Influence of steric demand on ruthenium-catalyzed cycloaddition of sterically hindered azides

Article abstract of DOI:10.1039/C6RA25403A

The RuAAC of sterically hindered 2,2-diaryl-2-azidoamines and terminal alkynes resulted in the unprecedented formation of 1,4-disubstituted-1,2,3-triazoles. A control experiment with 2-(azidomethyl)pyrrolidine revealed the usual selectivity with RuAAC and

Full text of DOI:10.1039/C6RA25403A

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Influence of steric demand on ruthenium-catalyzed
cycloaddition of sterically hindered azides†
Cite this: RSC Adv., 2017, 7, 3229
Venkata S. Sadu,a Sirisha Sadu,a Seji Kim,b In-Taek Hwang,b Ki-Jeong Kongb
ab
*
and Kee-In Lee
The RuAAC of sterically hindered 2,2-diaryl-2-azidoamines and terminal alkynes resulted in the
unprecedented formation of 1,4-disubstituted-1,2,3-triazoles. A control experiment with 2-(azidomethyl)
pyrrolidine revealed the usual selectivity with RuAAC and the reactions of azides with intermediate
bulkiness gave mixtures of 1,4- and 1,5-regioisomers. The results suggest that the steric demands could
annul the preference and influence on the regioselectivity of RuAAC substantially.
Received 18th October 2016
Accepted 17th December 2016
DOI: 10.1039/c6ra25403a
www.rsc.org/advances
The Huisgen 1,3-dipolar cycloaddition between azides and Scheme 1, so that the pairs could be used for comparison and
alkynes is the most convenient way to access 1,2,3-triazoles, but it validation studies in many different ways.5
produces a mixture of 1,4- and 1,5-disubstituted triazoles and
We envisioned that incorporation of triazole functionality
may require elevated temperatures.1 Aer the discovery of into the backbone of diarylprolinol may serve as a proline
copper-catalyzed azide-alkyne cycloaddition (CuAAC) leading to surrogate potentially useful for organocatalysis.6 Previously, the
the regioselective formation of 1,4-disubstituted 1,2,3-triazoles,2 sequential synthesis of highly hindered b-amino triazoles
the reaction enabled the rapid spread of triazole chemistry across bearing a gem-diaryl group has been accomplished from 1,1-
multilateral disciplines including medicinal chemistry, chemical diaryl-2-aminoethanols in part employing the copper catalysis.7
biology and material sciences due to its high degree of reliability, Attention next turned to the construction of pairwise surrogates.
specicity and biocompatibility.3 In addition, recent advances in During the investigation, we found an exclusive formation of 1,4-
ruthenium-catalyzed azide-alkyne cycloaddition (RuAAC) allow disubstituted triazoles from ruthenium-catalyzed cycloaddition
entry to 1,5-regioisomers as the complementary version to the particularly between sterically hindered azides and terminal
copper catalysis. Among them, ruthenium complexes containing alkynes even under the Cp*RuCl(PPh3)2 catalyst. Herein we wish
the pentamethylcyclopentadienyl ligand (Cp*) are the most to discuss the effect of steric factors on the regioselectivity of the
prominent class of catalysts showing high levels of regiose- RuAAC using azide partners embedded in the bulky group.
lectivity for a broad substrate scope.4 Particularly interesting are
The rst choice was Cp*RuCl(PPh3)2 as it has been widely used
approaches featuring the complementary pairings between for the construction of 1,5-disubstituted triazoles. However,
CuAAC and RuAAC to the same substrates as illustrated in surprisingly the product 2a from the reaction of 1a with phenyl-
acetylene was completely matched with the triazole from CuAAC.
The result is in contrast with the reported regioselectivity of the
RuAAC of terminal alkynes with Cp*RuCl(PPh3)2 that show the
preference for forming the 1,5-regioisomers. It seems we needed
to clarify an ambiguity of a possible coordination of the secondary
amine to a metal centre that may cause a change in the regiose-
lectivity. Hence, the reaction between N-tosyl-protected 1b and
Scheme
1 Schematic drawing of the complementarity between
ethyl propiolate was subjected and X-ray crystal structure of 2b
clearly revealed the 1,4-rigioisomer as shown in Scheme 2.† Even
both reactions were not completed in toluene at given times, the
reverse regioselectivity is quite unusual behaviour, as seen previ-
ously in the ruthenium complexes containing the Cp* ligand.
