Rhodium-Catalyzed Azide-Alkyne Cycloaddition of Internal Ynamides: Regioselective Assembly of 5-Amino-Triazoles under Mild Conditions

Article abstract of DOI:10.1021/acscatal.7b02558

A rhodium-catalyzed azide-alkyne cycloaddition of internal ynamides is described. The reaction could be performed in a wide range of solvents, including aqueous media, under mild conditions without careful exclusion of air and moisture, giving a variety o

Full text of DOI:10.1021/acscatal.7b02558

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Article
Rhodium-Catalyzed Azide-Alkyne Cycloaddition of Internal Ynamides:
Regioselective Assembly of 5-Amino-triazoles under Mild Conditions
Yun Liao, Qianqian Lu, Gui Chen, Yinghua Yu, Chunsen Li, and Xueliang Huang
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b02558 • Publication Date (Web): 22 Sep 2017
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RhodiumꢀCatalyzed AzideꢀAlkyne Cycloaddition of
Internal Ynamides: Regioselective Assembly of 5ꢀ
Aminoꢀtriazoles under Mild Conditions
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Yun Liao,a Qianqian Lu,b Gui Chen,a Yinghua Yu,a Chunsen Li,*b Xueliang Huang*a
a. Key Laboratory of Coal to Ethylene Glycol and Its Related Technology, Fujian Institute of
Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, Fujian 350002,
China
b. State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of
Matter, Chinese Academy of Sciences, Fuzhou, Fujian 350002, China.
ABSTRACT
A rhodiumꢀcatalyzed azideꢀalkyne cycloaddition of internal yanmides was described. The
reaction could be carried out in a wide range of solvents, including aqueous media, under mild
condition without careful exclusion of air and moisture, giving a variety of 5ꢀaminoꢀtriazoles as
single regioꢀisomer. The mechanism for the regioselective cycloaddition was rationalized by
means of DFT calculations.
KEYWORDS
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Click reaction, rhodium catalyst, azideꢀalkyne cycloaddition, ynamide, 5ꢀaminoꢀtriazoles.
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Introduction
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1,2,3ꢀTriazoles have emerged as versatile Nꢀheterocyclic compounds that have been
extensively used in various applications ranging from materials to biological molecules.1 As a
premier example of “Click chemistry”,2 the reaction of organic azides and alkynes,3 namely,
Huisgen 1,3ꢀdipolar cycloaddition, represents a straightforward and atom economical approach
to these heterocycles. However, because of the high activation barrier, the direct reaction of
unactivated alkyne with azide often requires high temperature to proceed, giving the target
triazole in low regioselectivity. In 2002, regioselective synthesis of 1,4ꢀdisubstituted triazoles
through copper(I)ꢀcatalyzed azideꢀalkyne cycloaddition (CuAAC) at ambient temperature was
realized by the groups of Sharpless, Forkin and Meldal independently.4 Mechanistically, the
formation of copper(I) acetylide intermediate is essential, thus efforts to achieve regioselective
CuAAC of internal alkynes is quite challenging.5,6
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Nevertheless, the above mentioned problems have been alleviated by recent advances through
judicious choice of transitionꢀmetal catalyst. For example, rutheniumꢀcatalyzed azideꢀalkyne
cycloadditions exhibited remarkably wide substrate scope, even when unactivated internal
alkynes were employed as reactants (Scheme 1a).7 Compared with the CuAACs, ruthenium
system is more sensitive to the reaction media, and Schlenck techniques were required during the
operation.7c,8 Although the recently reported IrAACs were generally less sensitive to air and
moisture, the reactions were limited to thioalkynes and activated alkynes,9 not applicable to
ynamides.10 5ꢀAminoꢀ1,2,3ꢀtriazoles are useful structural motifs that embedded in many
molecules with interesting biological activities (Scheme 2). 5ꢀAminoꢀ4ꢀcarbamoylꢀ1,2,3ꢀtriazole
1a is a calcium influx inhibitor with antiproliferative and antimetastatic activities.1f,1g As a
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heterocyclic analogue of imidazole, compound 1b has displayed increased potency in
anticoccidial.11 Triazolopyrimidine 2 derived from simple triazole 1c has been found have the
potential for treatment of inflammatory kidney diseases.12 Given the wellꢀestablished procedure
for the synthesis of ynamides,13 one may envision that regioselective cycloaddition of ynamides
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Scheme 1. Representative approaches to substituted 5ꢀaminoꢀtriazoles.
