Push-pull alkenes by reacting N,N′-dimethyl cyclic ketene N,N′-acetals with isocyanates: synthesis, structures, and reactivities

Article abstract of DOI:10.1016/j.tetlet.2009.02.160

N,N′-Dimethyl cyclic ketene N,N′-acetals react with two or three equivalents of isocyanates to generate tetrasubstituted push-pull alkene derivatives in one-pot sequential reactions. X-ray crystallography showed significant elongations and out of plane distorsions of the polarized carbon-carbon double bonds.

Full text of DOI:10.1016/j.tetlet.2009.02.160

Tetrahedron Letters 50 (2009) 2135–2139
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Push–pull alkenes by reacting N,N0-dimethyl cyclic ketene N,N0-acetals
with isocyanates: synthesis, structures, and reactivities
Guozhong Ye a, William P. Henry a, Chunlong Chen b, Aihua Zhou c, Charles U. Pittman Jr. a,
*
a Department of Chemistry, Mississippi State University, Mississippi State, MS 39762, USA
b Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA
c School of Pharmacy, University of Wisconsin-Madison, WI 53705, USA
a r t i c l e i n f o
a b s t r a c t
N,N0-Dimethyl cyclic ketene N,N0-acetals react with two or three equivalents of isocyanates to generate
tetrasubstituted push–pull alkene derivatives in one-pot sequential reactions. X-ray crystallography
showed significant elongations and out of plane distorsions of the polarized carbon–carbon double bonds.
Ó 2009 Elsevier Ltd. All rights reserved.
Article history:
Received 11 February 2009
Accepted 20 February 2009
Available online 25 February 2009
Ketene N,N0-acetals, which combine two enamine functions in
one functional group structure, exhibit significant nucleophilicity
at their b-carbons due to the delocalization of the lone-pair elec-
trons on both the nitrogens into the C@C double bond (Scheme 1).
Cyclic ketene N,N0-acetals are generally more nucleophilic than
acyclic analogs due to stereoelectronic effects. For example, five-
membered cyclic ketene N,N0-acetal 2 exhibited much higher reac-
tivity than its acyclic counterpart 1 in the inverse electron demand
Diels–Alder reactions (Scheme 2).1 The exceptional reactivity of 2
causes preparation, storage, and handling difficulties2,3 which ac-
count for how seldom they have been investigated in organic syn-
thesis. The six-membered ring analog 3 (Scheme 2) has never been
reported.
β
R1
R2
R1
R2
R1
R2
N
N
N
N
N
N
R3 R4
R3 R4
R3 R4
Scheme 1. Resonance structures of ketene N,N0-acetals.
N
N
N
N
N
N
1
2
3
Scheme 2. Ketene N,N0-acetals.
The electron-rich structures of cyclic ketene N,N0-acetals 2 and
3 make them ideal candidates for constructing push–pull alkenes
but no such conversions appear in the literature. A typical push–
pull alkene consists of electron-donating groups (push) and elec-
tron-withdrawing groups (pull) coupled through a double bond.
Intramolecular charge transfer from the electron-donating groups
to the electron-withdrawing groups leads to profound conse-
quences on the molecular structure and properties. These include
central double bond elongation,4 lowering of its rotational bar-
rier,5,6 existence of strong charge-transfer absorption bands,7 large
dipole moments,8 and high hyperpolarizabilities which are prere-
quisite for organic nonlinear optical materials.9–11 These special
properties provided impetus for the synthesis, characterization,
and applications of push–pull alkenes12–24 along with theoretical
investigations to understand and predict these effects.25–31 Re-
cently, Pittman’s group32,33 reported the reactions of cyclic ke-
tene-N,X-acetals (X = O, S) with isocyanates and isothiocyanates
to generate push–pull alkenes in excellent yields. In this Letter,
the conversion of cyclic ketene-N,N-acetals 2 and 3 to sterically
crowded push–pull alkenes via reactions with isocyanates will be
demonstrated and discussed for the first time.
Cyclic ketene N,N0-acetals 2 and 3 were prepared from diamines
(Scheme 3). The lanthanum(III) triflate-catalyzed condensation of
2%mol La(OSO2CF3)3
H
H2N
N
N
NH2
MeCN, reflux
70%
4
5
(1) n-BuLi/THF, 25°
(1) MeI/THF, 0°-25°
N
N
N
N
(2) MeI/THF, 0°-25°
(2) NaH/THF, 25°
55%
63%
6
2
N
N
N
N
Me 8% mol ZnCl2
(1) MeI/THF, 0°-25°
H2N
N
H
(2) NaH/THF, 25°
MeCN, reflux
8
45%
52%
9
3
* Corresponding author. Tel.: +1 662 325 7616; fax: +1 662 325 7611.
