One pot synthesis of α,α-bis(N-arylamido) lactams via iodide-catalyzed rearrangement of β,β-bis(N-arylamido) cyclic ketene-N,O-acetals

Article abstract of DOI:10.1016/j.tetlet.2010.11.148

Five and six-membered cyclic ketene-N,O-acetals, generated in situ from 2,3-dimethyl-2-oxazolinium iodide or 2,3-dimethyl-2-oxazinium iodide and triethylamine, reacted with aryl isocyanates in refluxing THF producing α,α-bis(N-arylamido) lactams via the i

Full text of DOI:10.1016/j.tetlet.2010.11.148

Tetrahedron Letters 52 (2011) 853–858
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
One pot synthesis of a,a-bis(N-arylamido) lactams via iodide-catalyzed
rearrangement of b,b-bis(N-arylamido) cyclic ketene-N,O-acetals
⇑
⇑
Yingquan Song , William P. Henry, Hondamuni I. De Silva, Guozhong Ye, Charles U. Pittman Jr.
Department of Chemistry, Mississippi State University, Mississippi State, MS 39762, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Five and six-membered cyclic ketene-N,O-acetals, generated in situ from 2,3-dimethyl-2-oxazolinium
Received 12 October 2010
Revised 25 November 2010
Accepted 29 November 2010
Available online 4 December 2010
iodide or 2,3-dimethyl-2-oxazinium iodide and triethylamine, reacted with aryl isocyanates in refluxing
THF producing
a,a-bis(N-arylamido) lactams via the iodide-catalyzed rearrangement of b,b-bis(N-ary-
lamido) cyclic ketene-N,O-acetal intermediates. The cyclic ketene-N,O-acetal generated in situ from
2,3,4,4-tetramethyl-2-oxazolinium iodide reacted with isocyanates to give b,b-bis(N-arylamido) cyclic
ketene-N,O-acetals, which do not readily rearrange. The two methyls at C-4 hindered the nucleophilic
attack of iodide on C-5, which is required for rearrangement.
Keywords:
Rearrangement
Cyclic ketene acetal
Lactam
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
_
+
ð1Þ
Cyclic ketene acetals (Fig. 1) with two electron-donating hetero-
atoms are nucleophiles.1 These two heteroatoms make the b-carbon
more electron rich and nucleophilic than vinyl ethers or enamines.
Cyclic ketene-N,O-acetals react with both aroyl and aliphatic acid
chlorides,2 isocyanates,3 and isothiocyanates.3a,b Cyclic ketene-N,O-
acetals were generated first in these previous reactions2,3a,b by
reacting 2,3,4,4-tetramethyl-2-oxazolinium iodide 1 or 2,3-di-
methyl-2-oxazinium iodide with sodium hydride. For example, an
acidic 2-methyl proton of 1 was quantitatively deprotonated by
NaH to form cyclic ketene-N,O-acetal 2 (Eq. 1). After purification of
The 2-methyl group of 1 may also be reversibly deprotonated by
triethylamine. Thus, we have now reacted 1 or its analog 4, trieth-
ylamine and an aryl isocyanate in one pot to generate cyclic
ketene-N,O-acetals 2 or 5 in situ (Scheme 1). Compound 2 or 5 then
react further with the aryl isocyanate to form b,b-bis(N-arylamido)
cyclic ketene-N,O-acetals 3 or 6 without isolation and purification
of 2 or 5. A mechanism accounting for this substitution reaction is
suggested below.
2
by distillation, conversion into b,b-bis(N-arylamido) cyclic
ketene-N,O-acetals 3 was performed by reacting 2 with 2 equiv aryl
isocyanates.
R1
O
R2
O
R1
O
R2
O
R1
O
R2
O
β
α
R1
R2
R1
R2
R1
R2
β
α
2
R3
R3
R3
O1
5
N
N
O
O
N
3
4
_ H+, + H+
R1, R2, R3: H, alkyl or aryl
Figure 1. Five-membered cyclic ketene-O,O- and -N,O-acetals.
⇑
Corresponding authors. Tel.: +1 662 325 7616; fax: +1 662 325 7611.
E-mail addresses: yingquan@gmail.com (Y. Song), cpittman@chemistry.msstate.
Scheme 1. Suggested mechanism for the one pot process to generate b,b-bis
(N-arylamido) cyclic ketene-N,O-acetals 3 or 6.
edu (C.U. Pittman Jr.).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.148

