New insights into the chemistry of lithium carbamoyls: Characterization of an adduct (R2NC(O)CLi(OLi)NR2)

Article abstract of DOI:10.1021/jo9908445

Studies of the reaction of lithium dicyclohexylamide with N,N- dibutylformamide, 1-formylpiperidine, and 4-formylmorpholine indicate that the equilibria resulting from these compounds are shifted toward the formation of an adduct, which quickly collapses to dicyclohexylamine and the lithiated carbamoyl anion derived from the initial disubstituted formamide. Further reactions of the lithium carbamoyl lead to a new adduct where a lithiated carbon is bounded to N, O, and a carbonyl functionality. The ¹³C NMR analysis of the reaction mixtures showed the presence of similar intermediates in all cases: adducts of this type have not been reported before. These dilithiated intermediates were trapped with methyl iodide giving the corresponding doubly methylated derivatives. Isolation of substituted glyoxylamides and quantitative determination of the products yields constitute further evidence of the whole reaction scheme proposed.

Full text of DOI:10.1021/jo9908445

J . Org. Chem. 2000, 65, 1629-1635
1629
New In sigh ts in to th e Ch em istr y of Lith iu m Ca r ba m oyls:
Ch a r a cter iza tion of a n Ad d u ct (R2NC(O)CLi(OLi)NR2)
Norma S. Nudelman* and Guadalupe E. Garc´ıa Lin˜ares
Departamento de Quı´mica Orga´nica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos
Aires, Pab. II, P. 3, Ciudad Universitaria, 1428 Buenos Aires, Argentina
Received May 24, 1999
Studies of the reaction of lithium dicyclohexylamide with N,N-dibutylformamide, 1-formylpiperidine,
and 4-formylmorpholine indicate that the equilibria resulting from these compounds are shifted
toward the formation of an adduct, which quickly collapses to dicyclohexylamine and the lithiated
carbamoyl anion derived from the initial disubstituted formamide. Further reactions of the lithium
carbamoyl lead to a new adduct where a lithiated carbon is bounded to N, O, and a carbonyl
functionality. The 13C NMR analysis of the reaction mixtures showed the presence of similar
intermediates in all cases: adducts of this type have not been reported before. These dilithiated
intermediates were trapped with methyl iodide giving the corresponding doubly methylated
derivatives. Isolation of substituted glyoxylamides and quantitative determination of the products
yields constitute further evidence of the whole reaction scheme proposed.
In tr od u ction
characterizing their structures both in solution13 and in
the solid state.14-17 Many complexes are difficult to obtain
as single crystals; hence, much of the present knowledge
comes from studies using NMR spectroscopy.18-21
The actual structure of lithiated intermediates gener-
ated during organic synthesis and how these structures
help to explain the course of the reactions are the subject
of active research at present.1-3 Acyl(formyl)lithium
species are key intermediates to afford nucleophilic
acylations, and the reaction of organolithium reagents
with carbon monoxide provides a fast way for the
preparation of a wide diversity of molecules.4,5 Despite
their intensive use in organic synthesis, it is only very
recently that an incisive insight into the knowledge of
the real nature of intermediate species in solution is
being developed.1,3,6 The knowledge of such species is not
only relevant to the mechanisms of the reactions involv-
ing it, but it could be constructively used to change the
course of those reactions into desired synthetic goals.2,7,8
On the other hand, the growing use of lithium bases
as reagents for organic and organometallic transforma-
tions has led to the realization of the role that aggrega-
tion plays in their reactivity and selectivity.9-12 Conse-
quently, much effort is currently being expended in
We have recently synthesized the first adduct, the
lithium dimorpholinemethoxide,3 affording evidence for
the first intermediate proposed in the carbonylation of
lithium amides, the carbamoyl species R1R2NC(O)Li. This
reaction is very useful for the synthesis of substituted
formamides22 and ureas;8 the procedure could be also
applied for the synthesis of substituted formamides that
were recently found to have an antimicrobial activity.23
These carbonylations have been fully investigated includ-
(10) Henderson, K. W.; Dorigo, A. E.; Williard, P. G.; Bernstein, P.
R. Angew. Chem., Int. Ed. Engl. 1996, 35, 1322.
(11) Ball, S. C.; Cragg-Hine, I.; Davidson, M. G.; Davies, R. P.;
Edwards, A. J .; Lopez-Solera, I.; Raithby, P. R.; Snaith, R. Angew.
Chem., Int. Ed. Engl. 1995, 34, 1002.
(12) Reviews on lithium structural chemistry: (a) Weiss, E. Angew.
Chem., Int. Ed. Engl. 1993, 32, 1501. (b) Mulvey, R. Chem. Soc. Rev.
