Beneficial effect of Mukaiyama reagent on macrobislactamization reactions

Article abstract of DOI:10.1055/s-2006-956483

An expeditious two-step procedure was developed to accede to new tetraamide macrocycles. The key step of this diversity-oriented procedure is a highly efficient Mukaiyama salt promoted macrobislactamization. Preliminary mechanistic investigations are also

Full text of DOI:10.1055/s-2006-956483

LETTER
3423
Beneficial Effect of Mukaiyama Reagent on Macrobislactamization Reactions
Effect of
Mukai
u
yam
a
Reage
c
nt on
M
acr
i
obislact
e
amizationReacti
V
ons andromme, David Monchaud, Marie-Paule Teulade–Fichou*
Laboratoire de Chimie des Interactions Moléculaires (CNRS, UPR285), Collège de France, 11 Place Marcelin Berthelot, 75005 Paris,
France
Fax +33(1)44271356; E-mail: mp.teulade-fichou@college-de-france.fr
Received 28 September 2006
theses. In that sense, the possibility of performing chal-
Abstract: An expeditious two-step procedure was developed to ac-
lenging, and unreported, macrobislactamization step
cede to new tetraamide macrocycles. The key step of this diversity-
between readily accessible dianilines and diacid moieties
was investigated.
oriented procedure is a highly efficient Mukaiyama salt promoted
macrobislactamization. Preliminary mechanistic investigations are
also reported.
We first focused our attention on the cyclization precur-
sors, namely the trisbenzo-, dibenzopyrido- and trispyri-
dodiamine 6, 7 and 8, respectively (Scheme 1). The
synthesis of 7 was reported by Sessler et al. as a three-step
procedure (80% yield),5 based on reaction between acti-
vated dipicolinic acid and mono-protected phenylene di-
amine. We developed an alternative three-step pathway to
obtain 7 and 8, based on classical N-ethyl-N¢-(3-dimethyl-
aminopropyl)carbodiimide (EDCI)-promoted coupling
reaction between dipicolinic acid and mono-protected
diamine (ortho-phenylene diamine and 3,4-diaminopyri-
dine, respectively); the subsequent acidic deprotection af-
forded 7 and 8 with good overall chemical yield (56% and
87% respectively, Scheme 1). More interestingly, we ob-
served that phenylene diamine can be coupled directly
without any particular reagent protection or activation,
which could be a major advantage to scale up the process.
The access to 6 and 7 was thus readily shortened to a one-
step procedure, with good yields (81% and 77% respec-
tively, Scheme 1).6
Key words: tetraamide macrocycles, Mukaiyama reagent, macro-
bislactamization
Tetraamide macrocycles have not been thoroughly ex-
ploited in host–guest chemistry,1 although they present in-
teresting electronic (aromaticity), structural (rigidity) and
coordination (convergent H-bond donating N–H amide
groups) properties.2 This low solicitation may originate
from the difficulties encountered to synthetically accede
to them, despite their apparent structural simplicity. We
were particularly surprised not to find any general route
for the synthesis of tetraaromatic tetraamide macrocycles
(Figure 1), with the exception of a brief communication
reporting on the positive effect of molecular crowding on
macrocyclization.3
O
O
O
O
X
Y
Our first idea was to benefit from the widely used pyridine
pre-organization via internal H-bond network (schemati-
cally represented as dotted line in Scheme 2).2 First mac-
robislactamization reactions were thus attempted with 7
and 8, following the classical Ruggli’s procedure,7 i.e.
high dilution conditions and slow addition of activated di-
acids. To our surprise, we were unable to isolate cyclized
products upon reaction between 7 and a broad panel of di-
acids. More astonishingly, only the starting material was
recovered when the reactions were performed with 8, de-
spite considerable efforts in varying the conditions. This
lack of reactivity seemed general since extensive trials al-
ways resulted in the same conclusions. The reactivity of 7
and 8 was then further investigated. Under more reactive
conditions as compared to macrocyclization ones (i.e. 3
equiv of more reactive AcCl) we obtained only moderate
amount of bisacetyl-7 and unmodified 8. These results
were explained by a complete deactivation of NH2 moiety
by the intracyclic nitrogen in para position in 8, besides a
steric hindrance which is invoked to explain the low reac-
tivity of 7.
