Copper(i)-catalyzed ring-opening cyanation of cyclopropanols

Article abstract of DOI:10.1039/c7ob00627f

A copper(i)-catalyzed ring-opening cyanation of cyclopropanols was developed. The reaction provides an alternative method to achieve β-cyano ketones efficiently. This reaction exhibits good functional group compatibility under mild conditions and can be scaled up to the gram scale. Preliminary mechanistic studies suggest that the reaction might go through a free radical process.

Full text of DOI:10.1039/c7ob00627f

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Takeharu Haino et al.
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DOI: 10.1039/C7OB00627F
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Copper(I)‐catalyzedꢀring‐openingꢀcyanationꢀofꢀ
cyclopropanols†ꢀ
a,b,c
a
a
a
a
Received 00th January 20xx,
Accepted 00th January 20xx
Yi‐Si Feng, Yong‐Jin Shu, Ping Cao, Tao Xu and Hua‐Jian Xu*
DOI: 10.1039/x0xx00000x
www.rsc.org/
A copper(I)‐catalyzed ring‐opening cyanation of cyclopropanols reaction shows excellent functional‐group tolerance under mild
was developed. The reaction provides an alternative method to conditions, offering a facile route to β‐trifluoromethyl ketones.
achieve β‐cyano ketones efficiently. This reaction exhibits good Herein, we described that the copper‐catalyzed cyanation of
functional group compatibility under mild conditions and can be cyclopropanols could result in facile formation of β‐cyano ketones
(
Scheme 1b). The significance of the present study is twofold: (1)
scaled up to gram scale. Preliminary mechanistic studies suggest
the reaction might go through a free radical process.
The copper‐catalyzed ring‐opening cyanation of cyclopropanols
expand the concept of C–C bond cleavage and C–C bond formation
strategy. (2) Our study also adds a new example of cyclopropanol
transformation chemistry and offers a mild and effective method
which access to β‐cyano ketones.
β‐Substituted ketones are useful building blocks in organic
1
synthesis. Among this group, β‐cyano ketones are useful starting
2
materials to synthesize a large range of important intermediates.
Many methods have been developed to synthesize β‐cyano ketones,
such as traditional hydrocyanation of α,β‐unsaturated ketones into
3
β‐cyano ketones using HCN or KCN reagents. Recently, Xing and
3
coworkers reported unactivated C(sp )−H bond functionalization of
3
g
alkyl nitriles with terminal vinylarenes to provide γ‐ketonitrile,
featuring metal‐free, simple operations, and a broad substrate
scope. For β‐cyano ketones, it is still necessary to develop an
effective general approach.
In recent years, cyclopropanols have emerged as powerful tools
for the regioselective synthesis of β‐functionalized ketones due to Scheme 1 Copper(I)-catalyzed ring-opening cross-coupling reactions.
4
We began our investigations with the use of 1a as the probe
their unique structure. Several research groups have applied the
5
6
substrate in the presence of a catalytic amount of Cu(CH CN) PF
6
coupling
strategy
for
8the
arylation,
alkynylation,
3
4
7
9
(
10 mol %) and hypervalent iodine 2a in DCE (Table 1, entry 1). To
heterocyclization,
amination
and organofluorination
of
our surprise, the β‐cyano ketone 3a was directly formed in 30%
yield. Cheeringly, testing of different copper catalysts (Table 1,
entries 2‐6) showed that CuI can dramatically improve the yield of
cyclopropanols. For example, Chiba and coworkers described
Mn(III)‐mediated reactions of cyclopropanols with vinyl azides to
7
a,7b
synthesize heterocyclics.
Loh and coworkers disclosed iron‐ or
9
a
3a to 83% (Table 1, entry 6). However, when the reaction was
silver‐catalyzed oxidative fluorination of cyclopropanols.
In
1
0
11
conducted in other solvents such as CH CN, CH Cl , THF, 1,4‐
addition, palladium‐catalyzed or copper‐catalysed cyclopropanol
ring‐opening cross‐couplings have also been successfully applied in
construction of C–C bonds. Our group described a Cu‐catalyzed ring‐
3
2
2
dioxane, DMF or MeOH, the yields of 3a were inferior (Table 1,
entries 7–12). When the loading of catalyst or solvent be changed,
the yield decreased slightly (Table 1, entries 13–15). Furthermore, a
lower yield was obtianed at higher reaction temperature or for a
shorter reaction time (Table 1, entries 16, 17). When the reaction
time was extended to 24 hours, the yield was not improved (Table 1,
entry 18). Finally, it should be noted that no desired product of 3a
was obtained in the absence of copper catalyst (Table 1, entry 19),
and only trace amount of 3a was detected under air (Table 1, entry
1
2
opening trifluoromethylation of cyclopropanols (Scheme 1a). The
a
School of Chemistry and Chemical Engineering, School of Biological and Medical
Engineering, Hefei University of Technology, Hefei 230009, P. R. China.