854
Y. Song et al. / Tetrahedron Letters 52 (2011) 853–858
reactions are given in Table 1 and Table 2. All reactions in Table 1 pro-
2. Results
ceeded through the 4,4-dimethyl-substituted cyclic ketene-N,O-acetal2.
The reaction sequence (Table 1) generated b,b-bis(N-arylamido)
cyclic ketene-N,O-acetals 3 nicely after 5 h refluxing in THF where
Three cyclic ketene-N,O-acetals and eight aryl isocyanates were
employed to explore this reaction. Selected results from these
Table 1
Reactions of in situ generated cyclic ketene-N,O-acetal 2 with isocyanates to form N,N0-diaryl-2-(3,4,4-trimethyl-oxazolidin-2-ylidene)-malonamide 3a
+
O
N
-
I
Entry
1
Iodide salt
Isocyanate
Product
Yieldb (%)
NCO
O
N
O
+
O
O
O
O
N
PhHN
NHPh
O
-
-
-
-
I
I
I
I
3a
3b
3c
79
O
O
NCO
NCO
+
N
N
H
N
H
2
3
76
76
N
O
O
F
F
O
+
N
N
N
F
H
H
N
O
NCO
O
O
O
O
O
+
N
MeO
N
N
H
4
5
6
H
3d
3e
3f
64
69
36
O
NCO
O
N
O
+
N
O
O
-
-
N
N
H
I
I
H
O
NCO
NC
CN
O
O
+
N
NC
N
H
N
H
N
O
O
O
NCO
F3C
CF3
+
O
O
N
-
-
I
I
N
H
N
F3C
7
8
H
3g
3h
82
76
N
O
O
NCO
Br
O
N
+
N
N
H
N
H
Br
Br
O
a
Reactions were run in refluxing THF for 5 h. Reactant molar ratio 1/Et3N/isocyanate = 1:1.3–1.5:2.2–2.3. Column chromatography (stationary phase: silica gel, eluting
solvent: acetone/hexanes or ethyl acetate/hexanes) was used for purification.
b
Isolated yield.

Table 2
Reactions of in situ generated cyclic ketene-N,O-acetals 5 and 9 with isocyanatesa
Entry
1c
Iodide salt
Isocyanate
Product 6
Yieldb (%)
Product 7 or 10
Yieldb (%)
NCO
O
O
O
+
O
O
O
O
N
_
_
_
_
N
O
H
N
H
None
7a
7a
7b
39
I
I
I
I
N
N
NCO
O
O
N
O
O
+
N
N
O
H
N
2d
6a
55
Trace
N
N
H
H
H
NCO
O
O
+
N
N
H
N
H
3
None
None
73
O
N
NCO
F
F
O
O
+
N
N
N
H
F
4
7c
85
O
H
N
NCO
MeO
OMe
O
O
+
N
O
_
N
H
N
MeO
5
6
7
None
7d
7e
7f
62
67
28
I
O
H
N
NCO
O
O
+
N
O
O
_
_
N
N
H
None
I
I
O
H
N
NC
CN
NC
CN
NCO
O
O
O
O
O
+
N
N
N
N
H
N
H
NC
6f
5
O
H
H
N
N
(continued on next page)