We next questioned that the observed selectivity is general
when employing different ruthenium complexes, which have
been addressed on the regioselective formation of the triazoles
in the literature. The Cp*-containing ruthenium catalysts such
as Cp*RuCl(PPh3)2,4a Cp*RuCl(COD),4a,b and [Cp*RuCl]4 (ref. 4c
and d) give 1,5-disubstituted triazoles with high regioselectivity,
CuAAC and RuAAC.
aMajor of Green Chemistry and Environmental Biotechnology, University of Science &
Technology, Taejon 305-350, Korea. E-mail: kilee@krict.re.kr
bGreen Chemistry Division, Korea Research Institute of Chemical Technology, Taejon
305-600, Korea
† Electronic supplementary information (ESI) available. CCDC 1503841 X-ray
crystallographic data of 2b have been deposited in the Cambridge
Crystallographic Data Centre database with accession number. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/c6ra25403a
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triazole but with slightly lower yield than the Cp*-containing
catalysts (entries 4 and 5). Regardless of the ruthenium catalysts
tested, the reactions exhibited 1,4-selectivity exclusively. Due to
the unique outcomes, we then needed to measure the thermal
contribution to the reaction and the result suggests that there is
no contribution from the thermal to the observed regioselectivity
(entry 6). By the way, supplementary attempts to obtain 1,5-
isomers were not fruitful, as applying alternative protocols based
on the generation of magnesium acetylide10a or the presence of
catalytic tetramethylammonium hydroxide,10b respectively.
We next turned our attention to other substrates as shown in
Table 2, which used previously in the CuAAC affording the exclu-
sive formation of 1,4-triazoles. The RuAAC reactions of 2,2-diaryl-2-
azidoamines derived from valine, phenylglycine, and phenylala-
nine reconrmed the exclusive formation of 1,4-regioisomers as
revealed by 1H and 13C NMR analysis (2c–2e). On the other hand,
interestingly, internal alkynes such as 1-phenyl-1-propyne11 and 3-
phenyl-2-propyn-1-ol4b with 1a were totally inactive in the RuAAC.
Over again, the azides lacking the amino group also produced the
single regioisomer (2f and 2g). Accordingly, we could rule out the
possible coordination of the amine moiety with metal centre which
may alter the catalytic activity.
Scheme
Cp*RuCl(PPh3)2 catalyst.
2 Observation of reverse selectivity under the
To understand inuence of the steric demand in the regiose-
lectivity, 2-(azidomethyl)pyrrolidine 3a was chosen and subjected
to the cycloadditions under the copper and ruthenium catalysts,
respectively, as shown in Scheme 3. Regioselective formation of
isomeric triazoles could be viable, as the CuAAC of 3a produced
1,4-regioisomer 4a6d and the corresponding 1,5-isomer 4b was
obtained by the RuAAC under the catalyst Cp*RuCl(PPh3)2. Two
whereas CpRuCl(PPh3)2 (ref. 4b) containing a cyclopentadienyl
ligand (Cp) shows marginal regioselectivity and catalytic activity
towards 1,5-regioisomers. On the other hand, Cp*/Cp-lacking
RuH2(CO)(PPh3)3 (ref. 8a) and RuH(h2-BH4)(CO)(PCy)2 (ref. 8b)
afford 1,4-regioisomers selectively. It seems clear that the Cp*
ligand serves as the key element responsible for the high 1,5-
selectivity in the ruthenium catalysis.
Examinations were thus undertaken with different Cp*-con-
taining catalysts, where DMF was the best choice and the reac-
tions were completed within 20 h. The tertiary azide proved to be
a relatively poor substrate quite possibly due to the steric
hindrance imposed by the two phenyl groups, however, the
RuAAC reactions were equally effective for the generation of 1,4-
regioisomer as the sole product (Table 1, entries 1–3). The
catalysts RuH2(CO)(PPh3)3 and Tp(PPh3)(EtNH2)RuN3 (Tp ¼
HB(pz)3, pz ¼ pyrazolyl)9 also produced the 1,4-disubstituted
Table 2 Regiospecific formation of 1,4-disubstituted triazole isomers
via RuAACa
Table 1 Screening of ruthenium catalysts by the reaction of 1a with
phenylacetylenea
Equiv. of
alkyne
Reaction
timeb (h)
Yield
Entry
Ru catalyst
of 2ac (%)
1
2
3
4
Cp*RuCl(PPh3)2
Cp*RuCl(COD)
[Cp*RuCl]4
RuH2(CO)(PPh3)3
Tp(PPh3)(EtNH2)RuN3
—
2
2
3
3
2
3
16
20
16
20
24
72
46
41
47
37
23
5
6d
—
e
a
Unless otherwise indicated, reaction conditions are as follows: 1a (1
mmol), Ru catalyst (1 mol%), phenylacetylene (2–3 equiv.), DMF,
b
150 ꢀC.
At a given time, 1a was completely consumed or
a
The reaction conditions are as follows: azide (1 mmol),
c
d
phenylacetylene (2.5 equiv.), Cp*RuCl(PPh3)2 (1 mol%), DMF, 150 ꢀC,
20 h.
decomposed.
No 1,5-regioisomer observed.
Thermal Huisgen
reaction performed without the catalyst. e No reaction observed.
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Scheme 3 Regioselective formation of isomeric triazoles by CuAAC
and RuAAC of 3a.
Scheme
intermediates.