Anhui Key Laboratory of Controllable Chemical Reaction and Material Chemical
b
Engineering, Hefei 230009, P. R. China. Fax: (+86)‐551‐62904405; E‐mail:
hjxu@hfut.edu.cn
c
Anhui Provincial Laboratory of Heterocyclic Chemistry, Maanshan 243110, China.
†
Electronic supplementary information (ESI) available: Experimental procedures, 20).
1 13
characterization data, and H and C NMR charts. See DOI: 10.1039/x0xx00000x
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Journal Name
a
a,b
Table 1 Optimization of the reaction conditions
Table 2 Substrate scope of cyclopropanols
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DOI: 10.1039/C7OB00627F
Time Yieldb
Entry
Catalyst
Cu(CH CN)
Solvents
T
(h)
(%)
1
2
3
4
5
6
7
8
9
3
4
PF
6
DCE
DCE
DCE
DCE
DCE
DCE
rt
rt
rt
rt
rt
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
6
30
CuTc
CuCN
CuCl
CuBr
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
‐‐
66
36
77
70
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
83(78)
15
CH
CH
THF
3
CN
2
Cl
2
77
12
10
11
12
1,4‐dioxane
DMF
MeOH
DCE
Trace
12
50
c
13
73
d
14
DCE
68
e
15
DCE
72
o
1
6
7
8
9
DCE
80 C
rt
56
a
Reaction conditions: 1a (0.2 mmol, 1 equiv), 2a (0.3 mmol, 1.5 equiv), CuI (10
1
1
1
DCE
66
mol %), DCE (0.5 mL), under a nitrogen atmosphere, at room temperature for 12
b
DCE
rt
24
12
12
81
h. Yields of isolated products are shown.
DCE
rt
NR
Trace
f
with the reaction conditions.
20
CuI
DCE
rt
We then explored the copper(I)‐catalyzed ring‐opening
cyanation of cyclopropanol for gram‐scale synthesis of 3a (Scheme
2). We decreased the amount of 2a and CuI catalyst from the
perspective of atom economy. To our delight, the reaction of 1a (10
mmol, 1.76 g) with hypervalent iodine 2a (12 mmol, 3.2 g), catalyst
CuI (5 mol %) gave the desired β‐cyano ketone (3a, 1.2 g) in 60%
yield.
a
Reaction conditions: 1a (0.2 mmol, 1 equiv), 2a (0.3 mmol, 1.5
equiv), copper catalyst (10 mol %), solvents (0.5 mL), under a
nitrogen atmosphere, at room temperature for 12 h. GC yields
with phenylacetonitrile as an internal standard, isolated yield in
parentheses. CuI (5 mol %). DCE (2 mL) DCE (1 mL). under air.
DCE = 1,2‐dichloroethane, THF = Tetrahydrofuran, DMF = N,N‐
Dimethylformamide, NR = no reaction.
b
c
d
e
f
With the optimized conditions in hand, we then studied that the
substrate scope of the copper(I)‐catalyzed ring‐opening cyanation
of cyclopropanols. We are pleased to find that the reaction can
tolerate many functional groups under mild reaction conditions
(Table 2). For aryl substituted cyclopropanols, both electron‐
donating groups such as ether (in product 3b) and electron‐ Scheme 2 Gram‐scale synthesis
withdrawing groups such as halide (in products 3c, 3d, 3e) could be
It is well known that ketones can undergo diverse
converted to the desired β‐cyano ketones in good to excellent transformations. Therefore, the products in present work can also
yields. For alkyl substituted cyclopropanols, we found that a variety be further transformed into potentially useful structural motifs
of cyclopropanols with different chain lengths could be successfully which contain a β‐cyano group. For example, carbonyl reduction
transformed to the desired products in good yields (42–78%). Many
functional groups, such as, phenyl (in product 3g), aryl ether (in
product 3o), primary and secondary TBS‐ether (in products 3l and
3
3
r), tosyl (in product 3k), epoxide (in product 3n), ester (in product
h), heterocyclic (in product 3s), trifluoromethyl (in product 3o),
chloride (in product 3p) functional groups were also compatible
Scheme 3 The reduction of the ketone group
2
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of 3a with NaBH
).
