Palladium-Catalyzed Pyrazole-Directed sp3 C?H Bond Arylation for the Synthesis of β-Phenethylamines

Article abstract of DOI:10.1002/anie.201611407

We have developed a method for palladium-catalyzed, pyrazole-directed sp³ C?H bond arylation by aryl iodides. The reaction employs a Pd(OAc)₂ catalyst at 5–10 mol % loading and silver(I) oxide as a halide-removal agent, and it proceeds in acetic acid or acetic acid/hexafluoroisopropanol solvent. Ozonolysis of the pyrazole moiety affords pharmaceutically important β-phenethylamines.

Full text of DOI:10.1002/anie.201611407

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201611407
German Edition: DOI: 10.1002/ange.201611407
Homogeneous Catalysis
3
À
Palladium-Catalyzed Pyrazole-Directed sp C H Bond Arylation for
the Synthesis of b-Phenethylamines
Nurbey Gulia and Olafs Daugulis*
Abstract: We have developed a method for palladium-
3
À
catalyzed, pyrazole-directed sp C H bond arylation by aryl
iodides. The reaction employs a Pd(OAc)2 catalyst at 5–
10 mol% loading and silver(I) oxide as a halide-removal
agent, and it proceeds in acetic acid or acetic acid/hexafluor-
oisopropanol solvent. Ozonolysis of the pyrazole moiety
affords pharmaceutically important b-phenethylamines.
I
n recent years, carbon–hydrogen bond functionalization
methods have developed from an organometallic curiosity
into a useful approach for the synthesis of complex natural
products and drug-like molecules.[1,2] The use of C H bonds
À
as transformable functional groups is advantageous since
these moieties are typically the most abundant functionalities
in organic molecules. Direct conversion of these bonds into
the desired functionality results in economic and ecological
benefits since less chemical waste is generated as a result of
shortened synthetic pathways.
Scheme 1. Arylation regioselectivity and amine b-functionalization.
During the last decade, many examples of directed
intermolecular sp3 C H bond functionalization reactions
À
have been disclosed.[3,4] However, several key issues are still
not solved. Perhaps the most challenging among them is
quaternary centers next to a nitrogen atom or strong base in
the deprotonation step. Additionally, relatively few auxilia-
ries besides bidentate monoanionic directing groups are
capable of promoting functionalization at unactivated meth-
ylene positions.[4c,d,e,7d,8] Among those, the perfluorinated
anilines reported by Yu and co-workers, are notable.[4d,e,8b]
À
control of the site selectivity of the C H functionalization.
Directing-group strategies allow functionalization at the 4-
position from the coordinating heteroatom owing to a prefer-
ence for five-membered metallacycle formation (Scheme
1A). This results in g-functionalization of amine and b-
functionalization of carboxylic acid derivatives.[3,4] Function-
alization of other positions is possible if the 4-position relative
to the coordinating heteroatom is blocked or hindered,
resulting in a limited reaction scope.[5] Another strategy
employs the higher reactivity of methyl relative to methylene
Clearly, additional methods are required to achieve conven-
3
À
ient and regioselective functionalization of unactivated sp C
H bonds. Especially interesting is the selective and general b-
arylation of aliphatic amines, since b-phenethylamines are
key structural components in important medicines and
groups in non-directed C H oxygenation, as shown by the
natural products.[9] We report herein a method for palla-
À
Sanford group.[6] Dong and co-workers have reported several
examples of the b-oxygenation of amine and alcohol deriv-
atives.[7a,b]
dium-catalyzed pyrazole-directed sp C H bond arylation by
3
À
aryl iodides. The reaction tolerates a wide range of functional
groups and allows removal of the directing group to reveal the
pharmaceutically important b-phenethylamine functionality.
Furthermore, this is the first example of using a pyrazole
There have been three reported b-arylations of aliphatic
amine derivatives (Scheme 1B,C).[7c,d,e] While conceptually
important, these methods are limited by the requirement for
moiety as a transformable directing group in sp3 C H
À
functionalization.
Arylpyrazoles can be cyclopalladated, which shows that
pyrazole is an efficient directing group.[10] Furthermore, the
[*] Dr. N. Gulia, Prof. O. Daugulis
Department of Chemistry, University of Houston
Houston, TX 77204-5003 (USA)
E-mail: olafs@uh.edu
pyrazole moiety has been extensively used as a directing
2
À
group for palladium- and ruthenium-catalyzed sp C H bond
arylation.[11] There are only a few isolated reports of pyrazole
Dr. N. Gulia
3
À
directing groups in palladium- and iridium-catalyzed sp C H
Department of Chemistry, University of Wrocław
14 F. Joliot-Curie, 50-383 Wrocław (Poland)
bond functionalization.[12] In 2006, we showed that 1-phenyl-
pyrazole can be ortho-arylated under the conditions that are
effective for 2-phenylpyridine functionalization.[11a] Since 2-
ethylpyridine is arylated under those conditions, it seemed
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
http://dx.doi.org/10.1002/anie.201611407.
