CuBr for KA2 reaction: En route to propargylic amines bearing a quaternary carbon center

Article abstract of DOI:10.1039/c3cc45301d

A highly efficient CuBr-catalyzed coupling of ketones, amines and alkynes (KA²) forming propargylic amines bearing a quaternary carbon center with the broadest scope so far has been developed.

Full text of DOI:10.1039/c3cc45301d

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CuBr for KA2 Reaction: En Route to Propargylic Amines Bearing a
Quaternary Carbon Center
†
Xinjun Tang,a Jinqiang Kuang,a Xue Zhang,a and Shengming Ma*a,
b
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
o
toluene with stirring at 100 C for 3 h afforded the propargylic
50 amine 4a in 88% yield (Table 1, entry 1)! Other solvents gave
lower yields (Table 1, entries 2ꢀ4). When we used CuCl as
catalyst, the yield was improved to 98% (Table 1, entry 5)! To
our delight, a quantative yield was obtained when CuBr was
applied (Table 1, entry 6). Further screening led to the
55 observation that this catalytic protocol is highly efficient: 1.5
mol% of CuBr is enough to produce 4a in a quantative yield
within 1 h (Table 1, entry 9)! Further reducing the reaction time
led to a lower yield (Table 1, entry 10). When we changed the
ratio of the starting material, the yield dropped (Table 1, entry
60 11). Thus, 1a (1 equiv), 2a (1.1 equiv), 3a (1.1 equiv), CuBr (1.5
A highly efficient CuBr-catalyzed coupling of ketones, amines
and alkynes (KA2) forming propargylic amines bearing a
quaternary carbon center with so far the broadest scope has
been developed.
10 Propargylic amines are important and useful building blocks in
the synthesis of natural products and bioactive compounds.1 The
most straight forward wellꢀestablished approach is the direct
couplings of aldehydeꢀamineꢀalkyne (A3) forming secondary
propargylic amines.2,3 However, the threeꢀcomponent couplings
15 of ketoneꢀamineꢀalkyne (KA2) have been largely underdeveloped
due to the extremely lower reactivity of ketones observed in this
reaction.4 The most commonly used catalysts are copper based:5ꢀ9
For example, Larsen et al. reported only one example that
relatively expensive and inconvenient Cu(OTf)2 (10 mol%) could
20 catalyze the reaction of 1ꢀoctyne, cyclohexanone and benzylꢀ
amine to afford the corresponding propargylic amine in 80%
yield;5 CuCl2 has also been used as the catalyst, however, the
ketones must be activated by the addition of 50 mol% of Ti(OEt)4
with a very slow reaction rate;6 Ramón et al. utilized Cu(OH)xꢀ
25 Fe3O4 for such a transformation of phenylacetylene with 3ꢀ
pentanone or acetophenone and hexahydroꢀpyridine yielding the
propargylic amines in very low yields (29ꢀ38% yields) taking 7
days.7 As a comparsion, Cu(I) seems much less active: Van der
Eychen et al. applied CuI (20 mol%) to yield the proparglic
30 amine in 30% yield from the single reaction of phenylacetylene,
acetone and PMBꢀNH2, which should be conducted under the
mediation of microwave.8 Thus, the challenge remains in the
extremely narrow scope of the ketones, slow reaction rate, and
large amounts of reagents applied. Remarkably, screening of
35 cheap Cu(I) catalysts and solvents in this laboratory revealed that
this reaction is indeed particularly rapid and efficient just with
CuBr as the catalyst in toluene. Herein, we wish to report a highly
efficient CuBrꢀcatalyzed coupling of ketones, amines and alkynes
forming propargylic amines bearing a quaternary carbon center
40 with a most broad scope.
mol%) and 4 Å MS (300 mg•mLꢀ1) in toluene at 100 C were
defined as the optimized reaction conditions for further study.
