Evidence for an umpolung type of [2+2] cycloaddition of 2-carbamoyl ketenes

Article abstract of DOI:10.1039/c7nj00830a

Ketenes generated during the thermal decomposition of 5-[(N-aryl/alkylamino)(hydroxyl)methylene]-2,2-dimethyl-1,3-dioxa-4,6-diones react with highly electrophilic iminium ions. The initial [2+2] cycloaddition product rearranges to 2-arylidene malonamide.

Full text of DOI:10.1039/c7nj00830a

View Article Online
View Journal
NJC
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: A. Zakaszewska, E.
Najda and S. Makowiec, New J. Chem., 2017, DOI: 10.1039/C7NJ00830A.
This is an Accepted Manuscript, which has been through the
Volume 40 Number
1 January 2016 Pages 1–846
Royal Society of Chemistry peer review process and has been
accepted for publication.
NJC
Accepted Manuscripts are published online shortly after
New Journal of Chemistry
www.rsc.org/njc
A journal for new directions in chemistry
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
ISSN 1144-0546
PAPER
Jason B. Benedict et al.
The role of atropisomers on the photo-reactivity and fatigue of
diarylethene-based metal–organic frameworks
rsc.li/njc

Please do not adjust margins
New Journal of Chemistry
Page 1 of 4
View Article Online
DOI: 10.1039/C7NJ00830A
Journal Name
COMMUNICATION
Evidence for umpolung type of [2+2] cycloaddition of 2-carbamoyl
ketenes
Anna Zakaszewska, Ewelina Najda-Mocarska and Sławomir Makowiec*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Ketenes generated during thermal decomposition of 5-[(N- reaction mechanism is the stepwise nucleophilic addition of
aryl/alkylamino)(hydroxyl)methylene]-2,2-dimethyl-1,3-dioxa-4,6- imine to ketene, which forms zwitterionic intermediate [20].
diones react with highly electrophilic iminium ions. The initial Depending on the experimental procedure and the order of
[2+2] cycloaddition product rearrange to 2-arylidene malonamide.
Mechanistic aspects of the process are presented.
addition of the reagent, acyl chloride can react with imine
even before the formation of ketene, however, it implies the
formation of the same zwitterionic product that is generated
consequently to nucleophilic attack of imine [21].
In organic chemistry β-lactams have
a well-established
position. They were first synthesized by Staudinger [1], and
even after more than 100 years have passed, compounds
containing 2-azetidinone fragment are being extensively
studied. This is not only because of their antimicrobial
properties [2–4] but also because of their other medicinal
value, for instance, they inhibit cholesterol transporter in the
treatment of hypercholesterolemia [5–10]. In addition they
have a purely synthetic application with reference to Ojima et
all’s Synthon Method [11] in the synthesis of amino acids [12],
hydroxyl acids [13] and peptides [14].
Despite the fact that various methods have been developed to
synthesize β-lactam [15], the classical Staudinger ketene–imine
cycloaddition remains the most useful method to the
formation of 2-azetidinones. Ketenes are the elimination
product formed from the activated derivatives of carboxylic
acids. Acyl chlorides are frequently used to generate ketenes
as they are readily available [16]. However, other more
advanced methods to activate carboxylic acids have also been
developed [4].
Electrophilic addition to ketenes has been previously reported
on few examples [22]. However, a better known–approach
was introduced by Wynberg [23] and later by Lectka [24], in
which a nucleophilic auxiliary was added to ketene to form
nucleophilic ketene–enolate adduct, which reacts with
electrophile. This idea was further developed and applied to
broaden the scope of ketene reaction, which allows the
conversion of ketenes to nucleophilic species [25]. Our
research has focused on the reactivity of ketenes thermally
generated from 5-[(N-aryl/alkylamino)(hydroxyl)methylene]-
2,2-dimethyl-1,3-dioxane-4,6-diones (1) with nucleophilic
agents [26–29]. In case of these acyl ketenes, a commonly
observed way of reaction reported by different research
groups, is nucleophilic attack on carbonyl carbon of previously
formed ketene (2) (Scheme 1) [30–36].
