following the general procedure, a mixture of 1,4-bis(tert-butoxy-
carbonyl)-1,4,7-triaazacyclononane (103 mg, 0.313 mmol), 4-bro-
motoluene (56 mg, 0.328 mmol), sodium 2,4,6-tri-tert-
butylphenolate (124 mg, 0.438 mmol), Pd(OAc)2 (312 μL,
1.56 × 10–2 mmol) and (t-Bu)3P (100 μL, 2.50 × 10–2 mmol) in
α,α,α-trifluorotoluene (2.7 mL) was heated to 100 °C for 1 h. The
crude product was purified by flash chromatography (SiO2, hexane–
EtOAc, 10:1) to provide the title compound as a white solid (125
mg, 95%); mp 113–116 °C.
Following the general procedure, a mixture of 1 (102 mg, 0.216
mmol), 2-bromopyridine (36 mg, 0.226 mmol), t-BuONa (29 mg,
0.302 mmol), Pd(OAc)2 (214 μL, 1.07 × 10–2 mmol), and (t-Bu)3P
(69 μL, 1.72 × 10–2 mmol) in α,α,α-trifluorotoluene (1.8 mL) was
heated to 100 °C for 1 h. The crude product was purified by flash
chromatography (SiO2, hexane–EtOAc, 2:1 to 1:1) to provide the ti-
tle compound as a slightly brown foam (48 mg, 40%). The analyti-
cal data were in agreement with the literature.16a
1H NMR (400 MHz, CD2Cl2, rotamers): δ = 7.02–6.97 (m, 2 H),
6.63–6.58 (m, 2 H), 3.57–3.45 (m, 4 H), 3.45–3.31 (m, 8 H), 1.47
(s, 9 H), 1.39 (s, 5 H), 1.36 (s, 4 H).
13C NMR (101 MHz, CD2Cl2, rotamers): δ = 156.03, 155.97, 155.8,
146.6, 146.2, 130.1, 130.0, 126.1, 125.9, 125.7, 113.2, 113.0, 112.9,
79.9, 79.8, 79.8, 53.25, 53.18, 53.0, 51.9, 51.0, 50.0, 49.9, 49.8,
49.6, 40.9, 48.6, 28.7, 28.6, 28.52, 28.46, 20.3.
1,4,7-Tris(tert-butoxycarbonyl)-10-[6-(2-methylquinolidinyl)]-
1,4,7,10-tetraazacyclododecane (Table 1, entry 12)
Following the general procedure, a mixture of 1 (105 mg, 0.222
mmol), 6-bromo-2-methylquinoline (52 mg, 0.233 mmol), sodium
2,4,6-tri-tert-butylphenolate (88 mg, 0.311 mmol), Pd(OAc)2 (222
μL, 1.11 × 10–2 mmol), and (t-Bu)3P (71 μL, 1.77 × 10–2 mmol) in
α,α,α-trifluorotoluene (1.8 mL) was heated to 120 °C for 1 h. The
crude product was purified by preparative HPLC (ACE 5 C18-PFP,
250 × 20 mm, isocratic H2O–MeOH, 20:80, 17 mL/min) to provide
the title compound as a colorless foam (82 mg, 60%).
HRMS (ESI): m/z calcd for C23H38N3O4: 420.2857 [M + H]+; found:
420.2862.
1H NMR (400 MHz, CD2Cl2): δ = 7.86 (d, J = 8.4 Hz, 1 H), 7.81 (d,
J = 9.3 Hz, 1 H), 7.23 (dd, J = 9.3, 2.8 Hz, 1 H), 7.18 (d, J = 8.4 Hz,
1 H), 6.85 (d, J = 2.8 Hz, 1 H), 3.60 (br s, 4 H), 3.51–3.33 (m, 8 H),
3.22 (br m, 4 H), 2.62 (s, 3 H), 1.47 (s, 17 H), 1.43 (s, 10 H).
