Intermolecular reactions of foiled carbenes with N-H bonds: Evidence for an ylidic pathway

Article abstract of DOI:10.1021/jo800802m

(Chemical Equation Presented) The chemistry of endo-tricyclo[6.2.1.0 ^2,7]undec-9-en-11-ylidene (10), an archetypal foiled carbene, has been investigated. The intermolecular reactions of 10 are most conveniently performed with oxadiazoline 6 because the corresponding diazirine can be obtained only in very low yield. Furthermore, the aziridinyl imine is difficult to decompose and the tosylhydrazone sodium salt poorly soluble in common organic solvents. Photolysis of 6 in diethylamine leads merely to a reduction of the diazo group and regeneration of acetyl hydrazone 5, whereas thermolysis cleanly affords tertiary amine 12_anti in 77% yield. Calculations show that even stabilized-nucleophilic carbenes react with amines through an ylidic pathway and not by a concerted insertion into the N-H bond. Nevertheless, in the gas phase, norbornen-7-ylidene (13) is predicted to be stabilized by one molecule of NH₃ more efficiently through a hydrogen bond than by ylide formation.

Full text of DOI:10.1021/jo800802m

Intermolecular Reactions of Foiled Carbenes with N-H Bonds:
Evidence for an Ylidic Pathway†,‡
Jean-Luc Mieusset,§ Alexander Bespokoev,§ Mirjana Pacar,§ Michael Abraham,§
Vladimir B. Arion,| and Udo H. Brinker*,§
Chair of Physical Organic and Structural Chemistry, Faculty of Chemistry, UniVersity of Vienna,
Wa¨hringer Str. 38, A-1090 Wien, Austria, and Institute of Inorganic Chemistry, Faculty of Chemistry,
UniVersity of Vienna, Wa¨hringer Str. 42, A-1090 Wien, Austria
udo.brinker@uniVie.ac.at
ReceiVed April 10, 2008
The chemistry of endo-tricyclo[6.2.1.02.7]undec-9-en-11-ylidene (10), an archetypal foiled carbene, has
been investigated. The intermolecular reactions of 10 are most conveniently performed with oxadiazoline
6 because the corresponding diazirine can be obtained only in very low yield. Furthermore, the aziridinyl
imine is difficult to decompose and the tosylhydrazone sodium salt poorly soluble in common organic
solvents. Photolysis of 6 in diethylamine leads merely to a reduction of the diazo group and regeneration
of acetyl hydrazone 5, whereas thermolysis cleanly affords tertiary amine 12anti in 77% yield. Calculations
show that even stabilized-nucleophilic carbenes react with amines through an ylidic pathway and not by
a concerted insertion into the N-H bond. Nevertheless, in the gas phase, norbornen-7-ylidene (13) is
predicted to be stabilized by one molecule of NH3 more efficiently through a hydrogen bond than by
ylide formation.
Introduction
order to prevent the formation of the intramolecular addition
product. Norbornen-7-ylidene (13), the classic example of a
foiled carbene, was first generated by Moss some 35 years ago.3
It has been shown that this type of carbene intramolecularly
prefers to react through a vinyl shift.3,4 However, the observation
of this reaction is not a sufficient condition to prove that a
carbene is foiled since, at any rate, a vinyl group is a good
migrating group.5,2f
We expect a better understanding of the properties of foiled
carbenes if their intermolecular reactions are studied. Calcula-
tions have established that a strong stabilization of the divalent
carbon atom induces a substantial distortion in the geometry at
In the last 10 years, the knowledge about the chemistry of
foiled carbenes1 has undergone a major revival.2 This is due to
the ready availability of computational methods which allow a
better understanding of the reactive behavior of these intermedi-
ates. In a foiled carbene,1,2 a functional group like a double
bond that usually readily reacts with carbenes is located in close
proximity to the divalent carbon atom leading to strong
interactions between the two functionalities. Of course, the
relative position of the two centers should be well designed in
* Corresponding author. Phone: +43-1-4277-52121. Fax: + 43-1-4277-52140.
† This paper is dedicated to Prof. Franz L. Dickert on the occasion of his
65th birthday.
‡ Carbene Rearrangements. 72. For part 71, see: Mieusset, J.-L.; Brinker, U. H.
Eur. J. Org. Chem. 2008, 3363.
(3) Moss, R. A.; Dolling, U.-H.; Whittle, J. R. Tetrahedron Lett. 1971, 12,
931.
§ Chair of Physical Organic and Structural Chemistry.
(4) (a) Brown, W. T.; Jones, W. M. J. Org. Chem. 1979, 44, 3090. (b) Brinker,
U. H.; Ritzer, J. J. Am. Chem. Soc. 1981, 103, 2116. (c) Kirmse, W.; Chiem,
P. V.; Henning, P. G. J. Am. Chem. Soc. 1983, 105, 1695. (d) Brinker, U. H.;
Ko¨nig, L. Chem. Lett. 1984, 45. (e) Baird, M. S.; Jefferies, I. Tetrahedron Lett.
1986, 27, 2493. (f) Fleischhauer, I.; Brinker, U. H. Chem. Ber. 1987, 120, 501.
(g) Jones, D. W.; Marmon, R. J. Tetrahedron Lett. 1989, 30, 5467.
(5) (a) Fickes, G. N.; Rose, C. B. J. Org. Chem. 1972, 37, 2898. (b) Fisch,
M. H.; Pierce, H. D. J. Chem. Soc., Chem. Commun. 1970, 503. (c) Kirmse,
W.; Kopannia, S. J. Org. Chem. 1998, 63, 1178.
| Institute of Inorganic Chemistry.
