β-carboline amides as intrinsic directing groups for C(sp2)-H functionalization

Article abstract of DOI:10.1021/jacs.6b12569

Many site-selective palladium-catalyzed C-H functionalization methods require directing groups. We report here β-carboline amides as intrinsic directing groups for C(sp²)-H functionalization. Various substrates including the natural product alangiobussinine and the marinacarboline core structure were functionalized using carboline-directed δ-C(sp²)-H alkynylations. This transformation proceeds under mild conditions and is compatible with a wide variety of β-aryIethamines. δ-Alkynylation of β-arylethamines via a six-membered palladacycle is favored over γ-C(sp²)-H bond functionalization when both positions are accessible. The versatility of β-carboline amides as directing groups is evidenced by other δ-C(sp²)-H functionalizations such as alkenylation, arylation, and C-N bond formation.

Full text of DOI:10.1021/jacs.6b12569

Subscriber access provided by - Access paid by the | UCLA Library
Article
#-Carboline Amides as Intrinsic Directing
Groups for C(sp2)–H Functionalization
Heléné M.-F Viart, Andreas Bachmann, William Kayitare, and Richmond Sarpong
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 01 Jan 2017
Downloaded from http://pubs.acs.org on January 1, 2017
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Journal of the American Chemical Society is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 7
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
β-Carboline Amides as Intrinsic Directing Groups for C(sp2)–H
Functionalization
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Hélène M.-F. Viart,† Andreas Bachmann, William Kayitare and Richmond Sarpong*
Department of Chemistry, University of California, Berkeley, California 94720, United States
ABSTRACT: Many site-selective palladium catalyzed C–H functionalization methods require directing groups. We report here β-
carboline amides as intrinsic directing groups for C(sp2)–H functionalization. Various substrates including the natural product alan-
giobussinine and the marinacarboline core structure were functionalized using carboline-directed δ-C(sp2)–H alkynylations. This
transformation proceeds under mild conditions and is compatible with a wide variety of β-arylethylamines. δ-Alkynylation of β-
arylethamines via a six-membered palladacycle is favored over γ-C(sp2)–H bond functionalization when both positions are accessi-
ble. The versatility of β-carboline amides as directing groups is evidenced by other δ-C(sp2)–H functionalizations such as alkenyla-
tion, arylation, and C–N bond formation.
1) INTRODUCTION
ed two variants of the picolinamide and 8-aminoquinoline
amide directing groups: the TBS-protected methylene hydrox-
yl group at the ortho position of the picolinamide (PAr),4 and
8-amino-5-methoxyquinoline (MQ) directing groups,5 which
are easily cleaved through intramolecular acyl transfer under
acidic conditions or with ceric ammonium nitrate under mild
conditions, respectively.
The emergence of powerful transition metal-catalyzed C–H
functionalization methods over the last decade and a half has
provided new tools for chemical synthesis. Despite continuing
efforts to identify traceless directing groups that can be intro-
duced and removed under the conditions used in the function-
alization reaction,1 most selective C–H functionalization
methods exploit intrinsic reactivity differences between C–H
bonds in a substrate, coupled with the ability of auxiliaries
(directing groups) to direct metallation at specific positions. In
the majority of cases, it is necessary to introduce the auxiliary
prior to C–H activation and then remove it at the end of the
functionalization. Therefore, typical drawbacks of this ap-
proach are an increased number of synthetic manipulations, as
well as the challenges inherent in introducing and removing
the directing group. Generally, directing groups are appended
to functional groups common in complex molecules, where C–
H functionalization technology is increasingly employed.2
On the contrary, instances where a picolinamide directing
group is employed in C–H functionalization and retained in
the targeted product are rare. Only a limited number of exam-
ples of bidentate directing groups that are found in or easily
derived to afford a target compound have been described. Ex-
amples are mostly found for C(sp3)–H functionalizations in the
synthesis and derivatizations of peptides and peptidomimetics,
where the auxiliary can be either an aminoacid itself,6 or trans-
formed into an aminoacid derivative. For instance, the 2-
methoxyiminoacetyl (MIA) directing group developed by Fan
and Ma has been transformed into a glycine moiety by hydro-
genation,7 and the α-amino oxazolinyl directing group devel-
oped by Shi and coworkers was opened and derivatized into
amides in a mild, one-pot procedure.8
Drawing inspiration from substrate-controlled (diastereose-
lective) processes, where the controlling element for stereose-
lectivity is inherent to the substrate, we envisioned an analo-
gous scenario for directed C–H functionalization, where the
directing group is resident in the substrate and in the product.
In this way, the requirement for removing the directing group
post C–H functionalization is obviated. For this purpose, we
have been especially drawn to directing groups based on pyri-
dine that utilize 2-point binding.
