Synthesis of 5-iodo-1,2,3-triazole-containing macrocycles using copper flow reactor technology

Article abstract of DOI:10.1021/ol201567s

A new macrocyclization strategy to synthesize 12- to 31-membered 5-iodo-1,2,3-triazole-containing macrocycles is described. The macrocycles have been generated using a simple and efficient copper-catalyzed cycloaddition in flow under environmentally frien

Full text of DOI:10.1021/ol201567s

ORGANIC
LETTERS
2011
Vol. 13, No. 15
4060–4063
Synthesis of 5-Iodo-1,2,3-triazole-Containing
Macrocycles Using Copper Flow Reactor
Technology
Andrew R. Bogdan and Keith James*
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road,
La Jolla, California 92037, United States
kjames@scripps.edu
Received June 10, 2011
ABSTRACT
A new macrocyclization strategy to synthesize 12- to 31-membered 5-iodo-1,2,3-triazole-containing macrocycles is described. The macrocycles
have been generated using a simple and efficient copper-catalyzed cycloaddition in flow under environmentally friendly conditions. This
methodology also permits the facile, regioselective synthesis of 1,4,5-trisubstituted-1,2,3-triazole-containing macrocyles using palladium-
catalyzed cross-coupling reactions.
Macrocyclic systems offer a compelling new approach to
modulating proteinÀprotein interactions,1 since their in-
trinsic conformational preorganization allows them to
span noncontiguous binding sites on shallow protein
surfaces, while retaining attractive drug properties.2 Con-
sequently, there is considerable interest in novel macro-
cyclization strategies that are applicable to drug discovery
programs and amenable to library development.3 In parti-
cular, there is a need for new macrocyclization protocols
capable of generating diverse, drug-like structures, without
resorting to high dilution conditions.4
advantageous. While ruthenium-catalyzed azideÀalkyne
cycloadditions6 and triazole functionalization7 have pro-
ven to be effective methods to synthesize trisubstituted
triazole rings, these methods can exhibit problematic
regiocontrol and limited scope. Hein et al. recently de-
scribed a copper-catalyzed, regiocontrolled synthesis of
5-iodo-1,2,3-triazoles that could be converted to 1,4,
5-trisubstituted-1,2,3-triazoles.8 Since the presence of such
an iodotriazole moiety would permit facile library devel-
opment via palladium-catalyzed cross-couplings, we have
(6) (a) Zhang, L.; Chen, X.; Xue, P.; Sun, Y. Y. H.; Williams, I. D.;
Sharpless, K. B.; Fokin, V. V. J. Am. Chem. Soc. 2005, 127, 15998.
(b) Boren, B. C.; Narayan, S.; Rasmussen, L. K.; Zhang, L.; Zhao, H.;
Lin, Z.; Jia, G.; Fokin, V. V. J. Am. Chem. Soc. 2008, 130, 8923.
(7) (a) Chuprakov, S.; Chernyak, N.; Dudnik, A. S.; Gevorgyan, V.
Org. Lett. 2007, 78, 645. (b) Fukuzawa, S.-I.; Shimizu, E.; Ogata, K.
Heterocycles 2009, 78, 645. (c) Iwasaki, M.; Yorimitsu, H.; Oshima, K.
Chem.;Asian J. 2007, 2, 1430. (d) Ackermann, L.; Vicente, R.; Born, R.
Adv. Synth. Catal. 2008, 350, 741. (e) Ackermann, L.; Potukuchi, H. K.;
Landsberg, D.; Vicente, R. Org. Lett. 2008, 10, 3081. (f) Ackermann, L.;
Potukuchi, H. K. Org. Biomol. Chem. 2010, 8, 4503.
(8) (a) Hein, J. E.; Tripp, J. C.; Krasnova, L. B.; Sharpless, K. B.;
Fokin, V. V. Angew. Chem., Int. Ed. 2009, 48, 8018–8021. (b) Spiteri, C.;
Moses, J. E. Angew. Chem., Int. Ed. 2010, 49, 31–33. (c) Kuijpers,
B. H. M.; Dijkmans, G. C. T.; Groothuys, S.; Quaedflieg, P. J. L. M.;
Blaauw, R. H.; van Delft, F. L.; Rutjes, F. P. J. T. Synlett 2005,
2059–3062.
Recently we reported the efficient construction of tria-
zole-containing macrocycles in flow using copper tubing.5
While this method proved to be effective for the synthesis
of1,4-disubstituted-1,2,3-triazole-containing macrocycles,
a general procedure for the synthesis of 1,4,5-trisub-
stituted-1,2,3-triazole-containing macrocycles would be
(1) Wells, J. A.; McClendon, L. Nature 2007, 450, 1001–1009.
(2) Driggers, E. M.; Hale, S. P.; Lee, J.; Terrett, N. K. Nat. Rev. Drug
Discovery 2008, 7, 608–624.
(3) Marsault, E.; Peterson, M. L. J. Med. Chem. 2011, 54, 1961–2004.
(4) Chouhan, G; James, K. Org. Lett. 2011, 13, 2754–2757.
(5) Bogdan, A. R.; James, K. Chem.;Eur. J. 2010, 16, 14506–14512.
r
10.1021/ol201567s
Published on Web 07/08/2011
2011 American Chemical Society

