Diamidocarbenes as versatile and reversible [2+1] cycloaddition reagents

Article abstract of DOI:10.1038/nchem.1267

We describe the synthesis of a variety of cyclopropanes and epoxides by combining a readily accessible and isolable N,N-2-diamidocarbene with a range of structurally and electronically diverse olefins and aldehydes, including electron-rich derivatives. Surprisingly, the cyclopropanation and epoxidation reactions were discovered to be rapid and thermally reversible at relatively low temperatures, two features often desired for applications that utilize dynamic covalent chemistry. In addition, a diamidocyclopropane derivative prepared via this method was hydrolysed successfully to form the corresponding linear carboxylic acid in a metal-and carbon monoxide-free hydrocarboxylation reaction. As such, diamidocarbenes are expected to find utility in the synthesis of cyclopropanes, epoxides and their derivatives, as well as in dynamic covalent chemistry applications.

Full text of DOI:10.1038/nchem.1267

ARTICLES
PUBLISHED ONLINE: 12 FEBRUARY 2012 | DOI: 10.1038/NCHEM.1267
Diamidocarbenes as versatile and reversible
[211] cycloaddition reagents
Jonathan P. Moerdyk and Christopher W. Bielawski
*
We describe the synthesis of a variety of cyclopropanes and epoxides by combining a readily accessible and isolable N,N′-
diamidocarbene with a range of structurally and electronically diverse olefins and aldehydes, including electron-rich
derivatives. Surprisingly, the cyclopropanation and epoxidation reactions were discovered to be rapid and thermally
reversible at relatively low temperatures, two features often desired for applications that utilize dynamic covalent
chemistry. In addition, a diamidocyclopropane derivative prepared via this method was hydrolysed successfully to form the
corresponding linear carboxylic acid in a metal- and carbon monoxide-free hydrocarboxylation reaction. As such,
diamidocarbenes are expected to find utility in the synthesis of cyclopropanes, epoxides and their derivatives, as well as in
dynamic covalent chemistry applications.
ighly strained rings, particularly cyclopropanes and epoxides, Moreover, the carbene carbon in DACs is in the same oxidation
enjoy extraordinary utility in a broad range of synthetic1–3 state as the carbon atom in carbon monoxide and bears amides
H
and biological4,5 applications. Moreover, from a fundamental that should be susceptible to hydrolysis. As such, we predicted
perspective, these compounds attract interest for their unique struc- that DACs could also serve as a masked equivalent of CO
tural and bonding characteristics6,7. An efficient method for the (a molecule that does not readily undergo [2 þ 1] cycloaddition
synthesis of three-membered carbocycles and oxacycles involves chemistry) for use in accessing synthetically versatile cyclopropa-
metal-mediated delivery of a carbene to an olefin or aldehyde8,9; none derivatives or other carbonyl-containing compounds.
however, free carbenes have also been employed successfully10–12
.
Indeed, as described below, we found that isolable DAC 1 not
Although most free carbenes used in [2 þ 1] cycloadditions are gen- only effected a broad range of cyclopropanation and epoxidation
erated in situ, the use of isolable derivatives as starting materials is reactions that involved electron-deficient as well as electron-rich
particularly attractive as they offer avenues to streamline the syn- olefins and aldehydes, but also that many of these reactions were
thetic procedure, aid in the discovery of novel transformations thermally reversible. Additionally, we found that hydrolysis of a
and provide opportunities to probe deeper into the mechanism diamidocyclopropane derivative afforded the corresponding linear
and structure of reactive organic species13,14. Unfortunately, [2 þ 1] carboxylic acid via a metal- and carbon monoxide-free hydrocar-
cycloadditions that involve isolable carbenes remain extremely rare.
boxylation, which presumably occurred through a cyclopropanone
The first example of an isolable free carbene capable of partici- intermediate39,40. During the course of our studies, we also discov-
pating in cyclopropanation and epoxidation reactions was the phos- ered an unprecedented formal [4 þ 1] cycloaddition between 1
phinosilylcarbene I (Fig. 1)15,16, which was reported by Bertrand and and a,b-unsaturated ketones, which provided rapid access to a
co-workers in 1989. Since then, the acyclic alkylamino II (in 2004) new class of dihydrofurans.
and diamino[3]ferrocenophane17 (III) (in 2010) carbenes were
found to display similar cyclopropanation reactivities18,19. The Results and discussion
chemistry displayed by the latter was particularly surprising, as Given that known, isolable carbenes react with electron-deficient
N-heterocyclic carbenes investigated previously20–23 yielded exo- olefins16,18,19,25–27, our initial efforts focused on studying the cyclo-
cyclic olefins rather than cyclopropane products24. Regardless, the addition chemistry of readily accessible 1 with methyl acrylate.
