Photochemical a-carboxyalkylation of tryptophols and tryptaminesviaC-H functionalization

Article abstract of DOI:10.1039/d0cc00847h

A process for the a-carboxyalkylation of tryptophols and tryptamines by the functionalization of C-H bonds under visible light irradiation has been developed. The photochemical strategy activated the C-Br bonds of a-bromo-alkylcarboxylic esters to provide carbon-centered radicals under the catalysis of Ir(iii) photocatalyst and coupled with indole derivatives. This methodology displayed wide functional group tolerance and excellent regioselectivity, and was applied to the late-stage functionalization and preparation of indole-containing hybrids.

Full text of DOI:10.1039/d0cc00847h

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DOI: 10.1039/D0CC00847H
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Photochemical -Carboxyalkylation of Tryptophols and
Tryptamines via CH Functionalization
Zhiqiang Pan,‡a Yuchang Liu,‡a Fengchi Hu,a Qinglong Liu,a Wenbin Shanga and Chengfeng Xia*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
An -carboxyalkylation of tryptophols and tryptamines by the alkylation of indoles via the formation of electron donor
functionalization of CH bond under visible light irradiation has acceptor (EDA) complexes between Katritzky salts and indoles
been developed. The photochemical strategy activated CBr bonds to generate -acetic radicals from the fragment of pyridinyl
of -bromo-alkylcarboxylic esters to provide carbon-centered radicals.17, 18The bromomalonate was successfully converted to
radicals under the catalysis of Ir(III) photocatalyst and coupled with
Table 1. Optimization of Reaction Conditions.
indole derivatives. This methodology displayed wide functional
OH
OH
group tolerance and excellent regioselectivity, and was applied to
the late-stage functionalization and the preparation of indole-
containing hybrids.
photocatalyst (2 mol%)
base (2 equiv), DCE
H
Br
CO2Me
blue LEDs, rt, Ar, 20 h
N
N
CO2Me
H
H
1a
2a
3a
The 2-acetic indole moiety is widely existed in many structurally
intricate and biologically important alkaloids, such as
akuammicine, vindoline, pandine, and vincadine. The
traditional methods for installation of acetic group on C2 of
indoles was implemented through multistep sequencesor
prepared from C2 substituted indoles. It was discovered that
pre-installed directing groups at the N1 position of indoles
Yield
(%)[b]
0
Entry
Catalyst
Base
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
Ru(bpy)3Cl2
Et3N
Et3N
fac-Ir(ppy)3
<5
0
Ir[(dFCF3ppy)2(dtbpy)]PF6
Ir[(dFCF3ppy)2(bpy)]PF6
Ir[(dtbbpy)(ppy)2]PF6
Et3N
Et3N
< 5
< 5
18
8
Et3N
Ir[(dmppy)2(dtbbpy)]PF6
Ir[(dtbbpy)(dtbppy)2]PF6
Ir[(dmppy)2(dtbbpy)]PF6
Ir[(dmppy)2(dtbbpy)]PF6
Ir[(dmppy)2(dtbbpy)]PF6
Ir[(dmppy)2(dtbbpy)]PF6
Ir[(dmppy)2(dtbbpy)]PF6
Ir[(dmppy)2(dtbbpy)]PF6
Ir[(dmppy)2(dtbbpy)]PF6
Ir[(dmppy)2(dtbbpy)]PF6
Ir[(dmppy)2(dtbbpy)]PF6
Et3N
facilitated
the
transitional
metal
catalyzed
CH
Et3N
functionalization to realize the -carboxyalkylation at C2
position.1-5 The direct -carboxyalkylation of indoles was
achieved by the activation of CBr bond with transition-metal
catalysis via the redox-type radical addition process.6-8 Although
these reactions were conducted under vigorous conditions (110
~ 130 oC), and substrate scopes were limited to very few
examples of indoles with low yields, the radical addition process
exhibited as practical protocol for the direct -
carboxyalkylation at the C2 position of indoles.