E-mail address: cpittman@chemistry.msstate.edu (C.U. Pittman Jr.).
Scheme 3. Preparation of 2 and 3.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.160

2136
G. Ye et al. / Tetrahedron Letters 50 (2009) 2135–2139
ethylenediamine 4 with acetonitrile gave 2-methylimidazoline 5,34
Table 1
Reactions of cyclic ketene N,N0-acetals with isocyanates
which generated 1,2-dimethylimidazoline 6 upon deprotonation
with butyllithium and subsequent methylation using MeI. Further
methylation with MeI and deprotonation gave 2 in a moderate
yield. The same sequence can be used to prepare the six-mem-
bered analog 3. However, we discovered that 1,2-dimethyl-
1,4,5,6-tetrahydro-pyrimidine 9 could be obtained directly from
inexpensive N-methyl-1,3-propanediamine 8 in MeCN using ZnCl2
catalysis (lanthanum(III) triflate is not effective for this conver-
sion). This is the first example of a ZnCl2-catalyzed synthesis of
1,2-dialkyl-1,4,5,6-tetrahydropyrimidines by condensation of N-al-
kyl-1,3-propanediamines with a nitrile.35 Subsequent treatment of
9 with MeI/THF and NaH/THF furnished ketene acetal 3.
H
R
N
O
N
R
O
N
H
2eq. RNCO
THF, rt
N
N
N
( )n
( )n
2, n=0
10, n=0
11, n=1
3, n=1
Substrate
Isocyanate
Product
Yielda (%)
Five-membered ring cyclic ketene-N,N-acetal 2 and its six-
membered analog 3, were individually reacted immediately after
synthesis with two equivalents of several different isocyanates in
THF at the room temperature (Table 1). The expected but previ-
ously unreported tetrasubstituted push–pull alkenes 10a–d and
11a–d were isolated in excellent yields (Table 1). The electron-
pushing five or six-membered cyclic ketene-N,N-acetal moieties
interact directly with the two amide groups in these push–pull
alkenes.
The mechanism shown in Scheme 4 accounts for the formation
of 10a. Nucleophilic attack of the b-carbon in 2 on the first equiv-
alent of phenyl isocyanate gives zwitterion 2a, which rapidly re-
moves the acidic hydrogen from the b-carbon intramolecularly to
produce mono-adduct 2b. The still nucleophilic b-carbon in 2b
NCO
NH
O
N
90
N
N
N
N
N
O
N
H
N
10a
NCO
NH
O
N
93
O
N
H
N
10b
O
NCO
O
NH
O
94
N
O
N
Ph
O
Ph
O
H
N
C
NH
C
O
O
OMe
Ph
C
N
N
H
H
C
β
N
β
10c
Ph
N
F
N
N
N
N
N
N
NCO
F
2
2a
2b
NH
N
O
95
84
N
N
N
N
O
N
Ph
O
Ph
O
Ph
O
H
H
NH
C
N
N
N
O
N
F
N
H
Ph
10d
N
H
N
N
NCO
NH
N
O
N
2c
10a
O
N
H
Scheme 4. Mechanism for the formation of push–pull alkene 2.
11a
Table 2
NCO
Reactions of push–pull alkenes with isocyanates
NH
N
O
H
R
O
H
H
81
89
93
N
N
N
N
N
R
O
R
O
O
N
H
N
N
O
N
O
N
R
N
N
H
N
R
2eq. RNCO
THF, rt
11b
N
N
N
10
11
12
13
( )n
, n=0
, n=0
( )n
NCO
NCO
NH
O
, n=1
, n=1
O
N
Substrate
Ra
Product
Yield (%)
H
N
N
10a
10b
10c
10d
11a
11b
11c
11d
Ph
No reaction
No reaction
No reaction
No reaction
13a
—
—
—
—
11c
p-CH3C6H4
p-MeOC6H4
p-FC6H4
Ph
p-CH3C6H4
CH2@CH–CH2–
t-Bu
NH
N
O
32
37
—
O
N
H
N
13b
No reaction
No reaction
N
—
11d
a
The R group in push–pull reagent alkenes and R group in isocyanates were the
same for each reaction reported here.
a
Yields are based on substrate 2 or 3.

G. Ye et al. / Tetrahedron Letters 50 (2009) 2135–2139
2137
then reacts with the second equivalent of phenyl isocyanate to
generate zwitterion 2c. Intramolecular proton abstraction in 2c fi-
nally gives structure 10a.