(1) Gleiter, R.; Hoffmann, R. J. Am. Chem. Soc. 1968, 90, 5457.
(2) (a) Freeman, P. K. J. Am. Chem. Soc. 1998, 120, 1619. (b) Freeman,
P. K.; Pugh, J. K. J. Org. Chem. 2000, 65, 6107. (c) Freeman, P. K.; Dacres,
J. E. J. Org. Chem. 2003, 68, 1386. (d) Mieusset, J.-L.; Brinker, U. H. J. Org.
Chem. 2005, 70, 10572. (e) Mieusset, J.-L.; Brinker, U. H. J. Org. Chem. 2006,
71, 6975. (f) Mieusset, J.-L.; Brinker, U. H. J. Am. Chem. Soc. 2006, 128, 15843.
(g) Mieusset, J.-L.; Brinker, U. H. J. Org. Chem. 2007, 72, 263.
10.1021/jo800802m CCC: $40.75
Published on Web 07/29/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 6551–6558 6551

Mieusset et al.
SCHEME 1. Synthesis of Tricyclo[6.2.1.02.7]undec-9-en-11-one (3)
SCHEME 2. Preparation of Carbene Precursors
the carbenic center leading to a bending of the carbene bridge
toward the double bond.1,2f,g For example, in norbornen-7-
ylidene (13), this interaction causes the divalent carbon bridge
to lean toward the double bond by 37° when compared to
norbornene.2f Thus, for intermolecular reactions at the side
opposite to the double bond, more space is available. Therefore,
real foiled carbenes are expected to react stereospecifically in
intermolecular reactions. Moreover, the electron donation from
the double bond to the carbenic center causes foiled carbenes
to possess an increased nucleophilicity which leads to their
classification as stabilized-nucleophilic carbenes.6 Unfortunately,
this strong stabilization makes foiled carbenes reluctant toward
intermolecular reactions. Therefore, at present only few experi-
mental results are available.7 Thus, it is only known that
norbornen-7-ylidene (13) can be trapped efficiently with metha-
nol after protonation7d and that it adds in extremely low yield
to cis-4-methylpent-2-ene (0.067%)7a and to tert-butylethylene
(0.1%).7c In this study, we took tricyclo[6.2.1.02.7]undec-9-en-
11-ylidene (10) as a model species and investigated its chemistry
experimentally and theoretically (see Scheme 3). As a result,
we demonstrate that the stabilized-nucleophilic carbene 10 reacts
cleanly and stereoselectively with diethylamine. Moreover, this
reaction provides evidence that even for a nucleophilic carbene,
the ylidic pathway is preferred over a concerted insertion into
the N-H bond. These results confirm the ambivalent behavior
of carbenes which are still able to react as electrophiles with
efficient electron donors even when their chemistry usually is
dominated by their nucleophilic reactivity.
Results and Discussion
hydrazide followed by oxidation in methanol.11 A mixture of
two diastereomers (ratio 1:1)12 was obtained that can be
activated thermally as well as photochemically under mild
conditions (λmax ) ca. 330 nm).13 2-Methoxy-2-methyl-∆3-1,3,4-
oxadiazolines are versatile precursors that are known to
decompose through a variety of pathways and finally generate
the carbenes, especially under photochemical conditions.13
Alternatively, some attempts have been made with pheny-
laziridinyl imine 4,14 which proved to be not as convenient as
6 (Scheme 2). In particular, the thermal decomposition did not
lead to carbene formation and the photolysis had to be carried
out at λ ) 240 nm. Since many compounds absorb light of this
wavelength and, therefore, may also be activated, this fact
significantly reduces the scope of the reaction. Here, a diazo
species is formed prior to carbene generation. Our first experi-
ments have been performed starting from norbornen-7-one (7)
with which two further precursors were tested. Sodium salts of
Synthesis of Precursors. Carbene 10 (Scheme 3) was
generated from two different precursors that were prepared from
endo-tricyclo[6.2.1.02.7]undec-9-en-11-one (3); see Scheme 1.
Ketone 3 was synthesized in three steps starting from a [4 +
2]-cycloaddition between 6,6-dimethoxy-2,3,4,5-tetrachlorocy-
clopentadiene and cyclohexene.8,9 In contrast to the methodology
described in the literature,8 a 3-4-fold excess of cyclohexene
was applied. Therefore, an autoclave was used in order to reach
the reaction temperature of 140 °C. These conditions gave better
yields because less dimer of 6,6-dimethoxy-2,3,4,5-tetrachlo-
rocyclopentadiene was formed. In addition, the subsequent
dechlorination was carried out in liquid ammonia10 instead of
refluxing THF/t-BuOH9 to get a cleaner crude product. Dechlo-
rination in presence of an alcohol to some extent leads to
hydrogenation of the double bond. Most of the experimental
work has been performed with oxadiazoline 6 which is readily
available from the condensation of ketone 3 with acetyl
(11) Yang, R.-Y.; Dai, L.-X. J. Org. Chem. 1993, 58, 3381.
(12) The oxygen atom but also the azo function of the oxadiazoline ring can
be positioned above the double bond of 6.
(13) (a) Majchrzak, M. W.; Be´khazi, M.; Tse-Sheepy, I.; Warkentin, J. J.
Org. Chem. 1989, 54, 1842. (b) Warkentin, J. J. Chem. Soc., Perkin Trans. 1
2000, 2161. (c) Czardybon, W.; Warkentin, J.; Werstiuk, N. H. J. Org. Chem.
