Chemo-, Regio-, and Enantioselective Rhodium-Catalyzed Allylation of Triazoles with Internal Alkynes and Terminal Allenes

Article abstract of DOI:10.1021/acs.orglett.7b03708

The rhodium-catalyzed asymmetric N¹-selective and regioselective coupling of triazole derivatives with internal alkynes and terminal allenes gives access to secondary and tertiary allylic triazoles in very good enantioselectivities. For this process, three new members of the JosPOphos ligand family have been prepared and employed in catalysis. The optimized reaction conditions enable the coupling of triazoles with internal alkynes as well as with allenes, displaying a high tolerance for functional groups. A gram scale reaction provided N¹-allyltriazole, which was subjected to various transformations highlighting synthetic utility.

Full text of DOI:10.1021/acs.orglett.7b03708

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Chemo‑, Regio‑, and Enantioselective Rhodium-Catalyzed Allylation
of Triazoles with Internal Alkynes and Terminal Allenes
Dino Berthold and Bernhard Breit*
Institut fur Organische Chemie and Freiburg, Institute for Advanced Studies (FRIAS), Albert-Ludwigs-Universitat Freiburg, Albertstr.
̈
̈
21, 79104 Freiburg im Breisgau, Germany
S
* Supporting Information
ABSTRACT: The rhodium-catalyzed asymmetric N1-selective
and regioselective coupling of triazole derivatives with internal
alkynes and terminal allenes gives access to secondary and
tertiary allylic triazoles in very good enantioselectivities. For
this process, three new members of the JosPOphos ligand
family have been prepared and employed in catalysis. The
optimized reaction conditions enable the coupling of triazoles
with internal alkynes as well as with allenes, displaying a high
tolerance for functional groups. A gram scale reaction provided N1-allyltriazole, which was subjected to various transformations
highlighting synthetic utility.
rhodium-catalyzed additions of benzotriazoles to aliphatic
terminal allenes (Scheme 1) depending on the rhodium
catalyst employed.7,8
ince chiral N-substituted triazoles possess broad ranges of
1a
anxiolytic,1b
Sbiological activities, such as antifungal,
antibacterial,1c and analgesic properties1d (Figure 1), the
development of new catalytic methods for their regio- and
stereoselective synthesis is in high demand in synthetic organic
chemistry.
Scheme 1. Previously Reported Regioselective and
Regiodivergent Addition of Benzotriazole to Aliphatic
Allenes
Figure 1. Bioactive compounds possessing an α-chiral benzotriazole
scaffold.
Given the pharmacological importance of chiral N1-alkylated
triazoles, we decided to develop a related asymmetric catalytic
variant. We anticipated that by the choice of an appropriate
JosPOphos ligand there might be an opportunity to control
enantioselectivity upon N1-selective addition of triazoles to
internal alkynes and terminal allenes.
We herein report on the rhodium-catalyzed regio- and
enantioselective addition of triazoles to internal alkynes and
terminal allenes providing access to secondary α-chiral N1-
allylated triazoles.
The synthesis of such N-alkylated chiral triazoles in
combination with the desired N-selectivity is troublesome
since the energy difference between the N1 and N2 tautomers in
solution is small.2 Thus, only a limited number of synthetic
methods exist, which mostly suffer from a lack of selectivity. N-
Alkylated chiral triazoles are usually prepared by either
nucleophilic substitution of chiral secondary alcohols,3a allylic
substitution,3b−d or organocatalytic Michael addition.3e−g
We recently reported on the rhodium-catalyzed and highly
regioselective addition of different pronucleophiles to allenes
and alkynes,4 a method that can be viewed as an atom-
economic alternative to transition-metal-catalyzed allylic
substitution5 and oxidation6 to generate branched allylic
products. Among these, we described N1- and N2-selective
For initial reactivity studies, derivatives of the JosPOphos
ligand family were required. These were prepared by a two-step
synthesis starting from Ugi’s amine (S)-(1) (Scheme 2). First,
Received: November 29, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03708
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
as for the diastereomerically pure J688-2 ligand (L1) (entry
4).10 Based on these results our new JosPOphos derivatives
were tested as mixtures of diastereomers. Unfortunately, neither
the more sterically demanding ligand L2 (entry 5) nor the
electron-rich or electron-poor ligands (L3 and L4, entries 6 and
7) resulted in higher enantioselectivities. Therefore, we focused
on optimizing the reaction with the initial JosPOphos J688-2
(L1). Most consistent results were obtained upon addition of
molecular sieves (4 Å) (entry 8).11
Scheme 2. Synthesis of JosPOphos Ligand SL-J688-2 and Its
Derivatives
Having the optimized reaction conditions in hand, we started
to explore the reaction scope by initially coupling symmetrical
and unsymmetrical triazoles to 1-phenyl-1-propyne (Scheme
3). We found a wide range of triazoles to be suitable reaction
the secondary phosphine oxide was installed by a directed
ortho-lithiation followed by trapping with a dichlorophosphine,
and subsequent hydrolysis of the remaining P−Cl bond. The
NMe2 moiety was substituted by heating in acetic acid with the
corresponding di-tert-butylphosphine yielding the desired
ligands with retention of configuration due to neighboring
group participation of the ferrocene unit.9 All ligands were
isolated as diastereomeric mixtures by virtue of the
configuration of the secondary phosphine oxide. For SL-J688-
2 (L1) a recrystallization was carried out to obtain the main
diastereomer in pure form.
