Microwave-assisted synthesis of macrocycles via intramolecular and/or bimolecular Ullmann coupling

Article abstract of DOI:10.1016/j.tetlet.2012.05.142

Microwave-assisted synthesis of macrocyclic diaryl ethers via intramolecular and/or bimolecular Ullmann coupling is described. Using the optimized conditions, a panel of macrocycles, with different substitution patterns, ring sizes, and linkers, has been successfully synthesized using microwave irradiation. To the best of our knowledge, this work represents the first examples of the microwave-assisted synthesis of macrocyclic diaryl ethers via intramolecular and/or bimolecular Ullmann coupling.

Full text of DOI:10.1016/j.tetlet.2012.05.142

Tetrahedron Letters 53 (2012) 4173–4178
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Microwave-assisted synthesis of macrocycles via intramolecular and/or
bimolecular Ullmann coupling
Li Shen a, Charles J. Simmons b, Dianqing Sun a,
⇑
a Department of Pharmaceutical Sciences, College of Pharmacy, University of Hawai’i at Hilo, Hilo, HI 96720, USA
b Department of Chemistry, University of Hawai’i at Hilo, Hilo, HI 96720, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Microwave-assisted synthesis of macrocyclic diaryl ethers via intramolecular and/or bimolecular Ull-
mann coupling is described. Using the optimized conditions, a panel of macrocycles, with different sub-
stitution patterns, ring sizes, and linkers, has been successfully synthesized using microwave irradiation.
To the best of our knowledge, this work represents the first examples of the microwave-assisted synthe-
sis of macrocyclic diaryl ethers via intramolecular and/or bimolecular Ullmann coupling.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 15 May 2012
Accepted 29 May 2012
Available online 7 June 2012
Keywords:
Microwave-assisted synthesis
Macrocycle
Diaryl ether
Intramolecular
Bimolecular
Ullmann coupling
Macrocyclic diaryl ether motifs are commonly found in natu-
rally occurring molecules (Fig. 1) and have been reported to medi-
ate a broad range of biological activities.1 The Ullmann coupling
reaction of phenols and aryl halides has been widely used for the
synthesis of diaryl ethers since its discovery; however, the scope
of Ullmann coupling has been limited by harsh reaction conditions
(e.g., high temperature and long reaction time) and low reaction
yields.2 Therefore, much effort has been devoted to the modifica-
tions of this classical coupling reaction.3 For example, the general-
ity has been improved by the introduction of palladium catalysts4
and with the assistance of novel ligands such as N,N-dimethylgly-
cine5 and biarylphosphine.6 So far, however, most improvements
have been achieved with the intermolecular Ullmann coupling of
small molecular aryl halides with phenols.
The application of microwave (MW) irradiation in promoting
organic reactions has been demonstrated successfully in recent
years.7 It has been shown in many studies that MW irradiation
can accelerate reaction rates and improve chemical yields. MW
heating has also been explored for intermolecular Ullmann reac-
tions8 and for the synthesis of diversified macrocycles based on
ring-closing metathesis (RCM),9 Suzuki–Miyaura cross-coupling,10
and solution and solid-phase synthesis of cyclic peptides and
peptidomimetics.11 However, no reports have been found in the
literature concerning MW-assisted intramolecular Ullmann macro-
cyclization. During the course of our continued effort to synthesize
diaryl ether macrocycles, we reported recently the first total syn-
thesis of macrocyclic engelhardione using a sealed pressure tube
which led ultimately to the structural revision of its published
structure.12 To further improve the efficiency and to develop a
modular synthesis of diaryl ether-based macrocycles, MW meth-
odology has been applied to the intramolecular Ullmann reaction.
Herein the synthesis of a panel of macrocycles with different sub-
stitution patterns, ring sizes, and linkers via the MW-assisted Ull-
mann cross-coupling is reported (Scheme 1).
To screen the reaction conditions, the macrocyclization of 1,7-
diarylheptan-3-one 1a to 2a (Table 1) was selected as a model
reaction. The reaction was conducted under an array of different
conditions, including conventional heating, sealed pressure tube,
and MW irradiation; the results are shown in Table 1. As noted pre-
viously,12 the reaction proceeded slowly under reflux at 150 °C for
20 h to give the macrocyclic product 2a in 33% yield (entry 1). An
improved yield and a significant decrease in reaction time were ob-
served when the reaction was conducted in a sealed pressure tube.
The reaction was completed after 4.5 h at 175 °C and 1 h at 200 °C
to provide 2a in 52% and 44% yields, respectively (entries 2 and 3).
Using the optimized reaction conditions in a sealed tube as a start-
ing point, further improvement was achieved when the reaction
was performed using MW irradiation. When the macrocyclization
step was initially performed at 175 °C using MW heating, approx-
imately 5% of 2a was produced after 10 min based on HPLC moni-
toring of the reaction mixture with the remaining as the unreacted
1a. After the temperature was increased to 200 °C, similar to the
reaction in a sealed tube, the reaction was completed in 1 h with
⇑
Corresponding author. Tel.: +1 808 933 2960; fax: +1 808 933 2974.
E-mail address: dianqing@hawaii.edu (D. Sun).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.142