In the reactivity of 1 we have observed some discrepancies
and irregularities. First of all, we observed different
distribution of the products depending on the reaction
condition. When HCl was present in the reaction mixture
composed of 1 with R1 = Ar and imine (3), 2-azetidinone (4)
was formed as the primary product.
Ketenes are ambiphilic, with a large contribution of carbonyl
carbon in the LUMO and a large contribution of α-carbon at
the HOMO orbitals, thus ketene can act as either a nucleophile
or an eletrophile [17]. In addition to the concerted reactions
[18], a number of studies have demonstrated the electrophilic
properties of ketenes [19].
In case of ketene–imine cycloaddition, a commonly accepted
a. Department of Organic Chemistry, Faculty of Chemistry, Gdansk University of
Technology Narutowicza 11/12, 80-233 Gdansk, Poland. E-mail: mak@pg.gda.pl;
Tel: +48-58-347-2883
Scheme 1 Typical reactivity of carbamoyl Meldrum’s acid.
Electronic
Supplementary
Information
(ESI)
available:
Spectroscopic
characterization of compounds 1c,f, 8aa-aa’-gc,gc’. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
New Journal of Chemistry
Page 2 of 4
COMMUNICATION
Journal Name
View Article Online
DOI: 10.1039/C7NJ00830A
Scheme 2 Cycloaddition [4+2] and [2+2] of imines to 2- Scheme 4 Plausible reaction mechanism for formation of
oxoketenes generated from 1. unsaturated malonamide.
Performing the reaction without saturation with HCl led to the 1 with R1 = Alk (the most basic among acyl derivative of
formation of 1,3-oxazine-5-carbamoyl-4,6-diones (5) [28] Meldrum’s acid) do not form β-lactam products at all.
(Scheme 2). Similar products distribution was observed by However, for the protonated imine 3’, there still cannot be
Watanabe et al and Kato in case of 5-acyl-2,2-dimethyl-1,3- completely excluded nucleophilic attack of imine 3 which exist
dioxane-4,6-diones [35].
in equilibrium. Therefore, we decided to check reaction of 1
However, when the reaction was performed with 1 where R1 =
Alk,, only 1,3-oxazine-5-carbamoyl-4,6-diones (5) were formed
with tertiary iminum salt 3’ (R4 = alkyl), to exclude the
existence
of
nucleophilic
imine.
Thus
5-[N-(3-
regardless of the application of HCl, however, we obtained chlorophenyl)(hydroxyl)methylene]-2,2-dimethyl-1,3-dioxane-
better yields without the addotion of HCl in the reaction 4,6-dione (1a) was heated in boiling chlorobenzene with
mixture [28].
excess of N-benzylidene-N-methylmethanaminium chloride
The aforementioned experimental facts are difficult to explain (3’a). The primary products isolated from the reaction mixture
on the basis of classical model of reactivity between acyl were two isomeric unsaturated malonamides 8aa, 8aa’ with
ketenes and imines, where acyl ketene plays the role of 95% yield. It is obvious, in case of R3 = alkyl, that intermediate
electrophile. Watanabe suggested, without experimental
7
cannot form stable 2-azetidinone ring, and after
confirmation, that protonation of imine may cause preferential intramolecular β-elimination, unsaturated malonamides 8, 8’
bond formation between carbonyl carbon of ketene and imine are formed (Scheme 4). Encouraged with the results of this
and formation of 2-azetidinone [35b]. To elucidate the preliminary experiment, we expanded our research to a wider
reaction mechanism, we propose the following hypothesis range of models; their results are presented in the table 1.