NH
NH
HN
HN
NH
NH
HN
HN
Z
Z
O
O
O
O
1
2: X = N and Y, Z = CH
3: X, Y = N and Z = CH
4: X, Z = N and Y = CH
5: X, Y, Z = N
Figure 1 Structures of targeted tetraamide macrocycles
In this context, and stimulated by recent reports on struc-
turally related compounds,2,4,5 we decided to investigate
the possibilities to synthesize tetraaromatic tetraamide
macrocycles. To this purpose, we focused our attention on
macrocycles ranging form previously reported tetraben-
zotetraamide to unknown tetrapyridotetraamide macrocy-
cles (1 and 5, respectively, Figure 1). Our initial plan was
devoted to establish short, convenient and scalable syn-
SYNLETT 2006, No. 20, pp 3423–3426
Advanced online publication: 08.12.2006
DOI: 10.1055/s-2006-956483; Art ID: G31006ST
© Georg Thieme Verlag Stuttgart · New York
1
8
.1
2
.2
0
0
6
To circumvent these reactivity problems, we turned our
attention to Mukaiyama’s reagent (N-methyl-2-chloro-
pyridinium iodide, Scheme 2). This salt has been widely

3424
L. Vandromme et al.
LETTER
NH2
R = H
Z
i
R = Boc
O
O
NHR
X
ii, iii
NH
HN
Z
Z
O
O
X
NH2
H2N
iv
OH
OH
6: X, Z = CH
NH2
NH2
7: X = N, Z = CH
8: X, Z = N
Scheme 1 Synthesis of 6, 7 and 8. Reagents and conditions: (i) (Boc)2O, THF, 77% (Z = CH), 100% (Z = N); (ii) EDCI, 1-hydroxyaza-
benzotriazole (HOAt), DMF, 100% (Z = CH), 99% (Z = N); (iii) TFA, CH2Cl2, 100% (7; X = N, Z = CH), 88% (8; Z, X = N); (iv) EDCI, HOAt,
DMF, 81% (6; X = CH) and 77% (7; X = N). See ref.6 for detailed experimental conditions.
used to perform lactamization reactions,8 bis- (<2%) were obtained upon reaction between 7 and the
lactamization9 and very efficient macrolactamization,10 geometrically non-optimized ortho- or para-disubstituted
but never for achieving concomitant macrobislactamiza- benzenedioic acid [phthalic (D) and terephthalic (E) acid,
tion. This reaction is generally assumed to involve an respectively]. Furthermore, we observed that, when the
intermediate resulting from ipso-substitution of highly re- substrate offers suitable geometrical dispositions (two
active chlorine atom by carboxylic function. It was thus acid functions in meta position), additional organizations
appealing to postulate that this intermediate could exist as (e.g. internal H-bonds) are not required. Indeed, as depict-
bispyridinium 9 (Scheme 2). Interestingly, this postulated ed in Table 1, the synthesis of macrocycle 2 was of com-
intermediate exhibits a remarkable shape complemen- parable efficiency when conducted with the internally H-
tarity with 7 (and/or 8). This could highly favor the forma- bonded 7 (upon reaction with diacid A, 73%) or with 6
tion of an organized transition state, based on the perfect (upon reaction with diacid B, 82%). The efficiency of the
p-stacking overlap between 7 and 9 (schematically re- process was evidenced by the high yielding synthesis of 1,
presented in Scheme 2).
from 6 and A which are not prone to internal organization
(85%, Table 1).