with azides perhaps represents an attractive approach to aminoꢀsubstituted triazoles.7c,14 Recently
an interrupted Cuꢀcatalyzed click reaction giving 5ꢀheteroatom functionalized triazoles was
realized by Xu’s laboratory (Scheme 1b).5f In the event, electrophilic amination reagents were
employed to trap the 5ꢀcuprated triazole intermediate. Although the reactions produce 5ꢀ
aminotriazoles in high yields and complete control of regioselectivity, the requirement of
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relatively large amount of molecular sieves and excess of strong base may limit the potential of
its future utility. Herein, we report the successful implementation of unprecedented RhAACs of
ynamides, affording 5ꢀaminoꢀtriazoles in completely regioselective control (Scheme 1c). The
current transformation is compatible with a variety of solvents, and proved to be not sensitive to
air and moisture. Moreover, a mechanistic rationale for the observed high regioselectivity is also
strongly supported by DFT calculations.
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Scheme 2. Representative examples of 5ꢀaminoꢀtriazole derivatives with interesting biological
activities.
Results and discussion
As part of our interest in goldꢀcatalyzed intermolecular nitrene transfer reactions with
ynamides,15 we sought to examine the reactivity of other transitionꢀmetal catalysts towards the
reaction of ynamide 3a and organic azide 4a. Typical cationic gold catalysts displayed no
reactivity (Table 1, entries 2 and 3).16 Wilkinson's catalyst could not catalyze the reaction either
(Table 1, entry 4). To our delight, when [Rh(COD)Cl]2 was employed as the catalyst, the formal
[3+2] cycloaddition adduct 5a was obtained in 21% isolated yield (Table 1, entry 5). Much to our
surprise, [Rh(CO)2Cl]2 proved to be a superb catalyst for the AAC of ynamide 3a. The reaction
was complete within 30 min, and 5ꢀaminoꢀtriazole 5a was isolated in nearly quantitative yield
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(Table 1, entry 1). Interestingly, Rh(II) catalyst was totally inactive (Table 1, entry 6). CuI,
which has been identified to be excellent catalyst for the reaction of 1ꢀiodoalkynes with azides,5a
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Table 1. Experiments on condition studies.a
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Bn
N
Ms
N
N
[Rh(CO)2Cl]2 (2 mol%)
MeCN (1 mL), RT
N
BnN3
Ms
+
N
Ph
Ph
5a
4a
3a
"standard conditions"
yield/%b
Entry
Variation from the standard conditions
time
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No change
30 min
24 h
94
-
Ph3PAuNTf2 was used as catalyst
JohnPhosAuNTf2 was used as catalyst
24 h
-
4
5
6
[Rh(Ph3P)3Cl] was used as catalyst
[Rh(COD)Cl]2 was used as catalyst
Rh2(OAc)4 was used as catalyst
24 h
24 h
24 h
-
21
-
7
CuI was used as catalyst
24 h
24 h
24 h
24 h
-
-
-
-
8
NiCl2 was used as catalyst
Pd(OAc)2 was used as catalyst
Co(acac)2 was used as catalyst
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[Ir(COD)Cl]2 was used as catalyst
Open flask reaction
24 h
trace
95
12c
30 min
a
3a (0.2 mmol), 4a (0.3 mmol), cat. (2 mol%), MeCN (1 mL), stirring under
atmosphere of Argon at room temperature. b Isolated yield. c The reaction was
carried out in 0.5 mmol scale, and the ratio of 3a : 4a was 1:1, MeCN (not dry,
0.5 M). JohnPhos = P(tBu)2(o-biphenyl), cod = cycloocta-1,5-diene, acac =
acetylacetonate.
could not catalyze the reaction as expected (Table 1, entry 7). Similarly, [Ir(COD)Cl]2, an
effective catalyst for the reaction of azides with thioalkynes, exhibits inferior activity as well
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(Table 1, entry 11).9a In presence of other transitionꢀmetal catalysts, including NiCl2, Pd(OAc)2
and Co(acac)2, completely recovery of the starting materials were observed (Table 1, entries 8ꢀ
10). Further experiments revealed that the exclusion of air and moisture was unnecessary, as the
current RhAAC of ynamide could proceed smoothly in an open flask in undried solvent while
maintaining similar efficiency (Table 1, entry 12). Furthermore, the current cycloaddition could
be carried out in a variety of solvents without erosion of the reaction yields.17
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With a set of effective conditions established, a range of readily available ynamides were
tested to prepare 5ꢀaminoꢀtriazole derivatives. As summarized in Table 2, these reactions were
operationally simple, not sensitive to air and moisture. We were pleased to see that most
ynamides could participate in the Rh(I)ꢀcatalyzed formal [3+2] cycloadditions, giving the
corresponding 5ꢀaminoꢀtriazoles 5 in good to excellent yields under mild conditions. Another
remarkable feature is that the current cycloaddition does not require the excess of either reaction
partners. The ratio of ynamide 3 to azide 4 is 1:1. As depicted, ynamides bearing different
protecting groups had no big influences on the reaction outcomes (cf. 5e to 5h). It is worth
mentioning that the reaction of ynamide with nosylꢀ group proceeded well, giving the triazole 5e
in 84% isolated yield. The relatively longer reaction time presumably results from strong
electronꢀwithdrawing character of the nosylꢀ group. Compared with the model ynamide 3a, the
reactions of paraꢀ methyl, methoxy, trifluoromethyl and chloro substituted ynamides afforded the
corresponding triazoles 5i, 5j, 5l and 5m in excellent yields regardless of the electronic nature.
