A new and concise way to enamides by fluoroalkanosulfonyl fluoride mediated Beckmann rearrangement of α,β-unsaturated ketoximes

Article abstract of DOI:10.1016/j.tetlet.2014.10.154

The reaction of α,β-unsaturated ketoximes with fluoroalkanosulfonyl fluorides in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) underwent the Beckmann rearrangement smoothly to afford the corresponding acid-sensitive enamides in moderate to excellent yields, which provides a new efficient method for the preparation of acid-sensitive enamides.

Full text of DOI:10.1016/j.tetlet.2014.10.154

Tetrahedron Letters 55 (2014) 7186–7189
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Tetrahedron Letters
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A new and concise way to enamides by fluoroalkanosulfonyl fluoride
mediated Beckmann rearrangement of a,b-unsaturated ketoximes
a
b,
Zhaohua Yan a, , Yun Xu , Weisheng Tian
⇑
⇑
a College of Chemistry, Nanchang University, Nanchang, Jiangxi Province 330031, China
b Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction of
a,b-unsaturated ketoximes with fluoroalkanosulfonyl fluorides in the presence of
Received 7 September 2014
Revised 24 October 2014
Accepted 31 October 2014
Available online 6 November 2014
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) underwent the Beckmann rearrangement smoothly to afford
the corresponding acid-sensitive enamides in moderate to excellent yields, which provides a new
efficient method for the preparation of acid-sensitive enamides.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Enamides
a,b-Unsaturated ketoximes
Fluoroalkanosulfonyl fluorides
Beckmann rearrangement
Enamide moiety exists in a number of biological active natural
products (Fig. 1), such as TMC-95A,1 crocacin A,2 chondriamide
A,3 salicylihalamide A,4 and lansiumamide I,5 etc;6 and it is a key
subunit related to the biological activity.7 Furthermore, as versatile
organic intermediates, enamides have been widely applied in the
synthesis of pyrrole derivatives,8 functionalized pyridines,9 oxazole
make their work-up procedure very easy to handle; On the other
hand, fluoroalkanesulfonic acid salt RfSOÀ3 M+ is a class of highly
valuable surfactants. RfSO2F has been used as hydroxyl group-
activating reagent for the synthesis of fluorinated compounds from
alcohols,19 for the preparation of cis-epoxides from chiral vicinal
diols resulting in the smooth total synthesis of (À)-dehydroclausen-
amide,20 for the homoallylic carbocation rearrangement of
19-hydroxymethyl steroid leading to a total synthesis of ( )-Spinif-
erin,21 and for cyclodehydration of b-hydroxy sulfonamides and
b-hydroxy thioamides leading to smooth formation of the
corresponding aziridines and thiazolines.22 Furthermore,
fluoroalkanosulfonyl fluoride has also been successfully employed
to activate the hydroxyl group of carboxylic acid as a condensing
agent for esterification, amidation, and anhydridization.23 As a
continuation of our previous report on the abnormal Beckmann
rearrangement of steroid 17-oximes using fluoroalkanosulfonyl
fluorides,24 herein we report the Beckmann rearrangement of
derivatives,10
a-bromohemiaminal, and a
-fluorohemiaminal,11
etc.12 A variety of methods have been developed for the construc-
tion of enamide motif, including the direct acylation of imine with
acyl chloride or anhydride and the thermal decomposition of
alkylidenbisamides,13 and the condensation of carbonyl com-
pounds with amide,14 etc.15 In recent years, Pd-, Cu-, and
Rh-catalyzed cross-coupling of amides with olefins or alkynes pro-
vided promising approach for the preparation of enamides.16
Among the various methods mentioned above, the Beckmann
rearrangement of
a,b-unsaturated ketoximes represents one of
the most efficient and straightforward means for the preparation
of enamides.17 However, due to the high acid-sensitive nature of
enamides, this reaction is largely underdeveloped and only limited
examples in cyclic systems are well known.18
a,b-unsaturated ketoximes with fluoroalkanosulfonyl fluoride in
basic media to afford the corresponding acid-sensitive enamides
in moderate to excellent yields.
