Catalytic C(sp3)?H Arylation of Free Primary Amines with an exo Directing Group Generated In Situ

Article abstract of DOI:10.1002/anie.201604268

Herein, we report the palladium-catalyzed direct arylation of unactivated aliphatic C?H bonds in free primary amines. This method takes advantage of an exo-imine-type directing group (DG) that can be generated and removed in situ. A range of unprotected aliphatic amines are suitable substrates, undergoing site-selective arylation at the γ-position. Methyl as well as cyclic and acyclic methylene groups can be activated. Furthermore, when aniline-derived substrates were used, preliminary success with δ-C?H arylation was achieved. The feasibility of using the DG component in a catalytic fashion was also demonstrated.

Full text of DOI:10.1002/anie.201604268

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201604268
German Edition: DOI: 10.1002/ange.201604268
À
C H Activation
Hot Paper
3
À
Catalytic C(sp ) H Arylation of Free Primary Amines with an exo
Directing Group Generated In Situ
Yan Xu+, Michael C. Young+, Chengpeng Wang, David M. Magness, and Guangbin Dong*
Dedicated to Professor Barry M. Trost on the occasion of his 75th birthday
Abstract: Herein, we report the palladium-catalyzed direct
À
arylation of unactivated aliphatic C H bonds in free primary
amines. This method takes advantage of an exo-imine-type
directing group (DG) that can be generated and removed
in situ. A range of unprotected aliphatic amines are suitable
substrates, undergoing site-selective arylation at the g-position.
Methyl as well as cyclic and acyclic methylene groups can be
activated. Furthermore, when aniline-derived substrates were
À
used, preliminary success with d-C H arylation was achieved.
The feasibility of using the DG component in a catalytic
fashion was also demonstrated.
A
mines are commonly found in approved drugs, agrochem-
icals, and other biologically important molecules.[1,2] While
still an on-going challenge, the site-selective functionalization
of unactivated C H bonds[3] in amines would offer a straight-
À
forward approach to access various derivatives and analogues,
which should consequently impact the development of
pharmaceuticals and agrochemicals. During the past decade,
significant progress has been made in terms of the transition-
metal-catalyzed functionalization of unactivated aliphatic
3
À
Scheme 1. DG-based strategies for amine C(sp ) H functionalization.
PG=protecting group.
À
C H bonds in amines by using directing group (DG)
strategies,[4] in which the amine moiety is often masked as
an amide,[5,6] sulfonamide,[7] hydrazone,[8] or urea,[9] or teth-
ered with another DG[10] (Scheme 1A). Albeit highly effec-
tive, these tactics typically require additional steps for the
installation and removal of the DG component. An ideal
approach would directly employ a free amine as the DG.
Recently, Gaunt and co-workers disclosed the first examples
free primary amines. Our laboratory has recently employed
an exo directing mode to realize the catalytic functionaliza-
[13]
À
tion of unactivated aliphatic C H bonds with oximes and
hydrazones[8] (Scheme 1C, Y= O and N-PG). An intriguing
question is whether a regular imine (Y= CRR’) can be
3
À
À
of free-amine-directed catalytic activation of primary C H
employed as an effective exo-DG for C(sp ) H activation.
bonds (Scheme 1B); in their study, the use of bulky,
disubstituted amine substrates appeared to be important.[11]
It is likely that the main difficulties of directly using a free
amine as the DG result from the lack of backbonding when
coordinated to transition metals as well as the susceptibility of
amines to both oxidants and electrophiles.[12]
Inspired by the aforementioned challenge, we sought to
use an in situ generated, exo-type DG (with the p-bond of the
DG outside the metallacycle) for the direct C H activation of
Compared to oximes and hydrazones, N-alkyl imines are
generally more labile towards hydrolysis; however, the
successful realization of such a transformation would enable
À
the use of free amines as substrates for remote C H
functionalization through in situ formation and removal of
the imine DG (Scheme 1D).[14–16] Seminal examples of using
aniline-derived imines as exo-DGs were reported by Sames
and co-workers in the total synthesis of rhazinilam[17] and the
core of teleocidin B4;[18] these syntheses involved the use of
stoichiometric amounts of platinum and palladium for
dehydrogenation, vinylation, and carbonylation reactions.
Herein, we describe the development of a Pd-catalyzed
À
[*] Y. Xu,[+] Dr. M. C. Young,[+] C. Wang, D. M. Magness, Prof. G. Dong
Department of Chemistry
À
direct arylation of the unactivated g- and d-C H bonds in free
University of Texas at Austin
Austin, TX 78712 (USA)
E-mail: gbdong@cm.utexas.edu
primary alkyl amines and anilines by using an 8-formylquino-
line-derived exo-DG, which enables the functionalization of
methyl as well as acyclic and cyclic methylene groups.
