Functionalized azobenzenes through cross-coupling with organotrifluoroborates

Article abstract of DOI:10.1016/j.tetlet.2006.12.043

The development of an azobenzene building block for Suzuki couplings and its application in the synthesis of photochromic agonists and antagonists is reported.

Full text of DOI:10.1016/j.tetlet.2006.12.043

Tetrahedron Letters 48 (2007) 1661–1664
Functionalized azobenzenes through cross-coupling
with organotrifluoroborates
Jessica H. Harvey, Brandon K. Butler and Dirk Trauner*
Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA
Received 3 November 2006; revised 7 December 2006; accepted 8 December 2006
Available online 22 January 2007
Abstract—The development of an azobenzene building block for Suzuki couplings and its application in the synthesis of photochro-
mic agonists and antagonists is reported.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Azobenzene photoswitches are valuable tools to influ-
ence protein activity.1–4 Generally, the strategies em-
ployed to this end have involved (a) covalent
attachment of an azobenzene derivative to the protein5
or (b) use of an azobenzene derivative as a noncova-
lently bound photochromic ligand, where one isomer
has a greater affinity for the protein than the other.6–8
functionalization possibilities have mostly been limited
to elaborations that do not involve the formation of car-
bon–carbon bonds. In the context of developing photo-
chromic ligands, we became interested in cross-coupling
azobenzenes with heterocyclic building blocks function-
alized as iodides. Although cross-couplings have been
reported for azo bond formation,10 they have rarely
been used to append azobenzenes to a ligand scaf-
fold.14–16 We now wish to report a general method for
attaching the azobenzene moiety onto aryl and vinyl
Classical methods for the synthesis of azobenzenes in-
clude electrophilic aromatic substitution involving aryl
diazonium salts, condensation of nitrosobenzenes with
anilines, and oxidative coupling of two anilines.9–12
More recently, Buchwald-type couplings of aryl hydra-
zines with aryl iodides, followed by oxidation, have been
employed (Fig. 1).13
N
N
Further functionalization of azobenzenes typically in-
volves amide, carbamate, ester, or ether linkages. Thus,
NH2
NH2
I
N
N
BR2
N
+
N
cross
coupling
N
N
N
N
Buchwald-type
coupling
1
3
2
R
N
N
condensation
diazotization
NH2
N
Figure 1. Azobenzene synthesis.
N
4: PP1
N
N
Keywords: Azobenzene; Cross-coupling; Trifluoroborate.
*
Corresponding author. Tel.: +1 510 642 5324; fax: +1 510 643
9480; e-mail: trauner@berkeley.edu
Figure 2. Retrosynthetic analysis of azobenzene 1.
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.12.043

1662
NH2
J. H. Harvey et al. / Tetrahedron Letters 48 (2007) 1661–1664
Tf2O, Py
1) NaNO2,
HCl/H2O, 0 C
O
O
KHF2, H2O,
N
OH
N
B
°
°
0 C to rt
N
N
CH3CN, rt
87%
99%
2) C6H6O,
8
°
H2O, 0 C
5
6
93%
Bis(pinacolato)diboron,
OTf
KOAc, dppf, dioxane
N
N
N
BF3K
N
PdCl2(dppf).CH2Cl2,
84%
12
N
7
N
OH
B
OH
O
N
B
N
N
NH2
I
NH2
O
PdCl2(dppf).CH2Cl2,
i Pr2NEt, EtOH,
N
N
N
+
12
9
8
N
N
reflux
59%
N
N
Scheme 1. Ester synthesis via diazotization.
2
1
Scheme 3. Suzuki coupling of the trifluoroborate azobenzene.
O
O
CH3CO2H
N O
+
H2N
B
90 °C
63%
pyrrolopyrimidine part of this molecule is derived from
the known Src kinase inhibitor PP1 (4).18 We planned to
form the central bond of 1 through cross-coupling of the
known iodo pyrrolopyrimidine 219 with an appropriate
azobenzene partner 3 (Fig. 2).
10
11
O
O
N
N
B
8
Our first target was therefore an azobenzene boronic
acid 9, which we hoped would undergo a cross-coupling
reaction with 2 (Scheme 1).20 Synthesis of the target azo-
benzene proceeded via two different possible routes. The
first route began with diazonium coupling of aniline
with phenol, followed by triflation to yield triflate 7. Pal-
ladium-catalyzed cross-coupling of 7 with bis(pinaco-
lato)diboron gave boronic ester 8 (Scheme 1). The
second route gave boronic ester 8 in one step via the
condensation of commercially available aniline boronic
ester 11 with nitrosobenzene 10 (Scheme 2).
Scheme 2. Ester synthesis via condensation.
iodides. This method proceeds via a Suzuki cross-
coupling reaction employing an azobenzene
trifluoroborate.17
Our interest in azobenzene derivatization was estab-
lished during the synthesis of compound 1, which was
developed as a photoswitchable kinase inhibitor. The
Table 1. Suzuki coupling reactions
R
N
BF3K
N
+
R-I
N
N
13
14
12
Product
R
Conditions
Yield (%)
72
14a
PdCl2(dppf), Cs2CO3, MeOH, 65 ꢁC, 3.5 h
PdCl2(dppf), Cs2CO3, MeOH, 65 ꢁC, 18 h
PdCl2(dppf), Cs2CO3, MeOH, 65 ꢁC, 4.7 h
O
O
O
14ba
41
49
O
O
CHO
14c
O
OH