(Scheme 3): 1 under pyrolytic condition lose acetone to form Structure of the formed product, as well as high yields, clearly
carboxylic-ketene (6) which in the presence of strong acid support our hypothesis. Yields obtained are approximately 20–
undergoes fast decarboxylation to ketene 2. At the crucial step 40% percent higher than in analogous reaction performed with
nucleophilic attack of 2 onto protonated imine 3’ led to the protonated iminum salts [26, 29] as
a result of high
formation of intermediate 7 and after ring closure finally to β- concentration of permanent electrophile. In contrast to the
lactam. Such an assumption explains the reason of formation reaction with iminium hydrochloride, we noticed that
of β-lactam rings only in the presence of HCl as well as the fact alkylcarbamoyl ketenes also react smoothly with iminium ion to
that
produce malonamides 8gc, 8’gc (Table 1, Entry 13). This
seeming contradiction, with cited experiments [26, 28] can be
explained by taking into consideration the acidity of reaction
medium and basicity of acyl ketenes. Alkylcarbamoyl
derivatives have the highest basicity among all used acylketene
models, thus in a strongly acidic solution of HCl in toluene not
only imine is protonated but also ketene. Protonated ketene is
less capable to nucleophilic attack; therefore, we were not
able to obtain β-lactam with alkylcarbamoyl side chain [26]. In
the present process, alkylcarbamoyl ketene can react without
obstacles with tertiary iminium ion.
Scheme
3 Electrophilic addition of iminium salt to 2-
oxoketene.
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 3 of 4
New Journal of Chemistry
Please do not adjust margins
Journal Name
COMMUNICATION
View Article Online
DOI: 10.1039/C7NJ00830A
Table 1. Reaction of 5-[(N-aryl/alkylamino)(hydroxyl)methylene]-2,2-dimethyl-1,3-dioxa-4,6-diones 1 with iminium salts 3’.
Run
1
2
3
4
5
6
7
8
1
a
a
a
b
b
b
c
d
e
f
a
f
R1
3-ClC6H4
3-ClC6H4
3-ClC6H4
Ph
3’
a
b
c
a
b
c
a
b
c
a
d
d
c
R2
Ph
4-MeC6H4
2-ClC6H4
Ph
4-MeC6H4
2-ClC6H4
Ph
4-MeC6H4
2-ClC6H4
Ph
R3
R4
8, 8’
aa
ab
ac
ba
bb
bc
ca
db
ec
fa
ad
fd
gc
8 : 8’ ratio
1.16
1.31
1
Yield [%]
95
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
97
89
80
85
74
95
57
80
91
68
77
89
0.95
0.7
1
2.39
0.73
1
1.33
1.61
1.45
3
Ph
Ph
4-MeC6H4
4-MeOC6H4
4-NO2C6H4
4-FC6H4
3-ClC6H4
4-FC6H4
Et
9
10
11
12
13
Ph
Ph
2-ClC6H4
–(CH2)5–
–(CH2)5–
g
CH3
CH3
For the final confirmation of our hypothesis we had to verify However, especially in the case of secondary amines, reaction
the formation of malonamides (8, 8’) during alternative rates and yield are lower unless TMSCl was used as an
processes (Scheme 5). Traces of water can hydrolyze iminium activator. We performed an independent control experiment
salt and produce equimolar amount of amine and aldehyde between dimethyl amine hydrochloride and 1a in boiling
(Scheme 5, equation a). Carbamoyl ketene (2) may react with chlorobenzene for 2 h, and we obtained N1-(3-chlorophenyl)-
amine and form malonamide (9), which in subsequent reaction N3,N3-dimethylmalonamide (9) but with only 45% yield
can condense with aldehyde and give unsaturated (Scheme 5, equation b). In addition, we checked if 9 can
malonamides (8, 8’). The reaction of amines with carbamoyl condense with benzaldehyde. After 4 h we did not observe any
ketenes proceed and has been studied in our laboratory [27].
traces of malonamides (8aa, 8’aa) in the reaction mixture
(Scheme 5, equation c). These facts exclude the first
alternative reaction path. Considering the potential reaction
paths, Mannich like process ― malonamide condensation with
iminium salt 3 (Scheme 5, equation d) cannot be ignored [37].