We envisioned β-carboline amides as inherent directing
groups that afford many of the advantages of these previously
described directing groups. Significantly, β-carbolines and
their associated derivatives, which may be accessed in a single
step, are found in a number of natural products and pharma-
ceutically relevant molecules (Figure 1).9 As such, these ‘func-
tional groups’ that are innate to the targeted compound may be
employed as directing groups for C–H functionalization.
The picolinamide and 8-aminoquinoline amide, first report-
ed by Daugulis for the palladium-catalyzed γ- and β-arylation
of aliphatic amine and carboxylic acid derivatives, respective-
ly,3 have emerged as a privileged directing group. However,
the removal of these directing groups has historically been
challenging. Several solutions to this challenge are beginning
to appear. For example, recently, Chen and coworkers report-
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 7
OMe
ly, La(OTf)3 could also be employed for the amidation reac-
H
N
O
tions (see the SI for details).17
1
2
NH
HN
H
N
tryptamine (2.0 equiv)
2-hydroxypyridine (0.3 equiv)
N
N
N
N
(1)
N
3
4
5
6
O
NH
N
N
OMe
N
R
NH
2a, 51%
N
1,4-dioxane
120 °C, 18 h
N
H
H
H
O
H
N
O
MeO
O
marinacarboline A: R = OMe
marinacarboline B: R = OH
marinacarboline C: R = H
antiplasmodial activity
H
O
1
peganumine A
cytotoxic activity against HL-60 cells
alangiobussinine
biological activity not explored
Alangiobussinine was subjected to the conditions for Pd-
catalyzed picolinamide-directed C(sp2)–H alkynylation report-
ed by Chen and coworkers.11b The desired alkynylated product
(4a) was isolated in 41% yield (Table 1, entry 1). A survey of
carboxylic acid additives known to play an important role in
the proposed concerted palladation-deprotonation step,18
showed that strong acids were detrimental, whereas acid addi-
tives with intermediate pKa (3.5–5) resulted in increased for-
mation of the alkynylated product. o-Phenyl benzoic acid (o-
PBA) has been shown to be an effective carboxylic acid pro-
moter for C(sp3)–H arylation reactions. In our hands, o-PBA
and PivOH led to comparable outcomes (Table 1, entries 2–3
and 18–19).11b,18 A survey of various bases revealed that the
nature of the counterion has a significant impact on the reac-
tion outcome with K2CO3 giving the best yield (entries 7–18).
Surprisingly, silver salts, which are generally believed to act
as halogen scavengers and are often beneficial in metal-
catalyzed C–H functionalizations, shut down the reaction (en-
tries 8 and 13). Finally, a clear solvent effect was observed:
coordinating solvents such as DMA, THF, and dioxane im-
pede the reaction, giving moderate yields, whereas chlorinated
solvents were superior, with DCE providing the best yields
(see the SI for details).
7
8
9
OMe
OMe
Cl
N
F
NH
N
N
N
N
Me
N
R2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Cl
R1
H
N
H
O
R3
NH
N
N
Bn
cytotoxic activity
against HTC 116 cells
R4
O
R2 = (H,H) or O
CXCR4 agonist
NITD609
antiplasmodial activity
Figure 1. Examples of natural products and biologically active
compounds featuring the β-carboline amide motif.
In the context of C–H functionalizations directed by β-
carboline amides, we envisioned alkynylations to be particu-
larly useful. Alkynes are versatile building blocks that may be
readily transformed into a wide range of functional groups and
substituents. Their importance is evidenced by the success of
the Sonogashira cross-coupling reaction. Thus, C–H function-
alization methods to complement this well-established cross-
coupling methodology10 would be highly useful.
Previous Work:
O
O
[Pd] or [Co]
TIPS Br
Reported by
Chen and
Balaraman
(A)
N
N
H
H
N
N
(Ref 11b and 11f)
H
TIPS
O
O
Pd(OAc)2
Table 1. Optimization of reaction conditionsa
(iPr)2N
(iPr)2N
Reported by
Zeng and Zhao
(Ref 12)
(B)
N
N
n
n
H
H
TIPS
Br
O
O
H
TIPS
n = 2,3
Pd(OAc)2 (10 mol%)
TIPS
H
H
TIPS
base (2.0 equiv)
acid additive (0.2 equiv)
N
N
N
N
+
NH
2a
NH
N
H
N
This Work:
DCE, 100 °C, 15 h
Br
H
O
O
3
4a
N
N
Ar/
Het
Ar/
Het
Pd(OAc)2
H
H
N
(C)
N
Yield (%)b,c
n
n
TIPS
Br
Entry
Base
Additive
NH
O
NH
O
n = 1,2
TIPS
1d
2
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
AgOAc
NaOAc
NaOTf
Cs2CO3
K2CO3
o-PBA
o-PBA
PivOH
AcOH
TFA
41e
While directed γ-C(sp2)–H alkynylations abound,11 to the
best of our knowledge, there has only been one report describ-
ing the palladium-catalyzed ortho C(sp2)–H alkynylation of
aminoalkyl arene derivatives at the δ position, which relies on
an oxalylamide directing group.12 As reported herein, using a
β-carboline amide directing group, we have achieved selective
palladium-catalyzed γ- and δ-C(sp2)–H alkynylations via five-
and six-membered palladacycle intermediates.12-14 Our method
has been applied to the syntheses of derivatives of the natural
products alangiobussinine and marinacarbolines.
