Gold catalyzed [3+2] cycloaddition of N-allenyl amides with azomethine imines

Article abstract of DOI:10.1039/c3cc41258j

Gold(i) catalyzed [3+2] cycloaddition of azomethine imines with N-allenyl amides was developed to provide two types of pyrazolyl based bicyclic heterocycles. Both pyrazolidin-3-one derived and dihydroisoquinoline derived azomethine imines reacted smoothly with N-allenyl amides to give 6-methylene bipyrazolidin-1-ones and 1-methylene hexahydropyrazolo[5,1-a] isoquinolines in moderate to good yields.

Full text of DOI:10.1039/c3cc41258j

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Gold catalyzed [3+2] cycloaddition of N-allenyl amides
with azomethine imines†
Wen Zhou,a Xiao-Xiao Li,a Guo-Hua Li,a Yun Wu*b and Zili Chen*a
Cite this: Chem. Commun., 2013,
49, 3552
Received 28th January 2013,
Accepted 4th March 2013
DOI: 10.1039/c3cc41258j
www.rsc.org/chemcomm
Gold(I) catalyzed [3+2] cycloaddition of azomethine imines with
N-allenyl amides was developed to provide two types of pyrazolyl based
bicyclic heterocycles. Both pyrazolidin-3-one derived and dihydroiso-
quinoline derived azomethine imines reacted smoothly with N-allenyl
amides to give 6-methylene bipyrazolidin-1-ones and 1-methylene
hexahydropyrazolo[5,1-a] isoquinolines in moderate to good yields.
1,3-Dipolar cycloadditions are powerful methods for constructing a
variety of five-membered heterocycles. Especially, the reactions of
azomethine imines with alkenes or alkynes have attracted great interest
in recent years.1,2 However, few examples of 1,3-dipolar cycloaddition of
azomethine imines with allenes have been reported to date.3
Recent advances in gold chemistry have led to a novel pathway for
the ring construction from allenes. The initial examples in this field
are documented as the gold(I) catalyzed intramolecular cycloaddition
of allenes with alkenes or dienes.4 Later on, intermolecular [2+2], [4+2]
cycloaddition of N-allenyl amides with electron rich alkenes was also
illustrated.5,6 Nevertheless, these results focused exclusively on carbo-
cycle synthesis. Using a gold–allene complex as the dipolarphile for
the synthesis of heterocycles has seldom been explored.7 Herein we
report a gold catalyzed cycloaddition reaction of N-allenyl amides8
with pyrazolidin-3-one derived azomethine imines to give 6-methylene
bipyrazolidin-1-ones with high diastereoselectivities.9,10 The regio-
selectivity of this reaction is different from the previous reports
(Scheme 1),3 due to the divergent reactivities between intermediates
A and B.11 In addition, the reaction of N-allenyl amides with
dihydroisoquinoline derived azomethine imines was also explored,
yielding regioselectively a series of 1-methylene hexahydropyrazolo
[5,1-a] isoquinolines.3c
Scheme 1 Allene derived intermediates and 1,3-dipolar cycloaddition with
azomethine imines.
Following a previous procedure,5a the reaction of 1 mol equiv. of 1a
with 1.2 mol equiv. of 2a was carried out under the condition of 5%
mol equiv. of Ph3PAuCl/AgSbF6 with the addition of 100 mg 4 Å MS.
The desired product 6-methylene bipyrazolidin-1-one 3a was then
obtained in 90% yield. Silver salts screening was performed, in
which, Ph3PAuCl/AgOTf was found to be the best silver combination
(Table 1, entry 2).12 Removing the 4 Å molecular sieve and reducing
the catalyst loading decreased the reaction yield considerably
(Table 1, entries 3 and 4). In the control experiment, two substrates
Table 1 Condition optimization for the reaction of 1a with 2aa
The reaction of N-allenyl amide 1a with azomethine imine 2a
was chosen as the model system for our initial investigation.
Catalyst (%)
Soln/temp (1C)/time (h)
3a Yieldb (%)
a Department of Chemistry, Renmin University of China, Beijing 100872, China.
E-mail: zilichen@ruc.edu.cn
1
Ph3PAuCl/AgSbF6 (5)
Ph3PAuCl/AgOTf (5)
Ph3PAuCl/AgOTf (5)
Ph3PAuCl/AgOTf (2.5)
No catalyst
DCM/rt/2
DCM/rt/2
DCM/rt/2
DCM/rt/2
90
97
86
76
2
3c
4
b State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical
Sciences, Peking University, Beijing 100191, PR China.