cycloaddition chemistry displayed by I–III was restricted to Stirring equimolar quantities of 1 and methyl acrylate for two
electron-deficient olefins16,18,19,25–27 and aldehydes16,28–30, and until hours in benzene ([1]0 ¼ 0.29 M) at ambient temperature, followed
now isolable carbenes have not been shown to engage in [2 þ 1] by the removal of the solvent and washing with cold hexanes,
1
cycloadditions with electron-rich olefins20.
afforded a white solid in 98% yield (Table 1). H NMR analysis of
Recently, we reported that diamidocarbenes (DACs)31–38, which this material revealed diagnostic signals at d ¼ 0.96, 1.63 and
can be prepared in two high-yielding steps from a 1,3-disubstituted 2.01 ppm (C6D6) consistent with the structure of cyclopropane 2a.
formamidine and malonyl dichloride, exhibit a wide range of To explore the scope of this cyclopropanation chemistry, a
nucleophilic and electrophilic characteristics. For example, akin to
nucleophilic carbenes, they were found to condense with CS2 and
ligate to various transition metals31,34,37,38. However, they were also
found to undergo transformations typical of more electrophilic
carbenes, such as ammonia activation34, C–H insertions31, reversible
coupling with carbon monoxide31,34,37 and irreversible coupling
with isonitriles33,34,37. Given this unique reactivity profile and their
reduced singlet–triplet gap33, we reasoned that DACs would be
excellent candidates for participating in [2 þ 1] cycloadditions.
Np
Np
Mes
Mes
Me3Si
P(N(i-Pr2))2
N
N
N
N
I
O
O
Fe
t-Bu
N(i-Pr)2
III
1
II
Figure 1 | Examples of isolable carbenes that may be used as [211]
cycloaddition reagents. Np ¼ neopentyl, Mes ¼ 2,4,6-trimethylphenyl.
Department of Chemistry and Biochemistry, The University of Texas at Austin, Austin, Texas 78712, USA. e-mail: bielawski@cm.utexas.edu
*
NATURE CHEMISTRY | VOL 4 | APRIL 2012 | www.nature.com/naturechemistry
© 2012 Macmillan Publishers Limited. All rights reserved.
275

NATURE CHEMISTRY DOI: 10.1038/NCHEM.1267
ARTICLES
(100–120 8C for two hours) were required, similar results were
obtained when 1 was treated with cis- or trans-stilbene, which
both formed trans-2k as the exclusive product, albeit in modest
yield (up to 39%). In contrast, treatment of 1 with one equivalent
of an 87:13 molar mixture of maleonitrile:fumaronitrile, prepared
via the method of Linstead and Whalley41, at ambient temperature
for one hour afforded an 87:13 ratio of the respective cis:trans pro-
ducts (2m:2l), as determined by NMR spectroscopy (C6D6). The
structure of the cis-diastereomer was confirmed subsequently by
single-crystal X-ray diffraction analysis (Fig. 2b). Whereas the reten-
tion of stereochemistry in the formation of 2m was consistent with a
concerted mechanism42–44, the rapid closure of a transient 1,3-dipole
cannot be ruled out. In contrast, formation of the trans-diastereomeric
cyclopropanes 2j and 2k from their respective cis-olefins is in accord
with a stepwise process that involves a 1,3-dipole intermediate capable
of bond rotation prior to ring closure. Collectively, these results
are similar to those observed with cycloheptatrienylidene, a
carbene that must be generated in situ via photolysis or thermolysis
Table 1 | Summary of cyclopropanations of DAC 1 with
various olefins.*
R1
N
R3
N
R2
Mes
R4
Mes
Mes
O
Mes
O
Olefin
N
N
O
O
2a–2p
1
Olefin
Product (isolated
yield†)
Olefin
Product (isolated
yield†)
2a (98%)
2j (93%, trans)
CO2Me
CO2Et
EtO2C
Ph
CO2Me
CN
Ph
2b (92%)
2c (96%)
2k (39%, trans)§
2l (52%, trans)
of the sodium salt of tropone tosylhydrazone45,46
.
CN
Building on the aforementioned cyclopropanation of p-methoxy-
styrene, subsequent efforts were directed towards evaluating the
ability of 1 to cyclopropanate electron-rich alkenes. Heating 1
([1]0 ¼ 0.4 M) in neat n-butyl vinyl ether (19 equiv.) to 100 8C
for two hours followed by purification of the reaction mixture
using silica-gel column chromatography afforded a white solid in
53% yield. The structure of this product was consistent with that
of 2n, as determined by a heteronuclear correlation NMR exper-
iment, in which the 1H signals observed at d ¼ 3.49 (1H) and
NC
NC
CN
CN
2d (92%)
2m (45%, cis)
OC4H9
2e R ¼ CF3 (71%)‡
2f R ¼ CI (82%)‡
2n (53%)§
2o (43%, exo)ꢀ
a
R
C25 C26
C1
C6H13
2g R ¼ F (74%)‡
2p (47%)§
2h R ¼ H (90%)‡
2i R ¼ OMe (76%)‡
* In general, the cycloaddition reactions were performed using equimolar concentrations of 1 and the
olefin indicated in C6H6 for two hours at ambient temperature except where noted. †Isolated yield of
the corresponding cyclopropane product. Where applicable, the stereochemistry of the cyclopropane
product is indicated in parentheses. ‡The reaction was performed at 60 8C for 16 hours. §The
reaction was performed neat at 100 8C for two hours. ꢀThe reaction was performed neat at
120 8C for two hours.
