Gold-Catalyzed Regiodivergent [2 + 2 + 2]-Cycloadditions of Allenes with Triazines

Article abstract of DOI:10.1021/acs.orglett.6b03691

Gold-catalyzed regiodivergent cycloadditions of functionalized allenes with 1,3,5-triazines, providing diverse N-heterocycles in moderate to excellent yields under mild reaction conditions, are reported. Importantly, different types of allenes exhibit distinct selectivity and reactivity for the reactions. Mechanistic investigations reveal that all of the cycloadditions proceed through a stepwise [2 + 2 + 2]-cycloaddition process.

Full text of DOI:10.1021/acs.orglett.6b03691

Letter
pubs.acs.org/OrgLett
Gold-Catalyzed Regiodivergent [2 + 2 + 2]-Cycloadditions of Allenes
with Triazines
Shiyong Peng, Shengyu Cao, and Jiangtao Sun*
Jiangsu Key Laboratory of Advanced Catalytic Materials & Technology and School of Pharmaceutical Engineering & Life Science,
Changzhou University, Changzhou 213164, P. R. China
S
* Supporting Information
ABSTRACT: Gold-catalyzed regiodivergent cycloadditions of function-
alized allenes with 1,3,5-triazines, providing diverse N-heterocycles in
moderate to excellent yields under mild reaction conditions, are
reported. Importantly, different types of allenes exhibit distinct
selectivity and reactivity for the reactions. Mechanistic investigations
reveal that all of the cycloadditions proceed through a stepwise [2 + 2 +
2]-cycloaddition process.
he soft carbophilic character of gold complexes enables
Scheme 1. Previous Reports and Our Utilization of 1,3,5-
Triazines
T
them to be ideal catalysts for activating carbon−carbon
multiple bonds for a wide range of organic transformations.1 In
particular, cycloadditions of two or more unsaturated
components under gold catalysis present important roles for
the construction of various cyclic compounds.2,3 However, the
regioselective cycloaddition of the orthogonal π-systems of
allenes remains challenging since different regioisomers form
during the addition process.4 Nevertheless, since the properties
of allenes have been strongly influenced by the functional
groups located at one or both double bonds, the allene involved
cycloadditions might be controlled regioselectively.4
On the other hand, as stable and readily available surrogates
for aryl imines, 1,3,5-tris(aryl)hexahydro-1,3,5-triazines have
been utilized as effective reagents in aminomethylation and
hydroaminomethylation reactions by incorporating the amino-
methyl group into a functionalized molecule. For example,
Krische and co-workers described the hydroaminomethylations
of allenes and 1,3-dienes through ruthenium-catalyzed
processes (Scheme 1, a).5 Feng and co-workers reported the
aminomethylation reaction of β-keto esters/amides by using
those triazines as excellent Mannich-type reagents (Scheme 1,
a).6 Recently, Huang and co-workers developed an elegant
palladium-catalyzed aminomethylamination of allenes employ-
ing tetrabenzylmethanediamine as the key substrate.7 Our
group discovered that 1,3,5-triazines can also serve as formal
1,4-dipoles in gold-catalyzed formal [4 + 1]/[4 + 3]-
cycloadditions with diazo compounds.8 Inspired by former
reports and in continuation with our ongoing interest in gold
catalysis,9 we report the gold-catalyzed cycloadditions of 1,3,5-
tris(aryl/benzyl)hexahydro-1,3,5-triazines with N-allenamides
and allenoates, which resulted in the discovery of unprece-
dented regioselective [2 + 2 + 2]-cycloadditions.
to achieve the optimal reaction conditions (Table 1). First,
without the addition of gold catalyst, the reaction did not react
in dichloromethane (DCM) at room temperature (entry 1).