Fluoroalkanosulfonyl fluorides including perfluoroalkanosulfo-
nyl fluorides and polyfluoroalkanosulfonyl fluorides (RfSO2F, such
as n-C8F17SO2F, n-C4F9SO2F, HCF2CF2OCF2CF2SO2F, etc) are commer-
cially available (in bulk quantities), and cost-effective, non-toxic,
and moisture-tolerant. In the RfSO2F-mediated reactions, by-prod-
ucts are water-soluble fluoroalkanesulfonic acid anions, which
We began our studies by choosing a steroidal
a,b-unsaturated
ketoxime, (3b,5 )-3-acetyloxypregn-16-en-20-one oxime (1a), as
a
a model substrate due to which we need its enamide in our project
of the synthesis of steroidal drugs. Treatment of 1a with n-C4F9SO2
F (1.2 equiv) in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU, 1.5 equiv) in CH2Cl2 at 0 °C for 1 h gave the desired enamide
N-[(3b,5a)-3-acetyloxyandrost-16-en-17-yl]acetamide (2a) in 53%
yield (Table 1).
⇑
Corresponding authors.
http://dx.doi.org/10.1016/j.tetlet.2014.10.154
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

Z. Yan et al. / Tetrahedron Letters 55 (2014) 7186–7189
7187
HN
OH
O
HO
OCH3
O
NH
N
H
O
H3CO
OCH3
O
O
NH
N
H
O
H
N
crocacin A
HO
O
NH2
H
N
NH
O
O
O
O
O
NH
N
H
chondriamide A
TMC-95A
H
N
O
OH
O
O
N
CH3
OH
CH3
salicylihalmide A
lansiumamide I
Figure 1. Some natural products with enamide moiety.
In order to further improve the reaction efficiency, the
reaction conditions were optimized. When the molar ratio of
1a/n-C4F9SO2F/DBU was increased to 1:1.5:3.0, a higher yield of
73% was obtained. However, addition of more amounts of
n-C4F9SO2F and DBU and prolonged reaction time did not lead to
a higher yield. Next, solvent effects on the transformation were
also investigated (Table 1). Among solvents screened for the
Beckmann rearrangement, chloroform was found to be the best
choice providing 2a in 87% yield (Table 1, entry 7), and the use of
other solvents proved to be less effective providing 2a in 62–78%
yields (Table 1, entries 1–6). When pyridine was used as solvent,
no reaction occurred (Table 1, entry 8). Further optimization of
reaction temperature revealed that 0–15 °C was the best choice
(Table 1, entries 7 and 13). Lower reaction temperature than 0 °C
resulted in the incomplete conversion of 1a (Table 1, entries
9–12), and higher temperature than 15 °C caused the formation
of more amounts of by-products (Table 1, entry 14). When Et3N
was used as the base instead of DBU, 2a was afforded in 73% yield
(Table 1, entry 15). Finally, we screened other fluoroalkanosulfonyl
fluoride reagents and found that both n-C8F17SO2F and HCF2CF2
OCF2CF2SO2F possessed similar activity to that of n-C4F9SO2F. It is
noteworthy that the by-products formed in the Beckmann
rearrangement of 1a were mainly (3b,5a)-3-acetyloxy-androstan-
17-one (the decomposition product of 2a and its structure was
confirmed by comparing with the authentic sample) and unreacted
starting material 1a.