72 (18)
69 (26)
69 (25)
13 (55)
65 (22)
64 (27)
<5 (>95)
30 (56)
7 (64)
3
4
5
6
DMBA
o-MBA
o-PBA
o-PBA
o-PBA
o-PBA
o-PBA
o-PBA
o-PBA
o-PBA
o-PBA
o-PBA
o-PBA
7
8
9
10
11
12
13
14
15
16
17
18
2) RESULTS AND DISCUSSION
7 (80)
Our investigations commenced with studies on the directed
alkynylation of alangiobussinine (2a), which was prepared in a
single step from the known β-carboline-1-methyl ester 1 by
activation of the ester moiety using 2-hydroxypyridine under
aerobic conditions (Eq 1).15 Our preparation of 2a from 1 is an
improvement in terms of step count and isolated yield over the
previously reported synthesis of this natural product.16 Apply-
ing this 2-hydroxypyridine mediated amidation method, a va-
riety of other β-carboline amide derivatives were accessed in
good yields from the corresponding methylesters. Alternative-
89 (<5)
4 (71)
Ag2CO3
tBuOK
NaHCO3
Na2CO3
KOAc
23 (68)
7 (83)
63 (28)
77 (15)
89 (5)
K2CO3
ACS Paragon Plus Environment

Page 3 of 7
Journal of the American Chemical Society
The β-carboline-directed C–H functionalization has proven
19
K2CO3
PivOH
90 (4)
to be highly general and versatile for C(sp2)–H alkynylation,
1
2
3
4
5
aReaction conditions: 2a (0.05 mmol), 3 (0.1 mmol), Pd(OAc)2
and has been extended to alkene functionalization (see 4o).
(10 mol%), base (2.0 equiv) acid additive (0.2 equiv), DCE (400
μL), 100 °C. bDetermined by NMR analysis of the crude mixture
using 1,1,2,2-tetrachloroethane as internal standard. cYield of
remaining 2a in parentheses. d5 mol% Pd(OAc)2 used instead.
eIsolated yield. DMBA: 2,6-dimethylbenzoic acid, o-MBA: o-
methylbenzoic acid.
Table 2. Substrate scope of the Pd-catalyzed C–H alkynyl-
ation reaction.a
6
7
TIPS
Br (3, 1.2 equiv)
N
Pd(OAc)2 (10 mol%)
PivOH (0.2 equiv), K2CO3 (2 equiv)
H
N
H
N
8
9
CA
n
n
R
R
Under our optimized conditions, alkynylated alangiobus-
sinine derivative 4a was isolated in 78% yield (Eq 2) and its
structure unambiguously confirmed by X-ray crystallographic
analysis.19
DCE, 100 °C, 15 h
NH
O
2b-u
4b-u
OMe
TIPS
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
CA
Cl
Br
F
H
H
H
H
N
N
N
N
CA
CA
CA
CA
TIPS
4b, 97% (90%)
TIPS
4c, 96% (89%)
TIPS
TIPS
TIPS
N
3 (2.0 equiv)
4d, >95% (89%)
4e, 97% (80%)
H
Pd(OAc)2 (10 mol%)
K2CO3 (2.0 equiv)
piv-OH (0.2 equiv)
N
2a
(2)
Me
NH
H
H
N
H
N
N
H
DCE, 100 °C, 15 h
N
Cl
CF3
Me
H
N
O
4a 90% (78%)
CA
CA
CA
CA
[X-ray]
TIPS
TIPS
TIPS
TIPS
4f, 91% (84%)
Using the optimized conditions (1.2 equiv (bro-
4gmono, 87% (73%)
4g(o+o')di, 7% (2%)
4h, 91% (80%)
4i, 88% (76%)
moethynyl)triisopropylsilane, 10 mol% Pd(OAc)2, 0.2 equiv
PivOH, 2.0 equiv K2CO3, DCE, 100 °C, 15 h),20 a variety of β-
carboline amide derivatives were successfully alkynylated at
the δ position (Table 2). Both electron-deficient and electron-
rich substrates bearing substituents at the ortho- or meta- posi-
tions were alkynylated in excellent yields favoring the less
sterically-hindered ortho-position (4b–4j). In some cases,
small amounts of dialkynylated products were formed and
isolated when meta-substituted substrates were employed (see
4g and 4j), consistent with observations in other C–H alkynyl-
ation reactions.12,11c Phenethylamine substrates lacking ortho-
or meta-substitution (4k–4n) gave mixtures of mono- and di-
alkynylated products under the standard conditions, but selec-
tivity toward the mono- or di-alkynylated product could be