The photochemistry provided an alternative strategy to
generate radicals for construction of CC bonds under mild
conditions.9-15 Gryko reported that the α-diazo ester was
efficiently converted to -acetic radical using Ru(bpy)3Cl2 as
photocatalyst for the alkylation of indoles.16 Glorious developed
4-MeOPhNPh2
NaHCO3
KHCO3
Na2CO3
K2CO3
10
10
56
70
50
84
42
64
27
79
56
33
0
Na2HPO4
K2HPO4
Na3PO4
K3PO4
[c]
Ir[(dmppy)2(dtbbpy)]PF6
Na2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
[d]
Ir[(dmppy)2(dtbbpy)]PF6
[e]
Ir[(dmppy)2(dtbbpy)]PF6
[f]
Ir[(dmppy)2(dtbbpy)]PF6
none
0
[a] Unless otherwise noted, reactions were performed with 1a (0.5 mmol), 2a (1.0
mmol), photocatalyst (0.01 mmol), and base (1.0 mmol) in 1.0 mL DCE, and were
placed at approximately 5 cm away from two parallel LED lamps (Ouying-5301,
Blue LEDs, 12 W, 44.5 mW/cm2). [b] Yield of isolated product. [c] Reaction was
added 5% H2O. [d] Reaction was conducted under air. [e] Reaction was placed at
approximately 5 cm away from four 23 W CFL. [f] Recation was conducted under
dark at 50 oC.
a. Key Laboratory of Medicinal Chemistry for Natural Resource (Ministry of
Education and Yunnan Province), School of Chemical Science and Technology,
Yunnan University, Kunming, Yunnan 650091, China. E-mail: xiacf@ynu.edu.cn
Electronic Supplementary Information (ESI) available: Experimental section and
copies of NMR spectra. See DOI: 10.1039/x0xx00000x
‡ Z. Pan and Y. Liu contributed equally.
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the malonyl radical by photocatalyst (such as Ru(bpy)3Cl2 or
bithiophenes) under visible light irradiation to couple with
indoles.19-22 Meanwhile, a tertiary amine was crucial as
sacrificial reductant for these photochemical reactions to cycle
the photocatalyst. Both Stephenson and Joo almost
simultaneously found that the -bromo-acetates could be
reduced to the corresponding radicals catalyzed by fac-Ir(ppy)3
under visible light irradiation.23, 24 Joo successfully coupled the
radicals with electron-rich heteroarenes including indoles, and
discovered that the subtle electronic effect of the heteroarene
significantly impacts the reactivity.24 Since most of indole
alkaloids contain 2-alkyl moieties instead of 2-malonic moieties,
and many complex indole substrates contain additional
functional groups, such as tryptophol and tryptamine
derivatives, we envisioned that the direct activation of -halo-
alkylcarboxylic esters by photocatalysts would be more
practical for syntheses or modification of natural products.
Tryptophol derivatives are common synthetic units in the
total synthesis. The traditional reaction normally required the
protection of both the nitrogen group and the hydroxyl group
of tryptophol. We initiated our research on the photochemical
-carboxyalkylation with the protecting group-free tryptophol
1a and methyl bromoacetate 2a as model substrates. We first
conducted the reaction by using Ru(bpy)3Cl2 or fac-Ir(ppy)3 as
photocatalyst and trimethylamine as sacrificial reductant to
activate the CBr bond.19, 23, 24 After irradiation under blue LEDs
(12 W, λmax = 450 nm) for 20 h, none -carboxyalkylated product
3a was detected for Ru(bpy)3Cl2 and trace amount of 3a was
detected for fac-Ir(ppy)3 (Table1, entries 1 and 2). Evaluation of
a variety of different photocatalysts (entries 3 - 7) found that
Ir[(dmppy)2(dtbbpy)]PF6 slightly improved the yields (entry 6).25
Because the trimethylamine might act as a hydrogen atom
source to reduce the acetate radical,19-21 the 4-MeOPhNPh2 was
then explored as reductant but resulted in lower yield too (entry
8). The -carboxyalkylation was distinctly improved to 56%
yield when an inorganic base KHCO3 was added to the reaction
mixture under the catalysis of Ir[(dmppy)2(dtbbpy)]PF6 (entry
10). Further screening other inorganic bases, such as Na2CO3,
K2CO3, NaH2PO4, KH2PO4, Na3PO4, etc. (entries 11 – 16),
identified that Na2HPO4 was the most effective base and the
alkylated product was afforded in 84% yield (entry 13). The dry
solvent was not necessary for this photochemical reaction,
while the presence of oxygen apparently decreased the yields
(entries 17 and 18). Moreover, the using of blue LEDs was
evidently superior to white CFLs (entry 19). The chloroacetate
was also subjected for the -carboxyalkylation but no products
were detected. The photochemical nature of this -
carboxyalkylation was incontestably confirmed as essentially no
product was observed when the controlled experiments were
performed under dark at 50 oC or without photocatalyst
(entries 20 and 21).