examined the use of this reaction in the construction of
drug-like macrocycles. We report herein a novel and effi-
cient methodology to synthesize drug-like 5-iodo-1,2,3-
triazole-containing macrocycles through the implementa-
tion of copper-catalyzed cycloaddition chemistry in flow,
together with examples of the elaboration of these systems
via palladium-catalyzed cross-coupling reactions.
Table 1. Optimization of Reaction Conditionsa
We were drawn to a flow methodology employing
copper tubing because the copper(I)-catalyzed azideÀ
acetylene cycloaddition (CuAAC) reaction9 has already
been reported using flow conditions to yield simple, linear
triazoles.10 It was anticipated that using 1-iodoalkynes
instead of terminal alkynes would lead to similarly high
yields for the cycloaddition, using the heterogeneous cop-
per tube as the catalyst source.
Macrocycle precursors were synthesized in short syn-
thetic sequences similar to Scheme 1. Chiral amino alcohol
fragments were coupled to an organic azide using standard
peptide coupling conditions, followed by an alkylation
using propargyl bromide. The alkyne was subsequently
iodinated using N-iodomorpholine hydrogeniodide11 and
time
T
DIPEA
equiv
1cc
1c
entry
(min)
(°C)
ligand
(%)
(%)
1
2
3
4
5
6
7
5
5
75
100
100
100
100
100
100
TTTA (0.1)b
TTTA (0.1)
TTTA (0.1)
TTTA (0.5)
TTTA (0.1)
TBTA (0.1)
TTTA (0.1)
À
77
42
16
50
4
4
39
À
5
1.0
1.0
2.0
2.0
2.0
64
5
32
5
78
5
6
73
10
0
86
(80)d
30
8
9
5
5
100
100
À
À
À
52
27
2.0
51
a Conditions: Accendo Conjure Flow Reactor, copper tubing (0.75 mm
inner diamter, 1.6 mL internal volume), [1c] = 0.017 M. b Number in
parentheses corresponds to equivalents of ligand. c Percent UV from LC/
MS analysis. d Number in parentheses corresponds to isolated yield. TTTA,
tris-((1-tert-butyl-1H-1,2,3-triazoyl)methyl)amine; TBTA, tris-((1-benzyl-
1H-1,2,3-triazoyl)methyl)amine; DIPEA, diisopropylethylamine.
Scheme 1. Synthesis of Azido-Iodoalkyne Macrocycle Precur-
sors
tubing as the copper source.12 The conditions for the
macrocyclization are outlined in Table 1. Optimization
was performed using MeCN after initial screening indi-
cated promising results. Furthermore, its low boiling point
simplifies the workup, allowing convenient solvent re-
moval in vacuo prior to column chromatography. As anti-
cipated from our previous macrocyclization studies5 and
the seminal publication from Hein et al.,8 the ligand tris-
((1-tert-butyl-1H-1,2,3-triazoyl)methyl)amine (TTTA) was
necessary to obtain high yields of macrocycle 1 (Table 1,
entry 9 versus 5). It was also noted that addition of DIPEA
to the reaction mixture increased the yield of 1 (Table 1,
entries 3 and 5 versus entry 2). Increasing the temperature
beyond 100 °C resulted in decomposition of the starting
material and blocked the reactor. Optimal conditions for
the macrocyclization were determined to be 10 min at
100 °C, with 10 mol % TTTA and 2.0 equiv of DIPEA
(Table 1, entry 7). 5-Iodo-1,2,3-triazole-containing macro-
cycle 1was characterized by X-ray crystallography (Figure 1).
Additionally, it was determined that the reaction did not
proceed to high yield when no additives were present
(Table 1, entry 8) or when DIPEA was used alone
(Table 1, entry 9).
catalytic CuI. Notably, no CuAAC-derived macrocyclic or
oligomeric products were detected by LC/MS analysis
during the alkyne iodination, despite the presence of
copper(I). Following column chromatography, azido-io-
doalkyne 1c could be isolated as a light-yellow oil.
Using azido-iodoalkyne 1c as the model system, the
macrocyclization was optimized in flow, using copper
(9) (a) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem. 2001,
113, 2056–2075. Angew. Chem., Int. Ed. 2001, 40, 2004–2021.
(b) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
Angew. Chem. 2002, 114, 2708–2711. Angew. Chem., Int. Ed. 2002, 41,
2596–2599. (c) Wu, P.; Fokin, V. V. Aldrichimica Acta 2007, 40, 7–17.
(d) Diez-Gonzalez, S. Catal. Sci. Technol. 2011, 1, 166. (e) Pedersen,
D. S.; Abell, A. Eur. J. Org. Chem. 2011, 2399. Hein, J. E.; Fokin, V. V.
Chem. Soc. Rev. 2010, 39, 1302.
(10) (a) Bogdan, A. R.; Sach, N. W. Adv. Synth. Catal. 2009, 351,
849–854. (b) Fuchs, M.; Goessler, W.; Pilger, C.; Kappe, C. O. Adv.
Synth. Catal. 2010, 352, 323–328. (c) Baxendale, I. R.; Ley, S. V.;
Mansfield, A. C.; Smith, C. D. Angew. Chem. 2009, 121, 4077–4081.
Angew. Chem., Int. Ed. 2009, 48, 4017–4021. (d) Smith, C. D.; Baxendale,
I. R.; Tranmer, G. K.; Baumann, M.; Smith, S. C.; Lewthwaite, R. A.;
Ley, S. V. Org. Biomol. Chem. 2007, 5, 1562–1568. (e) Smith, C. D.;
Baxendale, I. R.; Lanners, S.; Hayward, J. J.; Smith, S. C.; Ley, S. V. Org.
Biomol. Chem. 2007, 5, 1559–1561.
In order to establish the scope of this procedure, a series
of azido-iodoalkynes were synthesized and subjected to the
optimized macrocyclization conditions described above.
It was observed that macrocycles comprised of 12- to
(12) For the flow reactions, an Accendo Conjure Flow reactor was
used with copper tubing (0.75 mm inner diamter, 1.6 mL internal
volume). http://www.accendocorporation.com.
(11) Koyama, M.; Ohtani, N.; Kai, F.; Moriguchi, I.; Inouye, S.
J. Med. Chem. 1987, 30, 552–562.
Org. Lett., Vol. 13, No. 15, 2011
4061