The isolated products 10a–d and 11a–d, previously unknown,
were further treated with excess isocyanates to probe the reactiv-
ities of these tetrasubstituted polarized alkenes (Table 2). Triple
adducts 13a and 13b were obtained from the six-membered sys-
tems 11a and 11b, respectively. However, 10a–d and 11c–d did
not form analogous triadducts using the isocyanates examined
herein.
which is substantially longer than the normal carbon–carbon dou-
ble bond of ethylene (1.34 Å).36 In addition to the longer central
carbon–carbon double bond, a concomitant twisting of this double
bond occurs as shown in the dihedral angles C13–C14–C16–N2
(57.00°), C15–C14–C16–N1 (56.44°), C13–C14–C16–N1 (123.44°),
and C15–C14–C16–N2 (123.12°). This is the synergistic outcome
of (1) steric repulsion between the N-substituents and the b-car-
bon-substituents, and (2) the push–pull effect which reduces the
C14–C16 bond order, making it easier to twist out-of-plane. The
extent of twisting reflects a compromise between the relaxation
of the steric hindrance (energy drop) and the deviation of the al-
kene substituents from the ideal co-planar geometry (energy
rise).
The single crystal structure of 10d was determined and shown
in Figure 1. A remarkable feature in this crystal structure is the
elongated central carbon–carbon double bond (C14–C16: 1.45 Å),
Figure 1. Crystal structure of 10d. A water molecule is not shown for clarity. The thermal ellipsoids are drawn with 50% probability. CCDC: 689417.
Figure 2. Crystal structure of 11a. Disordered CHCl3 molecules are present and not shown for clarity. The thermal ellipsoids are drawn with 50% probability. CCDC: 719324.

2138
G. Ye et al. / Tetrahedron Letters 50 (2009) 2135–2139
O
N
O
N
O
N
O
N
O
N
O
steric repulsions between donor and accepter portions in 11a ver-
sus that in 10d. This larger twist angle is closer to the totally zwit-
terionic geometry (90° twist, Scheme 5). Thus, the minimum
δ−
RHN
NHR
RHN
NR
RHN
NHR
N
δ+
( )n
B
energy geometry of
a push–pull alkene with six-membered
VS
ketene-N,N-acetal donor has more zwitterionic character than
the five-membered analog. In other words, the acceptor portion
of a six-membered push–pull alkene is more negatively charged
and is more nucleophilic than the acceptor portions of the five-
membered analog. This explains the different (higher) reactivities
of 11a and 11b versus 10a and 10b.
The crystal structure of the triple adduct 13a was determined
( Fig. 3). Its central carbon–carbon double bond length (C8–C9:
1.47 Å) is comparable with that in 11a, but this double bond is fur-
ther twisted (C7–C8–C9–N2: 76.39°; C7–C8–C9–N3: 100.72°; C13–
C8–C9–N2: 108.25°; C13–C8–C9–N3: 74.65°) compared to 11a due
to 13a’s larger acceptor groups. Two intramolecular hydrogen-
bonds exist in the 13a crystal structure (O3ꢀ ꢀ ꢀH–N4 and O3ꢀ ꢀ ꢀH–
N1).
The five-membered ring N,O-analog, 14 (Fig. 4), was also syn-
thesized according to a literature method.32,33 The crystal structure
of 14 was determined in order to compare with those of 11d, 11a,
and 13a. The length of the central C6–C7 double bond in crystals of
14 (1.39 Å) is considerably shorter than those in 10d (1.45 Å), 11a
(1.47 Å), and 13a (1.47 Å). This was attributed to the weaker elec-
tron-donating ability of the N,O-ketene-acetal versus the stronger
donation by cyclic ketene-N,N-acetals. The central carbon–carbon
double bond of 14 is also less twisted versus those of 10d, 11a,
and 13a because one N-methyl group is replaced by oxygen atom.
This dramatically reduced the donor–acceptor steric repulsions.
In summary, we have successfully demonstrated nucleophilic
tandem reactions of cyclic ketene N,N0-acetals (2 and 3) with vari-
ous isocyanates to construct new, unreported push–pull alkenes.
The first ZnCl2-catalyzed condensation of an N-alkyl-1,3-propane-
diamine with nitrile was demonstrated to construct 1,2-dialkyl-
1,4,5,6-tetrahydropyrimidine system. Significant elongations and
torsions of the polarized carbon–carbon double bonds in these
push–pull alkenes were observed using the X-ray crystallography.