b
variety of 1-substituted and 1,1-disubstituted olefins were treated
with 1 (Table 1). In general, equimolar concentrations of 1 and an
olefin were subjected to the reaction conditions and purification
procedure described above. Using this method, the reaction of 1
with methyl methacrylate, acrylonitrile or methacrylonitrile
afforded the expected cyclopropane products 2b–2d in excellent
yield (92–96%). Likewise, styrene and a variety of its p-substituted
derivatives, including a relatively electron-rich derivative (p-meth-
oxystyrene), were cyclopropanated readily by 1, although a slightly
elevated temperature (60 8C) was required to obtain a high yield
of the corresponding products 2e–2i (71–90%). Cyclopropane
formation was determined unequivocally for 2e by single-crystal
X-ray diffraction analysis (Fig. 2a).
C27
C26
C1
Next, we turned our attention towards evaluating the ability of 1 Figure 2 | X-ray structures of the [211] cycloaddition products 2e and 2m.
to cyclopropanate 1,2-disubstituted olefins. The reaction of equi- a, ORTEP diagram of 2e with thermal ellipsoids drawn at 50% probability
molar quantities of diethyl maleate or diethyl fumarate with 1 was and H atoms omitted for clarity. Selected distances and angles: C1–C25,
found to proceed at ambient temperature in C6H6 and exclusively 1.497(6) Å; C1–C26, 1.551(6) Å; C25–C26, 1.501(6) Å; C25–C1–C26,
1
afforded the same product (2j), as determined by H NMR spec- 59.0(3)8; C25–C26–C1, 58.7(3)8; C1–C25–C26, 62.3(3)8. b, ORTEP diagram
troscopy, and in identical yield (93%, Fig. 3a). X-ray diffraction of 2m with thermal ellipsoids drawn at 50% probability and H atoms
analysis of a single crystal obtained from the reaction of 1 and omitted for clarity. Selected distances and angles: C1–C26, 1.518(3) Å;
diethyl maleate revealed that 2j was the trans-diastereomer C1–C27, 1.560(3) Å; C26–C27, 1.536(3) Å; C26–C1–C27, 59.85(12)8;
(see Supplementary Fig. S9). Although elevated temperatures C26–C27–C1, 58.73(12)8; C1–C26–C27, 61.42(12)8.
276
NATURE CHEMISTRY | VOL 4 | APRIL 2012 | www.nature.com/naturechemistry
© 2012 Macmillan Publishers Limited. All rights reserved.

NATURE CHEMISTRY DOI: 10.1038/NCHEM.1267
ARTICLES
were examined next, primarily to clarify the role of sterics. The
introduction of 1 to methyl-3-methyl-2-butenoate, a functionalized
olefin that features a disubstituted b-carbon, resulted in no reaction,
even at elevated temperatures (up to 100 8C). Hence, attack of the
carbene lone pair at the b-position in substituted olefins may be
pivotal in the cyclopropanation mechanism and inhibited by
steric bulk. In light of this result, we reasoned that a 1,1,2-trisubsti-
tuted olefin, such as methyl angelate, should be more prone to cyclo-
propanation. Although ,20% of the cyclopropanated product
formed when an equimolar mixture of methyl angelate and 1 was
heated at 60 8C for 16 hours in C6D6, a 56:44 ratio of methyl tigla-
te:methyl angelate was observed by 1H NMR spectroscopy (see
Supplementary Fig. S1). As a control experiment, methyl angelate
was heated to 100 8C for 24 hours (in the absence of 1), which
resulted in less than 2% isomerization. Collectively, these data are
consistent with a reversible interaction between 1 and methyl ange-
late, which enables scrambling of the olefin’s stereochemistry (see
below for additional discussion).