Metaꢀ or orthoꢀ substituents on the phenyl ring were tolerated as well (cf. 5k, 5n and 5o). The
ynamides containing heteroaromatic ring or additional alkenyl moiety were proved to be
Table 2. Reaction scope of ynamides 3 with benzyl azide 4a.a
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Bn
N
N
N
PG
R2
N
[Rh(CO)2Cl]2 (2 mol%)
R1
N
PG
+
BnN3
MeCN (1 mL)
RT, Time
R1
R2
3
4a, 0.5 mmol
, 0.5 mmol
5
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Bn
Bn
Bn
Bn
N
N
N
N
N
N
N
N
N
N
N
N
N
Ms
Bs
Ts
Ms
Ns
N
N
N
Ph
Ph
Ph
Bn
Ph
Bn
Bn
5c
, 5 h, 88%
5a
5d
, 4 h, 95%
, 0.5 h, 94%
5b
, 3 h, 93%
Bn
Bn
Bn
Bn
N
N
N
N
N
N
N
N
N
O
O
N
N
N
Ms
Ts
N
N
N
N
Ph
Ph
Ph
Ph
Bn
Ph
Ph
5e
5f, 3 h, 88%
5g, 2 h, 92%
5h, 11 h, 89%
, 21 h, 84%
Bn
Bn
Bn
Bn
N
N
N
N
N
N
N
N
N
N
N
N
Ms
Ms
Ms
Ms
N
N
N
N
OMe
OMe
5j
, 0.5 h, 90%
CF3
5l
, 0.5 h, 94%
5i
, 2.5 h, 96%
5k
, 2 h, 90%
Bn
Bn
Bn
N
Bn
N
N
N
N
N
N
N
N
N
N
N
N
N
Ms
Ms
Ms
Ms
N
N
Cl
S
Cl
Cl
5p
, 0.5 h, 86%
5n
5o
, 20 h, 93%
, 4 h, 93%
Bn
5m
, 0.5 h, 95%
Bn
N
Bn
Bn
N
N
N
N
N
N
N
N
N
N
N
Ms
Ms
Ms
Ts
N
N
N
N
COOEt
Bn
Ph
Ph
Ph
5r
, 11 h, 85%
5q
5s
, 22 h, 88%
, 7 h, 80%
5t
, 10 h, 85%
a Yield of isolated product. All reactions were run in open flask.
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good substrates for the RhAACs, generating 5p and 5q in very good yields and complete
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n
regioselectivity. Replacement of the aryl substituted ynamide with butyl has no significant
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influences on the yields of the corresponding triazoles (cf. 5r). The ynamide derived from ethyl
propiolate was also proved to be a suitable substrate. After stirring for 10 h under the standard
condition, the desired triazole 5t was obtained in 85% isolated yield. Of note such a structural
motif containing carboxyamidotriazole core may have the potential on druglike agents
synthesis.1f Xꢀray diffraction studies of product 5a and 5f further confirmed the structural
assignments on the regioselectivity.18
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Such an openꢀflask triazole synthesis can be applied to the reactions of ynamide with a variety
of alkyl azides. As depicted in Table 3, functional moieties including indolyl, alkenyl, carbonyl
groups were well tolerated. The reactions were complete in relatively short time (2 h to 9 h at
ambient temperature), and the corresponding triazoles (cf. 5u to 5z) were all obtained in high
yields. These functionalities offer ample opportunities for further manipulation on the
corresponding triazoles. The reactions of aryl azides under standard conditions were proved to be
sluggish, and only partial of the starting materials were converted to the target triazoles.
o
Elevating the temperature to 100 C, and increasing the catalyst loading to 5 mol%, the
cycloaddition adducts could be obtained up to 83% isolated yields (cf. 5aa to 5ad).
