Synthesis of spiroaminals by bimetallic Au/Sc relay catalysis: TMS as a traceless controlling group

Article abstract of DOI:10.1039/c4cc05610h

An efficient synthesis of spiroaminals over fused aminals has been successfully developed by bimetallic Au/Sc catalysis by using TMS as a traceless controlling group. This journal is

Full text of DOI:10.1039/c4cc05610h

ChemComm
View Article Online
View Journal
COMMUNICATION
Synthesis of spiroaminals by bimetallic Au/Sc relay
catalysis: TMS as a traceless controlling group†
Cite this:DOI: 10.1039/c4cc05610h
Shuo Zhang,a Zhengliang Xu,a Jiong Jia,*a Chen-Ho Tungab and Zhenghu Xu*a
Received 21st July 2014,
Accepted 15th August 2014
DOI: 10.1039/c4cc05610h
www.rsc.org/chemcomm
An efficient synthesis of spiroaminals over fused aminals has been
successfully developed by bimetallic Au/Sc catalysis by using TMS
as a traceless controlling group.
Multicomponent tandem reactions have been developed as the
most efficient synthetic strategy to build up molecular complexity
and diversity in shortest reaction steps.1 How to control reaction
selectivity, including chemoselectivity and stereoselectivity, to
get the target products over undesired isomers, is the most
essential issue in these reactions. Thus the switchable synthesis2
of different products from the same or similar starting materials
is very interesting, but very difficult, which not only maximizes
the diverse utility of reactants but also benefits the understanding
of the reaction mechanism. For example, the Carreira group
reported the elegant controllable synthesis of all the four stereo-
isomers by the rationale of combination of different primary
amine catalysts with different iridium complexes.3 The product
Scheme 1 Au/M(OTf)3 relay catalysis for the synthesis of aminals.
distribution, diastereoselectivity, and sometimes even enantio- which not only tuned the reaction to the desired pathway, but
selectivity could be tuned by using different transition metals4a also disappeared spontaneously, without further manipulation
or ligands,4b adding different additives or bases,4c–e and varying (Scheme 1).
the reaction temperatures4f or solvents.4g In 2013, the Luo group
Recently we reported an efficient gold/Lewis acid relay cata-
developed the switchable synthesis of endo- or exo-diastereomers lytic methodology toward fused bicyclic aminals by combining
using different Lewis acids in enantioselective [4+2] cycloaddition p-acid gold catalysis with another s metal Lewis acid.6,7 It was a
reactions.4a The Tang group reported the tunable carbonyl ylide gold-catalyzed intramolecular hydroamination cyclization that
reactions for the selective synthesis of dihydrofurans and dihydro- generated enamide M1, which isomerized into more stabilized
benzoxepines by choosing the appropriate ligands.4b Apart from internal enamide M2, and then reacted with another Lewis-acid
the above mentioned control of reaction pathways by catalysts activated electrophile through an inverse-electron-demand
or reaction conditions, we reported another strategy by using hetero-Diels–Alder (IED-HDA) reaction to produce the fused
a trimethylsilyl (TMS) group as a traceless controlling group,5 bicyclic aminals, instead of the spiroaminals as the original
plan. Spiroaminals containing natural products and bioactive
molecules show important biological activities, and are of special
importance for biological and synthetic chemists. Thus we
decided to finely tune the reaction conditions to trap enamide
M1 before its isomerization to get the spiroaminals over its fused
isomer. Different p-acid catalysts and s metal Lewis acids were
screened in different solvents. However, all these reactions exhi-
bited poor selectivities for the two isomers. Therefore a silicon
protecting group was installed on the terminal alkyne, and it was
a Key Lab for Colloid and Interface Chemistry of Education Ministry, School of
Chemistry and Chemical Engineering, Shandong University, Jinan 250100,
People’s Republic of China. E-mail: xuzh@sdu.edu.cn, jiongjia@sdu.edu.cn
b Key Laboratory of Photochemical Conversion and Optoelectronic Materials,
Technical Institute of Physics and Chemistry, Chinese Academy of Sciences,
Beijing 100190, P. R. China
† Electronic supplementary information (ESI) available: Detailed experimental
procedures and analytical data. CCDC 1013252 (4a). For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c4cc05610h
This journal is ©The Royal Society of Chemistry 2014
Chem. Commun.