2005, 70, 8431.
(6) Mieusset, J.-L.; Brinker, U. H. J. Org. Chem. 2008, 73, 1553.
(7) (a) Moss, R. A.; Dolling, U.-H. Tetrahedron Lett. 1972, 13, 5117. (b)
Alberti, J.; Siegfried, R.; Kirmse, W. Liebigs Ann. Chem. 1974, 1605. (c) Moss,
R. A.; Ho, C.-T. Tetrahedron Lett. 1976, 17, 1651. (d) Kirmse, W.; Meinert, T.
J. Chem. Soc., Chem. Commun. 1994, 1065.
(8) Hoch, P. E. J. Org. Chem. 1961, 26, 2066.
(9) Dauben, W. G.; Kellogg, M. S. J. Am. Chem. Soc. 1980, 102, 4456.
(10) Cotsaris, E.; Paddon-Row, M. N. J. Chem. Soc., Chem. Commun. 1984,
95.
(14) (a) Kirmse, W. Eur. J. Org. Chem. 1998, 201. (b) Hashmi, A. S. K. J.
Prakt. Chem. 1999, 341, 600. (c) May, J. A.; Stoltz, B. M. J. Am. Chem. Soc.
2002, 124, 12426.
6552 J. Org. Chem. Vol. 73, No. 17, 2008

Reactions of Foiled Carbenes with N-H Bonds
SCHEME 3. Reaction of Oxadiazoline 6 with Diethylamine
tosylhydrazones traditionally were one of the most popular
sources of carbenes. However, it was not really convenient to
work with 87d neither by photolysis nor by thermolysis, since
under apolar conditions low yields of products were obtained
because of the poor solubility of the carbene precursor. But the
sodium salts of tosylhydrazones are still our preferred source
of carbenes for gas phase pyrolyses. From a mechanistic point
of view, diazirine 9 represents the best carbene precursor, since
it is recognized that under photolytic conditions 9 directly
generates the carbene and only small amounts of the corres-
ponding diazo species. The product distributions obtained from
the irradiation of spiro[bicyclo[2.2.1]heptene-7,3′diazirine] (9)
in methanol suggest the intervention of only 4-6% of the diazo
compound.7d However, the synthesis of 9 with a satisfactory
yield remains a challenging task.7d
the prediction obtained from calculations with norbornen-7-
ylidene (13) and NH3 (Figure 1).
Computational Results. If a concerted insertion into the
N-H bond is assumed, the syn product 14syn (TS(13/14syn): 11.2
kcal/mol) is expected to be formed in a substantial excess over
14anti (TS(13/14anti): 11.8 kcal/mol). The stereochemical prefer-
ence is related to the high activation energy needed for this
conversion: at the respective transition structures, the carbenic
centers do not interact anymore with the double bond, a fact
which is reflected in the large C(2)-C(7) distance of 2.271 and
2.401 Å, respectively. Thereafter, the outcome of the reaction
is dominated by steric considerations which lead to a favored
approach above the double bond and a preferred formation of
the syn product. The same syn selectivity is observed for
example by the reduction of norbornen-7-one (7) with NaBH4.21
Since syn amine 12syn is not found experimentally in the reaction
of 6 and diethylamine and because the calculated barriers (more
than 15 kcal/mol from complex 13a for both TS(13/14), see
Figure 2) are prohibitively high for an alkyl carbene, the product
formation should occur through another pathway. It is well-
known that electrophilic and reactive carbenes form readily
ylides in the presence of efficient electron donors like nitrogen-
and sulfur-containing compounds. And indeed, even for the
nucleophilic 13, ylide formation is predicted to be strongly
preferred over the concerted insertion into the N-H bond
(Figure 2A).
Chemistry of endo-Tricyclo[6.2.1.02.7]undec-9-en-11-ylidene
(10). It has been shown previously that foiled carbenes react
efficiently with methanol7d and that they possess a predomi-
nantly nucleophilic behavior6 combined with a high proton
affinity.2f These results motivated us to try to intercept 10 with
slightly acidic compounds and with polar substances. Moreover,
it has been shown that a secondary amine like piperidine can
capture alkyl carbenes,15 and many other examples are known
for the insertion of carbenes into N-H bonds.16 In fact, despite
the relatively low acidity of amines (pKa of pyrrolidine in DMSO
) 44),17 during this work diethylamine has been revealed to be
one of the most efficient traps for 10. Thus, thermolysis of
With ammonia, carbene 13 specifically forms the anti ylide
15anti and the conversion occurs by overcoming a low barrier
(TS(13/15anti)) which is only 1.3 kcal/mol higher in energy than
the reactants (6.5 kcal/mol if complex 13a is taken as reference).
In the gas phase, as a polar species, ylide 15anti is predicted to
be higher in energy than the complex in which the carbene and
the ammonia molecule are held together by a hydrogen bridge.
Still, in the gas phase, product formation by rearrangement of
18
oxadiazoline 6 in Et2NH afforded tertiary amine 12anti in an
isolated yield of 77% (Scheme 2).19 The configuration of the
product was established by NMR spectroscopy, the most
characteristic signal being the cross peak between H(2), H(7),
and the CH2 of the ethyl group in the NOESY spectrum.
However, the stereoselectivity observed is in contradiction with
(15) Fernamberg, K.; Snoonian, J. R.; Platz, M. S. Tetrahedron Lett. 2001,
42, 8761.