As described, the current RhAAC tolerated a variety type of solvents. Pleasingly, the reaction
of ynamide 3a with benzyl azide 4a could also be run in aqueous media on gramꢀscale, while
without sacrifying efficiency, and triazole 5a was isolated in 89% yield (eq 1). Besides benzyl
azide 4a, other alkyl azides (4u, 4w, 4x and 4y) could react well with ynamide 3a in aqueous
media (see SI page S18 for details). The robustness was also evidenced by adding 1 equivalent of
agents containing variety of functionalities, ranging from benzoyl acid to pyridine oxide (see SI
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page S19 for details). Furthermore, the catalyst generated in situ by heating less costing RhCl3
rhodium salt solution in DMF for 30 min,19 was proved to be competent for current
transformation, and triazole 5a was obtained in high yield as well (eq 2).
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Table 3. Reaction scope of organic azides.a
R2
N
PG
N
[Rh(CO)2Cl]2 (2 mol%)
MeCN (1 mL), RT
R1
N
R2N3
N
+
GP
N
R1
4, 0.5 mmol
3, 0.5 mmol
Ms
5
Ns
N
N
N
N
Ph
N
N
N
Ph
N
N
N
N
N
Ph
N
Ph
N
Ms
5v, 1 h, 87%
5u, 2 h, 98%
5w, 2 h, 92%
O
Ms
N
N
N
N
O
N
N
N
N
Ph
Ms
Ph
Ph
N
Ph
O
N
N
N
O
O
N
Ms
5y, 6 h, 97%
5z
, 9 h, 84%
5x, 2 h, 93%
OMe
Br
Ph
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
Ph
Ph
Ph
Ph
5ad, 15 h, 68%b
Ms
Ms
Ms
Ms
5ac, 24 h, 22%
5aa, 24 h, 25%
5ab, 24 h, 17%
3 h, 83%b
4 h, 64%b
4 h, 69%b
a Yield of isolated product. All reactions were run in open flask. b The reactions were carried
out in 2 mL of MeCN at 100 oC, and 5 mol% [Rh(CO)2Cl]2 was employed .
To better understand the different behaviours between alkyl azides and aryl azides, a
competing experiment was carried out. Benzyl azide 4a, aryl azide 4ac and ynamide 3a were
added to same reaction flask in a ratio of 1:1:1. Interestingly, even after stirring at room
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temperature for 24 h, up to 50% of ynamide 3a was recovered, and triazoles 5a and 5ab were
isolated in 30% and 9% yields, respectively (eq 3). Further experiment revealed that addition of
catalytic amount of 5ab had no obvious effect on the reaction of ynamide 3a and benzyl azide 4a
(eq 4). Based on these results, we reasoned that the low conversion of benzyl azide 4a in eq 3
presumably resulted from partial poisoning of rhodium catalyst by aryl azide 4ab.7c This also
well explained the sluggish reactions observed when aryl azides were employed for the current
RhAACs.
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Figure 1. Three possible reactant complexes A, B and C.
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To further probe the details on the mechanism, DFT calculations were performed at the
M06/6ꢀ311+G(d,p)ꢀSDD//B3LYP/6ꢀ31G(d)ꢀLANL2DZ level. Solvation effects were accounted
by using the SMD model with acetonitrile as the solvent. Optimization of transition states and
intermediates in acetonitrile solvent do not have significant impact on the overall barriers and
regioselectivity (see Figure S3 in Supporting Information). For the cycloaddition of 3a and 4a,
the initial coordination of 3a and 4a to active catalyst [Rh(CO)2Cl] generates three possible
complexes A, B and C (Figure 1). Since C is less stable than A and B by about 8 kcal/mol,
reaction pathways from complexes A and B are calculated to be energetically more favourable
than those from C. The detailed energy profiles for cycloaddition mechanism from A are shown
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CO
Rh
N
CO
Rh
Ph
Ph
N
OC
Cl
Ms
N
Me
OC
Cl
Path A
Path A'
Ms
N
N
Me
N
Bn
Bn
CO
Rh
N
Ph
N
N
N
CO
OC
TS-II'
+18.0
Ph
N
CO
Rh
N
Ms
Ph
N
TS-I'
+14.3
OC
Cl
N
Cl
OC
Cl
Rh
N
Me
Ms
Bn
N
Ms
N
Int-I'
+5.9
Bn
Me
Bn
Me
N
N
CO
Rh
TS-I
+9.0
N
Ms
Me
OC
Cl
TS-II
+1.4
N
Int-II'
-0.8
A
0.0
Ph
CO
Ph
Ms
N
OC
Cl
N
Bn
Rh
N
N
N
N
Me
Int-I
-10.8
Int-II
-8.9
N
Bn
Ms
Me
Bn
CO
Rh
N
N
Ph
Ms
Ph
CO
CO
Rh
N
Ms
N
OC
Cl
Bn
Me
N
N
OC
Cl
Bn
N
N
N
Rh Cl
CO
Ph
Me
N
N
Int-III
-61.3
Me
5a-[Rh]
N
Ph
N
N
Ms
CO
Bn
N
N
5a'-[Rh]
Int-III'
Rh Cl
CO
-63.8
Figure 2. Energy profiles of cycloaddition from complex A.