The addition of 5 mol % of Ph3PAuCl afforded 3a in 47% yield
(entry 2). The yield was improved moderately when AgOTf
N-Allenamides are versatile building blocks and have been
utilized in various gold-catalyzed cycloadditions.9 Initially,
triazine 1a and allenamide 2a were utilized as model substrates
Received: December 11, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03691
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of the Reaction Conditions
Scheme 2. Scope for Reaction of Triazines with
ab
,
Allenamides
b
entry
catalyst
Ph3PAuCl
additive
solvent
DCM
yield (%)
1
2
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCE
47
73
79
95
<10
91
82
73
66
81
27
56
30
56
87
3
Ph3PAuCl
AgOTf
4
Ph3PAuCl
AgSbF6
NaBArF
NaBArF
NaBArF
NaBArF
NaBArF
NaBArF
NaBArF
NaBArF
NaBArF
NaBArF
NaBArF
NaBArF
5
Ph3PAuCl
6
IPrAuCl
7
(PhO)3PAuCl
XPhosAuCl
BINAP(AuCl)2
XantPhos(AuCl)2
Ph3PAuCl
8
9
10
11
12
13
14
Ph3PAuCl
THF
Ph3PAuCl
toluene
1,4-dioxane
DCM
DCM
Ph3PAuCl
c
15
Ph3PAuCl
d
16
Ph3PAuCl
a
Reaction conditions: 1a (0.2 mmol), 2a (0.2 mmol), catalyst (5 mol
b
c
%), additive (5 mol %), solvent (2.0 mL), rt, 12 h. Isolated yields. At
0 °C, 48 h. Catalyst (2 mol %), 48 h.
d
and AgSbF6 were used as additives (entries 3 and 4).
Gratifyingly, when 5 mol % of NaBArF (ArF: tetrakis[3,5-
bis(trifluoromethyl)phenyl]borate) was added as an additive,
the yield of 3a was increased to 95% (entry 5). Next, different
gold catalysts were examined with NaBArF as the additive. The
N-heterocyclic carbene gold catalyst was inactive in this
reaction (entry 6). Other phosphite and phosphine gold
catalysts were also examined, delivering 3a in moderate to good
yields (entries 7−10). Next, solvent screening showed that
DCM remained the best choice (entries 12−14). Lower
temperature or catalyst loading decreased the reaction
efficiency (entries 15 and 16).
a
With the optimal conditions in hand, we next set out to
investigate the generality of this reaction (Scheme 2). The
reactions of 2a with different substituted 1,3,5-triaryl-1,3,5-
triazines bearing either electron-donating or electron-with-
drawing substituents at the aryl moiety all proceeded smoothly
to afford the cycloaddition products in good to excellent yields.
Typically, tribenzyl-1,3,5-triazine and trimethylbenzyl-1,3,5-
triazine both reacted well and delivered the corresponding
products 3i and 3j in excellent yields. Next, various substituted
N-allenamides were subjected to this reaction. First, by
changing the substituent group from p-toluenesulfonyl (Ts)
to other groups such as methylsulfonyl (Ms), acetyl (Ac),
benzoyl (Bz), pivaloyl (Piv), and tert-butoxycarbonyl (Boc), the
cycloadditions proceeded well to give the final products in good
to excellent yields (3k−q). Second, the allenes bearing different
lactam groups were also tolerated, providing the corresponding
products in moderate to good yields (3r−w). Furthermore, the
reaction of 1a with bis-substituted N-allenamide 2i furnished 3x
in 91% yield. Notably, the bis-allenamide 2n also worked well
in the reaction and afforded 3y and 3z in excellent yields. The
structure of 3b was confirmed by X-ray analysis.10
Reaction conditions: 1 (0.2 mmol), 2 (0.2 mmol), Ph3PAuCl (5 mol
b
%), and NaBArF (5 mol %) in DCM (2 mL) at rt for 12 h. Isolated
c
yields. 1 (0.4 mmol) was used.
the formation of butenolides.1g,11a,b Moreover, the reactions of
allenoates with imines resulted in the formation of amino
esters11c or [3 + 2]-cycloaddition products11d in the presence of
a nucleophilic catalyst. Then the allenoates were examined in
the gold-catalyzed cycloadditions (Scheme 3). The reactions of
1a with different allenoates 2o−t were performed, and the
corresponding products 4a−f were isolated in moderate to
good yields in 48 h. Various triazines were tested, and the
corresponding products were also obtained in moderate to
good yields (4g−o). Notably, the allenic ketone 2u was also
tolerated, and the product 4p was obtained in 75% yield. The
structure of 4a was confirmed by X-ray analysis.10
To further understand the cycloaddition processes, control
and deuterium-labeling experiments were conducted (Scheme
4). The reaction of 1a and 1c with 2a was performed under
standard reaction conditions and afforded 3a and 3c in 46%
and 13% yields, respectively (Scheme 4a). The cross-cyclization
product 5 was also detected as an inseparable Z/E mixture,
The electron-deficient allenoates are also versatile inter-
mediates in organic synthesis. In particular, gold-catalyzed
cycloisomerizations of allenoates are well-known procedures for
1
which was determined by H NMR and HRMS analysis of the
B
DOI: 10.1021/acs.orglett.6b03691
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
of 3a, D-3a, and D-3a′ observed by HRMS analysis (Scheme
4b). Next, the reaction of 1b, 1c, and 2o was conducted, and
the cross-cycloaddition product 6 was confirmed by HRMS
analysis (Scheme 4c). A similar situation was observed for the
reaction of 1a, D-1a, and 2o. D-4a′ was determined by NMR
and HRMS analysis (Scheme 4d). The above experiments
indicated that the formation of six-membered N-heterocycles
proceeded through iterative additions of formaldimines with
allenes, which is quite different compared with literature
reports.5,6
Scheme 3. Scope for Reaction of Triazines with
Allenoates
a b
,
On the basis of former investigations, a plausible reaction
mechanism has been proposed. As shown in Scheme 5, the
Scheme 5. Proposed Reaction Mechanism
a
Reaction conditions: 1 (0.2 mmol), 2 (0.4 mmol), Ph3PAuCl (5 mol
b
%), and NaBArF (5 mol %) in DCM (2 mL) at rt for 48 h. Yields of
isolated products.