13C NMR (151 MHz, CD2Cl2): δ = 156.6, 156.2, 155.7, 147.0,
143.0, 134.7, 130.0, 127.9, 122.5, 121.6, 108.1, 80.1, 79.8, 78.2,
51.0, 50.6, 28.6, 25.0.
1,4,8-Tris(tert-butoxycarbonyl)-11-(4-methylphenyl)-1,4,8,11-
tetraazacyclotetradodecane (Table 2, entry 5)
Following the general procedure, a mixture of 1,4,8-tris(tert-but-
oxycarbonyl)-1,4,8,11-tetraaazacyclotetradodecane (55 mg, 0.110
mmol), 4-bromotoluene (20 mg, 0.115 mmol), sodium 2,4,6-tri-
tert-butylphenolate (44 mg, 0.154 mmol), Pd(OAc)2 (110 μL,
5.40 × 10–3 mmol), and (t-Bu)3P (35 μL, 8.70 × 10–3 mmol) in
α,α,α-trifluorotoluene (1 mL) was heated to 100 °C for 1 h. The
crude product was purified by flash chromatography (SiO2, hexane–
EtOAc, 3:1) to provide the title compound as a white foam (56 mg,
86%).
HRMS (ESI): m/z calcd for C33H52N5O6: 614.3912 [M + H]+; found:
614.3918.
N-(tert-Butoxycarbonyl)-N'-(4-methylphenyl)piperazine
(Table 2, entry 1)
1H NMR (400 MHz, CD2Cl2): δ = 6.99 (AA′XX′, 2 H), 6.68
(AA′XX′, 2 H), 3.48–3.15 (m, 16 H), 2.22 (s, 3 H), 1.90–1.71 (m, 4
H), 1.48 (s, 9 H), 1.46 (s, 9 H), 1.43 (s, 9 H).
13C NMR (101 MHz, CD2Cl2): δ = 156.0, 155.9, 147.3, 130.0,
126.5, 113.7, 79.9, 79.8, 79.7, 51.6, 49.9, 48.9, 47.4, 46.7, 30.1,
28.61, 28.60, 28.57, 20.3.
Following the general procedure, a mixture of N-(tert-butoxycar-
bonyl)piperazine (50 mg, 0.268 mmol), 4-bromotoluene (48 mg,
0.282 mmol), sodium 2,4,6-tri-tert-butylphenolate (107 mg, 0.376
mmol), Pd(OAc)2 (268 μL, 1.34 × 10–2 mmol), and (t-Bu)3P (86 μL,
2.14 × 10–2 mmol) in α,α,α-trifluorotoluene (2.3 mL) was heated to
100 °C for 1 h. The crude product was purified by flash chromatog-
raphy (SiO2, hexane–EtOAc, 50:1 to 10:1) to provide the title com-
pound as a white solid (71 mg, 96%); mp 103–106 °C (Lit.35 mp 105
°C).
HRMS (ESI): m/z calcd for C32H55N4O6: 591.4116 [M + H]+; found:
591.4122.
1,4,7-Tris(benzyloxycarbonyl)-10-(4-methylphenyl)-1,4,7,10-
tetraazacyclododecane (Table 3, entry 1)
1H NMR (400 MHz, CD2Cl2): δ = 7.06 (AA′XX′, 2 H), 6.82
(AA′XX′, 2 H), 3.58-3.49 (m, 4 H), 3.08–3.00 (m, 4 H), 2.25 (s, 3
H), 1.45 (s, 9 H).
Following the general procedure, a mixture of 1,4,7-tris(benzyloxy-
carbonyl)-1,4,7,10-tetraazacyclododecane (102 mg, 0.177 mmol),
4-bromotoluene (32 mg, 0.186 mmol), t-BuONa (24 mg, 0.248
mmol), Pd(OAc)2 (176 μL, 8.80 × 10–3 mmol), and (t-Bu)3P (57 μL,
1.41 × 10–2 mmol) in α,α,α-trifluorotoluene (1.6 mL) was heated to
100 °C for 1 h. The crude product was purified by flash chromatog-
raphy (SiO2, CH2Cl2–i-PrOH, 60:1) to provide the title compound
as a white foam (102 mg, 86%).
