Palladium-Catalyzed Regioselective Dehydrogenative C–H/C–H Cross-Coupling of Pyrroles and Pyridine N-Oxides

Article abstract of DOI:10.1002/ejoc.201600680

The palladium-catalyzed cross-dehydrogenative coupling of N-alkylpyrroles and pyridine N-oxides gave the corresponding pyrrolylpyridine N-oxides. Cu(OAc)₂·H₂O as a co-catalyst with air as the terminal oxidant led to preferential coupling in the β-position, whereas AgOAc as the stoichiometric oxidant resulted in preferential coupling in the α-position. N-(Benzyloxymethyl)pyrrole derivatives were deprotected by hydrogenolysis followed by basic hydrolysis.

Full text of DOI:10.1002/ejoc.201600680

DOI: 10.1002/ejoc.201600680
Communication
Cross-Coupling
Palladium-Catalyzed Regioselective Dehydrogenative C–H/C–H
Cross-Coupling of Pyrroles and Pyridine N-Oxides
Shanshan Liu[a] and C. Christoph Tzschucke*[a]
Abstract: The palladium-catalyzed cross-dehydrogenative cou- in the ꢀ-position, whereas AgOAc as the stoichiometric oxidant
pling of N-alkylpyrroles and pyridine N-oxides gave the corre- resulted in preferential coupling in the α-position. N-(Benzyl-
sponding pyrrolylpyridine N-oxides. Cu(OAc)2·H2O as a co-cata- oxymethyl)pyrrole derivatives were deprotected by hydrogenol-
lyst with air as the terminal oxidant led to preferential coupling ysis followed by basic hydrolysis.
Introduction
arylated with quinoxaline N-oxide.[3q] Similarly, N-pyridylpyrrole
was α-arylated with pyridine N-oxide, quinoline N-oxide, and
quinoxaline N-oxide in a chelation-assisted C–H/C–H cross-cou-
pling reaction.[3n] Herein, we report the oxidative cross-coupling
of pyridine N-oxides and pyrroles with catalyst-controlled re-
gioselectivity.[4]
The direct oxidative coupling of two arenes, in which a new
carbon–carbon bond is formed at the expense of two carbon–
hydrogen bonds (cross-dehydrogenative coupling, CDC), is a
particularly attractive synthetic approach to (hetero)biaryls, be-
cause it avoids the need for functional groups at the site of
coupling.[1e] Hence, the starting materials need to be less func-
tionalized than those used in other cross-coupling reactions Results and Discussion
and are, therefore, more readily commercially available or easily
Initially, we tested the reaction of unsubstituted pyridine N-ox-
prepared. One obvious obstacle for an efficient direct C–H/C–H
cross-coupling reaction is the presence of several C–H bonds of
similar reactivity in the starting material, which could lead to
different isomeric products. The other obvious interference is
the undesired homocoupling of the starting material. Despite
these inherent problems, numerous successful methods for di-
rect cross-coupling reactions have been reported in the last
years.[1]
ide (2a) with different N-substituted pyrroles 1 under conditions
previously reported by You et al. for the coupling of pyridine
N-oxides with thiophenes and furans (Table 1, Entries 1–6).[2j]
N-Methyl- and N-benzylpyrrole were coupled with pyridine N-
oxide and gave the corresponding products in promising yields
with preference for substitution at the ꢀ-position of the pyrrole
ring (Table 1, Entries 1 and 6), whereas the regioselectivity was
decreased for N-phenylpyrrole (Table 1, Entry 5). Although N-
tosylpyrrole showed nearly complete selectivity for the ꢀ-cou-
pled product, the yield was low (Table 1, Entry 2), possibly be-
cause the electron-withdrawing tosyl (Ts) group decreased the
nucleophilicity of the pyrrole ring, which indicated an electro-
philic mechanism for the activation of the pyrrole C–H bond.