To test such a possibility, we run reaction of 9 in boiling
chlorobenzene with N-benzylidene-N-methylmethanaminium
chloride (3’a). Consequently, we obtained malonamides 8aa
and 8’aa but with only 20% yield. At this point, it should be
noted, that Kurt et al performed series of multicomponent
macrocyclization reactions with the application of acyl
Medrum’s acids derivatives and Eschenmoser’s salt and amine.
However, they did not observe nucleophilic reaction of acyl
ketenes with Eschenmoser’s salt leading to the migration of
dialkyl amine moiety. Only classical electrophilic reaction of
acyl ketene with amine and subsequent Mannich condensation
with Eschenmoser’s salt were observed [37].
The last possible alternative reaction pathway is [2+2]
cycloaddition of ketene (2) with aldehyde leading to formation
of lactone (10) and its subsequent ring opening with amine
(Scheme 5, equation e). We run an experiment to verify such a
possibility. In the reaction of 1 eq of 1b with 2 eq of benzoic
aldehyde in boiling chlorobenzene, as a main product we
Scheme
5
Excluded alternative reaction pathways for isolated N1,N3-diphenylmalonamide (11) with 93% yield and
formation of unsaturated malonamides (8, 8’).
traces of acetanilide.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
New Journal of Chemistry
Page 4 of 4
COMMUNICATION
Journal Name
Lett., 2009, 11, 3858, e) J. M. Pons, M. Oblin, A.VPieowmAmrticileerO,nMline.
Rajzmann and D. Liotard, J. Am. Chem.DSOoIc:.1,01.1909379/,C171N9J,030383303A.
20 a) A. D. Allen and T. T. Tidwell, Eur. J. Org. Chem. 2012, 6,
1081, b) Y. Liang, L. Jiao, S. Zhang, Z. X. Yu and J. Xu, J. Am.
Chem. Soc., 2009, 131, 1542; c) L. Jiao, Y. Liang and J. Xu, J.
Am. Chem. Soc. 2006, 128, 6060; d) L. Jiao, Q. Zhang, Y.
Liang, S. Zhang, and J. Xu, J. Org. Chem., 2006, 71, 815.
21 a) Y. Wang, Y. Liang, L. Jiao, D. M. Du and J. Xu, J. Org. Chem.,
2006, 71, 6983, b) B. Li, Y. Wang, D. M. Du and J. Xu, J. Org.
Chem., 2007, 72, 990; c) J. E. Lynch, S. M. Riseman, W. L.
Laswell, D. M. Tschaen, R. P. Volante, G. B. Smith and I.
Shinkai, J. Org. Chem., 1989, 54, 3792; G. I. Georg and Z. Wu,
Tetrahedron Lett. 1994, 35, 381,
22 a) C. D. Hurd and R. D. Kimbrough, J. Am. Chem. Soc., 1961,
83, 236, b) A. T. Blomquist, R. W. Holley and O. J. Sweeting,
Tetrahedron, 1947, 69, 2356, c) M. Komatsu, N. Harada, H.
Kashiwagi, Y. Oshiro and T. Agawa, Phosphorus Sulfur, 1983,
16, 119.
23 H. Wynberg and E. G. J. Staring, J. Am. Chem. Soc. 1982, 104,
166.
24 a) A. E. Taggi, A. M. Hafez, H. Wack, B. Young, D. Ferraris and
T. Lectka, J. Am. Chem. Soc., 2002, 124, 6626, b) S. France, A.
Weatherwax, A. E. Taggi and T. Lectka, Acc, Chem. Res. 2004,
37, 592, c) C. R. Pitts and T. Lectka, Chem. Rev., 2014, 114,
7930.