The analytical data were in agreement with those reported in the lit-
erature.35
N-1-(tert-Butoxycarbonyl)-4-(4-methylphenyl)-1,4-diazepane
(Table 2, entry 2)
Following the general procedure, a mixture of 1-Boc-homopipera-
zine (52 mg, 0.260 mmol), 4-bromotoluene (47 mg, 0.272 mmol),
sodium 2,4,6-tri-tert-butylphenolate (103 mg, 0.363 mmol),
Pd(OAc)2 (258 μL, 1.29 × 10–2 mmol) and (t-Bu)3P (83 μL,
2.07 × 10–2 mmol) in α,α,α-trifluorotoluene (2.3 mL) was heated to
100 °C for 1 h. The crude product was purified by flash chromatog-
raphy (SiO2, hexane–EtOAc, 50:1 to 10:1) to provide the title com-
1H NMR (400 MHz, CD2Cl2): δ = 7.48–7.19 (m, 15 H), 7.05
(AA′XX′, 2 H), 6.69 (AA′XX′, 2H), 5.13 (s, 4 H), 5.01 (s, 2 H), 3.33
(br s, 16 H), 2.27 (s, 3 H).
13C NMR (101 MHz, CD2Cl2): δ = 157.0, 156.4, 147.7, 137.5,
137.3, 130.2, 128.8, 128.7, 128.5, 128.4, 128.2, 128.0, 117.9, 67.3,
67.1, 50.6, 49.9, 49.4, 20.5.
Synthesis 2013, 45, 777–784
© Georg Thieme Verlag Stuttgart · New York

PAPER
N-Arylation of Azamacrocycles
783
HRMS (ESI): m/z calcd for C39H45N4O6: 665.3334 [M + H]+; found:
665.3339.
(6) Krivickas, S. J.; Tamanini, E.; Todd, M. H.; Watkinson, M.
J. Org. Chem. 2007, 72, 8280.
(7) Michinobu, T.; Shinoda, S.; Nakanishi, T.; Hill, J. P.; Fujii,
K.; Player, T. N.; Tsukube, H.; Ariga, K. Phys. Chem. Chem.
Phys. 2011, 13, 4895.
(8) Li, N.; English, C.; Eaton, A.; Gillespie, A.; Ence, T. C.;
Christensen, T. J.; Sego, A.; Harrison, R. G.; Lamb, J. D.
J. Chromatogr., A 2012, 1245, 83.
(9) Wu, W.; Lei, P.; Liu, Q.; Hu, J.; Gunn, A. P.; Chen, M.; Rui,
Y.; Su, A.; Xie, Z.; Zhao, Y.-F.; Bush, A. I.; Li, Y. J. Biol.
Chem. 2008, 14, 31657.
(10) Pasey, S. J.; Sadler, P. J. Chem. Commun. 2004, 306.
(11) Suchý, M.; Hudson, R. H. E. Eur. J. Org. Chem. 2008, 73,
4847.
(12) Ravikumar, I.; Ghosh, P. Chem. Soc. Rev. 2012, 41, 3077.
(13) Erdélyi, M.; d’Auvergne, E.; Navarro-Vázquez, A.; Leonov,
A.; Griesinger, C. Chem. Eur. J. 2011, 17, 9368.
(14) Bühlmann, P.; Chen, L. D. Supramolecular Chemistry:
From Molecules to Nanomaterials; Wiley: New York, 2012,
2540.