Upon testing an N-carbamoyl substituent as a directing group,
the proportion of α-arylated pyrrole was increased; however,
the yield decreased, and this approach was not pursued any
further (Table 1, Entry 3). An N-tert-butoxycarbonyl (Boc) group
was not stable under the reaction conditions, and only a small
amount of the unprotected ꢀ-arylated product was isolated
(Table 1, Entry 4). For further optimization, N-benzylpyrrole was
chosen. Addition of phosphine ligands improved the regio-
selectivity, and 1,3-bis(diphenylphosphino)propane (dppp)
and 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl
(Dave-Phos) gave the best results (Table 1, Entry 8). Decreasing
the loading of the Cu(OAc)2·H2O oxidant to a substoichiometric
amount with air as the terminal oxidant decreased the yield
and regioselectivity (Table 1, Entry 9). However, the addition of
acetic acid restored the regioselectivity and increased the yield,
Pyridine N-oxides have been used as stable, readily available
starting materials in numerous C–H functionalization and C–C
bond-forming reactions.[2] Although there is a vast number of
examples for the direct arylation of indoles, pyrroles have been
used much less often in direct arylations owing to their instabil-
ity under oxidative conditions and to difficulties in controlling
the regioselectivity.[3] There are only a few isolated examples of
direct C–H/C–H cross-couplings of pyrrole derivatives with azine
N-oxides. 2,5-Dimethyl-N-phenylpyrrole was coupled with pyr-
idine N-oxide by using a palladium catalyst and Ag2CO3 as stoi-
chiometric oxidant.[2k] N-Tosylpyrrole was ꢀ-arylated with pyr-
idine N-oxide by using AgOAc as the oxidant.[3r] By using
Cu(OAc)2 as a stoichiometric oxidant, N-benzylpyrrole was ꢀ-
[a] Institut für Chemie und Biochemie, Freie Universität Berlin,
Takustrasse 3, 14195 Berlin, Germany
E-mail: tzschucke@chemie.fu-berlin.de
http://www.bcp.fu-berlin.de/en/chemie/chemie/forschung/OrgChem/
tzschucke/
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under http://dx.doi.org/10.1002/ejoc.201600680.
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Table 1. Optimization of the regioselective heteroarylation of pyrrole.[a]
Entry
R1
Additive/conditions
Yield[b] [%]
3/4
1
2
Me
Ts
CuBr (10 mol-%)
CuBr (10 mol-%)
49
24
80:20
99:1
3
4
5
6
7
8
CONMe2
Boc
Ph
Bn
Bn
CuBr (10 mol-%)
CuBr (10 mol-%)
CuBr (10 mol-%)
CuBr (10 mol-%)
–
34
13
43
55
48
52
58:42
99:1[c]
67:33
87:13
83:17
92:8
Bn
dppp (10 mol-%)
9
Bn
Bn
Bn
Bn
dppp (10 mol-%), Cu(OAc)2·H2O (0.5 equiv.)
CuCl (10 mol-%), dppp (10 mol-%), Cu(OAc)2·H2O (0.25 equiv.), HOAc (2 equiv.)
bpy (1 equiv.) instead of pyridine
45
75:25
93:7
50:50
20:80
10
11
12
67
43[d]
42[d]
bpy (0.4 equiv.) instead of pyridine, AgOAc (2.3 equiv.) instead of Cu(OAc)2·H2O
[a] Reaction conditions: 1 (0.25 mmol), 2a (1 mmol), catalyst (5 mol-%), co-catalyst (10 mol-%), pyridine (0.25 mmol), ligand, oxidant in dioxane (1 mL) at
110 °C for 60 h. [b] Yield of isolated product. [c] Only deprotection products were obtained. [d] Yield was determined by NMR spectroscopy.
which eventually allowed the loading of Cu(OAc)2·H2O to be oxide, whereas the regioselectivities depended more on the
decreased to 0.25 equiv. (Table 1, Entry 10). These conditions substituent and rarely exceeded 1:2 to 1:4 in favor of α-arylation
appeared to be fairly robust, as displacing the CuCl additive by of the pyrrole. Remarkable exceptions were the high regio-
tetrabutylammonium chloride or NaCl as the chloride source selectivities in the reactions with quinoline N-oxide, isoquin-
led to similar results, and replacing CuCl by a corresponding oline N-oxide, and pyrazine N-oxide (Table 2, Entries 14–16).