25 a) C. Zhu, X. Shen and S. G. Nelson, J. Am. Chem. Soc., 2004,
126, 5352; b) M. A. Calter, O. A. Tretyak, C. Flaschenriem,
Org. Lett. 2005, 7, 1809; c) X. Shen, A. S. Wasmuth, J. Zhao,
C. Zhu, S. G. Nelson, J. Am. Chem. Soc. 2006, 128, 7438, d) B.
L. Hodus and G. C. Fu, J. Am. Chem. Soc., 2002, 124, 1578;
26 K. Janikowska, N. Pawelska and S. Makowiec, Synthesis,
2011, 1, 69.
In summary, to the best of our knowledge we have
demonstrated the first example of evident electrophilic
addition of iminium ions to acylketenes thermally generated
from
5-[(N-aryl/alkylamino)(hydroxyl)methylene]-2,2-
dimethyl-1,3-dioxane-4,6-diones. Mechanistic insights gained
through series of control experiments clearly support our
hypothesis. Pseudo [2+2] cycloaddition process consists of two
steps: nucleophilic addition of ketene to iminium ion and
subsequent intramolecular β-elimination leading to the
unsaturated malonamides. In the near perspective, we are
planning to find practical application for the discovered
process.
Notes and references
1
H. Staudinger, Justus Liebigs Ann. Chem., 1907, 356, 51
A. Bruggink, Synthesis of b-Lactam Antibiotics: Chemistry,
Biocatalysis and Process Integration; Kluwer Academic
Publishers: Dordrecht, 2001.
a) R. B. Morin and M. Gorman, Chemistry and Biology of β-
lactam Antibiotics, Academic Press: New York, 1982; b) J. F.
Fisher, S. O. Meroueh and S. Mobashery, Chem. Rev. 2005,
105, 395.
G. I. Georg, The Organic Chemistry of β-Lactams, VCH, New
York, 1993.
2
3
4
5
6
J. L. Betters, and L. Yu, Clin. Pharm. Ther. 2010, 87, 117.
a) E. K. Gupta, and M. K. Ito, Heart Dis. 2002, 4, 399-409; b) J.
W. Clader, J. Med. Chem. 2004, 47, 1.
7
8
9
S. B. Rosenblum, T. Huynh, A. Afonso, H. R. Davis, N. Yumibe,
J. W. Clader, and D. A. Burnett, J. Med. Chem., 1998, 41, 973.
S. Karlsson and J. H. Sorensen, Org. Process Res. Dev., 2012,
16, 586-594.
W. Kramer, D. Corsiero, F. Girbig and G. Jähne, Biochim.
Biophys. Acta 2006, 1, 45.
27 a) K. Janikowska, S. Makowiec and J. Rachoń, Helv. Chim.
Acta, 2013, 96, 978; b) K. Janikowska and S. Makowiec,
Synth. Commun., 2012, 42, 975.
28 S. Makowiec, E. Najda and K. Janikowska, J. Heterocyclic
Chem., 2015, 52, 205.
29 A. Zakaszewska, E. Najda and S. Makowiec, New. J. Chem.,
2016, 40, 6546.
10 G. L. Wisler, US patent 20120071458 A1, 22 March 2012.
11 I. Ojima, Acc. Chem. Res. 1995, 28, 383.
30 a) H. Emtenäs, L. Alderin and F. Almqvist, J. Org. Chem.,
2001, 66, 6756; b) N. Pemberton, L. Jakobsson and F.
Almqvist, Org. Lett., 2006, 8, 935, c) N. Pemberton, H.
Emtenäs, D. Boström, P. J. Domaille, W. A. Greenberg, M. D.
Levin, Z. Zhu and F. Almqvist, Org. Lett., 2005, 7, 1019.