Table 2 (continued)
Entry
Iodide salt
Isocyanate
Product 6
Yieldb (%)
Product 7 or 10
Yieldb (%)
NCO
NCO
F3C
CF3
CF3
O
O
O
O
O
O
+
N
O
O
O
_
_
_
N
N
H
F3C
N
H
N
H
I
I
I
8
6g
14
7g
7g
69
H
N
O
O
O
N
N
F3C
O
O
+
N
9e
6g
6h
5
75
N
H
N
H
F3C
N
H
N
H
N
O
NCO
O
N
O
O
O
O
O
+
N
N
H
N
N
N
10
11f
12
29
7h
42
68
14
Br
H
H
H
Br
Br
Br
Br
Br
Br
N
O
NCO
Br
O
O
+
N
O
O
_
_
N
H
N
H
None
7h
I
I
N
NCO
O
O
+
N
N
H
N
H
None
None
None
10a
O
N
NCO
+
N
O
O
_
_
I
I
F
13
14
10b
10c
21
12
NCO
+
N
a
Reactions were run in refluxing THF for 5 h. Reactant molar ratio 4 (or 8)/Et3N/isocyanate = 1:1.3–1.5:2.2–2.3. Column chromatography (stationary phase: silica gel, eluting solvent: acetone/hexanes or ethyl acetate/hexanes)
was used for purification.
b
Isolated yield.
Reactant molar ratio: 4/Et3N/isocyanate = 1:1.3:1.1.
Reaction was run in THF at room temperature where rearrangement to lactam is exceedingly slow. The product was purified by recrystallization from DCM.
Reaction was run in refluxing THF for 13.5 h.
c
d
e
f
Reaction was run in refluxing anhydrous 1,4-dioxane for 11.5 h.

Y. Song et al. / Tetrahedron Letters 52 (2011) 853–858
857
R = methyl (Table 1, product 3, entries 1–8). However, when R = H,
the corresponding b,b-bis(N-arylamido) cyclic ketene-N,O-acetals 6
were not observed (Table 2, entries 1, 3–6) or only obtained in
small amounts (Table 2, entries 7,8,10) after 5 h refluxing in THF.
Unexpectedly, the rearranged
a,a-bis(N-arylamido) lactams 7
(Table 2, entries 1, 3–8, 10) resulted when cyclic ketene-N,O-acetal
5, without two methyl substituents on C-4, was used. The lactams
were obtained even when using only 1 equiv of aryl isocyanate.
This is shown for the reaction of phenyl isocyanate with 2,3-di-
methyl-2-oxazolinium iodide 4 (Table 2, entry 1).
The lactams were readily characterized by NMR and FTIR spec-
troscopy. The ring methylene hydrogens adjacent to nitrogen of
a,a-bis-substituted N-methyl-lactam 7a (Ar = Ph) exhibited an
NMR chemical shift at 2.7 ppm, sharply upfield from their original
chemical shift of 4.1 ppm at the C-5 position of the precursor, 2-(3-
methyl-oxazolidin-2-ylidene)-N,N0-diphenyl-malonamide, 6a. This
was characteristic of all the lactams 7a–h. The FTIR spectrum of 7a
(Ar = Ph) exhibited a characteristic tertiary amide carbonyl stretch-
ing band4 at 1696 cmꢀ1. X-ray crystallography confirmed this lac-
tam’s structure (Fig. 2).
Figure 3. Crystal structure of 2-(3-methyl-oxazolidin-2-ylidene)-N,N0-diphenyl-
malonamide 6a, CCDC number 794114.
Six-membered ring cyclic ketene-N,O-acetal 9, generated in situ
from 2,3-dimethyl-2-oxazinium iodide 8, reacted with aryl isocya-
nates giving rise to the rearranged lactams 10a–c in refluxing THF