reaction of cationic gold complex with N-allenamide generates
gold species I (route A). The nucleophilic addition of
formaldimine to I produces intermediate II. Subsequent
reaction with another molecule of formaldimine gives rise to
intermediate III. Then cyclization and deauration furnish 3 as
the final product. Alternatively, as a Lewis acid catalyst, the gold
complex can activate the carbonyl group of allenoate (route B).
The nucleophilic addition of formaldimine to allenoate
(Michael addition) generates intermediate IV. Subsequent
addition to another molecule of formaldimine and deauration
provides 4′, which would isomerize to 4 as the final product.
In summary, we have developed gold-catalyzed regiodiver-
gent cycloadditions of 1,3,5-triazines with allenes, providing the
six-membered N-heterocycles in moderate to excellent yields
under mild reaction conditions. Mechanism investigations
revealed that these cycloadditions proceed through stepwise
and iterative additions of formaldimines to the allene moieties.
Importantly, different functionalized allenes present quite
different cycloaddition pathways.
Scheme 4. Control Experiments
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03691.
Experimental procedures along with characterizing data
and NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
■
crude product. Moreover, the reaction of 1a and D-1a with 2a
delivered the cycloaddition products as an inseparable mixture
*E-mail: jtsun08@gmail.com, jtsun@cczu.edu.cn.
C
DOI: 10.1021/acs.orglett.6b03691
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
ORCID
Letter
(4) For selected reviews on allene chemistry, see: (a) Ma, S. Chem.
Rev. 2005, 105, 2829. (b) Ma, S. Acc. Chem. Res. 2009, 42, 1679.
Jiangtao Sun: 0000-0003-2516-3466
Notes
(c) Lop
(d) Lledo,
́
ez, F.; Mascarenas, J. L. Chem. Soc. Rev. 2014, 43, 2904.
A.; Pla-Quintana, A.; Roglans, A. Chem. Soc. Rev. 2016, 45,
̃
́
2010. (e) Kitagaki, S.; Inagaki, F.; Mukai, C. Chem. Soc. Rev. 2014, 43,
2956. (f) Wang, Z.; Xu, X.; Kwon, O. Chem. Soc. Rev. 2014, 43, 2927.
(g) Yang, W.; Hashmi, A. S. K. Chem. Soc. Rev. 2014, 43, 2941.
(h) Zimmer, R.; Reissig, H.-U. Chem. Soc. Rev. 2014, 43, 2888.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(i) Caneque, T.; Truscott, F. M.; Rodriguez, R.; Maestri, G.; Malacria,
̃
We thank the NSF of China (No. 21572024), Natural Science
Foundation of Jiangsu Province (BK20151184), and Jiangsu
Key Laboratory of Advanced Catalytic Materials and
Technology (BM2012110) for financial support.
M. Chem. Soc. Rev. 2014, 43, 2916.
(5) (a) Oda, S.; Sam, B.; Krische, M. J. Angew. Chem., Int. Ed. 2015,
54, 8525. (b) Oda, S.; Franke, J.; Krische, M. J. Chem. Sci. 2016, 7, 136.
(6) Lian, X.; Lin, L.; Fu, K.; Ma, B.; Liu, X.; Feng, X. Chem. Sci. 2017,
DOI: 10.1039/C6SC03902B.
(7) Hu, J.; Xie, Y.; Huang, H. Angew. Chem., Int. Ed. 2014, 53, 7272.
(8) Zhu, C.; Xu, G.; Sun, J. Angew. Chem., Int. Ed. 2016, 55, 11867.