31 F. Xu, J. D. Armstrong III, G. X. Zhou, B. Simmons, D. Hughes,
Z. Ge, E. J. Grabowski, J. Am. Chem. Soc. 2004, 126, 13002.
32 L. F. Tietze, A. Steinmetz and F. Balkenhohl, Bioorg. Med.
Chem. Lett. 1997, 10, 1303
33 A. D’Annibale, A. Pesce, S. Resta and C. Trogolo, Tetrahedron
Lett., 1996, 37, 7429
34 a) M. Sato, N. Yoneda and C. Kaneko, Chem. Pharm. Bull.
1986, 34, 621; b) M. Sato, H. Ban and C. Kaneko, Tetrahedron
Lett., 1997, 38, 6689.
35 a) Y. Yamamoto, Y. Watanabe and Shuhei Ohnishi, Chem.
Pharm. Bull. 1987, 35, 1860; b) Y. Yamamoto and Y.
Watanabe, Chem. Pharm. Bull. 1987, 35, 1871; c) M. Sato, H.
Ogasawara, E. Yoshizumi and T. Kato, Chem. Pharm. Bull.
1983, 31, 1902;
36 E. Fillion and D. Fishlock, Tetrahedron, 2009, 65, 6682
37 a) J. M. Knapp, J. S. Zhu, A. B. Wood and M. J. Kurth, ACS
Comb. Sci. 2012, 14, 85; b) J. M. Knapp, J. C. Fettinger and M.
J. Kurth, Org. Lett. 2011, 13, 4732
12 I. Ojima, H. Chen and X, Qiu, Tetrahedron 1988, 44, 5307.
13 I. Ojima, S. Suga and R. Abe, Chem. Lett. 1980, 853.
14 I. Ojima, K, Nakahashi, S. M. Brandstadter, and N, Hatanaka,
J. Am. Chem. Soc., 1987, 109, 1798.
15 a) M. Toyofuku, S. Fujiwara, T. Shinike, H. Kuniyasu and N.
Kambe, J. Am. Chem. Soc., 2005, 127, 9706; b) Q. Zhao and
Ch. Li, Org. Lett., 2008, 10, 4037; c) M. He and J. W. Bode, J.
Am. Chem. Soc., 2008, 130, 418; d) B. S. Gerstenberger, J. Lin,
Y. S. Mimieux, L. E. Brown, A. G. Oliver and J. P. Konopelski
Org. Lett., 2008, 10, 369.
16 a) C. Palomo, J. M. Aizpurua, J. M. García, R. Galarza, M.
Legido R. Urchegui, P. Román, A. Luque, J. Server-Carrió and
A. Linden, J. Org. Chem., 1997, 62, 2070; b) C. Palomo, J. M.
Aizpurua, I. Ganboa and M. Oiarbide, Eur. J. Org. Chem.,
1999, 12, 3223; c) J. Xu, Tetrahedron, 2012, 68, 10696; d) A.
Kamath and I. Ojima, Tetrahedron, 2015, 68, 10640.
17 T. T. Tidwell, Ketenes II; John Wiley and Sons, Hoboken, New
Jersey, 2006.
18 a) R. L. Danheiser and S. Savariar, Tetrahedron Lett. 1987, 28,
3299; b) B. C. Dutta, K. K. Das and B. N. Goswami, J. Chem.
Res. (S), 1999, 12, 36; c) Y. R. Zhang, H. Lv, D. Zhou and S. Ye,
Chem. Eur. J. 2008, 14, 8473; d) D. A. Evans and J. M. Janey,
Org. Lett. 2001, 3, 2125; e) S. G. Nelson, C. Zhu, X. Shen, J.
Am. Chem. Soc. 2004, 126, 14.
19 a) A. Kanazawa, S. Gillet, P. Delair and A. E. Greene, J. Org.
Chem., 1998, 63, 4660, b) S. D. Burke, C. W. Murtiashaw, J.
O. Saunders, J. A. Oplinger and M. S. Dike J. Am. Chem. Soc.,
1984, 106, 4558, c) E. D. Edstrom J. Am. Chem. Soc., 1991,
113, 6690, d) N. Duguet, A. M. Slawin and A. D. Smith, Org.
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins