Sunlight-Driven Forging of Amide/Ester Bonds from Three Independent Components: An Approach to Carbamates

Article abstract of DOI:10.1021/acs.orglett.6b02811

A photoredox catalytic route to carbamates enabled by visible irradiation (or simply sunlight) has been developed. This process leads to a novel approach to the construction of heterocyclic rings wherein the amide or ester motifs of carbamates were assembled from three isolated components. Large-scale experiments were realized by employing continuous flow techniques, and reuse of photocatalyst demonstrated the green and sustainable aspects of this method.

Full text of DOI:10.1021/acs.orglett.6b02811

Letter
pubs.acs.org/OrgLett
Sunlight-Driven Forging of Amide/Ester Bonds from Three
Independent Components: An Approach to Carbamates
Yating Zhao, Binbin Huang, Chao Yang, Qingqing Chen, and Wujiong Xia*
State Key Lab of Urban Water Resource and Environment, School of Chemistry and Chemical Engineering, Harbin Institute of
Technology, Harbin 150080, China
S
* Supporting Information
ABSTRACT: A photoredox catalytic route to carbamates
enabled by visible irradiation (or simply sunlight) has been
developed. This process leads to a novel approach to the
construction of heterocyclic rings wherein the amide or ester
motifs of carbamates were assembled from three isolated
components. Large-scale experiments were realized by employ-
ing continuous flow techniques, and reuse of photocatalyst
demonstrated the green and sustainable aspects of this method.
arbamates constitute a significant class of organic
catalyst.4,8 In the aspects of green chemistry and natural
abundance, CO2 has always been considered an attractive and
promising C1 building block in organic synthesis owing to its
favorable properties such as being ubiquitous, inexpensive, and
nontoxic. In addition, there are remarkable advances in
incorporating CO2 into organic compounds to yield carbamates,
wherein CO2 has been converted into the ester bonds in a
straightforward pathway (Figure 1B, b).9 However, the
inherently high oxidation state of carbon in CO2 makes it
quite stable, which hampers its facile activation and the
extension to substrate scope.10 Furthermore, other phosgene-
free approaches to carbamates have also been developed
through elegant transformations of isocyanates, azides,
aziridines, and so on.11
C
compounds in biological and medicinal science.1 They
are key building blocks in pharmaceutical and agrochemical
products, such as the HIV inhibitor efavirenz,2 progesterone
antagonist,3 and the analgesic Paraflex4 (Figure 1 A). In addition
Among the mentioned versatile synthetic methods, the
carbonyl moieties in carbamates were basically copied and
pasted from starting agents that contained the same carbonyl
bonds. Herein, we present an unconventional route to construct
the amide or ester motifs of carbamates from three independent
components under genuinely mild reaction conditions, wherein
the C atom in carbonyl was derived from CBr4 and the O atom
was from moisture in solvent or air (Figure 1 B, c), using
Ru(bpy)3Cl2 as the catalyst and sunlight as the energy source.
Initially, exposure of 1a to blue LED irradiation in the
presence of CBr4 as an oxidant and Ru(bpy)3Cl2 (λmax = 452
nm)12 as photosensitizer under an atmosphere of CO2
(balloon) afforded the heterocyclic carbamate 1b in 45% yield
(Table 1, entry 1). To our surprise, using ambient atmosphere
(air) instead of purified CO2 provided the same product 1b in
similar yield (entry 2). A control experiment was performed in
the anhydrous and air-free conditions, which led to the recovery
of starting material (entry 3). It was further established that the
addition of base had a significant influence on the reaction
Figure 1. Biologically active compounds containing benzo-fused
heterocycles and synthetic methods for building carbamate skeleton.
to their biological utilization, carbamates also have many
applications in organic synthesis by serving as key synthetic
intermediates5 and specific directing groups.6
Therefore, numerous efforts have been made to establish such
useful structures. The most conventional method to construct
the carbonyl motif in carbamate generally resorted to hazardous
phosgene and its derivates,7 which would have a detrimental
effect on the environment or create a stoichimetric amount of
waste after the reaction (Figure 1 B, a). Alternatively, the
carbonyl bond could be accessed by inserting CO directly into o-
amino alchohols or o-aminophenols enabled by transition-metal
Received: September 19, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02811
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Organic Letters
Letter
Table 1. Optimization of Reaction Conditions
a
b
entry
base
none
solvent
atmosphere
yield (%)
c
1
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DMF
CO2
air
45
45
c
2
none
c
3
none
N2
air
trace
60
c
4
K2CO3
5
6
7
8
K2CO3
air
62
2,6-lutidine
2,6-lutidine
2,6-lutidine
2,6-lutidine
air
air
86
33
DCM
air
65
d
9
MeCN
air
81
a
Unless otherwise noted, reactions were carried out with 1a (0.3
mmol, 1.0 equiv), CBr4 (1.0 equiv), base (3.0 equiv), and Ru(bpy)3Cl2
(5.0 mol %) in undried solvent (0.1 M) under 8 W blue LED bulb
b
c
irradiation for 16 h. Isolated yields. Dried solvent was used; reaction
d
for 24 h. Sunlight served as light source for 2 h.