1991, 20, 167.
(13) (a) Waldmu¨ller, D.; Kotsatos, B. J .; Nichols, M. A.; Williard, P.
G. J . Am. Chem. Soc. 1997, 119, 5479. (b) Abbotto, A.; Streitwieser,
A.; Schleyer, P. v. R. J . Am. Chem. Soc. 1997, 119, 11255. (c) Bauer,
W. J . Am. Chem. Soc. 1996, 118, 5450.
* To whom correspondence should be addressed. Fax: (5411) 576-
3346. E-mail: nudelman@qo.fcen.uba.ar.
(1) Ball, S. C.; Cragg-Hine, I.; Davidson, M. G.; Davies, R. P.;
Raithby, P. R.; Snaith, R. J . Chem. Soc., Chem. Commun. 1996, 1581.
(2) (a) Mu¨ller, A.; Marsch, M.; Harms, K.; Lohrenz, J . C. W.; Boche,
G. Angew. Chem., Int. Ed. Engl. 1996, 35, 1518. (b) Stiasny, H. C.;
Bo¨hm, V. P. W.; Hoffman, R. W. Chem. Ver. 1997, 130, 341.
(3) Nudelman, N. S.; Schulz, H.; Garc´ıa Lin˜ares, G.; Bonatti, A.;
Boche, G. Organometallics 1998, 17, 146.
(4) Seyferth, D.; Hui, R. C.; Wang, W. L. J . Org. Chem. 1993, 58,
5843 and references cited therein.
(5) Nudelman, N. S. Carbonylation of Main-Group Organometal
Compounds. In The Chemistry of Double Bonded Functional Groups;
Patai, S., Ed.; Wiley: Chichester, 1989.
(6) Davidson, M. G.; Davies, R. P.; Raithby, P. R.; Snaith, R. J .
Chem. Soc., Chem. Commun. 1996, 1695.
(7) Lucht, B. L.; Collum, D. B. J . Am. Chem. Soc. 1996, 118, 2217.
(8) (a) Nudelman, N. S.; Lewkowicz, E. S.; Perez, D. G. Synthesis
1990, 917. (b) Perez, D. G.; Nudelman, N. S. J . Org. Chem. 1988, 53,
408.
(9) (a) Abu-Hasanayn, F.; Streitwieser, A. J . Org. Chem. 1998, 63,
2954. (b) Leung, S. S-W.; Streitwieser, A., J . Am. Chem. Soc. 1998,
120, 10557. (c) Thompson, A.; Corley, E. G.; Huntington, M. F.;
Grabowski, E. J . J .; Remenar, J . F.; Collum, D. B. J . Am. Chem. Soc.
1998, 120, 2028.
(14) Williard, P. G.; Sun, C. J . Am. Chem. Soc. 1997, 119, 11693.
(15) Boche, G.; Langlotz, I.; Marsch, M.; Harms, K.; Nudelman, N.
S. Angew. Chem., Int. Ed. Engl. 1992, 104, 774.
(16) van Vliet, G. L. J .; de Kanter, F. J . J .; Schakel, M.; Klumpp, G.
W.; Spek, A. L.; Lutz, M. Chem. Eur. J . 1999, 5, 1091.
(17) Clegg, W.; Henderson, K. W.; Horsburgh, L.; Mackenzie, F. M.;
Mulvey, R. E. Chem.sEur. J . 1998, 4, 53.
(18) (a) Hilmersson, G.; Arvidsson, P. I.; Davidsson, O¨ .; Hakansson,
M. J . Am. Chem. Soc. 1998, 120, 8143. (b) Bauer, W. Magn. Reson.
Chem. 1996, 34, 532.
(19) (a) Hu¨ls, D.; Gu¨nther, H.; van Koten, G.; Wijkens, P.; J astr-
zebski, J . T. B. H. Angew. Chem., Int. Ed. Engl. 1997, 36, 2629. (b)
Khanjin, N. A.; Menger, F. M. J . Org. Chem. 1997, 62, 8923.
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D.; Duhamel, P. J . Am. Chem. Soc. 1997, 119, 10042.
(22) (a) Nudelman, N. S; Lewkowicz, E. S.; Furlong, J . P. J . J . Org.
Chem. 1993, 58, 1847. (b) Nudelman, N. S. Pure Appl. Chem. 1998,
70, 1939.