achieved by varying the equivalents of the bromoalkyne (see
the SI for experiments aimed at the selective synthesis of
4nmono and 4n(o+o’)di). Various functional groups are tolerated
under the reaction conditions, including bromide, nitrile, and
trifluoromethyl (4c, 4l, 4h, and 4m). Therefore, scaffolds dis-
playing a bromide may be further functionalized using Pd0
cross-coupling processes. Heteroaromatic compounds were
alkynylated in good to excellent yields (see 4a, 4u). In particu-
lar, the presence of a protecting group on the indole nitrogen
(see 2a) is not required, in stark contrast with previously re-
ported alkynylations of tryptamine derivatives.12
H
H
N
H
N
H
N
N
OMe
CA
CA
CA
CA
OMe
Br
CN
TIPS
4jmono, 63% (57%)
4j(o+o')di, 22% (13%)
TIPS
TIPS
TIPS
4mmono, 38% (35%)
4m(o+o')di, 44% (30%)
4kmono, 40% (32%)
4k(o+o')di, 48% (19%)
4lmono, 45% (37%)
4l(o+o')di, 39% (6%)
Cl
H
N
H
N
CA
N
CA
N
CA
CA
H
H
TIPS
TIPS
TIPS
TIPS
4nmono, 42% (37%)
4n(o+o')di, 40% (28%)
4o, 60% (54%)
4pmono, 34% (28%)b
4p(o+o')di, 45% (31%)b
4q, >95% (75%)b
F
OMe
H
CA
N
CA
N
N
S
CA
H
H
CA
N
H
TIPS
4r, 93% (91%)b
TIPS
4s, 95% (78%)b
TIPS
4u, 84% (77%)d
4tmono, 34% (33%)c
4t(o+o')di, 36% (45%)c
TIPS
aDetermined by NMR analysis of the crude mixture using
1,1,2,2-tetrachloroethane as internal standard. Isolated yields
b
shown in parentheses. 2.0 equiv 3 used instead at 120 °C for 15
c
d
h. at 120 °C for 15 h. 3.0 equiv 3, 140 °C for 30 min by micro-
wave heating.
TIPS
H
H
TBAF (4.2 equiv)
H
N
N
(3)
CA
CA
THF
The vast majority of directed C–H functionalizations, in-
cluding picolinamide-directed functionalizations, favor γ-
functionalization. Presumably, a kinetically favored five-
membered palladacycle predominates. However, the β-
carboline amide directing group favors functionalization at the
δ position via a six-membered palladacycle. We observe se-
lectivity toward δ-functionalization when functionalization via
five- and six-membered palladacycles is possible. For exam-
ple, 4tmono and 4t(o+o’)di were the sole products of C–H function-
alization of the precursor substrate. The identity of the dial-
kynylated product (4t(o+o’)di) was unambiguously confirmed by
X-ray crystallographic analysis of the di-alkynylated product
after cleavage of the TIPS protecting groups (Eq 3).19 Fur-
thermore, we have found that products that arise from func-
tionalization at the γ-position require slightly more demanding
conditions (e.g., for 4p–4s, functionalizations occurred at 120
°C instead of 100 °C).
0–25 °C, 1.5 h
TIPS
H
4t(o+o' )di
5t(o+o' )di, quant.
To highlight the scalability of this reaction, the carboline
amide derivative 2e was alkynylated on 1.0 g (2.90 mmol)
scale to afford 4e in 80% isolated yield. Further derivatizations
of 4e were achieved on terminal alkyne 5e, obtained in 88%
yield by TBAF mediated cleavage of the TIPS group (Scheme
1). Alkyne 5e was easily converted to triazole 6 by a copper-
catalyzed ‘click’ cycloaddition,21 hydrogenated to the corre-
sponding alkane (7) using Pd/C, and converted to aldehyde 8
through an anti-Markovnikov hydration using Grotjahn’s ru-
thenium complex.22
Scheme 1. Derivatizations of alkyne 5.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 7
the efficiency of the reaction (4a vs 4v), and higher tempera-
tures were required to access 4w in good yield.