1,4,7-Tris(formyl)-10-(4-methylphenyl)-1,4,7,10-tetraazacy-
clododecane (Table 3, entry 2)
Following the general procedure, a mixture of 1,4,7-tris(formyl)-
1,4,7,10-tetraazacyclododecane (106 mg, 0.414 mmol), 4-bromo-
toluene (74 mg, 0.434 mmol), sodium 2,4,6-tri-tert-butylphenolate
(165 mg, 0.578 mmol), Pd(OAc)2 (412 μL, 2.06 × 10–2 mmol) and
(t-Bu)3P (132 μL, 3.30 × 10–2 mmol) in α,α,α-trifluorotoluene–1,4-
dioxane (1:1, 3.5 mL) was heated to 100 °C for 1 h. The crude prod-
uct was purified by flash chromatography (SiO2, CH2Cl2–MeOH,
1:40) to provide the title compound as a white foam (86 mg, 60%).
The presence of rotamers in the acquired NMR spectra was con-
firmed by VT-NMR. The spectra at various temperatures are pro-
vided in the Supporting Information.
1H NMR (500 MHz, CD2Cl2): δ = 8.17–7.78 (several singlets, 3 H),
7.22–7.12 (m, 2 H), 7.01–6.96 (m, 1.2 H), 6.95–6.92 (m, 0.6 H),
6.88 (d, J = 8.4 Hz, 0.2 H), 3.80–3.74 (m, 0.4 H), 3.72–3.57 (m, 4.3
H), 3.58–3.51 (m, 1.3 H), 3.48–3.19 (m, 10 H).
13C NMR (126 MHz, CD2ClCD2Cl): δ = 165.0, 164.6, 164.4, 164.3,
164.2, 164.1, 164.0, 163.90, 163.86, 163.8, 163.54, 163.52, 147.5,
147.2, 147.1, 134.2, 134.0, 133.2, 130.7, 130.65, 130.4, 123.0,
122.7, 122.2, 121.4, 59.5, 57.4, 56.3, 55.4, 55.3, 54.4, 53.0, 52.1,
51.4, 50.3, 49.5, 48.4, 48.2, 48.0, 47.6, 47.5, 47.1, 47.0, 46.0, 45.8,
45.4, 45.0, 44.8, 44.6, 44.3, 43.9, 43.7, 43.4, 43.2, 43.1, 20.8, 20.74,
20.72, 20.70.
(15) Zhang, X.-X.; Buchwald, S. L. J. Org. Chem. 2000, 65,
8027.
(16) (a) Subat, M.; König, B. Synthesis 2001, 1818. (b) Stasny,
V.; Lhoták, P.; Stibor, I.; König, B. Tetrahedron 2006, 62,
5748. (c) Nakanishi, M.; Bolm, C. Adv. Synth. Catal. 2006,
348, 1823. (d) Burdette, S. C.; Lippard, S. J. Inorg. Chem.
2002, 41, 6816. (e) Beletskaya, I. P.; Averin, A. D.;
Bessmertnykh, A. G.; Denat, F.; Guilard, R. Tetrahedron
Lett. 2002, 43, 1193. (f) Beletskaya, I. P.; Bessmertnykh, A.
G.; Averin, A. D.; Denat, F.; Guillard, R. Eur. J. Org. Chem.
2005, 281. (g) Beletskaya, I. P.; Averin, A. D. Pure Appl.
Chem. 2004, 76, 1605.
HRMS (ESI): m/z calcd for C18H27N4O3: 347.2078 [M + H]+; found:
347.2083.
Acknowledgment
(17) Russo, F.; Odell, L. R.; Olofsson, K.; Nilsson, P.; Larhed, M.
In Microwaves in Organic Synthesis, 3rd ed., Vol. 2; de la
Hoz, A.; Loupy, A., Eds.; Wiley-VCH: Weinheim, 2012,
607–671.
(18) (a) Wan, Y.; Alterman, M.; Hallberg, A. Synthesis 2002,
1597. (b) Sharifi, A.; Hosseinzadeh, R.; Mirzaei, M.