View Article Online
Ir[(dmppy) (dtbbpy)]PF DOI: 10.1039/D0CC00847H
X
H
X
6 (2 mol%)
Na2HPO4 (2 equiv), DCE
2
Br
CO2Me
N
blue LEDs, rt, Ar
N
CO2Me
OH
H
H
1
2a
3
OH
OH
OH
N
N
H
N
N
CO2Me
CO2Me
CO2Me
CO2Me
H
Me
Bn
3a
3b
, 98%, 20 h
3c
, 93%, 20 h
3d, 98%, 20 h
, 78%,
10 mmol scale, 20 h
OH
OH
OH
OH
Me
Me
N
N
N
H
N
CO2Me
CO2Me
CO2Me
CO2Me
Me
H
H
H
3e
3f
3g
3h
, 75%, 20 h
, 81%, 20 h
OH
, 89%, 20 h
OH
, 78%, 20 h
OH
Br
Cl
Br
N
N
N
N
CO2Me
CO2Me
CO2Me
CO2Me
Cl
H
H
H
H
3k
3i
3j
, 67%, 40 h
3l, 64%, 40 h
, 66%, 40 h
NHAc
, 64%, 40 h
NHCbz
NHAc
NHCO2Me
N
CO2Me
N
N
N
H
CO2Me
CO2Me
CO2Me
Bn
H
H
3p
, 88%, 20 h
3m
3o
, 95%, 20 h
88%, 5 mmol scale
3n
, 76%, 20 h
, 85%, 20 h
CO2Me
CO2Me
CO2H
CO2Me
N
N
N
N
CO2Me
CO2Me
CO2Me
CO2Me
H
H
H
H
3q
3r
, 85%, 40 h
, 79%, 20 h
3s
3t
, 68%, 20 h
, 86%, 20 h
O
CN
CN
CHO
N
N
N
N
CO2Me
CO2Me
CO2Me
CO2Me
H
H
H
H
3u
3v
3z
3w
3x
, 63%, 40 h
, 71%, 70 h
, 54%, 40 h
, 51%, 60 h
Me
Me
N
CO2Me
N
N
CO2Me
CO2Me
O
CO2Me
H
H
H
3y
3aa
3ab
, 78%, 20 h
, 71%, 20 h
, 90%, 20 h
, 90%, 40 h
Scheme 1. Investigating the Substrate Scope of Indoles.
20 h at room temperature (3a, 78% yield). These results showed
that the photochemical reaction was of practical application in
preparation of large scale compounds. The homotryptophol
was an ideal substrate for the photoreaction and the -
carboxyalkylated product 3b was afforded in 98% yield. When
the tryptophol was N-alkylated with methyl or benzyl, they
served as perfect examples and resulted in excellent yields too
(3c and 3d). Different alkyl substitution patterns at the aromatic
moiety of tryptophols were well tolerated, regardless of their
position on the phenyl ring (3e - 3h), while the halo-substituted
derivatives resulted in relatively lower yields and longer
reaction times (3i - 3k). When there had another bromide on
the indole, it could not be activated by photocatalyst and thus
did not affect the -carboxyalkylation (3l).
Besides the tryptophol derivatives, the tryptamine
derivatives were then examined for the photochemical -
carboxyalkylation. The N-acetyl tryptamine was conducted
under the standard conditions, and the product 3m was
afforded in 95% yield. Similarly, the gram-scale reaction for N-
acetyl tryptamine also proceeded well and 88% yield was
achieved in 5 mmol scale. When the tryptamine was protected
with other groups, such as Cbz or methyl carbonate, good yields
With the optimized condition in hand, the substrate scope
of indole derivatives was investigated to measure the efficiency
and practicability of this photochemical -carboxyalkylation
(Scheme 1). For the synthetic purpose, we first tested the
photochemical reaction in gram scale. It was found that this
reaction was easily conducted in gram scale after irradiation for
2 | J. Name., 2012, 00, 1-3
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were also harvested (3n and 3o). Additional substation on the 3ar was obtained that was presumably due to the steric
View Article Online
N1 position did not affect the -carboxyalkylation (3p, 88% hindrance and the high stability of tertiaDryOaI:l1k0y.l10ra39d/iDc0aClsC.2060847H
yield). Indole derivatives with various functional groups, such as
With the wide substrate scope established, we then focused
formate, acetate, propionate, or even acetic acid, also reacted on the coupling of various indole alkaloids with methyl
smoothly to afford corresponding -carboxyalkylated products bromoacetate 2a (Scheme 3). The N-Boc-protected L-
in moderate to good yields (3q - 3t, 68 - 86% yields). The nitrile, tryptophan methyl ester was also directly C2 alkylated to form
ketone, and aldehyde were also well tolerated, which its analogue 3as in 73% yield without concomitant
demonstrated the wide substrate scope of the photochemical racemization. Brevianamide F, an indole diketopiperazine
-carboxyalkylation. Moreover, the 3-methyl, cyclohexyl, or alkaloid from holothurian-derived fungus Aspergillus
phenyl substituted indole was -carboxyalkylated to give fumigatus,27 was successfully -carboxyalkylation to afford the
products in good yields (3y – 3aa). This method was also product 3at in moderate yield (53%). Metergoline and pergolide
appropriate for functionalization of benzofuran, affording as ergot derivatives, which are psychoactive drugs and long-
corresponding product 3ab in excellent yield.