(19) It is worth noticing that this reaction does not give satisfactory results
under photochemical conditions. First of all, the photolysis of oxadiazoline 6 in
diethylamine is significantly slower than in other solvents. Moreover, only 12%
of 12anti are formed. Instead, acetylhydrazone 5 is isolated, a compound resulting
from reduction of the azo group followed by tautomerization and ring opening.
It has already been observed that amines are able to photoreduce azoalkanes;
see, for example: Adam, W.; Moorthy, J. N.; Nau, W. M.; Scaiano, J. C. J. Am.
Chem. Soc. 1997, 119, 6749.
(20) Calculations at this level of theory could only be performed for the
structures having Cs symmetry.
(21) (a) Cieplak, A. S. Chem. ReV. 1999, 99, 1265. (b) Brown, H. C.; Muzzio,
J. J. Am. Chem. Soc. 1966, 88, 2811. (c) Mehta, G.; Khan, F. A. Tetrahedron
Lett. 1992, 33, 3065. (d) Mehta, G.; Gunasekaran, G.; Gadre, S.; Shirsat, R. N.;
Ganguly, B.; Chandrasekhar, J. J. Org. Chem. 1994, 59, 1953.
(16) (a) Curtius, T. J. Prakt. Chem. 1888, 38, 396. For recent examples with
electrophilic metal carbenes, see: (b) Moody, C. J. Angew. Chem., Int. Ed. 2007,
46, 9148. (c) Baumann, L. K.; Mbuvi, H. M.; Du, G.; Woo, L. K. Organome-
tallics 2007, 16, 3995. (d) Lee, E. C.; Fu, G. C. J. Am. Chem. Soc. 2007, 129,
12066. With nucleophilic carbenes: (e) Frey, G. D.; Lavallo, V.; Donnadieu,
B.; Schoeller, W. W.; Bertrand, G. Science 2007, 316, 439.
(17) Bordwell, F. G.; Drucker, G. E.; Fried, H. E. J. Org. Chem. 1981, 46,
632.
(18) In this study, the description anti is given if the substituent is oriented
away from the alkenic bridge in order to facilitate the comparison between the
bicyclo[2.2.1]hept-2-ene and the tricyclo[6.2.1.02,7]undec-9-ene systems. Ac-
cording to the IUPAC Gold Book, the description anti should be used when the
group is oriented away from the lowest numbered bridge.
J. Org. Chem. Vol. 73, No. 17, 2008 6553

Mieusset et al.
FIGURE 1. Geometries and relative energies of the transition structures for the concerted insertion of carbene 13 into ammonia and for the most
stable conformer of bicyclo[2.2.1]hept-2-en-7-amines 14anti and 14syn according to B3LYP/6-31G(d) calculations. Values in bold: CCSD(T)/6-
31G(d)//B3LYP/6-31G(d), underlined and bold: CCSD(T)/6-31+G(d,p)//B3LYP/6-31G(d), in parentheses: MP2(FC)/6-31G(d), in italics: MP2(FC)/
6-31+G(d,p). Distances in Å and energies in kcal/mol.
TABLE 1. Comparison of the Reactivity of Ammonia and
Diethylamine (16) with Norbornen-7-ylidene (13)a
small changes in the geometry are required, i.e., elongation of
the C-N bond from 1.586 to 1.755 Å and rotation of the NH3
group by 60°. However, since the requirements in the electron
distribution are different, with 12.8 kcal/mol, the energy
difference is relatively high and this process is not very likely
to take place.
b
entry
reaction with NH3
reaction with 16c
a
b
13a
TS(13/14anti
-5.2
19
TS(13/18anti
TS(13/18anti)*
TS(13/18syn
TS(13/18dyn)*
TS(13/17anti
TS(13/17anti)*
TS(13/17syn
-5.3
13.0
12.9
13.7
12.5
3.4
)
)
11.8
)
c
TS(13/14syn
)
11.2
1.3
)
In fact, the reaction of 13 in ammonia is not well modeled
until two nitrogen-containing molecules are explicitly taken into
consideration (Figure 2B). Thereby, a pathway is found in which
no barrier is higher than 3 kcal/mol. Low barriers are a
precondition for the intermolecular trapping of alkyl carbenes
because they can easily rearrange intramolecularly. The second
ammonia molecule first helps to stabilize the polar reactive
intermediates 13 and 15 and, finally, catalyzes very efficiently
the rearrangement of the ylide by accepting a proton from the
amino group and concomitantly donating another proton to the
former carbenic center (TS(15′/14′)). A similar approach has
already been described for the insertion of carbenes into an O-H
bond.23
d
TS(13/15anti
)
3.2
e
f
g
h
TS(13/15syn
14anti
)
10.4
-70.9
-70.5
-1.0
)
10.8
-68.7
-66.1
-2.9
4.1
-7.7
-1.7
-4.2
-6.1
-6.7
-2.4
-10.8
-7.5
5.1
18anti
*
14syn
15anti
18syn
17anti
17anti
*
*
#
i
15syn
-5.8
17syn
17syn
*
#
j
k
l
13′anti
13′syn
15′anti
-7.3
-10.5
-11.9
19′anti
10′
17′anti*:Cx1
17′anti*:Cx2
17′syn*:Cx1
17′syn*:Cx2
TS(17′anti/18′anti)*
TS1anti
m
n
15′syn
-15.9
-9.3
Is it acceptable to replace in the calculations diethylamine
with ammonia? What are the differences between these two
reactions? To answer these questions, we repeated the calcula-
tions with diethylamine instead of ammonia. Overall, similar
results were obtained, and the same preference for formation
of the product with an anti configuration via the intermediacy
of an ylide is predicted. The main divergences arise from steric
hindrance between the ethyl groups and the norbornenyl moiety
causing higher activation barriers. In fact, the most stable
conformation of diethylamine is its linear form 16. However,
because of steric repulsion, this arrangement is impossible in
the products, i.e., tertiary amines 18*. Therefore, the terminal
methyl groups are pushed away from the bicyclic skeleton. The
energetic costs for this partial rotation can be estimated at 2.4
kcal/mol because conformer 16* is 2.4 kcal/mol higher in energy
than 16. A second value of 2.2 kcal/mol can be obtained from
a comparison of the exothermicity of the insertion reaction of
norbornenylidene 13 into ammonia and diethylamine, respec-
tively (Table 1, entry f). Formation of 18syn* is even less
favorable because of adverse interactions between the lone pair
on the nitrogen atom and the double bond (4.4 kcal/mol, entry
g).