Next, we carried out radical‐inhibiting experiments to gain
insights into the reaction mechanism (Scheme 4). The reaction in
presence of a radical scavenger, such as 2,2,6,6‐tetramethylpiperi‐
dine 1‐oxyl (TEMPO), butylated hydroxytoluene (BHT), or N‐tert‐
butyl‐α‐phenylnitrone (PBN), failed to produce the desired product.
These results suggested that the reaction might go through a free
radical process under the current conditions.
4
in MeOH provided alcohol 4 in 97% yield (Scheme
2001, 3, 2591; (d) Y. Liu and Y. Zhang, J. Chem. ReVsie.w, 2A0rti0c4le,O1n6lin3e;
e) T. Lakhlifi, A. Amechrouq, M .ChouDkOraI:d1,0.M10.39E/lC. 7IdOrBis0s0i6, 2M7F.
Bouachrine, M. El. Asri and B. Laude, Phys. & Chem. News, 2007,
3, 110; (f) J. Cai, L. Liu, K. H. Hong, P. Wang, L. Li, M. Cao, C.
Sun, X. Wu, X. Zong and J. Chen, Org. Biomol. Chem., 2015, 23,
57; (g) X. W. Lan, N. X. Wang, C. B. Bai, C. L. Lan, T. Zhang, S. L.
(
3
3
6
Chen and Y. Xing, Org. Lett., 2016, 18, 5986.
4
.
.
(a) O. Kulinkovich, Chem. Rev., 2003, 103, 2597; (b) A. Orellana
and A. Nikolaev, Synthesis, 2016, 48, 1741. (c) J.‐P. Barnier, V.
Morisson and L. Blanco, Synth. Commun., 2001, 31, 349.
(a) K. Cheng and P. J. Walsh, Org. Lett., 2013, 15, 2298; (b) D.
Rosa and A. Orellana, Chem. Commun., 2013, 49, 5420; (c) X.
Zhou, S. Yu, Z. Qi, L. Kong and X. Li, J. Org. Chem., 2016, 81,
5
4
6
869; (d) X. Zhou, S. Yu, L. Kong and X. Li, ACS Catal., 2016, 6,
47.
6.
(a) R. V. Murali, N. N. Rao and J. K. Cha, Org. Lett., 2015, 17,
3854; (b) S. Wang, L. N. Guo, H. Wang and X. H. Duan, Org. Lett.,
015, 17, 4798; (c) K. Jia, F. Zhang, H. Huang and Y. Chen, J. Am.
2
Chem. Soc., 2016, 138, 1514; (d) C. Y. Wang, R. J. Song, Y. X. Xie
and J. H. Li, Synthesis, 2016, 48, 223.
7
. (a) Y. F. Wang and S. Chiba, J. Am. Chem. Soc., 2009, 131, 12570;
b) Y. F. Wang, K. K. Toh, E. P. Ng and S. Chiba, J. Am. Chem.
(
Soc., 2011, 133, 6411.
. (a)Z. Ye and M. Dai, Org. Lett., 2015, 17, 2190; (b) M. H. Shen, X.
L. Lu and H. D. Xu, RSC Adv., 2015, 5, 98757.
Scheme 4 Radical‐inhibiting experiments
8
9.
(a) S. Ren, C. Feng and T. P. Loh, Org. Biomol. Chem., 2015, 13,
Conclusions
5
105; (b) Z. Ye, K. E. Gettys, X. Shen and M. Dai, Org. Lett., 2015,
In conclusion, we have presented a novel and efficient approach
for the preparation of β‐cyano ketones via Cu(I)‐catalyzed ring‐
opening cyanation of cyclopropanols. These transformations are
easy to conduct under mild reaction conditions. Many relevant
17, 6074; (c) Y. Li, Z. Ye, T. M. Bellman, T. Chi and M. Dai, Org.
Lett., 2015, 17, 2186; (d) D. G. Kananovich, Y. A. Konik, D. M.
Zubrytski, I. Jarving and M. Lopp, Chem. Commun., 2015, 51,
8349.
functional groups can be tolerated, including phenyl, aryl ether, 10. (a) S. B. Park and J. K. Cha; Org. Lett., 2000, 2, 147; (b) C. S.