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10.1021/jo9908445 CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/01/2000

1630 J . Org. Chem., Vol. 65, No. 6, 2000
Nudelman and Garc´ıa Lin˜ares
Sch em e 1
intermediates then collapse to the lithium morpholide
carbamoyl anion species, 4, and the corresponding amines,
5. 4 reacts with morpholine to give finally the lithium
dimorpholinemethoxide, 6, which was detected by 13C
NMR. An adduct like 6, which can be considered as an
adduct of an amide with lithium amide, had not been
characterized yet.5
Shortly after, the first adduct between an amine and
a carbonyl derivative was isolated in the solid state by
the reaction of N,N-dimethylbenzamide with phenyl-
lithium in diethyl ether (eq 1).28 The tetrahedral struc-
ture of the adduct was fully characterized; it is of
fundamental interest as a model for the “in vivo” acyla-
tion reactions,29 and because it shows a structure con-
sistent with the Dunitz trajectory in the addition of an
amine nucleophile to a carbonyl group toward a tetra-
hedral intermediate.30
ing the effect of metal catalysts24,25 and the presence of
radical scavengers.26 The addition of organometallic
compounds to disubstituted formamides has been re-
cently applied to the synthesis of N,N-dialkylamino-
cyclopropanes.27
In the present case, a system is chosen to study further
reaction of the first carbonylation adduct to a second
intermediate that allowed characterization of the nature
and structures of the species in solution. Thus, the
reaction of lithium dicyclohexylamide, 1d , with N,N-
dibutylformamide, 2a, 1-formylpiperidine, 2b, and 4-form-
ylmorpholine, 2c, was studied in THF at room temper-
ature using equimolar quantities of the reactants (see
eq 2). 1d was chosen for this study, in which complex
The specific lithium amide behavior against carbon
monoxide provides a useful additional tool for examining
the reagent structure in solution;22 thus, it could be used
to predict8 the formation of an amine-lithium amide
mixed dimer. The aggregate was synthesized and its
solid-state structure was characterized, the first mixed
dimer being reported in the literature.15 The equilibrium
between lithium dialkylamides and the corresponding
formamides is a key step in the mechanism of carbony-
lation since it could explain the dependence of the product
distribution on the reaction conditions. Concerning this
point, it has been previously observed that acyclic lithium
amides behave differently from cyclic ones, and probably
they do not form mixed aggregates.8b,22 Since the presence
of an amine plays an essential rol in the capture of the
first intermediate3 (see Scheme 1), it was of crucial
interest to study a system in which any mixed aggregates
were not involved, to get more insight into the structures
and further reactions of the lithium carbamoyl interme-
diates. We report herein an NMR and GC study of the
reaction between lithium dicyclohexylamide and disub-
stituted formamides.
equilibria were expected, since it is one of the less acidic
lithium amide-amine pairs,31 and the four species in-
volved in the equilibria with some other amides in THF
could be easily recognized by 13C NMR.31 The reaction
was initiated by mixing 2.0 mL of a 1 M solution of 1d
in THF with the corresponding neat formamide and then
allowed to react for 15 min before quenching with
saturated NH4Cl solution. The reaction mixture was
analyzed by gas chromatography; surprisingly, in all
cases the main product was dicyclohexylamine, 5d . The
Resu lts a n d Discu ssion
The reaction of lithium morpholide, 1c, with N,N-
dibutylformamide, 2a , and 1-formylpiperidine, 2b, has
been previously reported.3 Protonation reactions and
NMR investigations indicate that in the complex equi-
libria resulting from these compounds the mixed diamino
lithium alkoxides, 3, are formed first (Scheme 1). These
(24) Nudelman, N. S.; Garc´ıa Lin˜ares, G.; Schulz, H. Main Group
Metal Chem. 1995, 18, 147.
(28) Adler, M.; Marsch, M.; Nudelman, N. S.; Boche, G. Angew.
Chem., Int. Ed. Engl. 1999, 38, 1261.
(29) (a) Smith, R. M.; Hansen, D. E. J . Am. Chem. Soc. 1998, 120,
8910. (b) Venturini, A.; Lo´pez-Ortiz, F.; Alvarez, J . M.; Gonza´lez, J . J .
Am. Chem. Soc. 1998, 120, 1110. (c) Adalsteinsson, H.; Bruice, T. C.
J . Am. Chem. Soc. 1998, 120, 3440.
(30) (a) Bu¨rgi, H. B.; Dunitz, J . D.; Lehn, J . M.; Wipff, G. Tetrahe-
dron 1974, 30, 1563. (b) Bu¨rgi, H. B.; Dunitz, J . D.; Lehn, J . M.; Wipff,
G. J . Am. Chem. Soc. 1974, 96, 1956.
(25) (a) McCusker, J . E.; Abboud, K. A.; McElwee-White, L. Orga-
nometallics 1997, 16, 3863. (b) Ru¨lke, R. E.; Dolis, J . G. P.; Grost, A.
M.; Elsevier: C. J .; Van Leeuween, P. W. N. M.; Vrieze, K.; Goubitz,
K.; Schenk, H. J . Organomet. Chem. 1996, 511, 47.