To investigate this hypothesis, we tried to obtain macro-
cycles 2 and 3 following the classically reported lactam- Altogether these observations strongly support the forma-
ization protocol: a diluted dichloromethane solution of tion of the highly ordered transition state, which in turn
dipicolinic or isophthalic acid and 7 was heated at reflux greatly enhances the overall reactivity of the system.
overnight in presence of 2.5 equivalents of pyridinium salt However, we have so far not been able to isolate the reac-
and five equivalents of tri-n-butylamine (to scavenge re- tion intermediate 9 in order to fully confirm our hypothe-
leased HI and HCl). The reaction mixture was then sis.
cooled, and the final product precipitated upon addition of
Results are summarized in Table 1; only trisbenzo- and
diethyl ether. Macrocycles 2 and 3 were isolated in excel-
dibenzopyridodiamine 6 and 7 reacted under these condi-
lent yields (73% and 71%, respectively) and purity.6 In
tions, for reactivity reasons presented previously. Howev-
er, results obtained with 6 and 7 are quite impressive since
macrocycles 1, 2 and 3 were readily obtained in the yields
contrast, the reaction proceeded in only moderate yield
(29%) when conducted with 7 and the monoacid isobu-
tanoic acid (C, Table 1). Additionally, very low yields
I–
N
O
N
O
N
Cl
upon interaction
with 7
O
O
O
O
N
N
Mukaiyama
salt (2.5 equiv)
OH
OH
9
7
O
O
O
O
O
N
N
n-Bu3N
(5 equiv)
N
N
NH
NH
HN
H
H
N
N
O
NH2
O
H2N
HN
O
[n-Bu3NH][Cl]
O
N
and [n-Bu3NH][I]
N
O
9
3
Scheme 2 Mechanistic proposals for macrobislactamization reaction between dipicolinic acid and 7.
Synlett 2006, No. 20, 3423–3426 © Thieme Stuttgart · New York

LETTER
Effect of Mukaiyama Reagent on Macrobislactamization Reactions
3425
of 70–85%. This reaction appears somewhat sensitive to
electronic factors. Indeed, while the introduction of elec-
References and Notes
(1) (a) Schneider, H. J.; Yatsimirski, A. Principles and Methods
in Supramolecular Chemistry; Wiley: Somerset, 2000.
(b) Lehn, J.-M. Supramolecular Chemistry: Concepts and
Perspectives; VCH: Weinheim, 1995.
(2) (a) Chmielewski, M. J.; Jurczak, J. Chem. Eur. J. 2006, 12,
7652. (b) For recent reviews on anion receptor chemistry,
see the Coordination Chemistry Review special issue, ‘35
Years of Synthetic Anion Receptor Chemistry 1968-2003’:
Gale, P. A. Coord. Chem. Rev. 2003, 240, 1.
+
tron-donating moiety (NMe2, sp = –1.70)11 can be includ-
ed without disrupting the macrobislactamization
efficiency (7 + G, 72%), introducing an electron-with-
+
drawing one (Cl, sp = 0.11)11 alters significantly this ef-
ficiency (7 + F, 48%). This moderate yield probably
results from an electronically driven reduced probability
of forming bispyridinium intermediate, which in turn dis-
favors the cyclization step.
(3) Mo, Z.; Yang, W.; Gao, J.; Chen, H.; Kang, J. Synth.
Commun. 1999, 29, 2147.
Table 1 Chemical Yields of Macrobislactamization Step between
Various Diamines (6–8) and Acids (A–G)a,b
(4) (a) Szumna, A.; Jurczak, J. Eur. J. Org. Chem. 2001, 4031.
(b) Chmielewski, M. J.; Jurczak, J. Tetrahedron Lett. 2005,
46, 3085. (c) Zielinski, T.; Kedziorek, M.; Jurczak, J.
Tetrahedron Lett. 2005, 46, 6231. (d) Chmielewski, M. J.;
Jurczak, J. Chem. Eur. J. 2005, 11, 6080.
(5) (a) Sessler, J. L.; Katayev, E.; Pantos, G. D.; Ustynyuk, Y.
A. Chem. Commun. 2004, 1276. (b) Sessler, J. L.; Katayev,
E.; Pantos, G. D.; Scherbakov, P.; Reshetova, M. D.;
Khrustalev, V. N.; Lynch, V. M.; Ustynyuk, Y. A. J. Am.
Chem. Soc. 2005, 127, 11442.
A
B
C
D
E
F
G
6
7
8
(1) 85%
(2) 73%
(4) 0%
(2) 82%
(3) 71%
(5) 0%
n.a.c
29%
0%
n.a.c
>2%
n.a.c
n.a.c
>2%
n.a.c
n.a.c
48%
n.a.c
n.a.c
72%
n.a.c
a See below for structural description of 6–8 and A–G.
b See ref.6 for typical procedure description.
c n.a. = not attempted.