4174
L. Shen et al. / Tetrahedron Letters 53 (2012) 4173–4178
O
CO2Me
H
N
N
N
H
O
O
H
HN
NHMe
HO
NH2
NH
CO2H
O
MeO
O
HO
O
piperazinomycin
cycloisodityrosine
O
renieramide
O
OH
O
O
HO
O
O
HO
MeO
ovalifoliolatin B
HO
marchantin C
pterocarine
Figure 1. Representative examples of diaryl ether-based natural products.
X
trans
X
n
n
X
R2
R1
R1
and/or
CuO, K2CO3
Pyridine, MW
n
R2
R1
O
O
R2
R1
OH
Br
R2
O
n = 0, 1, or 2
X = O, or OH
2
n
3
X
1
Scheme 1. MW-assisted synthesis of macrocycles via intramolecular and/or bimolecular Ullmann reaction.
Table 1
Optimization of intramolecular macrocyclic Ullmann couplinga
O
O
CuO / K2CO3
Pyridine
MeO
OH
OMe
MeO
O
1a
Br
2a
MeO
Entry
Condition
Temp (°C)
Time
Yieldb (%)
1c
2c
3c
4d
5
6
7
8
Reflux
150
175
200
>200
175
200
220
230
20 h
4.5 h
1 h
30 h
10 min
1 h
33
52
44
52
5e
73
85
76
Sealed tube
Sealed tube
Sealed tube
Microwave
Microwave
Microwave
Microwave
35 min
15 min
a
b
c
All experiments except entry 4 were performed using 0.08 mmol of 1a, 0.2 mmol of CuO, 0.08 mmol of K2CO3, and 4 mL of pyridine.
Isolated yield based on flash column chromatography on silica gel.
Ref. 12.
Ref. 13.
d
e
HPLC yield of the reaction mixture.
a much higher yield (73% vs 44%, entries 6 and 3). Further im-
proved results were obtained when the temperature was raised
to 220 °C, the reaction finished after 35 min in excellent yield
(85%, entry 7). In contrast, the cyclic reaction was completed in
15 min at 230 °C, affording 2a in a comparable yield (76%, entry 8).
With the optimized MW conditions in hand, a panel of different
substrates 1b–r14 containing diverse phenol and aryl bromide moi-
eties was employed to evaluate the scope and generality of this
macrocyclic Ullmann condensation reaction; the results are shown
in Table 2. Initially, a set of substrates 1b–f with a seven-carbon
linker was investigated (entries 2–6). Consistent with the meta–
meta substituted 2a with a 14-membered ring (entry 1), the O-
MOM protected 2b was obtained in 85% yield using MW irradiation
for 40 min (entry 2). In contrast, a lower yield (63%) of 2b was iso-
lated using a sealed tube at 175 °C for 4 h. As expected, intramolec-
ular 15-membered macrocycles 2c,d were obtained for the para–
meta and meta–para substituted substrates 1c,d in 44% and 69%
yields, respectively (entries 3 and 4). It is worth noting that these