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reasonable that 1-ethylpyrazole and other alkylpyrazoles
could be reactive as well.
Optimization was carried out with respect to the silver
source and additives (Table 1). A reasonable arylation rate
was observed at 1308C in acetic acid, while reactions in other
solvents, such as H2O, DMF, acetonitrile, t-butanol, dioxane,
Table 1: Optimization of reaction conditions.[a]
Entry
Ag source
Additive(s)
Yield [%]
1
2
3
4
AgOAc
AgOAc
AgOAc
AgOAc
AgOCOCF3
AgOAc
Ag2O
none
NaOCOCF3
NaOTf
LiOTf
LiOTf
LiOTf/TFA
LiOTf/TFA
LiOTf/TFA
LiOTf/TFA/LiOAc
18
48
63
63
79
75
77
76
81
Scheme 2. Other directing groups.
5
6[b]
7[c]
8[d]
9[e]
methyl-substituted compounds gave arylation products in
yields that are slightly lower than those for 1-ethyl-3,5-
dimethylpyrazole (2-1 to 2-3). Pyrazoles possessing aryl
substituents are also reactive, and products were obtained in
fair to good yields (2-4, 2-5). Ethyltriazoles were not arylated
under the optimized conditions (2-6 and 2-7). This result
demonstrates the higher efficiency of bidentate coordination
Ag2O
Ag2O
[a] Pyrazole 0.2 mmol, 4-iodotoluene 0.6 mmol, AcOH 0.2 mL, additive
0.3 mmol. Yields were determined by GC analysis. [b] Additives: LiOTf
1.2 equiv, trifluoroacetic acid 1.5 equiv. [c] Silver oxide 0.75 equiv,
additives: LiOTf 1.2 equiv, trifluoroacetic acid 1.5 equiv. [d] Silver oxide
0.75 equiv, additives: LiOTf 1.2 equiv, trifluoroacetic acid 1.5 equiv,
hexafluoropropanol/AcOH solvent (3:1), 1208C. [e] Silver oxide
0.8 equiv, additives: LiOTf 1.2 equiv, trifluoroacetic acid 1.7 equiv, LiOAc
1.6 equiv, 1058C, yield of isolated product. OTf=ÀOSO2CF3,
TFA=CF3CO2H.
À
in C H functionalization, since triazoles possessing an addi-
À
tional chelating group are efficient auxiliaries for C H
functionalization.[4j,13] Overall, 3,5-dimethylpyrazole is the
optimal auxiliary for the arylation, based both on reactivity
and cost.
The reaction scope with respect to the aryl iodides is
presented in Table 2. The reactions were successful with both
electron-rich (entries 1–6) and electron-poor (entries 8–13)
aryl iodides. Various functionalities, such as methoxy
(entries 4, 6), chloro (entries 7, 8), trifluoromethyl (entry 9),
ester (entry 10), ketone (entry 11), trifuoromethoxy
(entry 12), and fluoro (entry 13) groups are tolerated. The
reaction can be scaled to 10 mmol without any loss in yield
(entry 7). Typically, the arylations with electron-poor aryl
iodides were slower than those with electron-rich substrates.
dichloroethane, and cyclooctane afforded very low conver-
sions. Entry 1 shows that arylation in acetic acid by using
silver acetate as the base and halide-removing agent gives
product in only 18% yield. Addition of sodium trifluoroace-
tate improved the yield to 48% (entry 2). Even higher yields
are obtained if sodium triflate is employed as an additive
(entry 3). Lithium triflate as an additive gave the same yield
as the sodium salt, thus showing that the anion is important in
arylation (entry 4). The use of silver trifluoroacetate in
combination with lithium triflate further improved the yield
to 79% (entry 5). Attempts to replace the expensive silver
trifluoroacetate with a cheaper silver source were fruitful, as
shown in entries 6 and 7. The use of a silver acetate mixture
with trifluoroacetic acid gave a 75% yield of arylation
product (entry 6). It is possible to replace AgOAc with
Ag2O, which is one of the cheapest commercially available
silver salts (entry 7). An acetic acid/hexafluoroisopropanol
solvent mixture gives the same yield as the reaction run in
pure acetic acid (entry 8); however, for electron-poor aryl
iodides, this is the best solvent combination. Finally, addition
of LiOAc slightly increases the yield, allows the reaction to
occur at 1058C, and gives more reproducible reaction yields at
larger scale (entry 9). No reaction was observed if Pd(OAc)2
was omitted. The use of bases other than silver salts resulted
in very low conversions.
