Microwave-assisted, Pd(0)-catalyzed cross-coupling of diazirines with aryl halides

Article abstract of DOI:10.1021/ol102434v

Pd(0)-catalyzed cross-coupling reactions of diazirines with aryl halides under microwave heating conditions afford a series of substituted olefins. A reaction mechanism involving the migratory insertion of the Pd carbene intermediate is proposed.

Full text of DOI:10.1021/ol102434v

ORGANIC
LETTERS
2010
Vol. 12, No. 23
5580-5583
Microwave-Assisted, Pd(0)-Catalyzed
Cross-Coupling of Diazirines with Aryl
Halides
Xia Zhao,† Guojiao Wu,† Chong Yan,† Kui Lu,† Hui Li,† Yan Zhang,† and
Jianbo Wang*,†,‡
Beijing National Laboratory of Molecular Sciences (BNLMS) and Key Laboratory of
Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of
Chemistry, Peking UniVersity, Beijing 100871, China, and State Key Laboratory of
Organometallic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
wangjb@pku.edu.cn
Received October 13, 2010
ABSTRACT
Pd(0)-catalyzed cross-coupling reactions of diazirines with aryl halides under microwave heating conditions afford a series of substituted
olefins. A reaction mechanism involving the migratory insertion of the Pd carbene intermediate is proposed.
In recent years, Pd-catalyzed cross-coupling reactions of
diazo compounds have emerged as a new type of synthetic
Scheme 1. Migratory Insertion of Pd Carbene
method for constructing C-C double bonds.1 In related
studies, Barluenga and co-workers first reported the Pd-
catalyzed cross-coupling of N-tosylhydrazones with aryl
halides.2a-c Recently, we have reported related coupling
reactions with N-tosylhydrazones.2d-g N-Tosylhydrazones are
commonly used as precursors for in situ generation of diazo
compounds (eq 1).3 In all the transformations mentioned
above, migratory insertion of Pd carbene is proposed as the
key step in the catalytic cycle (Scheme 1).
On the other hand, diazirines are important carbene
precursors, and their reaction mechanism upon photolysis
and thermolysis has been studied extensively over the past
decades.4 Diazirines are also widely used as photosensitive
groups of photoaffinity labeling techniques in biochemical
studies.5 Moreover, reactions of diazirines with transition
metal complexes have been documented in the literature.6
† Peking University.
‡ Chinese Academy of Sciences.
(1) (a) Greenman, K. L.; Carter, D. S.; Van Vranken, D. L. Tetrahedron
2001, 57, 5219. (b) Greenman, K. L.; Van Vranken, D. L. Tetrahedron
2005, 61, 6438. (c) Devine, S. K. J.; Van Vranken, D. L. Org. Lett. 2007,
9, 2047. (d) Devine, S. K. J.; Van Vranken, D. L. Org. Lett. 2008, 10,
1909. (e) Kudirka, R.; Van Vranken, D. L. J. Org. Chem. 2008, 73, 3585.
(f) Peng, C.; Wang, Y.; Wang, J. J. Am. Chem. Soc. 2008, 130, 1566. (g)
Chen, S.; Wang, J. Chem. Commun. 2008, 4198. (h) Yu, W.-Y.; Tsoi, Y.-
T.; Zhou, Z.; Chan, A. S. C. Org. Lett. 2009, 11, 469. (i) Kudirka, R.; Devine,
S. K. J.; Adams, C. S.; Van Vranken, D. L. Angew. Chem., Int. Ed. 2009,
48, 3677.
(2) (a) Barluenga, J.; Moriel, P.; Valde´s, C.; Aznar, F. Angew. Chem.,
Int. Ed. 2007, 46, 5587. (b) Barluenga, J.; Toma´s-Gamasa, M.; Moriel, P.;
Aznar, F.; Valde´s, C. Chem.-Eur. J. 2008, 14, 4792. (c) Barluenga, J.;
Escribano, M.; Moriel, P.; Aznar, F.; Valde´s., C. Chem.-Eur. J. 2009, 15,
3291. (d) Xiao, Q.; Ma, J.; Yang, Y.; Zhang, Y.; Wang, J. Org. Lett. 2009,
11, 4732. (e) Zhao, X.; Jing, J.; Lu, K.; Zhang, Y.; Wang, J. Chem. Commun.
2010, 1724. (f) Zhang, Z.; Liu, Y.; Gong, M.; Zhao, X.; Zhang, Y.; Wang,
J. Angew. Chem., Int. Ed. 2010, 49, 1139. (g) Zhou, L.; Ye, F.; Zhang, Y.;
Wang, J. J. Am. Chem. Soc. 2010, 132, 13590.
10.1021/ol102434v  2010 American Chemical Society
Published on Web 11/10/2010