o
Table 1 Optimization of Reaction Conditions: the Reaction of
65 Alkyne 1a, Ketone 2a and Pyrrolidine 3a a
Entry
1
CuX
CuI
CuI
CuI
CuI
CuCl
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
x (mol%)
10
t (h)
3
3
3
3
3
3
3
3
Yield of 4a(%)f
88
87
83
75
2b
3c
4d
5
10
10
10
10
98
6
7
8
9
10
100
100
92
100
95
1.5
0.5
1.5
1.5
1.5
1
0.5
1
10
11e
85
a The reaction was conducted using alkyne (1.0 mmol), ketone
(1.1 mmol), amine (1.1 mmol) and 4 Å MS (300 mg) at 100 oC in
1 mL of toluene. b 1 mL of dioxane was used instead of toluene. c
70 1 mL of DMF was used instead of toluene. d 1 mL of DMSO was
e
Our initial work began with phenylacetylene 1a, a rather
challenging acyclic 2ꢀhexanone 2a4 and pyrrolidine 3a under the
catalysis of Cu(I). For the purpose of removing the inꢀsitu formed
45 water in the step of ketiminium formation, 4 Å molecular sieves
(MS) were added. After numerous trials, we were happy to find
that the reaction of 1a (1 equiv), 2a (1.1 equiv), 3a (1.1 equiv)
and CuI (10 mol%) in the presence of 4 Å MS (300 mg•mLꢀ1) in
used instead of toluene. Alkyne (1.0 mmol), ketone (1.0 mmol)
and amine (1.0 mmol) were used. Determined by 1H NMR
f
analysis using mesitylene as the internal standard.
75
The scope of the reaction was then investigated by using the
optimal reaction conditions (Table 2). Phenylacetylene 1a and its
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3
analogues substituted by pꢀMeO, pꢀBr, mꢀBr, oꢀCl groups all
7
ꢀ(CH2)5ꢀ (2h)
93 (4o)
35 a The reaction was conducted using alkyne 1a (10 mmol), ketones
2 (11 mmol), pyrrolidine 3a (11 mmol), CuBr (1.5 mol%) and 4
Å MS (3 g) at 100 oC in 10 mL of toluene. b CuBr (5 mol%) was
used.
afforded excellent yields of the products (Table 2, entries 1ꢀ5).
The reaction could also be extended to terminal alkylꢀsubstituted
alkynes such as 1ꢀoctyne 1f, which gave the product in 85% yield
(Table 2, entry 6). Moreover, terminal propargylic alcohol 1g and
protected propargylic alcohol 1h are also suitable for this reaction
yielding products 4g and 4h in 86% and 78% yields, respectively,
showing the functionalityꢀtolerance ability of this protocol (Table
2, entries 7 and 8). The hydroxyl group and TBS protected
5
40
The reaction may also be extended to other cyclic amines such
as morphine and piperidine with relatively lower yields (Scheme
1). Other acyclic amines, such as benzylamine and dibenzylamine,
do not work under the current reaction condition, indicating the
effect of amine on this protocol.
10 hydroxyl group of the propargylic amines 4g and 4h could be
easily converted into other functional groups, which demonstrate
the potential of this method.
Table 2 The Scope of Terminal Alkynesa
15
Entry
R1 (1)
Ph (1a)
4ꢀMeOC6H4 (1b)
4ꢀBrC6H4 (1c)
3ꢀBrC6H4 (1d)
2ꢀClC6H4 (1e)
nꢀHex (1f)
t (h)
1
3.5
3
1.5
1
4
Isolated Yield of 4 (%)
92 (4a)
86 (4b)
87 (4c)
90 (4d)
92 (4e)
85 (4f)
86 (4g)
78 (4h)
45
1
2
3
4
5
6
7
8
Scheme 1 Cyclic Amines in KA2 Reaction
.
It is worthwhile to note that aromatic ketones, which are totally
inactive in the recently reported methods,6 also work in this
protocol: with 10 mol% of CuBr the corresponding product 4r
50 was formed in 46% yield (Eq. 1). 7
HO(Me)2CH (1g)
TBSOCH2 (1h)
2
4
a
The reaction was conducted using alkynes 1 (10 mmol), 2ꢀ
hexanone 2a (11 mmol), pyrrolidine 3a (11 mmol), CuBr (1.5
mol%) and 4 Å MS (3 g) at 100 oC in 10 mL of toluene. TBS = tertꢀ
butyldimethylsilyl.
It is easy to conduct the reaction on 50 mmol scale in benzene
to afford 4a and 4g in 92% and 95% yields just using a Deanꢀ
Stark trap to remove the inꢀsitu formed water in the step of
55 ketiminium formation (Scheme 2), thus, the addition of the
molecular sieves is not necessary in any large scale practical
application.
20
Encouraged by these results we further investigated a range of
different ketones with phenylacetylene 1a as the standard alkyne.