N3 (1.0 equiv)
1
2
3
4
5
6
7
8
OMe
(BimC4A)3 (1.0 equiv)
sodium ascorbate (4.0 equiv)
CuSO4.5H2O (1.0 equiv)
H
N
CA
IPA, DMSO
25 °C, 23 h
N
Scheme 3. Expansion of the C(sp2)–H alkynylation reaction
to other b-carboline amide derivatives.
N
N
6, 68%
OMe
OMe
H
H
N
OMe
Pd/C (10 mol%)
H2
N
TBAF (2.1 equiv)
H
N
CA
CA
TIPS
Br (2.0 equiv)
CA
CA
THF
0–25 °C, 2.5 h
A)
TIPS
N
Pd(OAc)2 (10 mol%)
K2CO3 (2.0 equiv)
PivOH (0.2 equiv)
EtOAc
25 °C, 4.5 h
H
H
N
N
TIPS
H
N
4e
5e 88%
7, quant.
NH
2v
NH
DCE, 100 °C, 15 h
N
N
OMe
9
H
O
O
[Ru(Cp)(MeCN)L2]PF6
(8.0 mol%)
Me
Me
N
PPh2
N
4v, 59% (48%)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
TIPS
L =
H2O/acetone, 70 °C, 4 h
O
B)
TIPS
Br (1.2 equiv)
t-Bu
8, 90%
Pd(OAc)2 (10 mol%)
K2CO3 (2.0 equiv)
PivOH (0.2 equiv)
O
O
NH
NH
To gain insight into the mechanism of the β-carboline di-
rected functionalization, 2a was subjected to stoichiometric
palladium acetate in DMA in the presence of tert-butyl isoni-
trile. The six-membered palladacycle (9) was isolated in 51%
yield and unambiguously characterized by X-ray crystallo-
graphic analysis (Scheme 2B).19
We propose that following C–H activation by a PdII species
to generate a six-membered palladacycle similar to 9, oxida-
tive addition into the TIPS-protected acetylene bromide gener-
ates a PdIV intermediate, consistent with the observations of
Shi and coworkers.11d Reductive elimination at this stage pro-
vides the alkynylated product. Finally, ligand exchange regen-
erates the requisite PdII species to perpetuate the catalytic cycle
(Scheme 2A).23
N
N
DCE, 120 °C, 15 h
N
N
H
H
4wmono, 37% (26%)
4w(o+o')di, 33% (32%)
2w
Gratifyingly, the β-carboline amide group directs other C–H
functionalization reactions (Scheme 4). For example, using 2e,
arylated and alkenylated products were isolated in high yields,
although more vigorous conditions were necessary (see
2e→10 and 2e→12). A C–N bond forming reaction could also
be achieved under mild conditions to afford the indoline de-
rivative 11.
Scheme 4. Generalization of β-carboline amide as directing
group for various C(sp2)–H functionalizations
Scheme 2. A) Proposed mechanism; B) Evidence for C–H
activation
A)
via
six-membered
PdX2
palladacycle.
OMe
Pd(OAc)2 (10 mol%)
K2CO3 (2.0 equiv)
PivOH (0.3 equiv)
H
N
4a
2a
CA
HX
H
HX
4-iodotoluene (10.0 equiv)
160 °C, 16 h
10, 84% (72%)
TIPS
NH
Br
H
L
X
N
N
Pd
N
Pd
N
O
N
Pd(OAc)2 (10 mol%)
PhI(OAc)2 (2.0 equiv)
OMe
OMe
N
H
N
N
O
NH
CA
11, 70% (44%)
OMe
CA
toluene, 100 °C, 105 min
TIPS
HX
2e
H
L
N
Br
Pd(OAc)2 (10 mol%)
K2CO3 (2.0 equiv)
PivOH (0.2 equiv)
Pd
N
H
N
N
CA
O
NH
1-iodocyclohexene (14.4 equiv)
160 °C, 15 h
B)
12, 88% (74%)
N
Pd(OAc)2 (1 equiv)
tBuNC (1 equiv)
H
N
2a
Pd
N
N
3) CONCLUSION
DMA, 0 °C-rt
15 min
O
NH
In conclusion, we report β-carboline amides as a new class
of directing groups for a variety of C–H functionalizations that
may proceed via five- or six-membered palladacycle interme-
diates. In particular, we report alkynylation reactions under
mild conditions that achieve the functionalization of various β-
arylethamine substrates and the natural product alangiobus-
sinine. The synthetic utility of the method was highlighted by
the direct derivatization of the alkynylated product into useful
groups such as a triazole or aldehyde. The generality of the
method is highlighted by the ability of the β-carboline amide
to direct other functionalizations such as δ-alkenylation, δ-
9, 51%
[X-ray]
Because a number of pharmaceutically relevant compounds
and natural products possess an N-alkylated β-carboline-1-
carboxylic acid N-alkylamide (e.g., 2v) or β-carboline-3-
carboxylic acid N-alkylamide (e.g., 2w) scaffold (see Figure
1), we sought to expand the carboline-directed alkynylations
described above to 2v and 2w (Scheme 3). Both alkynylated
products were successfully isolated. Of note, the presence of
the methyl group on the carboline nitrogen slightly decreased
ACS Paragon Plus Environment

Page 5 of 7
Journal of the American Chemical Society
Zhang, S.-Y.; Chen, G. Chem. Sci. 2014, 5, 3952. c) Zhang, S.-Y.; Li,
arylation, and a C–N bond formation to generate an indoline
Q.; He, G.; Nack, W. A.; Chen, G. J. Am. Chem. Soc. 2015, 137, 531.