Table 2
MW-assisted synthesis of macrocycles via intramolecular and/or bimolecular Ullmann chemistrya
Entry Substrate
Time
Product
Yieldb (%) Entry Substrate
Time
2.5 h
Product
Yieldb (%)
28 (7g)
O
O
O
O
MeO
O
HO
OMe
MeO
OMe
OMe
1
35 min
85
10
1a
1j
OMe
Br
OH
Br
MeO
O
O
MeO
MeO
2a
MeO
OMe
3j
O
O
O
O
O
MeO
O
MeO
MeO
Br
O
2
40 min
85 (63c) 11
5 h
18
1k
1b
OH
OH
Br
MeO
O
O
O
OMe
OMe
2b
OMe
3k
O
O
O
O
O
MeO
O
HO
OMe
Br
3
4
5
35 min
40 min
1.5 h
44 (12d) 12
2.5 h
18
48
56
1l
OMe
OMe
Br
MeO
O
OH
O
1c
2c
MeO
3l
O
O
OH
O
HO
O
69 (50d) 13
40 min
40 min
MeO
MeO
Br
MeO
MeO
OMe
MeO
1m
1d
OH
OH
OH
OH
Br
MeO
O
2m
MeO
2d
O
O
O
OH
HO
O
MeO
O
Br
MeO
MeO
21e
14
1e
O
OMe
2n
1n
OH
1o
Br
3e
O
O
OH
MeO
OMe
MeO
MeO
OMe
OMe
MeO
Br
O
1f
6
1 h
11e
15
1.5 h
44
OH
Br
O
O
OH
O
OMe
3o
OH
O
3f
(continued on next page)

Table 2 (continued)
Entry Substrate
Time
Product
Yieldb (%) Entry Substrate
Time
6 h
Product
Yieldb (%)
O
O
O
O
MeO
OMe
OMe
OMe
MeO
O
1g
7
40 min
85 (28f) 16
16
1p
OH
Br
OH
Br
O
O
2g
MeO
MeO
3p
O
O
O
O
8
9
50 min
40 min
83
73
17
18
2 h
1 h
0h
OMe
OH
1q
OMe
O
1h
OH
Br
Br
2h
MeO
O
O
O
O
25
MeO
OH Br
1r
O
2r
MeO
O
OH
1i
Br
2i
a
All experiments were performed using 0.08 mmol of substrate 1, 0.2 mmol of CuO, 0.08 mmol of K2CO3, and 4 mL of pyridine. Reaction mixtures were heated to 230 °C (220 °C for entries 1–3 and 18) using Biotage Initiator 8
Exp Microwave System and monitored by analytical HPLC.
b
Isolated yield based on flash column chromatography on silica gel.
Isolated yield using a sealed tube at 175 °C for 4 h.
Reported yields using sealed tubes in the same reaction system, see ref 13.
Intramolecular Ullmann coupling products 2e and 2f were also obtained in 10% and 9% yields, respectively.
Reaction was performed in a higher concentration (using 0.4 mmol of 1g, 1 mmol of CuO, 0.4 mmol of K2CO3, and 4 mL of pyridine) and completed in 15 min.
Reaction was performed under conventional reflux and was completed after 46 h.
Reaction mixture was heated at 220 °C for 1 h, and then at 230 °C for another 1 h.
c
d
e
f
g
h