TS(15′anti/14′anti
TS(15′syn/14′syn
)
5.2
-0.3
0.5
o
)
-11.4
TS(17′syn/18′syn)*
TS1syn
a The computations were performed at the B3LYP/6-31G(d) level of
theory. b Norbornenylidene and ammonia were taken as reference for
entries a-i. Norbornenylidene and the ammonia dimer were taken as
reference for entries j-o (0 kcal/mol). c Norbornenylidene and diethyl-
amine were taken as reference for entries a-i. Norbornenylidene and the
diethylamine dimer were taken as reference for entries j-o (0 kcal/mol).
the ylide remains difficult to model, probably because a
concerted process requires an antarafacial reaction mode.22
However, the decomposition of an ylide displays retention of
configuration in the majority of cases and is usually described
by occurring through a radical pair confined in a solvent cage.22
In our case, because the ylidic bond is very weak and only 2.3
kcal/mol are needed to cleave it, the most probable pathway
for this rearrangement would correspond to the same transition
structure described before for the concerted insertion of carbene
13 into a N-H bond (See Figure 1, TS(13/14anti)). Indeed, only
(22) (a) Heard, G. L.; Frankcombe, K. E.; Yates, B. F. Aust. J. Chem. 1993,
46, 1375. (b) Heard, G. L.; Yates, B. F. J. Org. Chem. 1996, 61, 7276. (c) Makita,
K.; Koketsu, J.; Ando, F.; Ninomiya, Y.; Koga, N. J. Am. Chem. Soc. 1998,
120, 5764.
(23) Pliego, J. R.; De Almeida, W. B. J. Phys. Chem. A 1999, 103, 3904.
6554 J. Org. Chem. Vol. 73, No. 17, 2008

Reactions of Foiled Carbenes with N-H Bonds
FIGURE 2. Energy diagram, geometries, and relative energies of the most relevant stationery points of the reaction between norbornen-7-ylidene
(13) and ammonia according to B3LYP/6-31G(d) calculations. Values in bold: CCSD(T)/6-31G(d)//B3LYP/6-31G(d), underlined and bold: CCSD(T)/
6-31+G(d,p)//B3LYP/6-31G(d),1 in parentheses: MP2(FC)/6-31G(d), in italics: MP2(FC)/6-31+G(d,p). Distances in Å and energies in kcal/mol.
This discrepancy is found again in the transition structures
modeling the concerted insertion into the NsH bond which are
1.2 kcal/mol (entry b) and 1.3 kcal/mol (entry c) higher in energy
when diethylamine is attacked instead of ammonia. Moreover,
the corresponding geometries of these transition structures have
changed. For example, by insertion into diethylamine the N-H
J. Org. Chem. Vol. 73, No. 17, 2008 6555

Mieusset et al.
FIGURE 3. Geometries and relative energies of the most relevant stationery points of the reaction between norbornen-7-ylidene (13) and diethylamine
#
(16) according to B3LYP/6-31G(d) calculations. For clarity, the hydrogen atoms of the ethyl groups are not shown in structures 17′anti*, 17′anti
,
TS(17′anti/18′anti)*, TS1anti, and 19′anti
.
bond is more broken (1.207 Å for TS(13/18anti)*, Figure 3
instead of 1.134 Å in TS(13/14anti), Figure 1) whereas the
distance between the carbon and the nitrogen atom of the
incipient C-N bond is getting larger (1.972 Å in TS(13/18anti)*
vs 1.755 Å in TS(13/14anti)).
similar energy barrier (TS1anti: 5.2 kcal/mol, 11.9 kcal/mol from
the reactant, entry n) although solvation effects have not been
taken into account. On the whole, ylides 17 generated from
diethylamine are predicted to have a better kinetic stability than
ylides 15 generated from ammonia.
Accordingly, ylide formation requires 1.9 and 0.4 kcal/mol
more energy with diethylamine than with ammonia (entries d
and e). However, these transition structures lead to the slightly
more stabilized ylides 17anti* and 17syn* (gain of 1.9 kcal/mol,
respectively, entries h and i). This increase in stability is
probably due to a better spreading of the positive charge through
the ethyl groups. Again, due to the steric requirements of the
alkyl chains, the N-H bond is virtually blocked above the C2H4
bridge: the alternative conformation 17anti# is 7.0 kcal/mol higher
in energy than 17anti*. This explains that a single diethylamine
Generally, steric hindrance is the reason why the N-H bond
catalyzed mechanism is not effective in the case of diethylamine.