6) Gong, W.; Zhang, G.; Liu, T.; Giri, R.; Yu, J.-Q. J. Am. Chem.
Soc. 2014, 136, 16940.
7) Fan, M.; Ma, D. Angew. Chem. Int. Ed. 2013, 52, 12152.
8) Chen, K.; Li, Z.-W.; Shen, P.-X.; Zhao, H.-W.; Shi, Z.-J. Chem.
Eur. J. 2015, 21, 7389.
1
2
3
4
derivative. Finally, we have demonstrated that β-carboline
amides can also direct γ-alkynylation, albeit under slightly
more demanding conditions, and exclusive δ-alkynylation is
achieved in the presence of a more accessible γ-C(sp2)–H
bond.
5
9) a) Wang, K.-B.; Di, Y.-T.; Bao, Y.; Yuan, C.-M.; Chen, G.; Li,
D.-H.; Bai, J.; He, H.-P.; Hao, X.-J.; Pei, Y.-H.; Jing, Y.-K.; Li, Z.-L.;
Hua, H.-M. Org. Lett. 2014, 16, 4028. b) Diallo, A. O.; Mehri, H.;
Iouzalen, L.; Plat, M. Phytochemistry 1995, 40, 975. c) Huang, H.;
Yao, Y.; He, Z.; Yang, T.; Ma, J.; Tian, X.; Li, Y.; Huang, C.; Chen,
X.; Li, W.; Zhang, S.; Zhang, C.; Ju, J. J. Nat. Prod. 2011, 74, 2122.
d) Xiao, Z.; Liu, Z.; Lei, C.; Wang, J.; Chen, Z.; Han, G.; Xiao, Y.;
He, H.; Chen, S. China Pat. Appl. CN103130800A, June, 05, 2013; e)
Clark, M.P.; Lockwood, M. A.; Wagner, F.F.; Natchus, M.G.; Doroh,
B.C.; Johnson, T.L.; Tahirovic, Y. A.; Wilson, L.; Wiseman, J. M.;
Skudlarek J. W. PCT Int. Appl. WO2009121063A2 October 01,
2009; f) Rottmann, M.; McNamara, C.; Yeung, B.K.S.; Lee, M.C.S.;
Zou, B.; Russell, B.; Seitz, P.; Plouffe, D.M.; Dharia, N.V.; Tan, J.;
6
7
8
9
ASSOCIATED CONTENT
Supporting Information
Experimental details and spectroscopic data. This material is
available free of charge via the Internet at http://pubs.acs.org.
Crystallographic data (CIF, CIF, CIF)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Procedures, single crystal X-ray data, NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
Cohen, S.B.; Spencer, K.R.; Gonzaĺ ez-Páez, G.E.; Lakshminarayana,
* rsarpong@berkeley.edu
S.B.; Goh, A.; Suwanarusk, R.; Jegla, T.; Schmitt, E.K.; Beck, H.-P.;
Brun, R.; Nosten, F.; Renia, L.; Dartois, V.; Keller, T.H.; Fidock,
D.A.; Winzeler, E.A.; Diagana, T.T. Science 2010, 329, 1175.
10) a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 16, 4467. b) Negishi, E.; Anastasia, L. Chem. Rev. 2003, 103,
1979. c) Chinchilla, R.; Nájera, C. Chem. Soc. Rev. 2011, 40, 5084.
11) For palladium-catalyzed γ-C(sp2)–H alkynylations, see: a) To-
bisu, M.; Ano, Y.; Chatani, N. Org. Lett. 2009, 11, 3250. b) Zhao, Y.;
He, G. ; Nack, W. A.; Chen, G. Org. Lett. 2012, 14, 2948. c) Ano, Y.;
Tobisu, M.; Chatani, N. Org. Lett. 2012, 14, 354. d) Ye, X.; Xu, C.;
Wojtas, L.; Akhmedov, N. G.; Chen, H.; Shi, X. Org. Lett. 2016, 18,
2970.