5
Xylene/reflux/12
Mixture
E-mail: wuyun_sioc@hotmail.com
a
† Electronic supplementary information (ESI) available: Experimental procedures
and data for all new compounds. CCDC 907213. For ESI and crystallographic data
in CIF or other electronic format see DOI: 10.1039/c3cc41258j
Unless noted, all reactions were carried out at the 0.1 mmol scale in
2 mL solvent with the addition of 5 mol% catalyst and 100 mg 4 Å MS,
b
c
(1a/2a = 1/1.2). Isolated yields. No 4 Å MS was added.
c
3552 Chem. Commun., 2013, 49, 3552--3554
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Table 2 The reaction of N-allenyl sulfonamide 1a with a series of azomethine
imines with different substitution patternsa,b
Table 3 The reaction of azomethine imine 2a with various N-allenyl amidesa
Reaction Yield
time (h) (%)
Entry Substrate 2
Product 4
Reaction
Entry Substrate 2
Product 3
3a, R = H
time (h) Yieldc/(dr)
1
2
1b, R1, R2, R3 = H
1c, R1, R2, R3 = CH3 4c, R1, R2, R3 = CH3
4b, R1, R2, R3 = H
2
3
90
78
1
2
3
4
5
6
2a, R = H
2b, R = p-OCH3 3b, R = p-OCH3
2c, R = p-Br
2d, R = p-F
2e, R = p-NO2 3e, R = p-NO2
1
3
2
2
2
2
97%
92%
95%
96%
82%
96%
3c, R = p-Br
3d, R = p-F
3
4
1d, R = H
1e, R = F
4d, R = H
4e, R = F
2.5
2
96
81
2f, R = m-Cl
3f, R = m-Cl
5
6
1f, R = n-Pr
1g, R =
2-tetrahydrofuryl
4f, R = n-Pr
4g, R =
2-tetrahydrofuryl
2
2
65
71
7
2g
3g
2
83%
8
9
10
11
2h, R = CH3
2i, R = n-Pr
2j, R = i-Pr
2k, R = Ph
3h, R = CH3
3i, R = n-Pr
3j, R = i-Pr
3k, R = Ph
5
2
2
2
95% (10/1)
83% (11/1)
90% (12/1)
92% (>20/1)
7
1h
4h
2
94
a
Unless noted, all reactions were carried out at the 0.1 mmol scale in
2 mL CH2Cl2 at rt under the conditions of 5 mol% equiv. of Ph3PAuCl/
AgOTf and 100 mg 4 Å MS (the ratio of 1/2a = 1/1.2).
[3+2] Cycloaddition of 2a with several N-allenyl amides were
subsequently investigated. Phenyl and benzyl substituted N-allenyl
amides 1b–d afforded 4b–d in moderate to good yields (Table 3,
entries 1 and 2). While alkylamine derived substrates 1f and 1g
afforded the desired products in slightly lower yields (Table 3,
entries 5 and 6). The reaction of 2-oxazolidinone derived substrate
1h with 2a proceeded smoothly to provide the corresponding
bicyclic adduct 4h in 94% yield (Table 3, entry 7).
12
2m
3m
2
96% (syn/
anti = 1.2/1)
a
Unless noted, all reactions were carried out at the 0.1 mmol scale in
2 mL CH2Cl2 at rt under the conditions of 5 mol% equiv. of Ph3PAuCl/
b
AgOTf and 100 mg 4 Å MS (the ratio of 1a/2 = 1/1.2). The structure only
c
shows relative configuration. The dr value was determined using
1H NMR spectral data.
The structure of 4h, as shown in Fig. 1, was determined to be
an N-vinylamide containing bicyclic pyrazolo [1,2-a] pyrazole
structure as identified by X-ray crystallography (Fig. 1).13
The gold catalyzed reaction of 3,4-dihydroisoquinoline derived
azomethine imine 5 with N-allenyl amides was also tested.3c As
shown in Table 4, the cyclic and phenyl substituted N-allenyl amides
1a and 1b gave 6a and 6b in good yields, while its 2,6-diisopropyl-
phenyl analog 1i afforded the desired product 6c in a relatively lower
were treated in xylene under reflux conditions, which gave a mixture
of undetermined products (Table 1, entry 5).‡
Next, we explored different substrate structures. A series of
pyrazolidinone derived azomethine imines 2a–2f were tested under
the optimized reaction conditions (Table 1, entry 2). As shown in
Table 2, both electron donating and electron withdrawing phenyl
substituents (Table 1, entries 1–6) worked very well to provide the
desired 6-methylene bipyrazolidin-1-one adducts 3a–f in high
yields. The pyridine group, which could coordinate with the Au(I)
cation competitively, did not affect the reaction yield (Table 1,
entry 7). C-4 or C-5 substituted pyrazolidinone derived azomethine
imines 2h–2m were also studied. Increasing the steric hindrance of
the C-5 substituent enhanced the stereoselectivity (Table 2, entries
9–11), in which, syn-3k was obtained as a single isomer. Never-
theless, C-4 substituted substrate 2m gave 3m in a low syn/anti
selectivity (Table 2, entry 12).12
Fig. 1 X-ray structure of compound 4h.
c
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Table 4 The reaction of 3,4-dihydroisoquinoline derived azomethine imine 5
with various N-allenyl amidesa
mixture in vacuum followed by flash column chromatography over SiO2
(hexane/EtOAc = 1/5) afforded 3a as a colorless oil in 97% yield.
