A Catalyst-free Addition Reaction of Zinc Amide Enolates to N-Sulfonyl Imines

Full text of DOI:10.1002/bkcs.11019

Note
DOI: 10.1002/bkcs.11019
BULLETIN OF THE
S.-R. Joo et al.
KOREAN CHEMICAL SOCIETY
A Catalyst-free Addition Reaction of Zinc Amide Enolates to
N-Sulfonyl Imines
Seong-Ryu Joo,† Pyeung-Won Im,† Jong-Sung Kim,† Soo-Youl Park,‡ and Seung-Hoi Kim†,
*
†Department of Chemistry, Dankook University, Cheonan 31116, Korea.
*E-mail: kimsemail@dankook.ac.kr
‡Interface Chemistry & Engineering Research Team, Korea Research Institute of Chemical Technology,
Daejon 34114, Korea
Received June 21, 2016, Accepted October 31, 2016, Published online December 2, 2016
Keywords: Uncatalyzed-addition, Zinc amide enolates, N-sulfonyl imines, Imino-Reformatsky reaction
For the introduction of amino functionality in complex
organic molecules, nitrile and imine derivatives possessing
a carbon-nitrogen multiple bond have been frequently uti-
lized as good substrates.1 When this type of reaction was
conducted with metal enolates and imines, called the
imino-Reformatsky reaction, 3-amino amide derivatives
were efficiently obtained.2 Due to the synthetic importance
of 3-amino acid and their derivatives, this approach has
been continuously considered and utilized as an efficient
tool for the introduction of amino functionality in the
3-position of esters and amides.3 To expand the scope of
this strategy, recent studies are heavily focused on the
asymmetrical approach of the imino-Reformatsky reaction.
Regarding this subject, several attempts have been under-
taken using various reaction systems as follows:
diethylzinc,4 diethylzinc/H2O,5 dimethylzinc/Ni(0),6 Zn/
sonication,7 Zn/dibromoethane,8 and diethylzinc/Rh(cat.).9
In addition, application to a large scale production was also
disclosed.10 Despite the remarkable expansion of the
imino-Reformatsky reaction, one interesting aspect is that,
to the best of our knowledge, zinc enolates derived solely
from α-halo esters have been mainly used in the recent
progress. In contrast, a few limited examples have been
reported concerning the application of zinc enolates derived
from α-halo amide to the imino-Reformatsky reaction. In
recent years, Rodriguez-Solla and co-workers reported the
addition reaction of samarium enolates derived from both
α-halo esters and amides to imines, resulting in the synthe-
sis of β-amino esters or amides.11 In their study, the pres-
ence of SmI2 in either stoichiometric or catalytic amounts
was very critical for completion of the reaction (Figure 1).
Albeit the positive outcome of the work, it would be more
attractive if the addition of zinc enolate to imine is carried
out using a more versatile metal enolate without any addi-
tives including a metal-catalyst.
positively, yielding the expected products. Thus, we herein
describe the results and suggest an alternative synthetic
route for the preparation of 3-amino amide derivatives. The
zinc enolates used in this study were easily prepared by the
reaction of active zinc with readily available α-chloro
acetamide.12d Also, the coupling partner N-tosyl imines
were efficiently obtained through the literature protocol,
which was
a
simple condensation procedure of
p-toluenesulfonamide and sodium p-toluenesulfinate with
the corresponding aldehydes in the presence of an acid cat-
alyst at room temperature.13
In order to examine closely the feasibility of our strategy,
a zinc enolate, 2-diethylamino-2-oxoethylzinc chloride (A),
derived from the reaction of highly active zinc (Zn*) with
α-chloro-N,N-diethyl acetamide, was first reacted with
N-benzylidene-4-methylbenzenesulfonamide in THF at
refluxing temperature in the absence of any additives. The
addition reaction was monitored by gas chromatography
(GC) and/or thin layer chromatography (TLC). The reaction
took place smoothly at room temperature to produce a cou-
pling product. A more efficient conversion to the coupling
product was achieved by a simple change of reaction tem-
perature to reflux. After being stirred at a refluxing temper-
ature for 1 h, an appropriate workup procedure was
executed to afford the product, N,N-diethyl-3-(4-methylphe-
nylsulfonamido)-3-phenylpropanamide (1a), in 85% iso-
lated yield (entry 1, Table 1). More results are summarized
in Table 1. Diverse coupling reactions of A with N-(tosy-
laryl) imines functionalized with Br, CN, Cl, and NO2 were
Considering both the simplicity of the reaction and our
previous results utilizing highly active zinc metal,12 we
have decided to investigate the direct addition reaction of
zinc enolates to N-tosyl imines in the absence of any addi-
tives. To our delight, the reactions proceeded very
Figure 1. Schematic diagram of the addition reactions of zinc
enolates to imines.