Bearing in mind that the carbene centre in 1 is in the same oxi-
dation state as the carbon atom in carbon monoxide, we reasoned
that the hydrolysis of the N,N′-diamidocyclopropanes described
above would afford the corresponding cyclopropanones and/or
their derivatives. To test this hypothesis, 2h was treated with
CH3CO2H/HCl. After two hours at 100 8C, hydrocinnamic acid
was obtained in 56% isolated yield (unoptimized). Moreover,
similar results were obtained when the two-step cyclopropanation/
hydrolysis reaction was performed in a single reaction vessel
(Fig. 3b). Considering that N,N′-dimesityl-2,2-dimethylmalona-
mide and its partially hydrolysed derivative 3-(mesitylamino)-2,2-
dimethyl-3-oxopropanoic acid were isolated as by-products from
this reaction, we believe that the hydrolysis of 2h affords a
cyclopropanone intermediate that readily adds water and rearranges
to give the corresponding propionic acid under aqueous con-
ditions39. Regardless, the DAC effectively enabled a formal
anti-Markovnikov hydrocarboxylation of an alkene to a linear
a
NC
CN
Mes
R
R
Mes
Mes
Mes
NC
CN
R
R
N
N
N
N
1
j: R = CO2Et
k: R = Ph
O
O
O
O
2m
2j,2k
b
O
i. 1, C6H6,
60 °C, 16 h
OH
ii. HCl/AcOH,
H2O,
100 °C, 2 h
Figure 3 | Stereospecificity of the [211] cycloaddition with 1 and the
formation of a linear carboxylic acid. a, Treatment of 1 with maleonitrile
afforded the cis-1,2-disubstituted cyclopropane 2m; in contrast, the trans-1,2-
disubstituted cyclopropanes 2j and 2k were obtained when 1 was treated
with diethyl maleate or cis-stilbene, respectively. Although the former is
consistent with a concerted mechanism, the latter examples may reflect a
stepwise cycloaddition process. Conditions for 2j and 2m: room temperature
(r.t.), two hours, C6H6. Conditions for 2k: 100 8C, two hours, neat.
b, Treatment of styrene with 1 followed by hydrolysis of the cyclopropane
product (that is, 2h) under acidic conditions afforded hydrocinnamic acid in
56% isolated yield (unoptimized).
0.84 ppm (2H) (C6D6) were correlated with the 13C signals found at
59.37 and 15.33 ppm, respectively. Similarly, cyclopropanes 2o and
2p were obtained in 43–47% yield by heating 1 for two hours in neat
norbornene (120 8C) or 1-octene (100 8C), respectively. NMR spec-
troscopy and X-ray crystallography identified the structure of 2o as
the exo-isomer (see Supplementary Fig. S11).
Having discovered that DAC 1 was capable of cyclopropanating
electronically diverse alkenes, a number of trisubstituted olefins
a
O
b
C26
R2
R3
C27
O3
R3
C25
C1
Mes
O
Mes
O
R1
Mes
N
N
R1
R2
O
N
Mes
O
N
a: R1 = R2 = H,R3 = Me (96%)
b: R1 = R2 = R3 = Me (94%)
c: R1 = R2 = R3 = H (84%)
O
1
3a–3c
c
d
O
R
O
Mes
O
Mes
N
N
Mes
O
Mes
O
H
R
N
N
a: R = Ph (96%)
: R = p-NO Ph (89%)
O
b
C25
C1
2
c: R = p-MeOPh (84%)
d: R = Cy (63%)
e: R = Me (94%)
O3
1
4a–4g
f : R = CH=CHPh (97%)
g: R = CH=CH2 (not isolated)
Figure 4 | Formal [411] cycloadditions of DAC 1 with a,b-unsaturated ketones and acrolein and [2 11] cycloadditions with aldehydes. a, Unlike the
other olefins studied, the addition of 1 to a,b-unsaturated ketones and acrolein afforded dihydrofuran derivatives rather than cyclopropanes. Conditions for
3a and 3b: r.t., two hours, C6H6. Conditions for 3c: 60 8C, 12 hours, C6H6. b, ORTEP diagram of 3a with thermal ellipsoids drawn at 50% probability and H
atoms omitted for clarity. Selected distances: C1–C25, 1.543(3) Å; C25–C26, 1.486(3) Å; C26–C27, 1.307(3) Å; C27–O3, 1.386(2) Å; O3–C1, 1.460(2) Å.
c, Combining 1 with a variety of aldehydes afforded the corresponding epoxides in good to excellent yields. Conditions: r.t., 2–24 h, C6H6. d, ORTEP diagram
of 4b with thermal ellipsoids drawn at 50% probability and H atoms omitted for clarity. Selected distances and angles: C1–O3, 1.442(3) Å; C1–C25,
1.481(3) Å; O3–C25, 1.450(3) Å; O3–C1–C25, 59.45(13)8; C1–O3–C25, 61.61(14)8; O3–C25–C1, 58.94(13)8.
NATURE CHEMISTRY | VOL 4 | APRIL 2012 | www.nature.com/naturechemistry
© 2012 Macmillan Publishers Limited. All rights reserved.
277

NATURE CHEMISTRY DOI: 10.1038/NCHEM.1267
ARTICLES
Ph
Mes
CO2Et
O
O
Mes
O
N
N
EtO2C
(1.15 equiv.)
(1.15 equiv.)
Ph
O
80 °C, 16 h
r.t., 2 h
EtO2C
Mes
CO2Et
Mes
Ph
Mes
O
4a
Mes
O
Mes
O
Mes
N
N
N
N
N
N
+
O
O
O
O
CO2Et
EtO2C
Mes
CO2Et
Mes
O
1
~80%
~20%
EtO2C
Ph (1.15 equiv.)