Monatsh. Chem. 2002, 133, 329. (c) Loones, K. T. J.; Maes,
B. U. W.; Rombouts, G.; Hostyn, S.; Diels, G. Tetrahedron
2005, 61, 10338.
The research leading to these results has received funding from the
European Union Seventh Framework Programme (FP7/2007-2013)
under grant agreement Nr. 259638. The support of the Swedish Re-
search Council (2011:4407) and the Carl Tryggers Foundation
(2010:95) is gratefully acknowledged. We thank Shawn C. Burdette
(Worcester Polytechnic Institute, USA) and Stephen J. Lippard
(Dept. of Chemistry, MIT, USA) for helpful discussion.
(19) (a) Hartwig, J. F.; Richards, S.; Baranano, D.; Paul, F. J. Am.
Chem. Soc. 1996, 118, 3626. (b) Baranano, D.; Hartwig, J. F.
J. Am. Chem. Soc. 1995, 117, 2937.
(20) Ogawa, A.; Curran, D. P. J. Org. Chem. 1997, 62, 450.
(21) Smith, J. A.; Jones, R. K.; Booker, G. W.; Pyke, S. M.
J. Org. Chem. 2008, 73, 8880.
(22) Hennings, D. D.; Iwama, T.; Rawal, V. H. Org. Lett. 1999,
8, 1205.
(23) Erdélyi, M.; Gogoll, A. J. Org. Chem. 2001, 66, 4165.
(24) Tundel, R. E.; Anderson, K. W.; Buchwald, S. L. J. Org.
Chem. 2006, 71, 430.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis. Included
are 1H and 13C NMR spectra.SungIoifnp
rioatmtrSupgnIopifoarmtrn
References
(1) (a) Urbanczyk-Pearson, L. M.; Meade, T. J. Nature Prot.
2008, 3, 341. (b) Werner, E. J.; Datta, A.; Jocher, C. J.;
Raymond, K. N. Angew. Chem. Int. Ed. 2008, 47, 8568.
(c) Merebach, A. E.; Tóth, É. The Chemistry of Contrast
Agents in Medical Magnetic Resonance Imaging; Wiley:
New York, 2001.
(25) Jensen, T. A.; Liang, X.; Tanner, D.; Skjaerbaek, N. J. Org.
Chem. 2004, 69, 4936.
(2) (a) Häussinger, D.; Huan, J.; Grzesiek, S. J. Am. Chem. Soc.
2009, 131, 1461. (b) Almeida, R. M.; Geraldes, C. F. G. C.;
Pauleta, S. R.; Moura, J. J. G. Inorg. Chem. 2011, 50, 10600.
(3) (a) Pershagen, E.; Nordholm, J.; Borbás, K. E. J. Am. Chem.
Soc. 2012, 134, 9832. (b) Chen, T.; Wang, X.; He, Y.;
Zhang, C.; Wu, Z.; Liao, K.; Wang, J.; Guo, Z. Inorg. Chem.
2009, 48, 5801. (c) Yu, M.; Price, J. R.; Jensen, P.; Lovitt, C.
J.; Shelper, T.; Duffy, S.; Windus, L. C.; Avery, V. M.;
Rutledge, P. J.; Todd, M. H. Inorg. Chem. 2011, 50, 12823.
(4) Butler, S. J.; Parker, D. Chem Soc. Rev. 2013, 42, 1652.
(5) (a) Pasquale, S.; Sattin, S.; Escudero-Adán, E. C.; Martinez-
Belmonte, M.; de Mendoza, J. Nature Commun. 2012, 3,
785. (b) Pieters, G.; Cazzolaro, A.; Bonomi, R.; Prins, L. J.
Chem. Commun. 2012, 48, 1916.
(26) Schulle, J. P. II; Tweedie, S. R. Synlett 2007, 2331.
(27) (a) Alcazar-Roman, L. M.; Hartwig, J. F. J. Am. Chem. Soc.