Scheme 3. Scope of the Addition of Triazoles to 1-Phenyl-1-
propyne
With the desired ligands in hand initial reactivity assays were
carried out using benzotriazole (3a) and 1-phenyl-1-propyne
(4a) in the presence of [{Rh(cod)Cl}2] (2.0 mol %), PPTS (10
mol %), and the respective chiral ligands (5.0 mol %) in toluene
at 80 °C (Table 1). To our delight, we obtained the branched
Table 1. Ligand Screening for Regio- and Enantioselective
N-Allylation of Benzotriazole (3a) with 1-Phenyl-1-propyne
a
(4a)
yield
c
ee
b
d
entry
ligand
additive
PPTS
N1/N2
(%)
(%)
1
2
3
4
5
6
7
8
J681-2
−
0
−
81
partners furnishing the corresponding allylic triazoles in good
to excellent yields, along with very good to excellent regio- and
enantioselectivities. At this point the absolute configuration
could be determined by X-ray crystal structure analysis of
product 5c.
e
L1
L1
PPTS
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
99
51
99
99
99
92
99
e
−
rac
81
72
63
73
81
L1 (dr = 2.3:1) PPTS
L2
L3
L4
PPTS
PPTS
PPTS
Furthermore, the coupling reactions of various substituted
internal alkynes using 4-phenyltriazole were explored.12 We
were pleased to obtain the desired allylation products in very
good yields, along with excellent nitrogen-position selectivity as
well as regio- and enantioselectivities (Scheme 4). Cyclopropyl-
and enyne-based internal alkynes reacted smoothly to give the
desired products (5l and 5m) as well as a broad variety of
different aryl substituents.
Based on these results, we were curious if our catalytic
system is also capable of the enantioselective hydroamination of
terminal allenes (Scheme 5). Indeed, the reaction of
benzotriazole with different allenes as well as the reaction of
various triazoles with 2-phenylethylallene gave good yields and
high regioselectivities along with good enantioselectivity. Even
an alkyl iodide moiety (6c)usually prone for enabling side
reactions by facile oxidative addition of the rhodium catalyst
was well tolerated and a disubstituted allene (6d) was a suitable
reaction partner for benzotriazole.13
f
L1 (dr = 2.3:1) PPTS, MS (4 Å)
a
Reaction conditions: benzotriazole (0.4 mmol) and 1-phenyl-1-
propyne (0.5 mmol) in toluene (1.0 mL) at 80 °C, 24 h.
b
Regioselectivity determined by 1H NMR analysis of the crude
c
d
reaction mixture. Yield of isolated product. Determined by chiral
e
f
HPLC analysis. dr > 95:5. 160 mg/mmol of MS (4 Å, pearls) were
used. cod = 1,5-cyclooctadiene, PPTS = pyridinium p-toluenesulfo-
nate.
N1-allylated benzotriazole in excellent yield as well as good
enantioselectivity (99%, 81% ee; entry 2) by using JosPOphos
J688-2 (L1). The presence of PPTS was crucial to obtain the
desired N1 product in high yield and enantioselectivity (entry
3). Next, we examined whether the configuration of the
secondary phosphine oxide affects the reaction in terms of
yield, N1-selectivity, and enantioselectivity. We were pleased to
observe the same results with the diastereomeric mixture of L1
B
DOI: 10.1021/acs.orglett.7b03708
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. Scope of the Addition of 4-Phenyltriazole to
Different Internal Alkynes
Scheme 7. Various Functionalizations of Allylated
Benzotriazole 5a
double bond, using our self-assembly ligand 6-diphenyl-
phosphinopyridone (6-DPPon), furnished aldehyde 7a in
good yield and with excellent linear/branched selectivity
(95:5).14 Cleavage of the alkene by ozonolysis of 5a followed
by reductive workup led to alcohol 7b in 88% yield.
Hydrogenation furnished 7c and hydroboration/oxidation
gave the alcohol 7d, while leaving the benzotriazole unit
untouched.