Present Addresses
† The Institute for Neurodegenerative Diseases, University of
California, San Francisco, Sandler Neurosciences Center, 675
Nelson Rising Lane, San Francisco, CA 94143-0518
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
for cobalt-catalyzed γ-C(sp2)–H alkynylations, see: e) Sauermann,
N.; Gonzaĺez, M. J.; Ackermann, L. Org. Lett., 2015, 17, 5316. f)
This work was supported by the NSF under the CCI Center for
Selective C–H Functionalization (CHE-1205646). We are grateful
to the Carlsberg Foundation for a postdoctoral scholarship to
H.M.-F.V., and to the NSF CCI Center for Selective C–H Func-
tionalization for a summer fellowship for W.K. We thank A.
DiPasquale (UC Berkeley) for solving the crystal structures of 4a,
5(o+o’)di and 9 (displayed with CYLView), supported by NIH
Shared Instrumentation Grant (S10-RR027172).
Landge, V. G.; Midya, S. P.; Rana, J.; Shinde, D. R.; Balaraman, E.
Org. Lett. 2016, 18, 5252.
For ruthenium-catalyzed γ-C(sp2)–H alkynylations, see: g) Ano,
Y.; Tobisu, M.; Chatani, N. Synlett 2012, 2763.
For rhodium-catalyzed γ-C(sp2)–H alkynylations, see: h) Xie, F.;
Qi, Z.-S.; Yu. S.-J.; Li, X.-W. J. Am. Chem. Soc. 2014, 136, 4780. i)
Feng, C.; Loh, T. P. Angew. Chem. Int. Ed. 2014, 53, 2722. j) Feng,
C.; Feng, D.; Luo, Y.; Loh, T. P. Org. Lett. 2014, 16, 5956.
For nickel-catalyzed γ-C(sp2)–H alkynylations, see: k) Liu, Y.-J.;
Liu, Y.-H.; Yana, S.-Y.; Shi, B.-F. Chem. Commun. 2015, 51, 6388.
For copper-catalyzed γ-C(sp2)–H alkynylations, see: l) Liu, Y.-J.;
Liu, Y.-H.; Yin, X.-S.; Gu, W.-J.; Shi, B.-F. Chem. Eur. J. 2015, 21,
205.
REFERENCES
1) a) Jun, C.-H.; Lee, H.; Hong, J.-B. J. Org. Chem. 1997, 62,
1200–1201. b) Mo, F.; Dong, G. Science 2014, 345, 68. c) Bedford,
R. B.; Coles, S. J.; Hursthouse, M. B.; Limmert, M. E. Angew. Chem.
Int. Ed. 2003, 42, 112. d) Lightburn, T. E.; Dombrowski, M. T.; Tan,
K. L. J. Am. Chem. Soc. 2008,ꢀ 130, 9210. e) Grünanger, C. U.; Breit,
12) Guan, M.; Chen, C.; Zhang, J.; Zeng, R.; Zhao, Y. Chem.
Commun. 2015, 51, 12103.
B. Angew. Chem. Int. Ed. 2008, 47, 7346. f) Luo, J.; Preciado, S.;
Larrosa, I. J. Am. Chem. Soc. 2014, 136, 4109. g) Zhang, F.-L.; Hong,
K.; Li, T.-J.; Park, H.; Yu, J.-Q. Science 2016, 351, 252.
13) C(sp)3–H functionalizations via a six-membered Pd-Cycle: a)
Subba Reddy, B. V.; Rajender Reddy, L.; Corey, E. J. Org. Lett.
2006, 8, 3391. b) He, G.; Zhao, Y.; Zhang, S.; Lu, C.; Chen, G. J.
Am. Chem. Soc. 2012, 134, 3. c) Nadres, E. T.; Daugulis, O. J. Am.
Chem. Soc. 2012, 134, 7. d) Zhang, S.-Y.; He, G.; Nack, W.A.; Zhao,
Y.; Li, Q.; Chen, G. J. Am. Chem. Soc. 2013, 135, 2124. e) Cui, W.;
Chen, S.; Wu, J.-Q.; Zhao, X.; Hu, W.; Wang, H. Org. Lett. 2014, 16,
4288. f) Xu, J.-W.; Zhang, Z.-Z.; Rao, W.-H.; Shi, B.-F. J. Am. Chem.
Soc. 2016, 138, 10750.
2) For selected reviews and examples of complex molecules syn-
thesis via C–H functionalization, see a) Feng, Y.; Chen, G. Angew.