À
This trend is also often observed for C H functionalization
when employing bidentate auxiliaries.[3b]
The reaction scope with respect to the alkyl on the
pyrazoles is presented in Table 3. The isopropyl derivative
was arylated in 50% yield (entry 1), while the s-butyl-
substituted compound reacted at the methyl group to afford
product in 60% yield (entry 2). Larger alkyl groups are
tolerated as well (entries 3 and 4). Phenethyl and phenyl-
propylpyrazoles afforded the products in 53 and 56% yields
(entries 5 and 6). A compound possessing an ester substitu-
tion was arylated in 55% yield (entry 7).
Directed functionalization of secondary, unactivated (not
3
À
benzylic or a to heteroatom) sp C H bonds is relatively rare.
Besides bidentate monoanionic auxiliaries, which can pro-
mote the activation of even some tertiary positions,[14] few
À
directing groups can effect methylene C H bond functional-
Other directing groups were tested under the optimized
conditions (Scheme 2). Unsubstituted ethylpyrazole and
ization. We were pleased to discover that dimethylpyrazole
À
directs the arylation of some secondary and even tertiary C
2
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Table 2: Reaction scope with respect to the aryl iodides.[a]
Table 2: (Continued)
Entry
Ar
Product
Yield [%]
65
11[c]
4-PhCOC6H4
Entry
1[b]
Ar
Product
Yield [%]
81
4-MeC6H4
12[c]
3-CF3OC6H4
67
75
2[b]
3[c]
4[d]
4-tBuC6H4
4-PhC6H4
68
63
76
13[c]
3-FC6H4
[a] Pyrazole 1 mmol, hexafluoroisopropanol 0.75 mL, AcOH 0.25 mL.
Yields of isolated product are given. See the Supporting information for
details. [b] Temperature: 1058C. [c] Temperature: 1208C. [d] Temper-
ature: 1108C. [e] Scale: 10 mmol.
H bonds (Scheme 3). Propylpyrazole gave a mixture of
products resulting from arylation of both the methylene and
methyl groups (3-2 and 3-3). Pyrazolyladamantane 3-4 was
arylated in 53% yield to give product 3-5. Compound 3-6,
which contains the dimethyladamantane moiety present in
memantine,[15] reacted well to give arylation product 3-7 in
45% yield. Interestingly, 2-adamantyl-substituted pyrazole 3-
8 was reactive and afforded three compounds. The major one
4-MeOC6H4
5[b]
3,5-Me2C6H3
71
70
6[d]
7[c]
8[c]
9[c]
3,4-(MeO)2C6H3
3-Cl-4-MeC6H3
4-ClC6H4
78
80[e]
76
69
4-CF3C6H4
10[c]
4-EtO2CC6H4
64
À
Scheme 3. Arylation of secondary and tertiary C H bonds.
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Table 3: Reaction scope with respect to the alkylpyrazoles.[a]
Entry
1
R
Product
Yield [%]
50
isopropyl
Scheme 4. Directing-group removal.
10 mol% loading and silver(I) oxide as a halide-removal
agent and base precursor, and it proceeds in either acetic acid
or acetic acid/hexafluoroisopropanol solvent. Ozonolysis of
the pyrazole moiety affords pharmaceutically significant b-
phenethylamines. Since N-substituted pyrazoles can be
obtained from alkylamines,[17] their arylation can be thought
of as b-funtionalization of aliphatic amines, which are
2
s-butyl
60
57
53
53
56
55
3
2-hexyl
revealed after ozonolysis. The chemistry described here is
3
À
a rare example of formal amine sp C H bond b-arylation.
4
4-Me-2-pentyl
1-phenethyl
Acknowledgements
We thank the Welch Foundation (Chair E-0044) and NIGMS
(Grant No. R01GM077635) for supporting this research.
5[b]
Conflict of interest
The authors declare no conflict of interest.
6
1-phenyl-2-propyl
1-methoxy-carbonyl-2-propyl
À
À
Keywords: arenes · C C coupling · C H activation ·
homogeneous catalysis · palladium
7
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4
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Manuscript received: November 21, 2016
Revised: December 21, 2016
Final Article published: && &&, &&&&
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Communications
Homogeneous Catalysis
N. Gulia, O. Daugulis*
&&&& — &&&&
Palladium-Catalyzed Pyrazole-Directed
3
À
sp C H Bond Arylation for the Synthesis
of b-Phenethylamines
Palladium-catalyzed, pyrazole-directed
sor, and it proceeds in either acetic acid
or acetic acid/hexafluoroisopropanol sol-
vent. Ozonolysis of the pyrazole moiety
affords pharmaceutically important b-
phenethylamines.
3
À
sp C H bond arylation by aryl iodides is
reported. The reaction employs a Pd-
(OAc)2 catalyst and silver(I) oxide as
a halide-removal agent and base precur-
6
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