The reaction showed
a very broad substrate scope: not
surprisingly, methyl ketones, such as 2ꢀbutanone 2b, 2ꢀoctanone
25 2c, benzylacetone 2d and 3ꢀmethylꢀ2ꢀbutanone 2e all afforded
propargylic amines 4iꢀ4l in 80~89% yields (Table 3, entries 1ꢀ4);
the reaction of ethyl ketone also worked (Table 3, entry 5); even
with heptaneꢀ4ꢀone 2g, the yield of propargylic amine 4n is 66%
although 5% of CuBr was applied (Table 3, entry 6); when
30 cyclohexanone 2h was used, the corresponding product 4o was
yielded in 93% (Table 3, entry 7).
Scheme 2 Approach to Propargylic Amine (4) on 50 mmol Scale
60 Using a DeanꢀStark Trap.
Table 3 The Scope of Unactivated Ketones and Aminesa
Conclusions
In summary, we have developed a highly efficient CuBrꢀ
catalyzed direct coupling of unactivated ketones, amines and
alkynes to form propargylic amines bearing a quaternary carbon
65 center. The mild reaction conditions, the broad scope of the
substrates and the high efficiency of the reaction show the
potentially synthetic utility of this method.10ꢀ12 Further studies
including the asymmetric studies and the application of the
propargylic amines are being conducted in our laboratory.
Entry R2, R3
t (h) Isolated Yield
of 4 (%)
2
1
Me, Et (2b)
87 (4i)
86 (4j)
89 (4k)
80 (4l)
84 (4m)
66 (4n)
1.5
2
2
Me, nꢀC6H13 (2c)
3
4
Me, CH2CH2Ph (2d)
Me, iꢀPr (2e)
2.5
2.5
8
70 Acknowledgements
5
6b
Et, (CH2)2CH3 (2f)
CH3(CH2)2, (CH2)2CH3 (2g)
Financial support from National Basic Research Program
2
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35
2008, 350, 1503. (c) S. B. Park, H. Alper, Chem. Commun. 2005,
1315. (d) C. Wei, C. ꢀJ. Li, J. Am. Chem. Soc. 2003, 125, 9584. (e) C.
ꢀJ. Li, C. Wei, Chem. Commun. 2002, 268. (f) S. Sakaguchi, T. Kubo,
Y. Ishii, Angew. Chem. Int. Ed. 2001, 40, 2534. (g) N. Gommermann,
C. Koradin, K. Polborn, P. Knochel, Angew. Chem. Int. Ed. 2003, 42,
5763. (h) N. Gommermann, P. Knochel, Chem. Commun. 2004,
2324. (i) N. Gommermann, P. Knochel, Chem. Commun. 2005, 4175.
(j) N. Gommermann, P. Knochel, Chem. Eur. J. 2006, 12, 4380. (k)
P. Aschwanden, C. R. J. Stephenson, E. M. Carreira. Org. Lett. 2006,
8, 2437. (l) V. K. ꢀY. Lo, Y. Liu, M. ꢀKin. Wong, C. ꢀM. Che, Org.
Lett. 2006, 8, 1529.
(2011CB808700) and National Natural Science Foundation of
China (21232006). We thank Mr. Rong Zeng of our research
group for reproducing the results presented in entry 8 in Table 2,
entry 6 in Table 3 and Eq. 5.
40
45
50
55
60
65
70
5
Notes and references
a State Key Laboratory of Organometallic Chemistry, Shanghai Institute
of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Lu,
Shanghai 200032, P. R. China
b Shanghai Key Laboratory of Green Chemistry and Chemical Process,
4
5
6
J. P. Guthrie, Can. J. Chem. 1975, 53, 898.
10 Department of Chemistry, East China Normal University, 3663 North
Zhongshan Road, Shanghai 200062, P.R. China
Fax: (+86)-21-6260-9305; e-mail: masm@sioc.ac.cn
C. E. Meyet, C. J. Pierce, C. H. Larsen, Org. Lett. 2012, 14, 964.
For CuCl2ꢀcatalyzed reaction with 0.5 equiv of Ti(OEt)4, see: C. J.
Pierce, M. Nguyen, C. H. Larsen, Angew. Chem. Int. Ed. 2012, 51,
12289.
For the only example using acetophenone, see: M. J. Aliaga, D. J.