Bull. Korean Chem. Soc. 2016, Vol. 37, 2084–2086
© 2016 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Wiley Online Library 2084

Note
BULLETIN OF THE
ISSN (Print) 0253-2964 | (Online) 1229-5949
KOREAN CHEMICAL SOCIETY
Table 1. Addition reaction of A with N-tosyl imines.
Table 2. Addition reaction of B with N-tosylimines.
Ts
Ts
O
O
O
O
NH
NH
Ts
Ts
no additive
N
no additive
ZnCl
N
+
ZnCl
+
N
N
24h
Ar(R)
reflux/
THF
N
R
N
h
reflux/1
THF
ArR)
1.0 eq
O
O
R
~
~
B (2.0 eq)
1a 1l
2a 2f
(2.0 eq)
1.0 eq
A
Ts
NH
Ts
Ts
Entry
Imine
Product
1a
Yielda
O
O
NH
O
NH
1
2
3
4
5
6
85
70
80
98
58
N
N
N
O
O
O
Cl
1b
Br
2a (69%)a
2b (55%)
2c (59%)
1c
Ts
Ts
NH
Ts
1d
O
NH
O
O
NH
O
N
N
1e
N
O
O
O
n
1f
69
62
n
2e (62%)
2f (72%)
2d (64%)
7
8
a
1g
Isolated yield (based on imine).
O
S
65
61
1h
1i
resulted in the formation of the desired products (2a, 2b,
and 2c, Table 2) after reacting for 24 h at reflux. Not only
alkyl but also heteroaromatic N-tosyl imine was success-
fully coupled with B to give N-tosylamino amides (2d and
2e, Table 2) in 64 and 62% isolated yields, respectively.
Imine containing a bulky substrate also underwent the
above reaction, affording 2f in 72% isolated yield.
Not only zinc enolates but also sulfonyl imines were diver-
sified using nitro aryl sulfonyl imines as well as hetero aryl
sulfonyl imines. Coupling reactions of A with various sulfo-
nyl imines were performed at the conditions used previously
in our study, resulting in the formation of amides (3a–3f)
with moderate yields. The results are summarized in Table 3.
Encouraged by the successful applications of A and B,
we tested a somewhat different type of enolate, the zinc
ester enolate (C), which was prepared using active zinc and
t-butyl chloroacetate. Zinc ester enolate was subjected to a
reaction with various aryl and alkyl N-tosyl imines under
the same conditions as above (no additives, refluxing tem-
perature in THF). Unfortunately, we found that the
expected coupling product was not obtained. Instead, the
starting material imine and several minor products were
identified even at elevated reaction temperatures.
Taking into account the fact that free amine functionality can
be readily obtained from N-tosyl amines using a simple
manipulation,14 1a was treated with lithium naphthalenide. The
β-amino amide (1aa) was obtained in 40% yield (Scheme 1).
In conclusion, we established a potential synthetic proto-
col for the preparation of β-amino amides. This work was
accomplished by the direct addition of zinc amide enolates
to N-sulfonyl imines in the absence of any metal-catalyst
under mild conditions.15 Due to the operational simplicity
of the proposed method, it can be further utilized in syn-
thetic organic chemistry. Further studies to elucidate the
scope of this approach are currently underway in our
laboratory.