4
Stereochemical analysis of possible ruthenacylclic
regioisomers are distinguished by the comparison to NMR spec-
troscopy. The contrasting results from 1a and 3a reveal the
substantial inuence on the regioselectivity of the RuAAC, and
thus suggest that the preference could be overridden by steric
demands imposed by bulky groups on the azide partners.
afforded 1,4-triazoles in good yields. In contrary, when benz-
hydryl azide and 2,6-diisopropyl-1-azidobenzene were treated
with the ruthenium catalyst, arguably, 1,4-regioisomers appeared
in both cases. For the same substrates, the thermal reactions gave
the regioisomeric mixtures at the ratio of 1/1, but only in very low
yield. In particular to adamantyl azide, the RuAAC solely gave 1,5-
regioisomers as the azide group can be freely exposed to the
metal centre presumably due to the congurationally con-
strained tricyclic backbone. It is now obvious that steric effect
plays an important role in the regioselectivity in the RuAAC.12
The RuAAC appears to proceed via oxidative coupling of the
azide and the alkyne to give a ruthenacycle which exerts
a complete control over regioselectivity. However, the formation
of the ruthenacycle I might be hampered considerably by the
stereo-demanding nature of steric bulkiness within such
a highly strained intermediacy and this may explain the
observed 1,5-regioisomer. Furthermore, an attempted product
2a0 would be extremely destabilised by the allylic strain exerting
between two substituents, as illustrated in Scheme 4. The
mechanistic considerations for this unprecedented observation
need much more studies, but we propose that spatial crowding
can alter the metal binding mode and eventually induce
a reverse orientation to the incoming alkyne, a CuAAC-like
ruthenacycle such as II. Likewise, inertness to internal alkyne
also supports this proposal.‡
Subsequently, we selected the substrates representing
a structural intermediacy in bulkiness with the intention of
deciphering the relationship between steric factors and selectivity
by the determination of product population. Thus, three different
types of 1,3-dipolar cycloaddition were undertaken separately
(Table 3). All CuAAC reactions of sterically hindered azides solely
Table 3 Dependency on the bulkiness of azides in the 1,3-dipolar
cycloaddition
Triazole (yield, ratio)
Azide
By CuAACa By RuAACb
By heatingc,d
e
5A (82%)
6A (77%)
7A (62%)
5B (52%)
—
6A/6B (47%, 1/3)f 6A/6B (10%, 1/1)f
7A/7B (54%, 1/3)f 7A/7B (10%, 1/1)f
‡ Many attempts at intercepting a possible Ru-triazole intermediate such as III
were unsuccessful; for the trapping of Cu-triazole intermediates: see, (a) W.
Wang, F. Wei, Y. Ma, C.-H. Tung and Z. Xu, Org. Lett., 2016, 18, 4158; (b) Y.-M.
Wu, J. Deng, Y. Li and Q.-Y. Chen, Synthesis, 2005, 1314; (c) X. Zhang, R. P.
Hsung and H. Li, Chem. Commun., 2007, 2420.
a
Reaction conditions: azide (1 mmol), phenylacetylene (1.2 equiv.),
CuSO4$5H2O (10 mol%), Na ascorbate (20 mol%), MeCN/H2O ¼ 1/1 (5
b
mL), rt, 16 h.
Azide (1 mmol), phenylacetylene (2.5 equiv.),
c
Cp*RuCl(PPh3)2 (1 mol%), DMF (5 mL), 150 ꢀC, 16 h. Azide (1
mmol), phenylacetylene (2.5 equiv.), DMF (5 mL), 150 ꢀC, 72 h.
d
f
e
Reaction not completed aer 72 h. Reaction not performed.
Isolated as mixtures and ratio based on NMR.
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In summary, we observed the unprecedented formation of
1,4-disubstituted-1,2,3-triazoles from the reaction of 2,2-diaryl-
2-azidoamines and terminal alkynes in the presence of ruthe-
nium catalysts bearing Cp* ligand. The reversal in regiose-
lectivity is presumably due to the steric congestion arose from
the geminal diaryl groups of the azide, as evidenced from the
control experiment with 2-(azidomethyl)pyrrolidine revealing
the usual selectivity with RuAAC. The contrasting results
suggest that the steric demands imposed by the bulky groups of
the azides could annul the preference and inuence the regio-
selectivity of RuAAC substantially. We thus surmise that the
formation of the ruthenacycle allowing the 1,5-regioselectivity
might be hampered considerably by the stereo-demanding
nature within such a highly strained intermediacy causing the
reverse orientation of the alkyne leading to the 1,4-regioisomer.
Furthermore, RuAAc of the bulky azides was inactive to internal
alkynes and this suggests that the mechanism is more likely to
resemble CuAAC pathway. In addition, the RuAAC reactions of
azides with intermediate bulkiness gave the mixtures of 1,4- and
1,5-regioisomers providing the additional support to this
hypothesis.
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Acknowledgements
This work was supported by the Creative Challenge Project
(KK1607-C03) of the Korea Research Institute of Chemical
Technology, Taejon, Korea.
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9 Tp-containing Ru catalyst is also known to give 1,5-
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3232 | RSC Adv., 2017, 7, 3229–3232
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