(26) (a) Nudelman, N. S.; Doctorovich, F., Garc´ıa Lin˜ares, G.; Schulz,
H. Gazz. Chim. Ital. 1996, 126, 19. (b) Nudelman, N. S.; Garc´ıa Lin˜ares,
G. An. Asoc. Quim. Arg. 1996, 619.
(27) Chaplinski, V.; de Meijere, A. Angew. Chem., Int. Ed. Engl.
1996, 35, 413.
(31) Furlong, J . J . P.; Lewkowicz, E. S.; Nudelman, N. S. J . Chem.
Soc., Perkin Trans. 2 1990, 1461.

Chemistry of Lithium Carbamoyls
J . Org. Chem., Vol. 65, No. 6, 2000 1631
Ta ble 1. 13C NMR Sh ifts of th e In d ivid u a l Sp eciesa
compd
Ca
Cb
Cc
27.6
Cd
27.6
Ce
Cf
1
62.3 40.1
2a
2b
2c
161.9 46.7/41.6 31.3/29.9 20.5/19.9 13.7/13.5
160.3 46.3/40.2 27.0/25.8 25.6/25.1
160.2 67.5/66.6b 45.8/40.7
2d
162.5 47.1/40.9 32.3/31.1 26.7/26.3 26.3/26.1
6a
6b
6c
6d
15a
15b
15c
50.0 32.7
47.6 27.4
68.3 47.2
53.2 34.9
189.0 157.2
187.1 155.6
187.0 155.3
20.8
25.8
14.0
26.8
47.5/45.2 30.8
46.5/44.0 24.4
25.4
20.2
25.5
13.7
66.8
44.4/41.8
a
b
δC/ppm; THF-C6D6 (5:1). Under the signal corresponding to
R-C of THF.
F igu r e 1. 13C NMR spectrum in THF-C6D6 (5:1) of the
reaction mixture of lithium dicyclohexylamide, 1d , with N,N-
dibutylformamide, 2a . The signals labeled a-d correspond to
the carbons in compound 5d ; the signals marked A-F and C′-
F′ correspond to the carbons in compound 9a .
Ch a r t 1
F igu r e 2. 13C NMR spectrum in THF-C6D6 (5:1) of the
reaction mixture of lithium dicyclohexylamide, 1d , with
1-formylpiperidine, 2b. The signals labeled a-d correspond to
the carbons in compound 5d ; the signals marked A-E and
C′-E′ correspond to the carbons in compound 9b.
retention times of the other products corresponded to the
formamides 2(a -d ) and the amines derived from the
initial formamides 5(a -c).
general definition is the ability of the nitrogen atom to
delocalize its lone pair over the whole C,N,O π system
so as to gain stabilization.33 Hence, in the case of the
disubstituted formamides 2, both alkyl groups are not
equivalent, which leads to two signals for each type of
carbon (see shifts for Cb-Ce separated by slashes in Table
1). This feature of the amide functionality was then
useful to characterize the new reaction intermediates.
The 13C NMR spectrum of the reaction mixture of
lithium dicyclohexylamide with N,N-dibutylformamide,
1d + 2a (see Figure 1), shows a set of signals in which
those due to the a-d carbons of dicyclohexylamine 5d
are clearly recognized, together with another set of 10
peaks that are marked A-F and C′-F′ in the spectrum.
Similarly, Figure 2 shows the 13C NMR spectrum of the
reaction mixture of 1 + 2b; one observes the presence of
peaks due to the a-d carbons of 5d together with other
eight peaks (A-E, C′-E′). The spectrum of 1d + 2c
shows again the signals for 5d and other six peaks (A-
D, C′-D′) (Figure 3). In any case, signals for the original
dialkylformamides 2 or for the corresponding dialkyl-
amines 5 were observed.
In principle, these products could be explained by eqs
2 and 3. Thus, similarly to Scheme 1, lithium dicyclo-
hexylamide 1d and a substituted formamide 2 would
form an adduct 7 (eq 2), which would collapse to dicy-
clohexylamine 5d and the lithium carbamoyl species,
8a -c, derived from formamide (eq 3). The lithium
carbamoyl, 8, had been previously called to be an “island
of stability in the area of acyl anions”.32 Nevertheless,
we have previously demonstrated that it is a highly
reactive intermediate, and it is unlikely that it could
survive unchanged in the reaction mixture.8
13C NMR Sp ectr a Evid en ce of In ter m ed ia tes. To
know more about the real nature of the intermediates
before hydrolysis, the different reaction mixtures were
analyzed by 13C NMR. The NMR shifts of the individual
species are given in Table 1, the assignments correspond-
ing to the carbons as labeled in Chart 1. As it is known,
the amide functional group is characterized by some
specific properties such as coplanarity of the groups
attached to the nitrogen atom and substantial rotational
barrier. These properties are readily rationalized with
the concept of the amide resonance, whose the most
The lithium carbamoyl 8, as a highly reactive inter-
mediate, can add to another moiety of 8 forming a new
(33) (a) Lauvergnat, D.; Hiberty, P. C. J . Am. Chem. Soc. 1997, 119,
9478. (b) Wiberg, K. B.; Rablen, P. R. J . Am. Chem. Soc. 1995, 117,
2201.