1 Reviews: (a) J. G. Schantl, Adv. Heterocycl. Chem., 2010, 99, 185;
(b) J. Svete, ARKIVOC (Gainesville, FL, U. S.), 2006, 7, 35;
(c) J. G. Schantl, J. Heterocycl. Chem., 2000, 37, 541.
2 Recent examples: (a) H. Kawai, Z. Yuan, E. Tokunaga and N. Shibata,
Org. Lett., 2012, 14, 5330; (b) T. Arai and Y. Ogino, Molecules, 2012,
17, 6170; (c) K. Yoshimura, T. Oishi, K. Yamaguchi and N. Mizuno,
Chem.–Eur. J., 2011, 17, 3827; (d) S. Shirakawa, P. J. Lombardi and
J. L. Leighton, J. Am. Chem. Soc., 2005, 127, 9974; (e) K. Tran,
P. J. Lombardi and J. L. Leighton, Org. lett., 2008, 10, 3165.
3 (a) R. Na, H. Liu, Z. Li, B. Wang, J. Liu, M.-A. Wang, M. Wang,
J. Zhong and H. Guo, Tetrahedron, 2012, 68, 2349; (b) R. Na, C. Jing,
Q. Xu, H. Jiang, X. Wu, J. Shi, J. Zhong, M. Wang, D. Benitez,
E. Tkatchouk, W. A. Goddard III, H. Guo and O. Kwon, J. Am. Chem.
Soc., 2011, 133, 13337; Phosphine mediated dipolar cycloaddition of
allenoates with dihydroisoquinoline derived azomethine imines was
also reported to give a divergent regioselectivity: (c) C. Jing, R. Na,
B. Wang, H. Liu, L. Zhang, J. Liu, M. Wang, J. Zhong, O. Kwon and
H. Guo, Adv. Synth. Catal., 2012, 354, 1023.
4 Examples for intramolecular [3+2] cycloaddition: (a) G.-Z. Zhang,
V. J. Catalano and L.-M. Zhang, J. Am. Chem. Soc., 2007, 129, 11358;
(b) X. Huang and L.-M. Zhang, J. Am. Chem. Soc., 2007, 129, 6398.
5 (a) X.-X. Li, L.-L. Zhu, W. Zhou and Z. Chen, Org. Lett., 2012, 14, 436;
a
Unless noted, all reactions were carried out at the 0.1 mmol scale in
2 mL CH2Cl2 at rt.
´
´
´
(b) S. Suarez-Pantiga, C. Hernandez-Dıaz, M. Piedrafita, E. Rubio and
´
J. M. Gonzalez, Adv. Synth. Catal., 2012, 354, 1651; (c) H. Faustino,
´
˜
P. Bernal, L. Castedo, F. Lopez and J. L. Mascarenas, Adv. Synth.
´
´
´
Catal., 2012, 354, 1658; (d) S. Suarez-Pantiga, C. Hernandez-Dıaz,
´
E. Rubio and J. M. Gonzalez, Angew. Chem., Int. Ed., 2012, 51, 11552.
´
˜
6 (a) H. Faustino, F. Lopez, L. Castedo and J. L. Mascarenas, Chem.
Sci., 2011, 2, 633; (b) J. Francos, F. Grande-Carmona, H. Faustino,
´
´
J. Iglesias-Sigu¨enza, E. Dıez, I. Alonso, R. Fernandez, J. M. Lassaletta,
´
˜
F. Lopez and J. L. Mascarenas, J. Am. Chem. Soc., 2012, 134, 14322.
7 Review for heterocycle synthesis via gold catalysis: M. Rudolph and
A. S. K. Hashmi, Chem. Commun., 2011, 47, 6536.
Scheme 2 A plausible mechanism for gold catalyzed [3+2] cycloaddition of
N-allenyl amides with azomethine imines.
8 Reviews on N-allenyl amides: (a) R. P. Hsung, L.-L. Wei and H. Xiong, Acc.
Chem. Res., 2003, 36, 773; (b) Examples of [3+2] cycloadditions using
yield (Table 4).12 Alkylamine substrate 1f and 2-oxazolidinone
substrate 1h also worked very well, providing the corresponding
cycloadducts 6d-e in moderate to good yields.