Penkett, R. O. Sims, R. French, L. Dray, S. J. Roome and P. B.
Hitchcock, Chem. Commun., 2005, 36, 1932; (c) C. S. Penkett, R.
O. Sims, P. W. Byrne, L. Kingston, R. French, L. Dray, S. Berritt, J.
Lai, A. G. Avent and P. B. Hitchcock, Tetrahedron, 2006, 62,
primary and secondary TBS‐ether, tosyl, epoxide, ester, heterocyclic,
trifluoromethyl, and chloride. Preliminary mechanistic studies
suggest that the current reaction might involve radical species. The
reaction can also be conducted on gram scale. This chemistry
demonstrates the significant potential of cyclopropanol as useful
ring‐opening cross‐coupling reactions.
3423; (d) C. S. Penkett, R. O. Sims, P. W. Byrne, S. Berritt, L. E.
Pennicott, S. P. Rushton, A. G. Avent and P. B. Hitchcock,
Tetrahedron, 2006, 62, 9403; (e) D. Rosa and A. Orellana, Org.
Lett., 2011, 13, 110; (f) D. Rosa and A. Orellana, Chem.
Commun., 2012, 48, 1922; (g) B. B. Parida, P. P. Das, M. Niocel
and J. K. Cha, Org. Lett., 2013, 15, 1780; (h) D. Rosa and A.
Orellana, Chem. Commun., 2013, 49, 5420; (i) N. Nithiy and A.
Orellana, Org. Lett., 2014, 16, 5854; (j) A. Nikolaev, N. Nithiy
and A. Orellana, Synlett, 2014, 25, 2301; (k) S. Ydhyam and J. K.
Cha, Org. Lett., 2015, 17, 5820;
We gratefully acknowledge financial support from the National
Natural Science Foundation of China (Nos. 21571047, 21472033,
21371044) and the Fundamental Research Funds for the Central
Universities. We thank Wei‐Ke Tang in this group for reproducing
the results of compounds 3d and 3o.
1
1. (a) L. Ryu, K. Matsumoto, Y. Kameyama, M. Ando, N. Kusumoto,
Notes and references
A. Ogawa, N. Kambe, S. Murai and N. Sonoda, J. Am. Chem. Soc.,
1.
(a) M. E. Jung, Tetrahedron, 1976, 32, 3; (b) R. E. Gawley,
Synthesis, 1976, 777; (c) X. Zhou, X. Xu, Z. Shi, K. Liu, H. Gao and
W. Li, Org. Biomol. Chem., 2016, 14, 5246.
1993, 115, 12330; (b) P. P. Das, K. Belmore and J. K. Cha, Angew.
Chem. Int. Ed., 2012, 51, 9517; (c) N. N. Rao, B. B. Parida and J.
K. Cha, Org. Lett., 2014, 16, 6208; (d) N. N. Rao and J. K. Cha, J.
Am. Chem. Soc., 2015, 137, 2243;(e) N. N. Rao and J. K. Cha,
Tetrahedron Letters, 2015, 56, 3298.
2.
(a) A. Gopalan, R. Lucero, H. Jacobs and K. Berryman, Synth.
Commun., 1991, 21, 1321; (b) R. Giovannini and M. Petrini,
Synlett, 1996, 1001; (c) B. A. Provencher, K. J. Bartelson, Y. Liu,
B. M. Foxman and L. Deng, Angew. Chem. Int. Ed., 2011, 50,
1
2. X. P. He, Y. J. Shu, J. J. Dai, W. M. Zhang, Y. S. Feng and H. J. Xu,
Org. Biomol. Chem., 2015, 13, 7159.
1056; (d) D. Wu and D. F. O’Shea, Org. Lett., 2013, 15, 3392; (e)
S. E. Franz, R. R. Watkins, L. A. Wright, B. A. Weaver, R. C.
Hartage, I. Ghiviriga, G. Gumina and B. D. Feske, Synthesis,
2013, 45, 2171.
3
. (a) W. Nagata and M. Yoshioka, Org. React., 1977, 25; (b) C. P. Y.
Ming and P. Knochel, Tetrahedron Lett., 1988, 29, 2395; (c) K.
Miura, N. Fujisawa, H. Saito, D. Wang and A. Hosomi, Org. Lett.,
This journal is © The Royal Society of Chemistry 20xx
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