(32) Rautenstrauch, V.; J oyeaux, M. Angew. Chem., Int. Ed. Engl.
1979, 18, 83.

1632 J . Org. Chem., Vol. 65, No. 6, 2000
Nudelman and Garc´ıa Lin˜ares
be present prior to workup in numerous organic synthe-
ses, it is difficult to obtain solid dilithiated compounds.34,35
To the best of our knowledge, this is the first time that
an entity with a lithiated carbon bonded to N, O, and a
carbonyl functionality is described.
The lithium carbamoyl 8 can also add to unreacted
formamide to give another monolithiated intermediate
10 (eq 5), whose NMR signals would be very similar to
those of intermediate 9. Searching evidences for 9, the
hydrogen-coupled 13C NMR spectra of the each reaction
mixture were determined, and they showed a doublet
plus a singlet for the signal corresponding to CB (see the
Supporting Information). This suggests that indeed both
9 (singlet for CB) and 10 (doublet for CB) intermediates
exist in the reaction mixture.
F igu r e 3. 13C NMR spectrum in THF-C6D6 (5:1) of the
reaction mixture of lithium dicyclohexylamide, 1d , with
1-formylmorpholine, 2c. The signals labeled a-d correspond
to the carbons in compound 5d ; the signals marked A-D and
C′-D′ correspond to the carbons in compound 9c.
Ta ble 2. 13C NMR Sh ifts of th e In ter m ed ia tes a n d
Rea ction P r od u ctsa
compd CA
CB
CC
CC′
CD
CD′
CE
CE′
9a b 180.4 87.5 46.5/46.0 50.1 33.3/31.6 30.3 20.9
21.5
25.5
9b
9c
178.6 90.4 46.6/43.4 48.3 27.5/26.8 26.8 25.9
179.0 89.5 67.7/67.4 65.0 46.4/45.6 47.7
To prove that the signals in the 13C NMR spectra
(Figures 1-3) indeed correspond to the proposed dilithi-
ated intermediate 9, an electrophile (methyl iodide) was
added to each reaction mixture to trap the intermediate.
The reaction mixture was analyzed by 13C NMR, GC, and
GC-MS. The NMR analysis showed in all cases the
presence of dicyclohexylamine, N-methyldicyclohexyl-
amine 11, and a set of signals corresponding to com-
pounds 12, which are the doubly methylated derivatives
of the dilithiated adducts 9. GC-MS analysis of the
reaction mixture, showed also the presence of the mono-
methylated derivatives of the intermediates 10, com-
pounds 13. This constitutes additional evidence that 9
is the proposed intermediate discussed above and that
10, obtained by addition of carbamoyl species to unre-
acted formamide, is also in the reaction mixture. The 13C
NMR shifts of compounds 12 are also shown in Table 2.
It is worthy of note that 11 was obtained in the presence
of methyl iodide even though the NMR spectrum showed
that lithium dicyclohexylamide was not present in the
reaction mixture. Thus, the reaction between dicyclo-
hexylamine and iodomethane was independently carried
out in THF giving, after 30 min, N-methyldicyclohexyl-
amine, 11, in 80% yield.
11
59.9 32.3 26.3
26.2
24.5
24.8
25.3
43.7
12a c 164.8 70.6 51.0
12bd 169.0 83.7 59.5
12ce 170.6 82.9 55.9
47.6/45.3 49.6
48.9/40.9 49.3
70.5/67.1 65.7
a
δC/ppm; THF-C6D6 (5:1). bAdditional signals: CF, 14.1; CF′,
14.6. cAdditional signals: CF, 30.4/29.7; CG, 20.5; CH, 13.9; CF′,
32.2; CG′, 20.7; CH′, 13.8. dAdditional signals: CF, 26.7/25.4; CG,
e
24.6; CF′, 25.8; CG′, 24.6. Additional signals: CF, 45.4; CF′, 48.0.
adduct 9 (eq 4). In fact, the 13C NMR spectrum (Table 2)
of each reaction mixture before hydrolysis (Figures 1-3)
suggests the formation of a similar intermediate, 9, in
all three cases. Table 2 shows the most relevant 13C NMR
signals for some intermediates and reaction products. In
the three cases, signals for both a carbonyl carbon and
for a tetrahedral highly deprotected carbon are observed,
which correspond to the CA and CB of intermediate 9; the
rest of the signals in each case correspond to the alkyl
group carbons (e.g., compare the signals with the corre-
sponding peaks for compounds 2 in Table 1).