With the optimized conditions in hand, we went on to explore
the scope and limitation of the reaction, and the results are
summarized in Table 2. A range of a,b-unsaturated ketoximes were
tested for conversion to enamides. All the substrates in Table 2
proceeded the Beckmann rearrangement on treatment with
n-C4F9SO2F in the presence of DBU affording the corresponding
enamides in moderate to excellent yields. The Beckmann
rearrangement of 3b-acetyloxy-prega-5,16-dien-20-one oxime
(1b) gave the corresponding enamide product 2b in an excellent
yield of 93% (Table 2, entry 2). Boruah and co-workers25 reported
the Beckmann rearrangement of 1b with POCl3 in Pyridine to give
2b in 81% yield. However, when we repeated this reaction under
the same condition of POCl3/Pyridine, 2b was only obtained in
61% yield. The reaction of 1c with n-C4F9SO2F provided 2c in 59%
yield along with 33% of unreacted 1c (Table 2, entry 3). Acyclic ket-
oxime substrates 1d and 1e worked well to afford enamides 2d and
2e in 81% and 71% yields, respectively (Table 2, entries 4 and 5).
However acyclic ketoxime 1f furnished enamide 2f only in poor
yield of 33%, accompanied by the formation of more polar
byproduct (Table 2, entry 6), which might result from the
concurrent competitive Neber rearrangement of 1f under the same
reaction conditions due to the presence of the active CH3 group. Cyc-
Table 1
Effects of solvent, temperature, and base on Beckmann rearrangement of 1aa
H3C
OH
N
NHAc
n-C4F9SO2F
solvent
base
AcO
temperature
AcO
H
H
1a
2a
Room temperature (°C) Base Yield of 2ab (%)
Entry Solvents
1
2
3
4
5
6
7
8
Toluene
0
0
0
0
0
0
0
0
DBU 69
DBU 77
DBU 73
DBU 73
DBU 62
DBU 78
DBU 87
Ethyl ether
Dichloromethane
Tetrahydrofuran
Acetonitrile
Acetone
lic a,b-unsaturated ketoxime 1g was also tested for the Beckmann
rearrangement to form the ring-enlargement product, and indeed,
seven-membered enamide 2g was obtained as expected, albeit in
poor yield (Table 2, entry 7). Likewise, the reason for low yield of
2g probably resulted from the Neber rearrangement due to the pres-
ence of the active methylene group. The Beckmann rearrangement
of two heteroarene substrates 1h and 1i also worked well and the
corresponding enamide products 2h and 2i were formed in 75%
and 65% yields, respectively (Table 2, entries 8 and 9).
To further evaluate the application of the above mentioned
method, 2d was treated with iodomethane in the presence of
NaH in THF at room temperature, affording the naturally occurring
enamide Lansiumamide-I5 3 in 90% yield (Scheme 1).
Chloroform
Pyridine
DBU
0
9
Chloroform
Chloroform
Chloroform
Chloroform
Chloroform
Chloroform
Chloroform
À40
À20
À10
À5
15
25
0
DBU 63
DBU 73
DBU 74
DBU 76
DBU 86
DBU 62
Et3N 73
10
11
12
13
14
15
a
Reaction conditions: 1a (1.0 mmol), n-C4F9SO2F (1.5 mmol), and DBU
(3.0 mmol) in solvent at different temperatures for 1 h.
b
Isolated yields.

7188
Z. Yan et al. / Tetrahedron Letters 55 (2014) 7186–7189
Table 2
RfSO2F-induced Beckmann rearrangement of
a
,b-unsaturated ketoximesa
OH
R2
H
N
n-C4F9SO2F
R2
N
R1
R1
DBU, CHCl3
O
0 o
C
1
2
Entry
Substrates
Products
Yield of 2b (%)
H3C
NHAc
NHAc
OH
N
1
87
AcO
H
2a
2b
AcO
H
1a
1b
H3C
OH
N
2
3
93
59
AcO
AcO
H3C
NHAc
OH
N
OMe
2c
OMe
N
1c
OH
H
N
Ph
Ph
Ph
Ph
4
5
6
81
71
33
Ph
Ph
Ph
1d
O
2d
OH
H
N
N
N
Ph
Ph
O
O
1e
2e
CH3
OH
H
N
Ph
CH
3 1f
2f
OH
O
N
CH3
CH2
H3C
HN
7c
31
CH3
H3C
2g
CH2
1g
O
S
S
8
9
75
65
N
H
S
N
OH
OH
S
1h
1i
2h
O
O
O
N
H
O
N
O
2i
a
b
c
Reaction conditions: 1 (1.0 mmol), n-C4F9SO2F (1.5 mmol), and DBU (3.0 mmol) in CHCl3 at 0 °C for 1 h.