acting dopamine agonists for the treatment of Parkinson’s
Disease,28, 29 reacted with 2a to give corresponding products
3au and 3av (67% and 95% yields).
X
X
Ir[(dmppy)2(dtbbpy)]PF6 (2 mol%)
Na2HPO4 (2 equiv), DCE
R
R
H
Br
CO2R2
NHCbz
S
CO2R2
N
blue LEDs, rt, Ar
N
H
H
O
1
2
3
N
NHBoc
CO2Me
H
H
OH
NHAc
OH
N
N
CO2H
H
H
N
O
H
N
N
N
N
H
CO2Me
CO2Me
CO2Me
CO2Me
N
H
N
H
N
N
H
H
Me
CO2Bn
CO2iPr
CO2tBu
CO2Ph
, 71%, 20 h
NHAc
H
H
3as
3at
3au
3av
, 73%, 40 h
, 53%, 40 h
O
, 67%, 40 h
, 95%, 20 h
3ac
3ad
3ae
3af
, 86%, 20 h
OH
, 82% , 20 h
NHAc
, 88%, 20 h
OH
H
CO2H
H
H
CO2H
Ph
CO2Me
O
O
H
H
H
H
N
N
N
N
CO2Me
CO2Me
CO2Me
O
O
N
H
H
H
H
H
N
H
H
3ag
3ah
3ai
3aj
, 82%, 100 h
OH
, 92%, 60 h
OH
, 78%, 40 h
NHAc
, 73%, 60 h
OH
3aw
3ax
, 77%, 20 h
, 55%, 20 h
H
NHAc
H
NHAc
H
CO2Me
H
OH
CO2Me
, 61%, 40 h
OH
CO2Me
O
O
H
H
H
H
O
O
N
N
N
CO2Me
N
O
N
H
N
H
H
H
H
H
H
O
3az
, 68%, 40 h
S
3ak
3al, 55%, 40 h
3am
3an
, 76%, 40 h
, 81%, 40 h
3ay
, 72%, 40 h
OH
OH
OH
S
N
O
O
O
CO2Me
OPh
NHAc
H
H
N
MeO2C
H
N
N
H
N
H
N
CO2Me
H
CO2Me
H
H
H
H
O
O
67%, 40 h
3ao
3ap
3aq
3ar
H
H
, 45%, 0.5 h
, 48%, 20 h
, 64%, 2 h
, 15%, 96 h
H
H
Br
O
O
N
H
N
H
Scheme 2. Investigating the Substrate Scope of -Bromo-alkylcarboxylic Esters.
3-bromoacetate-pregnenolone
pergolide
3ba
, pergolide-pregnenolone Hybrid
Scheme 3. Generation of Natural Product Hybrids.
To further explore the substrate scope and functional group
tolerance, different bromoacetate derivatives were then
examined for the photochemical carboxyalkylation (Scheme 2).