amount of Cu(OAc)2·H2O only slightly decreased the yield. A With 3-bromopyridine N-oxide, no product was obtained, be-
subsequent control experiment even showed that the diphos- cause the starting material decomposed under either set of re-
phine could be left out without notable effect (see also Table 2, action conditions. As expected, with 2,6-lutidine N-oxide no
Entries 24–32). A preliminary screening of the oxidant had indi- coupling product was observed, because both reactive posi-
cated that silver salts might lead to preferential C2-arylation.[5] tions of the N-oxide ring are blocked. We briefly examined the
However, even after considerable experimentation, N-benzyl- influence of substituents on the pyrrole ring. Under condi-
pyrrole (1b) could be α-arylated with pyridine N-oxide only in tions A, 2-ethyl-N-benzylpyrrole led to higher yields (Table 2,
modest yield and regioselectivity by using a catalytic amount Entries 17–20), whereas 2-methoxycarbonyl-N-benzylpyrrole led
of Pd(OAc)2 with 2,2′-bipyridine (bpy) as the ligand and a slight to slightly lower yields (Table 2, Entries 21 and 22), and the
excess of AgOAc as the oxidant (Table 1, Entry 12). Attempts to regioselectivity remained unaffected for both substrates. 3-Me-
lower the loading of the silver salt to a substoichiometric thoxycarbonyl-N-benzylpyrrole gave only the α-arylation prod-
amount in combination with a stoichiometric terminal oxidant uct in 26 % yield (Table 2, Entry 23). This apparent reversal in
were unsuccessful.
regioselectivity likely results simply from the steric influence of
the substituent. Under conditions B, the yields of 2-ethyl-N-
benzylpyrrole remained variable between 20 and 40 %, but the
regioselectivity increased considerably. For both sets of condi-
tions, the substituent effect on the yields was consistent with
mechanisms such as electrophilic aromatic substitution (SEAr)
or concerted carbometalation (Heck-type), for which the pyrrole
acts as the nucleophilic reaction partner.
The substrate scope was probed with a number of substi-
tuted pyridine N-oxides, which were coupled with N-benzyl-
pyrrole (Table 2). With Cu(OAc)2·H2O as the co-catalyst (condi-
tions A), pyridine N-oxides with a C4 substituent typically gave
yields >60 % and regioselectivities >10:1 in favor of ꢀ-arylation
(Table 2, Entries 1–9). The yields tended to be higher for sub-
strates with electron-withdrawing substituents than for elec-
tron-donating substituents (Table 2, Entry 1 vs. 3). This reactivity
When we replaced the N-benzyl substituent of the pyrrole
pattern resembles the trends observed for other palladium-cat- by an N-benzyloxymethyl (BOM; Table 2, Entries 24–30), N-(4-
alyzed arylation reactions of pyridine N-oxides.[2f,2g,2h] 4-Cyano- methoxy)benzyl (PMB; Table 2, Entry 31) or N-3,4-dimethoxy-
pyridine N-oxide is the exception (Table 2, Entry 9), with low benzyl group (DMB; Table 2, Entry 32), results similar to those
yield and diminished regioselectivity, possibly because of the previously obtained were found. However, N-(2-pyridyl)pyrrole
coordinating properties of the nitrile group. Pyridine N-oxides and N-(2-pyrimidyl)pyrrole, for which the substituent might act
with substituents in other positions gave lower yields and re- as a directing group, did not give any coupling product. The
gioselectivities. In comparison, with AgOAc as a stoichiometric pyridine N-oxide of the coupling products was efficiently de-
oxidant (conditions B), most yields were in the range of 30– oxygenated to the corresponding pyridine by treatment with
40 % and depended less on the substituent at the pyridine N- PCl3 (see the Supporting Information, Table S3).[6] Catalytic de-
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Table 2. Substrate scope of the oxidative coupling of pyrroles and pyridine N-oxides.[a]
Entry
R1
R2
R3
Yield[b] [%]
3/4
1
2
3
4
5
6
7
8
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
BOM
BOM
BOM
BOM
BOM
BOM
BOM
PMB
DMB[g]
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
4-CO2Et
4-Ph
4-OMe
4-Me
64 (33)
68 (34)
42 (36)
59 (42)
61 (36)
69 (33)
68 (33)
60 (34)
24 (18)
45 (32)
45 (21)
38 (11)
0 (16)
48 (29)
50 (28)