J. H. Harvey et al. / Tetrahedron Letters 48 (2007) 1661–1664
1663
Table 1 (continued)
Product
R
Conditions
Yield (%)
O
14d
14e
14f
PdCl2(dppf), K2CO3, MeOH, 65 ꢁC, 2 h
PdCl2(dppf), K2CO3, MeOH, 65 ꢁC, 2 h
65
61
61
S
NH2
Pd(OAc)2, PPh3, K2CO3, MeOH, 65 ꢁC, 14 h
NO2
14g
14h
PdCl2(dppf), Cs2CO3, MeOH, 65 ꢁC, 3.5 h
66
60
PdCl2(dppf), K2CO3, MeOH, 65 ꢁC, 17 h
O
O
O
F
14i
14j
PdCl2(dppf), Cs2CO3, MeOH, 65 ꢁC, 2 h
47
61
PdCl2(dppf), iPr2NEt, MeOH, 65 ꢁC, 2 h
OH
a The product was the methyl ester. When ethanol was used as the solvent, ethyl ester was produced in a 14% yield.
Unfortunately, attempted hydrolysis of 8 resulted in the
recovery of starting material, inseparable mixtures, or
decomposition.21–23 In one case, in which NaIO4 was
employed, the boronic ester was successfully hydro-
lyzed, but oxidation of the azo bond also occurred.
We therefore attempted the Suzuki coupling with the
parent boronic ester 8. However, these conditions
resulted in consistently low yields (<20%).
ing aldehydes, alcohols, ketones, anilines, phenols,
esters, aryl fluorides, and various heterocycles.
All of the starting iodides were commercially available
except 13b and 13i, which have been previously de-
scribed.25,26 The reaction was usually carried out with
PdCl2(dppf) in refluxing methanol. When triphenyl
phosphine was used as a ligand or under microwave
conditions, yields typically decreased.
We then decided to convert the boronic ester into the
corresponding trifluoroborate salt, using the conditions
developed by Molander.17 Hydrolysis of the ester using
KHF2 gave the azobenzene trifluoroborate salt 12,
which was again subjected to cross-coupling conditions
to afford the desired compound 1 in a 59% yield (Scheme
3).
In summary, we have described the application of a re-
cently developed variant of the Suzuki reaction for azo-
benzene functionalization via carbon–carbon bond
formation. The biological evaluation of compound 1 is
under investigation, and the results will be reported in
due course.
To map the functional group compatibility of this reac-
tion, we have employed the azobenzene trifluoroborate
12 in Suzuki reactions with a variety of vinylic and aro-
matic iodides (Table 1). The reaction was found to pro-
ceed well with both electron-donating and withdrawing
vinylic and aromatic iodides.24 A wide range of func-
tional groups was compatible with the reaction, includ-
Acknowledgments
Financial Support from Novartis is gratefully acknowl-
edged. We thank Ray Bateman for providing key pre-
cursors to 2 and Aubry Miller for providing the
starting iodides 13b and 13h.

1664
J. H. Harvey et al. / Tetrahedron Letters 48 (2007) 1661–1664
17. Molander, G. A.; Biolatto, B. J. Org. Chem. 2003, 68,
Supplementary data
4302.
18. Arnold, L. D.; Calderwood, D. J.; Dixon, R. W.;
Johnston, D. N.; Kamens, J. S.; Munschauer, R.; Rafferty,
P.; Ratnofsky, S. E. Bioorg. Med. Chem. Lett. 2000, 10,
2167.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/
j.tetlet.2006.12.043.
19. Tanaka, M.; Bateman, R.; Rauh, D.; Vaisberg, E.;
Ramachandani, S.; Zhang, C.; Hansen, K. C.; Burlin-
game, A. L.; Trauman, J. K.; Shokat, K. M.; Adams, C. L.
PloS Biol. 2005, 3, e128.
References and notes
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24. Representative procedure: To a solution of 12 (25 mg,
0.0868 mmol) in MeOH (1 mL) was added 2-iodo-thio-
phene (18.3 mg, 0.0868 mmol), anhydrous potassium car-
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bonate
(36.0 mg,
0.2604 mmol,
3 equiv),
and
PdCl2(dppf)ÆCH2Cl2 (0.708 mg, 0.000868 mmol). The
reaction mixture was stirred at 70 ꢁC for 2 h. After
cooling, it was extracted with CH2Cl2 (3 · 5 mL). The
combined organic phases were washed once with water,
dried over MgSO4, and evaporated in vacuo. Chromato-
graphy (1% MeOH/CH2Cl2) afforded 1-phenyl-2-(4-(thio-
phen-2-yl)phenyl)diazene, 14e, (14.0 mg, 61%) as an
orange crystalline solid. Rf 0.91 (9% MeOH/CH2Cl2).
1
UV kmax (100% DMSO): 374 nm; H NMR (400 MHz): d
7.95 (m, 4H), 7.76 (m, 2H), 7.52 (m, 3H), 7.41 (m, 1H),
7.34 (m, 1H), 7.12 (m, 1H). 13C NMR (500 MHz): 152.7,
151.6, 143.4, 136.9, 131.0, 129.1, 128.3, 126.3, 125.9, 124.1,
123.6, 122.9. IR: 3437, 1644, 1440 cmÀ1. HRMS (EI+)
calcd for C16H13N2S 265.0794, found 265.0758. See also
Supplementary data.
25. Liang, G.; Miller, A. K.; Trauner, D. Org. Lett. 2005, 7,
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15. Ando, H.; Takahashi, T.; Nakano, H.; Shirota, Y. Chem.
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26. Miller, A. K.; Byun, D. H.; Beaudry, C. M.; Trauner, D.
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