L. Shen et al. / Tetrahedron Letters 53 (2012) 4173–4178
4177
tionalities were carried out, and both reactions of 1m,n afforded
the expected intramolecular cyclic products 2m,n in moderate
and lower yields by comparing entries 13 and 14 with correspond-
ing entries 7 and 9. These data are consistent with the previous re-
ports indicating that the ketone functionality may play a role in
controlling the substrate’s conformation and facilitating subse-
quent polyketide macrocyclization.16 In the case of 1o, it should
be noted that the introduction of the secondary alcohol functional-
ity appeared to facilitate the intermolecular coupling and subse-
quent bimolecular macrocyclization and the reaction was
completed in a much shorter time (1.5 h vs 5 h), giving the bimo-
lecular macrocycle 3o in a higher yield (44% vs 18%) compared to
1k (entries 15 and 11).
Figure 2. ORTEP view of the molecular structure of 2a at 100 K; 30% probability
ellipsoids are shown.18
The cyclizations of the substrates 1p–r with an even shorter
three-carbon linker were then studied. Different from its close ana-
logues 1a and 1h with a longer seven- and five-carbon linker, the
intermolecular cyclization product 3p was obtained in low yield
(16%) for the reaction of the meta–meta substituted substrate 1p
(entry 16), whereas the intramolecular macrocycle 2r was afforded
in 25% yield for the reaction of the ortho–ortho substituted substrate
1r (entry 18); however, under the same MW conditions, no product
was isolated from the reaction of 1q with OH and Br groups in ortho
and meta positions, respectively (entry 17). The observed decrease
in reactivity is presumably due to further restricted conformational
flexibility originating from the conjugated ketone and unfavorable
ring strains. Finally, to test the effect of concentration on the out-
come of macrocyclization, the reaction of 1g with a fivefold higher
concentration (0.1 M) was tried. It was found that the intramolecu-
lar coupling product 2g was obtained as a sole product despite a
much lower yield (28%, entry 7),17 and no intermolecular cycliza-
tion product was observed.
yields under MW irradiation have been improved than reported
yields (12% and 50%, respectively) using sealed tubes.13 A similar
result was anticipated for the meta–ortho substituted substrate
1e; surprisingly, the dimeric macrocycle 3e was isolated as a major
product15 (21% yield) together with the intramolecular cyclic prod-
uct 2e in 10% yield (entry 5). To further investigate the effect of the
linker flexibility on the outcome of macrocyclization, the substrate
1f with a more rigid ketone-conjugated linker was explored, and,
as expected, a dramatic decrease of reactivity and reaction yield
was noted compared to its close analogue 1a; again, both the di-
meric macrocycle 3f and the intramolecular coupling product 2f
were afforded in 11% and 9% yields, respectively (entry 6).
Next, the macrocyclization reaction for a second set of sub-
strates with a shorter five-carbon linker was examined and, again,
in the case of the meta–meta substituted substrate 1g, the intramo-
lecular Ullmann coupling proceeded smoothly to give the 12-
membered macrocycle 2g in 40 min in 85% yield (entry 7). Compa-
rable and consistent results were obtained for the meta–meta
substituted 1h,i with only one substituted MeO group affording
the identical macrocycles 2h,i in good yields (entries 8 and 9).
However, interesting results were obtained for the other five-car-
bon linked substrates 1j–l with the para–meta, meta–para, and
meta–ortho substitution patterns (entries 10–12). In all cases, the
substrates 1j–l were much less reactive than 1g–i under the same
MW conditions and the bimolecular macrocyclization products 3j–
l were obtained in 18–28% yields after prolonged reaction times
(2.5–5 h);15 no intramolecular Ullmann coupling products were
observed (entries 10–12). The formation of the dimeric cyclic prod-
ucts is presumably due to further reduced conformational flexibil-
ity of the substrates and unfavorable ring strains needed to
perform the intramolecular coupling. Instead, the alternative inter-
molecular Ullmann coupling occurred first, followed by the bimo-
lecular macrocyclization. In comparison, only 7% of 3j was isolated
for the reaction performed under conventional reflux for 46 h (en-
try 10). Moreover, to study the potential effect of the carbonyl
group in the linker on macrocyclization, reactions of the corre-
sponding reduced variants 1m–o with the racemic alcohol func-
The macrocycles 2 and 3 were characterized by 1H, 13C, and 2D
NMR spectroscopy, and high-resolution mass spectrometry
(HRMS). The structures of the intramolecular product 2a and the
bimolecular macrocycle 3j were confirmed by X-ray crystallogra-
phy, their ORTEP drawings are shown in Figures
2 and 3,
respectively.18,19
In summary, a modular MW-assisted synthesis has been devel-
oped for the intramolecular and/or bimolecular Ullmann conden-
sation of macrocyclic diaryl ethers. Under the optimized MW
irradiation conditions, improved yields and shorter reaction times
of intramolecular Ullmann coupling were noted compared with
conventional heating and sealed tubes. These data show that the
outcome of intramolecular and/or bimolecular macrocyclization
depends on the linker length and substitution patterns of the sub-
strates. This study further demonstrates that the 14- and 12-mem-
bered intramolecular macrocyclization proceeded more favorably
for the meta–meta substituted substrates. To the best of our knowl-
edge, this work represents the first examples of the MW-assisted
synthesis of macrocycles via the Ullmann coupling chemistry. Fur-
ther biological testing is warranted to screen these macrocyclic no-
vel chemical entities as potential pharmacological tools and/or
useful molecular probes.
Figure 3. ORTEP views using 30% probability ellipsoids at 90 K of the two crystallographically independent molecules of 3j in the unit cell; each has inversion centers.19