80 °C, 16 h
(1.15 equiv.)
N
N
r.t., 2 h
O
O
2j
CO2Et
O
+
Ph
EtO2C
(1.15 equiv.)
(1.15 equiv.)
80 °C, 16 h
Figure 5 | Reversible [211] cycloadditions involving 1. Treatment of 1 with 1.15:1.15 equiv. of benzaldehyde:diethyl fumarate, 2j with 1.15 equiv. benzaldehyde
or 4a with 1.15 equiv. diethyl fumarate afforded the same product mixture. Conditions: 80 8C, 16 hours, C6D6.
carboxylic acid, an industrially useful process that typically requires major product and furan 3c as the minor product (5:1), as deter-
1
transition metals and/or high pressures of carbon monoxide40.
mined by H NMR spectroscopy. However, heating to 60 8C for
To further expand the utility of the cyclopropanation chemistry 12 hours or stirring this mixture for two weeks at ambient tempera-
described above and considering the central role of cyclopropyl ture in solution afforded 3c as the sole product, which was isolated
ketones in the synthesis of furans1, a,b-unsaturated ketones were subsequently in 84% yield (Fig. 4a,c). Thus far, attempts to hydro-
also explored as potential cycloaddition partners for DAC 1. lyse the diamidooxiranes have resulted in a range of products and
Treatment of 1 with an equimolar quantity of methyl vinyl ketone further investigation is underway.
in benzene at ambient temperature for two hours followed by
Although the conversion of 4g into 3c requires cleavage of the
removal of the solvent and washing of the residue with cold epoxide C–C bond47, a retro epoxidation reaction followed by
hexanes afforded a white solid in 96% yield. The lack of a nCO Michael addition would facilitate the formation of the observed
peak assignable to a ketone moiety in the infrared spectrum (KBr) product. To probe for such a retro [2 þ 1] cycloaddition, a series
and a signal indicative of a shielded olefinic proton (d ¼ 3.50 ppm of exchange reactions was performed. Heating a mixture of 4a
1
(C6D6)) in the H NMR spectrum of the product were consistent and diethyl fumarate (1.15 equiv.) to 80 8C in a sealed vial for 16
with the formation of dihydrofuran 3a (Fig. 4a). The structural hours followed by NMR analysis revealed an 83:17 mixture of
assignment of this compound was later confirmed by X-ray crystal- 2j:4a (Fig. 5). Similarly, heating a mixture of 2j and benzaldehyde
lography (Fig. 4b). Formally a [4 þ 1] cycloaddition, the aforemen- (1.15 equiv.) afforded the same ratio of the products after the
tioned transformation is unprecedented and may occur via the same amount of time. Although a 5:95 ratio of 2j:4a was observed
Michael addition of 1 with the a,b-unsaturated ketone followed after mixing diethyl fumarate, benzaldehyde and 1 (1.15:1.15:1)
by ring closure or via a 1,3-rearrangement of a [2 þ 1] cycloadduct for 30 minutes at ambient temperature, an 80:20 ratio of 2j:4a was
intermediate. Analogous results were obtained with 3-methyl-3- obtained on heating this mixture to 80 8C for 16 hours.
penten-2-one (which afforded a 93% yield of 3b), although no reac- Collectively, these results indicate that the cyclopropane and
tion was observed with 4-methyl-3-penten-2-one, even at 100 8C, epoxide cycloadducts of 1 are capable of undergoing formal retro
presumably because of steric inhibition.
[2 þ 1] cycloaddition reactions under mild conditions.
Subsequent attention shifted towards exploring the potential of 1 Additionally, heating 2j to 100 8C in C7D8 resulted in the liberation
to react with aldehydes. As shown in Fig. 4c, stirring benzaldehyde of diethyl fumarate as determined by variable-temperature NMR
with an equimolar quantity of 1 in C6H6 at ambient temperature for spectroscopy, although the free carbene 1 was not observed
two hours followed by washing the crude product with cold hexanes because of a competitive intramolecular C–H insertion process
afforded 4a in 96% yield. The structure of 4a was supported by the that is facilitated at elevated temperatures31. To the best of our
disappearance of the 1H NMR signal assigned to an aldehyde moiety knowledge, these are the first examples of thermally reversible
(d ¼ 9.63 ppm) and the appearance of a new signal diagnostic of an [2 þ 1] cycloadditions that involve an isolable carbene48.