Simple 2-butylamine (1a) was employed as the initial
model substrate. To generate the imine DG in situ, quinoline-
[+] These authors contributed equally.
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201604268.
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Table 2: Substrate scope with various alkyl amines.[a]
8-carbaldehyde (ArQCHO) was employed as the additive
owing to our previous success with this type of exo-DG.[13b]
After carefully examining a range of Pd precatalysts, addi-
tives, and solvents, the desired g-arylation product (3a) was
obtained in 75% yield when Pd(OPiv)2 was used as the
precatalyst, an aryl iodonium salt (Ph2IBF4) as the electro-
phile, base 2 as the additive, and dichloroethane (DCE) as the
À
solvent (Table 1, entry 1). The C H arylation occurred site-
selectively at the g-position, and no b-arylation was observed,
which is likely due to the preferred formation of the five-
membered palladacycle.
A series of control experiments were subsequently con-
ducted (Table 1). In the absence of either the Pd precatalyst
or quinoline-8-carbaldehyde, the desired product was not
observed (entries 2 and 3). The yield significantly diminished
when the reaction was run under air or at a lower temperature
(entries 4 and 5). The use of Pd(OAc)2 instead of Pd(OPiv)2
gave comparable results (entry 6). The counterion of the
iodonium salt slightly affected the efficiency of this trans-
formation, with BF4 being optimal (entries 7 and 8). A bulky,
non-coordinating substituted pyridine base (2) was employed
to neutralize the HBF4 generated, but insoluble inorganic
bases, such as Ba(OH)2, were also effective (entry 9). Finally,
whereas DCE proved to be the best solvent (entries 10 and
11), the reaction tolerated a stoichiometric amount of water
(entry 12).
The substrate scope of the g-arylation was then explored
(Table 2). Although the arylated free amine products could be
isolated upon workup (see below, Scheme 2), for ease of
isolation and also owing to the volatility of the alkyl amines,
all of the products were isolated as the benzoylamide
derivatives. Aryl groups with various electronic properties
were installed under the reaction conditions (4a–4h). Fur-
thermore, primary, secondary, and tertiary alkyl amines are all
suitable substrates for this reaction (4i–4l). A number of
Table 1: Control experiments for the g-arylation of amine 1a.
[a] All yields refer to the isolated products. Unless otherwise noted, the
gem-diarylation products were observed in less than 5%. [b] Benzoyla-
tion procedure: MeONH3Cl (4.0 equiv), NEt3 (0.3 mL), RT, 2 h; then
Bz2O (8.8 equiv), RT, 12 h. [c] 1008C. [d] 1058C. [e] 64 h. [f] The 1,1- and
1,5-diarylation products were isolated in a ratio of 1:4; the 1,5-diarylation
product was formed in 3:1 d.r. For details, see the Supporting
Information. Bz=benzoyl.
Entry
Variations from the standard
conditions
3a
Unreacted 1a
[%][a,b]
[%][a,b]
1
2
3
4
5
6
7
8
–
75
0
0
36
<10
71
61
65
56
41
24
70
10
73
50
18
74
7
24
18
23
29
54
15
functional groups, including electron-rich arenes (4g, 4q, and
4r) and benzyl ethers (4o, 4s, and 4t) as well as methylene-
dioxy (4r), cyano (4s), and nitro (4t) groups, were compatible
with the reaction conditions. It is noteworthy that aryl
chlorides (4p), bromides (4c), and iodides (4d), although
known to undergo Pd-catalyzed arylation reactions,[5–7] were
tolerated by this catalytic system, so that they can be used as
a handle for further functionalization. Remarkably, both
no Pd(OPiv)2
no ArQCHO
under air
at 708C
Pd(OAc)2 instead of Pd(OPiv)2
Ph2IOTf instead of Ph2IBF4
Ph2IPF6 instead of Ph2IBF4
Ba(OH)2 instead of 2
in CHCl3
9
10
11
12
À
cyclic and acyclic methylene C H bonds can be arylated with
in PhCl
with H2O (1 equiv)
good efficacies (4u–4w).
Isolation of the free amine products proved to be feasible.
After a simple workup with methoxyamine, free amine
product 3a, though volatile, was still isolated in 61% yield
on a 3 mmol scale (Scheme 2A). Furthermore, 3a could be
[a] Determined by 1H NMR spectroscopy using 1,1,2,2-tetrachloroethane
as the internal standard. [b] Sum of the protonated amine and the
corresponding imine condensed with ArQCHO. Piv=pivaloyl, Tf=tri-
fluoromethanesulfonyl.