View Article Online
Communication
ChemComm
Table 1 Silicon group as the directing group to control reaction pathways
Entrya Substrate Time
Conversion% Yield%b (4a) Yield%b (3a)
1
2
3
1b
1c
1b
1b
1b
1b
3 hours 100
3 hours
10 min 100
48 hours 100
10 min 100
40
0
83
22
0
34
0
8
56
0
0
0
Scheme 2 Kinetic and thermodynamic balance experiments.
4
5c
6d
10 min
0
0
Table 2 Substrate scope of the selective synthesis of spiroaminalsa
a
Reaction conditions: alkyne
1 (0.2 mmol), 2a (0.22 mmol),
b
PPh3AuNTf2 (5 mol%), Sc(OTf)3 (10 mol%), CH3CN (1 mL). Isolated
yield. Only PPh3AuNTf2 (5 mol%). Only Sc(OTf)3 (10 mol%).
c
d
anticipated that the electronic effect of silicon could stabilize the
derived enamide M3 to inhibit its isomerization (Scheme 1).
To test this hypothesis, two silicon protected alkyne amines
1b and 1c were synthesized according to the known procedure.
After a detailed screening of different gold catalysts and different
s metal Lewis acids, PPh3AuNTf2 and Sc(OTf)3 were found to be
the best partners in this reaction (for details, see ESI†).The
alkyne amine 1b bearing a TMS group was subjected to this
cascade reaction at 60 1C for 3 h. To our surprise, we did not get
any silicon containing products, but a mixture of spiro-isomer 4a
and fused isomer 3a in 40% and 34% isolated yields, respectively
(Table 1, entry 1). The reaction with only the Sc(OTf)3 catalyst
showed no desilylation product and the initial 1b remained
unreactive (entry 6). These results demonstrated that there was
a fast gold-catalyzed desilylation or silicon–gold transmetalation
process9 under these conditions and the original proposal on the
formation of enamide M3 was not possible. Then we carried out
the cyclization of silicon amine 1b using PPh3AuNTf2; no cycliza-
tion product M3 was produced, but the enamide dimerization
or oligomerization products acted as amine 1a in previous reac-
tions.6,8 Switching from the labile TMS group to the more stable
a
Reaction conditions: alkyne 1 (0.2 mmol), 2 (0.22 mmol), PPh3AuNTf2
(5 mol%), Sc(OTf)3 (10 mol%), CH3CN (1 mL); isolated yield of spiro-
aminals 4 is indicated in parentheses.
TBS group (tert-butyldimethyl silyl), alkyne 1c became very inert Table 2. Various unsaturated keto-esters bearing different
and remained intact under these conditions (Table 1, entry 2). aromatic substituents at the g-position reacted smoothly with
During optimization, we noted that the distribution of products alkyne amine 1b to give the spiro-N,O-aminal 4 in good to
was greatly influenced by reaction time, and actually the reaction excellent yields in less than 10 minutes. In these reactions, the
was very fast and completed in 10 minutes. The reaction was chemoselectivity and diastereoselectivity are very good. There
quenched rapidly and the target spiroaminal 4a was isolated in were very trace amounts of fused isomers on TLC and only
83% yield with a very good ratio of 4a/3a (10.5/1, entry 3). For endo-isomers of spiroaminal 4 were detected. The structure and
comparison, a 48 hours reaction was conducted and the ratio of the relative configuration of 4a were confirmed by X-ray analysis.