Indeed, norbornenylidene 13 can interact efficiently only with
one diethylamine molecule as can be seen for example in
structure 19′anti, the second diethylamine molecule remaining
far away from the carbenic center (4.091 Å) and the other
nitrogen atom (2.941 Å, see Figure 3).
Conclusion
molecule cannot efficiently catalyze the rearrangement of 17anti
*
This study provides further arguments in favor of the validity
of the B3LYP/6-31G(d) methodology for the modeling of
carbene reactions. Indeed, the results obtained are in good
agreement with the experimental results and with calculations
made with methods requiring more computational efforts like
to 18anti* (11.8 kcal/mol are required, compare TS(17′anti/18′anti)*
(entry n) with 17′anti*:Cx1 (entry l)). The transformation of 17
to 18 most probably occurs through protonation of the ylide;
for this reaction a transition structure could be located with a
6556 J. Org. Chem. Vol. 73, No. 17, 2008

Reactions of Foiled Carbenes with N-H Bonds
MP2 and CCSD(T). It has been revealed that even stabilized-
nucleophilic carbenes react with amines through an ylidic
pathway and not by a concerted insertion into the N-H bonds.
Nevertheless, in the gas phase, norbornen-7-ylidene (13) is
predicted to be stabilized by one molecule of NH3 or amine
more efficiently through a hydrogen bond than by ylide
formation. This study also shows that a carbene reaction which
proceeds through highly polar intermediates and transition
structures can be satisfactorily modeled by an explicit consider-
ation of two molecules of the substrate. In this case, ammonia,
especially if this substrate is small. Finally, foiled carbene 10
has been shown to react stereospecifically to form exclusively
Experimental Section
General Experimental Methods. Melting points are uncor-
1
rected. H and 13C NMR spectra were recorded on a 400 MHz
spectrometer. The chemical shifts at δ ) 7.26 ppm and 77.0 ppm
of CHCl3 were used as internal standards for H and 13C spectra.
1
Conventional 2D COSY, NOESY, HMBC, and HMQC spectra
were used to derive proton and carbon assignments.
endo-11,11-Dimethoxytricyclo[6.2.1.02.7]undec-9-ene (2).9 In
a 1 L three-necked flask fitted with a 250 mL dropping funnel and
a cooling finger filled with dry ice/acetone, dry ammonia (500 mL)
was liquefied at -78 °C. Afterward, sodium (35.51 g, 1.544 mol)
was added, accompanied by a blue coloring of the mixture. Then
a solution of 48.46 g (140 mmol) of endo-11,11-dimethoxy-
1,8,9,10-tetrachlorotricyclo[6.2.1.02.7]undec-9-ene (1) in 200 mL of
THF was added dropwise at -78 °C under stirring and argon over
1.5 h. Afterward, the mixture was kept stirring for an additional
30 min at the same temperature. The solution was then treated with
ammonium chloride until the blue color disappeared and the
ammonia was allowed to evaporate overnight. The obtained mixture
was taken up in water and saturated with sodium chloride and then
extracted six times with dichloromethane. The collected organic
phases were washed with brine, dried over magnesium sulfate, and
filtered through Celite, and the solvent was removed in vacuum.
Yield: 19.60 g (67%), oil.
amine 12anti
.
Computational Methods. The Gaussian 03 program24 was
used for density functional theory calculations, employing
Becke’s25 three-parameter hybrid method, and the exchange
functional of Lee, Yang, and Parr (B3LYP)26 and also for MP2
and CCSD(T) computations. Geometries were optimized at the
B3LYP/6-31G(d) and, for the smaller structures, at the MP2(FC)/
6-31G(d) and at MP2(FC)/6-31+G(d,p) levels of theory. These
results were confirmed using single-point calculations at the
CCSD(T)/6-31G(d) and at the CCSD(T)/6-31+G(d,p) level of
theory. This method represents a coupled cluster calculation
using single and double substitutions augmented by a non-
iterative treatment of triple excitations.27 The stationary points
were characterized by vibrational analysis. All reported energies
include zero-point corrections. For the CCSD(T) calculations,
the zero-point vibrational energies were taken from the B3LYP
calculations. Unless otherwise stated, all values in the text refer
to B3LYP/6-31G(d) calculations. A good agreement was
obtained with the other computational methods, especially with
CCSD(T)/6-31+G(d,p)//B3LYP/6-31G(d). Norbornen-7-ylidene
(13) and ammonia were taken as model compounds for carbene
10 and diethylamine in order to minimize the number of
conformations to be analyzed and to reduce calculation time
(see Figures 1 and 2). The B3LYP method is known to slightly
underestimate the strength of dative bonds whereas the MP2
methodology tends to overestimate this interaction.28 Moreover,
for normal reactions, predicted activation barriers are usually
slightly too high at the B3LYP/6-31G(d) level of theory and
too low with MP2/6-31G(d);29 for carbene rearrangements, the
opposite is true.30
endo-Tricyclo[6.2.1.02.7]undec-9-en-11-one (3).8,31 Dimethyl
ketal 2(19.55 g, 93.8 mmol) was stirred vigorously overnight with
100 mL of an aqueous 10% sulfuric acid solution. After extraction
with hexane, the crude product was washed with NaHCO3 and dried
over magnesium sulfate. The product was crystallized as white
1
needles at -78 °C from hexane. Yield: 9.06 g (60%). H NMR
(400 MHz, CDCl3): δ 6.46 (t, J ) 2.3 Hz, 2H), 2.80 (p, J ) 2.0
Hz, 2H), 2.25-2.19 (m, 2H), 1.64-1.58 (m, 2H), 1.41-1.33 (m,
4H), 1.08-0.96 (m, 2H) ppm. 13C NMR (100 MHz, CDCl3): δ
205.5, 131.8, 52.0, 34.6, 21.2, 19.3 ppm. MS (70 eV): m/z 162
(M+, 0.1), 134 (56), 119 (16), 105 (23), 91 (100), 78 (23).