However, to the best of our knowledge, the transition-metal-
catalyzed reaction of diazirines has not been reported. Since
diazirine can be converted into a diazo compound or carbene
upon photolysis or thermolysis (eq 1),7 we conceived that
diazirine might replace N-tosylhydrazone in a Pd-catalyzed
cross-coupling reaction. Herein we report the Pd(0)-catalyzed
cross-coupling of diazirines with aryl halides, which affords
substituted olefins in good yields.
Table 1. Reaction Condition Optimization with Pd-Catalyzed
Cross-Coupling of 1a and 2a
entry
cat. (mol %)
t (°C) solvent yield (%)a
1b c
Pd2(dba)3(2.5)/Xphos (10)
Pd(PPh3)4 (5)
90
100
100
100
100
100
100
100
110
110
110
DCE
MeCN
MeCN
THF
CHCl3
NMP
DCE
DCE
DCE
DCE
DCE
32
27
33
11
,
2b
3b
4b
5b
6b
7b
8e
9e
Pd2(dba)3(2.5)/Xphos (10)
Pd2(dba)3(2.5)/Xphos (10)
Pd2(dba)3(2.5)/Xphos (10)
Pd2(dba)3(2.5)/Xphos (10)
Pd2(dba)3(2.5)/Xphos (10)
Pd2(dba)3(2.5)/Xphos (10)
Pd2(dba)3(2.5)/Xphos (10)
Pd2(dba)3(2.5)/Xphos (10)
Xphos (10)
d
–
–
At the outset of this investigation, we explored the Pd-
catalyzed cross-coupling of 3-methyl-3-phenyldiazirine 1a with
p-bromotoluene 2a under oil bath heating conditions. To our
delight, cross-coupling product could indeed be formed, albeit
in low yield, by heating at 90 °C for 4 h (Table 1, entry 1).
The yield could not be further improved regardless of extensive
optimization attempts.8 We observed that the main side product
was styrene, which was derived from diazirine decomposition
through a carbene 1,2-hydrogen shift.4,9 Further optimization
experiments revealed that microwave irradiation could
slightly improve the yield with Pd(PPh3)4 as catalyst (entry
2).10 Switching the catalyst to Pd2(dba)3/Xphos (2-dicyclo-
hexylphosphino-2′,4′,6′-triisopropylbiphenyl) further im-
proved the reaction (entry 3). Since microwave-assisted
reactions are generally affected by solvents, we next at-
tempted to optimize the reaction by examining a series of
solvents, including 1,2-dichloroethane (DCE), N-methyl-2-
pyrrolidinone (NMP), THF, and CHCl3 (entries 4-7). DCE
d
37
40
64
78
10e f
11
,
g
–
a Isolated yields. b 1a:2a ) 1.1:1; concentration of 1a is 0.17 mol/L.
c Reaction was heated by an oil bath for 4 h. d Product 3a was not detected.
e Concentration of 1a is 1.0 mol/L. f 1a:2a ) 1.5:1. g 2a remained unchanged
while 1a decomposed to afford a complex mixture.
afforded better results compared with MeCN (entry 7), while
other solvents all gave inferior results (entries 4-6).
Subsequent experiments indicated that higher concentration
and higher reaction temperature could improve the reaction
(entries 8 and 9). Finally, the reaction was found to afford
optimal results by further changing the substrate ratio of 1a
to 2a from 1.1:1 to 1.5:1 (entry 10).
With the optimized reaction conditions in hand, the substrate
scope was examined with a series of diazirines 1a-g and halides
2a-n (Table 2). All the reactions were complete within 10 min
and afforded substituted olefins in moderate to excellent yields.
For the aromatic bromides, the reactions demonstrated high
functional group tolerance. The reaction proceeded smoothly
with ortho-, meta-, and para-substituted aryl bromides (entries
1, 12, and 20). Both electron-donating and -withdrawing groups
of the aryl bromides were tolerated (entries 2-6). Heterocyclic
aryl bromides could be employed in the coupling reaction (entry
7). Highly sterically hindered mesityl bromide (2j) could also