To conclude, we developed a regio- and enantioselective
addition of triazoles to internal alkynes and terminal allenes in
an atom-economic manner by using a rhodium/JosPOphos
catalyst system. The reaction displays a broad substrate range of
substituted triazoles, alkynes, and allenes to provide N1-allylated
triazoles in very good yields along with high regio- and
enantioselectivities.
Scheme 5. Scope of the Addition of Triazoles to Terminal
Allenes
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b03708.
Synthetic procedures for new compounds as well as their
1
analytical data, involving H NMR, 13C NMR spectra,
and scanned HPLC chromatograms for chiral com-
pounds (PDF)
Accession Codes
CCDC 1530594 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033.
To further explore the synthetic utility of N1-allylated
benzotriazoles, allylic benzotriazole 5a was prepared on
multigram scale (Scheme 6).
The allylic moiety of 5a was then subjected to assorted
transformations (Scheme 7). Hydroformylation of the terminal
Scheme 6. Gram Scale Preparation of 5a and Purification by
Single Recrystallization
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: bernhard.breit@chemie.uni-freiburg.de.
ORCID
Bernhard Breit: 0000-0002-2514-3898
Notes
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.7b03708
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(9) Landert, H.; Spindler, F.; Wyss, A.; Blaser, H.-U.; Pugin, B.;
Ribourduoille, Y.; Gschwend, B.; Ramalingam, B.; Pfaltz, A. Angew.
Chem. 2010, 122, 7025; Angew. Chem., Int. Ed. 2010, 49, 6873.
(10) We assume that under the acidic reaction conditions there is an
equilibrium of both secondary P-oxide diastereomers and the
tautomeric phosphinite.
(11) For further details concerning the optimization, see the
Supporting Information.
(12) Unfortunately, the addition to terminal alkynes such as prop-2-
yn-1-ylbenzene did not provide any product.
ACKNOWLEDGMENTS
■
This work was supported by the DFG. Laura Stachowiak is
thanked for her skillful technical assistance. Monika Lutterbeck
is acknowledged for her technical support during ligand
synthesis. We thank Dr. Daniel Kratzert for X-ray crystal
structure analysis and Dr. Manfred Keller for extensive H
NMR analysis during kinetic studies.
1
REFERENCES
(13) NMR analysis of all crude catalysis products never showed any
linear triazole allylation product.
■
(1) (a) Rezaei, Z.; Khabnadideh, S.; Pakshir, K.; Hossaini, Z.; Amiri,
F.; Assadpour, E. Eur. J. Med. Chem. 2009, 44, 3064. (b) Paluchowska,
M. H.; Bugno, R.; Charakchieva-Minol, S.; Bojarski, A. J.;
(14) (a) Breit, B. Angew. Chem. 2005, 117, 6976; Angew. Chem., Int.
Ed. 2005, 44, 6816. (b) Breit, B.; Seiche, W. J. Am. Chem. Soc. 2003,
125, 6608. (c) Gellrich, U.; Seiche, W.; Keller, M.; Breit, B. Angew.
Chem. 2012, 124, 11195; Angew. Chem., Int. Ed. 2012, 51, 11033.
(d) Agabekov, V.; Seiche, W.; Breit, B. Chem. Sci. 2013, 4, 2418.
́
Tatarczynska, E.; Chojnacka-Wojcik, E. Arch. Pharm. 2006, 339, 498.
(c) Cano, M.; Palomer, A.; Guglietta, A. (Ferrer Internacional, S. A.)
WO 2010000704 (A1), 2010. (d) Park, C.-E.; Min, K. H.; Shin, Y.-J.;
Yoon, H.-J.; Kim, W.; Ryu, E.-J.; Chung, C.-M.; Kim, H.-K. (SK
Biopharmaceuticals Co. Ltd.) US 20100311789 (A1), 2010.
́ ́
(2) (a) Catalan, J.; Sanchez-Cabezudo, M.; De Paz, J. L. G.; Elguero,
J.; Taft, R. W.; Anvia, F. J. Comput. Chem. 1989, 10, 426. (b) Tomas,
F.; Abboud, J. L. M.; Laynez, J.; Notario, R.; Santos, L.; Nilsson, S. O.;
Catalan, J.; Claramunt, R. M.; Elguero, J. J. Am. Chem. Soc. 1989, 111,
7348. (c) Escande, A.; Galigne, J. L.; Lapasset, J. Acta Crystallogr., Sect.
B: Struct. Crystallogr. Cryst. Chem. 1974, 30, 1490. (d) Tomas, F.;
́
Catalan, J.; Perez, P.; Elguero, J. J. Org. Chem. 1994, 59, 2799.