4a/3a changed to 1/2.6 and fused isomer 3a was the major product Substrates with different ester groups, either electron-withdrawing
(entry 4). Further studies showed that 4a could be transformed into or electron-donating groups, are all suitable substrates, giving the
3a in 68% yield with 4a recovered in 15% yield (Scheme 2, eqn (1)). spiro-aminals in good yields (4a–4e). Different functional groups
The reaction of 4a with another ketone ester 2b gave the fused such as halogens, CN, styryl, and OMe are all tolerated under these
products 3a and 3b in 53% and 15% yields, respectively (Scheme 2, conditions. The extention of this reaction to heterocyclic substrates
eqn (2)). These results clearly indicate that spiro-isomer 4a is the was also successful, and 2-thienylaminal 4i and 2-furylaminal
kinetic product and fused isomer 3a is the thermodynamic product, 4j in 85% and 78% yields were obtained, respectively. Another
and 4a could convert into 3a through retro Diels–Alder reaction, gem-diphenyl alkyne amine 1d was also synthesized to test its
isomerization, and the Diels–Alder reaction sequence.
reactivity. It also reacted efficiently with different electrophiles
With the optimal conditions established, we examined the with great chemoselectivity and stereoselectivity to furnish the
scope of this transformation and the results are summarized in corresponding spiroaminals in 82–89% yield (4l–n). However, the
Chem. Commun.
This journal is ©The Royal Society of Chemistry 2014

View Article Online
ChemComm
Communication
the reaction was performed at very low catalyst loading, the
desilylation intermediate M4 did not form a digold complex,
but went through protodeauration to form the desilylation
product 1a, which would generate fused products through the
M1–M2 sequence as our previous reaction (path B). The relative
inert reactivity of gem-diaurated species have been proved by
Gagne,12a and in this work, it was utilized to stabilize the exocyclic
´
double bond to tune the selectivity.
In summary, a highly efficient selective synthesis of spiro-
aminals was developed by introducing a small TMS group.
More importantly, the directing group disappeared in situ with-
out a further deprotection step. A very interesting kinetic–
thermodynamic balance was observed in this reaction and a
binuclear gold catalysis was proposed to explain the reaction
mechanism. A detailed study of the mechanism such as isola-
tion of gold intermediates is underway in our laboratory.
We are grateful for financial support from the Natural
Science Foundation of China (Grant No. 21102085), the funda-
mental research and subject construction funds of Shandong
University (No. 2014JC008, 104.205.2.5).
Scheme 3 Experiments at low catalyst loading.
reaction of alkyne amine 1e with one more carbon was not
successful; the desilylation product 5 was isolated in 80% yield
in 10 minutes (Scheme 3, eqn (1)).
All the above reactions were completed in 10 minutes, thus
making us to consider whether we could lower the catalyst loading.
The elegant work from Nolan10 and Shi7e has demonstrated that the
homogeneous gold catalyst could be decreased to the ppm level. At
the outset, keeping the loading of Sc(OTf)3 constant, when the
loading of the Au catalyst decreased to 1 mol%, the spiro-aminal 4a
was isolated in 67% yield in 10 min; however the chemoselectivity
decreased from previous 10.5/1 to 5/1 (Scheme 3, eqn (2), entry 1).
Upon further decreasing the loading to 0.1 mol%, amazingly, the
reaction still completed in 10 min, but the chemoselectivity further
decreased to 1.2/1 (Scheme 3, entry 2). In addition, trying to reduce
the amount of Sc(OTf)3 was not successful (entry 3).
Based on these experiments and previous reports, a dinuclear
gold catalysis mechanism is proposed in Scheme 4. Since
Houk and Toste proposed the dinuclear gold catalysis for the
first time in 2008,11 many digold s,p-acetylide complexes and
gem-diaurated complexes have been synthesized and charac-
terized by X-ray analysis.12 Recently the Hashmi group and
others have developed a series of elegant chemistry based on
digold catalysis.13 In this reaction, at the relatively elevated
temperature, the gold catalyst serve as the s acid first to form
the gold acetylide M4 through silicon gold transmetalation. When
there are more gold catalysts, they would coordinate with the
alkyne to form the digold s,p-acetylide complex M5, and lead to
intramolecular nucleophilic attack forming the gem-diaurated
intermediate M6, and subsequent slow proton deauration and
fast cyclization would form spiro-isomer 4 (path A). However when
Notes and references
´
1 For reviews, see (a) B. B. Toure and D. G. Hall, Chem. Rev., 2009,
109, 4439; (b) J. D. Sunderhaus and S. F. Martin, Chem. – Eur. J.,
2009, 15, 1300.