afford the coupling products 3m and 3p in good yields (entries
13 and 18).
(3) For a review, see: Fulton, J. R.; Aggarwal, V. K.; de Vicente, J.
Eur. J. Org. Chem. 2005, 1479.
(4) For reviews, see: (a) Moss, R. A. Acc. Chem. Res. 2006, 39, 267,
and references therein. (b) Liu, M. T. H., Ed. Chemistry of Diazirines; CRC
Press: Boca Raton, FL, 1987.
(5) For selected recent reports, see: (a) Mayer, T.; Maier, M. E. Eur. J.
Org. Chem. 2007, 4711. (b) Kumar, N. S.; Young, R; N. Bioorg. Med.
Chem. 2009, 17, 5388. (c) Chee, G.; Yalowich, J. C.; Bodner, A.; Wu, X.;
Hasinoff, B. B. Bioorg. Med. Chem. 2010, 18, 830. (d) Hashimoto, M.;
Furukawa, K.; Tomohiro, T.; Hatanaka, Y. Chem. Pharm. Bull. 2010, 58,
405.
(6) (a) Albini, A.; Kisch, H. In Topics in Current Chemistry; Springer
Berlin/Heidelberg Press, 1976; Vol. 65, p 5. (b) Chaloner, P. A.; Gary, D.;
Glick, G. D.; Moss, R. A. J. Chem. Soc., Chem. Commun. 1983, 880. (c)
Avent, A. G.; Benyunes, S. A.; Chaloner, P. A.; Hitchcock, P. B. J. Chem.
Soc., Chem. Commun. 1987, 1285. (d) Benyunes, S. A.; Chaloner, P. A. J.
Organomet. Chem. 1988, 341, C50. (e) Benyunes, S. A.; Chaloner, P. A.;
Hitchcock, P. B. J. Chem. Soc., Chem. Commun. 1989, 1491. (f) Avent,
A. G.; Benyunes, S. A.; Chaloner, P. A.; Gotts, N. G.; Hitchcock, P. B.
J. Chem. Soc., Dalton Trans. 1991, 1417. (g) Moss, R. A.; Fede´, J.; Yan,
S. J. Am. Chem. Soc. 2000, 122, 9878.
Tri- and tetrasubstituted olefins were obtained in good yields
by using the diazirines bearing alkyl substituents other than a
methyl group (entries 16-23). The stereoselectivity of the olefin
products varied depending on the substrates. It was noted that
the reaction of diazirines with ortho-substituted aryl bromides
could afford trisubstituted olefins with high stereoselectivity,
(7) For selected literature, see: (a) Amrich, M. J.; Bell, J. A. J. Am.
Chem. Soc. 1964, 86, 292. (b) Liu, M. T. H.; Ramakrishnan, K. J. Org.
Chem. 1977, 42, 3450. (c) Ammann, J. R.; Subramanian, R.; Sheridan, R. S.
J. Am. Chem. Soc. 1992, 114, 7592. (d) Nigam, M.; Platz, M. S.; Showalter,
B. M.; Toscano, J. P.; Johnson, R.; Abbot, S. C.; Kirchhof, M. M. J. Am.
Chem. Soc. 1998, 120, 8055. (e) Reinaldo, M.; Frances, L. C. Org. Lett.
2004, 6, 881. (f) Zhang, Y.; Burdzinski, G.; Kubicki, J.; Platz, M. S. J. Am.
Chem. Soc. 2008, 130, 16134. (g) Zhang, Y.; Vyas, S.; Hadad, C. M.; Platz,
M. S. J. Phys. Chem. A 2010, 114, 5902.
(11) Typical procedure for the Pd(0)-catalyzed cross-coupling. Aryl halide
(0.6 mmol), diazirine (0.9 mmol), triethylamine (0.9 mmol), Pd2(dba)3 (0.015
mmol, 2.5 mol %), XPhos (0.06 mmol, 10 mol %), and dioxane (0.6 mL)
were mixed in a microwave tube. The mixture was stirred at 110 °C for 10
min under microwave conditions (the highest power: 200 W; run time: 2 min;
hold time: 10 min; temperature: 110 °C). Upon the completion of the reaction,
the solution was filtered through a short silica gel column. The solvent was
evaporated under reduced pressure, and the crude residue was purified by flash
chromatography on silica gel.
(8) For details, see Supporting Information.
(9) (a) Schaefer, H. F., III Acc. Chem. Res. 1979, 12, 288. (b) Nikon,
A. Acc. Chem. Res. 1993, 26, 84
.
(10) For recent reviews on microwave-assisted reactions, see: (a) Kappe,
C. O. Angew. Chem., Int. Ed. 2004, 43, 6250. (b) Appukkuttan, P.; Van der
Eycken, E. Eur. J. Org. Chem. 2008, 1133 and references cited
therein.
Org. Lett., Vol. 12, No. 23, 2010
5581