2001, 123, 12905. (b) Martinelli, J. R.; Clark, T. P.; Watson,
D. A.; Munday, R. H.; Buchwald, S. L. Angew. Chem. Int.
Ed. 2004, 46, 8612.
(28) For ortho-substituted substrates, a β-hybride elimination
was observed, as discussed in larger detail in: Muci, A. R.;
Buchwald, S. R. Top. Curr. Chem. 2002, 219, 131.
(29) (a) Yoo, J.; Reichert, D. E.; Welch, M. J. Chem. Commun.
2003, 766. (b) Yoo, J.; Reichert, D. E.; Welch, M. J. J. Med.
Chem. 2004, 47, 6625. (c) Boldrini, V.; Giovenzana, G. B.;
Pagliarin, R.; Palmisano, G.; Sisti, M. Tetrahedron Lett.
2000, 41, 6527.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 777–784

784
A. X. Veiga et al.
PAPER
(30) Kawamura, M.; Hashihayata, T.; Sunami, S.; Sugimoto, T.;
Yamamoto, F.; Sato, Y.; Kamijom, K.; Mitsuya, M.;
Iwasawa, Y.; Komatani, H. (Merck Sharp & Dohme
Limited) EP 1790650A1, 2007.
(31) (a) Jablonski, L.; Billard, T.; Langois, B. R. Tetrahedron
Lett. 2003, 44, 1055. (b) Joubert, J.; Roussel, S.; Christophe,
C.; Billard, T.; Langlois, B. R.; Vidal, T. Angew. Chem. Int.
Ed. 2003, 42, 3133. (c) Jablonski, L.; Joubert, J.; Billard, T.;
Langlois, B. R. Synlett 2003, 230.
Lippard, S. J. Inorg. Chem. 2002, 41, 6816. (c) Yang, W.;
Giandomenico, C. M.; Sartori, M.; Moore, D. A.
Tetrahedron Lett. 2002, 43, 2481. (d) Boldrini, V.;
Givenzana, G. B.; Pagliarin, R.; Palmisano, G.; Sisti, M.
Tetrahedron Lett. 2000, 41, 6527. (e) Li, C.; Wong, W. T.
Tetrahedron 2004, 60, 5595. (f) Jagadish, B.; Brickert-
Albrecht, G. L.; Nichol, G. S.; Mash, E. A.; Raghunand, N.
Tetrahedron Lett. 2011, 52, 2058. (g) Fabbrizzi, L.; Foti, F.;
Lichelli, M.; Maccarini, P. M.; Sacchi, D.; Zema, M. Chem.
Eur. J. 2002, 8, 4965. (h) Nadler, A.; Hain, C.; Diederichsen,
U. Eur. J. Org. Chem. 2009, 4593.
(32) Hyemi, K.; Kyung-Soo, M.; Soyoung, S.; Jinsung, T. Chem.
Asian J. 2011, 6, 1987.
(33) Armarego, W. L. F.; Perrin, D. D. Purification of Laboratory
Chemicals; Butterworth Heinemann: Oxford, 2000.
(34) (a) Woods, M.; Kiefer, G. E.; Bott, S.; Castillo-Muzquiz, A.;
Eshelbrenner, C.; Michaudet, L.; McMillan, K.; Mudigunda,
S. D.; Ogrin, D.; Tircsó, G.; Zhang, S.; Zhao, P.; Sherry, D.
J. Am. Chem. Soc. 2004, 126, 9248. (b) Burdette, S. C.;
(35) Cawley, M. J.; Cloke, F. G. N.; Fitzmaurice, R. J.; Pearson,
S. E.; Scott, J. S.; Caddick, S. Org. Biomol. Chem. 2008, 6,
2820.
(36) Schön, U.; Messinger, J.; Buckendahl, M.; Prabhu, M. S.;
Konda, A. Tetrahedron 2009, 65, 8125.
Synthesis 2013, 45, 777–784
© Georg Thieme Verlag Stuttgart · New York