Isolated yields.
Compound 1g (1.0 mmol), n-C4F9SO2F (3.0 mmol), and DBU (6.0 mmol).
C-16 oxygen functionalization of steroidal D-ring is a funda-
mental reaction in organic synthesis. 16a-acetyloxy-17-ketones
can be prepared through a-halogenation of 17-ketones and subse-
CH3
N
H
CH3I
N
Ph
Ph
Ph
Ph
NaH, THF
O
O
quent hydrolysis, or via the formation of enol acetate of 17-ketones
25 o
90%
C
2d
3 ( Lansiumamide-I )
followed by epoxidation with peracids.26 In order to investigate the
application of enamides in the synthesis of steroidal 16a-acetyl-
Scheme 1. The preparation of Lansiumamide-I (3) from 2d.
oxy-17-ketones, we tentatively studied the one-pot procedure for
the preparation of 4 starting from 1a (Scheme 2). A few of epoxida-
tion agents and systems were screened to effect the epoxidation of
2a including m-CPBA/Na2HPO4, m-CPBA/K2CO3, m-CPBA/NaHCO3,
dimethyldioxirane, and n-C4F9SO2F/H2O2/NaOH. Among them,
m-CPBA/K2CO3 system led to the best result with the formation
of 4 in 45% overall yield for two steps from 1a after purification
via silica gel column chromatography. It was presumed that the

Z. Yan et al. / Tetrahedron Letters 55 (2014) 7186–7189
7189
OH
N
O
silica gel column
chromatography
NHAc
O
OAc
m-CPBA
n-C4F9SO2F
DBU
NaHCO3
AcO
H
AcO
4 (45% overall yield)
H
1a
HO
HN
NH
NH
HN
O
OH
HN
HO
O
O
OAc
OAc
HO
Scheme 2. The ring D functionalization of 1a.
Zi, Y.; Xu, X.-P.; Wang, S.-Y.; Ji, S.-J. Tetrahedron 2013, 69, 1600; (d) Xu, Y.-H.;
He, T.; Zhang, Q.-C.; Loh, T.-P. Chem. Commun. 2014, 2784.
formation of 4 may result from the opening of the epoxide ring and
the migration of the 17-acetyl group in the course of silica gel col-
umn chromatography induced by the weak acidity of silica gel26
(Scheme 2). Therefore our method can also be efficiently applied
in the C-16 oxygen functionalization of steroidal D-ring.
9. Zhao, M.-N.; Ren, Z.-H.; Wang, Y.-Y.; Guan, Z.-H. Chem. Commun. 2012, 8105.
10. (a) Cheung, C. W.; Buchwald, S. L. J. Org. Chem. 2012, 77, 7526; (b) Zheng, Y.; Li,
X.; Ren, C.; Zhang-Negrerie, D.; Du, Y.; Zhao, K. J. Org. Chem. 2012, 77, 10353.
11. (a) Honjo, T.; Phipps, R. J.; Rauniyar, V.; Toste, F. D. Angew. Chem., Int. Ed. 2012,
51, 9684; (b) Nocquet-Thibault, S.; Retailleau, P.; Cariou, K.; Dodd, R. H. Org.
Lett. 2013, 15, 1842; (c) Nocquet-Thibault, S.; Minard, C.; Retailleau, P.; Cariou,
K.; Dodd, R. H. Tetrahedron 2014, 70, 6769.