epoxide at d ¼ 4.03 ppm (C6D6). Analogous results were obtained
with electron-deficient and electron-rich derivatives of benzal- Conclusion
dehyde (4b and 4c, 84–89% yield); the structure of 4b was In summary, we report that DAC 1 is capable of participating in
confirmed by X-ray crystallography (Fig. 4d). Likewise, similar reac- [2 þ 1] cycloadditions with a wide range of olefins and aldehydes,
tivity was observed with the aliphatic derivatives cyclohexanecar- including electron-rich derivatives. Structural and mechanistic
boxaldehyde and acetaldehyde, which afforded the epoxides 4d studies support a stepwise addition process, although a cis-cyclo-
and 4e in 63% and 94% yield, respectively. Reflecting the chemos- propane was observed when maleonitrile was used as the starting
electivity of DACs towards aldehydes versus olefins, exposure of 1 material, which suggests to us that some cycloadditions may be
to cinnamaldehyde under similar conditions afforded the epoxide concerted. Whereas the ability of isolable carbenes to engage in
4f in 97% yield. Similarly, treatment of 1 with acrolein in benzene [2 þ 1] cycloaddition chemistry had been limited in scope (that
at ambient temperature for 16 hours yielded epoxide 4g as the is, restricted to electron-deficient olefins), the results reported
278
NATURE CHEMISTRY | VOL 4 | APRIL 2012 | www.nature.com/naturechemistry
© 2012 Macmillan Publishers Limited. All rights reserved.

NATURE CHEMISTRY DOI: 10.1038/NCHEM.1267
ARTICLES
16. Igau, A., Baceiredo, A., Trinquier, G. & Bertrand, G.
herein effectively expand the utility of carbenes in the construc-
tion of three-membered carbocycles and oxacycles. Additionally,
1 was found to undergo an unprecedented, formal [4 þ 1] cyclo-
addition with a,b-unsaturated ketones to afford dihydrofuran
derivatives rapidly. In light of the broad scope of olefins and alde-
hydes, and recalling that the DAC was constructed from readily
accessible and modular formamidine and malonyl precursors,
we envision that many derivatives of these cycloaddition partners
will be accessible using the methodology described above.
Furthermore, hydrolysis of the diamidocarbene cyclopropane 2h
afforded hydrocinnamic acid, a linear carboxylic acid, via a
formal metal- and carbon monoxide-free hydrocarboxylation of
styrene. Additional efforts to explore the utility of DACs in syn-
thesis and as masked carbon-monoxide equivalents are
in progress.
[Bis(diisopropylamino)phosphino]trimethylsilylcarbene: a stable nucleophilic
carbene. Angew. Chem. Int. Ed. 28, 621–622 (1989).
17. Khramov, D. M., Rosen, E. L., Lynch, V. M. & Bielawski, C. W.
Diaminocarbene[3]ferrocenophanes and their transition-metal complexes.
Angew. Chem. Int. Ed. 47, 2267–2270 (2008).
18. Lavallo, V. et al. Synthesis, reactivity, and ligand properties of a stable alkyl
carbene. J. Am. Chem. Soc. 126, 8670–8671 (2004).
19. Siemeling, U. et al. N-heterocyclic carbenes which readily add ammonia, carbon
monoxide and other small molecules. Chem. Sci. 1, 697–704 (2010).
20. Vignolle, J., Cattoe¨n, X. & Bourissou, D. Stable noncyclic singlet carbenes. Chem.
Rev. 109, 3333–3384 (2009).
21. Dro¨ge, T. & Glorius, F. The measure of all rings – N-heterocyclic carbenes.
Angew. Chem. Int. Ed. 49, 6940–6952 (2010).
22. Melami, M., Soleilhavoup, M. & Bertrand, G. Stable cyclic carbenes and
related species beyond diaminocarbenes. Angew. Chem. Int. Ed. 49,
8810–8849 (2010).
23. Martin, D., Soleilhavoup, M. & Bertrand, G. Stable singlet carbenes as mimics for
transition metal centers. Chem. Sci. 2, 389–399 (2011).
24. Enders, D. et al. Preparation, structure, and reactivity of 1,3,4-triphenyl-4,5-
dihydro-1H-1,2,4-triazol-5-ylidene, a new stable carbene. Angew. Chem. Int. Ed.
34, 1021–1023 (1995).
Beyond their synthetic utility, DACs were also found to enable
the first examples of reversible [2 þ 1] cycloaddition reactions that
proceed rapidly at relatively low temperatures, an advantage over
many other dynamic covalent reactions. This surprising discovery
is expected to initiate new fundamental studies and expand the
applications of stable carbenes to include uses as protecting
groups for olefins or aldehydes, or as latent sources of reactive inter-
mediates. Akin to other reversible cycloadditions, such as the Diels–
Alder reaction, reversible [2 þ 1] cycloaddition processes also hold
promise for use as the basis of structurally dynamic materials and
reversible covalent inhibitors, and to facilitate applications that
utilize dynamic combinatorial libraries (for example, sensor discov-
25. Goumri-Magnet, S., Kato, T., Gornitzka, H., Baceiredo, A. & Bertrand, G.
Stereoselectivity and stereospecificity of cyclopropanation reactions with stable
(phosphanyl)(silyl)carbenes. J. Am. Chem. Soc. 122, 4464–4470 (2000).