The stronger pushing effect of the six-membered cyclic ketene
( )n
( )n
A
C
Scheme 5. The dependence of the charge separation on the geometry of a push–
pull alkene. A: resonance structure showing no charge separation; B: resonance
structure showing partial charge separation and a partial central double bond
(central double bond may be twisted depending on steric factors); C: structure
showing full charge separation in the 90° twisted geometry where the central bond
is actually
a zwitterionic single bond because no conjugation (p-bonding) is
possible between donor and acceptor portions.
The short enamine carbon–nitrogen bonds (N1–C16: 1.33 Å;
N2–C16: 1.32 Å) and the near planar configurations (versus pyra-
midal) of N1 and N2 suggest that N1–C16 and N2–C16 bonds have
considerable double bond character. N1 and N2 are sp2-hybridized.
An intramolecular hydrogen-bond exists in the crystal (O1ꢀ ꢀ ꢀH–
N3), which stabilizes the observed molecular geometry in the
crystal.
The crystal structure of 11a was also obtained (Fig. 2). Its central
carbon–carbon double bond (C8–C16: 1.47 Å) is slightly longer
(ꢁ0.02 Å) than that in 10d. The length of the central double bond
was recently demonstrated to be the sole parameter able to gener-
ally quantify the push–pull effect in push–pull alkenes based on
NBO analysis (the longer the double bond, the stronger the
push–pull effect).30 The longer C@C bond length of 11a versus
10d helps to explain why the push–pull alkenes containing six-
membered cyclic ketene-N,N-acetal donors (11a and 11b) each
underwent a further reaction with isocyanates (phenyl and p-tolyl,
respectively), while those having five-membered cyclic ketene-
N,N-acetal donors (10a and 10b) did not.
The torsional angles about the central carbon–carbon double
bond in 11a (C7–C8–C16–N3: 67.87°; C7–C8–C16–N4: 111.72°;
C9–C8–C16–N4: 67°; C9–C8–C16–N3: 113.31°) have a larger twist
(ꢁ10°) than that in 10d. This enhanced twist is due to stronger
Figure 3. Crystal structure of 13a. The thermal ellipsoids are drawn with 50% probability. CCDC: 689418.

G. Ye et al. / Tetrahedron Letters 50 (2009) 2135–2139
2139
Figure 4. Crystal structure of 14. The thermal ellipsoids are drawn with 50% probability. CCDC: 719325.
9. Prasad, P. N.; Williams, D. J. Introduction to Nonlinear Optical Effects in Molecules
and Polymers; Wiley: New York, 1991.
10. Kanis, D. R.; Ratner, M. A.; Marks, T. J. Chem. Rev. 1994, 94, 195.
11. Dalton, L. R.; Harper, A. W.; Ghosn, R.; Steier, W. H.; Ziari, M.;
Fetterman, H.; Shi, Y.; Mustacich, R. V.; Jen, A. K.-Y.; Shea, K. J. Chem.
Mater. 1995, 7, 1060.
acetal portion in a push–pull alkene, versus the five-membered
analog, was detected by reactivity differences for the first time.
Acknowledgments
12. Markovic, R.; Shirazi, A.; Dzambaski, Z.; Baranac, M.; Minic, D. J. Serb. Chem. Soc.
2003, 68, 1.
13. Forni, A.; Destro, R. Chem. Eur. J. 2003, 9, 5528.
14. Stankovic, E.; Toma, S.; Van Boxel, R.; Asselberghs, I.; Persoons, A. J. Organomet.
Chem. 2001, 637.
The authors acknowledge the educational and general funds of
Mississippi State University for partial financial support of this work.
Supplementary data
15. Yavari, I.; Hazeri, N.; Maghsoodlou, M. T.; Moradi, A. J. Chem. Res., Synop. 2001,
7, 272.
16. Orlewska, C.; Shaker, R. M.; Dees, M.; Otto, H.-H. Monatsh. Chem. 2000, 131,
889.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.02.160.
17. Wilhelm, P.; Neuenschwander, M. Helv. Chim. Acta 1999, 82, 338.
18. Zhu, S.; Qin, C.; Xu, G.; Chu, Q. Tetrahedron Lett. 1998, 39, 5265.
19. Dees, M.; Otto, H.-H. Monatsh. Chem. 1998, 129, 689.
20. Kleinpeter, E.; Koch, A.; Heydenreich, M.; Chatterjee, S. K.; Rudorf, W.-D. J. Mol.
Struct. 1995, 356, 25.
References and notes
1. Gruseck, U.; Heuschmann, M. Tetrahedron Lett. 1987, 28, 6027. and references
cited therein.
21. Marder, S. R.; Cheng, L. T.; Tiemann, B. G.; Friedli, A. C.; Blanchard-Desce, M.;
Perry, J. W.; Skindhoej, J. Science 1994, 263, 511.
2. Many classes of ketene acetals are unstable and difficult to handle and store.
See: (a) Zhou, A.; Pittman, C. U., Jr. Synthesis 2006, 37; (b) Zhou, A.; Pittman, C.
U., Jr. Tetrahedron Lett. 2005, 46, 3801; (c) Wu, Z.; Cao, L.; Pittman, C. U., Jr.
Recent Res. Devel. Polym. Sci. 1998, 2, 467; (d) Zhu, P. C.; Pittman, C. U., Jr. J.
Polym. Sci., Part A: Polym. Chem. 1996, 34, 169; (e) Liu, Y.; Pittman, C. U., Jr. J.
Polym. Sci., Part A: Polym. Chem. 1997, 35, 3655; (f) Zhu, P. C.; Lin, J.; Pittman, C.
U., Jr. J. Org. Chem. 1995, 60, 5729; (g) Wu, Z.; Stanley, R. R.; Pittman, C. U., Jr. J.
Org. Chem. 1999, 64, 8386; (h) Cao, L. Ph.D. Dissertation, Mississippi State
University, 1999; (i) Li, H. MS, Thesis, Mississippi State University, 2005.
3. Cyclic ketene N,O-ketene acetals can be stored under N2 in base-treated
glassware and they can coexist with NaH or t-BuOK for several months without
appreciable deterioration.2h However, in our experience, this method can only
extend the life of the ketene N,N0-ketene acetals 2 and 3 (which are colorless
liquids) for several days before they become dark brown viscous gels,
presumably due to self-polymerization. It is best to use them as soon as they
are synthesized.
22. Maas, G.; Feith, B. Synth. Commun. 1984, 14, 1073.
23. Schubert, H.; Bast, I.; Regitz, M. Synthesis 1983, 661.
24. Lloyd, D.; McNab, H. Angew. Chem. 1976, 88, 496.
25. Rattananakin, P.; Pittman, C. U., Jr.; Collier, W. E.; Saebo, S. Struct. Chem. 2007,
18, 399. and references cited therein.
26. Kleinpeter, E.; Klod, S.; Rudorf, W.-D. J. Org. Chem. 2004, 69, 4317.
27. Kleinpeter, E. J. Serb. Chem. Soc. 2006, 71, 1.
28. Benassi, R.; Bertarini, C.; Kleinpeter, E.; Taddei, F. THEOCHEM 2000, 498,
217.
29. Pappalardo, R. R.; Marcos, E. S.; Ruiz-Lopez, M. F.; Rinaldi, D.; Rivail, J. L. J. Am
Chem. Soc. 1993, 115, 3722.
30. Kleinpeter, E.; Schulenburg, A. Tetrahedron Lett. 2005, 46, 5995.
31. Matus, M. H.; Contreras, R.; Cedillo, A.; Galvan, M. J. Chem. Phys. 2003, 119,
4112.
32. Zhou, A.; Cao, L.; Li, H.; Liu, Z.; Pittman, C. U., Jr. Synlett 2006, 201.
33. Zhou, A.; Cao, L.; Li, H.; Liu, Z.; Cho, H.; Henry, W. P.; Pittman, C. U., Jr.
Tetrahedron 2006, 62, 4188.
34. Forsberg, J. H.; Spaziano, V. T.; Balasubramanian, T. M.; Liu, G. K.; Kinsley, S. A.;
Duckworth, C. A.; Poteruca, J. J.; Brown, P. S.; Miller, J. L. J. Org. Chem. 1987, 52,
1017.
4. Adhikesavalu, D.; Venkatesan, K. Acta Crystallgr., Sect. C 1983, 39, 1044. and
references cited therein.
5. Fischer, G.; Rudorf, W.-D.; Kleinpeter, E. Magn. Reson. Chem. 1991, 29, 212.
6. Fischer, G.; Kleinpeter, E. Magn. Reson. Chem. 1991, 29, 204.
7. Inoue, S.; Aso, Y.; Otsubo, T. Chem. Commun. 1997, 12, 1105.
8. Trofimov, B. A.; Modonov, V. B.; Aksamentova, T. N.; Mikhaleva, A. I.; Korostova,
S. E.; Sobenina, L. N.; Nesterenko, R. N.; Polovnikova, R. I. Izv. Akad. Nauk. SSSR,
Ser. Khim. 1987, 6, 1322.
35. Other examples can be found in: Ye, G. Ph.D. Dissertation, Mississippi State
University, 2008.
36. Dewar, M. 1. S.; Thiel, W. J. Am. Chem. Soc. 1977, 99, 4907.