Intermediates of the type 9 are of great interest, and
recent work has concentrated on isolating and character-
izing lithium intermediates that occur during “one-pot”
organic synthesis involving lithium reagents.34 Of par-
ticular interest is the intermediacy of dilithiated organic
molecules. Although such species are often proposed to
We have recently shown by “ab initio” theoretical
calculations that carbamoyl intermediates of type 8 have,
in fact, a “carbene-like” structure.36 The chemistry of
carbenes has received increasing interest since Ar-
(35) Ball, S. C.; Cobb, J .; Davies, R. P.; Raithby, P. R.; Shields, G.
P.; Snaith, R. J . Organomet. Chem. 1997, 534, 241.
(36) Viruela-Martin, P.; Viruela-Martin, R.; Tomas, F.; Nudelman,
N. S. J . Am. Chem. Soc. 1994, 116, 10110.
(34) Ball, S. C.; Cragg-Hine, I.; Davidson, M. G.; Davies, R. P.;
Edwards, A. J .; Lopez-Solera, I.; Raithby, P. R.; Snaith, R. Angew.
Chem., Int. Ed. Engl. 1995, 34, 921.

Chemistry of Lithium Carbamoyls
J . Org. Chem., Vol. 65, No. 6, 2000 1633
F igu r e 4. 13C NMR spectrum 500 MHz in THF-d8 of the reaction mixture of lithium dicyclohexylamide, 1d , with 1-formylmor-
pholine, 2c. The signals labeled a-d correspond to the carbons in compound 5d ; the signals marked A-D and C′-D′ correspond
to the carbons in compound 9c and 10c, and the signal marked A′ correspond to CA′ in intermediate 14c.
duengo37 determined the first structure of a carbene, and
active research is being carried out at present.38,39
Coupling is one of the most typical reactions of carbene
intermediates; if the carbamoyl species 8 has an oxycar-
bene structure, we should find some evidence of the
coupling product, 14 (eq 6). However, in the NMR spectra
of each reaction mixture there is any signal that could
be assigned to CA′. The 13C NMR spectra were then
determined in a Bruker 500 MHz spectrometer; sensitiv-
ity enhancement allowed to reveal a signal around 140-
142 ppm, which would correspond to the CdC of the
intermediate proposed, 14 (see Figure 4; other spectra
are in the Supporting Information). This result confirms
the presence of 14 in the reaction mixture, in small
amounts since 8 is rapidly consumed to form 9 and 10.
In fact, once the location of the peak was determined from
the higher field spectra, the reaction between lithium
dicyclohexylamide and N,N-dibutylformamide carried out
at higher concentration showed a small signal around 140
ppm in the 13C NMR 200 MHz spectrum (see the
Supporting Information).
Qu a n tita tive GC An a lysis of th e Rea ction Mix-
tu r es. In light of the above results, if species 9 and 10
are the real intermediates in the reaction mixtures, they
would produce, by hydrolysis, double carbonylated com-
pounds: in both cases, dialkyl-substituted glyoxylamide,
15, and the corresponding amine, 5, should be the
products (eq 7). The dialkyl-substituted glyoxylamides
15(a -c) were independently prepared, and they showed
to have exactly the same retention times that the
corresponding dialkylformamides under the GC condi-
tions used in the present work. Isolation and character-
ization of the reaction products showed that glyoxyla-
mides 15 were the main carbonylated products in the
reaction mixture, while formamides 2 were in minor
amounts ([15]:[2] = 4). Further quantitative analysis by
gas chromatography shed new light on the complex
system, and the relative proportions of each products
were fully consistent with the proposed reaction mech-
anism shown in Scheme 2. As was stated at the beginning
of these section, in all cases the main product was,
surprisingly, dicyclohexylamine 5d ; the complete results
are summarized in Table 3.
On the other hand, in the 13C NMR 500 MHz spectra,
the signals around 178 and 90 ppm corresponding to CA
and CB, respectively, of 9 and 10 appeared as two peaks
in each case, which is a further evidence of the existence
of the two intermediates, mono- and dilithiated, that now,
under higher resolution, are shown as two differentiated
signals in each case (see Figure 4).