9
10
57
52
1j
11
12
a
1k
1l
77
Isolated yield (based on imine).
also conducted effectively to furnish the corresponding
amides (1b–1e) in good to excellent yields (entries 2–5,
Table 1), except in the case of NO2, which had marginally
lower yield. Under the same conditions, N-(tosylalkyl) imi-
nes were also appropriate substrates to couple with A, giving
rise to amide derivatives (1f–1g) in relatively low yields
(entries 6 and 7, Table 1). Imine containing a hetero aryl
moiety was also a suitable substrate in our system (entries
8 and 9, Table 1), providing 1h and 1i in 65 and 61% yields,
respectively. Extended efforts were demonstrated with more
imines including a fused ring (entries 10–12, Table 1)
furnishing the corresponding amides 1j, 1k, and 1l.
To explore the scope of the reaction, further experiments
were conducted with 2-morpholino-2-oxoethylzinc chloride
(B), which was easily prepared using readily available
4-chloroacetylmorpholine and highly active zinc. Once
again, all of the coupling reactions were carried out in the
absence of any additional additives and progressed well at
refluxing temperature in THF to provide the anticipated
products in the range of moderate to good isolated yields.
For the completion of the coupling, an extended reaction
time was required. The results are summarized in Table 2.
Treatment of zinc enolate B with N-(tosylaryl) imines
Bull. Korean Chem. Soc. 2016, Vol. 37, 2084–2086
© 2016 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de 2085

BULLETIN OF THE
Note
KOREAN CHEMICAL SOCIETY
6. P. G. Cozzi, E. Rivalta, Angew. Chem. Int. Ed. 2005,
44, 3600.
7. T. L. March, M. R. Johnston, P. J. Duggan, Org. Lett. 2012,
14, 182.
8. A. K. Awasthi, M. L. Boys, K. J. Cain-Janicki, P. J. Colson,
W. W. Doubleday, J. E. Duran, P. N. Farid, J. Org. Chem.
2005, 70, 5387.
Table 3. Addition reaction of A with various N-sulfonyl imines.
Ar
SO2
Ar
SO2
H
O
N
HN
O
ZnCl
THF
reflux/1h
N
N
+
A (2.0 eq)
~
3a 3f
1.0 eq
9. K. Kanai, H. Wakabayashi, H. Honda, Heterocycles 2002,
58, 47.
Entry
Ar’
Product
Yield (%)a
10. J. D. Clark, G. A. Weisenburger, D. K. Anderson,
P. J. Colson, A. D. Edney, D. J. Gallagher, H. P. Kleine,
C. M. Knable, M. K. Lantz, C. M. V. Moore, J. B. Murphy,
T. E. Rogers, P. G. Ruminski, A. S. Shah, N. Storer,
B. E. Wise, Org. Process Res. Dev. 2004, 8, 51.
11. (a) H. Rodriguez-Solla, A. Diaz-Pardo, C. Concellon, V. del
Amo, Synlett. 2014, 25, 1709; (b) J. M. Concellon,
H. Rodriguez-Solla, C. Simal, Adv. Synth. Catal. 2009, 351,
1238; (c) J. M. Concellon, H. Rodriguez-Solla, C. Simal, V.
del Amo, S. Garcia-Granda, M. R. Diaz, Adv. Synth. Catal.
2009, 351, 2991.
12. Recent examples, see: (a) H. S. Jung, S. H. Kim, Tetrahedron
Lett 2015, 56, 1004; (b) H. S. Jung, S. H. Kim, Synlett. 2015,
26, 666; (c) U. S. Shin, S. R. Joo, S. H. Kim, Bull. Korean
Chem. Soc. 2015, 36, 2565; (d) H. H. Cho, S. H. Kim, Bull.
Korean Chem. Soc. 2015, 36, 1274.
13. Y. Wang, J. Song, R. Hong, H. Li, L. Deng, J. Am. Chem.
Soc. 2006, 128, 8156, and references cited in there.
14. C. H. Heathcock, T. A. Blumenkopf, K. M. Smith, J. Org.
Chem. 1989, 54, 1548.
15. Representative addition reaction with an imine; preparation of
N,N-diethyl-3-(4-methylphenylsulfonamido)-3-(4-chlorophe-
nyl)propanamide (1d); Into a 25 mL round-bottomed flask
was added 4.0 mL of 2-(diethylamino)-2-oxoethylzinc chlo-
ride (0.5 M in THF, 2.0 mmol) under an argon atmosphere.