Macrocycles 2, 4, and 6 were characterized by X-ray
crystallography (Figure 3). Depending on ring size and the
inherent strain within the macrocycle, differing degrees of
atropisomerism were observed as a result of restricted
rotation of the iodotriazole. In the smaller, more strained
macrocycle 2 (a 12-membered ring), only a single product
was observed, representing one of two possible atropi-
somers arising due to the inability of the triazole ring to
rotate freely through the interior of the macrocycle. Thus,
the reaction isstereoselective, yielding the isomer where the
iodine and amide carbonyl are syn to each other. In the
slightly larger, but strained macrocycle 4 (a 15-membered
system containing a bridged ring junction), a mixture of
atropisomers was observed. Although the cycloaddition
generated both iodotriazole conformers, their rate of
interconversion is slow enough that the resultant atropi-
somers can be separated by chromatography at room
temperature. And finally, in the larger macrocycle 6
(a 22-membered ring), there appears to be little conforma-
tional strain present. In this case therefore, both triazole
conformers are formed and interconvert rapidly at room
temperature. Consequently, atropisomers are not ob-
served. This trend in conformational constraint is consis-
tent with the noted increase in yield from the more strained
to less strained macrocycles.
Figure 1. Crystal structure of iodotriazole macrocycle 1. Hydro-
gens omitted for clarity.
31-membered rings could be synthesized in modest to
excellent yields (Figure 2).
Figure 3. Crystal structures of iodotriazole macrocycles 2, 4, and
6 (clockwise from upper left). Hydrogens omitted for clarity.
Figure 2. Substrate scope for the copper flow-mediated iodo-
triazole macrocyclization. Percentages correspond to isolated
yields.
To demonstrate the potential of the 5-iodo-1,2,3-triazole
as a point of diversification in library synthesis, three
macrocycles (1, 3, and 7) were subjected to palladium-
catalyzed cross-coupling reactions (i.e., Suzuki, Heck, and
Sonogashira, respectively).13 High yields of the corre-
sponding 1,4,5-trisubstituted-1,2,3-triazole macrocycles
were obtained in all cases (Scheme 2). Interestingly, in the
case of the 14-membered trisubstituted macrocycle 11, a
mixture of atropisomers (∼1.2:1.0) was obtained.
Smaller macrocyclic rings such as 2 were obtained in
lower yields, as were systems that contained multiple
bridged rings within the macrocycle (5 and 9). Further-
more, larger macrocyclic rings (9 and 10) also showed a
significant amount of deiodination, yielding significant
amounts of the corresponding proteo triazole. This may
result from the rate of deiodination becoming competitive
with a slower rate of macrocyclization for these larger
rings. Since these isolated yields were obtained using
conditions which had been optimized for a 14-membered
macrocycle, it may be possible to increase the yields
of 5-iodo-1,2,3-triazole in these cases through further
optimization.
In this case, it was possible to separate the atropisomers
using chromatography and characterize them both using
X-ray crystallography (Figure 4). The two atropisomers
(13) Deng, J.; Wu, Y. M.; Chen, Q.-Y. Synthesis 2005, 16, 2730–2738.
Org. Lett., Vol. 13, No. 15, 2011
4062