2 For reviews, see (a) M. P. Sibi and M. Liu, Curr. Org. Chem., 2001,
´
5, 719; (b) M. Bartok, Chem. Rev., 2010, 110, 1663.
3 S. Krautwald, D. Sarlah, M. A. Schafroth and E. M. Carreira, Science,
2013, 340, 1065.
4 (a) J. Lv, L. Zhang, S. Luo and J.-P. Cheng, Angew. Chem., Int. Ed.,
2013, 52, 9786; (b) J.-L. Zhou, Y. Liang, C. Deng, H. Zhou, Z. Wang,
X.-L. Sun, J. Zheng, Z.-Y. Yu and Y. Tang, Angew. Chem., Int. Ed.,
2011, 51, 7874; (c) S. Ye, L. Yuan, Z. Huang, Y. Tang and L.-X. Dai,
J. Org. Chem., 2000, 65, 6257; (d) W. Liao, K. Li and Y. Tang, J. Am.
Chem. Soc., 2003, 125, 13030; (e) L. Ye, X.-L. Sun, C. Zhu and Y. Tang,
Org. Lett., 2006, 8, 3853; ( f ) Z. Huang, Y. Kang, J. Zhou, M. Ye and
Y. Tang, Org. Lett., 2004, 6, 1677; (g) J. Zhou, M. Ye, Z. Huang and
Y. Tang, J. Org. Chem., 2004, 69, 1309.
5 (a) A. H. Hoveyda, D. A. Evans and G. C. Fu, Chem. Rev., 1993,
93, 1307; (b) S. H. Cho and J. F. hartwig, Chem. Sci., 2014, 5, 694;
(c) C. Wang and H. Ge, Chem. – Eur. J., 2011, 17, 14371; (d) C. Huang,
B. Chattopadhyay and V. Gevorgyan, J. Am. Chem. Soc., 2011,
133, 12406.
6 (a) X. Wang, Z. Yao, S. Dong, F. Wei, H. Wang and Z. Xu, Org. Lett.,
2013, 15, 2234; (b) X. Wang, S. Dong, Z. Yao, L. Feng, P. Daka,
H. Wang and Z. Xu, Org. Lett., 2014, 16, 22.
7 (a) Y. Wang, L. Liu and L. Zhang, Chem. Sci., 2013, 4, 739; (b) M. Egi,
Y. Yamaguchi, N. Fujiwara and S. Akai, Org. Lett., 2008, 10, 1867;
(c) L. Ye and L. Zhang, Org. Lett., 2009, 11, 3646; (d) A. S. Demir,
M. Emrullahoglu and K. Buran, Chem. Commun., 2010, 46, 8032;
(e) Y. Xi, D. Wang, X. Ye, N. G. Akhmedov, J. L. Petersen and X. Shi,
Org. Lett., 2014, 16, 306; ( f ) Y. Xi, B. Dong, E. J. McClain, Q. Wang,
T. L. Gregg, J. L. Petersen and X. Shi, Angew. Chem., Int. Ed., 2014,
53, 4657; (g) Y. Shi, K. E. Roth, S. D. Ramgren and S. A. Blum, J. Am.
Chem. Soc., 2009, 131, 18022; (h) A. S. K. Hashmi, C. Lothschu¨tz,
¨
R. Dopp, M. Rudolph, T. D. Ramamurthi and F. Rominger, Angew.
Chem., Int. Ed., 2009, 48, 8243; (i) T. Lauterbach, M. Livendahl,
´
A. Rosellon, P. Espinet and A. M. Echavarren, Org. Lett., 2010, 12, 3006.
8 For dimerization of enamide, see: Y. Yu, C. Shu, T. Li and L. Ye,
Chem. – Asian J., 2013, 8, 2920.