´
N-allenyl amides: G. Broggini, L. Bruche and G. J. Zecchi, J. Chem. Soc.,
Perkin Trans. 1, 1990, 533; (c) Y. Horino, M. Kimura, S. Tanaka, T. Okajima
and Y. Tamaru, Chem.–Eur. J., 2003, 9, 2419; (d) J. Barluenga, R. Vicente,
´
L. A. Lopez and M. Tomas, J. Am. Chem. Soc., 2006, 128, 7050;
Based on previous reports, two gold activation mechanisms were
proposed. As shown in Scheme 2, the reaction could be started from
the outer-sphere nucleophilic addition of 2k to the gold–allene
complex B to give intermediate C (step Ia, Scheme 2).14 Alterna-
tively, coordination of azomethine imine 2k with gold catalyst
followed by an inner-sphere nucleophilic addition could also lead
to intermediate C (step Ib, Scheme 2).15 Step Ia is preferred because
of formation of the allene dimerization side products while reducing
azomethine imine’s equivalence.5a Subsequent intramolecular
cyclization of intermediate C yielded another iminium intermediate
D (step II), in which the vinylamine unit attacks the cationic
(e) A. Piperno, A. Rescifina, A. Corsaro, M. A. Chiacchio, A. Procopio
and R. Romeo, Eur. J. Org. Chem., 2007, 1517; ( f ) U. Chiacchio,
A. Corsaro, D. Iannazzo, A. Piperno, G. Romeo, R. Romeo, M. G. Saita
and A. Rescifina, Eur. J. Org. Chem., 2007, 4758; (g) Y. Zhu, S. Wen, G. Yin,
D. Hong, P. Lu and Y. Wang, Org. Lett., 2011, 13, 3553.
9 Examples of gold catalyzed cycloaddition involved with azomethine
imines: N. D. Shapiro, Y. Shi and F. D. Toste, J. Am. Chem. Soc., 2009,
131, 11654.
10 Review on gold-catalyzed cycloaddition: (a) A. M. Echavarren and
´
C. Nevado, Chem. Soc. Rev., 2004, 33, 431; (b) F. Lopez and
˜
J. L. Mascarenas, Beilstein J. Org. Chem., 2011, 7, 1075;
(c) S. Montserrat, G. Ujaque, F. Lopez, J. L. Mascarenas and
A. Lledos, Top. Curr. Chem., 2011, 302, 225; (d) D. Garayalde and
C. Nevado, ACS Catal., 2012, 2, 1462.
azomethine imine from the opposite side of the C-5 phenyl group 11 Recent reviews for phosphine mediated allenoate cycloaddition reac-
tions: (a) N. Krause and A. S. K. Hashmi, Modern Allene Chemistry,
Wiley, Weinheim, 2004; (b) L.-W. Ye, J. Zhou and Y. Tang, Chem. Soc.
Rev., 2008, 37, 1140; (c) S. Ma, Chem. Rev., 2005, 105, 2829;
to give a syn-configuration cycloadduct. Deauration via elimination
provided the [3+2] cycloadduct 3k and regenerated the cationic
gold catalyst. Steps II and III might be a concerted process to give
Z-configuration product selectivity.
(d) J. L. Methot and W. R. Roush, Adv. Synth. Catal., 2004, 346, 1035;
(e) T. M. V. D. Pinho e Melo, Curr. Org. Chem., 2009, 13, 1406.
12 The detailed optimization of the reaction conditions and determi-
nation of the relative stereochemistry of syn-3j, syn-3k and
Z-configuration of alkene group in Z-6d by NOE experiments were
shown in supporting information.
13 CCDC 907213 (4h)†.
14 Z. J. Wang, D. Benitez, E. Tkatchouk, W. A. Goddard III and
F. D. Toste, J. Am. Chem. Soc., 2010, 132, 13064.
Notes and references
‡ General procedure for the [3+2] cycloaddition reaction: a solution of
Ph3PAuCl/AgOTf (5 mol%) in dry CH2Cl2 (2 mL) with the addition of
100 mg activated 4 Å MS was stirred for three minutes. Then, N-allenyl
amide 1a (0.1 mmol) and azomethine imine 2a (0.12 mmol) were added.
The reaction mixture was stirred at rt until complete consumption of
the starting material (TLC monitoring). Concentration of the reaction
15 (a) X. Zeng, M. Soleilhavoup and G. Bertrand, Org. Lett., 2009, 11, 3166;
(b) N. Nishina and Y. Yamamoto, Tetrahedron, 2009, 65, 1799.
c
3554 Chem. Commun., 2013, 49, 3552--3554
This journal is The Royal Society of Chemistry 2013