(9) For selected gold-catalyzed annulations of allenamides, see:
REFERENCES
■
(1) For selected reviews, see: (a) Hashmi, A. S. K.; Hutchings, G. J.
Angew. Chem., Int. Ed. 2006, 45, 7896. (b) Furstner, A.; Davies, P. W.
Angew. Chem., Int. Ed. 2007, 46, 3410. (c) Hashmi, A. S. K. Chem. Rev.
̈
(a) Faustino, H.; Lop
2011, 2, 633. (b) Faustino, H.; Bernal, P.; Castedo, L.; Lop
́
ez, F.; Castedo, L.; Mascarenas, J. L. Chem. Sci.
̃
́
ez, F.;
2007, 107, 3180. (d) Jimen
2008, 108, 3326. (e) Gorin, D. J.; Sherry, B. D.; Toste, F. D. Chem.
Rev. 2008, 108, 3351. (f) Corma, A.; Leyva-Perez, A.; Sabater, M. J.
Chem. Rev. 2011, 111, 1657. (g) Krause, N.; Winter, C. Chem. Rev.
2011, 111, 1994. (h) Rudolph, M.; Hashmi, A. S. K. Chem. Soc. Rev.
2012, 41, 2448. (i) Muratore, M. E.; Homs, A.; Obradors, C.;
Echavarren, A. M. Chem. - Asian J. 2014, 9, 3066. (j) Dorel, R.;
Echavarren, A. M. Chem. Rev. 2015, 115, 9028. (k) Zheng, Z.; Wang,
Z.; Wang, Y.; Zhang, L. Chem. Soc. Rev. 2016, 45, 4448. (l) Pan, F.;
Shu, C.; Ye, L.-W. Org. Biomol. Chem. 2016, 14, 9456.
(2) For reviews on gold-catalyzed cycloadditions of two or more
unsaturated components, see: (a) Ma, S.; Yu, S.; Gu, Z. Angew. Chem.,
Int. Ed. 2006, 45, 200. (b) Lop
Chem. 2011, 7, 1075. (c) Lopez, F.; Mascarenas, J. L. Beilstein J. Org.
Chem. 2013, 9, 2250. (d) Asiri, A. M.; Hashmi, A. S. K. Chem. Soc. Rev.
2016, 45, 4471.
́
ez-Nunez, E.; Echavarren, A. M. Chem. Rev.
́
̃
Mascarenas, J. L. Adv. Synth. Catal. 2012, 354, 1658. (c) Zhou, W.; Li,
̃
X.-X.; Li, G.-H.; Wu, Y.; Chen, Z. Chem. Commun. 2013, 49, 3552.
́
́
(d) Faustino, H.; Alonso, I.; Mascarenas, J. L.; Lopez, F. Angew. Chem.,
̃
Int. Ed. 2013, 52, 6526. (e) Li, G.-H.; Zhou, W.; Li, X.-X.; Bi, Q.-W.;
Wang, Z.; Zhao, Z.-G.; Hu, W.-X.; Chen, Z. Chem. Commun. 2013, 49,
́
4770. (f) Faustino, H.; Varela, I.; Mascarenas, J. L.; Lopez, F. Chem.
̃
Sci. 2015, 6, 2903. (g) Wang, Y.; Zhang, P.; Qian, D.; Zhang, J. Angew.
Chem., Int. Ed. 2015, 54, 14849. (h) Jia, M.; Monari, M.; Yang, Q.-Q.;
Bandini, M. Chem. Commun. 2015, 51, 2320. (i) Wang, Y.; Zhang, P.;
Liu, Y.; Xia, F.; Zhang, J. Chem. Sci. 2015, 6, 5564. (j) Hernan
́
dez-Díaz,
C.; Rubio, E.; Gonzalez, J. M. Eur. J. Org. Chem. 2016, 2016, 265.
́
(10) CCDC 1517335 (3b) and CCDC 1517336 (4a) contain the
supplementary crystallographic data for this paper and can be obtained
free of charge from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
́
ez, F.; Mascarenas, J. L. Beilstein J. Org.
̃
́
̃
(11) (a) Kang, J.-E.; Lee, E.-S.; Park, S.-I.; Shin, S. Tetrahedron Lett.
(3) For selected examples on gold-catalyzed cycloadditions, see:
2005, 46, 7431. (b) Piera, J.; Krumlinde, P.; Strubing, D.; Backvall, J.-
̈
̈
(a) Suar
Gonzalez, J. M. Adv. Synth. Catal. 2012, 354, 1651. (b) Montserrat, S.;
Faustino, H.; Lledos, A.; Mascarenas, J. L.; Lopez, F.; Ujaque, G.