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model substrate, d-arylation was achieved under modified
reaction conditions (for detailed optimization studies, see the
Supporting Information). ArQCHO again afforded the opti-
mal DG. Whereas generating the DG in situ provided the
desired arylation product, higher yields were achieved when
the imines were preformed simply by premixing ArQCHO
and the amine substrate for 1 h and removing the solvent
in vacuo. Interestingly, SbPh3 is an effective additive to
achieve consistent yields, although its exact role remains
unclear. Molecular sieves (4 ꢀ) are critical for the arylation of
aniline 5a. Saturation of the molecular sieves with water
(100 mL added) led to no significant drop in yield, though
their replacement with base 2 inhibited the reaction.[19]
1-Adamantanecarboxylic acid (AdCO2H) also played a piv-
À
otal role, likely promoting the C H cyclopalladation step.
À
Scheme 2. Further studies on C H g-arylation. [a] A second batch of
Unlike the g-arylation reaction, this transformation can
tolerate air. Moreover, the aniline products could be directly
isolated upon workup without the need for further derivati-
zation.
the oxidant and base was added after 18 h. [b] Determined by 1H NMR
spectroscopy using 1,1,2,2-tetrachloroethane as the internal standard.
The product was observed as a mixture of the protonated amine and
the corresponding imine after condensation with ArQCHO. [c] Mono/
di=1:1.4. [d] Mono/di=1:1.5. brsm=based on recovered starting
material.
To better understand the role and coordination mode of
the exo-DG, we sought to explore the reaction of imine 7 with
stoichiometric Pd (Scheme 3).[20] Gratifyingly, palladacycle 8
was formed when using HOAc as the solvent and subse-
quently isolated, which enabled its characterization by X-ray
crystallography. Interestingly, when CD3COOD was used as
the solvent, no deuteration of the tert-butyl group was
observed, suggesting that the cyclometalation might not be
an equilibrium process under these conditions.[6q] The crystal
structure of 8 shows that while still maintaining a square-
planar geometry, the Pd center is removed from the quinoline
directly isolated from the reaction mixture (without methoxy-
amine workup) by chromatography, affording 3a in only
slightly decreased yield while recycling most of the ArQCHO
(Scheme 2A). Furthermore, owing to the reversibility of the
imine formation, the use of a catalytic amount of ArQCHO
was examined. To our delight, moderate catalytic activity was
observed, suggesting that imine formation and hydrolysis are
À
compatible with the C H arylation conditions (Scheme 2B).
Higher yields were obtained when the oxidant and base were
added in two batches.
plane by 188, which was not the case for a previously reported
[6q]
À
palladacycle formed by amide-directed C H metalation.
In summary, we have developed a method for the
3
À
Apart from alkyl amines, preliminary success was also
achieved for the C H arylation of aniline-derived substrates
(Table 3). When 2-tert-butylaniline (5a) was employed as the
palladium-catalyzed direct arylation of C(sp ) H bonds in
À
free primary amines. Using an in situ generated imine exo-
À
DG, a range of unactivated aliphatic C H bonds, including
methyl as well as cyclic and acyclic methylene groups, were
site-selectively activated. Given the excellent functional-
group compatibility and the ubiquity of amine functional
groups, it is expected that this method will streamline the
synthesis of nitrogen-containing compounds. The use of in situ
generated exo-DGs through the formation of dynamic
covalent bonds should also have broad implications beyond
this work. Efforts towards expanding the scope of this process,
particularly with aniline substrates, and enhancing the cata-
Table 3: Substrate scope with aniline-derived substrates.[a]
[a] Yields of isolated products are given. [b] Added in two portions.
[c] Yields determined by 1H NMR spectroscopy using 1,1,2,2-tetra-
chloroethane as the internal standard; the ratio of the mono- and
diarylated products is given in parentheses. Ad=adamantyl.
Scheme 3. Stoichiometric formation and isolation of palladacycle 8.
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underway.
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Acknowledgements
We thank the Frasche Foundation, the ACS PRF, and the
Welch Foundation (F-1781) for funding. G.D. is a Searle
Scholar and Sloan Fellow. D.M.M. thanks the NSF
(CAREER; CHE-1254935) for the program “Research
Experience for Veteran Students”. We thank Dr. Vince M.
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À
Keywords: arylation · C H activation · directing groups ·
palladium catalysis · primary amines
3
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À
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Received: May 2, 2016
Published online: && &&, &&&&
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Communications
À
C H Activation
Y. Xu, M. C. Young, C. Wang,
D. M. Magness,
G. Dong*
&&&& — &&&&
The direct arylation of unactivated ali-
aliphatic amines and anilines are suitable
3
À
À
Catalytic C(sp ) H Arylation of Free
Primary Amines with an exo Directing
Group Generated In Situ
phatic C H bonds in free primary amines
substrates, and methyl as well as cyclic
and acyclic methylene groups smoothly
underwent site-selective arylation.
was achieved by using an exo-imine-type
directing group (DG) that can be gener-
ated and removed in situ. Both primary
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