<5 (25)
60 (34)
80 (28)
74 (22)
79 (42)
45 (11)
57 (<5)
26 (14)
57[f] (37)
51[f] (43)
67[f] (45)
60[f] (35)
52[f] (37)
51[f] (41)
51[f] (43)
60[f] (35)
53[f] (33)
90:10 (20:80)
94:6 (17:83)
89:11 (56:44)
95:5 (43:57)
95:5 (25:75)
92:8 (20:80)
96:4 (20:80)
90:10 (11:89)
75:25 (20:80)
52:48 (25:75)
75:25 (33:67)
89:11 (20:80)
– (33:67)
50:50 (10:90)
75:25 (7:93)
– (< 1:99)
84:16 (20:80)
94:6 (< 1:99)
91:9 (< 1:99)
> 99:1 (9:91)
93:7 (33:67)
>99:1 (–)
< 1:99 (< 1:99)
88:12[f] (25:75)
> 99:1[f] (33:67)
91:9[f] (55:45)
92:8[f] (57:43)
> 99:1[f] (33:67)
> 99:1[f] (25:75)
> 99:1[f] (33:67)
93:7[f] (33:67)
90:10[f] (38:62)
4-tBu
4-COMe
4-OPh
4-CF3
4-CN
3-CO2Me
3-Me
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
2-Me
2-(2-pyridyl)
[c]
–
–
–
[d]
[e]
2-Et
2-Et
2-Et
2-Et
2-CO2Me
2-CO2Me
3-CO2Me
H
4-CO2Et
4-COMe
4-Ph
H
4-tBu
H
H
4-Ph
4-OMe
4-Me
4-tBu
4-CF3
4-COPh
H
H
H
H
H
H
H
H
H
H
H
[a] Reaction conditions A: 1 (0.25 mmol), 2 (1 mmol), Pd(OAc)2 (5 mol-%), CuCl (10 mol-%), dppp (5 mol-%), Cu(OAc)2·H2O (25 mol-%), pyridine (1 equiv.),
HOAc (2 equiv.) in dioxane(1 mL) at 110 °C for 60 h. Reaction conditions B: 1 (0.25 mmol), 2 (1 mmol), Pd(OAc)2 (5 mol-%), bpy (40 mol-%), AgOAc (2.3 equiv.)
in dioxane (1 mL) at 110 °C for 60 h. [b] Yield of isolated product obtained under reaction conditions A. Value in parentheses refers to reaction conditions B.
[c] Quinoline N-oxide. [d] Isoquinoline N-oxide. [e] Quinoxaline N-oxide. [f] No dppp was added, CuCl (15 mol-%) used. [g] 3,4-Dimethoxybenzyl.
oxygenation of 4ba with hydrogen (1 atm, Pd/C, MeOH, r.t.) conditions A, deuterium was incorporated into the 2- and 3-
resulted in only 62 % yield and the formation of unidentified positions of N-benzylpyrrole (1b) in a 1:1 ratio and to the same
decomposition products. Debenzylation of the N-benzylpyrr- extent as uncatalyzed deuteration occurred (10–15 %). This ob-
oles proved to be unsuccessful in our hands. Hydrogenation servation excludes reversible C–H activation of the pyrrole. Un-
with a catalytic amount of Pd/C resulted only in deoxygenation der conditions B, however, deuterium was incorporated to a
of the pyridine N-oxide, and increasing the pressure resulted in larger extent in a 3:1 ratio favoring the 2-position of the pyrrole
decomposition. Brønsted acids (e.g., H2SO4 and HCl) and Lewis ring (65–75 %), which suggests reversible SEAr-like metalation.
acids (e.g., AlCl3) did not convert the starting material. The PMB Deuterium incorporation into pyridine N-oxide (2a) occurred
group could be removed by treatment with a catalytic amount
of H2SO4 in trifluoroacetic acid, albeit in low yield. The BOM
group, however, was successfully removed by catalytic deben-
zylation with H2 and Pd/C followed by basic cleavage of the
surprisingly stable N-hydroxymethyl intermediate (Table 3).
only to a small extent and exclusively at the 2-position under
both sets of reaction conditions (7 %). For pyridine N-oxide, the
observed KIEs of kH/kD > 2.0 are consistent with rate-limiting
C–H activation of pyridine N-oxide, for example, by a concerted
metalation-deprotonation mechanism,[7] under either set of re-
We briefly investigated a possible mechanism for the reac- action conditions. For the pyrrole, small KIEs of kH/kD ≈ 0.9–1.5
tion by H/D exchange experiments and kinetic isotope effect were observed, consistent with electrophilic functionalization of
(KIE) measurements (see the Supporting Information). Under the pyrrole, for example, by SEAr-like metalation or by carbome-
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Table 3. Deprotection of pyrroles.[a]
Experimental Section
General Procedure for the Oxidative Coupling of Substituted
Pyridine N-Oxides with Pyrrole Derivatives
Conditions A: A Teflon-capped vial was charged with a stirrer bar,
pyridine N-oxide (1 mmol, 4 equiv.), Pd(OAc)2 (5 mol-%), CuCl
(10 mol-%), dppp (5 mol-%), Cu(OAc)2·H2O (25 mol-%), pyridine
(1 equiv.), AcOH (2 equiv.), and dioxane (0.25
M in substrate), and
the mixture was stirred for 10 min. Then, the substituted pyrrole
(0.25 mmol, 1.0 equiv.) was added, and the resulting mixture was
heated to 110 °C for 60 h and then cooled to room temperature.