In summary, we have developed a system of fluoroalkanosulfo-
nyl fluorides and base media mediated Beckmann rearrangement
12. (a) Lei, C.-H.; Wang, D.-X.; Zhao, L.; Zhu, J.; Wang, M.-X. Chem. Eur. J. 2013, 19,
16981; (b) Poittevin, C.; Liautard, V.; Beniazza, R.; Robert, F.; Landais, Y. Org.
Lett. 2013, 15, 2814; (c) Taber, D. F.; DeMatteo, P. W. J. Org. Chem. 2012, 77,
4235; (d) Gou, Q.; Deng, B.; Zhang, H.; Qin, J. Org. Lett. 2013, 15, 4604; (e)
Bekkaye, M.; Masson, G. Org. Lett. 2014, 16, 1510; (f) Gigant, N.; Gillaizeau, I.
Org. Lett. 2012, 14, 3304; (g) Huo, C.; Kang, L.; Xu, X.; Jia, X.; Wang, X.; Yuan, Y.;
Xie, H. Tetrahedron 2014, 70, 1055.
of
a,b-unsaturated ketoximes leading to the smooth formation of
the corresponding acid-sensitive enamides in moderate to excel-
lent yields.27 This protocol is mild and operationally simple, thus
providing an efficient method for the preparation of enamides.
Our results further extend the application of fluoroalkanosulfonyl
fluorides in organic synthesis.
13. (a) Lenz, G. R. Synthesis 1978, 489; (b) Dov, B.-I.; Reuven, G. Tetrahedron Lett.
1965, 50, 4523.
14. (a) Couture, A.; Deniau, E.; Grandclaudon, P. Tetrahedron Lett. 1993, 34, 1479;
(b) Wang, X.; Porco, J. A., Jr. J. Org. Chem. 2001, 66, 8215.
Acknowledgments
15. (a) Bayer, A.; Maier, M. E. Tetrahedron 2004, 60, 6665; (b) Wang, L.; Liu, C.; Bai,
R.; Pan, Y.; Lei, A. Chem. Commun. 2013, 7923; (c) Tang, W.; Capacci, A.;
Sarvestani, M.; Wei, X.; Yee, N. K.; Senanayake, C. H. J. Org. Chem. 2009, 74,
9528; (d) Nicolaou, K. C.; Mathison, C. J. N. Angew. Chem., Int. Ed. 2005, 44,
5992; (e) Chun, Y. S.; Ko, Y. O.; Shin, H.; Lee, S.-G. Org. Lett. 2009, 11, 3414.
16. (a) Panda, N.; Jena, A. K.; Raghavender, M. ACS Catal. 2012, 2, 539; (b) Liu, H.;
Zhou, Y.; Yan, X.; Chen, C.; Liu, Q.; Xi, C. Org. Lett. 2013, 15, 5174; (c) Panda, N.;
Mothkuri, R. J. Org. Chem. 2012, 77, 9407; (c) Feng, C.; Loh, T.-P. Org. Lett. 2014,
16, 3444.
We thank The National Natural Science Foundation of China
(21362022) and Key Laboratory of Synthetic Chemistry of Natural
Substances, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences, for financial supports.
Supplementary data
17. Gawly, R. E. Org. React. 1988, 35, 1. and references cited therein.
18. (a) Sato, T.; Wakatsuka, H.; Amano, K. Tetrahedron 1971, 27, 5381; (b)
Koval’skaya, S. S.; Kozlov, N. G. Russ. J. Org. Chem. 2006, 42, 1151.
19. (a) Bennua-Skalmowski, B.; Vorbrugen, H. Tetrahedron Lett. 1995, 36, 2677; (b)
Yin, J.; Zarkowsky, D. S.; Thomas, D. W.; Zhao, M. M.; Huffman, M. A. Org. Lett.
2004, 6, 1465; (c) Vorbrugen, H. Synthesis 2008, 1165.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.
10.154.