The reaction of 1d and 2 gives the tetrahedral inter-
mediate 7; a small amount of it (nearly 0.2 mmol)
collapses to the corresponding lithium amide and dicy-
clohexylformamide, 2d (eq 2). Nevertheless, because of
the less acidic character of dicyclohexylamine,31 the main
proportion collapses to give equimolar amounts of dicy-
clohexylamine (main product, 1.8-1.9 mmol) and the
lithium carbamoyl, 8 (eq 3). Further reaction of two
molecules of 8 (and of 8 + 2), produces intermediate 9
(and 10), to give 0.8-0.9 mmol of the main carbonylated
product, 15, and similar amounts of the corresponding
dialkylamine. The results shown in Table 3 are fully
consistent with these reactions.
(37) (a) Arduengo, A. J ., III; Harlow, R. L.; Kline, M. J . Am. Chem.
Soc. 1991, 113, 361.
(38) Boche, G.; Marsch, M.; Mu¨ller, A.; Harms, K. Angew. Chem.,
Int. Ed. Engl. 1993, 32, 1032.
(39) (a) Zuev, P. S.; Sheridan, R. S. J . Am. Chem. Soc. 1994, 116,
4123. (b) Arduengo, A. J ., III; Dias, H. V. R.; Harlow, R. L.; Kline, M.
J . Am. Chem. Soc. 1992, 114, 5530. (c) Arduengo, A. J ., III; Dias, H.
V. R.; Calabrese, J . C.; Davidson, F. J . Am. Chem. Soc. 1992, 114, 9724.

1634 J . Org. Chem., Vol. 65, No. 6, 2000
Nudelman and Garc´ıa Lin˜ares
Sch em e 2
of the intermediates and the mechanisms of reaction
when organolithium reagents are involved.
Exp er im en ta l Section
Gen er a l Com m en ts. All reactions involving organolithium
reagents were carried out by standard techniques for the
manipulation of air- and water-sensitive compounds.40 Dis-
tilled THF was refluxed over sodium benzophenone ketyl until
a dark blue solution was obtained and then distilled im-
mediately before use under dry oxygen-free nitrogen. Com-
mercial dialkylamines were left over sodium strings for several
days, refluxed and distilled over sodium, and then kept under
nitrogen in sealed ampules, which were opened immediately
prior to use. n -Bu tyllith iu m was prepared by cutting lithium
wire (4.6 g, 1 mol) in small pieces into a flask containing boiling
hexane (250 mL); the flask was capped with a nonair stopper
and kept at 54-58 °C. Butyl chloride (31.3 mL, 1 mol) was
syringed in small aliquots into the flask during 3 h and the
mixture left to react for 1 h at 55 °C. Lith iu m d icycloh exyl-
a m id e (1d ): cooled (0 °C) n-BuLi (2.5 mL, 0.8 M in hexane)
was syringed into a nonair stopper capped tube under nitrogen
atmosphere, and the freshly distilled dicyclohexylamine (2
mmol) was added. The white lithium amide precipitate was
worked up as previously described.8b
Ta ble 3. Rea ction of Lith iu m Dicycloh exyla m id e, 1d ,
w ith Disu bstitu ted F or m a m id esa
N,N-Dia lk ylfor m a m id es (2). Ten grams of the correspond-
ing amine was added in aliquots into a flask containing 10 g
of cooled (0 °C) formic acid. The salt formed solidified and
melted on heating. The corresponding formamide was purified
by distillation (yield 75%): 2a , bp 235 °C; 2b, bp 221 °C; 2c,
bp 237 °C; 2d was purified by recrystallization: mp 61 °C.
N,N-Dia lk ylglyoxyla m id es (15). Compounds 15 were
prepared by reductive ozonolysis of the diethyl tartrate in
methanol, followed by amidation and hydrolysis as previously
described (yield 65%).8b 15d : mp 115-117 °C (hexane); the
structure was confirmed by X-ray analysis.41 See 13C NMR in
Table 1. 15a was synthesized by carbonylation: a lithium
amide solution (0.5 M) in THF/HMPT (1:1) at 0 °C was exposed
to carbon monoxide at ca. 1013 mbar. Once the reaction was
completed, the solution was treated twice with H3PO4 (5%) and
washed with NaHCO3 and water. The organic layer was dried,
and distillation of the solvent rendered a vitreous mass (yield
> 90%). See 13C NMR in Table 1.
Rea ction betw een Lith iu m Dicycloh exyla m id e, 1d ,
a n d Su bstitu ted F or m a m id es, 2. A 2.0 mmol portion of 1
was dissolved in 2 mL of anhydrous THF in a nonair stopper
capped tube; 2.0 mmol of the corresponding neat formamide
was then added and allowed to react for 15 min before addition
of saturated NH4Cl solution. In the trapping reactions, methyl
iodide (shaked with NaHSO3 and passed through a column of
alumine oxide) was used instead of saturated NH4Cl solution.