Chem. - Eur. J. 2013, 19, 15248. (c) Bernal-Albert, P.; Faustino, H.;
Gimeno, A.; Asensio, G.; Mascarenas, J. L.; Lopez, F. Org. Lett. 2014,
́ ́
ez-Pantiga, S.; Hernandez-Díaz, C.; Piedrafita, M.; Rubio, E.;
E. Org. Lett. 2007, 9, 2235. (c) Cowen, B. J.; Saunders, L. B.; Miller, S.
J. J. Am. Chem. Soc. 2009, 131, 6105. (d) Xu, Z.; Lu, X. Tetrahedron
Lett. 1999, 40, 549.
́
́
́
̃
́
̃
16, 6196. (d) Ocello, R.; De Nisi, A.; Jia, M.; Yang, Q.-Q.; Monari, M.;
Giacinto, P.; Bottoni, A.; Miscione, G. P.; Bandini, M. Chem. - Eur. J.
2015, 21, 18445. (e) Zheng, Z.; Zhang, L. Org. Chem. Front. 2015, 2,
1556. (f) Wang, Y.; Zheng, Z.; Zhang, L. J. Am. Chem. Soc. 2015, 137,
5316. (g) Dorel, R.; Echavarren, A. M. J. Org. Chem. 2015, 80, 7321.
(h) Xu, W.; Wang, W.; Wang, X. Angew. Chem., Int. Ed. 2015, 54,
9546. (i) Huple, D. B.; Mokar, B. D.; Liu, R.-S. Angew. Chem., Int. Ed.
2015, 54, 14924. (j) Tokimizu, Y.; Oishi, S.; Fujii, N.; Ohno, H.
Angew. Chem., Int. Ed. 2015, 54, 7862. (k) Nakamura, I.; Gima, S.;
Kudo, Y.; Terada, M. Angew. Chem., Int. Ed. 2015, 54, 7154. (l) Chen,
M.; Chen, Y.; Sun, N.; Zhao, J.; Liu, Y.; Li, Y. Angew. Chem., Int. Ed.
2015, 54, 1200. (m) Shu, C.; Wang, Y.-H.; Zhou, B.; Li, X.-L.; Ping, Y.-
F.; Lu, X.; Ye, L.-W. J. Am. Chem. Soc. 2015, 137, 9567. (n) Li, L.;
Zhou, B.; Wang, Y.-H.; Shu, C.; Pan, Y.-F.; Lu, X.; Ye, L.-W. Angew.
Chem., Int. Ed. 2015, 54, 8245. (o) Zhou, A.-H.; He, Q.; Shu, C.; Yu,
Y.-F.; Liu, S.; Zhao, T.; Zhang, W.; Lu, X.; Ye, L.-W. Chem. Sci. 2015,
6, 1265. (p) Mei, L.-Y.; Wei, Y.; Tang, X.-Y.; Shi, M. J. Am. Chem. Soc.
2015, 137, 8131. (q) Zi, W.; Toste, F. D. Angew. Chem., Int. Ed. 2015,
54, 14447. (r) Zhang, L.; Wang, Y.; Yao, Z.-J.; Wang, S.; Yu, Z.-X. J.
Am. Chem. Soc. 2015, 137, 13290. (s) Rao, W.; Susanti, D.; Ayers, B. J.;
́
Chan, P. W. H. J. Am. Chem. Soc. 2015, 137, 6350. (t) Jimenez, T.;
Carreras, J.; Ceccon, J.; Echavarren, A. M. Org. Lett. 2016, 18, 1410.
(u) Hosseyni, S.; Wojtas, L.; Li, M.; Shi, X. J. Am. Chem. Soc. 2016,
138, 3994. (v) Ferrer, S.; Echavarren, A. M. Angew. Chem., Int. Ed.
2016, 55, 11178. (w) Jin, H.; Tian, B.; Song, X.; Xie, J.; Rudolph, M.;
Hashmi, A. S. K. Angew. Chem., Int. Ed. 2016, 55, 12688. (x) Mokar, B.
D.; Huple, D. B.; Liu, R.-S. Angew. Chem., Int. Ed. 2016, 55, 11892.
(y) Jin, H.; Huang, L.; Xie, J.; Rudolph, M.; Rominger, F.; Hashmi, A.
S. K. Angew. Chem., Int. Ed. 2016, 55, 794.
D
DOI: 10.1021/acs.orglett.6b03691
Org. Lett. XXXX, XXX, XXX−XXX