20. Yan, Z.; Wang, J.; Tian, W. Tetrahedron Lett. 2003, 44, 9383.
21. (a) Tian, W.-S.; Lei, Z.; Chen, L.; Huang, Y. J. Fluorine Chem. 2000, 101, 305; (b)
Sun, Y.-S.; Ding, K.; Tian, W.-S. Chem. Commun. 2011, 10437.
References and notes
22. Yan, Z.; Guan, C.; Yu, Z.; Tian, W. Tetrahedron Lett. 2013, 54, 5788.
23. Yan, Z.; Tian, W.; Zeng, F.; Dai, Y. Tetrahedron Lett. 2009, 50, 2727.
24. Gui, J.; Wang, Y.; Tian, H.; Gao, Y.; Tian, W. Tetrahedron Lett. 2014, 55, 4233.
25. Boruah, R. C.; Ahmed, S.; Sharma, U.; Sandhu, J. S. Indian J. Chem., Sect B Org.
Med. Chem. 1999, 38, 274.
1. Kohno, J.; Koguchi, Y.; Nishio, M.; Nakao, K.; Kuroda, M.; Shimizu, R.; Ohnuki,
T.; Komatsubara, S. J. Org. Chem. 2000, 65, 990.
2. Jansen, R.; Washausen, P.; Kunze, B.; Reichenbach, H.; Hofle, G. Eur. J. Org. Chem.
1999, 1085.
3. Palermo, J. A.; Flower, P. B.; Seldes, A. M. Tetrahedron Lett. 1992, 33, 3097.
4. Erickson, K. L.; Beutler, J. A.; Cardellina, J. H., II; Boyd, M. R. J. Org. Chem. 1997,
62, 8188.
26. (a) Leeds, N. S.; Fukushima, D. K.; Gallagher, T. F. J. Am. Chem. Soc. 1954, 76, 2943;
(b) Numazawa, M.; Ogata, M.; Abiko, K.; Nagaoka, M. Steroids 1985, 45, 403.
27. General procedure for the Beckmann rearrangement of
mediated by fluoroalkanosulfonyl fluorides RfSO2F in basic media: Under nitrogen
atmosphere, solution of (3.0 mmol) and n-C4F9SO2F (4.5 mmol) in
a,b-unsaturated ketoximes
5. (a) Lin, J.-H. Phytochemistry 1989, 28, 621; (b) Prakash, D.; Raj, K.; Kapil, R. S.;
Popli, S. P. Indian J. Chem., Sect B 1980, 19, 1075.
6. (a) Lin, H.-Y.; Chen, C. H.; You, B. J.; Lin, K. C. S. C.; Le, S.-S. J. Nat. Prod. 2000, 63,
1338; (b) Joullie, M. M.; Richard, D. J. Chem. Commun. 2004, 2011;
(c) Winn, M.; Goss, R. J. M.; Kimura, K. I.; Bugg, T. D. H. Nat. Prod. Rep. 2010,
27, 279.
7. Wu, Y.; Liao, X.; Wang, R.; Xie, X.-S.; De Brabander, J. K. J. Am. Chem. Soc. 2003,
124, 3245.
8. (a) Li, B.; Wang, N.; Liang, Y.; Xu, S.; Wang, B. Org. Lett. 2013, 15, 136; (b) Zhao,
M.-N.; Ren, Z.-H.; Wang, Y.-Y.; Guan, Z.-H. Org. Lett. 2014, 16, 608; (c) Xu, H.-Y.;
a
1
chloroform (20 mL) was stirred for 10 min at 0 °C. Then DBU (9.0 mmol) was
slowly added dropwise. The resulting mixture was continued to stir at 0 °C for
10–30 min. Evaporation of the reaction mixture under reduced pressure to
remove volatile components generated residue which was purified through
basic Al2O3 column chromatography using mixture of petroleum ether and
ethyl acetate as an eluent, providing the corresponding enamide products 2 in
the yields of 31–93%.