(endo-Tricyclo[6.2.1.02,7]undec-9-en-11-ylidene)(2-phenylaziridin-
1-yl)amine (4). Ketone 3 (540 mg, 3.333 mmol) was dissolved in
10 mL of benzene. To this solution was added 1-amino-2-
phenylaziridine32 (470 mg, 3.51 mmol). After 2 h at room
temperature, the solvent was rotary evaporated. The crude product
consists of a mixture of two diastereomers in a 56/44 ratio. The
major diastereomer was crystallized from methanol. Yield: 420 mg
(1.51 mmol, 45%). 1H NMR (400 MHz, CDCl3): δ 7.26-7.14 (m,
5H), 6.27 (dd, J ) 6.3, 3.2 Hz, 1H), 6.17 (dd, J ) 6.4, 3.2 Hz,
1H), 3.54-3.52 (m, 1H), 2.88-2.85 (m, 1H), 2.70 (dd, J ) 7.7,
4.8 Hz, 1H), 2.27 (d, J ) 7.7 Hz, 1H), 2.15 (d, J ) 4.8 Hz, 1H),
2.15-2.09 (m, 2H), 1.56-1.52 (m, 2H), 1.39-1.26 (4H), 0.95-0.84
(2H) ppm. 13C NMR (100 MHz, CDCl3): δ 180.4, 138.9, 134.4,
132.9, 128.3, 127.0, 126.4, 48.9, 45.2, 43.4, 40.2, 37.3, 36.0, 22.0,
21.7, 19.6 ppm. MS (70 eV): m/z 278 (M+, 0.3), 250 (1), 193 (1),
174 (5), 168 (8), 146 (17), 131 (39), 117 (70), 104 (56), 92 (100),
78 (40), 64 (27). Mp: 112-114 °C. Anal. Calcd for C19H22N2: C,
81.97; H, 7.97; N, 10.06. Found: C, 81.64; H, 8.11; N, 9.85.
(endo-Tricyclo[6.2.1.02,7]undec-9-en-11-ylidene)acetohydrazide
(5). Ketone 3 (3.3 g, 20.3 mmol) and acetyl hydrazine (1.65 g)
were dissolved in methanol (150 mL) and refluxed during 4 h. After
removal of the solvent, the resulting hydrazone was submitted
directly to the following step without further purification Yield:
4.44 g (100%). The NMR spectra reveal two set of peaks with a
(24) Gaussian 03: Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria,
G. E.; Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin,
K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.;
Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji,
H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.;
Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.;
Hratchian, H. P.; Cross, J. B.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann,
R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.;
Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.;
Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.;
Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.;
Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.;
Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill,
P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; and Pople, J. A.
Gaussian, Inc., Pittsburgh, PA, 2003.
1
ratio of 81/19. H NMR (400 MHz, CDCl3): major conformer: δ
8.67 (s, 1H), 6.41 (dd, J ) 6.3; 3.2 Hz, 1H), 6.25 (dd, J ) 6.3; 3.2
Hz, 1H), 3.51-3.46 (m, 1H), 3.02-2.98 (m, 1H), 2.26-2.04 (m,
(25) Becke, A. D. J. Chem. Phys. 1993, 98, 5648.
(26) Lee, C.; Yang, W.; Parr, R. G. Phys. ReV. B 1988, 37, 785.
(27) Pople, J. A.; Head-Gordon, M.; Raghavachari, K. J. Chem. Phys. 1987,
87, 5968.
(31) (a) Mihovilovic, M. D.; Snajdrova, R.; Winninger, A.; Rudroff, F. Synlett
2005, 2751. (b) Snajdrova, R.; Braun, I.; Bach, T.; Mereiter, K.; Mihovilovic,
M. D. J. Org. Chem. 2007, 72, 9597.
(28) Gilbert, T. M. J. Phys. Chem A 2004, 108, 2550.
(29) Guner, V.; Khuong, K. S.; Leach, A. G.; Lee, P. S.; Bartberger, M. D.;
Houk, K. N. J. Phys. Chem. A 2003, 107, 11445.
(30) Mieusset, J.-L.; Brinker, U. H. J. Org. Chem. 2007, 72, 263.
(32) (a) Mu¨ller, R. K.; Joos, R.; Felix, D.; Schreiber, J.; Wintner, C.;
Eschenmoser, A. Org. Synth. 1988, 6, 56. (b) Felix, D.; Wintner, C.; Eschen-
moser, A. Org. Synth. 1988, 6, 679.
J. Org. Chem. Vol. 73, No. 17, 2008 6557

Mieusset et al.
2H), 2.18 (s, 3H), 1.64-1.58 (m, 2H), 1.47-1.31 (m, 4H),
1.03-0.90 (m, 2H) ppm. Minor conformer, characteristic peaks: δ
8.17 (s, 1H), 6.22 (dd, J ) 6.3; 3.2 Hz, 1H), 3.38-3.35 (m, 1H),
3.16-3.13 (m, 1H), 2.01 (s, 3H) ppm. 13C NMR (100 MHz,
CDCl3): major conformer: δ 173.2, 166.5, 135.2, 132.3, 48.8, 42.5,
37.3, 36.42, 21.9, 21.7, 20.1, 19.54, 19.48 ppm. Minor conformer,
characteristic peaks: δ 135.7, 131.5, 48.9, 42.8, 36.9, 36.35 ppm.