The mixture was directly purified by flash column chromatography
to afford the analytically pure product.
Entry
R3
2-Arylpyrrole
Yield[b] [%]
3-Arylpyrrole
Yield[b] [%]
1
2
3
4
H
Me
tBu
OMe
4ja
4je
4jf
61
88
71
90
3ja
3je
3jf
74
82
60
84
Conditions B: A Teflon-capped vial was charged with a stirrer bar,
pyridine N-oxide (1 mmol, 4 equiv.), Pd(OAc)2 (5 mol-%), bipyridine
4jd
3jd
(40 mol-%), AgOAc (2.3 equiv.), and dioxane (0.25
M in substrate),
[a] Reaction conditions: (1) 3 or 4 (0.05 mmol), Pd/C (10 mol-%), H2 (1 atm),
0.05 HCl in MeOH/H2O (2.5 mL). (2) 0.5 HCl in MeOH/H2O (2.5 mL).
[b] Yield of isolated product.
M
M
and the mixture was stirred for 10 min. Then, the substituted
pyrrole (0.25 mmol, 1.0 equiv.) was added, and the resulting mixture
was heated to 110 °C for 60 h and then cooled to room tempera-
ture. The mixture was directly purified by flash column chromatog-
raphy to afford the analytically pure product.
talation (Heck-type mechanism).[8] Possible explanations for the
reagent-dependent regioselectivity might be that the co-oxi-
dant leads to a complete switch in mechanism or that the α-
and ꢀ-arylation products are formed by different mechanisms.
Thus, Cu(OAc)2 might form mixed Cu–Pd clusters,[9] which
might lead to carbometalation of the pyrrole. In this case, one
would expect preferential addition of the Pd catalyst to the
more electron-rich C2 position and arylation of the C3 position.
With AgOAc as the oxidant, more electrophilic, possibly cationic
Pd intermediates might be formed, which would cause electro-
philic palladation of the electron-rich C2 position. Subsequent
reductive elimination from the formed pyrrolyl–palladium com-
plex would lead to the observed α-arylation product. The fact
that the regioselectivities of pyrrole arylation depend on the
pyridine N-oxide coupling partner might be an indication that
activation of the pyridine N-oxide occurs first and that the re-
sulting aryl–palladium complex is involved in the activation of
the pyrrole ring. However, dimetallic mechanisms involving sep-
arate catalytic cycles for activation of the substrates and a trans-
metalation step would also be consistent with the experimental
observations.[10]
Acknowledgments
Funding by the Deutsche Forschungsgemeinschsft (DFG) (grant
Tz 68/3-1 to C. C. T.) is gratefully acknowledged. S. L. thanks the
China Scholarship Council (CSC) for support by a scholarship.
Keywords: Arylation · Biaryls · Cross-coupling ·
Palladium · Regioselectivity
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Conclusion
ꢀ-Selective arylation of protected pyrroles was achieved by use
of Cu(OAc)2·H2O as an oxidation co-catalyst in a preparatively
useful range and comparable to that of other oxidative cross-
couplings (also known as CDC reactions) without recourse to
sterically demanding N-protecting groups. However, α-selective
pyrrole arylation without the use of coordinating directing
groups cannot be considered a solved problem. While the re-
sults with AgOAc as terminal oxidant seem promising, the reac-
tion conditions are hardly practical because of the modest
yields and regioselectivities, high catalyst loading, and stoichio-
metric metal oxidant. Although previously noted,[3b,3c] it is
worth reiterating that in this and similar oxidative cross-cou-
pling reactions, not only do the CuII or AgI salts serve as oxid-
ants to regenerate the PdII catalyst, but they also serve distinct
and yet to be understood roles in the C–H functionalization
process.
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Received: June 3, 2016
Chlenov, D. M. Ho, J. Am. Chem. Soc. 2005, 127, 7759; b) M. Böttger, B.
Published Online: July 4, 2016
Eur. J. Org. Chem. 2016, 3509–3513
www.eurjoc.org
3513
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