26. Krysiak, J. et al. The first asymmetric cyclopropanation reactions involving a
stable carbene. J. Org. Chem. 66, 8240–8242 (2001).
27. Krysiak, J. et al. Stable optically pure phosphino(silyl)carbenes: reagents for
highly enantioselective cyclopropanation reactions. Chem. Eur. J. 10,
1982–1986 (2004).
28. Martin, D. et al. Theoretical and experimental investigation of the basicity of
phosphino(silyl)carbenes. J. Org. Chem. 70, 5671–5677 (2005).
ery and development)49,50
.
´
´
29. Illa, O., Alvarez-Larena, A., Baceiredo, A., Branchadell, V. & Ortun˜o, R. M.
Highly stereoselective and easy synthesis of enantiopure phosphoranyl oxiranes.
Tetrahedron: Asymmetry 18, 2617–2620 (2007).
Methods
30. Illa, O., Bagan, X., Baceiredo, A., Branchadell, V. & Ortun˜o, R. M. Understanding
the p-facial diastereoselectivity in the addition of chiral
Detailed descriptions of experimental, spectroscopic and crystallographic methods
and results are provided in the Supplementary Information.
diaminophosphino(silyl)carbenes to activated olefins. Tetrahedron: Asymmetry
19, 2353–2358 (2008).
Received 19 July 2011; accepted 9 January 2012;
published online 12 February 2012
31. Hudnall, T. W. & Bielawski, C. W. An N,N′-diamidocarbene: studies in C–H
insertion, reversible carbonylation, and transition-metal coordination chemistry.
J. Am. Chem. Soc. 131, 16039–16041 (2009).
´
32. Cesar, V., Lugan, N. & Lavigne, G. Reprogramming of a malonic N-heterocyclic
References
carbene: a simple backbone modification with dramatic consequences on the
ligand’s donor properties. Eur. J. Inorg. Chem. 361–365 (2010).
33. Hudnall, T. W., Moorhead, E. J., Gusev, D. G. & Bielawski, C. W.
N,N′-diamidoketenimines via coupling of isocyanides to an N-heterocyclic
carbene. J. Org. Chem. 75, 2763–2766 (2010).
34. Hudnall, T. W., Moerdyk, J. P. & Bielawski, C. W. Ammonia N–H activation by a
N,N′-diamidocarbene. Chem. Commun. 46, 4288–4290 (2010).
35. Braun, M., Frank, W., Reiss, G. J. & Ganter, C. An N-heterocyclic carbene
with an oxalamide backbone. Organometallics 29, 4418–4420 (2010).
36. Hobbs, M. G. et al. The influence of electron delocalization upon the
stability and structure of potential N-heterocyclic carbene precursors with
1,3-diaryl-imidazolidine-4,5-dione skeletons. New J. Chem. 34,
1295–1308 (2010).
37. Hudnall, T. W., Tennyson, A. G. & Bielawski, C. W. A seven-membered
N,N′-diamidocarbene. Organometallics 29, 4569–4578 (2010).
38. Moerdyk, J. P. & Bielawski, C. W. Olefin metathesis catalysts containing
N,N′-diamidocarbenes. Organometallics 30, 2278–2284 (2011).
39. Wasserman, H. H., Clark, G. M. & Turley, P. C. Recent aspects of
cyclopropanone chemistry. Top. Curr. Chem. 47, 73–156 (1974).
1. Reissig, H-U. & Zimmer, R. Donor–acceptor-substituted cyclopropane
derivatives and their application in organic synthesis. Chem. Rev. 103,
1151–1196 (2003).
2. McGarrigle, E. M. & Gilheany, D. G. Chromium- and manganese-salen
promoted epoxidation of alkenes. Chem. Rev. 105, 1563–1602 (2005).
3. Carson, C. A. & Kerr, M. A. Heterocycles from cyclopropanes: applications in
natural product synthesis. Chem. Soc. Rev. 38, 3051–3060 (2009).
4. Wessjohann, L. A. & Brandt, W. Biosynthesis and metabolism of cyclopropane
rings in natural products. Chem. Rev. 103, 1625–1647 (2003).
5. Marco-Contelles, J., Molina, M. T. & Anjum, S. Naturally occurring cyclohexane
epoxides: sources, biological activities, and synthesis. Chem. Rev. 104,
2857–2899 (2004).
6. Rademacher, P. Photoelectron spectra of cyclopropane and cyclopropene
compounds. Chem. Rev. 103, 933–975 (2003).
7. Herges, R. Topology in chemistry: designing Mo¨bius molecules. Chem. Rev. 106,
4820–4842 (2006).
8. Lebel, H., Marcoux, J-F., Molinaro, C. & Charette, A. B. Stereoselective
cyclopropanation reactions. Chem. Rev. 103, 977–1050 (2003).