MS (70 eV): m/z 218 (M+, 69), 194 (34), 179 (10), 161 (15), 136
(29), 116 (26), 105 (23), 94 (64), 91 (71), 74 (100). HRMS (70
eV): calcd for C13H18ON2 218.1419, found 218.1424. Mp: 172-174
°C.
rac-5-Methoxy-5-methylspiro[5H-[1,3,4]oxadiazole-2,11′-
endotricyclo[6.2.1.02,7]undec-9-ene] (6). Hydrazone 5 (4.44 g, 20.3
mmol) was dissolved in 150 mL of methanol and stirred in an ice
bath. PhI(OAc)2 (8.52 g, 26.5 mmol) was added within 5 min. After
an additional 15 min, the solvent was rotary evaporated. The two
diastereoisomers (ratio 1:1) were separated by column chromato-
graphy with hexane/dichloromethane (2:3) as eluent. Yield: 5.05 g
(88%). Diastereoisomer A: Rf ) 0.37. 1H NMR (400 MHz, CDCl3):
δ 6.30 (s, 2H), 3.03 (s, 3H), 2.73-2.92 (m, 3H), 2.65-2.64 (m,
1H), 1.73-1.62 (m, 2H), 1.57 (s, 3H), 1.51-1.40 (m, 4H),
1.09-0.99 (m, 2H) ppm. 13C NMR (100 MHz, CDCl3): δ 136.8,
133.2, 132.9, 120.0, 54.8, 53.7, 50.0, 36.2, 36.9, 22.9, 21.8, 21.7,
19.7 ppm. MS (70 eV): m/z 247 (M+ - 1, 0.5), 188 (3), 163 (9),
147 (29), 138 (56), 131 (44), 117 (76), 104 (41), 91 (100), 81 (42),
78 (54), 67 (28), 51 (27). HRMS (70 eV): calcd for C14H19O2N2
(M+ - 1) 247.1447, found 247.1443. Mp: 77-78 °C. Anal. Calcd
for C14H20O2N2: C, 67.71; H, 8.12; N, 11.28. Found: C, 68.11; H,
8.04; N, 11.22. Diastereoisomer B, Rf ) 0.18. 1H NMR (400 MHz,
CDCl3): δ 6.36 (ddd, J ) 6.4, 3.2, 0.6 Hz, 1H), 6.32 (ddd, J ) 6.4,
3.2, 0.6 Hz, 1H), 3.03 (s, 3H), 2.72-2.70 (m, 1H), 2.50-2.48 (m,
1H), 2.38-2.27 (m, 2H), 1.68-1.63 (m, 2H), 1.59 (s, 3H),
1.48-1.37 (m, 4H), 1.09-1.04 (m, 2H) ppm. 13C NMR (100 MHz,
CDCl3): δ 137.6, 133.0, 132.7, 132.2, 53.6, 52.7, 50.0, 37.8, 37.5,
23.4, 21.8, 21.6, 19.9 ppm. MS (70 eV): m/z 247 (M+
- 1, 1.5),
220 (3), 188 (5), 163 (15), 147 (35), 138 (81), 131 (64), 117 (93),
104 (61), 91 (100), 81 (62), 78 (58), 67 (31), 51 (29). HRMS (70
eV): calcd for C14H19O2N2 (M+ - 1) 247.1447, found 247.1443.
Mp: 99-100 °C. See also the crystallographic data in the Supporting
Information.
N,N-Diethyl-11-anti,endo-tricyclo[6.2.1.02,7]undec-9-en-11-
amine (12). Oxadiazoline 6 (250 mg, 1.008 mmol) was dissolved
in 13 mL of diethylamine and stirred for 4 h at 160 °C in a pressure
tube. After removal of the solvent, the crude product was submitted
to column chromatography with ethyl acetate as eluent. Yield: 168
mg (77%) oil. 1H NMR (400 MHz, CDCl3): δ 6.04 (t, J ) 2.2 Hz,
2H), 2.64-2.61 (m, 2H), 2.53 (q, J ) 7.1 Hz, 4H), 2.36-2.34 (m,
1H), 2.17-2.11 (m, 2H), 1.61-1.53 (m, 2H), 1.40-1.33 (m, 4H),
0.96-0.82 (m, 2H), 0.93 (t, J ) 7.1 Hz, 6H) ppm. 13C NMR (100
MHz, CDCl3): δ 135.2, 77.5, 48.7, 42.5, 36.1, 23.1, 20.4, 10.4 ppm.
MS (70 eV): m/z 219 (M+, 94), 204 (55), 190 (35), 176 (30), 162
(44), 147 (30), 122 (34), 110 (39), 99 (76), 91 (100), 86 (80), 79
(62), 67 (59). HRMS (70 eV): calcd for C15H25N 219.1987, found
219.1983.
Acknowledgment. Calculations were performed on the
Schro¨dinger III cluster at the University of Vienna.
1
Supporting Information Available: Copies of H and 13C
NMR spectra for all new compounds. Cartesian coordinates and
energies for all relevant stationary points, CIF (Crystallographic
Information File) for crystallographic data. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO800802M
6558 J. Org. Chem. Vol. 73, No. 17, 2008