Changing of the alcohol part of bromoacetate derivatives 2 did
not affect the coupling reaction, and corresponding products
3ac - 3af were obtained in good yields (71% - 88%). Beside the
bromoacetate, more -bromo-secondary alkyl carboxylic esters
were subjected for the photochemical reaction. Although
excellent yields for the carboxyalkylation were achieved too,
the reaction times were apparently prolonged up to 40 - 100 h,
probably due to the steric hindrance and less reactivities of -
aliphatate radicals (3ag - 3ak). The hydroxyl group on -bromo-
aliphatate was also tolerated with applicable yields (3al and
3am). We found that the 2-bromo-γ-butyrolactone was also a
suitable substrate for this carboxyalkylation with 76% yield
(3an). Furthermore, 2-hetero-acetates, such as the -bromo-N-
acetylglycine methyl ester and methyl -bromo-2-
phenoxyacetate, were also delivered products in acceptable
yields (3ao and 3ap). It was interesting to find that a tricyclic
compound 3aq was afforded in 64% yield with methyl -bromo-
2-methoxyacetate as substrate. Instead, a C6 alkylated product
It was discovered that hybrids by combination of parts of
different natural products be very promising in the
development of leads for both medicinal and agrochemical
31
applications.30,
The preparation of hybrid molecules is
normally performed in late-stage step, which requires the
coupling reaction should be efficient, mild, regioselective, and
wide functional group tolerance. Many natural products contain
hydroxyl groups, therefore it could be easily converted to -
bromo-alkylcarboxylic esters for the coupling with indoles at
the C2 position under mild visible light irradiation. Biological
active sterol derivatives were firstly esterified by bromoacetic
anhydride and then be subjected for coupling with different
indole derivatives to give corresponding hybrid products in
good yields (Scheme 3, 3aw - 3az). To demonstrate the
efficiency of this photoreaction, two complex natural products,
pergolide and pregnenolone, were selected for the preparation
of hybrid compounds. The pergolide was subjected for the
coupling with 3-bromoacetate-pregnenolone, obtaining the
pergolide-pregnenolone hybrid 3ba in 67% yield. These results
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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5
6
7
8
9
C. Wang, B. Maity, L. Cavallo and M. Rueping, Org. Lett.,
View Article Online
showed that the newly developed photochemical -
carboxyalkylation strategy was practical for the late-stage
synthesis C2 -carboxyalkylated indole derivatives and would
be a useful tool for exploring new drug leads.
2018, 20, 3105.
DOI: 10.1039/D0CC00847H
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photochemical
-carboxyalkylation,
two
controlled
experiments were conducted. The reactoin was completely
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indicating the formation of acetate radical (Scheme S1A in SI).
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2-bromo-2-
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cyclopropylacetate 2b gave a cyclopentane product 5 (Scheme
S1B in SI). We reasoned that the character of radical
intermediate was reversed from electrophilic 2c to nucleophilic
2d after ring-opening of cyclopropane. The 2d could not couple
with the electron-rich indoles, instead, it coupled with another
ring-opened compound 2e32 to give the cyclopentane radical 2g.
Finally, the electrophilic radical 2g reacted with indole to deliver
the product 5.
On basis of above results, a plausible mechanism was
proposed (Scheme S2 in SI). The photoexcited state of
Ir[(dmppy)2(dtbbpy)]PF6 (-0.87
V
vs SCE)25 reduced the
34
bromoacetates (≥ -0.88 V vs SCE)33,
to acetate radical A
through the single-electron transfer process.35-37 The acetate
radical electrophilically coupled with the electron-rich indole to
give the benzyl radical B.38 The subsequent oxidation of radical
B by Ir(IV) gave the benzyl cation C and regenerated the Ir(III)
photocatalyst. Aromatization of cation C by the deprotonation
under basic conditions afforded the C2 alkylated product.
In conclusion, we have developed a photochemical -
carboxyalkylation of functional indole derivatives. The reaction
directly activated the CX bond of -bromo-alkyl carboxylic
esters under the visible light irradiation to give the
corresponding radical, which coupled to the C2 position of
indoles to furnish -carboxyalkylated products. The developed
photoreaction displayed a wide substrate scope and excellent
functional groups tolerance and provided an efficient and
practical strategy to the late-stage functionalization and the
preparation of indole-containing hybrids.
This work was financially supported by the National Natural
Science Foundation of China (21602193 and 21871228), the
Natural Science Foundation of Yunnan Province (2018FY001-
015 and 2019FB-6), and the Program for Changjiang Scholars
and Innovative Research Team in University (IRT_17R94).
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32 R. Ding, Z.-D. Huang, Z.-L. Liu, T.-X. Wang, Y.-H. Xu and T.-P.
Loh, Chem. Commun., 2016, 52, 5617.
33 M. M. Baizer and J. L. Chruma, J. Org. Chem., 1972, 37, 1951.
34 R. J. Kolt, D. D. M. Wayner and D. Griller, J. Org. Chem., 1989,
54, 4259.
Conflicts of interest
There are no conflicts to declare.
35 H. Jiang, Y. Cheng, R. Wang, M. Zheng, Y. Zhang and S. Yu,
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36 K. Tong, T. Zheng, Y. Zhang and S. Yu, Adv. Synth. Cat., 2015,
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37 C. J. O’Brien, D. G. Droege, A. Y. Jiu, S. S. Gandhi, N. A. Paras,
S. H. Olson and J. Conrad, J. Org. Chem, 2018, 83, 8926.
38 Q.-Q. Yang, M. Marchini, W.-J. Xiao, P. Ceroni and M.
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