(6) Two-step Synthesis of Tetraaromatic Tetraamide
Macrocycles; General Procedure:
Step 1: One-Step Synthesis of Diamine 6 and 7
ortho-Phenylene diamine (1.85 mmol, 2.0 equiv), EDCI
(1.94 mmol, 2.1 equiv) and HOAt (0.37 mmol, 0.4 equiv)
were successively added to a solution of diacid derivative
(isophthalic or dipicolinic acid; 0.92 mmol, 1.0 equiv) in
DMF (50 mL) under an inert atmosphere. After the addition,
the reaction mixture was allowed to stir at r.t. for 16 h. The
mixture was concentrated under reduced pressure to a crude
oil that was purified by flash column chromatography (silica
gel, CH2Cl2–5% MeOH) to afford the expected diamine (6
or 7) as a pale yellow powder, with chemical yields given in
the text. Compound 6: Rf 0.6 (CH2Cl2–10% MeOH); mp 198
°C. 1H NMR (300 MHz, DMSO-d6): d = 9.77 (s, 2 H), 8.59
(s, 1 H), 8.15 (br d, J = 7.8 Hz, 2 H), 7.66 (t, J = 7.7 Hz, 1
H), 7.20 (d, J = 7.8 Hz, 2 H), 6.99 (td, J = 8.2 Hz, J¢ = 1.3
Hz, 2 H), 6.80 (dd, J = 8.1 Hz, J¢ = 1.2 Hz, 2 H), 6.62 (td,
J = 8.2 Hz, J¢ = 1.3 Hz, 2 H), 4.94 (br s, 4 H). 13C NMR (75.3
MHz, DMSO-d6): d = 165.0, 143.6, 135.2, 131.0, 128.8,
127.7, 127.2, 127.1, 123.5, 116.7, 116.6. Compound 7: Rf
0.17 (CH2Cl2–5% MeOH); mp 240 °C. 1H NMR (300 MHz,
DMSO-d6): d = 10.70 (s, 2 H), 8.18–8.35 (m, 3 H), 7.16 (dd,
J = 7.8 Hz, J¢ = 1.2 Hz, 2 H), 7.03 (td, J = 8.1 Hz, J¢ = 1.5
Hz, 2 H), 6.81 (dd, J = 8.1 Hz, J¢ = 1.2 Hz, 2 H), 6.63 (td,
J = 7.5 Hz, J¢ = 1.2 Hz, 2 H), 5.00 (br s, 4 H). 13C NMR (75.3
MHz, DMSO-d6): d = 162.5, 149.3, 144.5, 140.0, 128.0,
127.7, 125.2, 122.7, 116.7, 116.4.
O
O
OH
O
O O
OH
O
NH
HN
N
O
OH
OH
OH
NH2
H2N
C
A
B
6
O
O
O
O
O
O
OH
OH
O
N
O
NH
HN
OH
OH
D
E
NH2
H2N
7
Cl
N
N
O
O
O
O
NH
HN
N
N
N
OH
OH
OH
OH
F
G
NH2
H2N
8
In conclusion, we have developed a straightforward pro-
cedure to the unexplored family of tetraaromatic tetra-
amide macrocycles. Access to these molecules has been
shortened to a two-step procedure, via the development of
a very efficient Mukaiyama salt promoted macrobislac-
tamization step. The generality of the reaction has been
proven by the structural diversity of the macrocycles ob-
tained which opens perspectives for wider synthetic em-
ployments. First insights toward mechanistic elucidation
are also proposed. Preliminary complexation studies are
currently underway and the results will be reported in due
time.