Next, N-(4-chlorobenzylidene)-4-methylbenzenesulfonamide
(0.31 g, 1.0 mmol) dissolved in 2.0 mL of THF was slowly
added via a syringe while being stirred. The resulting mixture
was refluxed for 1 h, then cooled down to room temperature.
The reaction mixture was quenched with 3 M NH4Cl solution,
and then extracted with ethyl ether (10 mL ×3). The com-
bined organic layers were washed with saturated NaHCO3
(aq), Na2S2O3 (aq) solution and brine, and then dried over
anhydrous Na2SO4. Concentrated in vacuo to yield a crude
solid product. Recrystallization from ethyl ether afforded
0.40g of ꢀ1d in 98% isolated yield as a white solid. Mp =
134–138 C; 1H NMR (500 MHz, CDCl3): δ = 0.95 (t, J =
7.0 Hz, 3H), 1.01 (t, J = 7.0 Hz, 3H), 2.38 (s, 3H), 2.62 (dd,
J = 15.5, 5.0 Hz, 1H), 2.73 (dd, J = 15.5, 5.0 Hz, 1H), 3.03
(dq, J = 7.5, 3.0 Hz, 2H), 3.17–3.32 (m, 2H), 4.64 (dd, J =
11.0, 5.0 Hz, 1H), 7.06–7.09 (m, 3H), 7.11–7.16 (m, 4H),
7.57 (d, J = 8.5 Hz, 2H); 13C NMR (125 MHz, CDCl3): δ =
169.3, 143.1, 138.6, 137.6, 133.2, 129.3, 128.4, 128.2, 127.1,
54.5, 42.2, 40.4, 38.2, 21.5, 14.1, 12.9; HRMS Calcd for
C20H25ClN2O3S: 408.1274; Found: 408.1279.
1
2
3
4
5
6
a
p-NO2C6H4
o-NO2C6H4
2-thienyl
8-quinolyl
2-pyridyl
3a
3b
3c
3d
3e
3f
55
50
61
49
58
51
3-pyridyl
Isolated yield (based on imine).
Ts
NH2
O
HN
O
2.0 eq Li
N
N
10
%
Naphthalene
h
THF/rt/24
1a
1aa
40%
Scheme 1 Preparation of β-amino amide.
Acknowledgments. This work was supported in part by
DANKOOK ChemBio Specialization for Creative Korea
(CK)-II in 2016.
Supporting Information. Additional supporting informa-
tion is available in the online version of this article.
References
1. (a) D. Enders, U. Reinhold, Tetrahedron: Asymmetry 1997, 8,
1895; (b) R. Bloch, Chem. Rev. 1998, 98, 1407;
(c) M. Petrini, E. Torregiani, Synthesis 2007, XX, 159;
(d) A. R. Katritzky, Q. Hong, Z. Yang, J. Org. Chem. 1995,
60, 3405, and references cited therein; (e) J. Esquivias,
R. G. Arrayas, J. C. Carretero, Angew. Chem. Int. Ed. 2007,
46, 9257, and references cited therein.
2. H. Gilman, M. Speeter, J. Am. Chem. Soc. 1943, 65, 2255.
3. (a) F. A. Davis, B. Yang, J. Am. Chem. Soc. 2005, 127, 8398;
(b) G. Cardillo, C. Tomasini, Chem. Soc. Rev. 1996, XX, 117;
(c) D. Seebach, S. Abele, K. Gademann, B. Jaun, Angew.
Chem. Int. Ed. 1999, 8, 1595; (d) E. Juaristi,
V. A. Soloshonok Eds., Enantioselective Synthesis of β-Amino
Acids, Wiley-VCH, New York, 2005.
4. A. Tarui, H. Nishimura, T. Ikebata, A. Tahira, K. Sato, M. Omote,
H. Minami, Y. Miwa, A. Ando, Org. Lett. 2014, 16, 2080.
5. Y. Ukaji, S. Takenaka, Y. Horita, K. Inomata, Chem. Lett.
2001, 254.
Bull. Korean Chem. Soc. 2016, Vol. 37, 2084–2086
© 2016 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de 2086