Scheme 2. Synthesis of 1,2,5-Trisubstituted-1,2,3-Triazole
Macrocycles via Pd-Mediated Cross-Couplings
Figure 4. X-ray crystal structures of the atropisomers of 1,4,
5-trisubstituted-1,2,3-triazole macrocycle 11. The major syn
atropisomer is on the left, and the minor anti atropisomer is
on the right. Hydrogens omitted for clarity.
closure, the chemistry described herein creates a new,
versatile functional group that can be used in further
reactions. The resultant iodotriazoles can be converted
into 1,4,5-trisubstituted-1,2,3-triazoles using palladium
chemistry, thereby opening the way to their use in library
development. This is also therefore the first example of a
macrocyclization strategy that enables the efficient synth-
esis of a regiocontrolled, trisubstitued triazole ring. As a
result, we have been able to observe and characterize an
unusual atropisomerism resulting from restricted rotation
of a trisubstituted heterocyclic ring embedded within a
macrocyclic framework.
are diastereomeric by virtue of opposite chirality at the
newly created axial stereocenter, which again arises through
the inability of the trisubstituted triazole to rotate freely,
and therefore differ in the orientation of the trifluoro-
methylphenyl ring relative to the other macrocycle sub-
stituents. In the case of the major atropisomer, the two
phenyl rings attached to the macrocycle are syn, whereas
the phenyl rings are anti in the minor atropisomer. Using
variable temperature NMR, it was determined that macro-
cycle 11 begins to slowly atropisomerize when heated to
elevated temperatures (∼80 °C). In the larger macrocyclic
systems (12and 13), thisatropisomerism wasnotobserved,
presumably due to the flexible nature of the larger ring
allowing facile conversion between the triazole rotamers,
as discussed above.
Acknowledgment. This work was funded by Pfizer
Worldwide R&D, where K.J. is employed. The authors
would like to thank Neal Sach (Pfizer), Jason Hein, and
Valery Fokin (The Scripps Research Institute) for helpful
discussions and gifts of tris-triazole ligands; Khanh Tran
(Pfizer) for gifts of starting materials; and Curtis Moore
and Arnold Rheingold (UCSD Small-Molecule Lab) for
crystallographic data.
Inconclusion, we have demonstratedanefficient method
to synthesize 5-iodo-1,2,3-iodotriazole-containing macro-
cycles in a flow reactor using copper tubing as the catalyst
source. Unlike typical macrocyclization strategies that
generate no new reactive centers as a result of the ring
Supporting Information Available. Experimental pro-
cedures and full characterization (1H and 13C NMR data
and spectra, and HRMS) for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Org. Lett., Vol. 13, No. 15, 2011
4063