Step 2: Macrobislactamization Reaction for the
Synthesis of 1, 2 and 3
Mukaiyama salt (2-chloromethylpyridinium iodide; 0.75
mmol, 2.5 equiv), tri-n-butylamine (1.5 mmol, 5.0 equiv)
and the diamine derivative (6 or 7, 0.3 mmol, 1.0 equiv) were
successively added to a solution of diacid derivative
(isophthalic or dipicolinic acid, 0.30 mmol, 1.0 equiv) in
CH2Cl2 (100 mL) under an inert atmosphere. The reaction
mixture was stirred at reflux temperature for 16 h. After
cooling to r.t., Et2O (200 mL) was added providing a white
precipitate that was collected by filtration. The
corresponding tetraaromatic tetraamide macrocycles (1, 2 or
3) were obtained as a white powder, with chemical yields
given in Table 1. Compound 1: mp 310 °C. IR (KBr): 3240
(NH), 1648 (CO), 1603 (NH), 1303 (CN), 755 (CH) cm–1. 1H
NMR (300 MHz, DMSO-d6): d = 10.18 (br s, 4 H), 9.16 (d,
J = 5.4 Hz, 2 H), 8.50–8.63 (m, 3 H), 8.38 (d, J = 8.1 Hz,
Acknowledgment
The authors would like to gratefully acknowledge Sanofi-Aventis
for financial support (postdoctoral grant for L.V.) and Dr. Patrick
Mailliet for helpful scientific discussions.
Synlett 2006, No. 20, 3423–3426 © Thieme Stuttgart · New York

3426
L. Vandromme et al.
LETTER
(8) Bald, E.; Saigo, K.; Mukaiyama, T. Chem. Lett. 1975, 4,
2 H), 8.20 (d, J = 8.4 Hz, 1 H), 7.52–7.70 (m, 4 H), 7.22–7.40
(m, 4 H). EI–MS: m/z (%) = 477 (67) [M + H+]. Compound
2: mp 304 °C. IR (KBr): 3474 (NH), 3245 (CH), 1685 (CO),
1591 (NH), 1307 (CN), 749 (CH) cm–1. 1H NMR (300 MHz,
DMSO-d6): d = 10.94 (s, 2 H), 10.17 (s, 2 H), 8.24 (br t, 3
H), 8.00–8.12 (m, 1 H), 7.68 (br d, 2 H), 7.52 (m, 4 H), 7.21
(m, 4 H), 6.75 (m, 1 H). EI–MS: m/z (%) = 479 (100) [M +
1163.
(9) Popaj, K.; Gugisberg, A.; Hesse, M. Helv. Chim. Acta 2000,
83, 3021.
(10) (a) Jones, T. K.; Mills, S. G.; Reamer, R. A.; Askin, D.;
Desmond, R.; Volante, R. P.; Shinkai, I. J. Am. Chem. Soc.
1989, 111, 1157. (b) Roush, W. R.; Coffey, D. S.; Madar, D.
J. J. Am. Chem. Soc. 1997, 119, 11331. (c) Smith, A. B. III;
Wan, Z. J. Org. Chem. 2000, 65, 3738. (d) Penhoat, M.;
Bohn, P.; Dupas, G.; Papamicael, C.; Marsais, F.; Levacher,
V. Tetrahedron: Asymmetry 2006, 17, 281.
H+], 496 (8) [M + NH4 ]. Compound 3: mp 196 °C. IR
+
(KBr): 3423 (NH), 3247 (CH), 1677 (CO), 1600 (NH), 1308
(CN), 754 (CH) cm–1. 1H NMR (300 MHz, DMSO-d6): d =
11.00 (s, 4 H), 8.40 (d, J = 8.0 Hz, 4 H), 8.30 (t, J = 7.7 Hz,
2 H), 7.82–7.86 (m, 4 H), 7.37–7.41 (m, 4 H). EI–MS: m/z
(11) For the Brown and Okamoto’s electrophilic substituent
(%) = 479 (30) [M + H+], 496 (28) [M + NH4 ].
constants (sp ) determination, see: Brown, H. C.; Okamoto,
+
+
(7) (a) Dietrich, B.; Viout, P.; Lehn, J.-M. Macrocyclic
Chemistry; VCH: Weinheim, 1993. (b) Ruggli, P. Justus
Liebigs Ann. Chem. 1912, 392, 92. (c) Rossa, L.; Vögtle, F.
Top. Curr. Chem. 1983, 113, 1.
Y. J. Am. Chem. Soc. 1958, 80, 4979.
Synlett 2006, No. 20, 3423–3426 © Thieme Stuttgart · New York