Ramón, M. Yus, Org. Biomol. Chem. 2010, 8, 43.
†
Electronic supplementary information (ESI) available: The
1
7
8
9
experimental procedures, characterization data, and copies of H and 13C
15 NMR spectra for all products. For ESI or other electronic format see DOI:
O. P. Pereshivko, V. A. Peshkov, E. V. Van der Eycken, Org. Lett.
2010, 12, 2638.
1
(a) G. S. Kauffman, G. D. Harris, R. L. Dorow, B. R. P. Stone, R. L.
Parsons, J. A. Pesti, N. A. Magnus, J. M. Fortunak, P. N. Confalone,
W. A. Nugent, Org. Lett. 2000, 2, 3119. (b) M. A. Huffman, N.
Yasuda, A. E. DeCamp, E. J. J. Grabowski, J. Org. Chem. 1995, 60,
1590. (c) C. W. Ryan, C. Ainsworth, J. Org. Chem. 1961, 26, 1547.
(d) K. Yamada, K. Tomioka, Chem. Rev. 2008, 108, 2874. (e) K.
Mihara, T. Aoki, A. Moriguchi, H. Yamamoto, M. Maeda, N. Tojo,
T. Yamanaka, M. Ohkubo, N. Matsuoka, J. Seki, S. Mutoh, Drug
Development Research, 2004, 61, 233. (f) B. Jiang, Y. ꢀG. Si, Angew.
Chem. Int. Ed. 2004, 43, 216. (g) J. Clayden, M. Donnard, J. Lefranc,
D. J. Tetlow, Chem. Commun. 2011, 47, 4624.
For AuBr3ꢀcatalyzed KA2 reaction, see: M. Cheng, Q. Zhang, X. ꢀY.
Hu, B. ꢀG. Li, J. ꢀX. Ji, A. S. C. Chan, Adv. Synth. Catal. 2011, 353,
1274..
20
25
30
10 (a) J. Ye, S. Li, B. Chen, W. Fan, J. Kuang, J. Liu, Y. Liu, B. Miao,
B. Wan, Y. Wang, X. Xie, Q. Yu, W. Yuan, S. Ma, Org. Lett. 2012,
14, 1346. (b) J. Kuang, S. Ma, J. Am. Chem. Soc. 2010, 132, 1786.
11 J. Ye, W. Fan, S. Ma, Chem. Eur. J. 2013, 19, 716.
12 (a) V. K. ꢀY. Lo, C. ꢀY. Zhou, M. ꢀK. Wong, C. ꢀM. Che, Chem.
Commun. 2010, 46, 213. (b) V. K. ꢀY. Lo, M. ꢀK. Wong, C. ꢀM. Che,
Org. Lett. 2008, 10, 517. (c) V. K. ꢀY. Lo, Y. Liu, M. ꢀK. Wong, C. ꢀ
M. Che, Org. Lett. 2006, 8, 1529. (d) H. Nakamura, T. Kamakura, M.
Ishikura, J. ꢀF. Biellmann, J. Am. Chem. Soc. 2004, 126, 5958. (e) H.
Nakamura, S. Tashiro, T. Kamakura, Tetrahedron Lett. 2005, 46,
8333. (f) M. Periasamy, N. Sanjeevakumar, M. Dalai, R.
Gurubrahamam, P. O. Reddy, Org. Lett. 2012, 14, 2923.
2
3
For Reviews, see: (a) B. M. Trost, A. H. W, Adv. Synth. Catal. 2009,
351, 963. (b) L. Zani, C. Bolm, Chem. Commun. 2006, 4263. (c) C.
Wei, Z. Li, C. ꢀJ. Li, Synlett. 2004, 9, 1472. (d) W. ꢀJ. Yoo, L. Zhao,
C. ꢀJ. Li, Aldrichimica Acta 2011, 44, 43. (e) G. Blay, A. Monleón,
J. R. Pedro, Curr. Org. Chem. 2009, 13, 1498. (f) C. ꢀJ. Li, Acc.
Chem. Res. 2009, 42, 335.
(a) J. B. Bariwal, D, S. Ermolat’ev, E. V. Van der Eychen, Chem.
Eur. J. 2010, 16, 3281. (b) W. ꢀJ. Yoo, C. ꢀJ. Li, Adv. Synth. Catal.
This journal is © The Royal Society of Chemistry [year]
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