outcomes (entries 4 and 6). Notably, employing hydrous MeCN
did not diminish the reaction efficiency yet resulted in a very
slight improvement of the yield of product (entry 5). Screening
of solvents indicated MeCN to be the optimal medium for this
transformation (entries 7 and 8). More specifically, replacement
of blue LED with sunlight provided the same product 1b in a
much shorter reaction time, albeit with a negligible decrease in
yield (entry 9), and it was speculated that the sunlight might
provide not only the light but energy to warm the reaction
system. These results therefore represent optimal reaction
conditions to construct heterocyclic carbamate using o-amino
alcohol as the carbonyl acceptor in the presence of CBr4 (1.0
equiv), base (3.0 equiv), and Ru(bpy)3Cl2 (5.0 mol %) in
undried MeCN with sunlight irradiation in an ambient
atmosphere.
We next sought to test the scope of the carbonyl acceptors by
subjecting a series of o-amino alcohols and phenols to the
optimized reaction conditions (Figure 2). Various primary
amines possessing substitution on the phenyl ring were
evaluated, which afforded the corresponding heterocyclic
carbamates in good to excellent yields (2b and 5b−10b),
demonstrating that both electron-donating and electron-with-
drawing groups could be accommodated at diverse positions.
Naphthalamine was also tolerant under the reaction conditions
(11b). Significantly, this method was compatible with o-
aminophenols to provide five-membered heterocycles in good
yield (12b−13b). Furthermore, heteroaromatic substrates
(14b) could also be employed. However, it should be noted
that the presence of an aromatic amine, i.e., aniline, was critical
to the success of the reaction. For example, no product was
observed for the nonbenzo-fused heterocycle (15b). We
proposed that the phenyl ring connected to amine might
stabilize the amino radical that was formed in the process of the
reaction.
Figure 2. Scope of o-amino alcohols/phenols. (a) Isolated yields are
indicated. (b) K2CO3 (3.0 equiv) was used as the base in all primary
amine cases because 2,6-lutidine would result in a complex mixture. (c)
2,6-Lutidine (3.0 equiv) was used in all secondary amine cases. (d)
Ratio in parentheses refers to the integrated ratio of b to c (b/c) in 1H
NMR spectra for cases in which the brominated product c was
observed.
secondary or tertiary alcohol afforded not only b but also the Br-
substituted product c (3b−4b, 22b−25b, and 28b−29b).
Interestingly, the percentage of c in the mixed products was
reduced when R3 was phenyl instead of an alkyl group, and 25c
even could not be formed when R3 was diphenyl (only 25b was
obtained). Compound 24c was selected as a representative
brominated product for determing the Br-substituted position,
which was characterized on the para-position of the amine
group based on NMR analysis (see the Supporting Informa-
tion).
This protocol was further extended to tertiary amines (Table
2). Exposure of amines with both N-ethyl and N-benzyl
substituents (entry 1) led to a mixture of products, with
predominant fragmentation of the benzyl group to provide 1b as
the main product in 55% yield. Other tertiary amines bearing the
same substituents on the amine were examined as well,
providing products that resulted from the preferential loss of
the benzyl substituent (entries 5−8). Switching N-ethyl to N-
methyl with the same N-benzyl group led to the formation of the
same debenzylated product 16b (entry 9). We also examined
the effect of electron-donating and electron-withdrawing groups
on the reactivity of the N-benzyl substitutent in the reaction. We
found that electron-donating groups favored the formation of
the debenzylated carbamate products (entries 2 and 3).
Furthermore, the N,N-dibenzyl substrate led to only a trace
amount of 2b with removal of both benzyl substituents (entry
10). However, the irradiation of substrates in which the amine is
not benzylic led to the recovery of starting material (entry 4).
Photochemical reactions conducted under flow conditions
enable more efficient light penetration and more efficient
reaction.13 We therefore applied continuous flow techniques to
scale up the reaction for the synthesis of carbamate. We devised
two strategies for the recycling of the heterogeneous Ru-
(bpy)3Cl2 catalyst. As depicted in strategy A of Table 3, the
We then investigated a diverse range of secondary amine
substrates, and the results are outlined in Figure 2. Besides N-
ethyl (1b), substrates with N-methyl, N-phenyl, and N-benzyl
groups were equally accommodated, leading to corresponding
products in moderate to good yields (16b−21b). Moreover, N-
ethylamines bearing a substituent on the aromatic ring
functioned proficiently as well (26b and 27b). We further
note that regardless of primary or secondary amine, o-amino
B
DOI: 10.1021/acs.orglett.6b02811
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Initially, we postulated the carbonyl moieties in products
presumably stemmed from CO2 in air. To gain mechanistic
insight into this transformation, several control experiments
were therefore conducted. First, the starting mixture of 2a was
subjected to 13CO2 atmosphere under similar reaction
conditions (Scheme 1 a). However, the 13C-labeled product
Table 2. Scope of Tertiary Amines
Scheme 1. Control Experiments
a
b
Main products and corresponding isolated yields. Ratio in
parentheses referred to the proportion of debenzylated product to
c
ethyl removed product, determined by GC−MS. No reaction.