Chem. Int. Ed. 2010, 49, 958. b) Gutekunst, W. R.; Baran, P. S.
Chem. Soc. Rev. 2011, 40, 1976. and references therein. c) McMur-
ray, L.; O’Hara, F.; Gaunt, M. J. Chem. Soc. Rev. 2011, 40, 1885. and
references therein. d) Ting, C. P.; Maimone, T. J. Angew. Chem. Int.
Ed. 2014, 53, 3115. e) Dailler, D.; Danoun, G.; Baudoin, O. Angew.
Chem. Int. Ed. 2015, 54, 4919.
14) C(sp)2–H functionalizations via a six-membered Pd-Cycle: a)
Li, J.-J.; Mei, T.-S.; Yu, J.-Q. Angew. Chem. Int. Ed. 2008, 47, 6452.
b) Jordan-Hore, J. A.; Johansson, C.; Gulias, M.; Beck, E. M.; Gaunt,
M. J. J. Am. Chem. Soc. 2008, 130, 16184. c) Han, J.; Liu, P.; Wang,
C.; Zhao, Y.-S. Org. Lett. 2014, 16, 5682. d) Wang, C.; Chen, C.-P.;
Zhang, J.-Y.; Yao, Y.-M.; Zhao, Y.-S. Angew. Chem. Int. Ed. 2014,
53, 9884.
15) a) Openshaw, H.T.; Whittaker, N. J. Chem. Soc. C 1969, 89. b)
Wang, L.-H.; Zipse, H. Liebigs Ann. Chem. 1996, 1501.
16) Baiget, J.; Llona-Minguez, S.; Lang, S.; MacKay, S. P.; Suck-
ling, C. J.; Sutcliffe, O. B. Beilstein J. Org. Chem. 2011, 7, 1407.
3) Zaitsev, V. G.; Shabashov, D.; Daugulis, O. J. Am. Chem. Soc.
2005, 127, 13154.
4) a) He, G.; Chen, G. Angew. Chem. 2011, 123, 5298; Angew.
Chem. Int. Ed. 2011, 50, 5192. b) He, G.; Zhao, Y.; Zhang, S.; Lu, C.;
Chen, G. J. Am. Chem. Soc. 2012, 134, 3. c) Zhang, S.-Y.; He, G.;
Zhao, Y.; Wright, K.; Nack, W. A.; Chen, G. J. Am. Chem. Soc. 2012,
134, 7313. d) Zhang, S.-Y.; He, G.; Nack, W. A.; Zhao, Y.; Li, Q.;
Chen, G. J. Am. Chem. Soc. 2013, 135, 2124.
5) a) He, G.; Zhang, S.-Y.; Nack, W. A.; Li, Q.; Chen, G. Angew.
Chem. Int. Ed. 2013, 52, 11124. b) Wang, B.; Nack, W. A.; He, G.;
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 7
17) Morimoto, H.; Fujiwara, R.; Shimizu, Y.; Morisaki, K.;
21) V. O. Rodionov; S. I. Presolski; S. Gardinier; Y.-H. Lim; M. G.
Ohshima, T. Org. Lett. 2014, 16, 2018.
18) Feng, Y.; Wang, Y.; Landgraf, B.; Liu, S.; Chen, G. Org. Lett.
2010, 12, 3414 and references therein.
19) Most H’s removed for clarity. Atoms are shown at the 50%
probability level.
20) While other bromoacetylene derivatives were surveyed, only
the use of (bromoethynyl)triisopropylsilane resulted in productive
reactivity, consistent with the observations of Chen and
Chatani.(Refs. 11b,11c). Activation/cross-coupling mediated by other
metal complexes may be more successful and are currently being
investigated.
Finn; J. Am. Chem. Soc. 2007, 129, 12696–12704.
22) D. B. Grotjahn and D. A. Lev; J. Am. Chem. Soc. 2004, 126,
12232–12233.
23) Migratory insertion of the bromo-alkyne unit followed by β-Br
elimination, as proposed by Chatani (Refs. 11a, b), cannot be dis-
counted.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment

Page 7 of 7
TOC GRAPHIC:
Journal of the American Chemical Society
1
2
3
4
5
6
N
H
Pd(OAc)2 (1 equiv)
tBuNC (1 equiv)
H
N
NH
NH
O
DMA, 0 °C to rt
51% yield
Carboline amide
(CA)
alangiobussinine (natural product)
6-membered palladacycle isolated
[X-ray]
7
8
Catalytic conditions developed for:
9
HN
OMe
OMe
TIPS
H
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N
N
OMe
CA
CA
H
N
N
N
CA
O
NH
• Alkynylation
>25 examples
• Arylation
• Alkenylation
• C–N formation
7
ACS Paragon Plus Environment