N-Methylidene[bis(trimethylsilyl)methyl]amine: The first isolable and stable monomeric methanimine allowing thermal [2 + 2] cycloadditions with ketenes

Article abstract of DOI:10.1039/a607348d

N-Methylidene[bis(trimethylsilyl)methyl]amine acts as a stable methanimine synthon [CH₂=NH] equivalent in [2 + 2] cycloadditions to ketenes, generated from acid chlorides and triethylamine, to provide 4-unsubstituted β-lactams in a single step.

Full text of DOI:10.1039/a607348d

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N-Methylidene[bis(trimethylsilyl)methyl]amine: the first isolable and stable
monomeric methanimine allowing thermal [2 + 2] cycloadditions with ketenes
Claudio Palomo,* Jesus M. Aizpurua, Marta Legido and Regina Galarza
Departamento de Qu´ımica Orga´nica, Facultad de Qu´ımica, Universidad del Pais Vasco, Aptdo 1072, 20080 San Sebastia´n, Spain
N-Methylidene[bis(trimethylsilyl)methyl]amine acts as a
stable methanimine synthon [CH2NNH] equivalent in [2 + 2]
cycloadditions to ketenes, generated from acid chlorides and
triethylamine, to provide 4-unsubstituted b-lactams in a
single step.
the presence of important quantities of unreacted imine 2
(typically 30–35%) surviving these reaction conditions. After
several runs increasing the temperature by changing the solvent
and using two- and four-fold excesses of the acid chloride 3a
(entries 3 and 4) a reasonable 62% yield of the isolated b-lactam
4a was obtained after column chromatography. In view of this
result, we next examined the suitability of this approach to the
construction of the 3-amino 4-unsubstituted azetidin-2-one ring
owing to its importance as a key structural element for the
development of b-lactam antibiotics.6 Actually, comparatively
good yields of 4b (65%, mp 207–209 °C) and 4c {75%, mp
Although the chemistry of the CNN double bond has been
extensively exploited over the years, reactions with formal-
dehyde imines have been virtually ignored.1 Two main reasons
have contributed to this fact: on the one hand the inaccessibility
of monomeric methanimine in the condensed state2 and, on the
other hand, their great instability caused by spontaneous tri- or
oligo-merization.3 A very limited number of investigations
have been conducted to address this problem. For example,
Barluenga’s group4 has demonstrated that both N-methyl-
enearyl- and N-methylenealkyl-amines are stable at 260 °C and
can be generated in situ by the reaction of organometallic
reagents with N-(alkoxymethyl)arylamines and N-alkyl-N-
(alkylthiomethyl)ammonium chlorides, respectively. Independ-
ently to this group, Overman et al.5 has also revealed that
formaldehyde imines can be produced in solution, generally at
270 °C, from the reaction of N-(cyanomethyl)amines with
strong bases. Although these authors also noticed the low
temperature trapping of such methyleneamine species with
carbon nucleophiles, no report on the reactivity of a methani-
mine species withstanding higher temperature reaction condi-
tions has been published to date.
Here we report the chemical behaviour of some ketenes of
interest in the context of b-lactam antibiotic chemistry,6
(Scheme 1) towards the first isolable and stable methanimine,7
easily prepared by the simple mixing of 33% formaldehyde
aqueous solution and the readily available C,C-bis(trimethyl-
silyl)methylamine 1.8,† To establish the correct reaction
conditions for the expected [2 + 2] cycloaddition reaction,
Table 1, we investigated the behaviour of imine 2 towards
benzyloxyketene generated in situ from the carboxylic acid
chloride 3a and triethylamine. As entries 1 and 2 show, only
poor yields of the expected b-lactam were obtained when the
reactions were performed either at low temperature or under
reflux of CH2Cl2 but, interestingly, the chromatographic
analysis (GC–MS) of the reaction mixtures after 16 h revealed
25
150–151 °C, [a]D +89.6 (c 1.0, Cl2CH2)} could be reached,
without the need for an excess acid chloride, by simply
performing the reaction in refluxing benzene or chloroform as
solvents (entries 5 and 6). This result contrasts with the fact that
the cycloaddition between the Evans–Sjo¨gren acid chloride 3c
and methanimine trimers, derived from benzylamine and
trimethylsilylmethylamine, under the reported conditions9 only
affords traces of the expected b-lactams ( < 15%) together with
major amounts of 3-[(4S)-2-oxo-4-phenyloxazolidin-3-yl]-
acetic acid. In addition, the total asymmetric induction observed
during the single step convergent formation of the b-lactam 4c‡
was unaffected by the reaction temperature (entries 6 and 7),
and it was particularly noteworthy when compared with the
limited diastereomeric excesses achieved in comparable ap-
proaches reported to date.10
On the other hand, because the easy cleavage of the
bis(trimethylsilyl)methyl moiety was fundamental in b-lactams
4 finding synthetic applications, we tried several deprotection
25
methods using compound 5 {mp 124–126 °C, [a]D +13.6 (c
1.0, Cl2CH2)} as a model, Scheme 2. This compound was easily
obtained in 70% yield through the oxazolidinone moiety
cleavage11 and further N-Boc protection of the resulting free
amino derivative. After screening our previously reported
method12 we found that exposure of 5 to the action of
Table 1 Cycloaddition reaction of methanimine 2 with alkoxy- and amido-
ketenes derived from acyl chlorides 3
Conditionsa
Product
Entry
4
Solvent; T/°C; t/h
Yield (%)b
H
R
1
2
3
4
5
6
7
a
a
a
a
b
c
CH2Cl2; 278 ? 20; 16
CH2Cl2; 0 ? 40; 16
CHCl3; 0 ? 80c; 2
CHCl3; 80d; 1
C6H6; 0 ? 80; 16
C6H6; 0 ? 80; 16
CH2Cl2; 278 ? 20; 16
28
30
39
62
65
75e
33e
i
ii
H2N
SiMe3
SiMe3
N
SiMe3
SiMe3
N
SiMe3
SiMe3
O
4a R = BnO
b R = 1,2-C6H4(CO)2N
2
1
c
O
a
Unless otherwise stated, the acid chloride (1.2 equiv.) was added to the
imine 2 (1 equiv.) and triethylamine (2.4 equiv.) at the first temperature, and
O
c R =
N
the reaction mixture was then stirred at the second temperature for the
b
indicated time. Yields of pure isolated products after column chromato-
c
graphy (silica gel, hexanes). A twofold excess of the acid chloride and
Ph
triethylamine was used. d The acid chloride (4.0 equiv.) was dropwise added
to the imine 2 (1 equiv.) and triethylamine (8.0 equiv.) at reflux temperature.
e Product obtained as single stereoisomer.
Scheme 1 Reagents and conditions: i, 30% HCHO (1.2 equiv.), H2O, room
temp., 20 h, 75%; ii, RCH2COCl 3a–c, NEt3, for conditions, see Table 1
Chem. Commun., 1997
233

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O
H
O
H
N
BocHN
Ph
References
N
SiMe3
SiMe3
NH
O
O
1 The Chemistry of the Carbon-Nitrogen Double Bond in The Chemistry
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4c
7
iv
i, ii
H
H
BocHN
BocHN
iii
N
SiMe3
SiMe3
N
CHO
O
O
5
6
Scheme 2 Reagents and conditions: i, Li (6 equiv.), THF, ButOH, NH3
(10:1:33), 278 °C, 10 min, then 1 m HCl, 5 min, 70%; ii, (Boc)2O, room
temp., 3 h; iii (NH4)2Ce(NO3)6, MeCN, H2O, room temp., 3 h, 84%; iv,
NaHCO3, Na2CO3, Me2CO, H2O, room temp., 2 h, 78%
cerium(iv) ammonium nitrate in acetonitrile–water furnished
the intermediate formyl derivative 6 [mp 134–136 °C, [a]D
25
217.7 (c 1.0, Cl2CH2)] in a clean and high-yielding (90%)
reaction. Further exposure of 6 to N-deformylation under usual
conditions12,13 afforded 7 [mp 172–174 °C, [a]D 218.4 (c 1.0,
MeOH), lit.,14 mp 171–172 °C], which was identical in all
respects to that previously described. Therefore, the bis-
(trimethylsilyl)methyl group must be considered as a new
protecting group for b-lactam synthesis.15
9 O. Nakaguchi, T. Oku, H. Takeno, M. Hashimoto and T. Kamiya, Chem.
Pharm. Bull., 1987, 35, 3985.
This work was supported by Basque Government (Project PI
95/93) and, in part, by Basque Country University (EHU/
UPV:170.215-EB147/94). A grant from Ministerio de Educa-
cion y Ciencia (Spanish Government) to M. L. is gratefully
acknowledged.
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Chem., 1994, 59, 7934; Y. Narukawa, K. N. Juneau, D. Snustad,
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Footnotes
† In sharp contrast to this result, analogous condensation of C-trimethylsi-
lylmethylamine and formaldehyde afforded only the corresponding
1,3,5-tris(trimethylsilylmethyl)-1,3,5-triazine, see: T. Morimoto, Y. Nezu
and K. Achiwa, Chem. Pharm. Bull., 1985, 33, 4596.
‡ For 4c the 3S stereochemistry, relative to the known 4AS configuration of
the oxazolidinone ring, was unambiguously established by X-ray analysis.
Crystal data for 4c. C19H30N2O3Si2, M = 390.63; crystal dimension 0.20 3
0.15 3 0.30 mm, orthorhombic, P212121, a = 6.444(1), b = 22.025(2),
c = 32.083(3) Å, V = 4553.5(3) Å3, T = 293 K, Z = 8, Dc = 1.140 g
cm23, m (Cu-Ka) = 1.527 mm21, l = 1.54178 Å, 3608 total reflections,
1962 observed [I
> 2s(I)], 709 refined parameters, final conventinal
R = 0.047, wR = 0.067, residual electron density 0.25 eÅ3. The asymmetric
unit was formed by two independent molecules with different conformation
around the (SiMe3)2CH–N bond. Atomic coordinates, bond lengths and
angles and thermal parameters have been deposited at the Cambridge
Received, 28th October 1996; Com. 6/07348D
234
Chem. Commun., 1997