Table 3. Scale-up Reaction Performed in Continuous Flow
2b′ was not observed, while 2b was obtained instead as the only
product.14 In addition, the H218O-labeled experiment was also
carried out (Scheme 1 b). With increasing amounts of H218O,
the ratio of 18O-labeled product 2b″ increased accordingly (see
the Supporting Information), which however, could not account
for the distribution of the products with or without isotopic
label. These isotopic labeling experimental results indicated that
the carbonyl bond in the product was probably caused by
hydrolysis of any sensitive intermediate during reaction rather
than the incorporation of CO2 to substrate. To gain more
information about the conversion, we exposed 24b to the
standard reaction conditions to determine if b is converted to c
(Scheme 1 c). However, 24b remained intact after irradiation for
72 h, suggesting that the Br-substituted product c does not
result from further reaction of b.
entry
t (h)
recovery of catalyst (%)
yield of 27b (%)
Strategy A: Catalyst Was Recovered and Reused
a
1
2.5
2.5
2.5
86
84
81
67
63
64
b
2
b
3
Strategy B: Catalyst Was Reused in Situ without Recovery
a
4
2.5
4
c
Based upon the above results, a mechanism was therefore
proposed in Scheme 2. Having determined the reductive
potential of 1a (Ered = −0.97 V vs SCE) by cyclic voltammetry
tests, we envisioned the reaction was started from single-
electron reduction of CBr4 by the photoexcited state Ru-
5
c
d
d
6
4
89
58
a
27a (300 mg) and the aforementioned reagents with Ru(bpy)3Cl2 in
MeCN were pumped into flow reactor at a rate of 0.5 mL min−1.
b
Recovered catalyst from entry 1 was used for entries 2 and 3 in an
analogous manner. Another batch of starting mixture at the same
scale as entry 4, without Ru(bpy)3Cl2, was added directly into
•
(bpy)32+* (E1/2III/*II = −0.81 V vs SCE) to form CBr3 and
c
15
3+
Ru(bpy)3
,
which could accept an electron from amine a to
collection flask of entry 4, and entry 6 was completed in an analogous
d
manner. Calculated based on the total input of entries 4−6.
Scheme 2. Proposed Mechanism
Ru(bpy)3Cl2 was readily recovered by filtration on completion
of the reaction and reused in the subsequent entry (with only
subtle effects on the yield of 27b; entries 1−3). Moreover, the
recycled catalyst maintained its efficiency with respect to
reaction time. To avoid the recycling step, we have examined
a second approach, strategy B, reusing the catalyst in situ
without recovery to carry out the scale-up experiment in flow.
After two cycles, the catalyst could be recovered in 89% yield,
and the total yield of 27b was reduced to 58% on prolonged
irradiation (entries 4−6). The implementation of this
continuous flow approach suggests that the reaction could be
performed on a very large, i.e., industrial scale.
C
DOI: 10.1021/acs.orglett.6b02811
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
regenerate the Ru(bpy)32+ and deliver the radical cation 1. With
respect to the two kinds of products b and c, we proposed the
removal of the leaving group (LG) of 1 could occur via one of
two possible pathways. First, the LG could be removed directly
from 1 to form HBr and/or BnBr as well as the amine radical 2
(X = H), which could couple with •CBr3 to form the
intermediate 3. Afterward, the iminium 4 might result from
debromonation of 3 by a base- or Ru-catalyzed photocyclic
process, which would then proceed via intramolecular
nucleophilic attack reaction by hydroxy to provide 5 in the
presence of base. Subsequently, a similar debromonation
process would occur to form iminium 6, which then could be
attacked by water to give 7. At last, the final heterocyclic product
b (X = H) could be formed by base-promoted intramolecular
esterification. Alternatively, bromide ion could be regioselec-
tively added to radical cation 8 to provide the Br-substituted
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b02811.
Experimental procedures, product characterization, and
1H and 13C NMR spectra for all compounds (PDF)
́
2006, 8, 5717. (c) Nicolaou, K. C.; Krasovskiy, A.; Trepanier, V.; Chen,
AUTHOR INFORMATION
Corresponding Author
■
D. Y.-K. Angew. Chem., Int. Ed. 2008, 47, 4217. (d) Fontana, F.; Chen,
C. C.; Aggarwal, V. K. Org. Lett. 2011, 13, 3454. (e) Haufe, G.; Suzuki,
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Chem., Int. Ed. 2012, 51, 12275. (f) Yoshimura, A.; Luedtke, M. W.;
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*E-mail: xiawj@hit.edu.cn.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We are grateful for financial support from China NSFC (Nos.
21372055, 21472030, and 21672047), SKLUWRE (No.
2015DX01), and the Fundamental Research Funds for the
Central Universities (Grant No. HIT.BRETIV.201310).
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DOI: 10.1021/acs.orglett.6b02811
Org. Lett. XXXX, XXX, XXX−XXX