(Table 2, entries 12–14) but in much lower yields compared to
their five-membered ring analog 5.
3. Discussion
To see if the rearrangement is a pure thermal process, the b,b-
bis(N-phenylamido) cyclic ketene-N,O-acetal 6a was refluxed in
THF for 3 h, but 6a was recovered and no 7a formed. Thus, heating
alone does not cause the rearrangement. Is this rearrangement cat-
alyzed by a reaction component (triethylamine, iodide, triethyl-
amine hydrochloride salt, 2,3-dimethyl-2-oxazolinium ion, and
isocyanate)? Refluxing 6a for 5 h in THF with triethylamine gave
only recovered starting material. In contrast, refluxing 6a in THF,
in the presence of a catalytic amount (0.08 equiv) of tetrabutylam-
monium iodide, generated the rearranged product 7a in 59% yield
after 17 h (Eq. 2). Hence, this process is catalytic in iodide.
Figure 2. Crystal structure of
a,a-bis(N-phenylamido)-c-lactam 7a, CCDC number
794113.
+
Rearrangement to lactam 7a did not readily occur at room tem-
perature. Cyclic ketene-N,O-acetal 5 reacted with 2 equiv of phenyl
isocyanate (Table 2, entry 2) to give the b,b-bis(N-phenylamido)
cyclic ketene-N,O-acetal 6a almost exclusively at room tempera-
ture in THF. Only traces of the rearranged lactam 7a were detected
by TLC. The structure of 6a was confirmed by X-ray crystallography
(Fig. 3).
Somewhat slower rearrangement rates to lactams were found
with aryl isocyanates carrying an electron withdrawing group on
the phenyl ring (p-NC-PhNCO (Table 2, entry 7) and p-CF3PhNCO
(Table 2, entry 8)). Longer reaction times led to a higher rearrange-
ment yield (p-CF3PhNCO, Table 2, entry 9). o-Br-PhNCO also gave
incomplete rearrangement after 5 h refluxing in THF (Table 2, entry
10). Using 1,4-dioxane, which has a higher boiling point (101 °C)
than THF (66 °C), and longer reaction times drove the rearrange-
ment of b,b-bis(N-o-bromophenyl amido) cyclic ketene-N,O-acetal
6h to the lactam 7h quantitatively (Table 2, entry 11).
ð2Þ
A mechanism is proposed in Scheme 2. Iodide attacks C-5 next
to the ring oxygen in 6a. This carbon is susceptible to nucleophilic
attack by nucleophiles.5 The negative charge on the ring-opened
anion 11 is distributed over three oxygens and the b-carbon. After
bond rotation, the negatively charged b-carbon of 11 does an SN2
attack on the primary iodide-bearing carbon, displacing iodide,
and generating the five-membered ring lactam 7a. This catalytic
process finds analogy to the iodide-induced rearrangement of
[(N-aziridinomethylthio)methylene]-2-oxindoles to spiropyrrolidi-
nyl-oxindoles,6 where iodide attack on an aziridine ring set off a
rearrangement process.