9 For silicon–gold transmetallation, see: (a) S. Dupuy, A. M. Z. Slawin
and S. P. Nolan, Chem. – Eur. J., 2012, 18, 14923; (b) M. Michalska,
O. Songis, C. Taillier, S. P. Bew and V. Dalla, Adv. Synth. Catal., 2014,
356, 2040.
´
10 N. Marion, R. S. Ramon and S. P. Nolan, J. Am. Chem. Soc., 2009,
Scheme 4 Proposed digold participated mechanism.
131, 448.
This journal is ©The Royal Society of Chemistry 2014
Chem. Commun.

View Article Online
Communication
ChemComm
11 P. H. Y. Cheong, P. Morganelli, M. R. Luzung, K. N. Houk and
2013, 19, 3547; ( j) H. Schmidbaur and A. Schier, Chem. Soc. Rev.,
2012, 41, 370.
F. D. Toste, J. Am. Chem. Soc., 2008, 130, 4517.
´
´
´
12 (a) D. Weber, M. A. Tarselli and M. R. Gagne, Angew. Chem., Int. Ed., 13 For reviews, see: (a) A. Gomez-Suarez and S. P. Nolan, Angew. Chem., Int.
2009, 48, 5733; (b) G. Seidel, C. W. lehmann and A. Fu¨rster, Angew.
Chem., Int. Ed., 2010, 49, 8466; (c) T. N. Hooper, M. Green and
C. A. Russel, Chem. Commun., 2010, 46, 2313; (d) T. J. Brown and
R. A. Widenhoefer, Organometallics, 2011, 30, 6003; (e) D. Weber,
Ed., 2012, 51, 8156; (b) I. Braun, A. M. Asiri and A. S. K. Hashmi, ACS
Catal., 2013, 3, 1902; (c) A. S. K. Hashmi, Acc. Chem. Res., 2014, 47, 864.
For recent examples, see: (d) A. Odabachian, X. F. Le Goff and F. Gagosz,
¨
Chem. – Eur. J., 2009, 15, 8966; (e) A. S. K. Hashmi, I. Braun, P. Nosel,
´
¨
T. D. Jones, L. L. Adduci and M. R. Gagne, Angew. Chem., Int. Ed.,
J. Schadlich, M. Wieteck, M. Rudolph and F. Rominger, Angew. Chem.,
´
2012, 51, 2452; ( f ) T. J. Brown, D. Weber, M. R. Gagne and
Int. Ed., 2012, 51, 4456; ( f ) L. Ye, Y. Wang, D. H. Aue and L. Zhang, J. Am.
¨
R. A. Widenhoefer, J. Am. Chem. Soc., 2012, 134, 9134;
Chem. Soc., 2012, 134, 31; (g) A. S. K. Hashmi, T. Lauterbach, P. Nosel,
(g) J. E. heckler, M. Zeller, A. D. Hunter and T. G. Gray, Angew.
M. H. Vilhelmsen, M. Rudolph and F. Rominger, Chem. – Eur. J., 2013,
19, 1058; (h) A. S. K. Hashmi, I. Braun, M. Rudolph and F. Rominger,
Organometallics, 2012, 31, 644; (i) M. H. Vilhelmsen and A. S. K. Hashmi,
Chem. – Eur. J., 2014, 20, 1901.
´
´
Chem., Int. Ed., 2012, 51, 5924; (h) A. Gomez-Suarez, S. Dupuy,
A. M. Z. Slawin and S. P. Nolan, Angew. Chem., Int. Ed., 2013,
52, 938; (i) C. Obradors and A. M. Echavarren, Chem. – Eur. J.,
Chem. Commun.
This journal is ©The Royal Society of Chemistry 2014