Table 2. Pd(0)-Catalyzed Cross-Coupling with a Series of Diazirines and Aryl Halidesa 11
a Reaction conditions: 1a-g (0.9 mmol), 2a-n (0.6 mmol), Pd2(dba)3 (2.5 mol %), Xphos (10 mol %), Et3N (0.9 mmol), DCE (0.6 mL), MW 110 °C,
c
Pmax power 200 W, 10 min hold time. b Yield of isolated product after silica gel chromatography. Ratio determined by H NMR spectra.
1
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Org. Lett., Vol. 12, No. 23, 2010

affording predominantly Z-isomers (entries 18-19 and 23),
while in other cases, the reaction essentially showed no
selectivity (entries 20-22). The selectivity was found to be not
notably affected by electronic effects of the substituents on the
aryl bromide (entries 20-22). Finally, it was noteworthy that
aryl chlorides also worked, affording coupling products in
moderate yields (entries 14 and 15).
Scheme 2. Mechanistic Rationale
Since diazirines were synthesized by oxidation of diaz-
iridines with oxidants such as Ag2O and MnO2,5b we
explored the possibility of Pd-catalyzed cross-coupling of
diaziridines under oxidative conditions. It was demonstrated
that such oxidative cross-coupling was indeed possible. As
shown in eq 2, the Pd(0)-catalyzed cross-coupling of
4-bromotoluene (2a) with diaziridine (4a) proceeded smoothly
with Ag2O as oxidant.
In summary, we have reported a microwave-assisted cross-
coupling reaction of diazirines with aryl halides, which
provides various substituted olefins efficiently. To our
knowledge, this reaction represents the first example of a
transition-metal-catalyzed reaction of diazirines, which sig-
nificantly expands the chemistry of diazirines. Moreover, it
further demonstrates the generality and importance of the
transformations based on Pd carbene species.
A plausible mechanism for this Pd(0)-catalyzed cross-
coupling is proposed as shown in Scheme 2. The reaction is
initiated by oxidative addition of Pd(0) catalyst A to the aryl
halide to afford Pd(II) species B. On the other hand, diazirine
may be converted to a diazo compound or carbene species
under the thermolytic conditions,6 which then reacts with
Pd(II) species B to afford Pd carbene complex C. Migratory
insertion of the aryl group to the carbenic carbon affords
intermediate D, from which ꢀ-hydride elimination provides
the product and regenerates the Pd(0) species in the presence
of triethylamine.
Acknowledgment. The project is supported by the Natural
Science Foundation of China (Grant No. 20902005, 20832002,
20772003, 20821062, 21072009), National Basic Research
Program of China (973 Program, No. 2009CB825300).
Supporting Information Available: Experimental pro-
1
cedure, characterization data, H and 13C NMR spectra for
all new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL102434V
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