858
Y. Song et al. / Tetrahedron Letters 52 (2011) 853–858
-
-
-
-
-
-
Scheme 2. Proposed mechanism for iodide-catalyzed rearrangement of 2-(3-methyl-oxazolidin-2-ylidene)-N,N0-diphenyl-malonamide 6a.
It is likely that iodide attack is rate determining since the ring
Acknowledgment
closure step is intramolecular. Reaction of 6a with the cylindrical
nucleophile, isothiocyanate, and SCNꢀ was conducted in refluxing
THF (5 h). No ring opening was observed and 6a was recovered.
This emphasizes that a high anion nucleophilicity is needed to cat-
alyze this conversion. Electron withdrawing groups on the aryl
rings of 6f (Ar = p-NC-Ph) and 6g (Ar = p-CF3-Ph) may stabilize
the ring-opened anion 11 by slightly reducing the negative charge
density on the nucleophilic b-carbon of 11. However, these are dis-
tant functions and the anion is already highly stabilized. Com-
pound 6h with an o-Br-Ph function also rearranged to the lactam
7h more slowly, perhaps due to steric or stereoelectronic factors.
In the presence of the two methyl groups on C-4, the incoming
iodide is sterically hindered from attacking C-5 of 3a (Fig. 4). The
large iodide radius enhances this steric hindrance during nucleo-
philic attack on C-5. Thus, rearrangement in refluxing THF is not
readily achieved.
The authors acknowledge the educational and general funds of
Mississippi State University for the partial financial support of this
work.
Supplementary data
Supplementary data associated with (complete experimental
synthetic descriptions and full characterizations of all the com-
pounds) this article can be found, in the online version, at
doi:10.1016/j.tetlet.2010.11.148.
References and notes
1. (a) McElvain, S. M. Chem. Rev. 1949, 45, 453–492; (b) Zhu, P. C.; Pittman, C. U., Jr.
J. Polym. Sci., Part A: Polym. Chem. 1996, 34, 169–174; (c) Cao, L.; Wu, Z.; Zhu, P.
C., ; Pittman, C. U., Jr. Polym. Prepr. 1999, 39, 406–407; (d) Cao, L.; Wu, Z.;
Pittman, C. U., Jr. J. Polym. Sci., Part A: Polym. Chem. 1999, 37, 2841–2852; (e) Cao,
L., ; Pittman, C. U., Jr. J. Polym. Sci., Part A: Polym. Chem. 1999, 37, 2823–2840; (f)
Wu, Z.; Cao, L; Pittman, C. U., Jr. J. Polym. Sci., Part A: Polym. Chem. 1998, 36, 861–
871; (g) Yokozawa, T.; Hayashi, R.; Endo, T. Macromolecules 1992, 25, 3313–
3314; (h) Fukuda, H.; Oda, M.; Endo, T. Macromolecules 1996, 29, 3043–3045; (i)
Sanda, F.; Endo, T. J. Polym. Sci., Part A: Polym. Chem. 2000, 39, 265–276; (j)
Huang, Z.; Wang, M. Synth. Commun. 1991, 21, 1177–1187; (k) Huang, Z.; Wang,
M. J. Chem. Soc., Perkin Trans. 1 1993, 1085–1090; (l) Huang, Z.; Wang, M.
Tetrahedron 1992, 48, 2325–2332; (m) Huang, Z.; Wang, M. J. Org. Chem. 1992,
57, 184–190.
O
O
O
PhHN
H3C
NPh
H
N
-
I
H3C
2. Zhou, A.; Pittman, C. U., Jr. Synthesis 2006, 37–48.
3. (a) Zhou, A.; Cao, L.; Li, H.; Liu, Z.; Cho, H.; Henry, W. P.; Pittman, C. U., Jr.
Tetrahedron 2006, 62, 4188–4200; (b) Zhou, A.; Cao, L.; Li, H.; Liu, Z.; Pittman, C.
U., Jr. Synlett 2006, 201–206; (c) Fukuda, H.; Oda, M.; Endo, T. J. Polym. Sci., Part
A: Polym. Chem. 1999, 37, 699–702.
Figure 4. The 4,4-dimethyl groups prevent the iodide attack on C-5 of 3a.
The formation of a,a-bis(N-phenylamido) lactam 7a in the pres-
ence of only 1 equiv of phenyl isocyanate occurs because cyclic ke-
tene-N,O-acetal 5 was generated in situ from 4 during the reaction.
Thus, excess phenyl isocyanate was present as intermediate 5 was
formed. Under these conditions the second substitution occurred
to form b,b-bis(N-phenylamido) cyclic ketene-N,O-acetal 6a, which
rearranged to 7a.
4. Pretsch, E.; Bühlmann, P.; Affolter, C. In Structure Determination of Organic
Compounds, Tables of Spectral Data; Springer, 2000. p 296.
5. For examples of nucleophilic attack on this carbon to form ring-opened amides,
see: (a) Dreme, M.; Le Perchec, P.; Garapon, J.; Sillion, B. Tetrahedron Lett. 1982,
23, 73–74; (b) Zhu, P. C.; Lin, J.; Pittman, C. U., Jr. J. Org. Chem. 1995, 60, 5729–
5731; (c) Wu, Z.; Stanley, R. R.; Pittman, C. U., Jr. J. Org. Chem. 1999, 64, 8386–
8395; (d) Zhou, A.; Pittman, U., Jr. J. Comb. Chem. 2006, 8, 262–267.
6. Kumar, U. K. S.; Ila, H.; Junjappa, H. Org. Lett. 2001, 3, 4193–4196.
Whether this rearrangement reaction can be extended to ali-
phatic isocyanates and other electrophiles will be studied.