R ea ct ion b et w een Dicycloh exyla m in e a n d Met h yl
Iod id e. A 5.0 mmol portion of methyl iodide was added to 5
mL of a 1.0 M solution of dicyclohexylamine (5d ) in THF at
room temperature. After 5 min, a yellow solid precipitated.
The reaction mixture was kept at 25 °C for 30 min, after which
time the solid was filtered (mp 194-196 °C).
products\ formamide
6a
6b
6c 6d 15a 15b 15c
N,N-dibutylformamide 1.0
1-formylpiperidine
4-formylmorpholine
1.8 0.9b
1.9
1.0
0.8b
1.0 1.8
0.9b
a
Amounts of products (in mmoles) determined by GC after
hydrolysis. 2 mmol of each reactant was initially present in the
reaction mixture. bIn all cases e 0.2 mmol of dicyclohexylforma-
mide and e 0.2 mmol of the original formamide were also obtained.
Quantitative GC analysis of the reaction mixture after
treatment with methyl iodide affords further evidence of
the proposed reaction scheme. Thus, GC-MS analysis
showed the presence of dicyclohexylamine 5d (0.6 mmol),
N-methyldicyclohexylamine 11 (1.2 mmol), the doubly
methylated derivatives of the intermediate 9, 12 (0.6
mmol), the amine corresponding to the initial formamide
5a -c (0.5 mmol), and glyoxylamide 15a -c (0.4 mmol),
plus small amounts of the original formamide 2a -c (0.2
mmol), N,N-dicyclohexylformamide 2d (0.2 mmol), and
the monomethylated derivatives 13 of the intermediate
10 (approximately 0.2 mmol).
Con clu sion s
It is shown by 13C NMR and GC investigations that
the reaction between lithium dicyclohexylamide 1d and
N,N-dibutylformamide 2a , 1-formylpiperidine 2b, and
4-formylmorpholine 2c, respectively, produces mainly a
dilithiated intermediate in which a lithiated carbon atom
is bonded to N, O, and a carbonyl functionality. To the
best of our knowledge, such an entity has not been
described before; it is of fundamental interest to show
the real nature of carbonylation and other reaction
intermediates, as well as a model for tetrahedral adducts
of biological interest. The reaction between 1d and 2,
gives the first adduct 7, which collapses via proton
transfer to give dicyclohexylamine, 5d , and a lithiated
carbamoyl species, 8; further reactions of 8 give the
dilithiated intermediate, 9, which could be trapped with
methyl iodide. The results show that the product yield
after hydrolysis does not reflect the real situation in the
13C NMR Mea su r em en ts. 13C NMR spectra of THF/C6D6
(5:1) or THF-d8 solutions of all the involved amines, forma-
mides, and lithium amides were recorded in a Bruker 200
spectrometer. In all cases, shifts were determined with respect
to the central signal corresponding to deuterated benzene (δ
) 128.000 ppm) or CR of THF-d8 (δ ) 67.700 ppm). The spectra
of the lithium amide/formamide mixtures were determined as
follows: 0.5 mL of a 1.0 M solution of lithium dicyclohexyla-
mide (1) were syringed into a nitrogen-filled NMR tube capped
with a septum. An equimolar amount of the corresponding
formamide, 2, was syringed into the tube at room temperature
and shaked manually (in all cases some heating of the solution
(40) Shriver, D. F.; Drezdzon, M. A. The Manipulation of Air-
Sensitive Compounds, 2nd ed.; Wiley: New York, 1986.
(41) Nudelman, N. S.; Pe´rez, D.; Galloy, J .; Watson, W. Acta
Crystallogr., Sect. C: Cryst. Struct. Commun. 1983, C39, 393.
reaction mixture; this emphasizes the significance of 13
NMR investigations to get more insight into the nature
C

Chemistry of Lithium Carbamoyls
J . Org. Chem., Vol. 65, No. 6, 2000 1635
was observed). After 15 min, 1000-2000 scans of proton-
Technology of Argentina and from the European Com-
munity are acknowledged.
decoupled 13C spectra were accumulated.
Su p p or tin g In for m a tion Ava ila ble: Copies of 13C NMR
spectra 500 MHz and hydrogen-coupled 13C NMR spectra of
the reactions mixtures 1d + 2a , 1d + 2b, and 1d + 2c. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Ack n ow led gm en t. G.G.L. is grateful for a fellow-
ship from the University of Buenos Aires (UBA). The
authors are indebted to LANAIS CONICET RMN 500
for the 13C NMR 500 MHz spectra. Financial support
from UBA, the National Research Council (CONICET),
and the Agency for the Promotion of Science and
J O9908445