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in Figure 2.20 First, oxidative coupling of azide and alkyne occurs to generate metallabicyclic
Rhꢀcarbene intermediate. Since both alkyne carbons in A are available for the attack from the
terminal nitrogen of azide, there are two pathways to eventually deliver product 5a and its
regioisomer 5a’. In Path A, oxidative coupling between azide and the β carbon of alkyne occurs
via TS-I to give Rhꢀcarbene intermediate Int-I. Then Int-I isomerizes to Int-II, followed by
reductive elimination transition state TS-II to generate triazoleꢀcatalyst coordinated complex
Int-III. In this context, the overall energy barrier of Path A is +12.2 kcal/mol (Int-I→TS-II).
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While in Path A’, the oxidative coupling transition state TS-I’ is 5.3 kcal/mol higher than TS-I.
This is caused by the more electronꢀrich phenylꢀsubstituted β carbon of alkyne, as the NBO
charges of α carbon and β carbon of alkyne in A are 0.165 and ꢀ0.146, respectively (Table S1). In
addition, except for the productꢀcatalyst complex (i.e., Int-III and Int-III’), intermediates and
transition state involved in Path A’ are significantly less stable than those in Path A. Further
NBO charges analysis demonstrated that electron densities of Rh center of species involved in
Path A are remarkably larger than those in Path A’ (Table 4). Considering the decreased NBO
charge of N atom and the increased NBO charge of Rh during the conversion of A to Int-II/TS-
II, we proposed that the thermodynamic stability of species in Path A arises from the electronꢀ
donating property of α carbonꢀconnected N substituent. Note that although the minor product
Int-III’ is more stable than the major product Int-III, it has no impact on the regioselectivity
since the reductive elimination step is irreversible. Therefore, our calculated results indicate that
Path A is the dominant mechanism with the generation of triazole 5a, and this is in accordance
with the experimental observations.
Table 4. NBO charges analysis of selected intermediates and transition states
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NBO Charge on
Rh atom
NBO Charge on
N atom
Species
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ꢀ0.426
ꢀ0.510
ꢀ0.386
ꢀ0.414
ꢀ0.391
ꢀ0.725
ꢀ0.617
ꢀ0.742
ꢀ0.661
ꢀ0.757
A
Int-II
Int-II’
TS-II
TS-II’
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Conclusions
In summary, we have described the first rhodium(I)ꢀcatalyzed azideꢀalkyne cycloaddition of
internal ynamides, furnishing the corresponding 5ꢀaminoꢀtriazoles in good to excellent yields (up
to 98%) with exclusive control on the regioselectivity. The current transformation is
operationally simple, can be proceeded under mild condition in an open flask. Careful exclusion
of air and moisture is not required. It is also amenable to gramscale synthesis in aqueous media.
Control experiments revealed that partial poisoning of the rhodium catalyst might take place
when aryl azides were employed. Moreover, DFT calculations provided details on the energy
profiles for each plausible reaction pathways, and well explained the observed regioselectivity in
this work.
ASSOCIATED CONTENT
AUTHOR INFORMATION
Corresponding Author
*chunsen.li@fjirsm.ac.cn; huangxl@fjirsm.ac.cn.
Notes
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The authors declare no competing financial interests.
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Supporting Information.
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Supporting Information. Experimental details, characterization data, geometries of optimized
1
structure/transition states, and H and 13C NMR spectra of isolated compounds (PDF), crystal
data of compounds 5a and 5f (CIF)18
ACKNOWLEDGMENT
We thank the financial support by NSFC (Grant No. 21402197, 21502190), NSF of Fujian
(Grant No. 2015J05043, 2017J01031), HundredꢀTalent Program and the Strategic Priority
Research Program of the Chinese Academy of Sciences (Grant No. XDB20000000).
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(17) See Supporting Information for details.
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Supporting Information.
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