(3) (a) Yan, W.; Liao, T.; Tuguldur, O.; Zhong, C.; Petersen, J. L.;
Shi, X. Chem. - Asian J. 2011, 6, 2720. (b) Liu, W.; Zhang, D.; Zheng,
S.; Yue, Y.; Liu, D.; Zhao, X. Eur. J. Org. Chem. 2011, 2011, 6288.
(c) Zhang, M.; Guo, X.-W.; Zheng, S.-C.; Zhao, X.-M. Tetrahedron
Lett. 2012, 53, 6995. (d) Wang, H.; Yu, L.; Xie, M.; Wu, J.; Qu, G.;
Ding, K.; Guo, H. Chem. - Eur. J. 2017, DOI: 10.1002/
chem.201704772. (e) Wang, J.; Li, H.; Zu, L.; Wang, W. Org. Lett.
2006, 8, 1391. (f) Diner, P.; Nielsen, M.; Marigo, M.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2007, 46, 1983. (g) Wang, J.; Zu, L.; Li, H.; Xie,
H.; Wang, W. Synthesis 2007, 2007, 2576. (h) Luo, G.; Zhang, S.;
Duan, W.; Wang, W. Synthesis 2009, 2009, 1564.
(4) (a) For a review, see: Koschker, P.; Breit, B. Acc. Chem. Res.
2016, 49, 1524 For a review, see:. (b) Thieme, N.; Breit, B. Angew.
Chem. 2017, 129, 1542; Angew. Chem., Int. Ed. 2017, 56, 1520.
(c) Beck, T. M.; Breit, B. Angew. Chem. 2017, 129, 1929; Angew.
Chem., Int. Ed. 2017, 56, 1903. (d) Spreider, P. A.; Haydl, A.; Heinrich,
M.; Breit, B. Angew. Chem. 2016, 128, 15798; Angew. Chem., Int. Ed.
2016, 55, 15569.
(5) (a) Trost, B. M. Chem. Rev. 1996, 96, 395. (b) Trost, B. M.;
Crawley, M. L. Chem. Rev. 2003, 103, 2921. (c) Lu, Z.; Ma, S. Angew.
Chem., Int. Ed. 2008, 47, 258. (d) Vrieze, D. C.; Hoge, G. S.; Hoerter,
P. Z.; Van Haitsma, J. T.; Samas, B. M. Org. Lett. 2009, 11, 3140.
(e) Hayashi, T.; Okada, A.; Suzuka, T.; Kawatsura, M. Org. Lett. 2003,
5, 1713. (f) Evans, P. A.; Leahy, D. K. J. Am. Chem. Soc. 2002, 124,
7882. (g) Lipowsky, G.; Miller, N.; Helmchen, G. Angew. Chem. 2004,
116, 4695; Angew. Chem., Int. Ed. 2004, 43, 4595. (h) Ye, K.-Y.; He,
H.; Liu, W.-B.; Dai, L.-X.; Helmchen, G.; You, S.-L. J. Am. Chem. Soc.
2011, 133, 19006. (i) Chen, W.; Hartwig, J. F. J. Am. Chem. Soc. 2013,
135, 2068. (j) Chen, W.; Hartwig, J. F. J. Am. Chem. Soc. 2014, 136,
377. (k) Krautwald, S.; Sarlah, D.; Schafroth, M. A.; Carreira, E. M.
Science 2013, 340, 1065. (l) Hamilton, J. Y.; Sarlah, D.; Carreira, E. M.
Angew. Chem. 2013, 125, 7680; Angew. Chem., Int. Ed. 2013, 52, 7532.
(6) (a) Liu, G.; Wu, Y. Top. Curr. Chem. 2009, 292, 195. (b) Chen,
M. S.; White, M. C. J. Am. Chem. Soc. 2004, 126, 1346. (c) Liu, G.;
Stahl, S. S. J. Am. Chem. Soc. 2007, 129, 6328. (d) Yin, G.; Wu, Y.; Liu,
G. J. Am. Chem. Soc. 2010, 132, 11978.
(7) Xu, K.; Thieme, N.; Breit, B. Angew. Chem. 2014, 126, 7396;
Angew. Chem., Int. Ed. 2014, 53, 7268.
(8) (a) Chen, Q.-A.; Chen, Z.; Dong, V. M. J. Am. Chem. Soc. 2015,
137, 8392. (b) Cruz, F. A.; Chen, Z.; Kurtoic, S. I.; Dong, V. M. Chem.
Commun. 2016, 52, 5836. (c) Cruz, F. A.; Dong, V. M. J. Am. Chem.
Soc. 2017, 139, 1029. (d) Cruz, F. A.; Zhu, Y.; Tercenio, Q. D.; Shen,
Z.; Dong, V. M. J. Am. Chem. Soc. 2017, 139, 10641.
D
DOI: 10.1021/acs.orglett.7b03708
Org. Lett. XXXX, XXX, XXX−XXX