9. Pellissier, H. Recent developments in asymmetric cyclopropanation.
Tetrahedron 64, 7041–7095 (2008).
10. Moss, R. A. in Carbene Chemistry (ed. Bertrand, G.) 57–101
(Marcel Dekker, 2002).
11. Jones, M. Jr & Moss, R. A. in Reactive Intermediate Chemistry (eds Moss, R. A.,
Platz, M. S. & Jones, M. Jr) Ch. 7, 273–328 (Wiley-Interscience, 2004).
12. Cheng, Y. & Meth-Cohn, O. Heterocycles derived from heteroatom-substituted
carbenes. Chem. Rev. 104, 2507–2530 (2004).
13. Wang, J., Burdzinski, G., Kubicki, J. & Platz, M. S. Ultrafast UV-vis and IR
studies of p-biphenylyl acetyl and carbomethoxy carbenes. J. Am. Chem. Soc.
130, 11195–11209 (2008).
´
40. Olah, G. A. & Molnar, A. In Hydrocarbon Chemistry (ed. Lagowski, J. J.) Ch. 7,
371–395 (Wiley-Interscience, 2003).
41. Linstead, R. P. & Whalley, M. Conjugated macrocycles. Part XXII.
Tetrazaporphin and its metallic derivatives. J. Chem. Soc. 4839–4846 (1952).
42. Moss, R. A. & Huselton, J. K. Dimethoxycarbene: stereospecificity in the
additions of a nucleophilic carbene to b-deuteriostyrenes. J. Chem. Soc. Chem.
Commun. 950–951 (1976).
43. Mendez, F. & Garcia-Garibay, M. A. A hard–soft acid–base and DFT analysis of
singlet–triplet gaps and the addition of singlet carbenes to alkenes. J. Org. Chem.
64, 7061–7066 (1999).
44. Lecea, B. et al. Theoretical study on the mechanism of the [2þ1] thermal
cycloaddition between alkenes and stable singlet (phosphino)(silyl)carbenes.
J. Org. Chem. 72, 357–366 (2007).
45. Mukai, T., Nakazawa, T. & Isobe, K. Thermal decomposition of
troponetosylhydrazone. Tetrahedron Lett. 565–569 (1968).
14. Zhang, Y., Kubicki, J. & Platz, M. S. Ultrafast UV-visible and infrared
spectroscopic observation of a singlet vinylcarbene and the intramolecular
cyclopropenation reaction. J. Am. Chem. Soc. 131, 13602–13603 (2009).
15. Baceiredo, A., Bertrand, G. & Sicard, G. Synthesis of the first a-diazo
phosphines. Phosphorous–carbon multiple-bond character of
phosphinocarbenes. J. Am. Chem. Soc. 107, 4781–4783 (1985).
NATURE CHEMISTRY | VOL 4 | APRIL 2012 | www.nature.com/naturechemistry
279
© 2012 Macmillan Publishers Limited. All rights reserved.

NATURE CHEMISTRY DOI: 10.1038/NCHEM.1267
ARTICLES
46. Jones, W. M., Hamon, B. N., Joines, R. C. & Ennis, C. L. Stereochemistry of
the addition of cycloheptatrienylidene to electron deficient double bonds.
Tetrahedron Lett. 3909–3912 (1969).
Acknowledgements
We are grateful to the National Science Foundation (CHE-0645563), the Robert A. Welch
Foundation (F-1621) and the Sloan Foundation for their support.
47. Hamaguchi, M., Matsubara, H. & Nagai, T. Reaction of vinylcarbenoids with
benzaldehydes: formation of vinylcarbonyl ylides followed by ring closure to
oxiranes and dihydrofurans. J. Org. Chem. 66, 5395–5404 (2001).
48. Dolbier, W. R. Jr & Battiste, M. A. Structure, synthesis, and chemical reactions
of fluorinated cyclopropanes and cyclopropenes. Chem. Rev. 103,
1071–1098 (2003).
Author contributions
C.W.B. and J.P.M. conceived and designed the experiments, and co-wrote the paper. J.P.M.
performed the experiments and analysed the data. Both authors discussed the results and
commented on the manuscript.
49. Lehn, J-M. From supramolecular chemistry towards constitutional
dynamic chemistry and adaptive chemistry. Chem. Soc. Rev. 36,
151–160 (2007).
50. Hunt, R. A. R. & Otto, S. Dynamic combinatorial libraries: new opportunities in
systems chemistry. Chem. Commun. 47, 847–858 (2011).
Additional information
The authors declare no competing financial interests. Supplementary information and
chemical compound information accompany this paper at www.nature.com/
naturechemistry. Reprints and permission information is available online at http://www.
nature.com/reprints. Correspondence and requests for materials should be addressed to C.W.B.
280
NATURE CHEMISTRY | VOL 4 | APRIL 2012 | www.nature.com/naturechemistry
© 2012 Macmillan Publishers Limited. All rights reserved.