4178
L. Shen et al. / Tetrahedron Letters 53 (2012) 4173–4178
8. (a) He, H.; Wu, Y.-J. Tetrahedron Lett. 2003, 44, 3445; (b) Baqi, Y.; Müller, C. E.
Acknowledgments
Org. Lett. 2007, 9, 1271; (c) D’Angelo, N. D.; Peterson, J. J.; Booker, S. K.; Fellows,
I.; Dominguez, C.; Hungate, R.; Reider, P. J.; Kim, T.-S. Tetrahedron Lett. 2006, 47,
5045; (d) Lipshutz, B. H.; Unger, J. B.; Taft, B. R. Org. Lett. 2007, 9, 1089.
9. (a) Chapman, R. N.; Arora, P. S. Org. Lett. 2006, 8, 5825; (b) Pérez-Balado, C.;
Nebbioso, A.; Rodríguez-Graña, P.; Minichiello, A.; Miceli, M.; Altucci, L.; de
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We gratefully acknowledge funding from the NIH Academic Re-
search Enhancement Award (AREA) (R15AI092315) and UHH CoP
startup funds. We thank Drs. B. Clark and R. Borris at UHH CoP
for the assistance with HRMS analysis of macrocyclic compounds.
We also thank Dr. A. Wright at UHH CoP for his NMR assistance.
12. Shen, L.; Sun, D. Tetrahedron Lett. 2011, 52, 4570.
Supplementary data
13. (a) Bryant, V. C.; Kishore Kumar, G. D.; Nyong, A. M.; Natarajan, A. Bioorg. Med.
Chem. Lett. 2012, 22, 245; (b) Kishore Kumar, G. D.; Natarajan, A. Tetrahedron
Lett. 2008, 49, 2103.
Supplementary data (experimental procedures and character-
ization data, copies of NMR spectra and HPLC chromatographs)
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2012.05.142.
14. Substrates were synthesized according to the previously reported procedures12
or based on the simple modifications of available synthetic schemes (see
Supplementary data for details).
15. For related observations with a bimolecular cyclization lactone product, see:
(a) Nakahara, A.; Kanbe, M.; Nakada, M. Tetrahedron Lett. 2012, 53, 1518; For a
bimolecular cyclization lactam product, see: (b) Boger, D. L.; Yohannes, D.;
Zhou, J.; Patane, M. A. J. Am. Chem. Soc. 1993, 115, 3420.
16. (a) Pinto, A.; Wang, M.; Horsman, M.; Boddy, C. N. Org. Lett. 2012, 14, 2278; (b)
Aldrich, C. C.; Venkatraman, L.; Sherman, D. H.; Fecik, R. A. J. Am. Chem. Soc.
2005, 127, 8910.
References and notes
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Suryanarayana Murty, U.; Venkateswarlu, Y. Chem. Pharm. Bull. 2003, 51, 1081;
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3. (a) Marcoux, J.-F.; Doye, S.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 10539;
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102, 1359; (c) Cai, Q.; Zou, B.; Ma, D. Angew. Chem. 2006, 118, 1298.
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17.
A lower yield at higher concentration was also noted previously in the
synthesis of a similar ring-closing system by the Zhu group, see: Gonzalez, G. I.;
Zhu, J. J. Org. Chem. 1999, 64, 914.
18. Crystal data for 2a: C21H24O4, Mr = 340.42, orthorhombic space grou0p Pna21,
0
0
0
a = 9.6740(3) ÅA, b = 10.5427(3) ÅA, c = 17.4091(5) ÅA, V = 1775.56(8) ÅA3, Z = 4,
= 1.273 Mg/m3, T = 100 K, in the final least-squares refinement cycles on F,
the model converged at R1 = 0.041, wR2 = 0.035 and GOF = 1.976 for 1820
reflections with I >4 (I). Crystallographic data (excluding structure factors) for
q
r
2a (CCDC 878805) and 3j (CCDC 878806) have been deposited with the
Cambridge Crystallographic Data Centre. Copies of the data can be obtained,
free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK,
(fax: +44-(0)1223-336033 or e-mail: deposit@ccdc.cam.ac.uk).
5. Ma, D.; Cai, Q. Org. Lett. 2003, 5, 3799.
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Rev. 2007, 107, 2563; (d) Lew, A.; Krutzik, P. O.; Hart, M. E.; Chamberlin, A. R. J.
Comb. Chem. 2001, 4, 95.
ꢀ
19. Crystal data for 3j: C38H40O8, Mr = 624.73, triclinic space group P1, a = 8.1476(2)
0
0
0
ÅA, b = 13.7924(3) ÅA, c = 14.9725(3) ÅA,
c
a
= 79.7461(15)°, b = 74.6022(12)°,
= 1.338 Mg/m3, T = 90 K, in the
final least-squares refinement cycles on F, the model converged at R1 = 0.043,
wR2 = 0.064 and GOF = 1.556 for 5157 reflections with I >5 (I).
0
= 74.1882(15)°, V = 1550.60(6) ÅA3, Z = 2,
q
r